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.     

Efficacy and safety of alendronate and risedronate for postmenopausal osteoporosis

ABSTRACT

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.     

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.     

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.     

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.     

Review of ibandronate in the treatment of osteoporosis

Several antiresorptive treatments that reduce the risk of osteoporotic fracture are now available, including bisphosphonates. Ibandronate is a new potent bisphosphonate, currently under development, with unique features. In several animal models of human osteoporosis, it has been shown to inhibit bone resorption and improve bone mechanical properties. Ibandronate is more potent than most current bisphosphonates. Several dosages and schedules have been tested in humans. With the oral daily dose of 2.5 mg, a reduction of 62% in the incidence of vertebral fracture has been demonstrated in a randomised, placebo-controlled trial. In the same trial, a reduction of 50% has been observed - for the first time using a bisphosphonate - with an intermittent regimen (20 mg every other day for the first 24 days, followed by 9 weeks without the treatment). In contrast, another randomised, placebo-controlled trial failed to find a significant reduction in vertebral fracture risk using an dose of 1 mg i.v. every 3 months. Thus, ibandronate can be considered as a promising new option for the treatment of postmenopausal osteoporotic women.     

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.     

Cost-effectiveness of bisphosphonate therapies for women with postmenopausal osteoporosis: implications of improved persistence with less frequently administered oral bisphosphonates

ABSTRACT

Objective: Studies have shown that weekly bisphosphonate dosing results in improved persistence compared to daily dosing among patients with postmenopausal osteoporosis, yet more than 50% of patients discontinue therapy within a year. An oral, less frequent administration bisphosphonate provides an opportunity to improve persistence, a parameter not well modeled in previous cost-effectiveness analyses of osteoporosis therapies.

Research design and methods: We developed a Markov model to estimate the effect of improved persistence on the cost-effectiveness of bisphosphonates among postmenopausal women with established osteoporosis (vertebral fracture and bone mineral density T-score ≤ –2.5) and an average age of 78 years. Fracture risks, clinical efficacy, mortality, resource use, costs, and utilities were obtained from the published literature. Persistence rates were derived primarily from a published clinical trial. Approximately 50% greater persistence with a monthly versus a weekly therapy was assumed on the basis of the PERSIST study, a 6-month, randomized, head-to-head prospective study that investigated treatment persistence in postmenopausal osteoporotic women on monthly versus weekly bisphosphonate therapy. Persistence was extrapolated to a maximum of 5 years. Following discontinuation, treatment benefit declined linearly and proportionally to the duration of active treatment.

Results: Based on model estimates, more fractures were avoided (versus no treatment) with monthly bisphosphonate (58.1 per 1000 treated women) than with weekly bisphosphonates (33.8 per 1000 treated women), resulting in lower fracture care costs per woman ($7317 and $7548, respectively). The incremental cost per quality-adjusted life-year gained was lower with a monthly bisphosphonate ($13?749) than with weekly bisphosphonates ($16?657) when compared to no treatment. The incremental cost per quality-adjusted life-year of a monthly bisphosphonate was $9476 when compared to a weekly bisphosphonate.

Conclusions: In postmenopausal women with established osteoporosis, improvement in persistence with a less frequently administered oral bisphosphonate therapy could augment the fracture benefit and thereby improve cost-effectiveness. Further studies are required to refine the estimates of cost-effectiveness in order to address limited availability of adherence and fracture risk data.     

双膦酸盐类药物的药动学及药物相互作用研究进展

双膦酸盐类药物用于预防与治疗骨吸收相关疾病,包括第1代的依替膦酸二钠、替鲁膦酸二钠、氯膦酸二钠,第2代的帕米膦酸二钠、阿仑膦酸钠,第3代的利塞膦酸钠、伊班膦酸钠、唑来膦酸等。该类药物口服达峰时间较短,吸收率偏低,生物利用度很低;骨结合部分的半衰期较长,药物留存时间也较长。与双膦酸盐联用产生相互作用的药物主要为：含有二价阳离子药物、其他双膦酸盐药物、华法林、苯妥英、非甾体类抗炎药、抗癌药、激素、H2受体拮抗剂以及肾毒性药物。从药动学角度解释双膦酸的药物相互作用,以避免不良反应发生。     

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

INTRODUCTION: International guidelines on the treatment and prevention of osteoporosis recommend the use of bisphosphonates to prevent fractures in this population. However, low persistent use of bisphosphonates could considerably limit the prevention of fractures in clinical practice. 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.     

Relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures

ABSTRACT

Objectives: To investigate the relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures.

Methods: The PHARMO database was used to identify new female bisphosphonate users, aged ≥ 45 years or with diagnosed post-menopausal osteoporosis in the period of January 1996 – June 2004. Within this cohort a matched case–control study was performed. Cases were defined as patients who were hospitalized for an osteoporotic fracture and were matched to ten controls without a fracture by duration of follow-up. The duration of compliant bisphosphonate use (i.e., medication possession ratio ≥ 80%) preceding the outcome date was determined.

Results: Of 14 760 new female bisphosphonate users, 387 fracture patients fulfilled the inclusion criteria. These cases were matched to 3950 controls. Increasing duration of compliant bisphosphonate use was associated with a decreased risk of fracture (trend p < 0.01). Adjusted for several cofactors, 1–2 years of compliant bisphosphonate use and 3–4 years of compliant bisphosphonate use decreased fracture risk by 12% and 46%, respectively, compared to < 1 year of compliant bisphosphonate use (OR 0.88; 95% CI 0.66–1.18 and OR 0.54; 95% CI 0.35–0.84, respectively). Unexpectedly, 5–6 years of compliant bisphosphonate use was no longer associated with a decreased risk of fractures compared to < 1 year of compliant bisphosphonate use (OR 1.12, 95% CI 0.66–1.88).

Conclusions: These results show a direct link between duration of compliant bisphosphonate use and fracture risk, and confirm the importance of continuing the use of bisphosphonates to maintain optimal bone protection. However, this link is inconclusive for bisphosphonate use for more than 4 years.     

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.     

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.     

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.     

Review of risedronate in the treatment of osteoporosis

Risedronate (Actonel^®, Procter & Gamble and Aventis) is a novel, orally administered pyridinyl bisphosphonate. Preclinical studies have shown that risedronate is a potent inhibitor of osteoclasts. Risedronate inhibited bone resorption and increased bone density in the spine and hip. Prospective, randomised, placebo-controlled trials (RCTs) in patients with postmenopausal osteoporosis (PMO) have demonstrated that risedronate decreased the risk of vertebral fractures by up to 49% and of non-vertebral fractures by up to 39% over 3 years in postmenopausal women with one or more prevalent vertebral fractures. This reduction of the risk for vertebral fractures was significant from the first year of treatment (risk reduction up to 65%). Risedronate was the first bisphosphonate to be studied in a large RCT with prevention of hip fracture as the primary end point. In this study, risedronate reduced the risk of hip fracture by 40% in elderly women with low hip bone density and one clinical risk factor for hip fracture and by 60% in women with low bone density and a prevalent vertebral fracture at baseline. Risedronate was also effective in the prevention and treatment of bone loss in glucocorticoid-induced osteoporosis (GIO), with a positive effect on vertebral fractures within the first year. Risedronate was well-tolerated with a safety profile comparable to placebo in all clinical studies. Patients with a previous or current history of upper GI illness or who were taking NSAIDs or aspirin were not excluded from these studies. Importantly, the upper GI safety profile of risedronate was shown to be similar to that of placebo in endoscopic studies. There was no evidence of acute-phase reactions or primary mineralisation defects. The most appropriate dose of risedronate was 5 mg/day.     

Ibandronate produces significant,similar antifracture efficacy in North American and European women: new clinical findings from BONE

ABSTRACT

Objectives: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2?months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here.

Patients and methods: BONE was a randomized, double-blind, placebo-controlled, fracture-prevention study in 2946 postmenopausal women (age 55?years?80?years; ≥ 5?years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4?L4]). Participants received daily calcium (500?mg) and vitamin D (400?IU) plus either placebo, oral daily ibandronate (2.5?mg) or oral intermittent ibandronate (20?mg every other day for 12 doses every 3?months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations.

Results: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (?p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo.

Conclusions: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients’ geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.     

