Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis

Abstract

Bisphosphonates are the leading drugs for the treatment of osteoporosis. In randomized controlled trials (RCTs), alendronate, risedronate, and zoledronate have shown to reduce the risk of vertebral, nonvertebral, and hip fractures, whereas RCTs with ibandronate show antifracture efficacy at vertebral sites. Bisphosphonates are generally well tolerated and safe. Nevertheless, adverse events have been noted, and it is important to consider the strength of the evidence for causal relationships. Effects on the gastrointestinal tract and kidney function are well recognized, as are transient acute-phase reactions. Atrial fibrillation was first identified as a potential adverse event in a zoledronate trial, but subsequent trials and analyses failed to substantiate an association with bisphosphonates. Case reports have suggested a relationship between oral bisphosphonates and esophageal cancer, but this has not been demonstrated in epidemiologic studies. A possible association between bisphosphonate use and osteonecrosis of the jaw (ONJ) has also been suggested. However, the risk of ONJ in patients with osteoporosis appears to be very low, with no evidence from prospective RCTs of a causal association. There are reports of occasional occurrence of subtrochanteric or diaphyseal fractures in osteoporotic patients, but an association with bisphosphonate therapy is not substantiated by epidemiologic studies or prospective RCTs.

Keywords:

• bisphosphonates
• osteoporosis
• safety

Disclosure

In the early stages of preparation of this manuscript the authors received editorial/writing support funded by The Alliance for Better Bone Health (Procter & Gamble Pharmaceuticals and sanofi-aventis U.S., Inc). However, the authors are fully responsible for all content and editorial decisions.

M Pazianas has received grant/research support from the Alliance for Better Bone Health. C Cooper has received honoraria and/or consulting fees from the Alliance for Better Bone Health, MSD, Eli Lilly, Novartis, GSK, Roche, Shire, Medtronic, and Amgen. F H Ebetino is an employee of Warner Chilcott Pharmaceuticals. R G G Russell has had consultant/advisory activities with Amgen, Glaxo-Smith-Kline, Eli Lilly, Novartis, Roche, Procter & Gamble, Sanofi-Aventis, and Warner Chilcott Pharmaceuticals.

Notes

a All bisphosphonates exist as salts rather than acids at physiological pH, so it is not technically accurate for zoledronate to be called zoledronic acid. To be consistent with the nomenclature for other bisphosphonates, we have used the term zoledronate throughout this text.