Long-Term Tolerability of the Bisphosphonates in Postmenopausal Osteoporosis

Abstract

Osteoporosis in postmenopausal women is a growing health concern for society. Bisphosphonates have become the mainstay of prevention and treatment with the mounting evidence of their efficacy over the past two decades. This review article examines the use of the etidronate, alendronate and risedronate. The pivotal trials are reviewed for long-term tolerability, evidence regarding histological safety and gastrointestinal tolerance. Etidronate, alendronate and risedronate have also been examined in meta-analyses, which reviewed methodologically sound trials. Length of treatment, adverse events and medication discontinuation and patients lost to follow-up were evaluated. Etidronate trials and the recent meta-analysis support the safe clinical use of cyclical etidronate with no signs of osteomalacia or other skeletal pathology over 2 to 3 years. In addition to increased bone mineral density (BMD) and vertebral fracture risk reduction, patients tolerated cyclical etidronate well up to 4 years in randomised studies. Non-randomised data has shown safety up to 7 years with clinical and bone biopsy data. Alendronate studies demonstrated similar overall adverse event rates, study discontinuation rates and loss to follow-up rates between placebo and treatment arms, in addition to consistent improvements in BMD, vertebral and non-vertebral fracture risk reductions over 3 to 4 years. Histological safety has been demonstrated up to 3 years. Longer-term therapy in non-randomised trials up to 7 years showed similar clinical safety between alendronate and placebo. Risedronate trials and the meta-analysis also showed similar adverse event profiles between placebo and treatment arms, as well as improvements in BMD, vertebral and non-vertebral fracture risk reductions up to 3 years. Rates of discontinuation due to gastrointestinal events were similar between groups. Histological safety has also been demonstrated for risedronate up to 3 years. Each of these bisphosphonates have been shown to have comparable safety with placebo up to 3 to 4 years, with the most rigourous trials carried out for alendronate and risedronate. Long-term comparative studies are awaited.

Bisphosphonate use and subsequent prescription of acid suppressants

“…The results raise interesting questions regarding management of potential gastrointestinal events associated with bisphosphonate use and the implications for healthcare costs. While adverse oesophageal events associated with bisphosphonate use are well known, it is suggested from the randomized controlled studies that this can be minimized [4–6]. Further research is required to determine if the observed increase in utilization of acid suppressing medicines found in this study is related to lack of adherence to administration protocols and whether this is related to the adequacy of instructions, education and follow‐up to consumers regarding appropriate administration.…”

“…Reports of oesophagitis, oesophageal ulceration or oesophageal stricture associated with bisphosphonate use have been commonly reported via spontaneous adverse drug reaction reporting mechanisms [1, 2] and via prescription event monitoring studies [3]. Reviews of the clinical trial results suggest the incidence of upper adverse gastrointestinal events associated with bisphosphonate use are not significantly greater than placebo [4–6], suggesting this adverse event can be minimized. In an environment where there is potential for extensive use of bisphosphonates, with estimates that as many as 30% of postmenopausal women may require treatment and even greater potential for use if these medicines were used for primary prevention of osteoporosis, it becomes important, where possible, to minimize the occurrence of this adverse drug event.…”

The association between serious upper gastrointestinal bleeding and incident bisphosphonate use: a population-based nested cohort study

“…However, bisphosphonate treatment is not without risk and serious adverse drug reactions (ADRs), including osteonecrosis of the jaw [5], oral and gastric carcinomas [6-8], atypical femur fractures [9,10], and upper gastrointestinal bleeding (UGIB), although infrequent, have been described but remain controversial [11-15]. Drug induced dysphagia, esophagitis, and gastric ulcers are the most common of the gastrointestinal (GI) ADRs associated with oral bisphosphonate therapy.…”

Corrigendum: A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures

“…In a comparative review of pivotal trials of alendronic acid and risedronic acid including a meta-analysis, Kherani et al 114 concluded that both alendronic acid and risedronic acid result in similar rates of AEs as placebo.…”