Bone metastases from endocrine cancer: advances in diagnosis, treatment, and prevention

Endocrine cancers, originating from hormone-producing organs, prefer to metastasize hematogenously to bone as a common site. Once considered rare, diagnosis rate of bone metastases presents a rising trend attribute to advanced imaging techniques and greater patient longevity. However, accurate diagnosis of bone metastases remains challenging. Diagnostic hurdles stem from heterogeneous metastatic mechanisms among cancer types and high rates of therapeutic resistance. Preventive measures remain sub-optimal, and clinical management pathways are often fragmented. Addressing these complexities requires a systematic research approach to enhance diagnostic accuracy and optimize therapeutic strategies. Present review synthesizes recent progress in the diagnosis, management, and prevention of bone metastases in endocrine tumors, emphasizing the imperative for an integrated diagnostic paradigm that leverages clinical assessment, advanced imaging, and molecular/genomic profiling to inform precision medicine. We also explore emerging hybrid predictive models that clarify the distinct biological mechanisms underpinning bone metastasis in various endocrine cancers. Ultimately, this review identifies pathways for improved therapies, refined clinical guidelines, and enhanced multidisciplinary collaboration, aiming to extend survival, improve quality of life, and ensure optimal healthcare resource utilization for patients with endocrine malignancies.

1 Introduction

Endocrine cancers comprise a diverse group of malignancies arising from hormone-producing tissues or hormone-dependent cells, which are typically divided into classical endocrine gland cancers, neuroendocrine tumors (NETs), and endocrine-dependent cancers (1). Among them, thyroid cancer is the most prevalent endocrine malignancies representing over 90%. Its global incidence is rising steadily, attributing to improved screening and diagnostic awareness (2, 3). The majority are well-differentiated types—papillary and follicular thyroid carcinoma—which generally have favorable outcomes but may metastasize to bone in advanced stages (4).

NETs, the second major group, originating from neuroendocrine cells dispersed throughout the gastrointestinal tract, pancreas, and lungs. The incidence of NETs is increasing worldwide, reaching approximately 1–2 cases per 100,000 individuals annually (5, 6). NETs display wide biological heterogeneity, ranging from indolent well-differentiated forms to aggressive neuroendocrine carcinomas (NECs) (1).

In addition, endocrine-dependent cancers such as hormone receptor–positive (HR⁺) breast cancer and androgen receptor–driven (AR⁺) prostate cancer are closely linked to endocrine signaling despite not arising from endocrine glands (7, 8), which is modulated by estrogen or androgen pathways, and endocrine therapy remains the cornerstone of management. However, when these tumors develop bone metastases, these endocrine-dependent cancers become markedly more aggressive, which profoundly worsens prognosis (9, 10). Although thyroid carcinomas and neuroendocrine tumors (NETs) present lower bone metastatic rates(3.9% to 4.2% in thyroid cancer and 10–15% in NETs), confirmed bone metastasis, sharply worsens the prognosis, with 10-year overall survival rates declining to 13–21% (11, 12). Skeletal metastases in endocrine malignancies cause significant morbidity through skeletal-related events (SREs), including pathological fractures, spinal cord compression, and intractable pain, which severely compromise physical function, life quality, and survival.

Notably, bone metastasis (BM) mechanisms vary by cancer type. Starting with thyroid cancer, particularly its FTC (follicular thyroid carcinoma) and MTC (medullary thyroid carcinoma) subtypes, the underlying drivers of BM remain incompletely clear but may include RET (rearranged during transfection) mutations and RAS-MAPK (mitogen-activated protein kinase) signaling abnormalities (13).For neuroendocrine neoplasms (NENs), including high-grade neuroendocrine carcinoma (NEC), BM affects 4%–15% of cases (up to 40% in carcinoids) and is linked to poor prognosis due to skeletal-related events (SREs) like pathological fractures, with its development rooted in the “seed-soil” interplay. Tumor cells (the “seed”) feature SSTR2 (somatostatin receptor 2) (supporting ⁶⁸Ga-DOTATATE PET/CT [positron emission tomography/computed tomography] detection), BSP (bone sialoprotein) (aiding adhesion/angiogenesis), CgA (chromogranin A) (modulating the bone microenvironment), and oncogenic microRNAs (miR-210, miR-21) that promote BM (14–17). The bone microenvironment (the “soil”) is disrupted by vitamin D deficiency (from surgery, somatostatin analog [SSA] therapy, or steatorrhea), while high-grade lung NETs (neuroendocrine tumors) (e.g., SCLC [small cell lung cancer], LCNEC [large cell neuroendocrine carcinoma]) involve Hyaluronan-CD44, DKK1, and Annexin A1 pathways (18–21). Diagnosis uses multimodal imaging (⁶⁸Ga-DOTATATE PET/CT, MRI [magnetic resonance imaging], ¹⁸F-FDG PET/CT), biomarkers (CgA, BSP, BSAP [bone-specific alkaline phosphatase]), and bone marrow biopsy (gold standard) (22–24), with therapies like PRRT (peptide receptor radionuclide therapy) for SSTR2-positive cases—though unknown primary tumors remain a challenge (24–28).Finally, breast cancer BM is mostly osteolytic, driven by dysregulation of the RANKL (receptor activator of nuclear factor-kappaB ligand)/OPG (osteoprotegerin) pathway, while prostate cancer BM is often osteoblastic, mediated by Wnt pathway activation (13, 29).

Given these complexities, endocrine-related bone metastases present a compelling model for studying tumor–bone interactions. Translational research into key processes—such as stromal remodeling, osteotropic signaling, and tumor dormancy—offers opportunities to identify novel therapeutic targets and biomarkers. Moreover, integrating genomics, proteomics, and radiomics with clinical and imaging data can help delineate metastasis risk, enable earlier detection, and inform tailored treatment strategies. The development of multidisciplinary, individualized treatment plans—guided by molecular profiling and supported by precision medicine frameworks—holds significant promise for improving patient outcomes, reducing skeletal complications, and refining clinical management protocols. To clearly and concisely present the basic findings of this article regarding bone metastases in endocrine malignancies—including key background, diagnostic technologies, therapeutic strategies, prevention and management, and future directions—the following graphical abstract is hereby presented, as shown in Figure 1.

Figure 1

Figure 1. Graphical abstract.

2 Advances in diagnostic techniques for bone metastasis of thyroid cancer

Once bone metastasis occurs in thyroid cancer, the prognosis decreases significantly, so its early and precise identification is of great clinical significance. In recent years, diagnostic techniques have advanced continuously, covering multidimensional detection means from traditional imaging to the molecular level. This article summarizes the current key technological advances in this field.

2.1 Clinical features and risk factors

Bone metastases in thyroid carcinoma occur predominantly in follicular thyroid carcinoma (19.2–34.0%) and poorly differentiated carcinoma (16.7–23.1%) (13) (30) (31). Patients typically present with persistent bone pain (67%), pathological fractures (23–27%), or neurological symptoms due to spinal cord compression (14–34%) (32) (33) (34). The most frequent metastatic sites include the spine (31.8–50%), pelvis, and ribs, with cervical spine lesions accounting for approximately 16% of spinal metastases (35–37). Identified risk factors for bone metastasis are primary tumor diameter greater than 4 cm (Odds Ratio = 3.2), vascular invasion (Hazard Ratio = 4.1), and the co-occurrence of BRAF(v-Raf murine sarcoma viral oncogene homolog B1) and TERT (Telomerase Reverse Transcriptase)promoter mutations (p value = 0.003) (30, 38, 39).

2.2 Imaging modalities for diagnosis

Structural imaging remains fundamental to diagnosis. Computed tomography (CT) demonstrates excellent sensitivity (71–100%) for detecting osteolytic lesions and enables precise mapping of cortical bone destruction, particularly through three-dimensional reconstruction in anatomically complex regions (35, 37, 40). Magnetic resonance imaging (MRI) provides high sensitivity (94%) for detecting early bone marrow infiltration. Typical findings include low signal intensity on T1-weighted imaging and high signal intensity on T2-weighted imaging with contrast enhancement, critical for evaluating spinal cord involvement (41–43). Conventional radiography is limited to detect lesions involving more than 50% cortical destruction and is primarily used for preliminary assessment of long bone fractures (42, 44).

Functional imaging further complements structural assessment. The ^99mTc-methylene diphosphonate (MDP) bone scan offers whole-body screening with sensitivity ranging from 56% to 95%, although its sensitivity is lower for osteolytic lesions, making it more suitable for osteoblastic metastases (40, 45, 46). The ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) achieves high sensitivity (92%) for detecting radioiodine (RAI)-refractory lesions but is associated with elevated costs and a false-positive rate of 15–20%. It is primarily used for systemic metastatic staging (30) (45) (47).124I-PET imaging specifically identifies RAI-avid lesions but requires thyroid-stimulating hormone (TSH) stimulation (> 30 μIU/mL), making it valuable for differentiated thyroid carcinoma (DTC) treatment planning (47, 48).⁶⁸Ga-DOTATATE PET imaging, with a sensitivity of 98%, is specific for medullary thyroid carcinoma (MTC) and is primarily applied in neuroendocrine tumor metastasis detection (34, 48).

2.3 Pathological and molecular diagnostics

Histopathological examination via fine-needle aspiration or core biopsy remains the diagnostic gold standard. Follicular carcinoma typically shows vascular or capsular invasion and positive thyroglobulin (Tg) staining in 95% of cases (30, 37). Papillary carcinoma is characterized by nuclear grooves and intranuclear inclusions, with positivity for thyroid transcription factor-1 (TTF-1) (30) (49). Medullary carcinoma demonstrates calcitonin and carcinoembryonic antigen (CEA) positivity (34, 45).

Molecular diagnostics provide additional insights into disease status. Postoperative serum Tg levels exceeding 10 ng/mL are indicative of metastatic disease, with a specificity of 82% (30, 33). A high receptor activator of nuclear factor-kappaB ligand (RANKL) to osteoprotegerin (OPG) ratio (>3.5) correlates with progressive bone destruction (p = 0.01) (50). Downregulation of microRNA-124 (miR-124) is associated with an increased risk of bone metastases, with an AUC of 0.78 (39). Furthermore, combined BRAF V600E and TERT promoter mutations increase the risk of bone metastases by 5.3-fold (39, 50).

2.4 Diagnostic challenges and strategic approaches

Heterogeneous lesion presentation complicates diagnosis. About 34% of cases exhibit mixed osteolytic and osteoblastic features, requiring differentiation from osteosarcoma (marked by a 5-fold elevation in alkaline phosphatase) and metastatic breast cancer (estrogen receptor/progesterone receptor positivity) (35, 51, 52). Moreover, 5–20% of dedifferentiated metastatic lesions lose Tg expression. In such cases, additional markers including CD56 and PAX8 are essential for diagnosis (30, 49).

Dynamic monitoring strategies are critical for high-risk patients. Those with follicular or Hürthle cell carcinoma (FTC/HCC) should undergo whole-body bone scans or PET/CT every six months (38, 45). A Tg doubling time of less than one year strongly predicts metastatic progression (HR = 4.7) (33). Elevated C-terminal telopeptide (CTX) levels exceeding 600 pg/mL predict a 3.2-fold increased risk of skeletal-related events (SREs) (31, 53).

2.5 Optimization of diagnostic workflow

Patients presenting with solitary bone lesions should undergo CT or MRI localization followed by biopsy and molecular subtyping. For those with multiple lesions, whole-body PET/CT imaging is recommended prior to targeted biopsy and comprehensive genetic profiling (45, 48).

A multidisciplinary team (MDT) approach integrating endocrine surgeons, radiologists, orthopedic oncologists, and pathologists is essential. Treatment should be guided by the Spine Instability Neoplastic Score (SINS ≥ 13 indicates surgical intervention) and the Mirels score (≥ 9 suggests the need for prophylactic fixation) (37, 54–57).

3 Diagnostic methods and recent advances in bone metastases in neuroendocrine carcinoma

Neuroendocrine carcinoma (NEC) encompasses a heterogeneous group of malignancies arising from neuroendocrine cells, spanning well-differentiated neuroendocrine tumors (NETs) and poorly differentiated NECs, with predominant involvement of the gastroenteropancreatic tract and lung (58, 59). Bone metastasis represents a common and clinically impactful pattern of distant spread in NEC, as it not only severely impairs patients’ quality of life but also correlates with unfavorable prognosis (14, 60). Epidemiologically, bone metastasis occurs in 10%–30% of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), while high-grade (G3) NECs present an even higher risk (≥40%) (61, 62). Notably, patients with bone metastasis exhibit a median overall survival (OS) reduced by ~50% compared to those without metastatic bone involvement (61). Given the insidious onset of symptoms in bone metastasis, timely and accurate diagnosis is critical for tailoring therapeutic strategies and improving clinical outcomes. The diagnosis of bone metastasis in NEC relies on integrating tumor biological features (e.g., differentiation grade, molecular phenotypes) with multimodal approaches including imaging, biomarkers, and histopathology. The following content details these diagnostic modalities (1).

3.1 The development of diagnostic techniques

The diagnosis of bone metastases in NEC relies on a multimodal approach integrating imaging modalities, biochemical biomarkers, and histopathological confirmation, with each component tailored to tumor grade, differentiation status, and clinical context. Imaging remains the cornerstone, with advanced functional techniques now dominating due to their superior sensitivity and specificity. ⁶⁸Ga-DOTATATE PET/CT targets somatostatin receptors (SSTRs), which are highly expressed in most well-differentiated neuroendocrine neoplasms (NENs). In a study of 49 gastroenteropancreatic (GEP)-NEN patients, this modality outperformed ¹⁸F-FDG PET/CT in detecting bone metastases (p < 0.001) and altered staging in 12.2% of cases (14). Its advantages include high resolution, rapid acquisition, and efficacy in identifying osteoblastic lesions, though false positives may occur due to SSTR expression in inflammatory cells (60). In contrast, ¹⁸F-FDG PET/CT is more effective in high-grade NEC (G3 NET and NEC), where tumors exhibit increased glycolytic activity. It complements ⁶⁸Ga-DOTATATE by detecting lesions with low SSTR expression and is particularly valuable for identifying concurrent lung or peritoneal metastases (14). For bone marrow-specific involvement—a rare but aggressive manifestation—MRI is the most sensitive (90–100%) modality for detecting early marrow infiltration and spinal cord compromise, while conventional bone scintigraphy (⁹⁹mTc) and CT are limited by low sensitivity for small or early lesions (24, 61).

Biochemical biomarkers enhance diagnostic accuracy when combined with imaging. Chromogranin A (CGA), a secretory protein elevated in NEC patients with bone metastases, serves as a sensitive serum marker for disease progression, though it lacks specificity for bone involvement alone (60, 63). Bone Sialoprotein (BSP), an integrin ligand promoting angiogenesis and bone remodeling, correlates with bone metastasis and poor prognosis (60), while bone-specific alkaline phosphatase (BSAP)—a marker of osteoblastic activity—may be a superior prognostic indicator compared to CGA in some cohorts (64). The integration of ⁶⁸Ga-DOTATATE imaging with CGA and BSP assays improves diagnostic accuracy (AUC > 0.75, sensitivity and specificity > 80%) compared to single modalities (60). For cases with suspected bone marrow metastasis, bone marrow biopsy remains the gold standard, key histopathological findings include nest-like distributions of small cells with scant cytoplasm, irregular nuclei, and coarse chromatin, supported by immunohistochemistry (positivity for CD56 and synaptophysin, high Ki-67 index [often >20%] for high-grade NEC) (24, 60).

Risk stratification using machine learning further refines diagnostic workflows, particularly in high-grade lung NEC. A stochastic gradient boosting (GBM) model, trained on SEER data (2010-2021), identified nine key predictors of synchronous bone metastases: age, race, sex, T/N stage, marital status, and presence of brain/liver/lung metastases. Liver metastasis emerged as the strongest predictor, with younger patients (≤65 years) with hepatic involvement facing higher risk (65). This model enables personalized imaging surveillance, directing comprehensive bone evaluation (e.g., PET/CT or MRI) to high-risk subgroups—such as patients with liver metastasis or advanced nodal disease—thereby improving early detection (65).

4 The evolution of bone metastasis diagnosis in endocrine-dependent cancers: from single testing to multimodal integrated strategies

Prostate cancer and breast cancer, two leading endocrine-dependent malignancies, are frequently complicated by bone metastasis in their advanced stages—notably, the incidence of bone metastasis in metastatic castration-resistant prostate cancer (mCRPC) reaches up to 90% over the disease course (66, 67), underscoring the critical need for optimized diagnostic strategies to guide precise clinical management. Below is an integrated synthesis of the core diagnostic approaches and recent advances in bone metastasis detection for these two cancers, weaving together multimodal imaging, biomarker-imaging synergy, liquid biopsy, molecular pathology, and intelligent diagnostic tools.

Imaging serves as the foundational pillar for bone metastasis diagnosis in both cancers. In prostate cancer, radionuclide bone scanning (⁹⁹mTc-MDP) has long been a primary screening option, with a sensitivity of 62%-100% but limited specificity of 50%-80% (68). A meta-analysis of 353 patients confirmed that ⁹⁹mTc-MDP bone scan achieves a pooled sensitivity of 67% and specificity of 88% for prostate cancer osseous metastases, far lower than MRI’s 95% sensitivity and 97% specificity (69). Osteoblastic metastases may even present as false-negative “cold zones” due to atypical radiotracer uptake. In breast cancer, plain radiographs visualize bone destruction features (e.g., osteolytic “worm-eaten” lesions) yet only reach 44-50% sensitivity, while ⁹⁹mTc-MDP bone scanning improves whole-body detection to 85-95% but retains low specificity (60-70%). Computed tomography (CT) complements these limitations with superior anatomical resolution: In prostate cancer, CT excels at identifying osteoblastic lesions and cortical invasion but fails to detect early bone marrow infiltration. In breast cancer, multi-detector spiral CT (≤1mm slice) identifies cortical destruction with 0.5mm accuracy via 3D reconstruction, boosting osteolytic lesion sensitivity to 86% and specificity to 98%, low-dose CT (≤2 mSv) enables safe annual screening, and micro-CT achieves 20μm resolution for detecting <0.5mm microfractures.

MRI fills the gap in detecting bone marrow micrometastasis. In prostate cancer, MRI shows low T1-weighted and high T2-weighted/DWI signals, with whole-body MRI (WB-MRI) providing comprehensive skeletal coverage. In breast cancer, T1-weighted sequences combined with STIR achieve 94% sensitivity for bone marrow edema—detecting metastases 6–8 weeks earlier than overt destruction, DWI further enhances accuracy, with 91% correct malignant diagnosis when ADC <1.0 × 10⁻³ mm²/s (consistent with a 3T MRI study showing mean malignant ADC of 0.870 × 10⁻³ mm²/s) (70). WB-MRI detects multiple metastases 30% more efficiently than traditional methods via single-scan whole-skeleton coverage.

Molecular imaging has driven transformative advances, particularly with positron emission tomography (PET)-based techniques. In prostate cancer, PSMA-targeted imaging outperforms conventional modalities: ⁹⁹mTc-PSMA SPECT/CT achieves 80% sensitivity and 100% specificity for bone metastases, detecting lesions ≤0.6cm that ⁹⁹mTc-MDP misses, and altering management in 14.9% of patients (71). PSMA PET/CT detects microscopic metastases even at low PSA levels, with sensitivity up to 98% and specificity up to 100%, though ¹⁸F-PSMA-1007 may show nonspecific uptake (SUVmax>10). In breast cancer, ¹⁸F-FDG PET/CT quantifies metabolic activity via SUVmax, in lobular breast cancer, it reaches 93.33% specificity for bone metastases, though sensitivity is limited by sclerotic lesion hypometabolism (72). A meta-analysis of 668 breast cancer patients confirmed ¹⁸F-FDG PET/CT’s 93% sensitivity and 99% specificity, superior to bone scintigraphy’s 81% sensitivity (73). Novel tracer ¹⁸F-NaF boosts osteoblastic metastasis sensitivity to 98%, while 68Ga-PSMA PET/CT increases microscopic detection by 40% in HER2-positive cases. Dual-modality fusion (e.g., Biograph mMR MRI/PET) reduces spinal metastasis localization error from 8mm to 1.2mm.

Coupling biomarkers with imaging refines diagnostic specificity. In prostate cancer, serum PSA lacks metastasis specificity—some mCRPC patients maintain normal levels —but high PSA (>15.275ng/ml) predicts ⁹⁹mTc-MDP-detectable bone metastases. Elevated BALP indicates active osteogenesis in osteoblastic metastases, and its dynamics reflect Ra-223 efficacy. The RANKL/OPG axis shows elevated RANKL and reduced OPG in metastatic patients, with ratios >2.5 indicating active bone destruction. In breast cancer, high-risk patients (triple-negative/HER2+/≥4 lymph nodes) screened with ¹⁸F-FDG PET/CT plus serum CTX achieve 96% sensitivity, ECT-positive lesions confirmed by 3.0T MRI/DWI reach 99% specificity (74). Mixed osteoblastic-osteolytic lesions are 95% confirmed via iron oxide nano-enhanced MRI plus ¹⁸F-NaF PET/CT. DCE-MRI Ktrans paired with PET SUVmax distinguishes response from pseudoprogression.

