Improving Compliance and Persistence with Bisphosphonate Therapy for Osteoporosis

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1 The American Journal of Medicine (2006) Vol 119 (4A), 18S-24S Improving Compliance and Persistence with Bisphosphonate Therapy for Osteoporosis Ronald D. Emkey, MD, a Mark Ettinger, MD a,b a Radiant Research, Wyomissing, Pennsylvania, USA; and b Regional Osteoporosis Center, Stuart, Florida, USA ABSTRACT The successful treatment of patients at increased risk for fracture requires proper diagnosis and the development of a treatment plan that permits the patient to take medications in accordance with dosing guidelines and on the correct schedule. Data indicate that patients with osteoporosis who have good long-term medication compliance experience substantially lower risk of fracture. Persistence with therapy also correlates with better bone mineral density and improved suppression of bone turnover markers. Although bisphosphonates are the most potent currently approved antiresorptive agents, they have special dosing issues that can have a negative impact on long-term persistence. The inconvenience and complexity of some dosing requirements; the potential for adverse effects, especially when dosing recommendations are not followed; and very low absorption rates even under ideal conditions all contribute to poor outcomes. Extension of the dosing interval from a once-daily to a once-weekly regimen is associated with comparable efficacy, theoretically may improve gastrointestinal safety, and is associated with substantial improvement in persistence with therapy. However, compliance with weekly regimens remains suboptimal. Monthly dosing of ibandronate, a bisphosphonate, was recently approved by the US Food and Drug Administration (FDA). Although extending the dosing interval may improve compliance and persistence with bisphosphonate therapy, it is important to recognize that missed doses or improper dosing may have greater consequences with extended dosing intervals. This article highlights the importance of educating patients about their diagnosis and long-term treatment plan, including the importance of persistence with therapy and compliance with dosing recommendations Elsevier Inc. All rights reserved. KEYWORDS: Bisphosphonates; Compliance; Osteoporosis; Persistence Both prevention and management of osteoporosis require long-term therapy to reduce fracture risk and, ultimately, to maintain the patient s quality of life. Successful treatment of patients at increased risk for fracture has several prerequisites. First, patients at risk for osteoporosis must be identified. Second, a plan must be developed for long-term therapy that considers concomitant conditions, current medications, and the necessity for lifestyle modifications. In addition, the physician must assess whether the patient is likely to follow treatment recommendations; lifestyle changes in particular may be difficult to implement for many patients. Third, long-term patient education is needed Requests for reprints should be addressed to Ronald D. Emkey, MD, Radiant Research, 1235 Penn Avenue, Suite 200, Wyomissing, Pennsylvania address: bonedocron@yahoo.com. to foster understanding and the willingness to participate in an extended treatment program. Over the longer term, the patient must take medications properly, according to schedule, and persistently. CURRENT STATE OF DIAGNOSIS AND TREATMENT OF OSTEOPOROSIS A retrospective study conducted by Gehlbach and colleagues 1 illustrates the failure to recognize and treat patients with fracture (Figure 1A). In this study, vertebral fractures in the thoracic region were retrospectively identified by radiologists and compared with diagnoses made at the time of hospitalization. Moderate or severe vertebral fractures were found in 132 (14.1%) women aged 60 years who were hospitalized for any reason. In these patients, only 50% of radiology reports and 17% of medical records or /$ -see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 Emkey and Ettinger Improving Compliance and Persistence with Bisphosphonate Therapy for Osteoporosis 19S Figure 1 (A) Unrecognized vertebral fracture in women 60 years of age, hospitalized for various reasons (n 132 of 934). (B) Undertreatment of hip fracture for hospitalized patients (N 1,076) from 4 Midwestern hospitals. BP blood pressure; DXA dual X-ray absorptiometry. (Adapted from Osteoporos Int 1 and Arthritis Rheum. 