Efficacy and safety of alendronate and risedronate for postmenopausal osteoporosis

INTRODUCTION: This paper discusses the efficacy and safety of alendronate and risedronate in the treatment of postmenopausal osteoporosis. METHODS: The literature was searched with the PubMed from 1996 to the present, with respect to strictly conducted systematic reviews with homogeneity, meta-analyses with homogeneity, and randomized controlled trials (RCTs) with narrow Confidence Interval. RESULTS: According to the results of large randomized controlled trials (RCTs), bisphosphonates (alendronate, risedronate, and ibandronate), raloxifene, calcitonin, parathyroid hormone (PTH), and strontium ranelate effectively prevent vertebral fractures in postmenopausal women with osteoporosis. Because raloxifene has been shown to be effective in preventing the initial vertebral fracture in postmenopausal osteoporotic women without prevalent vertebral fractures, it is considered in the treatment of postmenopausal women with mild osteoporosis or osteopenia with some risk factors for fractures. RCTs have also demonstrated that alendronate, risedronate, PTH, and strontium are useful to prevent non-vertebral fractures and that alendronate and risedronate prevent hip fractures, thus alendronate or risedronate are primarily considered as the first-line drugs in the treatment of elderly women with osteoporosis having some risk factors for falls. While it has been suggested that PTH may be considered in patients with severe osteoporosis, the use of PTH in the treatment for osteoporosis is limited to 2 years or less, and it may be appropriate to use other anti-resorptive drugs after the completion of PTH treatment to maintain the skeletal effects gained during the treatment. RCTs have demonstrated that the incidence of gastrointestinal tract adverse events in postmenopausal osteoporotic women treated with bisphosphonates and placebo are similar, and also the long-term efficacy and safety of alendronate and risedronate. CONCLUSION: The evidence derived from the literature, based on strict evidence-based medicine guidelines, suggests that there is long-term efficacy and safety with alendronate and risedronate in the treatment of osteoporosis in postmenopausal women.     

Effects of antifracture drugs in postmenopausal, male and glucocorticoid-induced osteoporosis--usefulness of alendronate and risedronate

The purpose of this paper is to discuss the effects of antifracture drugs on postmenopausal, male and glucocorticoid-induced osteoporosis, focussing on the efficacy and safety of alendronate and risedronate. A search of the literature was conducted using PubMed for strictly conducted systematic reviews published from 1995 to present with homogeneity, meta-analyses with homogeneity, and randomized controlled trials (RCTs) with a narrow confidence interval. According to the results of the systematic reviews and meta-analyses, alendronate and risedronate are useful for the prevention of vertebral and non-vertebral fractures in postmenopausal women with osteoporosis. The results of RCTs have shown the antifracture efficacy of raloxifene and ibandronate against vertebral fractures and that of strontium and parathyroid hormone against vertebral and non-vertebral fractures in postmenopausal women with osteoporosis. In addition, the long-term safety of alendronate, risedronate and raloxifene has been established. On the other hand, RCTs have shown that, only alendronate prevents vertebral fractures in men with osteoporosis, and that alendronate and risedronate can prevent vertebral fractures in patients receiving glucocorticoid treatment. There seems to be less evidence of the antifracture efficacy of the drugs in male and glucocorticoid-induced osteoporosis. They have limitations related to long-term compliance, gastrointestinal intolerance and poor and variable absorption form gastrointestinal tract. Thus, intermittent intravenous administration of bisphosphonates such as ibandronate and zoledronate or subcutaneous administration of denosumab might address some of these problems, although the antifracture efficacy of these drugs needs be established. However, antifracture efficacy and long-term safety are important points in the choice of drugs for the treatment of osteoporosis. Thus, the evidence derived from the literature, based on strict evidence-based medicine guidelines, suggests the antifracture efficacy and safety of alendronate in postmenopausal, male and glucocorticoid-induced osteoporosis, and those of risedronate in postmenopausal and glucocorticoid-induced osteoporosis.     

Oral nitrogen-containing bisphosphonates: a systematic review of randomized clinical trials and vertebral fractures

ABSTRACT

Background: Vertebral fractures are the most common osteoporotic fracture. They are associated with increased morbidity and mortality, and also predict future vertebral and non-vertebral fracture risk. Bisphosphonates are the current mainstay for the treatment of postmenopausal osteoporosis. Health authority guidelines request that assessment of vertebral fracture risk reduction is part of the evaluation of bisphosphonate efficacy. In this review, we compare the published evidence for the efficacy of the nitrogen-containing oral bisphosphonates in reducing the risk of vertebral fractures.

