Drug-Related Adverse Events of Osteoporosis Therapy

2010

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.

Osteoporosis International, 2012

Journal of Clinical Rheumatology and Immunology

Osteoporosis is a systemic skeletal disorder that affects bone microarchitecture resulting to fragility fractures. Randomized controlled trials have shown efficacy of antiresorptives and osteoanabolic agents in addressing concerns of osteoporosis especially in the older population. However, published guidance from several organizations started to focus as well on the perceived harms most especially of bisphosphonates considering their persistent effect on the bones. Similar to other chronic diseases, decision on whether or not to continue therapy depends on factors that might persistently provide signal on the individual’s further risk of unwanted but preventable outcomes.

2002

O steoporosis is in part a natural consequence of aging, although endogenous estrogen deficiency is an important pathophysiologic contribution to its occurrence in women. Age-related bone loss is the main cause of hip and vertebral fractures in elderly people. In addition to the morbidity and costs associated with these fractures, there is the nontrivial mortality. About 20% of patients with hip fracture die within the year, and about the same percentage require longterm care. 1 Vertebral fractures due to osteoporosis also contribute significantly to increased mortality 2,3 and prolonged disability. 4 The age-adjusted relative risk of dying from any clinical fracture more than doubles for individuals over the age of 60 years (relative risk [RR] 2.5, 95% confidence interval [CI] 1.37-3.42). Osteoporosis can be detected by measurements of bone mineral density (BMD) or inferred from the presence of pre-existing osteoporosis-related fractures such as vertebral or hip fractures. Among patients with osteoporosis (by BMD measurements but without pre-existing fractures), the 3-4-year incidence of new vertebral fractures ranges from 2% to 4%, 6-8 whereas hip fracture rates range from 1.1% to 5.1%. The presence of pre-existing osteoporosis-related fractures is markedly associated with an increase in risk for future fractures at many skeletal sites (over a comparable time frame), such that vertebral fracture incidence increases to 15%-29%, 7,8,10-14 and hip fracture incidence increases to 2.2%-5.7%. 9,12-14 These fracture rates were observed in randomized placebo-controlled clinical trials designed to assess the efficacy of new pharmaceutical drugs intended to reduce incident fracture rates. Although the inclusion criteria for enrolment of subjects into these trials were not strictly comparable, the fracture incidence data in placebotreated patients consistently demonstrate that a pre-existing osteoporosis-related fracture serves as a harbinger of an increased risk of subsequent fracture, even if the patient takes modest calcium and vitamin D supplements.

Cureus

Postmenopausal women who have osteoporosis are at increased risk of future fractures. Bisphosphonates are drugs that are used to treat osteoporosis by acting on the osteoclasts to inhibit bone resorption. Several studies have shown that bisphosphonates can maintain or even increase bone mineral density in osteoporosis patients. This review study analyzed the literature on clinical experiments with bisphosphonate therapy in postmenopausal women to determine if these drugs are efficacious in preventing future fractures. Four out of five studies found that women treated with bisphosphonates were at a decreased risk of future fractures, and six of six studies found that bisphosphonate therapy increases bone mineral density relative to placebo control. Although further work is warranted to understand the level of bone mineral density increase that is associated with fracture prevention, this study implies that bisphosphonate therapy can be used to help prevent future fractures in postmenopausal osteoporotic women. The study is significant in that it helps to underscore the efficacy of bisphosphonate therapy in postmenopausal women, and it may be generalizable to other populations with osteoporosis who are at increased risk of fractures.

