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.     

激素替代疗法联合阿仑膦酸钠治疗绝经后骨质疏松的临床研究

目的观察激素替代疗法(HRT)联合阿仑膦酸钠治疗绝经后骨质疏松患者的疗效。方法采用随机、对照研究。69例绝经后骨质疏松症患者,随机分为联合用药组(联合组)、雌激素替代治疗组(雌激素组)和阿仑膦酸钠治疗组(阿仑膦酸钠组),每组23例。联合组每2周服尼尔雌醇片1mg,每3个月末10d加服安宫黄体酮6mg/d,同时给予阿仑膦酸钠70mg,每周1次口服。雌激素组为安慰剂+尼尔雌醇片和安宫黄体酮,阿仑膦酸钠组为安慰剂+阿仑膦酸钠。所有受试者均加服钙尔奇D600mg/d(每片含元素钙600mg和VitD125IU)。观察各组治疗后患者腰椎骨密度、血钙、血磷等骨代谢指标的变化及疼痛症状改善情况。结果通过1年治疗,3组患者的L1～4骨密度均有显著上升,其中联合组骨密度的上升更为明显(P<0.01),骨痛症状明显缓解,总有效率为100%,联合组的显效率高于其他两组。结论HRT联合阿仑膦酸钠治疗绝经后骨质疏松症,较单独用药更能有效地改善骨痛,提高骨密度值。     

European women's preference for osteoporosis treatment: influence of clinical effectiveness and dosing frequency

ABSTRACT

Objective: To determine participant preference for weekly versus monthly bisphosphonate therapy for osteoporosis after being informed about differences in fracture efficacy.

Design: 20‐minute, semi-structured, face-to-face or telephone interviews. Two bisphosphonate choices were presented on the basis of block randomization: weekly therapy with proven efficacy to reduce fracture risk at the spine and hip, or monthly therapy with proven efficacy to reduce fracture risk at the spine but not the hip.

Subjects: Women from the UK, Germany, France, Spain and Italy, with postmenopausal osteoporosis and aged ≥ 55 years. Fifty percent were currently taking a weekly bisphosphonate; 50% had no history of taking any bisphosphonate.

Measures: An efficacy rating scale and an intention-to-use rating scale were developed for this study. The primary endpoint was preference for weekly or monthly therapy. Reasons for preference were recorded.

Results: A preference was recorded for 1248 women (1253 were recruited). More women preferred weekly to monthly therapy (82% vs. 18%, respectively; p < 0.001). Among women who preferred weekly therapy, efficacy was the most commonly cited reason (65%). Ninety-two percent of the total cohort rated the efficacy of the weekly therapy as ‘excellent/good’ versus 38% for monthly (?p < 0.001). Sixty-nine percent intended to use weekly bisphosphonates compared with 34% for monthly (?p < 0.001).

Conclusions: When informed about differences in fracture efficacy in weekly and monthly bisphosphonates, a significantly greater proportion (82%) of women preferred a weekly bisphosphonate with proven fracture efficacy at the spine and hip over a monthly bisphosphonate with proven fracture efficacy only at the spine.     

Sustained vertebral antifracture efficacy of oral anti-osteoporotic therapies in postmenopausal osteoporosis

Abstract

Objective:

Vertebral fractures are common in women with postmenopausal osteoporosis, a chronic condition requiring long-term treatment with anti-osteoporotic treatments. Therefore, it is important to assess sustainability of antifracture efficacy.     

Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis

SUMMARY

Objective: The efficacy and tolerability of risedronate once-a-week dosing (35 and 50?mg) were compared with risedronate daily dosing (5?mg) in a 2-year study in women with osteoporosis.

Design and methods: This was a randomized, double-blind, active-control study with lumbar spine bone mineral density (BMD) as the primary efficacy endpoint at 1?year. Subjects were women aged 50?years or older, postmenopausal for at least 5?years, and had either a BMD T-score of –2.5 or lower (lumbar spine or total proximal femur) or a T-score lower than -2 and at least one prevalent vertebral fracture. In addition to risedronate treatment, the subjects received 1000?mg daily of elemental calcium supplementation and received vitamin D if the baseline serum 25-hydroxyvitamin D₃ level was low.

Results: The results after 1?year of treatment were previously published. Of the 1456 women who were randomized and received study medication, 1127 (77%) completed the 2-year study. Over the 2?years of treatment, the incidence of both new vertebral fractures (2.9, 1.5, and 1.7% for the 5, 35, and 50?mg groups, respectively; p = 0.298) and osteoporosis-related non-vertebral fractures reported as adverse events (5.0, 4.9, and 4.5% for the 5, 35, and 50?mg groups, respectively; p = 0.918) was similar for all 3 treatment groups. The reduction from baseline at Month 24 in bone turnover markers was similar based on an analysis of variance for the 5?mg daily and the 35?mg once-a-week groups. The mean percentage change in lumbar spine BMD after 24?months was 5.17, 4.74, and 5.47% for the 5, 35, and 50?mg groups, respectively. Both the 35 and 50?mg once-a-week treatment groups met the pre-specified criterion of non-inferiority to the 5?mg daily treatment group. No apparent difference in the pattern or distribution of serious and upper gastrointestinal adverse events was observed.

