Supplements Fracture Prevention in Osteoporosis
Assessment of the Prevalence and Costs of Osteoporosis Treatment Options in a Real-world Setting
Osteoporosis-related nonvertebral fractures increase the risks for morbidity and mortality and add substantially to treatment costs. As an adjunct to controlled, clinical trials, observational studies based on information from large, integrated medical and pharmaceutical claims databases provide an opportunity to assess the "real-world" cost effectiveness of treatment options aimed at reducing osteoporotic fracture risk. Although they lack the stringent controls required to establish causation, these studies include a large treatment population that reflects current disease prevalence, prescribing practices, and treatment- cost patterns in the managed care setting. This article reviews data from key observational studies that used analyses of the large Protocare Sciences Integrated Medical and Pharmaceutical Claims Database, which includes claims and eligibility records for >3 million individuals covered annually under various public and private benefit plans, to explore the cost effectiveness of oral bisphosphonatesâ€”risedronate and alendronateâ€”in reducing the risk for nonvertebral fracture. In addition, the data from the Protocare database were used to examine the cost implications of differences in gastrointestinal tolerability in these agents.
(Am J Manag Care. 2006;12:S191-S198)
Osteoporosis is responsible for more than 1.5 million fractures annually, mostly (850 000) nonvertebral.1 Osteoporosis-related nonvertebral fractures spur disconcerting increases in the risks for disability and early mortality, especially in women. In 2001, 315 000 individuals in the United States >45 years of age were admitted to the hospital for hip fracture, the most common nonvertebral fracture type secondary to osteoporosis.2 Further, 20% of individuals who were ambulatory before a hip fracture required long-term care afterwards; and the mortality rate for individuals >50 years of age who experienced a hip fracture soared to almost 25% during the first year after a fracture. Not surprisingly, the direct costs related to hospital and nursing home care for osteoporotic hip fractures is substantial–$ 18 billion in 2002–and expected to grow in coming decades.
The results of long-term, placebo-controlled trials reveal potentially important differences among common oral treatments for osteoporosis in terms of nonvertebral fracture risk reduction (Figure 1).3-12
All oral agents–raloxifene and the bisphosphonates–yield at least some reduction in the relative risk for vertebral fracture. With risedronate treatment, for example, significant reductions are discerned within 6 months of treatment initiation.13 But, in the real-world, managed-care setting, what do these clinical trial results mean in terms of improved clinical and cost outcomes? To help answer that question, this article, using observational data from real-world, administrative claims databases, assessed the economic impact of different osteoporosis-treatment options, mainly bisphosphonates, in reducing fracture-related costs, as well as the costs associated with bisphosphonate-related gastrointestinal adverse events, providing a picture of the treatment costs relevant to a managed care setting.
Observational Database Studies
For a variety of reasons, no prospective head-to-head studies have been conducted to date comparing antiresorptive agents using fracture risk as the primary endpoint. Because the absolute risk of osteoporosis-related fracture is small in clinical trials, large study populations, perhaps in the tens of thousands, might be needed to provide adequate statistical power to discern significant differences in fracture rates between treatments. In addition, these trials would be time consuming and expensive for the sponsor. Moreover, about 80% of patients prescribed drugs for the management of osteoporosis in the real world would be ineligible for such clinical studies.14 The main reasons for ineligibility would likely include the presence of comorbidities, such as gastrointestinal disorders; the use of prior osteoporosis treatments; and current therapy with glucocorticoids, anticoagulants, or anticonvulsants. Yet, these excluded patients reflect a patient mix typically encountered in the clinical setting. As a consequence, the applicability of standard clinical trial results to the broader managed care population should be viewed with appropriate caution.
As an alternative, observational database research may represent the best remaining strategy for exploring the antifracture cost effectiveness of osteoporosis treatments. The benefits of observational database research include a large, relevant patient population, with copious longitudinal data that spans many types of health plans and physician specialties. Detection of treatment patterns that occur in the real-world managed care setting represents the chief potential benefit of this approach. Yet, at the same time, observational database research is fraught with important limitations–chiefly, absence of chart reviews to validate codes, inability to control extraneous variables or demonstrate causation, inability to assess the use of over-the-counter products, as well as the possible presence of selection bias.15 This article will review 2 studies conducted using a national insurance claims database assessing the incidence and economic impact of fractures and the gastrointestinal consequences of treatment.
Nonvertebral Fracture Risk Reduction: Risedronate, Alendronate, and Calcitonin Compared
In a 2004 study, Watts and colleagues investigated the effectiveness of risedronate and alendronate, relative to nasal calcitonin and each other, in reducing the risk of nonvertebral fractures.16 Used as a data source in this study, the Protocare Sciences Integrated Medical and Pharmaceutical Claims Database includes claims and eligibility records for > 3 million individuals covered annually under various public and private benefit plans.
