What is the effect of anti-resorptive drugs (ARDs) on the development of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients: A systematic review
Introduction
Osteoporosis is a major public health concern with over 200 million people suffering from this disease around the globe (Cooper et al., 1992). In Germany alone 6.3 million persons have osteoporosis with more patients are expected to develop osteoporosis each year (Hadji et al., 2013). More than 75 million people in Europe, Japan and the USA have osteoporosis and more than 2.3 million fractures occur as a result of osteoporosis each year in Europe and the USA alone (WHO, 2003). These fractures affect significantly patients' quality of life and cause an enormous economic and social burden in addition to increasing the morbidity and mortality rates. The disease is expected to be more prevalent due to the ageing of the whole population (Lane, 2006, Hadji et al., 2013).
Osteoporosis is defined as a skeletal disorder characterized by low bone density and micro-architectural deterioration of bone tissue predisposing it to an increased risk of fracture (Klibanski et al., 2001). WHO diagnostic criterion for osteoporosis depends on bone mineral density (BMD) (Cooper et al., 1992, Cosman et al., 2014). BMD correlates with fracture rates, so as it increases the fracture risk decreases. Therefore, the treatment or prevention of osteoporosis aims to improve BMD and to increase bone density and strength. FDA-approved medications for the management of osteoporosis are, bisphosphonates (BPs) (alendronate, alendronate plus D, ibandronate, risedronate and zoledronate), estrogens, estrogen agonist/antagonist (raloxifene), tissue-selective estrogen complex (conjugated estrogens/bazedoxifene), parathyroid hormone (teriparatide), and the receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (denosumab) (Cosman et al., 2014).
Bisphosphonates (BPs) are one of the most prescribed medications worldwide (Paiva-Fonseca et al., 2014). They are also indicated in a variety of less common diseases such as Paget's disease of the bone, osteogenesis imperfecta and cancer (Ruggiero et al., 2014). More than 190 million prescriptions of BPs are written per year (Ruggiero et al., 2014). Oral BPs (alendronate, risedronate and ibandronate) are the most commonly used BPs for osteoporosis. However, an intravenous single yearly dose of zoledronate (Reclast®) and three-monthly intravenous injections of ibandronate (Boniva®) are approved for the prevention and treatment of osteoporosis as a more convenient and less compliance-demanding alternative therapy to oral BPs. In addition, denosumab (Prolia®) as twice-yearly subcutaneous injections is approved for management of osteoporosis and has been shown to be an effective treatment (Bone et al., 2013, Papapoulos et al., 2015).
BPs are generally well tolerated, however, some related side effects such as esophagitis, musculoskeletal pain, hypocalcemia, ocular inflammation, and osteonecrosis of the jaws can occur (Kennel and Drake, 2009). Since the first report of BP-related osteonecrosis of the jaw (BRONJ) in 2003, many similar cases have been reported. Intravenous BPs, which are used mostly for oncological indications, have been linked to jaw osteonecrosis in an incidence of 3–18% (Bamias et al., 2005, Walter et al., 2008). On the other hand, oral BPs have been estimated to cause jaw osteonecrosis at a significantly lower rate, 1.04 to 69 patients in 100,000 patients (Khan et al., 2015). In contrast, the Kaiser Permanente PROBE study reported a higher prevalence in 8572 patients who had received chronic oral BP therapy of 0.10% and 0.21% in those with more than four years of BPs use (Lo et al., 2010). More recently, osteonecrosis of the jaw has been observed in association with other medications such as denosumab and antiangiogenic drugs (Otto et al., 2013a, Papapoulos et al., 2015, Bagan et al., 2016). Therefore, the American Association of Oral and Maxillofacial Surgeons (AAOMS) has suggested a new nomenclature of BPs-related osteonecrosis of the jaws (BRONJ) to be medication-related osteonecrosis of the jaw (MRONJ) in order to include all the medications which have been implicated in the development of osteonecrosis of the jaw (Ruggiero et al., 2014).
Several risk factors appear to be associated with the development of MRONJ. The duration of BPs has been identified as a potential risk factor, which makes BPs long-term use in osteoporosis patients an important issue (Ruggiero et al., 2009). Recognizing other risk factors and comorbidities may also help to minimize the risk and severity of the disease. The increase in MRONJ reported cases had raised the public awareness of the use of ARDs worldwide in osteoporotic patients to help to improve the knowledge about MRONJ in this large group of patients.
Thus, the primary goal of this study is to conduct a systematic review of the literature to elucidate the effect of ARDs (type, duration and route of administration) on MRONJ development in osteoporosis patients. In addition, a secondary goal is to identify the associated risk factors, demographic and clinical characteristics.
Section snippets
Materials and methods
This search was registered at PROSPERO International Prospective Register of Systematic Reviews (registration number: CRD42016052011) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher et al., 2009) to answer the following question: “what is the effect of ARDs on MRONJ development in osteoporosis patients?”. Another question to be answered is “what are the risk factors, demographical and clinical characteristics associated
Results
The results of the literature search are presented in the flow chart, showing study selection in accordance with PRISMA statement (Fig. 1). The initial search strategy resulted in 2044 articles from electronic search: 774 results from keywords search in PubMed, 123 publications from the MeSH search in PubMed, 61 publications from Cochrane library and 1086 publications from Web of Sciences. Nine publications were identified using hand search of the relevant reference lists. The total number of
Discussion
The main objective of our systematic review is to detect the effect of ARDs and their administration characteristics in the development of MRONJ in osteoporosis patients. The related demographic and clinical characteristics and the potential local and systemic risk factors were thoroughly investigated. Osteonecrosis of the jaw has been reported in osteoporosis patients treated by ARDs, as a rare but potentially serious side effect of these medications (Farrugia et al., 2006, Diniz-Freitas
Conclusion
In conclusion, many potential risk factors can play a role in MRONJ development in osteoporosis patients. It is crucial to recognize these factors, to identify the preventable and the unpreventable ones, and to plan strategies to minimize the risk of MRONJ. The duration of BPs intake and local infection seem to be the main risk factors. Patients who are under treatment with corticosteroids and/or immunosuppressants may have a higher risk to develop MRONJ even if the BPs duration is less than 4
Conflicts of interest
Suad Aljohani, Riham Fliefel, Jacob Ihbe, Jan Kühnisch, Michael Ehrenfeld and Sven Otto declare that they have no conflict of interest.
Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgments
SO and RF acknowledge the financial support of AO foundation (AOCMF 14-070) on medication related osteonecrosis of the jaw (MRONJ) research over the years. SO acknowledges the financial support of Friedrich-Bauer and Curt-Bohnewand foundations. SO has received honoraria for scientific talks from Nobel Biocare, CAMLOG and AMGEN.
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