Methods: A review of publications in the treatment of postmenopausal osteoporosis and the most frequently prescribed oral bisphosphonate therapies (alendronate, ibandronate and risedronate) was carried out using the Dialog (Embase and Medline) and Cochrane online scientific citation databases. Eligible publications were those reporting randomized, placebo-controlled trials that included vertebral fracture as the primary or secondary endpoint (any time-point).

Results: Of 159 publications identified, six studies assessing alendronate, ibandronate and risedronate met the pre-defined eligibility criteria. In total, 14?083 women were included in the studies, with 8182 patients receiving active treatment. Most studies were 3?years in duration. Discontinuation rates varied from 11 to 45%, being highest in those studies that specified one or more vertebral fracture as part of the inclusion criteria. Across these studies, the reduction in the risk of vertebral fractures ranged from 41 to 62% (44–48% for alendronate; 41–49% for risedronate; 62% for ibandronate).

Conclusions: Nitrogen-containing oral bisphosphonates effectively reduce the risk of osteoporotic vertebral fracture, with the magnitude of effect ranging from 41 to 62%.     

Role of vitamin K2 in the treatment of postmenopausal osteoporosis

Vitamin K2, raloxifene, and bisphosphonates, such as etidronate, alendronate, and risedronate, are widely used in the treatment of postmenopausal osteoporosis in Japan. A meta-analysis study has demonstrated the efficacy of anti-resorptive agents: raloxifene and etidronate have been shown to reduce the incidence of vertebral fractures, and alendronate and risedronate have been shown to reduce the incidence of both vertebral and hip fractures. Furthermore, a report of the World Health Organization (WHO) has provided evidence from a randomized controlled trial suggesting that vitamin K2, which may stimulate bone formation via gamma-carboxylation of osteocalcin and/or steroid and xenobiotic receptors (SXRs), reduces the incidence of vertebral fractures, despite having only modest effects on the bone mineral density (BMD). Based on the weight of the currently available evidence, it is recommended that alendronate and risedronate, rather than vitamin K2, should be chosen initially for the treatment of postmenopausal osteoporosis, because these agents have been shown to be the most efficacious for reducing the incidence of both vertebral and hip fractures among the current range of commercially available agents. However, the more potent anti-fracture efficacy of combined treatment with the anti-resorptive and commercially available anabolic agents may need to be established. Some studies have shown that combined treatment with a bisphosphonate and vitamin K2 may be more effective than treatment with a bisphosphonate alone in preventing vertebral fractures. On the other hand, the results of a preclinical study do suggest the possible efficacy of combined treatment with vitamin K2 and raloxifene in the prevention of vertebral and hip fractures in postmenopausal women, although no clinical studies have reported on the effects of combined treatment with vitamin K2 and raloxifene in postmenopausal women with osteoporosis. Vitamin K deficiency, as indicated by high serum levels of undercarboxylated osteocalcin, has been shown to contribute to the occurrence of hip fractures in elderly women. Thus, we propose that the important role of vitamin K2 used in combination with bisphosphonates or raloxifene should not be underestimated in the prevention of fractures in postmenopausal women with osteoporosis with vitamin K deficiency.     

Health-economic comparison of three recommended drugs for the treatment of osteoporosis