A Bayesian analysis of bisphosphonate effects and cost‐effectiveness in post‐menopausal osteoporosis

Objective — Effects of oral bisphosphonates on the rate of vertebral fractures in post‐menopausal osteoporotic women have been found in clinical trials. We wanted to compare the effects of two bisphosphonates, alendronate and etidronate, and calculate the price difference that would give the same cost‐effectiveness for the two drugs. We also intended to give, by means of Bayesian statistics, probability distributions and point and interval estimates for key parameters. Methods — We used published, double‐blind, randomized placebo controlled studies describing the results of occurrence of vertebral fractures at 3‐year follow‐up in post‐menopausal women taking bisphosphonates. Four studies were identified, including altogether 3510 women. The women had either suffered a fracture at entry or had a bone density at least 2.5 SD below the mean value for young women. Two of the studies dealt with alendronate and two with etidronate. Results — According to three of the studies, the number of women out of 100 avoiding vertebral fractures during a 3‐year observation period varied from two to seven. The fourth study did not contain the necessary data. The four studies showed that, for the incidence rate, the multiplicative treatment effects were respectively 0.45, 0.74, 0.40 and 0.36, where values less than 1 indicate positive treatment effects. Using data from all four studies, a comparison of the two drugs gave a point estimate of 0.247 with 95% credibility interval (CI): −0.051 to 0.496 for a difference in effect in favour of alendronate measured in terms of risk ratio of fracture and 0.302 (CI: 0.099 to 0.539) measured as incidence rate ratio. Based on two studies, showing about the same prevalence of fractures in the control groups, the difference in the risk difference between the two drugs was 0.028 (CI: −0.039 to 0.079). Conclusions — Bisphosphonates effectively reduce risk of new vertebral fractures, but alendronate is somewhat more effective than etidronate. To obtain equal cost‐effectiveness alendronate should be priced 40 – 70% higher than etidronate. Copyright © 2000 John Wiley & Sons, Ltd.     

Impact of noncompliance with alendronate and risedronate on the incidence of nonvertebral osteoporotic fractures in elderly women

AIMS

To evaluate the association between noncompliance with alendronate and risedronate and the risk of nonvertebral osteoporotic fracture in community-dwelling elderly women.

METHODS

A nested case–control study was conducted using the Quebec administrative health databases. To be included in the cohort, women needed to be aged ≥ 68 years and to have initiated treatment with alendronate or risedronate between 1 January 2002 and 31 March 2005. Cases consisted of all women with an incident nonvertebral osteoporotic fracture occurring ≥ 1 year after initiation of therapy. Each case was matched with up to 20 controls using incidence density sampling, according to age (± 1 year) and follow-up duration. A woman was noncompliant if she had a medication possession ratio (MPR) <80% for total follow-up duration. Rate ratios (RR) for fracture were estimated through conditional logistic regression analysis, adjusting for potential confounders.

RESULTS

Among the 30 259 women included in the cohort, 1036 nonvertebral fracture cases were identified and were matched to 20 069 controls. Compared with women with a MPR ≥ 80%, those with a MPR < 80% had a greater risk of nonvertebral fracture [adjusted RR 1.27, 95% confidence interval (CI) 1.12, 1.44]. Considering hip fracture only, the multivariate model yielded similar results, (adjusted RR 1.28, 95% CI 1.02, 1.61).

CONCLUSIONS

Among community-dwelling elderly women, noncompliance with alendronate or risedronate is associated with an increased risk of nonvertebral fracture.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Compliance with alendronate and risedronate is suboptimal.
• Few studies have specifically evaluated the impact of noncompliance with alendronate or risedronate on the incidence of osteoporotic fractures in community-dwelling elderly women.

WHAT THIS STUDY ADDS

• Among community-dwelling elderly women, noncompliance [defined as medication possession ratio (MPR) < 80%] with alendronate or risedronate was associated with a 27% increased risk of nonvertebral fracture [rate ratio (RR) 1.27, 95% confidence interval (CI) 1.12, 1.44].
• This study is the first to assess the impact of noncompliance with bisphosphonates in a subgroup of women aged > 80 years.
• Among women aged > 80 years, MPR < 80% was associated with a 48% greater risk of sustaining a nonvertebral fracture (RR 1.48, 95% CI 1.19, 1.85), compared with women with a MPR ≥ 80%.