Abstract
Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders requiring lifelong glucocorticoid (GC) therapy. Skeletal health remains incompletely characterized, particularly during adolescence. The pubertal transition represents a critical window for peak bone mass acquisition, during which chronic GC exposure, altered pubertal timing and abnormal sex steroid exposure may exert lasting effects on bone density, and quality. This mini-review examines current evidence on bone health in adolescents with CAH, focusing on the complex interplay among GC therapy, alterations in androgen levels and pubertal maturation. Most available data derive from patients with 21-hydroxylase deficiency and reveal heterogeneous bone mineral density outcomes, largely influenced by cumulative GC exposure, bone age advancement and body composition. Notably, studies adjusting bone density for age demonstrate impaired bone accrual masked by accelerated skeletal maturation. Emerging longitudinal data suggest that puberty does not fully compensate for early skeletal deficits and that divergence from reference populations may progress. Evidence regarding rarer CAH forms remains scarce. In 11β-hydroxylase deficiency, pronounced androgen excess is associated with advanced bone maturation, yet data on bone density and fracture risk are lacking. Conversely, 17α-hydroxylase/17,20-lyase deficiency is characterized by profound sex steroid deficiency, delayed puberty and distinct alterations in bone microarchitecture. Overall, adolescents with CAH are at risk of suboptimal peak bone mass acquisition. Optimizing skeletal outcomes requires individualized GC replacement, careful monitoring of pubertal progression and bone age-adjusted assessment of bone density. Longitudinal, phenotype-specific studies incorporating advanced imaging are needed to better define fracture risk and guide evidence-based management across the lifespan.
Graphical Abstract
1 Introduction
Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders of adrenal steroidogenesis characterized by impaired cortisol synthesis, chronic activation of the hypothalamic-pituitary-adrenal axis and variable alterations in adrenal androgen production. 21-hydroxylase deficiency (21OHD) accounts for approximately 90%–95% of all CAH cases worldwide, representing the most prevalent and clinically studied form of the disease (). Rarer enzymatic defects, including 11β-hydroxylase deficiency (11βOHD) and 17α-hydroxylase/17,20-lyase deficiency (17OHD), contribute to the remaining cases and are associated with distinct hormonal profiles, patterns of pubertal development and growth trajectories (, ).
The long-term management of CAH remains challenging, as it requires balancing adequate cortisol replacement and suppression of adrenocorticotropic hormone (ACTH)-driven steroid excess, while minimizing the adverse effects of chronic glucocorticoid (GC) exposure on growth, pubertal development, metabolic outcomes and bone health (, ). Advances in neonatal screening, endocrine management and multidisciplinary care have markedly improved survival and quality of life, shifting the clinical focus toward long-term outcomes and comorbidities across the lifespan ().
While long-term outcomes in CAH have been predominantly evaluated in terms of cardiometabolic risk, less is known about skeletal health, particularly during adolescence, a critical window for peak bone mass acquisition. Data specifically addressing bone health during adolescence remain limited and often conflicting, reflecting heterogeneity in study design, disease severity and treatment regimens, thereby pinpointing the need for a focused synthesis of the available evidence (). Moreover, most available evidence is derived from 21OHD, whereas the skeletal implications of rarer CAH forms, characterized by either marked androgen excess (11βOHD) or sex steroid deficiency (17OHD), remain poorly defined.
This mini-review aims to explore the pathophysiological interplay between GC therapy, androgen excess or deficiency and pubertal maturation in adolescents with CAH, summarize current clinical evidence regarding bone density, microarchitecture and fracture risk and discuss implications for clinical management and future research directions.
2 Bone health during adolescence
Adolescence is a critical period for skeletal development, during which ∼40%–60% of peak bone mass is accrued (, ). Pubertal increases in sex steroids are essential: estrogens promote epiphyseal maturation and trabecular mineralization, while androgens enhance periosteal apposition and cortical expansion, particularly in males (). The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis further stimulates osteoblast activity and bone mineralization, while mechanical loading the supports adaptive remodeling (), as reassumed in Figure 1.
Figure 1
Altered hormonal balance or pubertal timing can impair peak bone mass, increasing later-life fracture risk. Chronic GC therapy, as required in classic CAH, adds further skeletal challenges (). In adolescents with CAH, bone outcomes reflect complex interactions between supraphysiologic GC exposure, sexual hormone imbalance, impaired bone age and altered body composition, leading to heterogeneous study results (, ).