The subset of patients captured in this study included men and women =45 years of age who required a new prescription for nasal calcitonin, alendronate (5 mg or 10 mg daily, and 35 mg or 70 mg weekly), or risedronate (5 mg daily or 30 mg weekly) between July 1, 2000, and December 31, 2001. A total of 7081 patients were included, with 774 prescribed nasal calcitonin, 1000 risedronate, and 5307 alendronate, a distribution reflecting prescribing patterns at the time of the study.
In the 6-month pretreatment period, individual fracture histories were examined; patients with =1 fractures of the hip, vertebrae, or wrist were considered to have a prior fragility fracture. In the post-treatment period an assessment of the incidence of nonvertebral fractures–clavicle, leg, wrist, hip, pelvis, and humerus–was performed after 6 and 12 months of treatment. An analysis of baseline characteristics, however, discerned several statistical differences among groups (Table 1).
Most notably, significantly fewer patients receiving calcitonin used hormone therapy when compared with those receiving risedronate or alendronate. Further, a significant increase in the mean number of concomitant medications and the mean number of physician visits emerged in the calcitonin group versus the bisphosphonate groups.
The 6-month results revealed, versus calcitonin, relative risk reductions for nonvertebral fracture of 26% and 69% for alendronate and risedronate, respectively (Figure 2). Similar findings were seen in the 12-month analysis with relative risk reductions of 25% and 75%, respectively, for alendronate and risedronate compared with calcitonin. Moreover, risedronate treatment yielded relative risk reduction of 54% and 59% after 6 months and 12 months, respectively, versus alendronate. Findings from the Watts study, an observational analysis of "real-world" data from an actual large claims database, suggest that risedronate treatment can be more effective than either calcitonin or alendronate in reducing the risk for nonvertebral fractures early in treatment.
These findings were consistent with those from controlled clinical trials, in which comparable reductions surfaced in the risk for osteoporotic nonvertebral fractures with risedronate after 3 years' therapy (59%) and with alendronate after up to 4 years' therapy (32%-40%).5,13
Cost-benefits Analysis. From a managed care perspective, however, a central question remains unanswered: What is the economic benefit of reducing nonvertebral fracture risk with risedronate versus calcitonin or alendronate? Brixner and colleagues addressed this issue in a study that estimated direct medical costs for nonvertebral fractures in the first year of therapy in patients treated with risedronate, alendronate, or calcitonin using cost data from the Protocare Integrated Medical and Pharmaceutical Claims Database.17
This 12-month economic evaluation (from the start of new therapy) included 5024 patients: 656 receiving nasal calcitonin, 652 risedronate, and 3716 alendronate. The Medicare fee schedule for fracture-related payments, based on selected diagnosis-related group (DRG) and Current Procedural Terminology (CPT) codes, was used to standardize costs. When the 12-month nonvertebral fracture reduction data from the Watts study (Figure 2) were applied to nonvertebral fracture costs gleaned from the Medicare fee schedule, substantial differences emerged in the annual nonvertebral fracture-related cost per patient per year for calcitonin, alendronate, and risedronate treatment, with risedronate treatment yielding significantly reduced costs (Figure 3).
Table 2 provides a further breakdown of the data, showing individual nonvertebral fracture sites and the per-patient, per-year costs for these fractures in the groups treated with calcitonin, alendronate, or risedronate.
These results suggest that for patients at least 45 years of age initiating treatment for osteoporosis, the use of risedronate can lower medical costs related to nonvertebral fractures during the first year of therapy. It seems reasonable to speculate that this cost benefit may be greatest in higher risk patients.
GI Tolerability and Cost Implications. Bisphosphonates have been linked to the development of upper gastrointestinal (GI) events, from nausea to ulceration, that can limit the usefulness of these products and increase treatment costs.18 Yet, in standard clinical studies, it is difficult to discern the real-world risk for bisphosphonate-related GI side effects, since high-risk individuals, such as those with active or previous GI disease or those taking antisecretory drugs, are typically excluded. For instance, 2 clinical studies compared the gastric ulcer-inducing potential of risedronate (5 mg) and alendronate (10 mg) in healthy postmenopausal women with no evidence of GI lesions at baseline.19,20 In these 2-week studies, endoscopic examinations, performed on days 8 and 15 of therapy, revealed that, compared with alendronate, risedronate reduced the risk for gastric ulceration by 50% to 70%, with the absolute incidence of gastric ulceration about 12% with alendronate and 4% to 6% with risedronate. But do these clinical trial findings correspond with the real-world findings that would reflect the population-based managed healthcare experience with these products?
To examine the differences in GI events between alendronate and risedronate, Miller and colleagues conducted a retrospective cohort study using the Protocare database.21 The study included men and women at least 65 years of age with new risedronate (5 mg) and alendronate (5 or 10 mg daily and 35 or 70 mg weekly) prescriptions between November 1, 2000, and May 31, 2002, a 19- month capture period. Excluded were patients with a diagnosis of Paget's disease, patients taking risedronate 30 mg or alendronate 40 mg daily (presumptive Paget's disease patients), as well as patients who switched products during the treatment period.