Osteoporosis is a large and growing disease with significant health consequences. Based on an evaluation of clinical evidence, the German osteology umbrella organization DVO (Dachverband Osteologie deutschsprachiger wissenschaftlicher Fachgesellschaften) published guidelines in March 2003 for the diagnosis and treatment of osteoporosis. For prevention of fractures in women with postmenopausal and senile osteoporosis, these guidelines recommend three treatment options as first-line therapy: risedronate, alendronate and raloxifene. No evidence is currently available for the reduction of hip fractures by raloxifene. Only risedronate and alendronate, therefore, are recommended for prevention of hip fractures. Information on the cost-effectiveness of preventing and treating osteoporosis may support decision makers in more efficient allocation of resources. Accordingly, the objective of this study is the comparative assessment of the cost-effectiveness of risedronate, alendronate and raloxifene for patient populations in Germany at high risk of osteoporotic fracture due to low bone mineral density (BMD) (i.e., T-score < -2.5) and resulting from a history of at least one previous vertebral fracture, as compared to osteoporotic patients with no treatment. Target variables for the economic comparison are costs per hip fracture avoided and costs per quality-adjusted life year (QALY) gained. Hip fractures are the most costly and best-documented complication of osteoporosis. A cost-effectiveness analysis was therefore conducted, using as criteria for evaluating intervention the incremental cost per hip fracture avoided and the cost per QALY gained. We used a fracture-incidence-based Markov model of osteoporosis, with analysis of patients' transition across outcome states over time (e.g., fracture, healthy, dead). Base-case analysis was conducted on a cohort of 1,000 women aged 70 with low spine BMD and prevalent vertebral fracture, over 3 years of treatment with risedronate, alendronate or raloxifene, and with application of a 10-year analytic time horizon. Model inputs included hip and vertebral fracture incidence rates; relative risk of fracture given low BMD and prevalent vertebral fracture, fracture cost, treatment prices/day (risedronate: 35 mg, 1.76 euro; alendronate: 70 mg, 1.82 euro; raloxifene: 60 mg, 1.82 euro); health utility; and efficacy in terms of relative-risk reduction of fracture of the hip (60% risedronate; 51% alendronate; not significant raloxifene) and vertebrae (49% risedronate; 47% alendronate; 30% raloxifene). A 5% discount rate was applied to cost and outcomes. In the base case, treatment with risedronate reduces costs from the social insurance perspective with respect to both endpoints: i.e., costs per averted hip fracture and QALY. Over the 3-year treatment period and 10-year observation, furthermore, risedronate proved superior to alendronate and raloxifene (i.e., risedronate was less expensive and more effective). From the perspective of statutory health insurance, the cost per averted hip fracture is 37,348 euro for risedronate and 48,349 euro for alendronate (costs for raloxifene were not calculated due to a nonsignificant effect on prevention of hip fractures); and cost per QALY gained is 32,092 euro for risedronate, in comparison to patients in Germany with no therapy (alendronate 41,302 euro; raloxifene 1,247,119 euro). This cost-effectiveness analysis gives evidence that bisphosphonates are cost effective. Under consideration of current prices and the published clinical evidence, risedronate dominates the comparison of DVO-recommended drugs.     

New findings with old drugs for osteoporosis

Background: Postmenopausal osteoporosis is common and is associated with stooped posture, loss of height, back pain and fractures. Objectives/methods: This evaluation is of clinical outcome trials with tibolone (Long-Term Intervention of Fractures with Tibolone) and strontium ranelate (Spinal Osteoporosis Therapeutic Intervention) in postmenopausal osteoporosis. Results: Although the Long-Term Intervention of Fractures with Tibolone trial established that tibolone decreased the incidence of vertebral and non-vertebral fractures in postmenopausal osteoporosis, it also showed that tibolone caused a small increase in the incidence of stoke. The Spinal Osteoporosis Therapeutic Intervention trial established that strontium ranelate decreased the incidence of vertebral fractures, but had little effect on the incidence of non-vertebral fractures. Conclusions: As some of the bisphosphonates (alendronate, risedronate, zoledronic acid) have been shown to prevent hip fractures without increasing the incidence of stroke, they should be preferred to tibolone and strontium in the treatment of postmenopausal osteoporosis.     

Efficacy of antiresorptive agents for preventing fractures in Japanese patients with an increased fracture risk: review of the literature

The aim of the present review was to clarify the efficacy of currently available potent antiresorptive agents for preventing fractures in Japanese patients with an increased fracture risk. PubMed was used to search the literature for randomized controlled trials (RCTs), with the following search terms: fracture, etidronate, alendronate, risedronate, minodronate, raloxifene, bazedoxifene and Japan. The inclusion criteria were papers written in English, ≥50 subjects per group and a study period of ≥1 year. Fourteen RCTs met these criteria. The efficacy of antiresorptive agents for preventing vertebral, nonvertebral and hip fractures was investigated. There was evidence that raloxifene reduced the incidence of clinical vertebral fractures, while etidronate, alendronate and minodronate (but not bazedoxifene) reduced the incidence of morphometric vertebral fractures in patients with postmenopausal or involutional osteoporosis. Head-to-head trials showed that alendronate and raloxifene had similar efficacy for preventing vertebral fractures in patients with postmenopausal osteoporosis, while risedronate was not inferior to etidronate for reducing the incidence of morphometric vertebral fractures in patients with involutional osteoporosis. Alendronate reduced the incidence of hip fractures in patients with Parkinson's disease, and risedronate reduced the incidence of nonvertebral fractures and hip fractures in patients with Alzheimer's disease or stroke. In conclusion, the present review confirmed the efficacy of etidronate, minodronate and raloxifene for the prevention of vertebral fractures, the efficacy of alendronate for vertebral and hip fractures, and the efficacy of risedronate for vertebral, nonvertebral and hip fractures in Japanese patients with an increased fracture risk.     