2 ) discharge summaries identified the presence of a fracture. Only 18% of medical records indicated that patients had been prescribed any therapy for osteoporosis (e.g., calcium, vitamin D, estrogen replacement, or an antiresorptive agent). Although patients with previous hip fracture are at extremely high risk for additional fragility fractures, data indicate that the majority of these patients also receive inadequate treatment. In a study conducted by Harrington and colleagues, 2 clinical and bone densitometry (dual x-ray absorptiometry [DXA]) records for patients with hip fracture in 4 Midwestern US health systems were reviewed 4 months after fracture admission to examine the frequency of DXA use, calcium and vitamin D supplementation, and antiresorptive drug treatment. In this high-risk population, only 12% to 24% of patients received DXA. Calcium and vitamin D were prescribed for 5% to 27% of patients; the percentage of patients who received any antiresorptive treatment ranged from 5% to 37%, with only 2% to 10% receiving bisphosphonates (Figure 1B). 2 The low percentage of these patients who experienced a hip fracture and received bisphosphonates is important to note, because among the currently approved medications for the treatment of osteoporosis, only bisphosphonates have shown prospective reduction of hip fracture risk. A second study, conducted by Andrade and colleagues, 3 suggests that the results of the Harrington study may be generalized to nationwide clinical practice. In this study, which used data from 7 large health maintenance organizations, only 24% of patients aged 60 years who were diagnosed with a fracture of the hip, vertebra, or wrist received osteoporosis treatment during the year following the fracture. Paradoxically, this study also found that increasing age the most important risk factor for fracture was associated with a significant decrease in the dispensing of drugs to treat osteoporosis. Specifically, patients aged 70 to 75 years were 32% less likely to receive osteoporosis treatment compared with patients aged 60 to 65 years; patients aged 80 years were 72% less likely to receive osteoporosis treatment than younger patients. Additional studies provide further evidence that osteoporosis is undertreated. 4 6 Together, these data show that orthopedic surgeons who treat acute hip fracture generally

3 20S The American Journal of Medicine, Vol 119 (4A), April 2006 do not institute therapy for osteoporosis immediately following hip fracture, and that the physicians who provided follow-up care for these patients did not initiate osteoporosis therapy. Furthermore, even those at very high risk of fracture older elderly patients with preexisting fracture are not receiving optimal treatment. The average life expectancy of a 75-year-old woman is 12 years; and these patients are frequently capable of maintaining full function later in life. Because significant reduction in fracture risk is observed within 1 to 2 years of initiation of bisphosphonate therapy, even older elderly patients are likely to benefit substantially from initiation of osteoporosis treatment. 7 Adequate treatment of the older elderly patient will increase in importance as the population ages. Primary care providers can act to bridge these gaps by ensuring that their patients are receiving appropriate treatment. CURRENT STATE OF COMPLIANCE AND PERSISTENCE WITH OSTEOPOROSIS THERAPY The data summarized above clearly indicate a large gap between the need and the initial prescription for osteoporosis treatment. A second hurdle that must be overcome in the treatment of osteoporosis is ensuring that patients who receive therapy take their medications on schedule and remain on therapy as long as needed. Good compliance and persistence are essential to ensure the best long-term pharmacotherapy results. Accurate real-world data about compliance and persistence with medications for osteoporosis as well as other conditions have been difficult to obtain for several reasons. First, medication compliance in clinical trials is always better than that in clinical practice because patients are closely monitored. Second, patients who volunteer for clinical studies may be more motivated than the overall patient population. Third, published reports on medication compliance and persistence use different definitions of compliance. Fourth, patient self-reporting of medication history is often inaccurate. Although retrospective data, such as prescription refills, can be studied without introducing patient behavioral bias, there are a number of limitations to this methodology. For example, it assumes that possession of medication is an accurate surrogate for properly taking medications, and this may or may not be accurate. In addition, patients will appear to be no longer persistent if they are lost to a particular database being monitored. For example, patients who switch to pharmacies or health plans that are not part of the study may be categorized as nonpersistent even though they are still taking medication. In addition, if patients receive enough sample medications then they may delay their prescription refills, which may be inaccurately