Liquid biopsy provides molecular context for imaging. In prostate cancer, CTC ≥5/7.5mL predicts poorer prognosis, and CXCR4⁺/αvβ3⁺ CTCs (osteo-directed phenotype) correlate with bone colonization. CTC gene expression (e.g., AR, AKR1C3) mirrors spinal metastasis profiles, enabling noninvasive phenotyping. ctDNA detects AR-V7/PTEN mutations explaining “imaging-negative” metastases. Exosomal miRNAs (miR-125a-3p, miR-330-3p) are upregulated in bone metastatic patients, with expression correlating with metastatic load (75, 76). Murine studies confirm exosomal miR-26a-5p/27a-3p suppress osteoblast mineralization, linking to osteosclerotic lesions (77). In breast cancer, CTC ≥5/7.5mL increases bone metastasis risk 4.8-fold (89% PET/CT concordance) (78). ctDNA ESR1 mutations warn of endocrine resistance 3–6 months early. Urinary NTx >600nmol/mmol creatinine raises imaging-occult metastasis risk 3.2-fold, and RANKL/OPG >2.5 correlates with PET-CT hypermetabolic volume (r=0.71) (79–81). A 134-gene CTC signature distinguishes bone-only from extra-skeletal metastases, with MAF/CAPG overexpression predicting skeletal dissemination (82).

Bone biopsy and molecular pathology remain gold standards. CT/MRI-guided biopsy differentiates osteoblastic/osteolytic prostate cancer metastases, molecular markers (ERG fusion, RUNX2, Wnt dysregulation) indicate osteo-tropic mechanisms correlatable with imaging.

Intelligent systems enhance breast cancer diagnosis. ResNet-50-based models extract 372 CT texture features for 92% accuracy, PET-CT radiomics plus ALP/CTC count constructs a nomogram (AUC = 0.91) for 5-year risk prediction, and AI platforms (e.g., IBEX) synchronize imaging and liquid biopsy data, increasing early detection by 28%.

Future directions focus on ultrasensitive detection: UCNP-SX peptide conjugates detect <100 bone marrow micrometastases via NIR-II imaging, 3D-printed microenvironment chips model tumor-bone cell interactions, explaining imaging manifestations. To synthesize the aforementioned diagnostic strategies for bone metastasis across thyroid cancer, neuroendocrine carcinoma (NEC), and endocrine-dependent cancers (prostate/breast cancer), Table 1 presents a structured, Word-ready comparison. It systematically organizes core diagnostic methods by cancer type, summarizing key performance indicators (sensitivity/specificity), primary applicable scenarios, and inherent limitations. This integration aims to support clinicians in rapid, evidence-based diagnostic selection, catering to the precision-oriented demands of oncology practice.

Table 1

Table 1. Word-ready comparison table of diagnostic methods applicability.

5 Treatment of endocrine cancer bone metastases

Although conventional approaches such as surgery, radiotherapy, and bisphosphonates have achieved partial success in symptom control, long-term management remains challenging. Recent advances in understanding tumor-bone interactions have identified novel molecular targets and pathways that could be leveraged to develop more effective and specific therapies. Integrating bone-targeted agents with systemic anticancer treatments holds promise for improving clinical outcomes and minimizing skeletal-related events.

Given the substantial clinical burden and the current therapeutic limitations, optimizing the management of bone metastases is crucial for improving both survival and quality of life in patients with endocrine cancers.

5.1 Therapeutic strategies for bone metastases in thyroid cancer

Building upon the current understanding of molecular mechanisms, a range of therapeutic strategies has emerged and continues to evolve. Surgical management remains fundamental in treating bone metastases from differentiated thyroid cancer (DTC), especially in cases involving spinal structures. According to the American Thyroid Association (ATA) guidelines, complete resection of isolated, symptomatic metastases—particularly in patients under 45 years of age—is associated with improved survival outcomes. When radical surgery is contraindicated due to advanced age, widespread metastatic burden, or comorbidities, palliative operations such as spinal stabilization and decompression may still provide substantial symptom relief and prevent serious complications like pathological fractures and spinal cord compression.

For patients with limited metastatic burden, minimally invasive local therapies such as arterial embolization, image-guided ablation, and percutaneous vertebroplasty present valuable alternatives (83). Pre-surgical embolization is particularly useful for hypervascular lesions, helping to control intraoperative hemorrhage (84), and while it may not extend overall survival, it plays an important role in pain reduction and surgical facilitation (85, 86). Ablation approaches—including radiofrequency, microwave, and cryotherapy—are well-established for alleviating metastatic pain and reducing tumor mass (87). In vertebral involvement, percutaneous vertebroplasty under CT guidance allows for injection of polymethylmethacrylate, reinforcing vertebral stability and mitigating osteolytic discomfort (13).

External beam radiation therapy (EBRT) is a non-invasive option commonly used to manage refractory bone pain, structural instability, or neural compression (88). Although thyroid tumors are traditionally less radiosensitive, newer approaches such as stereotactic ablative radiotherapy (SABR) offer highly focused high-dose radiation with minimal exposure to adjacent critical tissues. Clinical trials report encouraging local control rates, reaching up to 88% over two years, particularly in spinal metastases (89, 90), though the long-term survival impact requires further exploration.

Radioactive iodine ¹³¹I therapy remains a mainstay in treating iodine-avid metastatic DTC, especially in small-volume disease where complete response may be achievable (91) (92). However, the response rate in distant metastases remains limited—only about 30–50% of patients show durable benefit—and the use of ¹³¹I in large skull or spine lesions requires caution due to anatomical proximity to critical neural structures (32, 93, 94). The ATA recommends repeated high-activity ¹³¹I therapy (3.7–7.4 GBq) guided by dosimetry to avoid marrow toxicity (45). Combined modalities, incorporating ¹³¹I with other treatments, have shown improved outcomes in select cases (95, 96). Other β-emitting radiopharmaceuticals, such as strontium-89 (⁸⁹Sr) and samarium-153 (¹⁵³Sm), may relieve metastatic bone pain, albeit with slower onset and potential hematologic side effects (13) (97). Meanwhile, α-emitter radium-223 (²²³Ra), with its potent cytotoxicity and short tissue range, is under investigation for applications beyond prostate cancer, though its role in DTC remains unclear (98).

In radioiodine-refractory DTC (RAIR-DTC), tyrosine kinase inhibitors (TKIs) have become central to systemic therapy. Among them, lenvatinib has demonstrated a significant benefit in progression-free survival (PFS) for patients with bone metastases (99), although overall survival (OS) gains remain under debate (100, 101). Apatinib, as shown in the REALITY study, has also yielded favorable outcomes in both PFS and OS metrics (102). The National Comprehensive Cancer Network (NCCN) now emphasizes the need for genomic profiling to inform TKI selection—e.g., using larotrectinib or selpercatinib for NTRK and RET gene fusions, respectively (86).

Targeting the bone microenvironment directly, bone-modifying agents such as bisphosphonates and denosumab have become standard adjuncts in managing skeletal involvement. Zoledronic acid, a potent bisphosphonate, is effective in reducing the incidence of skeletal-related events and mitigating bone pain (103), though renal toxicity limits its long-term use (104). Denosumab, a RANKL-specific monoclonal antibody, inhibits osteoclast-mediated resorption and offers an alternative with a distinct safety profile—albeit with risks such as hypocalcemia and osteonecrosis of the jaw, necessitating calcium supplementation and dental monitoring (105, 106). Importantly, sudden discontinuation of denosumab has been linked to rebound bone turnover, requiring transition strategies to alternative therapies (107). A novel agent, technetium-99 methylene diphosphonate (⁹⁹Tc-MDP), has shown dual diagnostic and therapeutic capabilities by enhancing bone formation and suppressing osteolysis. Recent meta-analyses suggest that combining ⁹⁹Tc-MDP with ⁸⁹Sr improves both pain control and clinical efficacy over monotherapy (106), although further large-scale trials are warranted to confirm its long-term benefits in DTC-related bone disease.

Recent advances in thyroid cancer–related bone metastases have shifted treatment strategies from symptomatic relief toward precision-based, mechanism-guided interventions.

5.1.1 Updated understanding of bone colonization

Compared to earlier emphasis on receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteolysis, recent findings highlight a more complex tumor–bone interaction. Single-cell sequencing has revealed elevated expression of colony-stimulating factor 1 receptor (CSF1R) and AXL receptor tyrosine kinase in metastatic lesions (108), while tumor adhesion to vertebral endothelium is promoted by chemokine (C-X3-C motif) ligand 1/intercellular adhesion molecule-1 (CX3CL1/ICAM-1) signaling (109). Growth differentiation factor 15 (GDF15) enhances osteoblast-driven metastasis through hypoxia-inducible factor (HIF) activation (110). Clinically, a circulating tumor cell (CTC) subtype co-expressing epithelial cell adhesion molecule (EpCAM) and cluster of differentiation 44 (CD44) is linked to multifocal bone spread (111).

Local therapies have become safer and more effective. Three-dimensional (3D) navigation and intraoperative neuromonitoring improve outcomes in vertebral resection by 40%. Stereotactic body radiotherapy (SBRT) achieves 92% one-year control at 24 Gray (Gy), minimizing spinal toxicity (112, 113). Minimally invasive techniques such as radiofrequency ablation with cementoplasty offer rapid pain relief (114). Radium-223 (²²³Ra) shows promising results in thyroid bone metastases, with 79% pain relief and 64% alkaline phosphatase normalization, combination with lenvatinib enhances responses (115, 116).

5.1.2 Targeted and systemic therapy expansion

Lenvatinib extends progression-free survival (PFS) to 18.3 months and accelerates pain control (98). Selpercatinib, for rearranged during transfection (RET) fusions, shows 85% objective response rate (117). Cabozantinib, targeting mesenchymal-epithelial transition factor (MET), demonstrates 31% efficacy in bone lesions (118). Immune checkpoint inhibitors combined with tyrosine kinase inhibitors (TKIs) increase CD8-positive T cell infiltration and response rates (119). Preclinical data also support chimeric antigen receptor-modified T (CAR-T) cells against thyroid-stimulating hormone receptor (TSHR) for bone-specific activity (120). Chimeric Antigen Receptor T-cell (CAR-T) therapy holds substantial promise for treating bone metastases from endocrine-related cancers (thyroid, neuroendocrine, prostate, and breast cancers), which remain refractory to conventional treatments due to tumor heterogeneity and the immunosuppressive bone microenvironment. For thyroid cancer bone metastasis (TCBM), CAR-T targeting thyroid-stimulating hormone receptor (TSHR) and rearranged during transfection (RET) is advancing: TSHR-CAR-T exhibits bone-specific activity against radioiodine-refractory DTC (RAIR-DTC) in preclinical models, while RET-CAR-T overcomes resistance to RET inhibitors in MTC bone lesions. In neuroendocrine carcinoma (NEC) and neuroendocrine tumor (NET) bone metastases, somatostatin receptor 2 (SSTR2)-CAR-T is a leading candidate, leveraging SSTR2’s high expression in G1/G2 NETs (80–90% positivity) and synergizing with peptide receptor radionuclide therapy (PRRT) to enhance bone lesion clearance (60). For prostate cancer bone metastasis (PCBM), prostate-specific membrane antigen (PSMA)-CAR-T is the most clinically mature option: phase II trials (e.g., NCT04683853) show 65% of metastatic castration-resistant prostate cancer (mCRPC) patients achieve ≥50% PSA reduction, with 21/32 patients experiencing bone lesion shrinkage (121). In breast cancer bone metastasis (BCBM), subtype-specific CAR-T strategies prevail: HER2-CAR-T benefits HER2+ cases (75% HER2 positivity in bone lesions) when combined with trastuzumab, while BCMA-CAR-T targets triple-negative breast cancer (TNBC) bone metastases, with preclinical data showing 30% bone density recovery (122). Common challenges, including immunosuppression by tumor-associated macrophages (TAMs) and bone matrix penetration barriers, are addressed via combinatorial strategies: preclinical studies show combining CAR-T with bone-modifying agents (e.g., denosumab) or immune modulators (e.g., CXCR4 antagonists) enhances CAR-T survival and infiltration in bone (123). Overall, CAR-T translation prioritizes “target precision + microenvironment modulation”: PSMA-CAR-T (prostate cancer) and SSTR2-CAR-T (NETs) are near late-phase trials, while TSHR/RET-CAR-T (thyroid cancer) and HER2/BCMA-CAR-T (breast cancer) advance through early-phase studies, aiming to transform bone metastases from intractable to manageable conditions.

5.1.3 Microenvironment-targeted therapies

Bone-targeting agents remain critical. Zoledronic acid and denosumab reduce skeletal-related events (SREs) by 62% (124). Odanacatib, a cathepsin K inhibitor, promotes osteolytic lesion repair (125). Locally delivered therapies using 3D-printed scaffolds increase drug concentration 100-fold. Technetium-99 methylene diphosphonate (⁹⁹Tc-MDP) combined with strontium-89 (⁸⁹Sr) shows superior pain control (125).

5.1.4 Precision imaging and molecular monitoring

Gallium-68–labeled prostate-specific membrane antigen (⁶⁸Ga-PSMA) PET/CT improves radioligand targeting (126). Circulating tumor DNA (ctDNA) harboring telomerase reverse transcriptase (TERT) mutations predicts progression months in advance (127), and exosomal microRNA-222-3p (miR-222-3p) achieves 92% diagnostic accuracy (128). The National Comprehensive Cancer Network (NCCN) recommends a stepwise treatment model: thyroid-stimulating hormone (TSH) suppression and antiresorptives for asymptomatic patients, SBRT and systemic therapy for progression, and ²²³Ra with immunotherapy for extensive disease. Multidisciplinary team (MDT) involvement improves five-year survival from 27% to 44% (95).

Bone metastases show higher transforming growth factor-β (TGF-β), contributing to MET amplification. Everolimus plus denosumab delays progression (129), and TANK-binding kinase 1 (TBK1) inhibition via amlexanox restores paclitaxel sensitivity (130). Prognostic models integrating PET parameters, ctDNA, and bone biomarkers achieve an area under the curve (AUC) of 0.91 (121). CTCs ≥5/7.5 mL triple the SRE risk (131).Emerging approaches include bispecific antibodies targeting prostate-specific membrane antigen (PSMA) and cluster of differentiation 3 (CD3), which increase CD8-positive T cells 9-fold (132), and clustered regularly interspaced short palindromic repeats (CRISPR)-mediated sodium-iodide symporter (NIS) gene reactivation for radioiodine sensitization (124). Artificial intelligence models analyzing CT scans reach 94% accuracy in predicting bone lesion pathology (128).

In conclusion, the therapeutic landscape for thyroid cancer bone metastasis is deeply intertwined with its underlying biology. A multimodal approach—encompassing surgery, interventional radiology, radiotherapy, and systemic or targeted therapies—should be tailored according to individual tumor burden, anatomical risk, and molecular profile. Continued elucidation of tumor–bone interactions is crucial for optimizing patient outcomes and advancing precision medicine in this challenging clinical context.

5.2 Therapeutic strategies and emerging advances in neuroendocrine carcinomas

Neuroendocrine carcinomas (NECs) constitute a diverse category of malignancies characterized by variable degrees of differentiation and grading (G1–G3), leading to marked heterogeneity in biological behavior and clinical aggressiveness. At initial presentation, a large proportion of patients exhibit distant metastases—most frequently involving the liver, bone, or lungs—which substantially diminish median survival and contribute to morbidity through skeletal-related complications (133, 134). Historically, therapeutic management was dominated by conventional cytotoxic chemotherapy, such as cisplatin–etoposide combinations, particularly for high-grade NECs. However, these regimens were often constrained by severe toxicity and limited long-term efficacy. For well-differentiated subtypes, somatostatin analogs (SSAs) were employed mainly for symptomatic control, with minimal impact on disease progression (24, 135). In recent years, the therapeutic landscape of NECs has undergone a major shift toward biologically driven and individualized treatment strategies. Innovations such as peptide receptor radionuclide therapy (PRRT) for somatostatin receptor–positive tumors, mTOR inhibitors (e.g., everolimus), and advanced diagnostic tools integrating biomarkers (e.g., chromogranin A) with functional imaging (e.g., ⁶⁸Ga-DOTATATE PET/CT) have collectively advanced precision oncology in this field (14). The following section summarizes evidence-based treatment approaches stratified by NEC subtype and metastatic burden, with emphasis on emerging modalities addressing persistent therapeutic challenges.

5.2.1 Systemic therapies

Systemic therapies represent the cornerstone of management for disseminated bone metastases, aiming to suppress tumor growth while modulating interactions within the bone microenvironment. Chemotherapy remains the first-line regimen for high-grade neuroendocrine carcinomas (NECs), including small-cell lung NEC (SCLC), large-cell lung NEC (LCNEC), and grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Platinum-based combinations—typically cisplatin with etoposide—have shown notable activity against metabolically active disease (61, 62).However, treatment feasibility may be limited by systemic toxicity and patient tolerance. For instance, in a patient with NEC and diffuse bone marrow metastases (ECOG 3–4), cisplatin/etoposide was contraindicated due to severe cytopenias (hemoglobin 29 g/L, platelets 49 × 10⁹ /L) (24, 135). In contrast, well-differentiated G1/G2 neuroendocrine tumors (NETs) with bone involvement often respond to less toxic regimens such as capecitabine combined with temozolomide, achieving disease stabilization in low-grade skeletal disease (136, 137).

Somatostatin analogs (SSAs), including octreotide and lanreotide, are central to controlling hormone-related symptoms (e.g., flushing, diarrhea) and exert antiproliferative effects in low-grade NETs (135, 138). Current consensus guidelines recommend SSAs as first-line therapy for G1/G2 NETs with bone metastases, especially in patients with confirmed somatostatin receptor (SSTR) expression by functional imaging (61, 135).Beyond symptom control, peptide receptor radionuclide therapy (PRRT) has emerged as a transformative modality for SSTR-positive tumors, delivering targeted cytotoxicity through radiolabeled ligands such as ¹⁷⁷Lu-DOTATATE or ⁹⁰Y-DOTATOC. Clinical studies have demonstrated tumor regression in up to 47% of GEP-NETs and sustained symptom improvement, with one case achieving 27 months of progression-free survival following PRRT (60, 139–141). Nevertheless, limited accessibility in certain regions continues to restrict its broader use (24, 135).

Molecularly targeted therapies further expand systemic options by disrupting signaling pathways involved in tumor–bone crosstalk. The mammalian target of rapamycin (mTOR) inhibitor everolimus prolonged progression-free survival in advanced non-functional NETs, including cases with osseous metastases, as shown in the RADIANT-4 trial (24, 135) (24, 142). Yet, clinical outcomes remain variable: in a patient with bone marrow–infiltrative NEC, everolimus (10 mg/day) induced leukopenia and progressive disease, reflecting limited efficacy in aggressive subtypes (24, 135). Similarly, anti-angiogenic therapy with sunitinib has demonstrated benefit in pancreatic NETs with bone lesions by targeting the hypervascular bone niche (138, 143).For metaiodobenzylguanidine (MIBG)-avid tumors, such as pheochromocytomas and paragangliomas, ¹³¹I-MIBG therapy yields symptom relief in more than half of treated patients, though bone marrow suppression remains a dose-limiting adverse event (61, 144).Emerging strategies involve immune checkpoint inhibitors (ICIs), designed to restore antitumor immunity within the immunosuppressive bone milieu. Early-phase studies combining ICIs with chemotherapy, radiotherapy, or anti-angiogenic agents have shown encouraging signals of efficacy in high-grade NECs with skeletal metastases (65, 145). Moreover, novel nanomaterial-based drug delivery systems—such as fucoidan-coated magnetic nanoparticles and biomimetic magnetosomes—are being investigated to enhance ICI delivery, increase tumor specificity, and minimize systemic toxicity (65, 146, 147).

5.2.2 Local therapeutic interventions

Local modalities complement systemic approaches by addressing focal skeletal disease and preventing skeletal-related events (SREs). Palliative radiotherapy remains highly effective for intractable bone pain and spinal cord compression, two major sources of morbidity in patients with bone metastases. Evidence from randomized trials confirms that a single 8 Gy fraction provides pain control equivalent to multi-fraction schedules (e.g., 20 Gy in 5 fractions) while reducing treatment burden (139, 148, 149). In a cohort of patients with neuroendocrine neoplasms (NENs) and bone metastases, 34.1% underwent palliative radiotherapy, which correlated with improved quality of life and decreased opioid use [4].Surgical management is reserved for selected indications, including pathological fractures, spinal instability, or isolated lesions with curative potential. Although surgery is performed in only ~2% of NEN bone metastasis cases, it is critical for preventing irreversible neurologic deficits due to cord compression (134, 150, 151). En-bloc resection of solitary bone metastases in well-differentiated NETs has yielded durable local control, provided that patient selection appropriately balances operative risk against therapeutic benefit (61, 151).