Prevention of vertebral fractures in osteoporosis: mixed treatment comparison of bisphosphonate therapies

ABSTRACT

Objective: The objective was to compare the efficacy of bisphosphonates regarding the prevention of vertebral fractures in postmenopausal women with osteoporosis.

Methods: Seven randomized placebo controlled trials investigating the effects of zoledronic acid (one study), alendronate (three studies), ibandronate (one study), and risedronate (two studies) in terms of fractures with a follow-up of 3 years were identified with a systematic literature search. The endpoint of interest was vertebral fractures. Results of all trials were analyzed simultaneously with a Bayesian mixed treatment comparison (MTC). With MTC the relative treatment effect of one intervention to another can be obtained in the absence of head-to-head evidence. MTC can be considered a valid method when included studies are comparable regarding effect modifying baseline patient and study characteristics.

Results: There is a 98% probability that zoledronic acid shows the greatest reduction in vertebral fractures of all four bisphophonates compared. Zoledronic acid showed an OR of 0.28 (95% Credible Interval 0.22; 0.35) relative to placebo, an OR of 0.57 (0.36; 0.92) relative to ibandronate, an OR of 0.54 (0.39; 0.75) relative to alendronate, and an OR of 0.49 (0.34; 0.69) relative to risedronate. Alendronate, ibandronate, and risedronate showed comparable vertebral fracture reductions. Indirect comparisons using a conservative random effects model supported these findings.

Conclusion: An indirect comparison of findings from placebo controlled randomized studies indicates that zoledronic acid provides a greater vertebral fracture risk reduction in postmenopausal women with osteoporosis than ibandronate, alendronate, or risedronate.     

Cost-effectiveness of alternative treatments for women with osteoporosis in Canada

ABSTRACT

Background: During the years following menopause, estrogen levels decline leading to accelerated bone loss and an increased risk of osteoporosis and osteoporosis-related fractures.

Methods: Using a Markov model and decision analytic techniques, the long-term costs and outcomes of five treatment and secondary prevention strategies for osteoporosis were compared: ‘no intervention’, alendronate, etidronate, risedronate, and raloxifene. The base case analysis examined postmenopausal (65 year old) osteoporotic women without prior fracture. Probabilistic sensitivity analysis (PSA) was used to incorporate the impact of parameter uncertainty, and deterministic sensitivity analysis (DSA) was used to compare alternative patient populations and modeling assumptions. Life years and Quality Adjusted Life Years (QALYs) were used as measures of effectiveness.

Results: In the base case analysis, risedronate was dominated by etidronate and alendronate. Alendronate and etidronate were projected to have similar costs and QALYs, and the efficiency frontier was represented by ‘no intervention’, etidronate, alendronate, and raloxifene (Can$32?571, Can$38?623 and Can$114?070 per QALY respectively). Alternative assumptions of raloxifene's impact on CHD and breast cancer, alternative discount rates and alternative patient risk factors (e.g., starting age of therapy, CHD risk, and prior fracture risk) had significant impacts on the overall cost-effectiveness results for both the bisphosphonates and raloxifene.

Discussion: Using conventionally quoted benchmarks and compared to no therapy, alendronate, etidronate, and raloxifene would all be considered cost-effective alternatives for treating women with osteoporosis. Potential limitations of this study include the usual caveats and cautions associated with long-term projection models and the fact that not all inputs into the model are Canadian data sources.     

