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.     

Review of raloxifene and its clinical applications in osteoporosis

Raloxifene, a selective oestrogen receptor modulator, is currently utilised for both the prevention and treatment of postmenopausal osteoporosis. Prevention studies with raloxifene have demonstrated preservation of bone density, suppression of markers of bone turnover and maintenance of normal bone histology for up to 4 years in young postmenopausal women. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial, the pivotal treatment trial of raloxifene, demonstrated significant reductions in the risk of vertebral fractures after 1 and 3 years, which is comparable to other currently available agents. Significant reductions in non-vertebral fractures with raloxifene have not been demonstrated yet. In addition to the effects of raloxifene on bone, a number of beneficial non-skeletal effects have been reported on the breast, uterus and cardiovascular system. These latter findings are mainly derived from secondary end points and analyses of the large osteoporosis studies with raloxifene. Two large, prospective, randomised, double-blind studies examining the effects of raloxifene on breast cancer prevention and cardiovascular protection are now underway. Recent information on the effects of raloxifene in postmenopausal osteoporosis, breast cancer prevention and cardiovascular disease in high-risk women and those with uterine disorders is reviewed in this article.     

Antiresorptive agents, raloxifene, and PHARMAC

Antiresorptive agents have become the cornerstone for the treatment of established osteoporosis. Since the significant decrease in the use of hormone replacement therapy as treatment for osteoporosis, bisphosphonates have become the cornerstone of osteoporosis treatment. For many years, vitamin D analogues had been subsidised with very little evidence of efficacy. Older bisphosphonates with difficult dosing regimes have also been available. It has taken 10 years of intense effort to ensure better availability of a new generation bisphosphonate while others remain unfunded. Raloxifene, a selective oestrogen receptor modulator, has also undergone this evaluation for some 5 years as a second-line agent for the prevention of vertebral fractures in postmenopausal women. It is hoped that the recent objectiveness shown by PHARMAC to access criteria for a newer bisphosphonate will enable raloxifene to be available to postmenopausal women with osteoporosis in a shorter timeframe. Access to alternative antiresorptives and anabolic agents is awaited with interest.     

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.     

Current approaches to the prevention and treatment of postmenopausal osteoporosis.

Current approaches to the prevention, detection, treatment, and monitoring of postmenopausal osteoporosis are discussed. In the United States, 44 million men and women ages 50 years or older have low bone mass or osteoporosis. The most devastating consequence of this disease is fractures. The assessment of osteoporosis risk includes determining risk factors, conducting laboratory and physical examinations, and measuring bone density and bone-turnover markers. Once risk has been established, nonpharmacologic strategies, such as exercise, appropriate dietary habits, and discontinuing tobacco and alcohol use, are helpful. Fall prevention and adequate intake of calcium and vitamin D are critical. When pharmacologic therapy is warranted, bisphosphonates have shown the greatest benefit in preventing bone loss and lowering fracture rates. Selective estrogen-receptor modulators and calcitonin are also options for prevention or treatment of osteoporosis. Estrogen should not be used for the sole purpose of osteoporosis prevention; however, short-term use is acceptable for women with vasomotor symptoms or in whom the benefits outweigh the risks. Parathyroid hormone may offer another treatment alternative. A variety of pharmacologic options are available for patients with osteoporosis in whom lifestyle modifications have proven insufficient. Bisphosphonates are the mainstay of drug therapy.     

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.     

Bisphosphonates in osteoporosis: recent clinical experience

Bisphosphonates are potent inhibitors of bone resorption that have come to play a prominent role in the prevention and treatment of various forms of osteoporosis and other metabolic bone disorders. Therapy in women with osteoporosis and at high fracture risk substantially reduces the incidence of vertebral and non-vertebral fractures. In younger postmenopausal women, bisphosphonates are attractive alternatives to oestrogen to prevent bone loss and the subsequent development of osteoporosis. Bisphosphonates have recently become the treatment of choice to prevent and treat the skeletal consequences of chronic corticosteroid therapy. When administered appropriately, these drugs are very well tolerated and have an excellent safety profile. The challenges now to clinicians are to identify the patients for whom bisphosphonate therapy is indicated and to devise dosing and monitoring strategies to enhance the long-term adherence to therapy required to realise the full benefits of these treatments.     