interpreted as nonpersistence in a retrospective prescription database study. Switching from one dosing schedule to another for example, from once-daily to once-weekly dosing of a bisphosphonate would appear to represent nonpersistence of the originally prescribed medication. Regardless of the methodology used to study compliance and persistence with medication, it is apparent that across disease states or severity the majority of patients fail to take their therapy properly and on schedule. Long-term persistence varies among diseases and for different medications used; however, across all diseases, patients generally take 50% of their medications as prescribed. A study conducted by Jackevicius and colleagues 8 examined compliance with statin therapy in elderly patients with and without acute coronary syndromes (ACS). In this study, 2-year adherence rates were only 40.1% among patients with ACS and 36.1% for patients with chronic coronary artery disease. Among patients receiving statins for primary prevention, only about 25% remained adherent after 2 years of follow-up. Similarly, patients with asthma take, on average, only 50% of prescribed medication. 9 Among patients with human immunodeficiency virus, in which adherence to therapy is essential to preserve both T-cell count and options for second- and third-line therapy, 36% of patients remain on treatment at 1 year. 10 These data indicate that poor compliance is common even among patients with severe disease. In conditions in which the consequences of failure to take medication are not immediate as in osteoporosis the rates of compliance are even lower. One study found that only 69% of patients who received raloxifene and 82% of patients who received alendronate for osteoporosis remained compliant at 6-month follow-up. 11 In a second study, conducted by Yood and colleagues, % of patients who agreed to be treated with a bisphosphonate remained on therapy after 1 year. Published percentages for 1- and 2-year compliance with osteoporosis therapies show wide variation, but all studies show suboptimal compliance. IMPACT OF COMPLIANCE AND PERSISTENCE ON OSTEOPOROSIS TREATMENT OUTCOMES A 2-year study conducted using healthcare database information on 11,249 women with osteoporosis found that those who took 80% of their prescribed medication doses had a 16% lower risk of fracture compared with less long-term compliant patients. 13 Another recent study showed that patients who took 80% of their osteoporosis medications had 26% reduction in fractures compared with other patients with lower long-term compliance. 14 Moreover, persistence with bisphosphonate therapy has been directly and significantly correlated with increases in hip and spine bone mineral density (BMD) and reductions in metabolic markers of bone resorption in women with low bone mass before initiating treatment. 12,15 Among patients receiving glucocorticoid equivalents of 6 mg/day of prednisone, BMD was maintained if they were compliant with bisphosphonate therapy; in contrast, those who discontinued therapy early and continued to take glucocorticoids experienced substantial losses of BMD at the spine and hip. 16

4 Emkey and Ettinger Improving Compliance and Persistence with Bisphosphonate Therapy for Osteoporosis 21S Figure 2 Patients on existing bisphosphonate therapy who remained on therapy after 12 months. (Adapted from Arthritis Rheum. 24 ) INFLUENCES ON LONG-TERM PERSISTENCE WITH OSTEOPOROSIS THERAPY Many issues may impact long-term persistence with osteoporosis medication, including cost and availability, real or perceived adverse effects, dosing frequency and convenience, the number of concomitant diseases and medications, and patients understanding of their test results and need for therapy. Cost and ready availability of medication are critical factors in ensuring compliance. As a direct result of cost, patients frequently do not have their prescriptions dispensed, take a lower dose of their medicine, or take it less often to make their prescription last longer Moreover, patients in fair or poor health and those with higher out-ofpocket prescription costs are more likely to be poorly compliant because of cost. The primary care provider must emphasize that such short-term savings have serious health implications, including fracture, and must work with the patient to develop a sustainable long-term therapy plan. Adverse events or the fear of adverse events may negatively impact medication compliance. Because patients must follow complex dosing guidelines when taking bisphosphonates to ensure optimal tolerability and absorption, patients taking these agents are particularly prone to discontinuation. In 1 study, 76% of patients who discontinued treatment with the bisphosphonate risedronate did so because of gastrointestinal adverse effects. 