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The Safety of Bisphosphonates for Primary Osteoporosis: An Overview of Systematic Reviews and Meta-analysis

Liqing Lu, Yongchang Chen, Jian Li, Jianping Zhang


Introduction Bisphosphonates (BPs) are the first-line therapy for osteoporosis, especially primary osteoporosis, but many systematic reviews exist with conflicting conclusions about the safety of BPs. We performed an overview of systematic reviews to evaluate the risk of adverse events of BPs used in primary osteoporosis.

Methods We identified systematic reviews with meta-analyses of RCTs published in English that evaluated the safety of BPs.Data sources used include the Cochrane library, PubMed, the Web of Science and hand-searching of reference lists. A standardized form was used for data extraction. The methodological quality of each systematic review was assessed by two reviewers using the AMSTAR tool, and the quality of evidence for adverse events was assessed using the GRADE approach. We made a new meta-analysis for the primary outcomes as the conflicting results of the original systematic reviews.

Results 1362 potentially relevant citations were identified, of which only 15 systematic reviews with meta-analyses met the eligibility criteria. All included reviews were published between 2009 and 2016, and documented the pooled estimates of RR or OR and their 95% CI for the incidence of adverse events. The median AMSTAR score was 9. The majority of the quality of evidence for safety outcomes in the findings judged as low even very low quality, but in our new meta-analysis judged as moderate or high quality.

Conclusions This overview provides a comprehensive assessment on the safety of BPs. In our meta-analysis, BPs significantly increased the risk of atrial fibrillation and serious atrial fibrillation when compared with placebo or other anti-osteoporosis drug, but did not significantly increase the risk of gastrointestinal events, stroke, cardiovascular death, atypical fracture or fracture union. The risk of atypical fracture and fracture union of BPs used needs further research.


bisphosphonates, primary osteoporosis, safety, overviews of systematic reviews, meta-analysis

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