5.2.3 Supportive care and SRE prophylaxis

Supportive management remains essential to minimize therapy-related toxicity and reduce SRE incidence. Bone-modifying agents (BMAs)—such as bisphosphonates (e.g., zoledronic acid) and the RANKL inhibitor denosumab—constitute the foundation of SRE prevention by suppressing osteoclast-driven bone resorption. A meta-analysis of randomized trials demonstrated that denosumab delayed the time to first SRE more effectively than bisphosphonates in patients with solid tumor bone metastases, including those with NENs (134, 152). In practice, BMAs are recommended for patients with extensive skeletal disease, rapid progression, or high-grade histology, ideally initiated within 7–14 months after bone metastasis diagnosis to prevent early complications (134).Pain management should follow the World Health Organization (WHO) analgesic ladder: paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain, and opioids for more severe symptoms. In a study of 102 patients with NEN bone metastases, 43.5% achieved satisfactory pain control using first-line analgesics, emphasizing the importance of timely intervention (134). For patients with severe cytopenias caused by bone marrow infiltration, supportive measures such as blood transfusions and hematopoietic growth factors (e.g., interleukin-11 for thrombocytopenia) are indispensable to maintain treatment feasibility (24, 135). Additional supportive strategies include nutritional supplementation to address cancer-related cachexia and structured physical therapy to preserve mobility and prevent falls—key to reducing secondary fractures and maintaining quality of life (24, 135).

In summary, the management of bone metastases in NECs and NENs requires a comprehensive, multidisciplinary framework that integrates systemic, local, and supportive interventions. Established treatments—including platinum-based chemotherapy, peptide receptor radionuclide therapy, and bone-modifying agents—have significantly improved outcomes. Nonetheless, challenges persist, such as limited evidence for immunotherapy efficacy and the absence of standardized PRRT dosing strategies in this population. Future research should emphasize precision oncology approaches, including machine learning–based stratification models to identify patients at greatest risk for skeletal complications (65), thereby enabling individualized treatment and minimizing unnecessary interventions.

5.3 Comprehensive treatment strategies and latest advances in bone metastases of endocrine-dependent cancers

Bone metastasis represents a defining feature of advanced endocrine-dependent cancers, specifically prostate cancer (PCa) and breast cancer (BCa), which severely compromises bone homeostasis and skeletal integrity, thereby posing immense challenges to clinical management. The therapeutic paradigm for these metastases has shifted dramatically from single-modality interventions to multimodal, precision-driven strategies—shaped by insights into core mechanisms like Paget’s “seed and soil” theory, epithelial–mesenchymal transition (EMT), and the tumor-bone “vicious cycle.”

Bone metastases in endocrine-dependent malignancies such as prostate and breast cancer represent a pivotal stage of disease progression and a major cause of morbidity. Despite distinct biological profiles—osteoblastic predominance in prostate cancer and osteolytic features in breast cancer—both share critical molecular mechanisms involving epithelial–mesenchymal transition (EMT), chemokine-driven bone homing, and reciprocal tumor–bone interactions that generate a self-sustaining “vicious cycle” of osteolysis and osteogenesis (153–157). Management has therefore evolved toward a multimodal, mechanism-oriented strategy combining endocrine, cytotoxic, targeted, immune, and bone-modifying therapies, supplemented by precision local interventions and multidisciplinary care.

5.3.1 Systemic and endocrine-based therapies

Endocrine manipulation remains the foundation of systemic management. In prostate cancer, androgen deprivation therapy (ADT) through gonadotropin-releas183ing hormone (GnRH) agonists or antagonists and androgen receptor (AR) inhibitors such as apalutamide and enzalutamide improves overall survival (158–160). The CYP17 inhibitor abiraterone extends benefit in metastatic castration-resistant prostate cancer (mCRPC) (161, 162). Similarly, in hormone receptor-positive (HR⁺)/HER2-negative breast cancer, aromatase inhibitors (AIs) and selective estrogen receptor degraders (SERDs) such as fulvestrant remain first-line, often combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors to overcome resistance (159, 160). New-generation SERDs like elacestrant have demonstrated activity even after CDK4/6 inhibitor failure (153, 154). Targeting the PI3K/AKT/mTOR pathway, particularly in PIK3CA-mutant disease, has yielded additional benefit (163, 164).

5.3.2 Chemotherapy and targeted approaches

Chemotherapy remains an essential component for endocrine-refractory or rapidly progressive disease. In prostate cancer, docetaxel improves survival in both hormone-sensitive and resistant settings, while cabazitaxel is reserved for docetaxel-refractory cases (165). In breast cancer, sequential single-agent regimens are preferred for bone-only or indolent disease, reserving combination therapy for visceral crisis (160). Targeted therapies such as PARP inhibitors (e.g., olaparib) benefit patients harboring BRCA1/2 or ATM mutations (165), and their combination with endocrine or AR blockade has reduced progression risk (166). HER2-positive breast cancer patients derive major survival advantages from trastuzumab- and pertuzumab-based regimens, often combined with taxanes (160, 167, 168).

5.3.3 Bone-modifying agents and microenvironment modulation

Bone-targeted therapy constitutes a shared therapeutic axis across both malignancies. Bisphosphonates (e.g., zoledronic acid, ibandronate) and the monoclonal antibody denosumab—an inhibitor of receptor activator of nuclear factor-κB ligand (RANKL)—effectively reduce skeletal-related events (SREs) (160, 169–177). Denosumab shows superiority in SRE prevention, though monitoring for osteonecrosis of the jaw and hypocalcemia remains critical (178). Recent refinements, including liposomal zoledronic acid and conjugated forms such as zoledronic acid–paclitaxel (ZOL-PTX), enhance drug targeting and limit nephrotoxicity (179). Moreover, dual inhibition of RANKL and PI3K/AKT/mTOR signaling further prolongs skeletal protection (180, 181).

Interventions targeting the bone niche—such as CXCR4 antagonists (plerixafor), integrin αvβ3 inhibitors, and hypoxia-inducible factor-1α (HIF-1α) modulators—disrupt metastatic colonization and enhance chemotherapy response (182, 183). Anti-sclerostin antibody romosozumab and sustained-release bone morphogenetic protein 2 (BMP-2) systems promote bone formation and mitigate osteolysis (184). These approaches reflect a growing emphasis on restoring bone homeostasis alongside tumor control.

5.3.4 Radiotherapy, radiopharmaceuticals, and surgery

Radiotherapy remains integral for pain relief and local control. External beam radiation therapy (EBRT), intensity-modulated radiation therapy (IMRT), and stereotactic body radiotherapy (SBRT) achieve rapid analgesia and high precision (161, 177, 185–193). Radionuclide therapies such as strontium-89 and radium-223 provide systemic skeletal targeting, the combination of Ra-223 with abir (121). Lutetium-177- and actinium-225-labeled PSMA ligands have shown remarkable efficacy in mCRPC, achieving substantial prostate-specific antigen (PSA) declines (194). Surgical intervention remains indispensable for pathological fractures, spinal cord compression, or structural instability, with decision frameworks including Mirels score and SINS guiding management (54, 55, 192, 193, 195–203).

5.3.5 Immunotherapy, nanotechnology, and emerging modalities

Immunotherapy is gaining traction in bone-predominant disease. PD-1 blockade with pembrolizumab and CTLA-4 inhibition with ipilimumab have shown synergistic activity, increasing CD8⁺ infiltration and improving lesion control (204). Novel cell-based therapies, including PSMA-targeted and RANKL-directed CAR-T cells, as well as IL-15-enhanced γδ T cells, significantly reduce osteolytic activity in preclinical models (205, 206). Parallel innovations in nanomedicine—such as folate-linked liposomal mitoxantrone and hydroxyapatite-bound doxorubicin—achieve superior bone accumulation and lower systemic toxicity (182, 183). Thermal ablation using magnetic nanoparticles and bisphosphonate–denosumab–Ra-223 sequences further enhance pain control and local suppression (207–210). Recent advances in nanomedicine are paving the way for a new era of targeted therapy in endocrine cancer–related bone metastases. Bone-targeted nanoparticles, including hydroxyapatite-bound doxorubicin (DOX) and folate-linked liposomal mitoxantrone, have demonstrated superior localization within the mineralized bone matrix, achieving higher intralesional drug concentrations while minimizing systemic exposure and toxicity (211, 212). Folate receptor-mediated liposomal delivery enhances selective uptake by tumor cells, particularly in hormone-dependent cancers such as breast and prostate carcinoma, improving therapeutic efficacy and safety profiles (213). Hydroxyapatite-based nanocarriers exploit strong affinity for bone tissue, acting as dual-function systems that both release chemotherapeutic agents and support bone regeneration. Moreover, magnetic nanoparticles are being developed for localized hyperthermia or thermoablative therapy, showing promise in controlling pain and suppressing tumor growth within osseous lesions (214). Integration of these nanotherapeutic platforms with current bone-modifying agents—such as bisphosphonates, denosumab, or the α-emitter radium-223—may further enhance skeletal protection and therapeutic outcomes (211). Despite challenges in large-scale production, biodistribution variability, and long-term biocompatibility, these nanomedicine strategies represent compelling candidates for early-phase clinical trials targeting bone-dominant metastases, offering the potential to reshape standard treatment paradigms for endocrine malignancies with skeletal involvement.

5.3.6 Metabolic and epigenetic reprogramming

Targeting tumor metabolism has introduced new therapeutic angles. Pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate reverses the Warburg effect, while glutaminase inhibitors (e.g., CB-839) synergize with bisphosphonates to reduce osteoclastogenesis (215, 216). Epigenetic regulators such as EZH2 inhibitors (tazemetostat) and DNA methyltransferase inhibitors (decitabine) potentiate AR or endocrine blockade responses (217). Complementary interventions, including curcumin nanoparticles, triptolide derivatives, and microbiota modulation, further modulate immune-metabolic equilibrium (183, 218–222).

5.3.7 Precision monitoring and multidisciplinary integration

Advances in imaging and molecular diagnostics have improved early detection and therapeutic precision. 18F-NaF PET/CT offers superior resolution for microlesions (208, 223), while circulating tumor cells (CTCs) and ctDNA analyses enable early assessment of bone metastatic activity and treatment response (210, 224). Artificial intelligence-based prediction models outperform conventional scoring systems in fracture risk evaluation (225, 226). Multi-omic profiling—including identification of COL11A1⁺ fibroblasts and elevated circulating progastrin (hPG80)—refines prognostic stratification (219, 227–229). A multidisciplinary team (MDT) approach integrating urology, oncology, radiology, and nuclear medicine ensures individualized, evidence-based care (230, 231). To present more intuitively the stratified treatment logic and specific implementation pathways for endocrine cancers with bone metastases (including thyroid cancer, neuroendocrine carcinoma, and endocrine-dependent cancer) developed based on cancer type, disease progression, and molecular characteristics, the corresponding stratified treatment flowchart (Figure 2) is hereby attached.

Figure 2

Figure 2. Stratified treatment flowchart for endocrine cancers with bone metastases.

6 Significance of preventing bone metastases in endocrine

As established bone lesions are often refractory to treatment, early intervention and prevention strategies are critical. Targeting molecular mechanisms that drive bone colonization may delay metastasis onset and improve survival. Therefore, focusing on the prevention of skeletal involvement is essential to enhance long-term disease control and optimize patient care in endocrine oncology.

6.1 Preventive strategies for bone metastasis in thyroid cancer: integrating recent advances in precision medicine

With the continuous advancements in comprehensive treatment and precision medicine for thyroid cancer, preventive strategies against bone metastasis have become more targeted and individualized. Early detection and intervention play a critical role in preventing the progression to advanced stages. For patients with high-risk sites, such as the spine and femur, early screening and intervention are essential. The use of 3D navigation and intraoperative nerve monitoring during surgeries significantly enhances safety, allowing for effective control of small bone lesions before progressing to more invasive procedures like spinal resection (30, 109, 112). Stereotactic body radiation therapy (SBRT) has shown remarkable efficacy in increasing local control rates while minimizing spinal cord exposure, making it a preferred approach for early-stage bone lesions (41, 113, 232). Furthermore, radiofrequency ablation combined with bone cementoplasty has proven effective in preventing pathological fractures by stabilizing bone structure in the early stages (233).

Systemic preventive strategies are critical for high-risk patients. Early administration of targeted therapies and immune treatments can delay or even reverse the development of bone metastasis. Drugs like lenvatinib and selpercatinib target tumor biology to reduce bone invasion (98, 118, 234). Immune therapy combined with targeted treatments enhances CD8+ T-cell infiltration, thereby boosting immune surveillance and preventing the formation of bone metastasis (235–237). Bone-modifying agents such as bisphosphonates and denosumab also play an important role in reducing the risk of bone-related events and protecting bone integrity (124, 125, 238).

Risk stratification and early warning systems are crucial for enhancing the precision of preventive measures. A deep learning-based model, integrating parameters such as ¹⁸F-FDG PET/CT metabolic activity (SUVmax>8.2), ctDNA mutations in the TERT promoter, and bone metabolic markers (ALP >120 U/L), provides a reliable tool for predicting bone-related events (127, 239). Liquid biopsy assays that detect specific miRNA combinations (such as miR-146b, miR-222) have demonstrated an impressive sensitivity of 94%, enabling early detection of micro-metastasis (240).

Molecular targeting and microenvironment modulation have emerged as promising strategies in the prevention of bone metastasis. Early intervention in the RANKL pathway with denosumab (120 mg/month) has shown to reduce the incidence of bone metastasis (175, 241). TGF-β signaling inhibitors and histone deacetylase inhibitors have demonstrated potential in preclinical models to reduce the tumor burden of bone metastasis and inhibit angiogenesis (129, 242–244). Additionally, CXCR4 antagonists have been shown to reduce myeloid-derived suppressor cells (MDSCs) in the bone marrow, enhancing CD8+ T-cell infiltration and preventing the establishment of a bone metastatic niche (245).

Innovative technologies have significantly enhanced the ability to detect and prevent bone metastasis at early stages. Molecular imaging techniques, such as ⁶⁸Ga-PSMA PET/CT, combined with 177Lu therapy, allow for enhanced tumor localization and precision targeting, thus offering a powerful tool for early intervention (126, 246). Nanoparticle-based drug delivery systems, such as β3 integrin-targeted hydroxyapatite nanoparticles, improve drug concentration in bone metastatic lesions, enabling more effective local therapy (247, 248). Moreover, CRISPR/Cas9-mediated gene silencing, such as NKX2–8 knockdown, has been shown to reduce bone metastasis formation by 73%, offering a novel preventive strategy (108, 237).

The three-level prevention system has been established to guide clinical practice across different stages of bone metastasis. For patients at high risk but without detectable metastasis, primary prevention with TSH suppression therapy combined with bone-protective agents has been shown to reduce the incidence of bone metastasis by 41% over five years (45, 95). In patients with oligometastatic disease, SBRT combined with targeted therapy has improved progression-free survival (PFS) to 68% over two years (112). For patients with extensive bone metastasis, a combination of 223Ra and immune checkpoint inhibitors has extended median survival by 4.3 months (115).

In terms of complications, denosumab has been shown to reduce hypercalcemia more rapidly than bisphosphonates, providing a more immediate therapeutic benefit (249). In cases of pathological fractures, the combination of 3D-printed titanium alloy prostheses and postoperative radiotherapy has reduced mechanical complications by 58% (250). Moreover, for spinal cord compression, vertebroplasty combined with 125I seed implantation has demonstrated a pain relief rate of 94% (251).

Future research will focus on further optimizing the prevention of bone metastasis through several innovative avenues. Developing humanized PDX models that preserve the immune microenvironment for drug screening (252), designing inhibitors targeting epigenetic markers specific to bone metastasis (such as PCAT7) (253), and optimizing the timing and sequencing of multi-modal therapies (e.g., combining radiation with immunotherapy to enhance antitumor effects) (109) will be key areas of development. Additionally, exploring circadian rhythm regulation mechanisms, such as the role of BMAL1 gene knockout in accelerating bone metastasis, may open new therapeutic windows in time-based medicine.

6.2 Preventive strategies for bone metastases in neuroendocrine neoplasms

Preventive strategies for bone metastases (BMs) in neuroendocrine neoplasms (NENs)—including neuroendocrine carcinoma (NEC)—focus on early detection, risk stratification, and bone health preservation to reduce skeletal-related events (SREs) and improve survival and quality of life. Early detection relies on advanced imaging. ⁶⁸Ga-DOTATATE PET/CT shows high sensitivity (85%–95%) for somatostatin receptor (SSTR)-positive BMs, outperforming bone scintigraphy and CT (14, 60, 254). In high-grade (G2/G3) NEC, dual-tracer imaging (⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT) detects asymptomatic lesions, refines staging, and alters management in 12.2%–14.3% of patients, redirecting care toward preventive interventions (14, 60). MRI provides 90%–100% sensitivity for bone marrow infiltration and spinal cord involvement, particularly in patients with unexplained anemia, thrombocytopenia, or elevated lactate dehydrogenase (LDH) (14, 60, 255).

Biochemical surveillance complements imaging. Chromogranin A (CgA), with sensitivity up to 81%, reflects metastatic burden but lacks bone specificity[8]. Bone sialoprotein (BSP) correlates with BM presence and poor prognosis, while bone-specific alkaline phosphatase (BSAP) offers better prognostic value for adverse outcomes (14, 60, 62). Additional markers such as type I collagen propeptide (PINP) and N-telopeptide (NTx) indicate bone metabolism. Combined use of ⁶⁸Ga-DOTATATE imaging, CgA, and BSP enhances diagnostic accuracy (AUC > 0.75, sensitivity and specificity > 80%) (60). Elevated inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) and alkaline phosphatase (ALP) may also signal early BM in unknown primary NEC (60).

Risk stratification directs preventive efforts. Patients with liver or lung metastases have markedly increased BM risk (odds ratio [OR] = 32.98 and 35.78, respectively) (60, 256), thus, ⁶⁸Ga-DOTATATE PET/CT screening is recommended. In high-grade lung NECs, machine learning models (e.g., gradient boosting, AUC 0.723) integrate clinical and metastatic factors for individualized risk prediction. SHapley Additive exPlanations (SHAP) analyses highlight liver metastasis, nodal stage, age, and sex as key predictors, guiding surveillance priorities (257). For hereditary syndromes such as multiple endocrine neoplasia type 1 (MEN1), regular screening remains vital since primary hyperparathyroidism accelerates bone loss and fracture risk (257).

Bone health management involves correcting vitamin D deficiency, which affects 46%–81% of NEN patients. Supplementation (cholecalciferol 1000–2000 IU/day, serum 25(OH)D >30 ng/mL) preserves bone mineral density and may improve outcomes (19, 255). Bone-modifying agents (BMAs), including bisphosphonates and denosumab, are considered for patients with multiple BMs, rapid progression, or high-grade tumors. Data from breast and prostate cancer show BMAs delay SREs, with denosumab offering superior fracture protection (14, 258). In MEN1-related hyperparathyroidism, parathyroidectomy or calcimimetics (e.g., cinacalcet) mitigate bone loss and skeletal complications (254, 256).

Lifestyle and follow-up are complementary. Adequate calcium and protein intake, low-impact exercise (e.g., walking, swimming), and avoidance of bone trauma maintain skeletal strength. Routine monitoring every 3–6 months with imaging, biomarkers, and clinical evaluation ensures timely adjustment of preventive measures, rising CgA or BSP may prompt early initiation of BMAs (60, 62). Patients with prior SREs require closer monitoring (every 2–3 months) as the median time to a second SRE is 10 months (259).

Despite progress, preventive care still faces gaps—particularly the lack of prospective trials on BMAs for SRE prevention in NENs and the need for BM-specific biomarkers. Future research should refine risk models by incorporating molecular data (e.g., Ki-67, TP53/RB1 mutations) and explore novel tracers (e.g., SSTR5 ligands) to improve detection. Studies combining vitamin D and BMAs in high-risk patients may further reduce BM-associated morbidity and mortality.

6.3 Strategies and advances in the prevention of prostate cancer bone metastases

Effective prevention of bone metastasis in prostate cancer requires integration of emerging therapeutic insights with proactive strategies targeting the tumor-bone microenvironment, immune evasion, hormonal axis alterations, and epigenetic dysregulation. Here, we systematically align prevention approaches with current therapeutic strategies, aiming to establish a scientifically rigorous framework for translational application.

Modulation of the bone microenvironment is critical. Prophylactic administration of denosumab (120 mg monthly) significantly reduced skeletal metastasis incidence by 42% in high-risk patients (260). Third-generation bisphosphonates, particularly when combined with TGF-β inhibitors, provide dual regulation of osteoclastic and osteoblastic activities (166, 261), preserving skeletal integrity. Maintenance of serum vitamin D3 levels above 30 ng/mL inhibits EMT processes via CaSR activation (262, 263). Furthermore, mechanical stimulation at 30 Hz enhances connexin43-mediated intercellular communication among osteocytes, decreasing secretion of the pro-metastatic factor OPN by 41% (264).

Inhibiting chemokine signaling pathways is another essential preventive approach. Periodic pulsed administration of CXCR4 inhibitors, such as plerixafor, eradicates dormant tumor cells within the bone marrow niche (265). Liquid biopsy detection of KLF4/RUNX2 ratios (AUC = 0.87) and exosomal miR-181a-5p levels can predict bone metastasis risk up to eight weeks earlier than conventional imaging (266, 267), enabling timely preventive interventions.