The safety and tolerability profile of therapies for the prevention and treatment of osteoporosis in postmenopausal women

At a time when the prevalence of osteoporosis and related fractures is increasing, initiation and continuation of pharmacologic therapies for prevention and treatment of postmenopausal osteoporosis have declined. This decline has been at least in part attributable to concerns about safety of these agents, such as atypical fractures with bisphosphonates and breast cancer with estrogen/progestin therapy, particularly when they are used long term by older women. However, in many cases, absolute risk of serious adverse effects is small and should be balanced against the larger potential for fracture reduction. Here, we review the safety and tolerability of available therapies for postmenopausal osteoporosis. Taking into consideration their relative efficacy, we also provide strategies for optimization of the risk:benefit ratio.     

Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer

Osteoporosis is an important complication of androgen deprivation therapy for prostate cancer. Androgen deprivation therapy either by bilateral orchiectomies or treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density (BMD) and increases the risk of fracture. Dietary factors and lifestyle may contribute to bone loss. There are limited prospective data about treatment or prevention of osteoporosis in men with prostate cancer and many recommendations are based on studies of postmenopausal osteoporosis. Lifestyle modification including smoking cessation, moderation of alcohol consumption, and regular weight bearing exercise should be encouraged. Supplemental calcium and vitamin D are recommended. Additional treatment may be warranted for men with osteoporosis, fractures, or high rates of bone loss during androgen deprivation therapy. Recent studies have evaluated the efficacy of bisphosphonates to prevent bone loss during androgen deprivation therapy. Pamidronate (pamidronic acid), a second-generation bisphosphonate, prevents bone loss in the hip and spine during androgen deprivation therapy. Zoledronic acid, a more potent third-generation bisphosphonate, not only prevents bone loss but also increases BMD in the hip and spine. Alendronate (alendronic acid) is approved for the treatment of osteoporosis in men although its efficacy and that of other oral bisphosphonates has not been evaluated in men receiving androgen deprivation therapy. Additional prospective studies are needed to evaluate the long-term effects of bisphosphonates on fracture risk and disease-related outcomes.     

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.     

Section Review: Oncologic,Endocrine & Metabolic: Drugs in development for the treatment of metabolic bone disease

The development of potent inhibitors of bone resorption has revolutionised the treatment of common metabolic bone diseases. In the near future, bisphosphonates provide the best means to achieve appropriate clinical responses in Paget's disease and tumour-related bone diseases. In addition to bisphosphonates, newer forms of oestrogen replacement have a future role for the treatment of osteoporosis, because of potential cardiovascular benefits. In the longer term, agents that directly increase bone formation and density may become available, and have a greater role in the treatment of patients with more established osteoporosis.     

Pharmacological management of osteoporosis in postmenopausal women: a comparative review

Optimising lifestyle and diet are important in the management of osteoporosis, however, they cannot completely prevent postmenopausal bone loss. Calcium supplementation significantly retards but does not completely arrest bone loss, but several small controlled studies suggest that it reduces fracture incidence. Thiazide diuretics slow bone loss similarly but their effects on fracture incidence remain to be determined. Hormone replacement therapy (HRT) increases or maintains bone density, prevents height loss and prevents vertebral fractures. There is observational evidence that HRT decreases cardiovascular disease and increases the risks of thromboembolic disease and breast cancer. The selective estrogen receptor modulator (SERM) raloxifene also slows postmenopausal bone loss although it is less effective that HRT. It also increases the risk of thromboembolic disease but is associated with a significantly reduced risk of breast cancer. The bisphosphonates are of comparable efficacy to HRT in the prevention of bone loss and have been shown to halve the risk of fractures of the vertebrae, forearm and hip. The maintenance of normal vitamin D (colecalciferol) status is important, particularly in the elderly. HRT, the bisphosphonates and raloxifene are all suitable for use in the prevention of postmenopausal bone loss, but the former 2 are to be preferred in the treatment of established disease. The most comprehensive long term safety data are available for HRT. Clinical trials are underway at present with more potent bisphosphonates which may make possible longer dose intervals and alternative routes of administration. There is a need for an effective bone anabolic factor but those which have been trialled to date have not proceeded because of significant adverse effects.     