Present and future pharmacotherapy for osteoporosis

Although neither calcium nor vitamin D has been shown to prevent osteoporosis in postmenopausal women alone, the combination does. Both calcium and vitamin D are commonly used in the treatment of osteoporosis. The estrogens and raloxifene both prevent bone loss in postmenopausal women, and the estrogens probably also decrease the risk of first fracture. There is good evidence that raloxifene prevents further fractures in postmenopausal women who have already had fractures and some evidence that estrogen does as well. Calcitonin increases bone mineral density in early postmenopausal women and men with idiopathic osteoporosis, and also reduces the risk of new fractures in osteoporotic women. The bisphosphonate alendronate prevents bone loss and reduces fractures in healthy and osteoporotic postmenopausal women, and in osteoporotic men. Risedronate is more potent and has fewer upper gastrointestinal side effects than alendronate, and reduces the incidence of fractures in osteoporotic women. Intermittent use of the potent bisphosphonate zoledronate also increases bone mineral density and may become an alternative in the prevention and treatment of osteoporosis. All of the agents discussed above prevent bone resorption, whereas teriparatide increases bone formation and is effective in the treatment of osteoporotic women and men. In the treatment of secondary osteoporosis associated with the use of glucocorticoids to treat inflammation or prevent rejection after transplantation, the bisphosphonates are effective. The agents that have undergone some clinical trialing as new or alternative drugs for the treatment of osteoporosis include tibolone, new SERMs, androgens, growth hormone, insulin-like growth factor-1 and stontium ranelate. The targets/drugs that are being developed to inhibit bone resorption include the OPG/ RANKL/RANK system, cathepsin K inhibitors, vitronectin receptor antagonists, estren, the interleukin-6 and gp130 system, cytokines and growth factors. New drugs/targets to promote bone formation include the commonly used lipid-lowering statins and the calcilytic release of PTH.     

双膦酸盐预防中国妇女绝经后骨质疏松骨折的系统评价及药物经济学分析

目的：评估3种双膦酸盐预防中国妇女绝经后骨质疏松骨折的有效性、安全性和经济性。方法：计算机检索国内外常用文献数据库中使用阿仑膦酸、利塞膦酸、唑来膦酸预防中国妇女绝经后骨质疏松骨折的随机对照试验（RCT）,提取资料后进行Meta分析,并建立决策树模型进行成本-效果分析。结果：Meta分析结果显示,与单用钙剂/维生素D₃方案相比,联用双膦酸盐能显著减少中国妇女绝经后骨质疏松的椎体骨折[RR 0.50,95%CI（0.33,0.74）]和非椎体骨折[RR 0.36,95%CI（0.20,0.65）]的风险,差异有统计学意义（P<0.01）。亚组分析显示,唑来膦酸能显著减少中国妇女绝经后骨质疏松椎体骨折[RR 0.44,95% CI（0.25,0.77）]风险,阿仑膦酸和利塞膦酸亦表现出减少绝经后骨质疏松非椎体骨折的风险的优势[RR 0.16,95% CI（0.04,0.72）和RR 0.28,95% CI（0.10,0.80）]。安全性方面,加用双膦酸盐期间不良事件的发生率与对照组比较差异无统计学意义。成本-效果分析显示,联用双膦酸盐较单用钙剂和维生素D₃方案经济性更优,阿仑膦酸联合钙剂/维生素D₃方案为经济性最优方案。结论：联用双膦酸盐（尤其是阿仑膦酸）较单用钙剂/维生素D₃方案能显著地减少中国妇女绝经后骨质疏松骨折的风险,安全性较好,经济性更优。     

Full length parathyroid hormone,PTH(1-84), for the treatment of severe osteoporosis in postmenopausal women

ABSTRACT

Objective: To review and analyse the evidence supporting the use of full length parathyroid hormone, PTH(1-84), in the treatment of osteoporosis based on a search of several literature sources; articles selected for review were published between 1990 and 2008.

Background: PTH(1-84) is approved for the treatment of osteoporosis in postmenopausal women at high risk of fracture in Europe. It was well tolerated in clinical trials and demonstrated bone building properties and fracture prevention particularly for the lumbar spine in the treatment of postmenopausal women.

Results: The TOP clinical trial showed that PTH(1-84) treatment for 18 months resulted in a 61% reduction (p = 0.001) in new vertebral fracture incidence when compared with placebo and reduced the risk of a first vertebral fracture by 68% (p = 0.006) in women without a prevalent fracture at baseline. PTH(1-84) increased bone mineral density (BMD) at vertebral and non-vertebral sites the lumbar spine BMD increasing regardless of T-score, age, prior osteoporosis therapy or number of years post-menopause. The PaTH study showed that treatment with PTH(1-84) for 12 months increased BMD at the trabecular spine and hip. Lumbar spine BMD gains were largest with sequential administration of PTH(1-84) followed by alendronate but were smaller with concurrent administration involving anabolic and antiresorptive agents. Lumbar spine BMD increases were also seen in trials involving PTH with raloxifene and PTH in combination with hormone replacement therapy.