In addition, vitamin D insufficiency has been frequently reported in pediatric patients with CAH and may further compromise bone mineralization during the critical window of peak bone mass acquisition (). In the context of chronic GC therapy and altered pubertal timing, suboptimal vitamin D status may represent a modifiable contributor to impaired skeletal accrual in adolescence.
3 Glucocorticoid therapy and androgen excess in CAH
Glucocorticoids increase bone resorption and suppress bone formation, impairing microarchitecture and increasing fracture risk (). Additional effects include altered calcium handling and secondary hyperparathyroidism driven by reduced intestinal calcium absorption (through antagonism of vitamin D signaling) and increased renal calcium excretion, leading to negative calcium balance and compensatory PTH elevation. This mechanism may be particularly detrimental during adolescence, when optimal calcium retention is required for peak bone mass acquisition ().
In CAH, skeletal impact depends on cumulative GC exposure, treatment duration, and supraphysiologic dosing needed to suppress ACTH-driven androgen excess. Androgens have anabolic effects by stimulating osteoblast proliferation; therefore, androgen excess may partially compensate for GC-related bone loss. However, chronic supraphysiologic androgen levels accelerate bone maturation, advance bone age, and shorten the bone accrual window, limiting net benefit (–). In physiological conditions, adrenal androgens (particularly DHEAS) rise during adrenarche and preferentially promote cortical bone expansion and periosteal apposition. In classic CAH, however, alterations in DHEAS dynamics, either blunted due to GC overtreatment or dysregulated due to ACTH excess, may impair this physiological cortical bone accrual, potentially exacerbating GC-induced skeletal deficits (–).
4 Pubertal timing and progression in CAH: implications for bone health
Puberty is pivotal for skeletal development. In CAH, either in classic and non-classic forms, adrenal androgens excess may trigger premature pubarche, advanced bone age and early epiphyseal closure, potentially limiting peak bone mass. Conversely, GC overtreatment may delay puberty by suppressing gonadotropins and the GH/IGF-1 axis, creating complex effects on growth and bone mineralization (–). GnRH agonists (GnRHa) may be used to slow puberty in selected patients, prolonging skeletal growth, but their impact on BMD depends on timing, duration and androgen/GC control. Delayed puberty may also reduce bone accrual, highlighting the risk of both under and overtreatment ().
Sex-specific differences are important: in females, hyperandrogenism may confer partial anabolic effects, whereas in males adrenal or testicular androgen effects are harder to distinguish. Peripheral aromatization of androgens to estrogens indirectly supports trabecular bone mineralization (, ).
5 Classic vs. non-classic 21-hydroxylase deficiency: implications for bone health during adolescence
5.1 Skeletal impairment in CAH
CAH due to 21OHD encompasses a spectrum from severe classic forms to milder non-classic variants (NCCAH). Classic CAH (salt-wasting and simple virilizing) is characterized by early, persistent cortisol deficiency and marked adrenal androgen excess, leading to advanced bone age, altered pubertal timing. To effectively control the impaired adrenal steroidogenesis, lifelong supraphysiologic GC therapy is often required (, ).
NCCAH shows partial enzyme impairment, later-onset androgen excess, and in most cases needs intermittent or lower-dose GC therapy, thus skeletal effects are milder. Adolescents with NCCAH may have modest bone age advancement, but direct evidence on BMD and fracture risk is limited (, ). No data regarding bone turnover markers in patients with NCCAH are currently available (). According to older studies, patients with NCCAH experience fewer fractures than those with more severe forms of the disease (, ). However, few more recent studies on fracture risk in adult patients show conflicting results in NCCAH (, , ).
5.2 Adolescent skeletal outcomes in congenital adrenal hyperplasia: bone density trajectories and long-term implications
Several studies combine classic and non-classic forms, potentially concealing phenotype-specific skeletal trajectories, highlighting the need to differentiate these subgroups (, , ). The available literature on bone health in adolescents with CAH is limited and heterogeneous (Table 1). Several consistent themes emerge when skeletal outcomes are interpreted within the context of pubertal development, bone age advancement and cumulative GC exposure.