Treatment needs and current options for postmenopausal osteoporosis

Introduction: Osteoporosis is a chronic, skeletal disorder characterized by compromised bone strength and increased risk of fractures, affecting up to 50% of postmenopausal women worldwide. Over the past 2 decades there have been consistent developments in the pharmacotherapy of osteoporosis with the availability of potent inhibitors of bone resorption (bisphosphonates, and denosumab) or stimulators of bone formation (PTH analogs) with substantial improvements over calcitonin or estrogen replacement.

Areas covered: In this review we summarize the effects of existing treatment options for postmenopausal osteoporosis along with the unmet clinical needs and we discuss about the potential benefits of new compounds under development.

Expert opinion: Despite the recent progresses, there are still limitations and unmeet needs with all the available drugs, mainly concerning treatment adherence, efficacy on the prevention of nonvertebral fractures and the long-term adverse events of antiresorptive regimens. Moreover, PTH analogs are the only available compounds able to stimulate bone formation, but with a restricted anabolic window of no more than 2 years. Of interest, the more recent advances in bone biology identified new targets for the development of drugs with a more potent and selective activity on either osteoclasts or osteoblasts, thus making possible to uncouple bone formation from bone resorption.     

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。     

Clodronate: mechanisms of action on bone remodelling and clinical use in osteometabolic disorders

Clodronate (CI2MBP) is a non-aminated bisphosphonate that inhibits bone resorption. Studies on the mechanisms of action of this molecule on bone metabolism have been limited and only recently has information on the molecular machinery that underlies its effects on the bone remodelling process become available. Pharmacological and clinical studies have demonstrated the effectiveness of clodronate in the treatment of postmenopausal osteoporosis and in all conditions of excessive bone resorption, such as Paget's disease, hypercalcaemia of malignancy and osteolytic metastases. Clodronate is the only bisphosphonate currently available on the market for both oral and parenteral administration. Treatment with clodronate via intramuscular administration of doses of 100 mg/week has shown significant effects on bone mineral density after 6 months in patients with postmenopausal osteoporosis and these effects are maintained 3 years after the start of the treatment. In a recent controlled clinical study, a significant increase in bone mineral density was observed, associated with a 46% reduction in the incidence of vertebral fractures. However, most relevant studies have been small, unblinded and short-term and have not systematically examined the effects of the dose and dosing intervals on bone mineral density and markers of bone turnover. Ongoing controlled clinical studies may offer answers regarding potential use of clodronate in osteoporosis and also about dosage of intermittent administration. This review summarises the accumulated knowledge in the mechanisms of action of clodronate on bone remodelling. Moreover, the clinical trials on the use of clodronate in metabolic bone diseases are described in-depth. We believe that this work will help to better focus on the need for more research on a compound which has potential applications in prevention and therapy of osteoporosis. However, studies that demonstrate an effect on the rate of fractures are needed before any recommendation can be made.     

Clodronate: mechanisms of action on bone remodelling and clinical use in osteometabolic disorders

