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

Highlights

• Osteonecrosis of the jaw has been reported in osteoporosis patients.

• Although medication-related osteonecrosis of the jaw (MRONJ) prevalence in osteoporosis patients is very low, it increases significantly with long-term anti-resorptive drugs (ARDs) administration.

• Comorbidities and triggering factors play role in MRONJ.

Abstract

Purpose

To conduct a systematic review of the literature to detect the effect of anti-resorptive drugs (ARDs) and their administration characteristics in the development of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients.

Methods

Systematic search in PubMed, Web of Sciences and Cochrane Library was performed for relevant studies to July 2016. Population variables (age, gender, comorbidities, medications, preceding events, number of patients with MRONJ), ARDs and clinical variables were abstracted independently from these articles.

Results

The 44 eligible studies described 680 MRONJ cases in osteoporotic patients. The mean age of MRONJ patients was 69.7 ± 5.2 years. It was more common in females. Mandible was the most common site. Alendronate was the most frequently administered ARD. Oral route of administration was noted in 86.7% of the patients. The mean duration of BPs intake was 50.4 ± 19 months. Extraction was the most frequently preceding event followed by dentoalveolar surgery. Corticosteroids or immunosuppressants were the most common concomitant medications in MRONJ.

Conclusion

A long duration of ARDs administration seems to be an important risk factor in MRONJ development. Patients under treatment with corticosteroids or immunosuppressants might be at a higher risk even if the BPs duration is less than 4 years.

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.