Table 1
| Study design | Number and age (years) | Skeletal assessment | Quantitative outcomes | Key findings | |
|---|---|---|---|---|---|
| Garcia Alves Junior et al. (2014) () | Cross-sectional study | 14 (classic CAH), 5–19 | Total body and LS DXA | TB Z-score −0.76; LS Z-score −0.26 (bone age–adjusted); Z-scores within normal range when adjusted for chronological age | Advanced bone age masks impaired bone accrual |
| Espinosa Reyes et al. (2021) () | Cross-sectional study | 25 (classic CAH), 15.9 ± 5.8 | LS and femur DXA | LS BMD 0.83 vs. 0.98 g/cm² in controls (p = 0.004); femoral BMD not significantly different | GC dose negatively associated; androgen exposure partially protective |
| Wiromrat et al. (2023) (36) | Retrospective - prospective cohort study | 33 (classic CAH), 14.6 ± 3.6 | LS DXA; bone turnover markers | Annual %Δ LS BMD 3.6%; lower accrual with higher GC dose and prednisolone; CTX and OC predictive of BMD accrual | Bone accrual is GC dose- and compound-dependent |
| Ryabets-Lienhard et al. (2025) () | Cross-sectional study | 35 (classic CAH), 12.3 ± 3.2 | Whole body and LS DXA | LS aBMDHAZ inversely correlated with visceral, subcutaneous and total fat mass (p < 0.05) | Adiposity adversely affects bone independent of GC dose |
| Navardauskaitė et al. (2024) () | Cross-sectional (CAH matched controls) | 32 (classic CAH), 14–37 | Whole body and LS DXA | Mean LS and whole-body BMD Z-scores within normal range; early growth velocity positively associated with later BMD (p < 0.05) | Higher early-life growth velocity predicts higher LS and whole-body BMD |
| Flokas et al. (2024) () | Retrospective longitudinal cohort study | 61 (classic CAH, of which 20 received GnRHa), Pediatric to adult | Whole body DXA | No difference in adult BMD between GnRHa-treated vs. untreated patients; progressive decline in BMD Z-scores over time | BMD decline likely reflects chronic GC exposure |
| Stancampiano et al. (2025) (35) | Retrospective cohort study | 56 (classic CAH), Prepubertal to adult | Whole body and LS DXA | Progressive decline in whole-body and LS BMD Z-scores from prepuberty to adulthood; greater decline in males | Puberty does not restore early skeletal deficits; sex-specific vulnerability |
Bone outcomes in children and adolescents with congenital adrenal hyperplasia due to 21OHD.
DXA, dual-energy x-ray absorptiometry; LS, lumbar spine; WB, whole body; FN, femoral neck; TH, total hip; DR, distal radius; GC, glucocorticoids; GnRHa, gonadotropin-releasing hormone analogs; CTX, C-terminal telopeptide; OC, osteocalcin; aBMDHAZ, height-adjusted areal bone mineral density Z-score.
Most paediatric and adolescent studies have relied on dual-energy x-ray absorptiometry (DXA) to evaluate BMD, with conflicting results largely attributable to methodological differences. A key issue is the frequent discrepancy between chronological age and advanced bone age in CAH. Garcia Alves Junior et al. reported that BMD Z-scores appear normal or even elevated when interpreted according to chronological age, but are significantly reduced when normalized for bone age, revealing a true impairment in bone accrual masked by accelerated skeletal maturation (). This finding pinpoints the importance of bone age-adjusted interpretation in adolescents with CAH. Cross-sectional studies including adolescents and Tanner-matched controls further support a site-specific skeletal vulnerability. A significantly reduced lumbar spine BMD in adolescents with CAH compared with controls was reported, whereas femoral BMD was less consistently affected. Importantly, daily GC dose showed a negative association with BMD, whilst higher androgen exposure correlated positively with bone parameters, suggesting partial anabolic compensation (). More recent papers including adolescents and young adults have largely found normal whole-body and lumbar spine BMD Z-scores. However, these findings should be interpreted cautiously, as they may reflect persistence of earlier skeletal deficits into young adulthood rather than optimal pubertal bone accrual. Notably, early growth velocity during infancy was identified as a positive determinant of later BMD, highlighting that skeletal trajectories in CAH may be programmed before puberty ().
Beyond GC dose and androgen exposure, body composition has emerged as an additional determinant of skeletal health in adolescents with CAH. Ryabets-Lienhard et al. reported an inverse association between lumbar spine height-adjusted BMD Z-scores and total, visceral and subcutaneous fat mass, irrespective of CG dose, suggesting that excess adiposity may exert a direct detrimental effect on bone accrual during puberty ().
Longitudinal data provide critical insight into dynamic skeletal changes during and after puberty. In a cohort followed from pubertal onset to adult height, the treatment with GnRHa did not adversely affect BMD outcomes. However, BMD Z-scores declined over time across multiple skeletal sites in both GnRHa-treated and untreated patients, indicating a progressive divergence from reference populations during late adolescence and early adulthood (). Similarly, a marked decline in BMD Z-scores from prepuberty to adulthood, particularly in males, was observed with whole-body and lumbar spine deficits becoming more evident after completion of puberty (35). Taken together, these studies suggest that puberty does not constitute a window for recovery of skeletal deficits in CAH; rather, sustained GC exposure and an altered sex steroid milieu may progressively limit the acquisition of peak bone mass.