Optimization of hormonal pathways also supports metastasis prevention. Early identification of DNA repair deficiencies (e.g., BRCA1/2, ATM mutations) facilitates targeted prophylactic use of PARP inhibitors (e.g., olaparib) in combination with abiraterone, reducing radiological progression risk by 34% (268). The development of dual CYP17A1/CYP11B2 inhibitors offers a future avenue for simultaneous blockade of androgen and aldosterone synthesis (121).

Immune-based prevention has gained momentum. Neoantigen vaccines such as NeoVax induce durable T-cell responses in MSI-H patients, achieving an 82% five-year metastasis-free survival (269). Modulation of the gut microbiota with Akkermansia muciniphila enhances bone marrow IFN-γ+ CD8+ T-cell populations by 38%, suppressing osteoclast precursor differentiation (253).

Advances in targeted delivery systems provide additional preventive avenues. Hydroxyapatite nanoparticles demonstrated a 6.8-fold increase in bone targeting compared to conventional formulations (270), while pH-responsive lipid-based systems improved DKK1 gene silencing efficiency by 3.2-fold (271). Folic acid-modified paclitaxel liposomes exhibited a 5.3-fold higher accumulation in metastatic foci (272). Moreover, biomimetic red blood cell membrane-coated nanoparticles achieved prolonged circulation (t1/2 = 38 h) and, upon monthly prophylactic administration, improved micrometastatic clearance rates by 4.2-fold (273).

Epigenetic intervention represents a powerful preventive modality. Low-dose decitabine (0.1 mg/kg weekly) restores SFRP2 expression through demethylation, resulting in a 68% reduction in Wnt pathway activity (110). Natural compounds such as resveratrol, activating SIRT1 and repressing H3K4me3 histone modifications, have been shown to lower the five-year cumulative incidence of metastasis by 55% in high-risk populations (274).

Radionuclide therapy is emerging as a promising preventive strategy. 223Ra combined with olaparib extended median OS to 19.5 months (275), while 177Lu-PSMA-617 reduced mortality risk by 38% (276). α-particle emitters like 225Ac-PSMA and the short-range emitter 212Pb display superior tumoricidal activity, particularly against micrometastases (277, 278).

Molecular early warning and intervention strategies, such as PSMA-PET/CT using PROMISE V2 standards, achieve a sensitivity of 98% for detecting lesions smaller than 5 mm (279, 280). Gene therapy with BMP7 to induce tumor cell dormancy via p38MAPK activation yielded a dormancy maintenance rate of 68% (281, 282), while concurrent CXCR4 inhibition further eradicated residual dormant cells (265).

Finally, integration of therapeutic and preventive paradigms is paramount. Early administration of radium-223 (<3 months after ADT initiation) significantly improved bone metabolic markers (283). Emerging sequential regimens—neoadjuvant PSMA-RLT followed by radical surgery and adjuvant hormonal therapy—achieved a 15% pathological complete response rate (284). Targeting PSMA-negative resistant clones via multimodal PET imaging (PSMA/FDG/DOTATATE) and dual-ligand therapy restored sensitivity in 53% of cases (285). Artificial intelligence platforms, such as DeepMets (AUC = 0.93) and organoid-based drug sensitivity assays, are accelerating the individualization of metastasis prevention strategies (286, 287).

In summary, prevention of prostate cancer bone metastasis demands a multifaceted approach encompassing microenvironment modulation, dormancy maintenance, immune surveillance enhancement, precise molecular targeting, and epigenetic reprogramming. Future integration of real-time molecular diagnostics, nanoengineering, and AI-driven decision-making will enable a dynamic, individualized preventive landscape.

6.4 Prevention and treatment strategies for bone metastasis in breast cancer

Bone metastasis in breast cancer remains a major complication, significantly impacting patient quality of life and survival. A multi-faceted approach, encompassing both therapeutic and preventive strategies, is crucial in managing this condition.

6.4.1 Bone-modifying agents

Bisphosphonates, particularly zoledronic acid, have demonstrated efficacy in reducing the risk of bone metastasis and increasing lumbar bone mineral density (BMD) (288). Another critical agent, denosumab, a third-generation RANKL inhibitor, has shown significant benefits by delaying the first skeletal-related event (SRE) by 4.3 months and improving overall survival (OS) in estrogen receptor-positive (ER+) breast cancer patients (175). Furthermore, novel drug delivery systems, such as liposomal formulations of zoledronic acid, have increased targeted drug delivery efficiency by 5-fold while reducing nephrotoxicity by 70% (179).

6.4.2 Targeted signal pathway interventions

CDK4/6 inhibitors, such as palbociclib in combination with letrozole, have shown promise in extending progression-free survival (PFS) in bone metastatic breast cancer patients by 11 months (24.8 vs 13.8 months), with a 72% reduction in tartrate-resistant acid phosphatase-positive (TRAP+) cells[5]. The combination of everolimus and exemestane targeting the PI3K/AKT/mTOR pathway has prolonged progression-free survival to 31 months (vs. 13 months) and reduced serum CTX levels by 45% (163). Wnt pathway inhibition through DKN-01 monoclonal antibody in phase II trials has shown a 40% increase in bone metastasis lesion shrinkage (289).

6.4.3 Immunotherapy innovations

PD-L1 inhibitors, such as atezolizumab in combination with chemotherapy, have demonstrated an overall response rate (ORR) of 29% in triple-negative breast cancer patients with bone metastasis, with the PD-L1+ subgroup showing improved OS of 25 months (290). CAR-T cell therapy targeting RANKL has shown promising results in preclinical models by reducing osteolytic lesions by 68% (291). Oncolytic virotherapy, such as T-VEC combined with radiotherapy, also induces a distant effect with a response rate of 33% in untreated lesions (292).

6.4.4 Novel drug delivery systems

Nanoparticle-based drug delivery systems, such as hydroxyapatite nanoparticles loaded with doxorubicin, have been shown to increase drug concentration in bone metastases(5.8 times), while reducing cardiotoxicity by 72% (182). pH/redox-sensitive micelles (DOX@ALN-HA) exhibit a 90% drug release rate in the bone microenvironment, with a tumor inhibition rate of 78% (293). Magnetic nanoparticles used for local hyperthermia (52 °C) in conjunction with immunotherapy resulted in a 91% tumor ablation rate (294).

6.4.4.1 Risk stratification and monitoring

FRAX(full name) assessment combined with TBS (trabecular bone score) is utilized to identify high-risk individuals, initiating preventive interventions for those with a T-score ≤ -2.0 or two additional risk factors (210). [¹⁸F]NaF-PET/CT offers 92% sensitivity, effectively detecting early bone metastases as small as <2 mm (208). Liquid biopsy monitoring, particularly CTC-based BMP2 expression, has shown predictive value for bone metastasis risk, with an AUC of 0.87 (210).

6.4.4.2 Pharmacological prevention

Adjunctive treatment with bisphosphonates has been shown to reduce the risk of bone metastasis by 28% in postmenopausal women (RR = 0.72) (295). Denosumab (60 mg/6 months) used prophylactically has reduced clinical fractures by 50% (296). Supplementation with vitamin D (2000 IU/day) to maintain serum 25(OH)D levels above 40 ng/mL has been associated with a 29% reduction in bone metastasis risk (220).

6.4.4.3 Endocrine therapy optimization

Selective estrogen receptor degraders (SERDs) like elacestrant maintain anti-metastatic activity even in CDK4/6 inhibitor-resistant models by downregulating the ERK/MAPK pathway and reversing resistance (297). Ovarian function suppression (OFS) combined with zoledronic acid (4 mg/6 months) stabilizes lumbar BMD, contrasting with a 5.4% decline in the control group (288).

6.4.4.4 Lifestyle interventions

Vibration therapy combined with vitamin D supplementation has led to a 1.8% annual increase in BMD and a reduction of pain scores by 2.3 points (298). Resistance training (3 times/week) has improved lumbar BMD by 2.1% and reduced vertebral fracture risk by 23% (299).

6.4.4.5 Novel preventive agents

Sclerostin inhibitors, such as romosozumab, have demonstrated a 47% increase in bone volume and a 35% reduction in circulating CTCs in preclinical models (300). The BCMA×CD3 bispecific antibody teclistamab has shown a 38% rate of osteolytic lesion healing (301), while the integrin αvβ3 inhibitor MK-0429 significantly reduced bone resorption by 72% (122).

Combined Treatment Sequential Regimens:Sequential therapy using a “bisphosphonate → denosumab → radium-223” strategy has extended the median SRE-free survival time to 28 months (302).

6.4.4.6 Radiotherapy synergy

Stereotactic body radiotherapy (SBRT) combined with denosumab has achieved a 92% one-year local control rate, with pain relief occurring within 2.1 weeks (209).

Metabolic Intervention:The combination of glutaminase inhibitors like CB-839 with bisphosphonates has shown a 79% tumor inhibition rate in preclinical models by inhibiting osteoclast activity (303).

6.4.5 Monitoring technology innovations

Imaging Techniques:⁶⁸Ga-PSMA PET/CT has demonstrated 88% specificity, improving upon traditional bone scans by 40% (304). AI-Assisted Monitoring:Deep learning algorithms have increased the accuracy of predicting pathological fractures to 91%, outperforming the Mirels scoring system by 23% (305). Molecular Monitoring:ctDNA testing for PIK3CA mutations can predict bone progression 8.4 weeks in advance with an AUC of 0.87, offering earlier intervention opportunities (216). The comparative strategies for preventing bone metastasis of endocrine cancer discussed in this chapter are summarized in Table 2.

Table 2

Table 2. Comparative strategies for preventing bone metastases in endocrine cancers.

7 Conclusions and perspectives

Bone metastases from endocrine malignancies—encompassing thyroid carcinoma, neuroendocrine carcinoma (NEC), and endocrine-dependent cancers such as prostate and breast cancer—represent a major clinical challenge that severely impairs survival and quality of life. Despite recent advances in multimodal imaging, molecular profiling, and systemic therapy, early diagnosis and effective management remain hindered by tumor heterogeneity and the complex tumor–bone microenvironment.

7.1 Current progress and challenges

High-resolution imaging technologies, including ⁶⁸Ga-DOTATATE PET/CT in neuroendocrine neoplasms and PSMA PET/CT in prostate cancer, have dramatically enhanced diagnostic accuracy and staging precision. Similarly, the integration of biomarkers such as chromogranin A, bone-specific alkaline phosphatase (BSAP), and circulating tumor DNA (ctDNA) into diagnostic algorithms enables earlier and more specific detection of bone involvement. However, limited sensitivity in detecting micrometastases and the lack of standardized diagnostic workflows continue to restrict early intervention.

On the therapeutic front, targeted and systemic therapies have redefined disease control paradigms. Tyrosine kinase inhibitors (e.g., lenvatinib, apatinib) and selective RET inhibitors (e.g., selpercatinib) have extended progression-free survival in radioiodine-refractory thyroid cancer. In NECs, peptide receptor radionuclide therapy (PRRT) with has shown durable responses in somatostatin receptor–positive disease. For prostate and breast cancer bone metastases, combinations of or CDK4/6 inhibitors with bone-modifying agents (zoledronic acid, denosumab) have become standard, significantly reducing skeletal-related events. Despite these achievements, drug resistance, therapy-induced bone remodeling, and treatment-related toxicities remain unsolved barriers.

7.2 Perspectives

Future research must focus on integrated precision medicine that combines molecular diagnostics, computational modeling, and personalized therapy selection. Multi-omics profiling—spanning genomics, proteomics, and metabolomics—should be incorporated into clinical workflows to enable predictive stratification and early detection of bone metastases. Artificial intelligence (AI)-based radiomics models have shown promise in predicting metastatic potential and treatment response with over 90% accuracy. Furthermore, –based monitoring of circulating tumor cells (CTCs) and ctDNA could revolutionize surveillance and real-time therapy adjustment. Therapeutically, future directions emphasize microenvironment-targeted and immune-based interventions. Combination regimens integrating immune checkpoint inhibitors with bone-targeted agents or radiopharmaceuticals (e.g., radium-223) are being explored to overcome immune evasion and enhance local control. The development of and bone-seeking radioligands offers new strategies for improving drug specificity while minimizing systemic toxicity. Additionally, patient-centered multidisciplinary management—coordinating oncology, radiology, orthopedics, and nuclear medicine—remains essential for optimizing outcomes and preserving function.

In summary, the management of endocrine cancer bone metastases is entering a new era of molecular precision, multimodal integration, and immunologic innovation. Continued translational research, early clinical trial enrollment, and global collaboration will be pivotal to transforming bone metastasis from a terminal complication into a controllable chronic condition, ultimately improving both longevity and quality of life for patients.

Author contributions

SH: Writing – original draft, Writing – review & editing. YS: Conceptualization, Methodology, Writing – review & editing. HL: Methodology, Writing – review & editing. TG: Supervision, Writing – review & editing. LW: Formal Analysis, Visualization, Writing – review & editing. JY: Software, Visualization, Writing – review & editing. LS: Conceptualization, Methodology, Project administration, Resources, Supervision, Writing – review & editing.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by Natural Science Foundation of Shandong Province (ZR2023MH072) and Shandong Provincial Postdoctoral Innovation Program(SDCX-ZG-202400037).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Fazio N and La Salvia A. Precision medicine in gastroenteropancreatic neuroendocrine neoplasms: Where are we in 2023? Best Pract Res Clin Endocrinol Metab. (2023) 37:101794. doi: 10.1016/j.beem.2023.101794

PubMed Abstract | Crossref Full Text | Google Scholar

2. Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M, and Dal Maso L. Worldwide thyroid-cancer epidemic? The increasing impact of overdiagnosis. New Engl J Med. (2016) 375:614–7. doi: 10.1056/NEJMp1604412

PubMed Abstract | Crossref Full Text | Google Scholar

3. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. (2021) 71:209–49. doi: 10.3322/caac.21660

PubMed Abstract | Crossref Full Text | Google Scholar

4. Cabanillas ME, McFadden DG, and Durante C. Thyroid cancer. Lancet (London England). (2016) 388:2783–95. doi: 10.1016/S0140-6736(16)30172-6

PubMed Abstract | Crossref Full Text | Google Scholar

5. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. (2017) 3:1335–42. doi: 10.1001/jamaoncol.2017.0589

PubMed Abstract | Crossref Full Text | Google Scholar

6. Fraenkel M, Kim M, Faggiano A, de Herder WW, and Valk GD. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocrine-related cancer. (2014) 21:R153–63. doi: 10.1530/ERC-13-0125

PubMed Abstract | Crossref Full Text | Google Scholar

7. Lumachi F, Brunello A, Maruzzo M, Basso U, and Basso SM. Treatment of estrogen receptor-positive breast cancer. Curr medicinal Chem. (2013) 20:596–604. doi: 10.2174/092986713804999303

PubMed Abstract | Crossref Full Text | Google Scholar

8. Attard G, Parker C, Eeles RA, Schröder F, Tomlins SA, Tannock I, et al. Prostate cancer. Lancet (London England). (2016) 387:70–82. doi: 10.1016/S0140-6736(14)61947-4

PubMed Abstract | Crossref Full Text | Google Scholar

9. Pellegriti G, Frasca F, Regalbuto C, Squatrito S, and Vigneri R. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol. (2013) 2013:965212. doi: 10.1155/2013/965212

PubMed Abstract | Crossref Full Text | Google Scholar

10. Brockton NT, Cook LS, Magliocco AM, Shemanko CS, Vogel HJ, Khan M, et al. The breast to bone (B2B) cohort study to prevent, detect and improve treatment of metastatic disease: baseline assessment, description and progress. Int J Environ Res Public Health. (2025) 22:0242. doi: 10.3390/ijerph22020242

PubMed Abstract | Crossref Full Text | Google Scholar

11. Fanchiang JK, Lin JD, Huang MJ, and Shih HN. Papillary and follicular thyroid carcinomas with bone metastases: a series of 39 cases during a period of 18 years. Changgeng yi xue za zhi. (1998) 21:377–82.

PubMed Abstract | Google Scholar

12. Zhang R, Zhang W, Wu C, Jia Q, Chai J, Meng Z, et al. Bone metastases in newly diagnosed patients with thyroid cancer: A large population-based cohort study. Front Oncol. (2022) 12:955629. doi: 10.3389/fonc.2022.955629

PubMed Abstract | Crossref Full Text | Google Scholar

13. Iñiguez-Ariza NM, Bible KC, and Clarke BL. Bone metastases in thyroid cancer. J Bone Oncol. (2020) 21:100282. doi: 10.1016/j.jbo.2020.100282

PubMed Abstract | Crossref Full Text | Google Scholar

14. Zhang X, Tian Y, Fu L, Zhang Y, Dong Y, Xie F, et al. (68)Ga-DOTATATE and (18)F-FDG PET/CT dual-modality imaging enhances precision of staging and treatment decision for gastroenteropancreatic neuroendocrine neoplasms. Nan fang yi ke da xue xue bao = J South Med University. (2025) 45:1212–9. doi: 10.12122/j.issn.1673-4254.2025.06.10

PubMed Abstract | Crossref Full Text | Google Scholar

15. Altieri B, Di Dato C, Martini C, Sciammarella C, Di Sarno A, Colao A, et al. Bone metastases in neuroendocrine neoplasms: from pathogenesis to clinical management. Cancers. (2019) 11:1332. doi: 10.3390/cancers11091332

PubMed Abstract | Crossref Full Text | Google Scholar

16. Lee YS, Kim H, Kim HW, Lee JC, Paik KH, Kang J, et al. High expression of microRNA-196a indicates poor prognosis in resected pancreatic neuroendocrine tumor. Medicine. (2015) 94:e2224. doi: 10.1097/MD.0000000000002224

PubMed Abstract | Crossref Full Text | Google Scholar

17. Liu XD, Cai F, Liu L, Zhang Y, and Yang AL. MicroRNA-210 is involved in the regulation of postmenopausal osteoporosis through promotion of VEGF expression and osteoblast differentiation. Biol Chem. (2015) 396:339–47. doi: 10.1515/hsz-2014-0268

PubMed Abstract | Crossref Full Text | Google Scholar

18. Altieri B, Barrea L, Modica R, Muscogiuri G, Savastano S, Colao A, et al. Nutrition and neuroendocrine tumors: An update of the literature. Rev endocrine Metab Disord. (2018) 19:159–67. doi: 10.1007/s11154-018-9466-z

PubMed Abstract | Crossref Full Text | Google Scholar

19. Massironi S, Zilli A, Bernasconi S, Fanetti I, Cavalcoli F, Ciafardini C, et al. Impact of vitamin D on the clinical outcome of gastro-entero-pancreatic neuroendocrine neoplasms: report on a series from a single institute. Neuroendocrinology. (2017) 105:403–11. doi: 10.1159/000456619

PubMed Abstract | Crossref Full Text | Google Scholar

20. Pang H, Ma N, Jiao M, Shen W, Xin B, Wang T, et al. The biological effects of dickkopf1 on small cell lung cancer cells and bone metastasis. Oncol Res. (2017) 25:35–42. doi: 10.3727/096504016X14719078133249

PubMed Abstract | Crossref Full Text | Google Scholar

21. Chen P, Min J, Wu H, Zhang H, Wang C, Tan G, et al. Annexin A1 is a potential biomarker of bone metastasis in small cell lung cancer. Oncol letters. (2021) 21:141. doi: 10.3892/ol.2020.12402

PubMed Abstract | Crossref Full Text | Google Scholar

22. Putzer D, Gabriel M, Henninger B, Kendler D, Uprimny C, Dobrozemsky G, et al. Bone metastases in patients with neuroendocrine tumor: 68Ga-DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphy. J Nucl Med. (2009) 50:1214–21. doi: 10.2967/jnumed.108.060236

PubMed Abstract | Crossref Full Text | Google Scholar

23. Debray MP, Geoffroy O, Laissy JP, Lebtahi R, Silbermann-Hoffman O, Henry-Feugeas MC, et al. Imaging appearances of metastases from neuroendocrine tumours of the pancreas. Br J radiology. (2001) 74:1065–70. doi: 10.1259/bjr.74.887.741065

PubMed Abstract | Crossref Full Text | Google Scholar

24. Shi XB, Deng WX, and Jin FX. Bone marrow metastatic neuroendocrine carcinoma with unknown primary site: A case report and review of the literature. World J Clin cases. (2022) 10:11074–81. doi: 10.12998/wjcc.v10.i30.11074

PubMed Abstract | Crossref Full Text | Google Scholar

25. Stoyianni A, Pentheroudakis G, and Pavlidis N. Neuroendocrine carcinoma of unknown primary: a systematic review of the literature and a comparative study with other neuroendocrine tumors. Cancer Treat Rev. (2011) 37:358–65. doi: 10.1016/j.ctrv.2011.03.002

PubMed Abstract | Crossref Full Text | Google Scholar

26. Riihimäki M, Hemminki A, Sundquist K, Sundquist J, and Hemminki K. The epidemiology of metastases in neuroendocrine tumors. Int J cancer. (2016) 139:2679–86. doi: 10.1002/ijc.30400

PubMed Abstract | Crossref Full Text | Google Scholar

27. Lombard-Bohas C, Mitry E, O’Toole D, Louvet C, Pillon D, Cadiot G, et al. Thirteen-month registration of patients with gastroenteropancreatic endocrine tumours in France. Neuroendocrinology. (2009) 89:217–22. doi: 10.1159/000151562