Conclusions: The 2-year data agree with the 1-year results demonstrating that the risedronate once-a-week doses are comparable in efficacy and safety to the 5?mg daily dose. Risedronate 35?mg once a week is considered the optimal dose for women with postmenopausal osteoporosis who want a once-a-week dosing regimen.     

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.     

Long dosing intervals in the treatment of postmenopausal osteoporosis

ABSTRACT

Background: Osteoporosis is a common disease associ­ated with diminished bone strength and increased risk of fracture. With the aging of the population, the number of people with osteoporosis, particularly postmenopausal women, is expected to increase. There are excellent tools for diagnosing osteoporosis and widely available treat­ments that are safe and effective. Nevertheless, osteo­porosis is underdiagnosed and undertreated. Even among those who are diagnosed and treated, widespread non­adherence with treatment regimens undermines the efficacy of osteoporosis therapy.

Purpose: To examine the pharmacological options for the treatment of postmenopausal osteoporosis and the influence of extended dosing intervals upon outcomes, medication adherence, and patient preference.

Methods: A Medline and Cochrane Review database search was conducted for appropriate clinical trials, meta-analyses, and systematic reviews published between 1987 and 2007.

Findings: The causes of nonadherence include poor understanding of the consequences of a silent disease, concern regarding potential side-effects of medications, the inconvenience associated with administration of some osteoporosis medications, and medication costs. The recent development of effective oral and injectable osteo­porosis medications that can be given with long dosing intervals may improve patient adherence. Less frequent dosing lessens the inconvenience of administration, and dosing by injection assures that the medication is 100% bioavailable. Osteoporosis patients have shown a preference for monthly bisphosphonate dosing compared with weekly dosing.

Conclusion: Enhanced adherence with new dosing regimens can be expected to improve treatment efficacy, reduce fracture risk, and lessen the burden of osteo­porosis on patients and society. Further study is required to fully elucidate the relationship between extended dosing, adherence, and positive outcomes.     

Denosumab治疗绝经后骨质疏松症的临床研究进展

狄诺塞单抗(Denosumab)是首个上市的抗核因子κB受体活化因子配体(RANKL)治疗性单克隆抗体产品,主要用于治疗骨质疏松症和其他骨骼疾病.本文主要综述其近年国外治疗绝经后骨质疏松症的临床研究进展.     

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.     

Risedronate,a novel pyridinyl bisphosphonate for the treatment of osteoporosis and Paget’s disease of bone

Osteoporosis and Paget’s disease of bone are the most common metabolic bone diseases. They cause considerable disability and pain, and reduce quality of life. The elderly are at greatest risk of osteoporotic fractures, and in an ageing world population, the burden of the disease is likely to increase. Bisphosphonates are known to be effective antiresorptive agents for the treatment of Paget’s disease of bone, postmenopausal osteoporosis (PMO) and corticosteroid-induced osteoporosis (CIO). However, some bisphosphonates have been associated with troublesome gastrointestinal side-effects. Risedronate is a novel pyridinyl bisphosphonate recently approved in the USA for the treatment of Paget’s disease, and is under development for the treatment of PMO and CIO. Risedronate is effective and well-tolerated in the treatment of Paget’s disease. It has the shortest treatment regimen of any oral bisphosphonate; a two month course of therapy results in sustained remission, as determined by biochemical indices. The results of recent clinical trials suggest that risedronate is also an effective, well-tolerated therapy for PMO and CIO. Risedronate represents an advance in the therapeutic options available for the treatment of Paget’s disease, and is expected to be of further value for treatment of PMO and CIO when it receives approval for use in these conditions.     

Patient compliance with alendronate,risedronate and raloxifene for the treatment of osteoporosis in postmenopausal women

ABSTRACT

Objectives: The aim was to investigate patient compliance with different osteoporosis medications commonly prescribed in clinical practice, to determine risk factors associated with discontinuation and to evaluate quality of life changes.

Research design and methods: We conducted a 1-year observational study of patients of age ≥ 60 years in a clinical setting at 917 sites in 10 European countries (Germany, Greece, UK, Sweden, Netherlands, Romania, Norway, Finland, Denmark, Estonia), Lebanon and South Africa. Demographic data, concomitant diseases, the reasons for intervention, educational, socio-economical status and disease knowledge were captured at baseline. Self-reported compliance, discontinuation data and health status were collected.