Beyond static BMD measurements, recent studies have begun to evaluate bone dynamics during adolescence in CAH. Higher GC doses and the use of prednisolone were associated with reduced annual lumbar spine BMD accrual compared to hydrocortisone therapy. Importantly, bone turnover markers adjusted for bone age, particularly C-terminal telopeptide (CTX), independently predicted subsequent BMD accrual, suggesting a potential role for dynamic biomarkers in monitoring skeletal health during adolescence (36). Collectively, these findings support a dose- and compound-dependent detrimental effect of GC therapy on adolescent bone development, emphasizing the need to avoid supraphysiologic exposure during periods of rapid skeletal modeling.
Paediatric and adolescent studies consistently report positive associations between androgen levels and BMD, particularly at trabecular-rich sites (, ). However, chronic androgen excess also accelerates skeletal maturation and advances epiphyseal closure, potentially shortening the window for optimal pubertal bone development. Evidence from adult cohorts suggests that higher GC doses and greater androgen suppression during adolescence are associated with lower BMD later in life (, ), supporting the concept that hormonal balance during puberty has long-term effects on future skeletal health.
Direct data on bone microarchitecture and fracture risk in adolescents with CAH are currently lacking. Nevertheless, studies in adult CAH populations using advanced imaging techniques demonstrate cortical thinning and trabecular deterioration even in individuals with normal DXA-derived BMD (35). Epidemiological studies and registry-based cohorts further indicate an increased fracture prevalence, often manifesting in early adulthood (, ). These observations strongly suggest that qualitative skeletal deficits originate during childhood and adolescence, remaining subclinical until later life. The absence of fractures during adolescence should therefore not be interpreted as evidence of preserved bone strength.
6 Bone health in rare forms of congenital adrenal hyperplasia
Rare forms of CAH other than 21OHD are characterized by distinct hormonal profiles that significantly influence skeletal maturation and peak bone mass acquisition. However, compared with classical 21OHD, systematic data on BMD, bone microarchitecture, and fracture risk, especially during adolescence, remain very limited.
CYP11B1 deficiency (11β-OHD) is associated with cortisol deficiency, mineralocorticoid precursor excess with hypertension and marked hyperandrogenism (37). The skeletal phenotype reflects chronic androgen excess during childhood, with advanced bone age, accelerated growth, early or precocious puberty and premature epiphyseal closure (38–40). Evidence is largely based on auxological and radiological findings, while densitometric and microarchitectural data in adolescents are scarce (, 41).
In contrast, CYP17A1 deficiency (17OHD) is characterized by profound hypoandrogenism and hypoestrogenism, resulting in delayed bone age, absent pubertal growth spurt and delayed epiphyseal closure. The lack of sex steroids during puberty raises concerns about impaired peak bone mass acquisition (42, 43). Limited high-resolution imaging studies suggest reduced cortical and trabecular volumetric BMD, cortical thinning and increased porosity (44), but adolescent-specific longitudinal data and fracture risk assessments are lacking.
Other rare defects, including POR mutations (PORD), STAR deficiency (lipoid CAH) and HSD3B2 deficiency, combine variable degrees of cortisol and sex steroid deficiency, sometimes with congenital skeletal malformations (particularly in PORD) (45). Overall, evidence on skeletal health in these rare CAH subtypes is lacking and dedicated longitudinal studies during adolescence are needed to clarify their impact on peak bone mass and long-term fracture risk.
7 Practical implications for clinical management during pubertal transition
7.1 Tailoring glucocorticoid therapy
During adolescence, hydrocortisone is preferred for its shorter half-life and flexibility, allowing dose adjustments during growth and bone development (46). During puberty disease control can be challenging due to increased hydrocortisone clearance; therefore, careful monitoring and adjustment of GC therapy may be required to ensure adequate androgen suppression (47). Excess GC (>17 mg/m²/day) should be avoided as well, since it is inversely associated with final height and bone mass. Long-acting GC are less prescribed and generally reserved for post-growth phases due to higher skeletal risk (48).
Modified-release hydrocortisone offers more physiological 24-hour cortisol profiles providing enhanced suppression of the morning androgen surge and potentially reducing GC-related skeletal side effects; however, experience in adolescents remains limited (49, 50). In parallel, mineralocorticoid requirements evolve across development and should be reassessed during adolescence to avoid both over- and under-replacement (51). Overall, careful adjustment of both GC and mineralocorticoid therapy during puberty and adolescence is central to optimizing long-term outcomes in CAH (52, 53).