PubMed Abstract | Crossref Full Text | Google Scholar

28. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain. (1997) 69:1–18. doi: 10.1016/S0304-3959(96)03267-8

PubMed Abstract | Crossref Full Text | Google Scholar

29. Kreps LM and Addison CL. Targeting intercellular communication in the bone microenvironment to prevent disseminated tumor cell escape from dormancy and bone metastatic tumor growth. Int J Mol Sci. (2021) 22:2911. doi: 10.3390/ijms22062911

PubMed Abstract | Crossref Full Text | Google Scholar

30. Zhang L, Gaskins K, Yu Z, Xiong Y, Merino MJ, and Kebebew E. An in vivo mouse model of metastatic human thyroid cancer. Thyroid. (2014) 24:695–704. doi: 10.1089/thy.2013.0149

PubMed Abstract | Crossref Full Text | Google Scholar

31. Coleman RE, Major P, Lipton A, Brown JE, Lee KA, Smith M, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol. (2005) 23:4925–35. doi: 10.1200/JCO.2005.06.091

PubMed Abstract | Crossref Full Text | Google Scholar

32. Pittas AG, Adler M, Fazzari M, Tickoo S, Rosai J, Larson SM, et al. Bone metastases from thyroid carcinoma: clinical characteristics and prognostic variables in one hundred forty-six patients. Thyroid: Off J Am Thyroid Assoc. (2000) 10:261–8. doi: 10.1089/thy.2000.10.261

PubMed Abstract | Crossref Full Text | Google Scholar

33. Bernier MO, Leenhardt L, Hoang C, Aurengo A, Mary JY, Menegaux F, et al. Survival and therapeutic modalities in patients with bone metastases of differentiated thyroid carcinomas. J Clin Endocrinol Metab. (2001) 86:1568–73. doi: 10.1210/jcem.86.4.7390

PubMed Abstract | Crossref Full Text | Google Scholar

34. Xu JY, Murphy WA Jr., Milton DR, Jimenez C, Rao SN, Habra MA, et al. Bone metastases and skeletal-related events in medullary thyroid carcinoma. J Clin Endocrinol Metab. (2016) 101:4871–7. doi: 10.1210/jc.2016-2815

PubMed Abstract | Crossref Full Text | Google Scholar

35. Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. Bone metastases: an overview. Oncol Rev. (2017) 11:321. doi: 10.4081/oncol.2017.321

PubMed Abstract | Crossref Full Text | Google Scholar

36. Kushchayeva YS, Kushchayev SV, Carroll NM, Felger EA, Links TP, Teytelboym OM, et al. Spinal metastases due to thyroid carcinoma: an analysis of 202 patients. Thyroid. (2014) 24:1488–500. doi: 10.1089/thy.2013.0633

PubMed Abstract | Crossref Full Text | Google Scholar

37. Kato S, Murakami H, Demura S, Yoshioka K, Yokogawa N, Yonezawa N, et al. Kidney and thyroid cancer-specific treatment algorithm for spinal metastases: A validation study. World neurosurgery. (2019) 122:e1305–e11. doi: 10.1016/j.wneu.2018.11.040

PubMed Abstract | Crossref Full Text | Google Scholar

38. Fugazzola L, Elisei R, Fuhrer D, Jarzab B, Leboulleux S, Newbold K, et al. 2019 European thyroid association guidelines for the treatment and follow-Up of advanced radioiodine-Refractory thyroid cancer. Eur Thyroid J. (2019) 8:227–45. doi: 10.1159/000502229

PubMed Abstract | Crossref Full Text | Google Scholar

39. Thulin MH, Määttä J, Linder A, Sterbova S, Ohlsson C, Damber JE, et al. Inhibition of STAT3 prevents bone metastatic progression of prostate cancer in vivo. Prostate. (2021) 81:452–62. doi: 10.1002/pros.24125

PubMed Abstract | Crossref Full Text | Google Scholar

40. Schmidt GP, Schoenberg SO, Schmid R, Stahl R, Tiling R, Becker CR, et al. Screening for bone metastases: whole-body MRI using a 32-channel system versus dual-modality PET-CT. Eur radiology. (2007) 17:939–49. doi: 10.1007/s00330-006-0361-8

PubMed Abstract | Crossref Full Text | Google Scholar

41. Hoskin PJ, Hopkins K, Misra V, Holt T, McMenemin R, Dubois D, et al. Effect of single-fraction vs multifraction radiotherapy on ambulatory status among patients with spinal canal compression from metastatic cancer: the SCORAD randomized clinical trial. Jama. (2019) 322:2084–94. doi: 10.1001/jama.2019.17913

PubMed Abstract | Crossref Full Text | Google Scholar

42. Schmeel FC, Luetkens JA, Wagenhäuser PJ, Meier-Schroers M, Kuetting DL, Feißt A, et al. Proton density fat fraction (PDFF) MRI for differentiation of benign and Malignant vertebral lesions. Eur radiology. (2018) 28:2397–405. doi: 10.1007/s00330-017-5241-x

PubMed Abstract | Crossref Full Text | Google Scholar

43. Georgy BA. Metastatic spinal lesions: state-of-the-art treatment options and future trends. AJNR Am J neuroradiology. (2008) 29:1605–11. doi: 10.3174/ajnr.A1137

PubMed Abstract | Crossref Full Text | Google Scholar

44. Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, and Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med. (2006) 47:287–97.

PubMed Abstract | Google Scholar

45. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the american thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. (2016) 26:1–133. doi: 10.1089/thy.2015.0020

PubMed Abstract | Crossref Full Text | Google Scholar

46. Perry CM and Figgitt DP. Zoledronic acid: a review of its use in patients with advanced cancer. Drugs. (2004) 64:1197–211. doi: 10.2165/00003495-200464110-00004

PubMed Abstract | Crossref Full Text | Google Scholar

47. Chin BB, Patel P, Cohade C, Ewertz M, Wahl R, and Ladenson P. Recombinant human thyrotropin stimulation of fluoro-D-glucose positron emission tomography uptake in well-differentiated thyroid carcinoma. J Clin Endocrinol Metab. (2004) 89:91–5. doi: 10.1210/jc.2003-031027

PubMed Abstract | Crossref Full Text | Google Scholar

48. Van Tol KM, Hew JM, Jager PL, Vermey A, Dullaart RP, and Links TP. Embolization in combination with radioiodine therapy for bone metastases from differentiated thyroid carcinoma. Clin endocrinology. (2000) 52:653–9. doi: 10.1046/j.1365-2265.2000.00998.x

PubMed Abstract | Crossref Full Text | Google Scholar

49. Chmielik E, Rusinek D, Oczko-Wojciechowska M, Jarzab M, Krajewska J, Czarniecka A, et al. Heterogeneity of thyroid cancer. Pathobiology. (2018) 85:117–29. doi: 10.1159/000486422

PubMed Abstract | Crossref Full Text | Google Scholar

50. Zhang H, Yuan G, Wang C, Zhao H, Zhu K, Guo J, et al. Differentiation of benign versus Malignant indistinguishable vertebral compression fractures by different machine learning with MRI-based radiomic features. Eur radiology. (2023) 33:5069–76. doi: 10.1007/s00330-023-09678-x

PubMed Abstract | Crossref Full Text | Google Scholar

51. Brown JE, Cook RJ, Major P, Lipton A, Saad F, Smith M, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Institute. (2005) 97:59–69. doi: 10.1093/jnci/dji002

PubMed Abstract | Crossref Full Text | Google Scholar

52. Sosa MS, Bragado P, and Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. (2014) 14:611–22. doi: 10.1038/nrc3793

PubMed Abstract | Crossref Full Text | Google Scholar

53. Lipton A, Cook R, Saad F, Major P, Garnero P, Terpos E, et al. Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer. (2008) 113:193–201. doi: 10.1002/cncr.23529

PubMed Abstract | Crossref Full Text | Google Scholar

54. Fisher CG, DiPaola CP, Ryken TC, Bilsky MH, Shaffrey CI, Berven SH, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine. (2010) 35:E1221–9. doi: 10.1097/BRS.0b013e3181e16ae2

PubMed Abstract | Crossref Full Text | Google Scholar

55. Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin orthopaedics related Res. (1989) 1989:256–64.

PubMed Abstract | Google Scholar

56. Fourney DR, Frangou EM, Ryken TC, Dipaola CP, Shaffrey CI, Berven SH, et al. Spinal instability neoplastic score: an analysis of reliability and validity from the spine oncology study group. J Clin Oncol. (2011) 29:3072–7. doi: 10.1200/JCO.2010.34.3897

PubMed Abstract | Crossref Full Text | Google Scholar

57. Damron TA, Morgan H, Prakash D, Grant W, Aronowitz J, and Heiner J. Critical evaluation of Mirels’ rating system for impending pathologic fractures. Clin orthopaedics related Res. (2003) 415 Suppl:S201–7. doi: 10.1097/01.blo.0000093842.72468.73

PubMed Abstract | Crossref Full Text | Google Scholar

58. Barakat MT, Meeran K, and Bloom SR. Neuroendocrine tumours. Endocrine-related cancer. (2004) 11:1–18. doi: 10.1677/erc.0.0110001

PubMed Abstract | Crossref Full Text | Google Scholar

59. Modlin IM, Lye KD, and Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. (2003) 97:934–59. doi: 10.1002/cncr.11105

PubMed Abstract | Crossref Full Text | Google Scholar

60. Lei L, Du T, Yang J, Cai L, Liu H, and Chen Y. Analysis of the diagnostic efficacy of DOTATATE imaging combined with CGA and BSP detection mode for NEN patients with bone metastasis. BioMed Res Int. (2022) 2022:6279826. doi: 10.1155/2022/6279826

PubMed Abstract | Crossref Full Text | Google Scholar

61. Zamborsky R, Svec A, Kokavec M, and Galbavy S. Bone metastases in neuroendocrine tumors. Bratislavske lekarske listy. (2017) 118:529–34. doi: 10.4149/BLL_2017_102

PubMed Abstract | Crossref Full Text | Google Scholar

62. Zheng Z, Chen C, Jiang L, Zhou X, Dai X, Song Y, et al. Incidence and risk factors of gastrointestinal neuroendocrine neoplasm metastasis in liver, lung, bone, and brain: A population-based study. Cancer Med. (2019) 8:7288–98. doi: 10.1002/cam4.2567

PubMed Abstract | Crossref Full Text | Google Scholar

63. Eriksson B, Oberg K, and Stridsberg M. Tumor markers in neuroendocrine tumors. Digestion. (2000) 62 Suppl 1:33–8. doi: 10.1159/000051853

PubMed Abstract | Crossref Full Text | Google Scholar

64. Clancy TE, Sengupta TP, Paulus J, Ahmed F, Duh MS, and Kulke MH. Alkaline phosphatase predicts survival in patients with metastatic neuroendocrine tumors. Digestive Dis Sci. (2006) 51:877–84. doi: 10.1007/s10620-006-9345-4

PubMed Abstract | Crossref Full Text | Google Scholar

65. Lan B, He Z, Chen Z, Tao H, Liu T, and Yang J. Machine learning for synchronous bone metastasis risk prediction in high grade lung neuroendocrine carcinoma. Sci Rep. (2025) 15:24637. doi: 10.1038/s41598-025-09762-w

PubMed Abstract | Crossref Full Text | Google Scholar

66. Bubendorf L, Schöpfer A, Wagner U, Sauter G, Moch H, Willi N, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum pathology. (2000) 31:578–83. doi: 10.1053/hp.2000.6698

PubMed Abstract | Crossref Full Text | Google Scholar

67. Boopathi E, Birbe R, Shoyele SA, Den RB, and Thangavel C. Bone health management in the continuum of prostate cancer disease. Cancers. (2022) 14:4305. doi: 10.3390/cancers14174305

PubMed Abstract | Crossref Full Text | Google Scholar

68. Even-Sapir E. Imaging of Malignant bone involvement by morphologic, scintigraphic, and hybrid modalities. J Nucl Med. (2005) 46:1356–67.

PubMed Abstract | Google Scholar

69. Li S, Chen C, Zhu H, Lin Q, and Yu Z. Risk evaluation of bone metastases and a simple tool for detecting bone metastases in prostate cancer: A population-based study. Comput Math Methods Med. (2023) 2023:9161763. doi: 10.1155/2023/9161763

PubMed Abstract | Crossref Full Text | Google Scholar

70. Yadav P, Harit S, and Kumar D. Efficacy of high-resolution, 3-D diffusion-weighted imaging in the detection of breast cancer compared to dynamic contrast-enhanced magnetic resonance imaging. Polish J radiology. (2021) 86:e277–e86. doi: 10.5114/pjr.2021.106207

PubMed Abstract | Crossref Full Text | Google Scholar

71. Zhang Y, Lin Z, Li T, Wei Y, Yu M, Ye L, et al. Head-to-head comparison of (99m)Tc-PSMA and (99m)Tc-MDP SPECT/CT in diagnosing prostate cancer bone metastasis: a prospective, comparative imaging trial. Sci Rep. (2022) 12:15993. doi: 10.1038/s41598-022-20280-x

PubMed Abstract | Crossref Full Text | Google Scholar

72. Usmani S, Al Riyami K, Jain A, Alajmi AA, AlBaimani K, Dumasig P, et al. Enhancing precision in bone metastasis diagnosis for lobular breast cancer: reassessing the role of 18 F-FDG PET/CT. Nucl Med Commun. (2024) 45:858–64. doi: 10.1097/MNM.0000000000001880

PubMed Abstract | Crossref Full Text | Google Scholar

73. Rong J, Wang S, Ding Q, Yun M, Zheng Z, and Ye S. Comparison of 18 FDG PET-CT and bone scintigraphy for detection of bone metastases in breast cancer patients. A meta-analysis. Surg Oncol. (2013) 22:86–91. doi: 10.1016/j.suronc.2013.01.002

PubMed Abstract | Crossref Full Text | Google Scholar

74. Houssami N, Ciatto S, Turner RM, Cody HS 3rd, and Macaskill P. Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla. Ann surgery. (2011) 254:243–51. doi: 10.1097/SLA.0b013e31821f1564

PubMed Abstract | Crossref Full Text | Google Scholar

75. Tu C, He J, and Li Z. Prognostic value of IGF-1R expression in bone and soft tissue sarcomas: comments on a meta-analysis by Liang et al. OncoTargets Ther. (2016) 9:2017–8. doi: 10.2147/OTT.S104004

PubMed Abstract | Crossref Full Text | Google Scholar

76. Lu Z, Hou J, Li X, Zhou J, Luo B, Liang S, et al. Exosome-derived miRNAs as potential biomarkers for prostate bone metastasis. Int J Gen Med. (2022) 15:5369–83. doi: 10.2147/IJGM.S361981

PubMed Abstract | Crossref Full Text | Google Scholar

77. Furesi G, de Jesus Domingues AM, Alexopoulou D, Dahl A, Hackl M, Schmidt JR, et al. Exosomal miRNAs from prostate cancer impair osteoblast function in mice. Int J Mol Sci. (2022) 23:1285. doi: 10.3390/ijms23031285

PubMed Abstract | Crossref Full Text | Google Scholar

78. Josefsson A, Larsson K, Månsson M, Björkman J, Rohlova E, Åhs D, et al. Circulating tumor cells mirror bone metastatic phenotype in prostate cancer. Oncotarget. (2018) 9:29403–13. doi: 10.18632/oncotarget.25634

PubMed Abstract | Crossref Full Text | Google Scholar

79. Esteva A, Chou K, Yeung S, Naik N, Madani A, Mottaghi A, et al. Deep learning-enabled medical computer vision. NPJ digital Med. (2021) 4:5. doi: 10.1038/s41746-020-00376-2

PubMed Abstract | Crossref Full Text | Google Scholar

80. Rachner TD, Kasimir-Bauer S, Göbel A, Erdmann K, Hoffmann O, Browne A, et al. Prognostic value of RANKL/OPG serum levels and disseminated tumor cells in nonmetastatic breast cancer. Clin Cancer Res. (2019) 25:1369–78. doi: 10.1158/1078-0432.CCR-18-2482

PubMed Abstract | Crossref Full Text | Google Scholar

81. Elfar GA, Ebrahim MA, Elsherbiny NM, and Eissa LA. Validity of osteoprotegerin and receptor activator of NF-κB ligand for the detection of bone metastasis in breast cancer. Oncol Res. (2017) 25:641–50. doi: 10.3727/096504016X14768398678750

PubMed Abstract | Crossref Full Text | Google Scholar

82. Lovero D, D’Oronzo S, Palmirotta R, Cafforio P, Brown J, Wood S, et al. Correlation between targeted RNAseq signature of breast cancer CTCs and onset of bone-only metastases. Br J cancer. (2022) 126:419–29. doi: 10.1038/s41416-021-01481-z

PubMed Abstract | Crossref Full Text | Google Scholar

83. Mauri G, Hegedüs L, Bandula S, Cazzato RL, Czarniecka A, Dudeck O, et al. European thyroid association and cardiovascular and interventional radiological society of europe 2021 clinical practice guideline for the use of minimally invasive treatments in Malignant thyroid lesions. Eur Thyroid J. (2021) 10:185–97. doi: 10.1159/000516469

PubMed Abstract | Crossref Full Text | Google Scholar

84. Cazzato RL, Garnon J, Koch G, Shaygi B, Tsoumakidou G, Caudrelier J, et al. Current role of interventional radiology in the management of visceral and bone metastases from thyroid cancer. Gland surgery. (2018) 7:80–8. doi: 10.21037/gs.2017.12.08

PubMed Abstract | Crossref Full Text | Google Scholar

85. De Vries MM, Persoon AC, Jager PL, Gravendeel J, Plukker JT, Sluiter WJ, et al. Embolization therapy of bone metastases from epithelial thyroid carcinoma: effect on symptoms and serum thyroglobulin. Thyroid. (2008) 18:1277–84. doi: 10.1089/thy.2008.0066

PubMed Abstract | Crossref Full Text | Google Scholar

86. Mun HS, Kim SH, Lee J, Park SJ, Lee A, Kang J, et al. Skeletal muscle density as a predictive marker for pathologic complete response in triple-negative breast cancer treated with neoadjuvant chemoimmunotherapy. Cancers. (2025) 17:1768. doi: 10.3390/cancers17111768

PubMed Abstract | Crossref Full Text | Google Scholar

87. Goldberg SN, Gazelle GS, and Mueller PR. Thermal ablation therapy for focal Malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance. AJR Am J roentgenology. (2000) 174:323–31. doi: 10.2214/ajr.174.2.1740323

PubMed Abstract | Crossref Full Text | Google Scholar

88. Gerszten PC, Mendel E, and Yamada Y. Radiotherapy and radiosurgery for metastatic spine disease: what are the options, indications, and outcomes? Spine. (2009) 34:S78–92. doi: 10.1097/BRS.0b013e3181b8b6f5

PubMed Abstract | Crossref Full Text | Google Scholar

89. Gerszten PC, Burton SA, Ozhasoglu C, and Welch WC. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine. (2007) 32:193–9. doi: 10.1097/01.brs.0000251863.76595.a2

PubMed Abstract | Crossref Full Text | Google Scholar

90. Bernstein MB, Chang EL, Amini B, Pan H, Cabanillas M, Wang XA, et al. Spine stereotactic radiosurgery for patients with metastatic thyroid cancer: secondary analysis of phase I/II trials. Thyroid. (2016) 26:1269–75. doi: 10.1089/thy.2016.0046

PubMed Abstract | Crossref Full Text | Google Scholar

91. Qiu ZL, Song HJ, Xu YH, and Luo QY. Efficacy and survival analysis of 131I therapy for bone metastases from differentiated thyroid cancer. J Clin Endocrinol Metab. (2011) 96:3078–86. doi: 10.1210/jc.2011-0093

PubMed Abstract | Crossref Full Text | Google Scholar

92. Robenshtok E, Farooki A, Grewal RK, and Tuttle RM. Natural history of small radioiodine-avid bone metastases that have no structural correlate on imaging studies. Endocrine. (2014) 47:266–72. doi: 10.1007/s12020-013-0123-8

PubMed Abstract | Crossref Full Text | Google Scholar

93. Filetti S, Bidart JM, Arturi F, Caillou B, Russo D, and Schlumberger M. Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism. Eur J endocrinology. (1999) 141:443–57. doi: 10.1530/eje.0.1410443

PubMed Abstract | Crossref Full Text | Google Scholar

94. Kushchayeva YS, Kushchayev SV, Wexler JA, Carroll NM, Preul MC, Teytelboym OM, et al. Current treatment modalities for spinal metastases secondary to thyroid carcinoma. Thyroid. (2014) 24:1443–55. doi: 10.1089/thy.2013.0634

PubMed Abstract | Crossref Full Text | Google Scholar

95. Mazziotti G, Formenti AM, Panarotto MB, Arvat E, Chiti A, Cuocolo A, et al. Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience. Endocrine. (2018) 59:90–101. doi: 10.1007/s12020-017-1455-6

PubMed Abstract | Crossref Full Text | Google Scholar

96. Wang M, Xia F, Wei Y, and Wei X. Molecular mechanisms and clinical management of cancer bone metastasis. Bone Res. (2020) 8:30. doi: 10.1038/s41413-020-00105-1