Breast Care, 2010

Drug Therapies Approved for Postmenopausal Osteoporosis Adequate supply of vitamin D and calcium is recommended as a baseline therapy for the prevention and treatment of osteo porosis in all patients, but is not sufficient for the treatment of prevalent osteoporosis [5, 6]. Vitamin D and calcium supplementation is included in most clinical trials evaluating novel drug candidates. Most drugs approved for the treatment of osteoporosis are antiresorptive agents that improve bone strength and reduce the risk of fractures primarily by decreasing the bone turnover and maintaining or increasing the BMD. These drugs include orally and intravenously applied bisphosphonates, selective estrogen receptor modulators (SERMs), and salmon calcitonin (table 1) [5-7]. In contrast, anabolic agents such as teriparatide and recombinant human parathyroid hormone (PTH) act by increasing bone formation. Strontium ranelate has antiresorptive and anabolic properties and is therefore classified as a dual-acting bone agent (DABA). Numerous clinical trials have demonstrated the efficacy of the drugs mentioned above. However, therapy with these agents is limited by side effects, schemes for intake, restricted duration of treatment and, not least, cost of the drugs. Oral bisphosphonates generally have a low bioavailability. Adverse gastrointestinal effects and restrictive application schemes contribute to suboptimal patient compliance and/or premature cessation of therapy in many patients. A systematic review found that the average duration of therapy with osteoporosis treatments, primarily bisphosphonates, was generally less than 1 year [8]. More recently intravenous

Current Obstetrics & Gynaecology, 1996

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2015

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with pr...

Current Therapeutic Research, 1997

Osteoporosis is characterized by a reduction of bone in the skeleton, associated with skeletal fragility and an increased risk of fracture after minimal trauma. The three major osteoporotic fractures are those of the forearm, vertebral body, and hip, although fractures of the humerus, tibia, pelvis, and ribs are also common. Osteoporotic fractures are a major cause of morbidity and mortality, and lead to increased health and social service expenditures in both sexes. The main objective in treating patients with osteoporosis is to reduce the risk of fractures. Bisphosphonates are an important group of therapeutic agents for the management of osteoporosis, as they inhibit bone resorption and increase bone density, thereby potentially decreasing fracture risk. The demonstration of a reduction in fracture incidence requires large randomized, double-masked, placebocontrolled trials with the statistical power to detect increases in bone density and a significant reduction in fracture incidence. Although cyclical etidronate apparently decreases the risk of vertebral fractures in a manner comparable with hormone replacement therapy and calcitonin, there are no randomized controlled trials that show a reduction in forearm or hip fractures. Alendronate is the only agent that has been shown in large randomized controlled trials to statistically significantly decrease the risk of symptomatic fractures of the forearm, spine, and hip by 4896, 55%, and 51%, respectively. In addition to the efficacy of any treatment for osteoporosis, compliance and tolerability must also be satisfactory. The most common adverse events with cyclical etidronate and alendronate are mild gastrointestinal disturbances, but the incidence is similar to that seen with placebo or calcium. In clinical practice, esophagitis has been rarely reported with alendronate, and in the majority of cases, this effect is related to a failure to follow the recommendations for administration. Although cyclical etidronate therapy may lead to histologic evidence of focal osteomalacia, clinical osteomalacia has not been observed when the recommended cyclical regimen has been used. Iliac crest bone biopsies show no evidence of a mineralization defect with alendronate. Long-term data on bone density and fracture incidence are needed from large-scale controlled studies with other bisphosphonates, such as clodronate, tiludronate,

2019

Objective: To estimate the efficacy of bisphosphonates in preventing osteoporotic fractures in postmenopausal women systematic review and meta-analysis. Methods: Published reports were searched through electronic database including MEDLINE and the Cochrane Library from inception to November 2015. We selected randomized controlled trials (RCTs) examining efficacy of bisphosphonates compared with placebo and/or calcium plus vitamin D with outcomes of incidence of bone fracture. Results: Sixteen RCTs with duration of 1 – 3 years met the eligibility criteria. Meta-analysis showed that alendronate (5 - 10 mg/day) and risedronate (2.5 and 5 mg/day) could prevent vertebral fracture by 45% (RR = 0.55; 95% CI: 0.46, 0.67) and 38% (RR = 0.62; 95% CI: 0.51, 0.75), respectively. Alendronate, risedronate and zoledronate (5 mg/day) could prevent non-vertebral fractures by 15% (RR = 85; 95% CI: 0.75, 0.97), 19% (RR = 0.81; 95% CI: 0.72, 0.90) and 24% (RR = 0.76; 95% CI: 0.66, 0.88), respectively.T...