21 Less-frequent dosing and greater convenience has been associated with improved adherence to therapy in several disease states. For daily therapies, studies have demonstrated that the number of prescribed doses per day is inversely related to compliance. 22 Among patients with diabetes mellitus starting newly prescribed oral agents, 35.8% who received a twice-daily agent remained compliant with therapy at 1 year compared with 44.4% who received a once-daily formulation (P 0.018); this difference occurred despite a greater total pill burden in the latter group. 23 Similarly, persistence with therapy has been shown to improve among patients taking once-weekly bisphosphonate therapy compared with those taking once-daily therapy. In a retrospective study conducted by Ettinger and colleagues, a longitudinal patient database representing all reported prescriptions dispensed from approximately 25% of US retail pharmacies was used to examine persistence in women aged 50 years who received either alendronate or risedronate. 24 A total of 33,767 and 177,522 patients were receiving daily and weekly bisphosphonates, respectively. Of these, the majority in each group had received the same therapy during the prestudy period. Persistence in both groups gradually declined over the study period. After 12 months, 36.9% of patients who received daily bisphosphonates and 54.6% of those receiving weekly bisphosphonates remained on therapy (Figure 2). 24 In addition to dosing frequency issues, overall pill burden should be assessed. All osteoporosis therapies must be taken with daily calcium and vitamin D supplements. Although both calcium and vitamin D are required to obtain a therapeutic response to therapy, the resulting increase in pill burden may potentially result in decreases in the rate of compliance with therapy. The importance of calcium and vitamin D should therefore be emphasized to all patients who receive therapy for osteoporosis. Studies suggest that the greatest risk of discontinuation of therapy occurs during the first 6 to 12 months of therapy. In the study by Ettinger and colleagues, 24 the persistence rate at 1 year among patients newly prescribed with daily therapy was 15.7% compared with 39.0% for patients who had been taking daily therapy prior to the study period; a similar trend was observed in those taking weekly therapies (P ). This retrospective, prescription-based study is subject to the limitations mentioned earlier. However, despite the fact that lack of persistence may be overestimated by certain factors such as the possibility of some patients switching to other health plans or pharmacies, or appearing to stop medication but in fact just changing to a different dosing regimen these data still suggest very suboptimal

5 22S The American Journal of Medicine, Vol 119 (4A), April 2006 Figure 3 Changes in lumbar spine bone mineral density with daily risedronate (5 mg) and 2 formulations of once-weekly risedronate (35 mg and 50 mg). (Adapted from Calcif Tissue Int. 28 ) long-term treatment persistence for patients newly treated with a bisphosphonate. COMPLIANCE AND PERSISTENCE WITH BISPHOSPHONATES: KEY ISSUES Although bisphosphonates are the most potent antiresorptive agents currently available, they have special requirements that may negatively impact long-term persistence. Bisphosphonates must be taken according to strict treatment guidelines to achieve optimum absorption and minimize the risk of adverse gastrointestinal events. Patients must avoid food or drink for 30 to 60 minutes before taking the medication and the dose must be accompanied by water. Patients are then required to remain upright for 30 minutes. Failure to follow these guidelines may increase the risk of drug-related gastrointestinal side effects. Moreover, bisphosphonates are poorly absorbed even under ideal conditions; compliance with dosing recommendations is therefore essential for patients to achieve optimum therapeutic benefit Weekly dosing of bisphosphonates has become common. By limiting the need to comply with these dosing requirements to once a week, such intermittent regimens have increased the likelihood that patients will continue with therapy. Pharmacokinetic data and bone-remodeling theory predict similar efficacy for daily and weekly dosing if cumulative doses are equivalent. Although comparative fracture rates are generally not available from the noninferiority trials that compare daily and intermittent dosing, recent clinical data using surrogate markers indicate that these regimens are therapeutically equivalent. In a randomized, double-blind, active-controlled study conducted by Brown and colleagues, 28 the efficacy and tolerability of once-weekly risedronate (35 mg and 50 mg) were compared with those of once-daily risedronate (5 mg) in patients with postmenopausal osteoporosis. Mean percentage increases in lumbar spine BMD were similar in the 5-mg daily (4.0%), 35-mg weekly (3.9%), and 50-mg weekly (4.2%) groups (Figure 3); BMD increases at other sites and safety evaluations were also similar among groups. Similar results were obtained in a study comparing daily and weekly alendronate. 