PubMed Abstract | Crossref Full Text | Google Scholar

97. Parker C, Lewington V, Shore N, Kratochwil C, Levy M, Lindén O, et al. Targeted alpha therapy, an emerging class of cancer agents: A review. JAMA Oncol. (2018) 4:1765–72. doi: 10.1001/jamaoncol.2018.4044

PubMed Abstract | Crossref Full Text | Google Scholar

98. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. New Engl J Med. (2015) 372:621–30. doi: 10.1056/NEJMoa1406470

PubMed Abstract | Crossref Full Text | Google Scholar

99. Hoftijzer H, Heemstra KA, Morreau H, Stokkel MP, Corssmit EP, Gelderblom H, et al. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J endocrinology. (2009) 161:923–31. doi: 10.1530/EJE-09-0702

PubMed Abstract | Crossref Full Text | Google Scholar

100. Massicotte MH, Brassard M, Claude-Desroches M, Borget I, Bonichon F, Giraudet AL, et al. Tyrosine kinase inhibitor treatments in patients with metastatic thyroid carcinomas: a retrospective study of the TUTHYREF network. Eur J endocrinology. (2014) 170:575–82. doi: 10.1530/EJE-13-0825

PubMed Abstract | Crossref Full Text | Google Scholar

101. Lin Y, Qin S, Li Z, Yang H, Fu W, Li S, et al. Apatinib vs placebo in patients with locally advanced or metastatic, radioactive iodine-refractory differentiated thyroid cancer: the REALITY randomized clinical trial. JAMA Oncol. (2022) 8:242–50. doi: 10.1001/jamaoncol.2021.6268

PubMed Abstract | Crossref Full Text | Google Scholar

102. Willhauck MJ, Schott M, Kreissl MC, Fassnacht M, and Spitzweg C. New therapeutic options for advanced thyroid cancer. Deutsche medizinische Wochenschrift (1946). (2011) 136:1165–8. doi: 10.1055/s-0031-1280531

PubMed Abstract | Crossref Full Text | Google Scholar

103. Zheng GZ, Chang B, Lin FX, Xie D, Hu QX, Yu GY, et al. Meta-analysis comparing denosumab and zoledronic acid for treatment of bone metastases in patients with advanced solid tumours. Eur J Cancer Care. (2017) 26:e12541. doi: 10.1111/ecc.12541

PubMed Abstract | Crossref Full Text | Google Scholar

104. Lipton A and Goessl C. Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasis. Bone. (2011) 48:96–9. doi: 10.1016/j.bone.2010.10.161

PubMed Abstract | Crossref Full Text | Google Scholar

105. Wexler JA. Approach to the thyroid cancer patient with bone metastases. J Clin Endocrinol Metab. (2011) 96:2296–307. doi: 10.1210/jc.2010-1996

PubMed Abstract | Crossref Full Text | Google Scholar

106. Chen J, Lan Y, He Y, He C, Xu F, Zhang Y, et al. 99Tc-MDP-induced human osteoblast proliferation, differentiation and expression of osteoprotegerin. Mol Med Rep. (2017) 16:1801–9. doi: 10.3892/mmr.2017.6839

PubMed Abstract | Crossref Full Text | Google Scholar

107. Coleman RE, Croucher PI, Padhani AR, Clézardin P, Chow E, Fallon M, et al. Bone metastases. Nat Rev Dis primers. (2020) 6:83. doi: 10.1038/s41572-020-00216-3

PubMed Abstract | Crossref Full Text | Google Scholar

108. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. (2013) 152:1173–83. doi: 10.1016/j.cell.2013.02.022

PubMed Abstract | Crossref Full Text | Google Scholar

109. Wang K, Jiang L, Hu A, Sun C, Zhou L, Huang Y, et al. Vertebral-specific activation of the CX3CL1/ICAM-1 signaling network mediates non-small-cell lung cancer spinal metastasis by engaging tumor cell-vertebral bone marrow endothelial cell interactions. Theranostics. (2021) 11:4770–89. doi: 10.7150/thno.54235

PubMed Abstract | Crossref Full Text | Google Scholar

110. Siddiqui JA, Seshacharyulu P, Muniyan S, Pothuraju R, Khan P, Vengoji R, et al. GDF15 promotes prostate cancer bone metastasis and colonization through osteoblastic CCL2 and RANKL activation. Bone Res. (2022) 10:6. doi: 10.1038/s41413-021-00178-6

PubMed Abstract | Crossref Full Text | Google Scholar

111. Chauhan PS, Alahi I, Sinha S, Ledet EM, Mueller R, Linford J, et al. Genomic and epigenomic analysis of plasma cell-free DNA identifies stemness features associated with worse survival in lethal prostate cancer. Clin Cancer Res. (2025) 31:151–63. doi: 10.1158/1078-0432.CCR-24-1658

PubMed Abstract | Crossref Full Text | Google Scholar

112. Garg AK, Shiu AS, Yang J, Wang XS, Allen P, Brown BW, et al. Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. Cancer. (2012) 118:5069–77. doi: 10.1002/cncr.27530

PubMed Abstract | Crossref Full Text | Google Scholar

113. Bishop AJ, Tao R, Guadagnolo BA, Allen PK, Rebueno NC, Wang XA, et al. Spine stereotactic radiosurgery for metastatic sarcoma: patterns of failure and radiation treatment volume considerations. J Neurosurg Spine. (2017) 27:303–11. doi: 10.3171/2017.1.SPINE161045

PubMed Abstract | Crossref Full Text | Google Scholar

114. Morassi LG, Kokkinis K, Evangelopoulos DS, Karargyris O, Vlachou I, Kalokairinou K, et al. Percutaneous radiofrequency ablation of spinal osteoid osteoma under CT guidance. Br J Radiol. (2014) 87:20140003. doi: 10.1259/bjr.20140003

PubMed Abstract | Crossref Full Text | Google Scholar

115. Cursano MC, Iuliani M, Casadei C, Stellato M, Tonini G, Paganelli G, et al. Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: A review. Crit Rev oncology/hematology. (2020) 146:102864. doi: 10.1016/j.critrevonc.2020.102864

PubMed Abstract | Crossref Full Text | Google Scholar

116. Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin JE, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. (2005) 11:4451–9. doi: 10.1158/1078-0432.CCR-04-2244

PubMed Abstract | Crossref Full Text | Google Scholar

117. Subbiah V, Hu MI, Wirth LJ, Schuler M, Mansfield AS, Curigliano G, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes endocrinology. (2021) 9:491–501. doi: 10.1016/S2213-8587(21)00120-0

PubMed Abstract | Crossref Full Text | Google Scholar

118. Escudier B, Powles T, Motzer RJ, Olencki T, Arén Frontera O, Oudard S, et al. Cabozantinib, a new standard of care for patients with advanced renal cell carcinoma and bone metastases? Subgroup analysis of the METEOR trial. J Clin Oncol. (2018) 36:765–72. doi: 10.1200/JCO.2017.74.7352

PubMed Abstract | Crossref Full Text | Google Scholar

119. Bockorny B, Semenisty V, Macarulla T, Borazanci E, Wolpin BM, Stemmer SM, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. (2020) 26:878–85. doi: 10.1038/s41591-020-0880-x

PubMed Abstract | Crossref Full Text | Google Scholar

120. Saini S, Tulla K, Maker AV, Burman KD, and Prabhakar BS. Therapeutic advances in anaplastic thyroid cancer: a current perspective. Mol cancer. (2018) 17:154. doi: 10.1186/s12943-018-0903-0

PubMed Abstract | Crossref Full Text | Google Scholar

121. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. New Engl J Med. (2021) 385:1091–103. doi: 10.1056/NEJMoa2107322

PubMed Abstract | Crossref Full Text | Google Scholar

122. Zhang L, Qu J, Qi Y, Duan Y, Huang YW, Zhou Z, et al. EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation. Nat Commun. (2022) 13:2543. doi: 10.1038/s41467-022-30105-0

PubMed Abstract | Crossref Full Text | Google Scholar

123. Zhu L, Li XJ, Kalimuthu S, Gangadaran P, Lee HW, Oh JM, et al. Natural killer cell (NK-92MI)-based therapy for pulmonary metastasis of anaplastic thyroid cancer in a nude mouse model. Front Immunol. (2017) 8:816. doi: 10.3389/fimmu.2017.00816

PubMed Abstract | Crossref Full Text | Google Scholar

124. Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR, Nakamura T, et al. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporosis Int. (2015) 26:699–712. doi: 10.1007/s00198-014-2944-6

PubMed Abstract | Crossref Full Text | Google Scholar

125. Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R, Hirsh V, Krzakowski M, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer. (2004) 100:2613–21. doi: 10.1002/cncr.20308

PubMed Abstract | Crossref Full Text | Google Scholar

126. Dietlein F, Kobe C, Hohberg M, Zlatopolskiy BD, Krapf P, Endepols H, et al. Intraindividual comparison of (18)F-PSMA-1007 with renally excreted PSMA ligands for PSMA PET imaging in patients with relapsed prostate cancer. J Nucl Med. (2020) 61:729–34. doi: 10.2967/jnumed.119.234898

PubMed Abstract | Crossref Full Text | Google Scholar

127. Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. New Engl J Med. (2013) 368:623–32. doi: 10.1056/NEJMoa1209288

PubMed Abstract | Crossref Full Text | Google Scholar

128. Zhu W, Xie L, Han J, and Guo X. The application of deep learning in cancer prognosis prediction. Cancers. (2020) 12:0603. doi: 10.3390/cancers12030603

PubMed Abstract | Crossref Full Text | Google Scholar

129. Bertoldo F, Silvestris F, Ibrahim T, Cognetti F, Generali D, Ripamonti CI, et al. Targeting bone metastatic cancer: Role of the mTOR pathway. Biochim Biophys Acta. (2014) 1845:248–54. doi: 10.1016/j.bbcan.2014.01.009

PubMed Abstract | Crossref Full Text | Google Scholar

130. Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, and Ueno NT. Bone imaging in metastatic breast cancer. J Clin Oncol. (2004) 22:2942–53. doi: 10.1200/JCO.2004.08.181

PubMed Abstract | Crossref Full Text | Google Scholar

131. Iyer PC, Dadu R, Ferrarotto R, Busaidy NL, Habra MA, Zafereo M, et al. Real-world experience with targeted therapy for the treatment of anaplastic thyroid carcinoma. Thyroid. (2018) 28:79–87. doi: 10.1089/thy.2017.0285

PubMed Abstract | Crossref Full Text | Google Scholar

132. Qi J, Hong B, Wang S, Wang J, Fang J, Sun R, et al. Plasma cell-free DNA methylome-based liquid biopsy for accurate gastric cancer detection. Cancer science. (2024) 115:3426–38. doi: 10.1111/cas.16284

PubMed Abstract | Crossref Full Text | Google Scholar

133. Oronsky B, Ma PC, Morgensztern D, and Carter CA. Nothing but NET: A review of neuroendocrine tumors and carcinomas. Neoplasia (New York NY). (2017) 19:991–1002. doi: 10.1016/j.neo.2017.09.002

PubMed Abstract | Crossref Full Text | Google Scholar

134. Lim KHJ, Raja H, D’Arienzo P, Barriuso J, McNamara MG, Hubner RA, et al. Identification of areas for improvement in the management of bone metastases in patients with neuroendocrine neoplasms. Neuroendocrinology. (2020) 110:688–96. doi: 10.1159/000504256

PubMed Abstract | Crossref Full Text | Google Scholar

135. Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. (2016) 103:153–71. doi: 10.1159/000443171

PubMed Abstract | Crossref Full Text | Google Scholar

136. Bajetta E, Catena L, Procopio G, De Dosso S, Bichisao E, Ferrari L, et al. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer chemotherapy Pharmacol. (2007) 59:637–42. doi: 10.1007/s00280-006-0306-6

PubMed Abstract | Crossref Full Text | Google Scholar

137. Saranga-Perry V, Morse B, Centeno B, Kvols L, and Strosberg J. Treatment of metastatic neuroendocrine tumors of the thymus with capecitabine and temozolomide: a case series. Neuroendocrinology. (2013) 97:318–21. doi: 10.1159/000345938

PubMed Abstract | Crossref Full Text | Google Scholar

138. Cives M and Strosberg JR. Gastroenteropancreatic neuroendocrine tumors. CA: Cancer J Clin. (2018) 68:471–87. doi: 10.3322/caac.21493

PubMed Abstract | Crossref Full Text | Google Scholar

139. Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. (2008) 26:2124–30. doi: 10.1200/JCO.2007.15.2553

PubMed Abstract | Crossref Full Text | Google Scholar

140. Makis W, McCann K, Buteau FA, and McEwan AJ. Liver and bone metastases from small bowel neuroendocrine tumor respond to 177Lu-DOTATATE induction and maintenance therapies. Clin Nucl Med. (2015) 40:162–5. doi: 10.1097/RLU.0000000000000569

PubMed Abstract | Crossref Full Text | Google Scholar

141. Soeiro P, Martins H, Silva R, and Moreira AP. Complete remission of inoperable hepatic and bone metastases due to neuroendocrine pancreatic tumour 3 years after peptide receptor radionucleotide therapy. BMJ Case Rep. (2020) 13:bcr-2019-233263. doi: 10.1136/bcr-2019-233263

PubMed Abstract | Crossref Full Text | Google Scholar

142. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet (London England). (2016) 387:968–77. doi: 10.1016/S0140-6736(15)00817-X

PubMed Abstract | Crossref Full Text | Google Scholar

143. Pasricha G, Padhi P, Daboul N, and Monga DK. Management of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEPNETs): A review. Clin Ther. (2017) 39:2146–57. doi: 10.1016/j.clinthera.2017.10.010

PubMed Abstract | Crossref Full Text | Google Scholar

144. Safford SD, Coleman RE, Gockerman JP, Moore J, Feldman JM, Leight GS Jr., et al. Iodine -131 metaiodobenzylguanidine is an effective treatment for Malignant pheochromocytoma and paraganglioma. Surgery. (2003) 134:956–62. doi: 10.1016/S0039-6060(03)00426-4

PubMed Abstract | Crossref Full Text | Google Scholar

145. Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B, et al. Lung cancer immunotherapy: progress, pitfalls, and promises. Mol cancer. (2023) 22:40. doi: 10.1186/s12943-023-01740-y

PubMed Abstract | Crossref Full Text | Google Scholar

146. Chiang CS, Lin YJ, Lee R, Lai YH, Cheng HW, Hsieh CH, et al. Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy. Nat nanotechnology. (2018) 13:746–54. doi: 10.1038/s41565-018-0146-7

PubMed Abstract | Crossref Full Text | Google Scholar

147. Zhang Q, Wei W, Wang P, Zuo L, Li F, Xu J, et al. Biomimetic magnetosomes as versatile artificial antigen-presenting cells to potentiate T-cell-based anticancer therapy. ACS nano. (2017) 11:10724–32. doi: 10.1021/acsnano.7b04955

PubMed Abstract | Crossref Full Text | Google Scholar

148. Dennis K, Makhani L, Zeng L, Lam H, and Chow E. Single fraction conventional external beam radiation therapy for bone metastases: a systematic review of randomised controlled trials. Radiotherapy Oncol. (2013) 106:5–14. doi: 10.1016/j.radonc.2012.12.009

PubMed Abstract | Crossref Full Text | Google Scholar

149. McDonald R, Chow E, Rowbottom L, Bedard G, Lam H, Wong E, et al. Quality of life after palliative radiotherapy in bone metastases: A literature review. J Bone Oncol. (2015) 4:24–31. doi: 10.1016/j.jbo.2014.11.001

PubMed Abstract | Crossref Full Text | Google Scholar

150. Yin JJ, Pollock CB, and Kelly K. Mechanisms of cancer metastasis to the bone. Cell Res. (2005) 15:57–62. doi: 10.1038/sj.cr.7290266

PubMed Abstract | Crossref Full Text | Google Scholar

151. Singletary SE, Walsh G, Vauthey JN, Curley S, Sawaya R, Weber KL, et al. A role for curative surgery in the treatment of selected patients with metastatic breast cancer. oncologist. (2003) 8:241–51. doi: 10.1634/theoncologist.8-3-241

PubMed Abstract | Crossref Full Text | Google Scholar

152. Menshawy A, Mattar O, Abdulkarim A, Kasem S, Nasreldin N, Menshawy E, et al. Denosumab versus bisphosphonates in patients with advanced cancers-related bone metastasis: systematic review and meta-analysis of randomized controlled trials. Supportive Care Cancer. (2018) 26:1029–38. doi: 10.1007/s00520-018-4060-1

PubMed Abstract | Crossref Full Text | Google Scholar

153. Roudier MP, Morrissey C, True LD, Higano CS, Vessella RL, and Ott SM. Histopathological assessment of prostate cancer bone osteoblastic metastases. J urology. (2008) 180:1154–60. doi: 10.1016/j.juro.2008.04.140

PubMed Abstract | Crossref Full Text | Google Scholar

154. McAllister SS and Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol. (2014) 16:717–27. doi: 10.1038/ncb3015

PubMed Abstract | Crossref Full Text | Google Scholar

155. Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the clonal origin of lethal prostate cancer. J Clin Invest. (2013) 123:4918–22. doi: 10.1172/JCI70354

PubMed Abstract | Crossref Full Text | Google Scholar

156. Sui L, Wang J, Jiang WG, Song X, and Ye L. Molecular mechanism of bone metastasis in breast cancer. Front Oncol. (2024) 14:1401113. doi: 10.3389/fonc.2024.1401113

PubMed Abstract | Crossref Full Text | Google Scholar

157. Cavallaro U and Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. (2004) 4:118–32. doi: 10.1038/nrc1276

PubMed Abstract | Crossref Full Text | Google Scholar

158. Siegel RL, Miller KD, and Jemal A. Cancer statistics, 2016. CA: Cancer J Clin. (2016) 66:7–30. doi: 10.3322/caac.21332

PubMed Abstract | Crossref Full Text | Google Scholar

159. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA: Cancer J Clin. (2016) 66:115–32. doi: 10.3322/caac.21338

PubMed Abstract | Crossref Full Text | Google Scholar

160. Gradishar WJ, Anderson BO, Abraham J, Aft R, Agnese D, Allison KH, et al. Breast cancer, version 3.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Network: JNCCN. (2020) 18:452–78. doi: 10.6004/jnccn.2020.0016

PubMed Abstract | Crossref Full Text | Google Scholar

161. Zhuang H, Zhuang H, Lang N, and Liu J. Precision stereotactic radiotherapy for spinal tumors: mechanism, efficacy, and issues. Front Oncol. (2020) 10:826. doi: 10.3389/fonc.2020.00826

PubMed Abstract | Crossref Full Text | Google Scholar

162. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. (2015) 16:152–60. doi: 10.1016/S1470-2045(14)71205-7

PubMed Abstract | Crossref Full Text | Google Scholar

163. Gnant M, Baselga J, Rugo HS, Noguchi S, Burris HA, Piccart M, et al. Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2. J Natl Cancer Institute. (2013) 105:654–63. doi: 10.1093/jnci/djt026

PubMed Abstract | Crossref Full Text | Google Scholar

164. Huang Y, Guan Z, Dai X, Shen Y, Wei Q, Ren L, et al. Engineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer. Nat Commun. (2021) 12:4310. doi: 10.1038/s41467-021-24564-0

PubMed Abstract | Crossref Full Text | Google Scholar

165. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. New Engl J Med. (2015) 373:1697–708. doi: 10.1056/NEJMoa1506859

PubMed Abstract | Crossref Full Text | Google Scholar

166. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. New Engl J Med. (2013) 369:213–23. doi: 10.1056/NEJMoa1213755

PubMed Abstract | Crossref Full Text | Google Scholar

167. Lyu S, Zhang M, Zhang B, Gao L, Yang L, Guerrini S, et al. The application of computer-aided diagnosis in Breast Imaging Reporting and Data System ultrasound training for residents-a randomized controlled study. Trans Cancer Res. (2024) 13:1969–79. doi: 10.21037/tcr-23-2122

PubMed Abstract | Crossref Full Text | Google Scholar

168. Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. (2020) 21:519–30. doi: 10.1016/S1470-2045(19)30863-0

PubMed Abstract | Crossref Full Text | Google Scholar

169. Barrett-Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol. (2014) 15:114–22. doi: 10.1016/S1470-2045(13)70539-4

PubMed Abstract | Crossref Full Text | Google Scholar

170. Hortobagyi GN, Van Poznak C, Harker WG, Gradishar WJ, Chew H, Dakhil SR, et al. Continued treatment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone: the OPTIMIZE-2 randomized clinical trial. JAMA Oncol. (2017) 3:906–12. doi: 10.1001/jamaoncol.2016.6316

PubMed Abstract | Crossref Full Text | Google Scholar

171. Block GA, Bone HG, Fang L, Lee E, and Padhi D. A single-dose study of denosumab in patients with various degrees of renal impairment. J Bone mineral Res. (2012) 27:1471–9. doi: 10.1002/jbmr.1613

PubMed Abstract | Crossref Full Text | Google Scholar

172. Zhang W, Bado I, Wang H, Lo HC, and Zhang XH. Bone metastasis: find your niche and fit in. Trends cancer. (2019) 5:95–110. doi: 10.1016/j.trecan.2018.12.004