7.2 Monitoring bone health
Annual bone age assessment is essential to interpret BMD in adolescents with advanced skeletal maturation (54). DXA remains the primary tool, ideally interpreted with bone age and height-adjusted references. In high-risk cases, HR-pQCT may provide additional data on cortical and trabecular integrity, though mainly in research settings (35, 44). Fracture history, GC exposure and sex-specific vulnerability should guide monitoring. Males may be more prone to trabecular deficits, while females may benefit partially from androgen excess, although early epiphyseal closure and chronic GC limit gains (, ).
Lifestyle and nutritional factors are important modifiable determinants of bone health in adolescents with CAH. Adequate calcium intake is essential to support bone mineralization, particularly in the context of glucocorticoid-induced alterations in calcium balance. Vitamin D plays a central role in calcium absorption and skeletal homeostasis, and vitamin D insufficiency has been frequently reported in pediatric CAH populations, supporting the need for routine monitoring and supplementation when appropriate ().
Regular weight-bearing physical activity promotes bone formation and improves bone geometry, partially counteracting glucocorticoid-related skeletal effects. Conversely, sedentary behavior, increased adiposity and reduced lean mass may impair bone accrual, as suggested by the inverse relationship between fat mass and bone density observed in adolescents with CAH (). Additional lifestyle factors, including smoking and suboptimal dietary habits, may further compromise bone health. Overall, optimization of these modifiable factors represents a practical and effective strategy to support peak bone mass acquisition (55).
8 Transition from pediatric to adult care: implications for bone health
The transition from pediatric to adult care represents a critical phase for adolescents with CAH, coinciding with the final stages of peak bone mass acquisition. Discontinuity of care, reduced adherence to therapy, and differences in monitoring strategies may negatively affect hormonal control and skeletal outcomes in patients with rare endocrine diseases (56). This period is further complicated by the shift in treatment goals from growth optimization to long-term metabolic and reproductive health.
During transition, glucocorticoid regimens are often modified, sometimes introducing longer-acting compounds. While this may improve disease control, it can increase cumulative glucocorticoid exposure, potentially worsening bone health if not carefully titrated. At the same time, subtle skeletal deficits may remain under-recognized, as fracture risk is rarely apparent at this stage. Persistent hyperandrogenism or, conversely, excessive androgen suppression due to overtreatment may both impair bone accrual.
Structured transition programs involving coordinated pediatric and adult endocrine care, along with standardized assessment of bone density and pubertal status are therefore essential to preserve skeletal health and reduce long-term fracture risk (57).
9 Conclusions and future perspectives
Adolescents with CAH are at increased risk of impaired skeletal development due to chronic GC exposure, androgen excess and altered pubertal timing. Puberty alone does not fully restore skeletal deficits and cumulative hormonal exposures during growth influence peak bone mass. Major gaps remain, particularly the scarcity of longitudinal data into adulthood and limited assessment of bone quality beyond DXA, with sex-specific trajectories. Optimizing bone health requires individualized GC replacement, careful monitoring of growth and pubertal progression, and targeted use of advanced imaging in high-risk patients. Further multicenter longitudinal studies are needed to define long-term skeletal outcomes and guide evidence-based management.
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IT: Data curation, Investigation, Writing – original draft. FC: Supervision, Writing – review & editing. MB: Investigation, Methodology, Supervision, Writing – original draft.
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References
1.
AuerMKNordenströmALajicSReischN. Congenital adrenal hyperplasia. Lancet (London, England). (2023) 401(10372):227–44. 10.1016/S0140-6736(22)01330-7
2.
MallappaAMerkeDP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol. (2022) 18(6):337–52. 10.1038/s41574-022-00655-w
3.
SpeiserPWArltWAuchusRJBaskinLSConwayGSMerkeDPet al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society* clinical practice guideline. J Clin Endocrinol Metab. (2018) 103(11):4043–88. 10.1210/jc.2018-01865
4.
El-MaoucheDArltWMerkeDP. Congenital adrenal hyperplasia. Lancet. (2017) 390(10108):2194–210. 10.1016/S0140-6736(17)31431-9
5.
Claahsen-van der GrintenHLSpeiserPWAhmedSFArltWAuchusRJFalhammarHet al. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocr Rev. (2022) 43(1):91–159. 10.1210/endrev/bnab016
6.