29 In a recent report comparing daily ibandronate (25 mg) with monthly ibandronate (100/150 mg) in postmenopausal women, investigators noted that a monthly regimen was at least as effective as the daily regimen at increasing BMD at the spine and hip and suppressing markers of BMD turnover. 30 A report of 2-year data comparing 2.5 mg daily ibandronate with monthly regimens suggest that the 150 mg/month dosage is statistically superior to the 2.5 mg/day dosage in terms of change in BMD at the lumbar spine (Figure 4). 31 Monthly oral ibandronate appeared to be a safe and effective alternative to current daily and weekly oral bisphosphonate regimens in postmenopausal women; however, no data yet support its efficacy in the prevention of nonvertebral fracture. Although weekly or monthly administration of bisphosphonates may improve compliance and persistence with therapy, the extension of dosing intervals increases the importance of full compliance with therapy because the therapeutic consequences of missing a monthly dose of bisphosphonate may be more substantial than with a weekly or daily dose. It is, however, likely that intermittent bisphosphonates may be taken within a

6 Emkey and Ettinger Improving Compliance and Persistence with Bisphosphonate Therapy for Osteoporosis 23S Figure 4 Changes in lumbar spine bone mineral density (BMD) with daily ibandronate (2.5 mg) and 3 formulations of once-monthly ibandronate (50/50 mg, 100 mg, and 150 mg). P vs daily regimen. (Adapted from Once-monthly Oral Ibandronate Dosing Is Highly Efficacious in Postmenopausal Osteoporosis. 31 ) window of days (for weekly therapy) or weeks (for monthly therapy) surrounding the designated day for dosing without a substantial negative impact on therapeutic efficacy. SUMMARY The relatively low rate of patient compliance and persistence with osteoporosis therapy means that only a small percentage of patients are receiving adequate therapy. The ready availability of tools to assess BMD permits the identification of women with osteoporosis well before they experience the consequences of this disease. Implementing osteoporosis prevention strategies lifestyle modification, dietary changes, and pharmacologic treatment should reduce fracture-related morbidity and mortality as well as reduce overall costs to the healthcare system. Primary care providers, because of their close relationship with patients, are in a good position not only to identify those in need of treatment but also to encourage patients to remain on treatment. The value of compliance and persistence with osteoporosis therapy is evident. Patients who remain on therapy have a substantially lower risk of fracture; by extension, improved compliance is associated with less functional impairment, better quality of life, and reduced morbidity. Again, the close relationship, trust, and open avenues of communication between patients and regular care providers should be leveraged to optimize osteoporosis treatment for all patients at risk for fracture. From studies comparing daily and weekly bisphosphonates, it is clear that less frequent dosing improves compliance with therapy without compromising efficacy or safety. The impact of the newer once-monthly bisphosphonate formulation on persistence remains to be determined; however, it seems likely that less frequent dosing will be associated with additional incremental improvements in compliance and persistence. The convenience of less frequent dosing may be of particular interest in younger postmenopausal patients who remain in the workforce or who have active lifestyles. In addition, compliance in elderly patients with osteoporosis who often have multiple concomitant conditions that require polypharmacy may also be substantially improved by less frequent dosing. The unique bond that develops between patients and primary care providers, obstetricians/gynecologists, or specialty consultants promotes communication and confidence in the choices the physicians and patients make for the latter s care. Because these physicians have long-term relationships with their patients, they have a critical role to play in screening for, and possibly treating, conditions like osteoporosis before they become debilitating. By ensuring that patients receive treatment and regular follow-up care for osteoporosis, these caregivers can have an important impact on the long-term health and quality of life of their patients.

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