Bisphosphonate therapy in osteogenesis imperfecta: why does it cause no osteonecrosis of the jaws in children?
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1
Second University of Naples, Multidisciplinary Department of Medical-Surgical and Odontostomatological Specialties, Italy
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2
Sapienza University of Rome, Department of Oral and Maxillo-facial Sciences, Italy
Aim: Bisphosphonates (BPs) are a group of molecules able to inhibit bone-resorbing osteoclasts and to decrease osteoblast and osteocyte apoptosis, thereby improving bone density and contrasting the bone fragility, useful in bone diseases, severe osteoporosis and some cancers.
Based on the modes of action and their molecular structure, BPs are categorized into two major groups. The nitrogenous-BPs (including pamidronate) and the no-nitrogenous-BPs. All BPs are structural analogues of pyrophosphates and, when administered either orally or intravenously (IV), they are adsorbed onto bone surfaces being slowly released into the bone matrix: here they bind to hydroxyapatite and inhibit osteoclastic activity. Thus the action of BPs may last many years, even after stopping the drug.
Scientific literature reports the evidence that the prolonged BPs use is associated with osteonecrosis of the jaws (BRONJs) in adults needing for tooth extraction or other invasive dental procedures, due to inhibition of osteoclast resorption and their anti-angiogenic properties in presence of initiating factors such as older age, local inflammation, periodontal disease, glucocorticoid treatment for chronic conditions and oestrogen treatments.
Since the ‘90s, BPs therapy has been used for the symptomatic control of mild-to-severe types of Osteogenesis imperfecta (OI), in children and adolescents, to increase the bone density and reduce the incidence of bone fractures.
OI syndromes (also known as “brittle bone diseases”) are a group of genetically heterogeneous disorders of connective tissue, based on quantitative and qualitative abnormalities of Type I collagen, with an estimated incidence of 1 per 20,000 live births. Type I collagen is the main protein in bone, and its qualitative and/or quantitative abnormalities in OI are responsible for the tendency of bones to deform and fracture. In addiction, OI may be also associated to extraskeletal manifestations, such as cardiovascular and neurological affections, hearing loss, blue sclerae and, with regard to the oro-facial region, triangularly shaped face, prominent frontal bossing, severe skeletal Class III malocclusions, drastic open bites, impacted molars and dentinogenesis imperfecta (DI), characterized by opalescent brittle teeth, often misshapen and, hence, needing special care.
To date, several types of OI have been identified and grouped, basing on their inheritance, phenotype and gravity.
BPs therapy in OI is palliative and aims to prevent or reduce bone pain, bone fragility and deformity and the fracture incidence, with a good impact on the quality of life of the patients. In this disease, IV pamidronate is the most commonly used BP; but, recently, zolendronate has been proposed and applied, due to the fastest IV infusion and superior potency.
The present work aims to review the literature to establish BRONJ occurrence in children affected by OI undergoing BPs therapy, and to understand the reasons of a possible different behaviour.
Materials and Methods: For the purpose, Pubmed was used to search, on August, 2018, the terms “bisphosphonate, osteogenesis imperfecta, osteonecrosis of the jaws” and their acronyms. Inclusion criteria were English-language papers, studies of children and young adults (until 24 years old) including dental examinations and/or dental extractions. After an exclusion based on title/abstract, the remaining articles have been considered for full-text examination.
Results: After excluding 5/20 articles by title/abstract, the remaining 15 were considered for full-text evaluation. Among them, 9 were original researches (4 case series/report and 5 retrospective studies), while, the remaining 6 were reviews dealing with BPs in childhood, dental effects and similar.
For establishing BRONJ occurrence in OI children, the 9 original researches were considered. Among the original papers, IV pamidronate was the largest BP used, followed by the use of IV zolendronate or IV noredronate. In some cases, the dental procedures were performed during the BPs therapy, while in other cases after stopping it, but extremely variable durations, dosage and cumulative BPs doses were found among them. Each of the three case reports were related to the study of one patient; the case series described 15 cases; the five retrospective studies involved 37, 64, 221, 102 and 26 subjects respectively. In 7 of the original papers, dental interventions were performed, such as dental extractions of deciduous and/or permanent teeth for dental infections or to guide further dental eruptions; in the remaining 2 papers considered, no dental procedures were performed due to the observational and not-interventive nature of the works. The antibiotic prophylaxis was not always performed, and the follow-up largely varied and was not always specified. Despite the heterogeneity of the protocols among the papers, all works unanimously reported no signs of BRONJ, and some of them also considered the healing times (always reported as “normal” or “not delayed”) and the absence of complications.
Once reported the absence of BRONJ in children affected by OI undergoing BPs therapy, we reconsidered the original papers and evaluated the 6 reviews to understand the reasons of such different BPs behaviour in children.
Based on the conclusions of the 9 original works and on what reported in the 6 reviews, the main and more frequent hypothesis was related to the BPs dosages in OI diseases, which are mainly smaller and administered in a shorter time than in other adult pathologies (cancer metastases, osteoporosis, and other bone diseases). Other authors suggest the decreased bone turnover in adult as the main difference. Many others refer to comorbidities in adults as factors precipitating BRONJ.
Discussion: To date, scientific literature unanimously agrees on the absence of BRONJ occurrence in paediatric population affected by OI and treated with IV BPs, but why it does not happen is still unclear. Heterogeneity in BPs therapies and in pre-surgical strategies did not allow understanding the real factors responsible for this different behaviour. Once these factors will be clearly identified, we could hypothesize to approach adults in BPs therapy with the aim to reduce their risk of BRONJ occurrence.
References
1. Ascani G, Campisi G, Junquera Gutierrez LM. Current controversies in classification, management, and prevention of bisphosphonate-related osteonecrosis of the jaw. Int J Dent. 2014;2014:565743. doi: 10.1155/2014/565743.
2. Astrom E, Soderhall S. Beneficial effect of bisphosphonate during five years of treatment of severe osteogenesis imperfecta. Acta Paediatr 1998; 87: 64−68.
3. Barros ER, Saraiva GL, de Oliveira TP, Lazaretti-Castro M. Safety and efficacy of a 1-year treatment with zoledronic acid compared with pamidronate in children with osteogenesis imperfecta. J Pediatr Endocrinol Metab. 2012; 25:485-491.
Keywords:
Bisphosphonate (BP),
Osteogenesis Imperfecta,
Osteonecrosis of the jaws (ONJ),
BRONJ (bisphosphonate-related osteonecrosis of the jaw),
Children
Conference:
5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine., Ancona, Italy, 19 Oct - 20 Oct, 2018.
Presentation Type:
Poster Presentation
Topic:
Medications-related osteonecrosis of the Jaws
Citation:
Contaldo
M,
Santoro
R,
Luzzi
V,
Gaetano
I,
Serpico
R and
Polimeni
A
(2019). Bisphosphonate therapy in osteogenesis imperfecta: why does it cause no osteonecrosis of the jaws in children?.
Front. Physiol.
Conference Abstract:
5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine..
doi: 10.3389/conf.fphys.2019.27.00047
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Received:
01 Nov 2018;
Published Online:
09 Dec 2019.
*
Correspondence:
Dr. Maria Contaldo, Second University of Naples, Multidisciplinary Department of Medical-Surgical and Odontostomatological Specialties, Naples, Campania, 80138, Italy, maria.contaldo@gmail.com