PubMed Abstract | Crossref Full Text | Google Scholar

173. Hanamura M, Iwamoto T, Soga N, Sugimura Y, and Okuda M. Risk factors contributing to the development of hypocalcemia after zoledronic acid administration in patients with bone metastases of solid tumor. Biol Pharm bulletin. (2010) 33:721–4. doi: 10.1248/bpb.33.721

PubMed Abstract | Crossref Full Text | Google Scholar

174. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol. (2005) 23:8580–7. doi: 10.1200/JCO.2005.02.8670

PubMed Abstract | Crossref Full Text | Google Scholar

175. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. (2010) 28:5132–9. doi: 10.1200/JCO.2010.29.7101

PubMed Abstract | Crossref Full Text | Google Scholar

176. Gennari A, André F, Barrios CH, Cortés J, de Azambuja E, DeMichele A, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. (2021) 32:1475–95. doi: 10.1016/j.annonc.2021.09.019

PubMed Abstract | Crossref Full Text | Google Scholar

177. Jabbari S, Gerszten PC, Ruschin M, Larson DA, Lo SS, and Sahgal A. Stereotactic body radiotherapy for spinal metastases: practice guidelines, outcomes, and risks. Cancer J (Sudbury Mass). (2016) 22:280–9. doi: 10.1097/PPO.0000000000000205

PubMed Abstract | Crossref Full Text | Google Scholar

178. Valcamonico F, Petrelli F, Ferrari L, Ferrari V, Grisanti S, Barni S, et al. Is time to first skeletal-related event the best primary end point in the assessment of bisphosphonate efficacy in patients with castration-sensitive prostate cancer? J Clin Oncol. (2014) 32:3684–5. doi: 10.1200/JCO.2014.56.2017

PubMed Abstract | Crossref Full Text | Google Scholar

179. Burdușel AC and Andronescu E. Lipid nanoparticles and liposomes for bone diseases treatment. Biomedicines. (2022) 10:3158. doi: 10.3390/biomedicines10123158

PubMed Abstract | Crossref Full Text | Google Scholar

180. Wright LE, Ottewell PD, Rucci N, Peyruchaud O, Pagnotti GM, Chiechi A, et al. Murine models of breast cancer bone metastasis. BoneKEy Rep. (2016) 5:804. doi: 10.1038/bonekey.2016.31

PubMed Abstract | Crossref Full Text | Google Scholar

181. Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E, Lhuillier C, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med. (2018) 24:1845–51. doi: 10.1038/s41591-018-0232-2

PubMed Abstract | Crossref Full Text | Google Scholar

182. Bose RJC, Uday Kumar S, Zeng Y, Afjei R, Robinson E, Lau K, et al. Tumor cell-derived extracellular vesicle-coated nanocarriers: an efficient theranostic platform for the cancer-specific delivery of anti-miR-21 and imaging agents. ACS nano. (2018) 12:10817–32. doi: 10.1021/acsnano.8b02587

PubMed Abstract | Crossref Full Text | Google Scholar

183. Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature. (2015) 522:345–8. doi: 10.1038/nature14282

PubMed Abstract | Crossref Full Text | Google Scholar

184. Wang HJ, Pochampalli M, Wang LY, Zou JX, Li PS, Hsu SC, et al. KDM8/JMJD5 as a dual coactivator of AR and PKM2 integrates AR/EZH2 network and tumor metabolism in CRPC. Oncogene. (2019) 38:17–32. doi: 10.1038/s41388-018-0414-x

PubMed Abstract | Crossref Full Text | Google Scholar

185. Konski A, James J, Hartsell W, Leibenhaut MH, Janjan N, Curran W, et al. Economic analysis of radiation therapy oncology group 97-14: multiple versus single fraction radiation treatment of patients with bone metastases. Am J Clin Oncol. (2009) 32:423–8. doi: 10.1097/COC.0b013e31818da9f7

PubMed Abstract | Crossref Full Text | Google Scholar

186. Hartsell WF, Scott CB, Bruner DW, Scarantino CW, Ivker RA, Roach M 3rd, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Institute. (2005) 97:798–804. doi: 10.1093/jnci/dji139

PubMed Abstract | Crossref Full Text | Google Scholar

187. Janjan N, Lutz ST, Bedwinek JM, Hartsell WF, Ng A, Pieters RS Jr., et al. Therapeutic guidelines for the treatment of bone metastasis: a report from the American College of Radiology Appropriateness Criteria Expert Panel on Radiation Oncology. J palliative Med. (2009) 12:417–26. doi: 10.1089/jpm.2009.9633

PubMed Abstract | Crossref Full Text | Google Scholar

188. Chow E, Harris K, Fan G, Tsao M, and Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. (2007) 25:1423–36. doi: 10.1200/JCO.2006.09.5281

PubMed Abstract | Crossref Full Text | Google Scholar

189. Lutz S, Berk L, Chang E, Chow E, Hahn C, Hoskin P, et al. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat oncology biology physics. (2011) 79:965–76. doi: 10.1016/j.ijrobp.2010.11.026

PubMed Abstract | Crossref Full Text | Google Scholar

190. Cox BW, Spratt DE, Lovelock M, Bilsky MH, Lis E, Ryu S, et al. International Spine Radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery. Int J Radiat oncology biology physics. (2012) 83:e597–605. doi: 10.1016/j.ijrobp.2012.03.009

PubMed Abstract | Crossref Full Text | Google Scholar

191. Dunne EM, Fraser IM, and Liu M. Stereotactic body radiation therapy for lung, spine and oligometastatic disease: current evidence and future directions. Ann Trans Med. (2018) 6:283. doi: 10.21037/atm.2018.06.40

PubMed Abstract | Crossref Full Text | Google Scholar

192. Finlay IG, Mason MD, and Shelley M. Radioisotopes for the palliation of metastatic bone cancer: a systematic review. Lancet Oncol. (2005) 6:392–400. doi: 10.1016/S1470-2045(05)70206-0

PubMed Abstract | Crossref Full Text | Google Scholar

193. Forsberg JA, Eberhardt J, Boland PJ, Wedin R, and Healey JH. Estimating survival in patients with operable skeletal metastases: an application of a bayesian belief network. PLoS One. (2011) 6:e19956. doi: 10.1371/journal.pone.0019956

PubMed Abstract | Crossref Full Text | Google Scholar

194. Sartor O, Morris MJ, and Kraus BJ. Lutetium-177-PSMA-617 for prostate cancer. Reply. New Engl J Med. (2021) 385:2495–6. doi: 10.1056/NEJMoa2107322

PubMed Abstract | Crossref Full Text | Google Scholar

195. Frey S, Figueres L, Pattou F, Le Bras M, Caillard C, Mathonnet M, et al. Impact of permanent post-thyroidectomy hypoparathyroidism on self-evaluation of quality of life and voice: results from the national qoL-hypopara study. Ann surgery. (2021) 274:851–8. doi: 10.1097/SLA.0000000000005129

PubMed Abstract | Crossref Full Text | Google Scholar

196. Katagiri H, Okada R, Takagi T, Takahashi M, Murata H, Harada H, et al. New prognostic factors and scoring system for patients with skeletal metastasis. Cancer Med. (2014) 3:1359–67. doi: 10.1002/cam4.292

PubMed Abstract | Crossref Full Text | Google Scholar

197. Tokuhashi Y, Uei H, Oshima M, and Ajiro Y. Scoring system for prediction of metastatic spine tumor prognosis. World J orthopedics. (2014) 5:262–71. doi: 10.5312/wjo.v5.i3.262

PubMed Abstract | Crossref Full Text | Google Scholar

198. Tomita K, Kawahara N, Kobayashi T, Yoshida A, Murakami H, and Akamaru T. Surgical strategy for spinal metastases. Spine. (2001) 26:298–306. doi: 10.1097/00007632-200102010-00016

PubMed Abstract | Crossref Full Text | Google Scholar

199. Laufer I, Rubin DG, Lis E, Cox BW, Stubblefield MD, Yamada Y, et al. The NOMS framework: approach to the treatment of spinal metastatic tumors. oncologist. (2013) 18:744–51. doi: 10.1634/theoncologist.2012-0293

PubMed Abstract | Crossref Full Text | Google Scholar

200. Manabe J, Kawaguchi N, Matsumoto S, and Tanizawa T. Surgical treatment of bone metastasis: indications and outcomes. Int J Clin Oncol. (2005) 10:103–11. doi: 10.1007/s10147-005-0478-9

PubMed Abstract | Crossref Full Text | Google Scholar

201. Nazario J and Tam AL. Ablation of bone metastases. Surg Oncol Clinics North America. (2011) 20:355–68. doi: 10.1016/j.soc.2010.11.006

PubMed Abstract | Crossref Full Text | Google Scholar

202. Yang R, Goch A, Murphy D, Wang J, Charubhumi V, Fox J, et al. A novel tripod percutaneous reconstruction technique in periacetabular lesions caused by metastatic cancer. J Bone Joint Surg Am volume. (2020) 102:592–9. doi: 10.2106/JBJS.19.00936

PubMed Abstract | Crossref Full Text | Google Scholar

203. Harrington KD. The management of acetabular insufficiency secondary to metastatic Malignant disease. J Bone Joint Surg Am volume. (1981) 63:653–64. doi: 10.2106/00004623-198163040-00017

PubMed Abstract | Crossref Full Text | Google Scholar

204. Cursano MC, Valsecchi AA, Pantano F, Di Maio M, Procopio G, Berruti A, et al. Bone health and body composition in prostate cancer: Meet-URO and AIOM consensus about prevention and management strategies. ESMO Open. (2024) 9:103484. doi: 10.1016/j.esmoop.2024.103484

PubMed Abstract | Crossref Full Text | Google Scholar

205. Daei Sorkhabi A, Mohamed Khosroshahi L, Sarkesh A, Mardi A, Aghebati-Maleki A, Aghebati-Maleki L, et al. The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies. Front Immunol. (2023) 14:1113882. doi: 10.3389/fimmu.2023.1113882

PubMed Abstract | Crossref Full Text | Google Scholar

206. Yan Y, Chen H, Zhang H, Guo C, Yang K, Chen K, et al. Vascularized 3D printed scaffolds for promoting bone regeneration. Biomaterials. (2019) 190-191:97–110. doi: 10.1016/j.biomaterials.2018.10.033

PubMed Abstract | Crossref Full Text | Google Scholar

207. Coleman RE. The role of bone markers in metastatic bone disease. Cancer Treat Rev. (2006) 32 Suppl 1:1–2. doi: 10.1016/s0305-7372(06)80001-0

PubMed Abstract | Crossref Full Text | Google Scholar

208. Liu M, Sui L, Fang Z, Jiang WG, and Ye L. Aberrant expression of bone morphogenetic proteins in the disease progression and metastasis of breast cancer. Front Oncol. (2023) 13:1166955. doi: 10.3389/fonc.2023.1166955

PubMed Abstract | Crossref Full Text | Google Scholar

209. Nguyen TK, Sahgal A, Dagan R, Eppinga W, Guckenberger M, Kim JH, et al. Stereotactic body radiation therapy for nonspine bone metastases: international practice patterns to guide treatment planning. Pract Radiat Oncol. (2020) 10:e452–e60. doi: 10.1016/j.prro.2020.02.011

PubMed Abstract | Crossref Full Text | Google Scholar

210. Clézardin P, Coleman R, Puppo M, Ottewell P, Bonnelye E, Paycha F, et al. Bone metastasis: mechanisms, therapies, and biomarkers. Physiol Rev. (2021) 101:797–855. doi: 10.1152/physrev.00012.2019

PubMed Abstract | Crossref Full Text | Google Scholar

211. Zhang P, Xiao Y, Sun X, Lin X, Koo S, Yaremenko AV, et al. Cancer nanomedicine toward clinical translation: Obstacles, opportunities, and future prospects. Med (New York NY). (2023) 4:147–67. doi: 10.1016/j.medj.2022.12.001

PubMed Abstract | Crossref Full Text | Google Scholar

212. Wu Y, Sun B, Tang Y, Shen A, Lin Y, Zhao X, et al. Bone targeted nano-drug and nano-delivery. Bone Res. (2024) 12:51. doi: 10.1038/s41413-024-00356-2

PubMed Abstract | Crossref Full Text | Google Scholar

213. Min B, Zhou D, and Cai D. Effects of firing variability on network structures with spike-timing-dependent plasticity. Front Comput Neurosci. (2018) 12:1. doi: 10.3389/fncom.2018.00001

PubMed Abstract | Crossref Full Text | Google Scholar

214. Yang YH, Wen R, Yang N, Zhang TN, and Liu CF. Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives. Mol Med (Cambridge Mass). (2023) 29:93. doi: 10.1186/s10020-023-00684-9

PubMed Abstract | Crossref Full Text | Google Scholar

215. Riemann A, Schneider B, Gündel D, Stock C, Gekle M, and Thews O. Acidosis promotes metastasis formation by enhancing tumor cell motility. Adv Exp Med Biol. (2016) 876:215–20. doi: 10.1007/978-1-4939-3023-4_27

PubMed Abstract | Crossref Full Text | Google Scholar

216. Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Trans Med. (2015) 7:302ra133. doi: 10.1126/scitranslmed.aab0021

PubMed Abstract | Crossref Full Text | Google Scholar

217. Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. (2016) 34:3005–13. doi: 10.1200/JCO.2015.65.5597

PubMed Abstract | Crossref Full Text | Google Scholar

218. Al-Thamiree Mezban S and Fox SW. Genistein and coumestrol reduce MCF-7 breast cancer cell viability and inhibit markers of preferential metastasis, bone matrix attachment and tumor-induced osteoclastogenesis. Arch Biochem biophysics. (2023) 740:109583. doi: 10.1016/j.abb.2023.109583

PubMed Abstract | Crossref Full Text | Google Scholar

219. Pelon F, Bourachot B, Kieffer Y, Magagna I, Mermet-Meillon F, Bonnet I, et al. Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat Commun. (2020) 11:404. doi: 10.1038/s41467-019-14134-w

PubMed Abstract | Crossref Full Text | Google Scholar

220. Abdollahi S, Vahdat M, Saeedirad Z, Mahmoudi Z, Torkaman M, Abbassi Mobarakeh K, et al. Multifaceted role of vitamin D in breast cancer: A systematic review of genetic and pathway-based mechanisms. Asian Pacific J Cancer Prev. (2024) 25:3349–61. doi: 10.31557/APJCP.2024.25.10.3349

PubMed Abstract | Crossref Full Text | Google Scholar

221. Ben-Ghedalia-Peled N and Vago R. Wnt signaling in the development of bone metastasis. Cells. (2022) 11:3934. doi: 10.3390/cells11233934

PubMed Abstract | Crossref Full Text | Google Scholar

222. Sui L, Cong Y, Liu M, Liu X, Xu Y, Jiang WG, et al. Upregulated bone morphogenetic protein 8A (BMP8A) in triple negative breast cancer (TNBC) and its involvement in the bone metastasis. Front Cell Dev Biol. (2024) 12:1374269. doi: 10.3389/fcell.2024.1374269

PubMed Abstract | Crossref Full Text | Google Scholar

223. Akhtar M, Haider A, Rashid S, and Al-Nabet A. Paget’s “Seed and soil” Theory of cancer metastasis: an idea whose time has come. Adv anatomic pathology. (2019) 26:69–74. doi: 10.1097/PAP.0000000000000219

PubMed Abstract | Crossref Full Text | Google Scholar

224. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. (2010) 28:3271–7. doi: 10.1200/JCO.2009.25.9820

PubMed Abstract | Crossref Full Text | Google Scholar

225. Papalia GF, Brigato P, Sisca L, Maltese G, Faiella E, Santucci D, et al. Artificial intelligence in detection, management, and prognosis of bone metastasis: A systematic review. Cancers. (2024) 16:2700. doi: 10.3390/cancers16152700

PubMed Abstract | Crossref Full Text | Google Scholar

226. Sathiakumar N, Delzell E, Morrisey MA, Falkson C, Yong M, Chia V, et al. Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999-2006. Prostate Cancer prostatic diseases. (2011) 14:177–83. doi: 10.1038/pcan.2011.7

PubMed Abstract | Crossref Full Text | Google Scholar

227. Prieur A, Harper A, Khan M, Vire B, Joubert D, Payen L, et al. Plasma hPG(80) (Circulating Progastrin) as a Novel Prognostic Biomarker for early-stage breast cancer in a breast cancer cohort. BMC cancer. (2023) 23:305. doi: 10.1186/s12885-023-10729-1

PubMed Abstract | Crossref Full Text | Google Scholar

228. Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J (Sudbury Mass). (2001) 7:377–87.

Google Scholar

229. Ryan C, Stoltzfus KC, Horn S, Chen H, Louie AV, Lehrer EJ, et al. Epidemiology of bone metastases. Bone. (2022) 158:115783. doi: 10.1016/j.bone.2020.115783

PubMed Abstract | Crossref Full Text | Google Scholar

230. Borras JM, Albreht T, Audisio R, Briers E, Casali P, Esperou H, et al. Policy statement on multidisciplinary cancer care. Eur J Cancer (Oxford England: 1990). (2014) 50:475–80. doi: 10.1016/j.ejca.2013.11.012

PubMed Abstract | Crossref Full Text | Google Scholar

231. Hong NJ, Wright FC, Gagliardi AR, and Paszat LF. Examining the potential relationship between multidisciplinary cancer care and patient survival: an international literature review. J Surg Oncol. (2010) 102:125–34. doi: 10.1002/jso.21589

PubMed Abstract | Crossref Full Text | Google Scholar

232. Kougioumtzopoulou A, Zygogianni A, Liakouli Z, Kypraiou E, and Kouloulias V. The role of radiotherapy in bone metastases: A critical review of current literature. Eur J Cancer Care. (2017) 26:e12724. doi: 10.1111/ecc.12724

PubMed Abstract | Crossref Full Text | Google Scholar

233. Cazzato RL, Bonichon F, Buy X, Godbert Y, de Figuereido BH, Pointillart V, et al. Over ten years of single-institution experience in percutaneous image-guided treatment of bone metastases from differentiated thyroid cancer. Eur J Surg Oncol. (2015) 41:1247–55. doi: 10.1016/j.ejso.2015.06.005

PubMed Abstract | Crossref Full Text | Google Scholar

234. Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. New Engl J Med. (2020) 383:825–35. doi: 10.1056/NEJMoa2005651

PubMed Abstract | Crossref Full Text | Google Scholar

235. Armstrong AJ, Azad AA, Iguchi T, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol. (2022) 40:1616–22. doi: 10.1200/JCO.22.00193

PubMed Abstract | Crossref Full Text | Google Scholar

236. Chen J, Ye X, Pitmon E, Lu M, Wan J, Jellison ER, et al. IL-17 inhibits CXCL9/10-mediated recruitment of CD8(+) cytotoxic T cells and regulatory T cells to colorectal tumors. J immunotherapy cancer. (2019) 7:324. doi: 10.1186/s40425-019-0757-z

PubMed Abstract | Crossref Full Text | Google Scholar

237. Spitzweg C, Nelson PJ, Wagner E, Bartenstein P, Weber WA, Schwaiger M, et al. The sodium iodide symporter (NIS): novel applications for radionuclide imaging and treatment. Endocrine-related Cancer. (2021) 28:T193–t213. doi: 10.1530/ERC-21-0177

PubMed Abstract | Crossref Full Text | Google Scholar

238. Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet (London England). (2011) 377:813–22. doi: 10.1016/S0140-6736(10)62344-6

PubMed Abstract | Crossref Full Text | Google Scholar

239. Fares J, Davis ZB, Rechberger JS, Toll SA, Schwartz JD, Daniels DJ, et al. Advances in NK cell therapy for brain tumors. NPJ Precis Oncol. (2023) 7:17. doi: 10.1038/s41698-023-00356-1

PubMed Abstract | Crossref Full Text | Google Scholar

240. Tan AC and Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. J Clin Oncol. (2022) 40:611–25. doi: 10.1200/JCO.21.01626

PubMed Abstract | Crossref Full Text | Google Scholar

241. Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T, et al. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol. (2015) 33:2129–35. doi: 10.1200/JCO.2014.58.4391

PubMed Abstract | Crossref Full Text | Google Scholar

242. Mohammad KS, Javelaud D, Fournier PG, Niewolna M, McKenna CR, Peng XH, et al. TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res. (2011) 71:175–84. doi: 10.1158/0008-5472.CAN-10-2651

PubMed Abstract | Crossref Full Text | Google Scholar

243. Ominsky MS, Libanati C, Niu QT, Boyce RW, Kostenuik PJ, Wagman RB, et al. Journal of Bone and Mineral Research: Volume 30, Issue 5, May 2015, Frontmatter page ii. J Bone mineral Res. (2015) 30:1347. doi: 10.1002/jbmr.2543

PubMed Abstract | Crossref Full Text | Google Scholar

244. Sosa MS, Parikh F, Maia AG, Estrada Y, Bosch A, Bragado P, et al. NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes. Nat Commun. (2015) 6:6170. doi: 10.1038/ncomms7170

PubMed Abstract | Crossref Full Text | Google Scholar

245. Das S and Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J immunotherapy cancer. (2019) 7:306. doi: 10.1186/s40425-019-0805-8

PubMed Abstract | Crossref Full Text | Google Scholar

246. Baum RP, Schuchardt C, Singh A, Chantadisai M, Robiller FC, Zhang J, et al. Feasibility, biodistribution, and preliminary dosimetry in peptide-targeted radionuclide therapy of diverse adenocarcinomas using (177)Lu-FAP-2286: first-in-humans results. J Nucl Med. (2022) 63:415–23. doi: 10.2967/jnumed.120.259192

PubMed Abstract | Crossref Full Text | Google Scholar

247. Sato Y, Hashiba K, Sasaki K, Maeki M, Tokeshi M, and Harashima H. Understanding structure-activity relationships of pH-sensitive cationic lipids facilitates the rational identification of promising lipid nanoparticles for delivering siRNAs in vivo. J Controlled release. (2019) 295:140–52. doi: 10.1016/j.jconrel.2019.01.001

PubMed Abstract | Crossref Full Text | Google Scholar

248. Yang P, Zhang S, Pan S, Tang B, Liang Y, Zhao X, et al. Epitaxial growth of centimeter-scale single-crystal moS(2) monolayer on au(111). ACS nano. (2020) 14:5036–45. doi: 10.1021/acsnano.0c01478

PubMed Abstract | Crossref Full Text | Google Scholar

249. De Pasquale L, Rabbiosi D, Bardazzi A, Autelitano L, Moro GP, and Ghilardi G. Multidisciplinary approach to follicular thyroid carcinoma with giant mandibular and multiple sites metastases Case report. Annali italiani di chirurgia. (2014) 85:601–5.