SaggeseGBaroncelliGIBertelloniS. Puberty and bone development. Best Pract Res Clin Endocrinol Metab. (2002) 16(1):53–64. 10.1053/beem.2001.0180
7.
HerefordTKellishASamoraJBReid NicholsL. Understanding the importance of peak bone mass. J Pediatr Orthop Soc North Am. (2024) 7:100031. 10.1016/j.jposna.2024.100031
8.
WeaverCM. Adolescence the period of dramatic bone growth. Endocrine. (2002) 17(1):43–8. 10.1385/ENDO:17:1:43
9.
GiustinaAMazziottiGCanalisE. Growth hormone, insulin-like growth factors, and the Skeleton. Endocr Rev. (2008) 29(5):535–59. 10.1210/er.2007-0036
10.
BonjourJ-PChevalleyT. Pubertal timing, bone acquisition, and risk of fracture throughout life. Endocr Rev. (2014) 35(5):820–47. 10.1210/er.2014-1007
11.
Garcia Alves JuniorPASchueftanDLGde MendonçaLMCFariasMLFBeserraICR. Bone mineral density in children and adolescents with congenital adrenal hyperplasia. Int J Endocrinol. (2014) 2014:1–6. 10.1155/2014/806895
12.
NavardauskaiteRVanckavicieneAVerkauskieneR. Bone mineral density determinants in adolescents and young adults with congenital adrenal hyperplasia. Front Pediatr. (2024) 12:1456679. 10.3389/fped.2024.1456679
13.
DemirelFKaraÖTepeDEsenİ. Bone mineral density and vitamin D status in children and adolescents with congenital adrenal hyperplasia. Turkish J Med Sci. (2014) 44:109–14. 10.3906/sag-1301-114
14.
ChotiyarnwongPMcCloskeyEV. Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat Rev Endocrinol. (2020) 16(8):437–47. 10.1038/s41574-020-0341-0
15.
KasperkCHWakleyGKHierlTZieglerR. Gonadal and adrenal androgens are potent regulators of human bone cell metabolism in vitro. J Bone Miner Res. (1997) 12(3):464–71. 10.1359/jbmr.1997.12.3.464
16.
El-MaoucheDCollierSPrasadMReynoldsJCMerkeDP. Cortical bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol (Oxf). (2015) 82(3):330–7. 10.1111/cen.12507
17.
LeeDHKongSHJangHNAhnCHLimSGLeeYAet al. Association of androgen excess and bone mineral density in women with classical congenital adrenal hyperplasia with 21-hydroxylase deficiency. Arch Osteoporos. (2022) 17(1):45. 10.1007/s11657-022-01090-0
18.
HalperASanchezBHodgesJSKellyASDengelDNathanBMet al. Bone mineral density and body composition in children with congenital adrenal hyperplasia. Clin Endocrinol (Oxf). (2018) 88(6):813–9. 10.1111/cen.13580
19.
SellersEPMacgillivrayMH. Blunted adrenarche in patients with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Res. (1995) 21(3):537–44. 10.1080/07435809509030471
20.
FalhammarHFilipssonHHolmdahlGJansonP-ONordenskjöldAHagenfeldtKet al. Fractures and bone mineral density in adult women with 21-hydroxylase deficiency. J Clin Endocrinol Metab. (2007) 92(12):4643–9. 10.1210/jc.2007-0744
21.
FalhammarHFilipsson NyströmHWedellABrismarKThorénM. Bone mineral density, bone markers, and fractures in adult males with congenital adrenal hyperplasia. Eur J Endocrinol. (2013) 168(3):331–41. 10.1530/EJE-12-0865
22.
CeccatoFBarbotMAlbigerNZilioMDe ToniPLuisettoGet al. Long-term glucocorticoid effect on bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol. (2016) 175(2):101–6. 10.1530/EJE-16-0104
23.
RiehlGReischNRoehleRvan der GrintenHCFalhammarHQuinklerM. Bone mineral density and fractures in congenital adrenal hyperplasia: findings from the dsd-LIFE study. Clin Endocrinol (Oxf). (2020) 92(4):284–94. 10.1111/cen.14149
24.
CharmandariEBrookCHindmarshP. Classic congenital adrenal hyperplasia and puberty. Eur J Endocrinol. (2004) 151:U77–82. 10.1530/eje.0.151u077
25.
TrogerTSommerGLang-MuritanoMKonradDKuhlmannBZumstegUet al. Characteristics of growth in children with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency during adrenarche and beyond. J Clin Endocrinol Metab. (2022) 107(2):e487–99. 10.1210/clinem/dgab701
26.
