Safety Issues With Bisphosphonate Therapy for Osteoporosis

Ernest Suresh; Michael Pazianas; Bo Abrahamsen


Rheumatology. 2014;53(1):19-31. 

In This Article

Abstract and Introduction


Randomized controlled trials have demonstrated the efficacy of bisphosphonates (BP) in improving BMD and reducing fracture risk. Various safety issues that were not noted in clinical trials have, however, now emerged with post-marketing surveillance and increasing clinical experience. The risk of atypical femoral fracture could increase with long-term use of BP, although absolute risk is very small, particularly when balanced against benefits. A drug holiday should be considered after 5 years of treatment for patients at low risk of fracture, although there is no official recommendation regarding this to guide clinicians. Osteonecrosis of the jaw from low-dose BP used for osteoporosis is very rare, and mainly a complication with high-dose i.v. BP used in oncology. The risk of atrial fibrillation too is negligible, and a definite link cannot be established between BP and oesophageal cancer. BP should be avoided in patients with severe renal impairment and during pregnancy and lactation because of limited safety data. Further epidemiological and clinical data are required to establish safety of BP in long-term users (>5 years) and provide evidence-based management.


Bisphosphonates (BP) are potent inhibitors of osteoclast-mediated bone resorption. Several large, randomized controlled trials among post-menopausal women have demonstrated their efficacy in improving BMD and reducing risk of osteoporotic vertebral, non-vertebral and hip fractures.[1–8] Additionally, alendronate and risedronate have been shown to reduce vertebral fractures in patients with glucocorticoid-induced osteoporosis (although not in primary analysis of study data),[9,10] and alendronate and zolendronate to reduce vertebral fractures in men.[11,12] There is also evidence for improvement in morbidity and mortality and reduced overall health care costs with BP therapy.[13–16] It is therefore not surprising that BP are the most commonly prescribed drugs for patients at risk of fragility fractures, with several millions of prescriptions written every year.

At the time when the first BP, alendronate, was approved in 1995, the only notable adverse effect mentioned in the product monograph was upper gastrointestinal intolerance. Recently, however, various other safety issues have triggered widespread debate and received extensive media coverage. Pathologies such as osteonecrosis of the jaw (ONJ), atrial fibrillation, oesophageal cancer and atypical femoral fracture (AFF) have been associated with BP exposure.

This review aims to provide an evidence-based update on these safety issues and discuss current thinking on long-term use of BP and need for drug holidays. Safety issues that are relevant to specific groups of patients such as women of childbearing age and those with age-related decline in renal function are also discussed.