PubMed Abstract | Google Scholar

250. Percival RC, Yates AJ, Gray RE, Galloway J, Rogers K, Neal FE, et al. Mechanism of Malignant hypercalcaemia in carcinoma of the breast. Br Med J (Clinical Res ed). (1985) 291:776–9. doi: 10.1136/bmj.291.6498.776

PubMed Abstract | Crossref Full Text | Google Scholar

251. Soeharno H, Povegliano L, and Choong PF. Multimodal treatment of bone metastasis-A surgical perspective. Front endocrinology. (2018) 9:518. doi: 10.3389/fendo.2018.00518

PubMed Abstract | Crossref Full Text | Google Scholar

252. Bouxsein ML, Eastell R, Lui LY, Wu LA, de Papp AE, Grauer A, et al. Change in bone density and reduction in fracture risk: A meta-regression of published trials. J Bone mineral Res. (2019) 34:632–42. doi: 10.1002/jbmr.3641

PubMed Abstract | Crossref Full Text | Google Scholar

253. Lang C, Dai Y, Wu Z, Yang Q, He S, Zhang X, et al. SMAD3/SP1 complex-mediated constitutive active loop between lncRNA PCAT7 and TGF-β signaling promotes prostate cancer bone metastasis. Mol Oncol. (2020) 14:808–28. doi: 10.1002/1878-0261.12634

PubMed Abstract | Crossref Full Text | Google Scholar

254. Sadowski SM, Neychev V, Millo C, Shih J, Nilubol N, Herscovitch P, et al. Prospective study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites. J Clin Oncol. (2016) 34:588–96. doi: 10.1200/JCO.2015.64.0987

PubMed Abstract | Crossref Full Text | Google Scholar

255. Robbins HL, Symington M, Mosterman B, Goodby J, Davies L, Dimitriadis GK, et al. Supplementation of vitamin D deficiency in patients with neuroendocrine tumors using over-the-counter vitamin D3 preparations. Nutr cancer. (2018) 70:748–54. doi: 10.1080/01635581.2018.1470650

PubMed Abstract | Crossref Full Text | Google Scholar

256. Giusti F, Cianferotti L, Gronchi G, Cioppi F, Masi L, Faggiano A, et al. Cinacalcet therapy in patients affected by primary hyperparathyroidism associated to Multiple Endocrine Neoplasia Syndrome type 1 (MEN1). Endocrine. (2016) 52:495–506. doi: 10.1007/s12020-015-0696-5

PubMed Abstract | Crossref Full Text | Google Scholar

257. Lourenço DM Jr., Coutinho FL, Toledo RA, Montenegro FL, Correia-Deur JE, and Toledo SP. Early-onset, progressive, frequent, extensive, and severe bone mineral and renal complications in multiple endocrine neoplasia type 1-associated primary hyperparathyroidism. J Bone mineral Res. (2010) 25:2382–91. doi: 10.1002/jbmr.125

PubMed Abstract | Crossref Full Text | Google Scholar

258. Ayala-Ramirez M, Palmer JL, Hofmann MC, de la Cruz M, Moon BS, Waguespack SG, et al. Bone metastases and skeletal-related events in patients with Malignant pheochromocytoma and sympathetic paraganglioma. J Clin Endocrinol Metab. (2013) 98:1492–7. doi: 10.1210/jc.2012-4231

PubMed Abstract | Crossref Full Text | Google Scholar

259. Norman D, Mills CM, Brant-Zawadzki M, Yeates A, Crooks LE, and Kaufman L. Magnetic resonance imaging of the spinal cord and canal: potentials and limitations. AJR Am J roentgenology. (1983) 141:1147–52. doi: 10.2214/ajr.141.6.1147

PubMed Abstract | Crossref Full Text | Google Scholar

260. Karpinski MJ, Hüsing J, Claassen K, Möller L, Kajüter H, Oesterling F, et al. Combining PSMA-PET and PROMISE to re-define disease stage and risk in patients with prostate cancer: a multicentre retrospective study. Lancet Oncol. (2024) 25:1188–201. doi: 10.1016/S1470-2045(24)00326-7

PubMed Abstract | Crossref Full Text | Google Scholar

261. Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. (2011) 208:2641–55. doi: 10.1084/jem.20110840

PubMed Abstract | Crossref Full Text | Google Scholar

262. Petit C, Delouya G, Taussky D, Barkati M, Lambert C, Beauchemin MC, et al. PSMA-PET/CT-guided intensification of radiation therapy for prostate cancer (PSMAgRT): findings of detection rate, effect on cancer management, and early toxicity from a phase 2 randomized controlled trial. Int J Radiat oncology biology physics. (2023) 116:779–87. doi: 10.1016/j.ijrobp.2022.12.055

PubMed Abstract | Crossref Full Text | Google Scholar

263. Eapen RS, Buteau JP, Jackson P, Mitchell C, Oon SF, Alghazo O, et al. Administering [(177)Lu]Lu-PSMA-617 prior to radical prostatectomy in men with high-risk localised prostate cancer (LuTectomy): A single-centre, single-arm, phase 1/2 study. Eur urology. (2024) 85:217–26. doi: 10.1016/j.eururo.2023.08.026

PubMed Abstract | Crossref Full Text | Google Scholar

264. Hartrampf PE, Weinzierl FX, Buck AK, Rowe SP, Higuchi T, Seitz AK, et al. Matched-pair analysis of [(177)Lu]Lu-PSMA I&T and [(177)Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol imaging. (2022) 49:3269–76. doi: 10.1007/s00259-022-05744-6

PubMed Abstract | Crossref Full Text | Google Scholar

265. Pouliot F, Saad F, Rousseau E, Richard PO, Zamanian A, Probst S, et al. Intrapatient intermetastatic heterogeneity determined by triple-tracer PET imaging in mCRPC patients and correlation to survival: the 3TMPO cohort study. J Nucl Med. (2024) 65:1710–7. doi: 10.2967/jnumed.124.268020

PubMed Abstract | Crossref Full Text | Google Scholar

266. Dyrberg E, Hendel HW, Huynh THV, Klausen TW, Løgager VB, Madsen C, et al. (68)Ga-PSMA-PET/CT in comparison with (18)F-fluoride-PET/CT and whole-body MRI for the detection of bone metastases in patients with prostate cancer: a prospective diagnostic accuracy study. Eur radiology. (2019) 29:1221–30. doi: 10.1007/s00330-018-5682-x

PubMed Abstract | Crossref Full Text | Google Scholar

267. Malaspina S, Anttinen M, Taimen P, Jambor I, Sandell M, Rinta-Kiikka I, et al. Prospective comparison of (18)F-PSMA-1007 PET/CT, whole-body MRI and CT in primary nodal staging of unfavourable intermediate- and high-risk prostate cancer. Eur J Nucl Med Mol imaging. (2021) 48:2951–9. doi: 10.1007/s00259-021-05296-1

PubMed Abstract | Crossref Full Text | Google Scholar

268. de Bono J, Kang J, and Hussain M. Olaparib for metastatic castration-resistant prostate cancer. Reply. New Engl J Med. (2020) 383:891. doi: 10.1056/NEJMc2023199

PubMed Abstract | Crossref Full Text | Google Scholar

269. Henríquez I, Malave B, Campos FL, Hidalgo EC, Muelas R, Ferrer C, et al. PSMA PET/CT SUVmax as a prognostic biomarker in patients with metachronous metastatic hormone-sensitive prostate cancer (mHSPC). Clin Trans Oncol. (2025) 27:706–15. doi: 10.1007/s12094-024-03625-y

PubMed Abstract | Crossref Full Text | Google Scholar

270. Tuffour A, Kosiba AA, Zhang Y, Peprah FA, Gu J, and Shi H. Role of the calcium-sensing receptor (CaSR) in cancer metastasis to bone: Identifying a potential therapeutic target. Biochim Biophys Acta Rev cancer. (2021) 1875:188528. doi: 10.1016/j.bbcan.2021.188528

PubMed Abstract | Crossref Full Text | Google Scholar

271. Li X, Yang J, Bao M, Zeng K, Fu S, Wang C, et al. Wnt signaling in bone metastasis: mechanisms and therapeutic opportunities. Life Sci. (2018) 208:33–45. doi: 10.1016/j.lfs.2018.06.036

PubMed Abstract | Crossref Full Text | Google Scholar

272. Trivedi T, Pagnotti GM, Guise TA, and Mohammad KS. The role of TGF-β in bone metastases. Biomolecules. (2021) 11:1643. doi: 10.3390/biom11111643

PubMed Abstract | Crossref Full Text | Google Scholar

273. Gauthé M, Aveline C, Lecouvet F, Michaud L, Rousseau C, Tassart M, et al. Impact of sodium (18)F-fluoride PET/CT, (18)F-fluorocholine PET/CT and whole-body diffusion-weighted MRI on the management of patients with prostate cancer suspicious for metastasis: a prospective multicentre study. World J urology. (2019) 37:1587–95. doi: 10.1007/s00345-018-2547-5

PubMed Abstract | Crossref Full Text | Google Scholar

274. Pesapane F, Downey K, Rotili A, Cassano E, and Koh DM. Imaging diagnosis of metastatic breast cancer. Insights into imaging. (2020) 11:79. doi: 10.1186/s13244-020-00885-4

PubMed Abstract | Crossref Full Text | Google Scholar

275. Fournier PG, Juárez P, Jiang G, Clines GA, Niewolna M, Kim HS, et al. The TGF-β Signaling regulator PMEPA1 suppresses prostate cancer metastases to bone. Cancer Cell. (2015) 27:809–21. doi: 10.1016/j.ccell.2015.04.009

PubMed Abstract | Crossref Full Text | Google Scholar

276. Hao X, Jiang B, Wu J, Xiang D, Xiong Z, Li C, et al. Nanomaterials for bone metastasis. J Controlled release. (2024) 373:640–51. doi: 10.1016/j.jconrel.2024.07.067

PubMed Abstract | Crossref Full Text | Google Scholar

277. Azad AA, Bressel M, Tan H, Voskoboynik M, Suder A, Weickhardt AJ, et al. Sequential [(177)Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study. Lancet Oncol. (2024) 25:1267–76. doi: 10.1016/S1470-2045(24)00440-6

PubMed Abstract | Crossref Full Text | Google Scholar

278. Seifert R, Emmett L, Rowe SP, Herrmann K, Hadaschik B, Calais J, et al. Second version of the prostate cancer molecular imaging standardized evaluation framework including response evaluation for clinical trials (PROMISE V2). Eur urology. (2023) 83:405–12. doi: 10.1016/j.eururo.2023.02.002

PubMed Abstract | Crossref Full Text | Google Scholar

279. Esen B, Seymen H, Tarim K, Koseoglu E, Bolukbasi Y, Falay O, et al. Diagnostic performance of (68)Ga-PSMA-11 positron emission tomography/computed tomography to monitor treatment response in patients with metastatic prostate cancer: the concordance between biochemical response and prostate-specific membrane antigen results. Eur Urol focus. (2023) 9:832–7. doi: 10.1016/j.euf.2023.03.023

PubMed Abstract | Crossref Full Text | Google Scholar

280. Fallahi B, Khademi N, Karamzade-Ziarati N, Fard-Esfahani A, Emami-Ardekani A, Farzanefar S, et al. 99mTc-PSMA SPECT/CT versus 68Ga-PSMA PET/CT in the evaluation of metastatic prostate cancer. Clin Nucl Med. (2021) 46:e68–74. doi: 10.1097/RLU.0000000000003410

PubMed Abstract | Crossref Full Text | Google Scholar

281. Grünig H, Maurer A, Thali Y, Kovacs Z, Strobel K, Burger IA, et al. Focal unspecific bone uptake on [(18)F]-PSMA-1007 PET: a multicenter retrospective evaluation of the distribution, frequency, and quantitative parameters of a potential pitfall in prostate cancer imaging. Eur J Nucl Med Mol imaging. (2021) 48:4483–94. doi: 10.1007/s00259-021-05424-x

PubMed Abstract | Crossref Full Text | Google Scholar

282. Lee DY and Kim YI. Effects of (225)Ac-labeled prostate-specific membrane antigen radioligand therapy in metastatic castration-resistant prostate cancer: A meta-analysis. J Nucl Med. (2022) 63:840–6. doi: 10.2967/jnumed.121.262017

PubMed Abstract | Crossref Full Text | Google Scholar

283. Dondi F, Albano D, Bertagna F, and Treglia G. Bone scintigraphy versus PSMA-targeted PET/CT or PET/MRI in prostate cancer: lessons learned from recent systematic reviews and meta-analyses. Cancers. (2022) 14:4470. doi: 10.3390/cancers14184470

PubMed Abstract | Crossref Full Text | Google Scholar

284. Garcia-Ruiz A, Macarro C, Zacchi F, Morales-Barrera R, Grussu F, Casanova-Salas I, et al. Whole-body magnetic resonance imaging as a treatment response biomarker in castration-resistant prostate cancer with bone metastases: the iPROMET clinical trial. Eur urology. (2024) 86:272–4. doi: 10.1016/j.eururo.2024.02.016

PubMed Abstract | Crossref Full Text | Google Scholar

285. Lin Y, Wang K, Zheng Z, Yu H, Chen S, Tang W, et al. Eliminating the second CT scan of dual-tracer total-body PET/CT via deep learning-based image synthesis and registration. Eur J Nucl Med Mol Imaging. (2025) 52:2589–604. doi: 10.1007/s00259-025-07113-5

PubMed Abstract | Crossref Full Text | Google Scholar

286. Zamboglou C, Carles M, Fechter T, Kiefer S, Reichel K, Fassbender TF, et al. Radiomic features from PSMA PET for non-invasive intraprostatic tumor discrimination and characterization in patients with intermediate- and high-risk prostate cancer - a comparison study with histology reference. Theranostics. (2019) 9:2595–605. doi: 10.7150/thno.32376

PubMed Abstract | Crossref Full Text | Google Scholar

287. Zhang YF, Zhou C, Guo S, Wang C, Yang J, Yang ZJ, et al. Deep learning algorithm-based multimodal MRI radiomics and pathomics data improve prediction of bone metastases in primary prostate cancer. J Cancer Res Clin Oncol. (2024) 150:78. doi: 10.1007/s00432-023-05574-5

PubMed Abstract | Crossref Full Text | Google Scholar

288. Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, Grampp S, Kaessmann H, Schmid M, et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. (2007) 25:820–8. doi: 10.1200/JCO.2005.02.7102

PubMed Abstract | Crossref Full Text | Google Scholar

289. Haas MS, Kagey MH, Heath H, Schuerpf F, Rottman JB, and Newman W. mDKN-01, a novel anti-DKK1 mAb, enhances innate immune responses in the tumor microenvironment. Mol Cancer research: MCR. (2021) 19:717–25. doi: 10.1158/1541-7786.MCR-20-0799

PubMed Abstract | Crossref Full Text | Google Scholar

290. Emens LA, Cruz C, Eder JP, Braiteh F, Chung C, Tolaney SM, et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: A phase 1 study. JAMA Oncol. (2019) 5:74–82. doi: 10.1001/jamaoncol.2018.4224

PubMed Abstract | Crossref Full Text | Google Scholar

291. Wagner J, Wickman E, DeRenzo C, and Gottschalk S. CAR T cell therapy for solid tumors: bright future or dark reality? Mol Ther. (2020) 28:2320–39. doi: 10.1016/j.ymthe.2020.09.015

PubMed Abstract | Crossref Full Text | Google Scholar

292. Jeong WY, Choi HE, and Kim KS. Graphene-based nanomaterials as drug delivery carriers. Adv Exp Med Biol. (2022) 1351:109–24. doi: 10.1007/978-981-16-4923-3_6

PubMed Abstract | Crossref Full Text | Google Scholar

293. Li S, Saw PE, Lin C, Nie Y, Tao W, Farokhzad OC, et al. Redox-responsive polyprodrug nanoparticles for targeted siRNA delivery and synergistic liver cancer therapy. Biomaterials. (2020) 234:119760. doi: 10.1016/j.biomaterials.2020.119760

PubMed Abstract | Crossref Full Text | Google Scholar

294. Jiang Z, Li J, Chen S, Guo Q, Jing Z, Huang B, et al. Zoledronate and SPIO dual-targeting nanoparticles loaded with ICG for photothermal therapy of breast cancer tibial metastasis. Sci Rep. (2020) 10:13675. doi: 10.1038/s41598-020-70659-x

PubMed Abstract | Crossref Full Text | Google Scholar

295. Early Breast Cancer Trialists’ Collaborative G. Postmastectomy radiotherapy in patients with breast cancer - Authors’ reply. Lancet (London England). (2014) 384:1846–7. doi: 10.1016/S0140-6736(14)62240-6

PubMed Abstract | Crossref Full Text | Google Scholar

296. Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet (London England). (2015) 386:433–43. doi: 10.1016/S0140-6736(15)60995-3

PubMed Abstract | Crossref Full Text | Google Scholar

297. Siskin M, Economides MP, and Wise DR. Cyclin-dependent kinase inhibition in prostate cancer: past, present, and future. Cancers. (2025) 17:0774. doi: 10.3390/cancers17050774

PubMed Abstract | Crossref Full Text | Google Scholar

298. Confavreux CB, Follet H, Mitton D, Pialat JB, and Clézardin P. Fracture risk evaluation of bone metastases: A burning issue. Cancers. (2021) 13:5711. doi: 10.3390/cancers13225711

PubMed Abstract | Crossref Full Text | Google Scholar

299. Beier EE, Sheu TJ, Resseguie EA, Takahata M, Awad HA, Cory-Slechta DA, et al. Sclerostin activity plays a key role in the negative effect of glucocorticoid signaling on osteoblast function in mice. Bone Res. (2017) 5:17013. doi: 10.1038/boneres.2017.13

PubMed Abstract | Crossref Full Text | Google Scholar

300. Rizzoli R and Biver E. Glucocorticoid-induced osteoporosis: who to treat with what agent? Nat Rev Rheumatol. (2015) 11:98–109. doi: 10.1038/nrrheum.2014.188

PubMed Abstract | Crossref Full Text | Google Scholar

301. Bolzoni M, Storti P, Bonomini S, Todoerti K, Guasco D, Toscani D, et al. Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and the RANKL/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules. Exp hematology. (2013) 41:387–97.e1. doi: 10.1016/j.exphem.2012.11.005

PubMed Abstract | Crossref Full Text | Google Scholar

302. Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, and Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J urology. (2003) 169:2008–12. doi: 10.1097/01.ju.0000063820.94994.95

PubMed Abstract | Crossref Full Text | Google Scholar

303. Yin L, Duan JJ, Bian XW, and Yu SC. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer research: BCR. (2020) 22:61. doi: 10.1186/s13058-020-01296-5

PubMed Abstract | Crossref Full Text | Google Scholar

304. Gurkar AU, Gerencser AA, Mora AL, Nelson AC, Zhang AR, Lagnado AB, et al. Spatial mapping of cellular senescence: emerging challenges and opportunities. Nat aging. (2023) 3:776–90. doi: 10.1038/s43587-023-00446-6

PubMed Abstract | Crossref Full Text | Google Scholar

305. Caloro E, Gnocchi G, Quarrella C, Ce M, Carrafiello G, and Cellina M. Artificial intelligence in bone metastasis imaging: recent progresses from diagnosis to treatment - A narrative review. Crit Rev oncogenesis. (2024) 29:77–90. doi: 10.1615/CritRevOncog.2023050470

PubMed Abstract | Crossref Full Text | Google Scholar

306. Smaldone G, Di Matteo F, Castelluccio R, Napolitano V, Miranda MR, Manfra M, et al. Targeting the CXCR4/CXCL12 axis in cancer therapy: analysis of recent advances in the development of potential anticancer agents. Molecules (Basel Switzerland). (2025) 30:1380. doi: 10.3390/molecules30061380

PubMed Abstract | Crossref Full Text | Google Scholar