Main outcome measures: Out of 5198 patients, 3490 (67.1%) patients received 60?mg daily raloxifene (RAL), 452 (8.7%) 10?mg daily alendronate (AQD), 769 (14.8%) 70?mg once weekly alendronate (AQW) and 487 (9.4%) 5?mg daily risedronate (RIS). Among patients completing the study (4231, 81%), the percentage of patients with high compliance was 80% (RAL), 79% (AQD), 65% (AQW) and 76% (RIS). The discontinuation due to side effects was highest on AQW (7.0%), followed by AQD (6.4%), RAL (3.8%) and RIS (3.4%). The discontinuation-rate was higher for patients with a history of surgical menopause, increased age, lack of knowledge about medical prevention of osteoporosis and thin frame as a reason for intervention. The EQ-5D weighted index showed the highest improvement for RIS (0.13), followed by RAL (0.11), AQD (0.08) and AQW (0.07).

Conclusions: Data from this non-interventional observational study indicate moderate overall compliance and discontinuation rate with the prescribed osteoporosis medications.     

Treating osteoporosis: economic aspects of bisphosphonate therapy

Each year, fractures associated with osteoporosis place a significant burden on healthcare spending and result in unnecessary morbidity, mortality and reductions in quality of life for individual patients. Several treatments are available that can improve the course of this chronic bone disease, and lead to significant reductions in fractures. Bisphosphonates have proven efficacy, are widely available and currently recommended as the first-line of therapy for osteoporosis in many practice guidelines. In addition to demonstrating clinical benefit, from a health-policy perspective, the economic benefits regarding prevention and treatment must be established. In recent years, several health economic studies have examined the cost-effectiveness and cost-utility of bisphosphonates in various patient groups. This paper reviews a number of these studies regarding the economic benefits of treating osteoporosis with bisphosphonates and considers for whom prevention and/or treatment is most warranted.     

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.     

A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis

AIMS: Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation. METHODS AND RESULTS: Using selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the alpha chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a "kinetics of drug action" or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing. CONCLUSIONS: This validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.     

Diagnosis and treatment of osteoporosis in postmenopausal women with distal radius fracture in Germany

ABSTRACT

Objective: The aim of this study was to evaluate osteoporosis diagnosis and treatment on the basis of medical history, at hospital discharge, and 6–12 months after discharge, as well as to assess the frequency of subsequent fractures in postmenopausal women with distal radius fracture.

Research design and methods: A prospective, observational study of hospitalized women aged 55 years and older with an isolated distal radius fracture from minimal trauma. Subjects were recruited in 242 acute care hospitals in Germany.

Outcome measures: Potential risk factors for osteoporosis, frequency of osteoporosis assessment, frequency of medication treatment and subsequent fractures 6–12 months after discharge.

Results: Among 2031 patients we identified 652 appropriate postmenopausal women. Less than one-third of patient histories contained any bone density parameters, and only a minority of subjects (33%, 217) underwent bone density assessment while in hospital. Of these, 55% (119) were diagnosed with low bone density, yet only 30% of those were prescribed supplements (calcium/vitamin D) and/or specific osteoporosis medication (mostly bisphosphonates) at discharge. Six to twelve months after hospital discharge, the low rate of treatment had not changed substantially. In the interval, 4.3% had sustained a subsequent fracture from minimal trauma: 1.4% a distal radius fracture (0.3% a refracture) and 2.9% a hip joint or other fracture (not specified). A significant age difference between those with and without subsequent distal radius fractures was found (?p = 0.01) but not a significant difference between patients with or without osteoporosis medication (?p = 0.79), primarily because the case numbers were too small.

Conclusions: A substantial proportion of postmenopausal women hospitalized with distal radius fracture were not sufficiently evaluated or treated for their potential risk of osteoporosis.     

The role and efficacy of denosumab in the treatment of osteoporosis: an update

Introduction: Bone strength determinants such as bone mineral density and bone quality parameters are determined by life-long remodeling of skeletal tissue. Denosumab is a fully human mAb receptor activator of NF-κB ligand, which selectively inhibits osteoclastogenesis, the end product of a cascade interaction among numerous systemic and local factors and osteoblasts. It has been approved for clinical use by the FDA in the US and by the European Medicines Agency in Europe since June 2010 (trade name Prolia^?, Amgen, Thousand Oaks, CA, USA).

Areas covered: This review establishes the concerns and provides insights in issues concerning the cost-effectiveness and safety profile of this new pharmaceutical agent. There is an effort to clarify the special characteristics and the anti-catabolic role of denosumab in the bone tissue homeostasis and more specifically its potential clinical applications and clinical results in the field of postmenopausal osteoporosis.

Expert opinion: Administrated as a subcutaneous injection every 6 months, denosumab has been shown to decrease bone turnover and increase bone mineral density in postmenopausal women with low bone mass or osteoporosis and reduce vertebral, hip and nonvertebral fracture risk in postmenopausal women with osteoporosis. The rapid, sustained and reversible effect in suppressing osteoclastic bone resorption, the return of responsiveness on rechallenge, its good tolerability and ease of administration are features that distinguish it from other antiresorptive therapies.