The management of osteoporosis is a major priority for public health. The disease affects about one-third of women over the age of 50 years, with a combined lifetime risk of hip, forearm, or vertebral fracture of around 50%, on a par with the risk associated with cardiovascular disease [1
]. The total direct costs in Europe were estimated at €31.7 billion in 2000 and are expected to nearly double by 2050 due to demographic changes in the population [2
]. Effective and safe treatments are clearly essential to reduce this burden.
Fortunately, there is currently a wide range of osteoporosis treatments, which reduce the risk for vertebral fracture from 40 to 75% and, in some cases, nonvertebral fractures by about 20% and hip fractures up to 40% [3
]. Like any disease, the pharmacological management of patients with osteoporosis should always involve consideration of the balance between the risk of adverse drug reactions and beneficial effects in terms of reduction in the risk of outcome. For osteoporosis, the outcome is vertebral and nonvertebral fracture, which is associated with significant levels of morbidity and disability and, in the case of vertebral and hip fracture, an increase in mortality. Treatment decisions should be made to attain the maximum reduction in risk of fracture with the minimum occurrence of adverse reactions. On the whole, osteoporosis treatments are remarkably well tolerated, though pharmacovigilance and case studies have highlighted some rare serious adverse drug reactions, which deserve further investigation.
The Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) has focused on adverse reactions and drug–drug interactions in the management of women with osteoporosis. This review was prepared following these discussions.
An adverse drug reaction
is defined as an unintended harmful or unpleasant response to a medicinal product, which predicts hazard for future administration and warrants prevention or specific treatment, alteration of dosage, or discontinuation [4
]. In general medicine, adverse drug reactions are far more common than many physicians suppose [5
]. In one prospective observational analysis of nearly 20,000 hospital admissions, 6.5% of patients had some form of adverse drug reaction, mainly due to aspirin, diuretics, warfarin, and nonsteroidal anti-inflammatory drugs [6
]. The overall fatality in that analysis was 0.15%. Despite this, many of the reactions are preventable through proper surveillance and education of physicians and patients.
In this review, we examine the evidence for adverse drug reactions with the following osteoporosis treatments: bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid), denosumab, selective estrogen receptor modulators (SERMs, raloxifene and bazedoxifene), strontium ranelate, teriparatide, and PTH(1–84). We report the prevalence of side effects and adverse reactions according to the definitions used by the European Medicines Agency (EMA): common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), and very rare (<1/10,000).
Accurate interpretation of the risk of adverse reactions and drug–drug interactions is difficult due to the variety of sources of information that provide varying levels of evidence. The detection of an adverse reaction depends on the relative frequency of the event and the temporality, the mechanism of drug-induced toxicity, the number of patients exposed to the drug, and the methods used to detect the effect. There are three main sources of information in addition to regulatory documents: randomized controlled trials (RCTs), pharmacovigilance, and case reports [4
]. Table summarizes the source of evidence for the various adverse reactions with the osteoporosis treatments described herein and the duration of postapproval surveillance for each agent. Evidence from RCTs is restricted to the most common adverse reactions due to the small population size limited, at most, to a few thousand patients, as well as the relatively short observation times. On the other hand, rare side effects may not be detectable by RCTs and only become evident in pharmacovigilance surveys, which can cover hundreds of thousands of patients over many treatment years. Case reports also constitute an important source of information for the very rare events, though causality is not always easy to establish. It should be noted that the osteoporosis treatments that have been in clinical use for longer are more likely to have reported cases of rare adverse reactions than more recent arrivals to the therapeutic armamentarium.
Source of evidence for adverse reactions to treatments in osteoporosis