Conclusions: PTH(1-84) has demonstrated effective bone building qualities and extends the therapeutic options available to osteoporotic women. The use of PTH(1-84) followed by sequential administration of an antiresorptive has proved effective at increasing trabecular BMD and points towards new treatment regimens offering improvements in BMD and fracture prevention.     

Recent important clinical trials of drugs in osteoporosis

The antiresorptive therapies (raloxifene, bisphosphonates) commonly used to treat postmenopausal osteoporotic women, reduce the rate of bone remodeling and lowers the fracture rate, but do not increase bone mass. Strontium ranelate has the advantage of also stimulating bone formation. In the Spinal Osteoporosis Intervention study, at the end of 1 year, there was a lower incidence of fractures in the strontium ranelate group than the placebo group (12.2 and 6.4%, placebo and strontium, respectively) and this difference was maintained over the 3 years (32.8 and 20.9%, placebo and strontium, respectively). With the demise of oestrogen treatment for postmenopausal osteoporosis, it is useful that strontium ranelate is emerging as a promising drug in this condition. Secondary osteoporosis (e.g., due to glucocorticoid treatment after cardiac transplantation) tends to be more severe than primary osteoporosis. In a recent trial comparing calcitriol to alendronate after cardiac transplantation, both showed similar abilities to prevent bone loss. As hypercalcaemia is a relatively common adverse effect with calcitriol in the treatment of secondary osteoporosis, requiring monitoring of calcium levels, alendronate is the easier agent to use.     

Recent important clinical trials of drugs in osteoporosis

The antiresorptive therapies (raloxifene, bisphosphonates) commonly used to treat postmenopausal osteoporotic women, reduce the rate of bone remodeling and lowers the fracture rate, but do not increase bone mass. Strontium ranelate has the advantage of also stimulating bone formation. In the Spinal Osteoporosis Intervention study, at the end of 1 year, there was a lower incidence of fractures in the strontium ranelate group than the placebo group (12.2 and 6.4%, placebo and strontium, respectively) and this difference was maintained over the 3 years (32.8 and 20.9%, placebo and strontium, respectively). With the demise of oestrogen treatment for postmenopausal osteoporosis, it is useful that strontium ranelate is emerging as a promising drug in this condition. Secondary osteoporosis (e.g., due to glucocorticoid treatment after cardiac transplantation) tends to be more severe than primary osteoporosis. In a recent trial comparing calcitriol to alendronate after cardiac transplantation, both showed similar abilities to prevent bone loss. As hypercalcaemia is a relatively common adverse effect with calcitriol in the treatment of secondary osteoporosis, requiring monitoring of calcium levels, alendronate is the easier agent to use.     

Cost-effectiveness of alternative treatments for women with osteoporosis in Canada

BACKGROUND: During the years following menopause, estrogen levels decline leading to accelerated bone loss and an increased risk of osteoporosis and osteoporosis-related fractures. METHODS: Using a Markov model and decision analytic techniques, the long-term costs and outcomes of five treatment and secondary prevention strategies for osteoporosis were compared: 'no intervention', alendronate, etidronate, risedronate, and raloxifene. The base case analysis examined postmenopausal (65 year old) osteoporotic women without prior fracture. Probabilistic sensitivity analysis (PSA) was used to incorporate the impact of parameter uncertainty, and deterministic sensitivity analysis (DSA) was used to compare alternative patient populations and modeling assumptions. Life years and Quality Adjusted Life Years (QALYs) were used as measures of effectiveness. RESULTS: In the base case analysis, risedronate was dominated by etidronate and alendronate. Alendronate and etidronate were projected to have similar costs and QALYs, and the efficiency frontier was represented by 'no intervention', etidronate, alendronate, and raloxifene (Can$32 571, Can$38 623 and Can$114 070 per QALY respectively). Alternative assumptions of raloxifene's impact on CHD and breast cancer, alternative discount rates and alternative patient risk factors (e.g., starting age of therapy, CHD risk, and prior fracture risk) had significant impacts on the overall cost-effectiveness results for both the bisphosphonates and raloxifene. DISCUSSION: Using conventionally quoted benchmarks and compared to no therapy, alendronate, etidronate, and raloxifene would all be considered cost-effective alternatives for treating women with osteoporosis. Potential limitations of this study include the usual caveats and cautions associated with long-term projection models and the fact that not all inputs into the model are Canadian data sources.     