CipollaCSoderoGCammisaITurriziani ColonnaAGiulianoSAmarIDet al. AI. The impact of glucocorticoids on bone health and growth: endocrine and non-endocrine effects in children and young patients. Minerva Pediatr. (2023) 75(6):896–904. 10.23736/S2724-5276.22.07074-4
27.
FlokasMEWakimPKollenderSSinaiiNMerkeDP. Gonadotropin-Releasing hormone agonist therapy and longitudinal bone mineral density in congenital adrenal hyperplasia. J Clin Endocrinol Metab. (2024) 109(2):498–504. 10.1210/clinem/dgad514
28.
VanderschuerenDVandenputLBoonenSLindbergMKBouillonROhlssonC. Androgens and bone. Endocr Rev. (2004) 25(3):389–425. 10.1210/er.2003-0003
29.
LoliPMenottiSdi FilippoLGiustinaA. Non-classical congenital adrenal hyperplasia: current insights into clinical implications, diagnosis and treatment. Endocrine. (2025) 90(1):1–16. 10.1007/s12020-025-04341-5
30.
KimJHChoiSLeeYALeeJKimSG. Epidemiology and long-term adverse outcomes in Korean patients with congenital adrenal hyperplasia: a nationwide study. Endocrinol Metab. (2022) 37(1):138–47. 10.3803/EnM.2021.1328
31.
FinkielstainGPKimMSSinaiiNNishitaniMVan RyzinCHillSCet al. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. (2012) 97(12):4429–38. 10.1210/jc.2012-2102
32.
MnifMFKamounMMnifFCharfiNKallelNBen NaceurBet al. Long-Term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Am J Med Sci. (2012) 344(5):363–73. 10.1097/MAJ.0b013e31824369e4
33.
Espinosa ReyesTMLeyva GonzálezGDomÃnguez AlonsoEFalhammarH. Bone mass in young patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res Paediatr. (2021) 94(1–2):1–8. 10.1159/000515833
34.
Ryabets-LienhardANguyenJNPickeringTAFragaNRDerasEAGeffnerMEet al. Bone health in youth with congenital adrenal hyperplasia: abdominal and total adiposity is associated with bone mineral density. Horm Res Paediatr. (2025) 30:1–12. 10.1159/000548651
35.
StancampianoMRPiteaMMarucaKMeroniSLCBucoloCRussoGet al. Bone mineral density in patients with congenital adrenal hyperplasia from prepubertal to adult age. J Clin Endocrinol Metab. (2025) 110(11):e3850–6. 10.1210/clinem/dgaf123
36.
WiromratPNamphaisanPWongsurawatNPanamontaONasomyontN. Elevated bone turnover markers predict bone mineral density accrual in adolescents with 21-hydroxylase deficiency. Clin Endocrinol (Oxf). (2023) 99(5):462–9. 10.1111/cen.14809
37.
CeccatoFManteroF. Monogenic forms of hypertension. Endocrinol Metab Clin North Am. (2019) 48(4):795–810.
38.
AuchusRJ. The classic and nonclassic concenital adrenal hyperplasias. Endocr Pract. (2015) 21(4):383–9. 10.4158/EP14474.RA
39.
NourMAPacaudD. Height augmentation in 11β-hydroxylase deficiency congenital adrenal hyperplasia. Int J Pediatr Endocrinol. (2015) 2015(1):12. 10.1186/s13633-015-0008-0
40.
KhattabAHaiderSKumarADhawanSAlamDRomeroRet al. Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Proc Natl Acad Sci U S A. (2017) 114(10):E1933–40. 10.1073/pnas.1621082114
41.
BreilTYakovenkoVIntaIChoukairDKloseDMittnachtJet al. Typical characteristics of children with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: a single-centre experience and review of the literature. J Pediatr Endocrinol Metab. (2019) 32(3):259–67. 10.1515/jpem-2018-0298
42.
SiklarZCamtosunEBoluSYildizMAkinciABasFet al. 17α Hydroxylase/17,20 lyase deficiency: clinical features and genetic insights from a large Turkey cohort. Endocrine. (2024) 85(3):1407–16. 10.1007/s12020-024-03962-6
43.
WillemsenALTorpyDJDe SousaSMCFalhammarHRushworthRL. 17α-Hydroxylase/17,20-lyase Deficiency (17-OHD): a meta-analysis of reported cases. J Clin Endocrinol Metab. (2025) 110(4):e1261–71. 10.1210/clinem/dgae773
44.