Clodronate (CI2MBP) is a non-aminated bisphosphonate that inhibits bone resorption. Studies on the mechanisms of action of this molecule on bone metabolism have been limited and only recently has information on the molecular machinery that underlies its effects on the bone remodelling process become available. Pharmacological and clinical studies have demonstrated the effectiveness of clodronate in the treatment of postmenopausal osteoporosis and in all conditions of excessive bone resorption, such as Paget’s disease, hypercalcaemia of malignancy and osteolytic metastases. Clodronate is the only bisphosphonate currently available on the market for both oral and parenteral administration. Treatment with clodronate via intramuscular administration of doses of 100 mg/week has shown significant effects on bone mineral density after 6 months in patients with postmenopausal osteoporosis and these effects are maintained 3 years after the start of the treatment. In a recent controlled clinical study, a significant increase in bone mineral density was observed, associated with a 46% reduction in the incidence of vertebral fractures. However, most relevant studies have been small, unblinded and short-term and have not systematically examined the effects of the dose and dosing intervals on bone mineral density and markers of bone turnover. Ongoing controlled clinical studies may offer answers regarding potential use of clodronate in osteoporosis and also about dosage of intermittent administration. This review summarises the accumulated knowledge in the mechanisms of action of clodronate on bone remodelling. Moreover, the clinical trials on the use of clodronate in metabolic bone diseases are described in-depth. We believe that this work will help to better focus on the need for more research on a compound which has potential applications in prevention and therapy of osteoporosis. However, studies that demonstrate an effect on the rate of fractures are needed before any recommendation can be made.     

Non-vertebral fracture risk reduction with oral bisphosphonates: challenges with interpreting clinical trial data

BACKGROUND: To license a therapy for the treatment of postmenopausal osteoporosis pharmacological agents must show ability to reduce the incidence of morphometric vertebral fractures versus placebo over a 3-year study period. In Europe, recent registration guidelines require evidence of reduction of vertebral and non-vertebral fracture incidence over a minimum of 2 years compared with placebo. There is much interest in the prevention of non-vertebral fractures. While morphometric vertebral fractures are assessed and statistically powered as the registration primary endpoint in clinical trials, non-vertebral fractures are often measured as secondary endpoints or captured as adverse events, which have selection biases in data capturing. AIM: To describe factors that influence fracture risk and the rate of osteoporotic non-vertebral fractures observed in randomized controlled studies of the oral nitrogen-containing bisphosphonates licensed for the treatment of postmenopausal osteoporosis (alendronate, risedronate and ibandronate). METHODS: A literature search was conducted using PubMed and ISI Web of Knowledge and using keywords representing drug names and trial types. Results were screened using selection criteria based on trial type and vertebral fracture endpoint of trials published from 1990 to 2007. Findings and conclusion: Without comparative head-to-head antifracture studies, current evidence does not support a clear differentiation in fracture reduction among the different bisphosphonates. The rate of fracture in a clinical study is dependent on different factors (e.g., skeletal fragility), which may vary from study to study. Even in trials assessing non-vertebral fractures as a primary endpoint, differences in study design, randomized population and varying definitions of what constitutes a non-vertebral fracture can influence outcomes. In addition, falls and fall-related risk factors have never been controlled for in or between individual studies. Although etidronate, administered with an extended between-dose interval, has demonstrated a significant reduction in fracture risk, this was in a subgroup population, with the addition of phosphate or when only data from weeks 61-150 of the study were included in the analysis. None of the remaining currently registered non-daily oral bisphosphonates have prospective fracture data, and have, therefore, been registered on the basis of non-inferiority (surrogate marker bone mineral density and bone turnover marker) endpoints. However, a lack of evidence, if the appropriately designed studies have not been completed, does not necessarily indicate a lack of efficacy. Such a conclusion can only be drawn if a suitable study has been completed that definitively shows a lack of effect on non-vertebral fractures.     

Prevention of glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis. The role of the Wnt signaling pathway in bone formation and the ratio of receptor activator for NF-κB ligand versus osteoprotegerin in bone resorption are exciting new insights. The absolute fracture risk helps both clinicians and patients to interpret the results of bone density measurement, which may have a positive influence on adherence to therapy. The bisphosphonates alendronate and risedronate are the first-line treatment in the prevention of glucocorticoid-induced osteoporosis, because both increase the bone mineral density of the spine and hips and reduce the vertebral fracture rate. Treatment with the anabolic agent parathyroid hormone (1 – 34) strongly stimulates bone turnover, and seems to be superior to treatment with alendronate. It might be attractive for glucocorticoid-treated patients with new vertebral fractures during treatment with bisphosphonates, and/or with severe fracture risk.     

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.     

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.