Potential risks of rare serious adverse effects related to long‐term use of bisphosphonates: An overview of systematic reviews

WHAT IS KNOWN AND OBJECTIVE: There have been concerns about a potential link between long-term use of bisphosphonates (BPs) for the treatment of osteoporosis and rare serious adverse effects, such as atypical femoral fractures. However, many reviews exist with conflicting conclusions about this issue. The aim of this overview of reviews was to systematically evaluate the risk of rare serious adverse effects of long-term use of BPs for the treatment of osteoporosis. METHODS: We identified systematic reviews with meta-analyses of randomized controlled trials (RCTs) and (or) observational studies published in English or Chinese that evaluated the safety of BPs through to December 2018. The Cochrane library, PubMed, Web of Science and hand-searching of reference lists and clinical practice guidelines were electronically searched for data sources. Carcinogenicity, atypical fracture, osteonecrosis of jaw (ONJ) and fracture union time were specified as the primary outcomes. The methodological quality of each systematic review was assessed by two reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR) tool, and the quality of evidence for key outcomes was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS AND DISCUSSION: In total, 1376 potentially relevant citations were identified, of which only 8 systematic reviews with meta-analyses met the eligibility criteria. All the included reviews were published between 2012 and 2015 and documented the pooled estimates of effect size (relative risk [RR], odds ratio [OR] or hazard ratio [HR] and their 95% confidence intervals [95% CI]) for the incidence of adverse events. All included systematic reviews were of moderate or high quality. The median AMSTAR score was 7.5 (interquartile range, 5-10). However, evidence of the key outcomes was mainly of very low or moderate quality. BP treatment only increased the risk of atypical fracture and ONJ, and prolonged union time compared with placebo or other anti-osteoporosis drugs (P .05). WHAT IS NEW AND CONCLUSION: This study indicated that long-term use of BPs could increase the risk of rare serious adverse effects, but the relationship between long-term use of BPs and carcinogenicity was often uncertain. Therefore, high-quality research and more complete inclusion criteria are needed.