SunXWuYLuLXiaWZhangLChenSet al. Bone microarchitecture and volumetric mineral density assessed by HR-pQCT in patients with 21- and 17α-hydroxylase deficiency. Calcif Tissue Int. (2023) 113(5):515–25. 10.1007/s00223-023-01132-w
45.
AuchusRJ. The uncommon forms of congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. (2022) 29(3):263–70. 10.1097/MED.0000000000000727
46.
SchulzJFreyKRCooperMSZopfKVentzMDiederichSet al. Reduction in daily hydrocortisone dose improves bone health in primary adrenal insufficiency. Eur J Endocrinol. (2016) 174(4):531–8. 10.1530/EJE-15-1096
47.
CharmandariEHindmarshPCJohnstonABrookCGD. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: alterations in cortisol pharmacokinetics at puberty. J Clin Endocrinol Metab. (2001) 86(6):2701–8. 10.1210/jcem.86.6.7522
48.
BonfigWBechtoldSSchmidtHKnorrDSchwarzHP. Reduced final height outcome in congenital adrenal hyperplasia under prednisone treatment: deceleration of growth velocity during puberty. J Clin Endocrinol Metab. (2007) 92(5):1635–9. 10.1210/jc.2006-2109
49.
LawrenceNRDawsonJLangZ-QPreteABaranowskiESSchifferLet al. Modelling adrenal steroid profiles to inform monitoring guidance in congenital adrenal hyperplasia. eBioMedicine. (2025) 116:105749. 10.1016/j.ebiom.2025.105749
50.
NeumannUBlankensteinOClaahsen-van der GrintenHL. PERSPECTIVE: treatment with hydrocortisone modified-release capsules in children and adolescents with congenital adrenal hyperplasia: an expert opinion. Endocr Connect. (2025) 14(5):e240619. 10.1530/EC-24-0619
51.
CeccatoFTorchioMTizianelIPeleg FalbMBarbotMSabbadinCet al. Renin and electrolytes indicate the mineralocorticoid activity of fludrocortisone: a 6 year study in primary adrenal insufficiency. J Endocrinol Invest. (2023) 46(1):111–22. 10.1007/s40618-022-01889-1
52.
ArltWWillisDSWildSHKroneNDohertyEJHahnerSet al. Health Status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. (2010) 95(11):5110–21. 10.1210/jc.2010-0917
53.
IervolinoLLFerraz-de-SouzaBMartinRMCostaFCMirandaMCMendonçaBBet al. Real-world impact of glucocorticoid replacement therapy on bone mineral density: retrospective experience of a large single-center CAH cohort spanning 24 years. Osteoporos Int. (2020) 31(5):905–12. 10.1007/s00198-019-05268-0
54.
SchaefferTLTryggestadJBMallappaAHannaAEKrishnanSChernausekSDet al. An evidence-based model of multidisciplinary care for patients and families affected by classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Int J Pediatr Endocrinol. (2010) 2010:1–13. 10.1155/2010/692439
55.
ZhangWWangXLiuYHeQDingQMeiJet al. Effects of exercise on bone mass and bone metabolism in adolescents: a systematic review and meta-analysis. Front Physiol. (2024) 15:1512822. 10.3389/fphys.2024.1512822
56.
SabbadinCMarinLMansoJMozzatoCCamozziVAndrisaniAet al. Transition from pediatrics to adult health care in girls with turner syndrome. Expert Rev Endocrinol Metab. (2024) 19(3):229–40. 10.1080/17446651.2024.2347265
57.
BalagamageCArshadAElhassanYSBen SaidWKroneREGleesonHet al. Management aspects of congenital adrenal hyperplasia during adolescence and transition to adult care. Clin Endocrinol (Oxf. (2024) 101(4):332–45. 10.1111/cen.14992
Summary
Keywords
androgens, bone, congenital adrenal hyperplasia, glucocorticoid therapy, puberty, transition
Citation
Tizianel I, Ceccato F and Barbot M (2026) Bone health in adolescents with congenital adrenal hyperplasia: exploring the interplay between glucocorticoid therapy, hormonal imbalance and puberty. Front. Adolesc. Med. 4:1827315. doi: 10.3389/fradm.2026.1827315
Received
10 March 2026
Revised
01 May 2026
Accepted
04 June 2026
Published
18 June 2026
Volume
4 - 2026
Edited by
Silvano Bertelloni, University of Pisa, Italy
Reviewed by
Gabriela Paula Finkielstain, QED Therapeutics Inc, United States
Updates
Copyright
© 2026 Tizianel, Ceccato and Barbot.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Filippo Ceccato filippo.ceccato@unipd.it
Disclaimer
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