The cost effectiveness of bisphosphonates for the prevention and treatment of osteoporosis: a structured review of the literature

Osteoporotic fragility fractures constitute a significant public health concern. The lifetime risk of any osteoporotic fracture is very high (40-50% in women and 13-22% in men). Fractures are associated with significant mortality and morbidity and represent a substantial economic burden to society. Bisphosphonates (alendronate, etidronate, risedronate and ibandronate) are indicated for the treatment and prevention of osteoporosis but are costly compared with other treatments, such as vitamin D and calcium.Our search identified 23 studies evaluating the cost effectiveness of bisphosphonate therapy for the treatment and prevention of fragility fractures; these studies were from five geographical areas and employed a variety of comparators and assumptions. We identified 11 studies investigating bisphosphonates in women with low bone mineral density (BMD) [T-score >2.5 standard deviations {SDs} below normal {mean} peak values for young adults] and previous fractures, five studies investigating bisphosphonates in women with low BMD and no previous fracture, one study of bisphosphonates in women with osteopenia, five studies involving screening and two studies of bisphosphonates in special populations (women initiating corticosteroid treatment and men). In women with low BMD and previous fractures, bisphosphonate therapy was most cost effective in populations aged > or =70 years and was unlikely to be cost effective in populations aged < or =50 years. There was uncertainty concerning the cost effectiveness of bisphosphonates in such populations aged 60-69 years. In women with low BMD without previous fractures, treatment with alendronate or risedronate appeared to be cost effective across countries (UK, US, Denmark), but there was some uncertainty about the cost effectiveness of etidronate in patients in the highest age groups.Identifying risk factors for fractures through means such as spine radiographs to detect vertebral deformities improves the cost effectiveness of treatment. In women with osteopenia, alendronate therapy may be cost effective in women with a T-score of -2.4SD in the US. Screening for low BMD and treatment with alendronate or etidronate appears to be cost effective in postmenopausal women in general and in women with rheumatoid arthritis initiating corticosteroid therapy. Alendronate therapy without screening was also shown to be potentially cost effective in certain at-risk male populations, as well as in women initiating corticosteroid therapy after the age of 40 years.Decision makers in the US, UK and Sweden should consider funding the use of bisphosphonates for the prevention and treatment of osteoporosis in women aged >70 years, particularly if they have other risk factors for fracture. Further studies are required to make more definitive conclusions in other countries and patient populations. Screening strategies for low BMD followed by bisphosphonate treatment should also be considered in the general female population aged >65 years in the UK and US and in patients with rheumatoid arthritis initiating corticosteroid therapy.     

Persistent bisphosphonate use and the risk of osteoporotic fractures in clinical practice: a database analysis study*

ABSTRACT

Objective: This study aimed to investigate the association between persistent use of bisphosphonates and the risk of osteoporotic fractures in clinical practice.

Methods: Data were obtained from the PHARMO Record Linkage System, which includes, among other databases, drug-dispensing records from community pharmacies linked to hospital discharge records of more than two million subjects in defined areas in the Netherlands. Persistence with bisphosphonate therapy was assessed during a period of 3 years. A nested matched case control study (cases:controls = 1:10) was performed to study the association between persistent bisphosphonate use and hospitalisation for osteoporotic fractures and analysed by conditional logistic regression analysis. The analyses were adjusted for patient characteristics such as previous hospitalisations for fractures, co-morbidity and co-medication.

Results: 14?760 new female users of bisphosphonates were identified of which 541 women had a hospitalisation for osteoporotic fracture after start of bisphosphonate treatment (1–3 years follow-up). One-year persistence rates increased from 33% with alendronate daily to 48% with alendronate weekly, an increase of 15%. Similar results were obtained with risedronate daily and weekly. One year persistent use of bisphosphonates resulted in a statistical significant 26% lower fracture rate (OR 0.74; 95%CI 0.57–0.95) whereas 2 year persistent use resulted in a 32% lower rate (OR 0.68; 95%CI 0.47–0.96).

Conclusions: Persistent use of bisphosphonates decreases the risk of osteoporotic fractures in clinical practice. Approximately 6% of fractures among users of bisphosphonates could be prevented if persistence was improved by 20%. However, current persistence with bisphosphonate therapy is suboptimal and strategies that further increase persistence are likely to further prevent the number of fractures.     

Drug Evaluation Oncologic,Endocrine & Metabolic: Alendronate (Fosamax®): clinical utility in metabolic bone disease

Alendronate is a member of the class of drugs known as bisphosphonates, potent inhibitors of bone resorption which act via inhibition of osteoclast function. Unlike first generation bisphosphonates, alendronate does not appear to have deleterious effects on bone mineralisation at doses which inhibit bone resorption. Bisphosphonates have been studied in the management of a broad range of skeletal disorders characterised by increased bone turnover, including hypercalcaemia of malignancy, metastatic bone disease, primary and secondary hyperparathyroidism, and Paget's disease of bone. More recently, bisphosphonates have also been studied in the prevention and treatment of established bone loss in patients with osteoporosis. In this respect, alendronate has recently been shown to increase bone mass in the spine, femoral neck and total body of postmenopausal women with osteoporosis, and to reduce the incidence of vertebral, hip and wrist fractures, the progression of vertebral deformities and height loss in these subjects. The drug appears to be safe and well tolerated apart from a low incidence of chemical oesophagitis. Alendronate therefore offers a promising alternative to hormone replacement therapy for treatment of osteoporosis in postmenopausal women and may also play a role in the management of other types of osteoporosis.     

Cost effectiveness of denosumab compared with oral bisphosphonates in the treatment of post-menopausal osteoporotic women in Belgium

Background: Denosumab has recently been shown to be well tolerated, to increase bone mineral density (BMD) and to significantly reduce the risk of hip, vertebral and non-vertebral fractures in the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial. It is becoming increasingly important to evaluate not only the therapeutic value of a new drug but also the cost effectiveness compared with the most relevant treatment alternatives. Objective: The objective of this study was to estimate the cost effectiveness of denosumab compared with oral bisphosphonates (branded and generic drugs) in the treatment of post-menopausal osteoporotic women in Belgium. Methods: Cost effectiveness of 3 years of treatment with denosumab was compared with branded risedronate and branded and generic alendronate using an updated version of a previously validated Markov microsimulation model. The model was populated with relevant cost, adherence and epidemiological data for Belgium from a payer perspective and the results were presented as costs per QALY gained (&U20AC;, year 2009 values). Analyses were performed in populations (aged ≥60 years) in which osteoporosis medications are currently reimbursed in many European countries, i.e. those with BMD T-score of -2.5 or less or prevalent vertebral fracture. Patients receiving denosumab were assumed to have a 46% lower risk of discontinuation than those receiving oral bisphosphonates, and the effect of denosumab after treatment cessation was assumed to decline linearly to zero over a maximum of 1 year. Results: Denosumab was cost effective compared with all other therapies, assuming a willingness to pay of &U20AC;40?000 per QALY gained. In particular, denosumab was found to be cost effective compared with branded alendronate and risedronate at a threshold value of &U20AC;30?000 per QALY and denosumab was dominant (i.e. lower cost and greater effectiveness) compared with risedronate from the age of 70 years in women with a T-score of -2.5 or less and no prior fractures. The cost effectiveness of denosumab compared with generic alendronate was estimated at &U20AC;38?514, &U20AC;22?220 and &U20AC;27?862 per QALY for women aged 60, 70 and 80 years, respectively, with T-scores of -2.5 or less. The equivalent values were &U20AC;37?167, &U20AC;19?718 and &U20AC;19?638 per QALY for women with prevalent vertebral fractures. Conclusion: This study suggests, on the basis of currently available data, that denosumab is a cost-effective strategy compared with oral bisphosphonates (including generic alendronate) for the treatment of post-menopausal osteoporotic women, aged ≥60 years in Belgium. Denosumab therefore appears to have the potential to become a first-line treatment for post-menopausal women with osteoporosis. However, further studies would be required to evaluate the long-term safety and adherence of denosumab in real-world clinical practice as well as head-to-head effectiveness compared with oral bisphosphonates.