Osteoporotic fractures are common and costly, with an

ORIGINAL Endocrine ARTICLE Care The Economics of Improving Medication Adherence in Osteoporosis: Validation and Application of a Simulation Model Amanda R. Patrick, John T. Schousboe, Elena Losina, and Daniel H. Solomon Division of Pharmacoepidemiology and Pharmacoeconomics (A.R.P., D.H.S.), and Division of Rheumatology (E.L., D.H.S.), Department of Medicine, and Department of Orthopedic Surgery (E.L.), Brigham and Women s Hospital, Boston, Massachusetts 02120; Park Nicollet Health Services and Division of Health Policy and Management (J.T.S.), University of Minnesota, Minneapolis, Minnesota 55416 Context: Adherence to osteoporosis treatment is low. Although new therapies and behavioral interventions may improve medication adherence, questions are likely to arise regarding their cost-effectiveness. Objective: Our objectives were to develop and validate a model to simulate the clinical outcomes and costs arising from various osteoporosis medication adherence patterns among women initiating bisphosphonate treatment and to estimate the cost-effectiveness of a hypothetical intervention to improve medication adherence. Design: We constructed a computer simulation using estimates of fracture rates, bisphosphonate treatment effects, costs, and utilities for health states drawn from the published literature. Probabilities of transitioning on and off treatment were estimated from administrative claims data. Setting and Patients: Patients were women initiating bisphosphonate therapy from the general community. Intervention: We evaluated a hypothetical behavioral intervention to improve medication adherence. Main Outcome Measures: Changes in 10-yr fracture rates and incremental cost-effectiveness ratios were evaluated. Results: A hypothetical intervention with a one-time cost of $250 and reducing bisphosphonate discontinuation by 30% had an incremental cost-effectiveness ratio (ICER) of $29,571 per qualityadjusted life year in 65-yr-old women initiating bisphosphonates. Although the ICER depended on patient age, intervention effectiveness, and intervention cost, the ICERs were less than $50,000 per quality-adjusted life year for the majority of intervention cost and effectiveness scenarios evaluated. Results were sensitive to bisphosphonate cost and effectiveness and assumptions about the rate at which intervention and treatment effects decline over time. Conclusions: Our results suggests that behavioral interventions to improve osteoporosis medication adherence will likely have favorable ICERs if their efficacy can be sustained. (J Clin Endocrinol Metab 96: 2762 2770, 2011) Osteoporotic fractures are common and costly, with an estimated 2 million fractures occurring in the United States each year, resulting in direct medical costs of $19 billion (1). Randomized controlled trials have demonstrated the efficacy of bisphosphonate therapy to reduce vertebral and nonvertebral fractures in patients with osteoporosis, with estimated risk reduction of 40 50 and 20 40%, respectively (2). However, many patients initi- ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright 2011 by The Endocrine Society doi: 10.1210/jc.2011-0575 Received March 3, 2011. Accepted June 15, 2011. First Published Online July 6, 2011 Abbreviations: ICER, Incremental cost-effectiveness ratio; PACE, Pennsylvania Pharmaceutical Assistance Contract for the Elderly; QALY, quality-adjusted life year. 2762 jcem.endojournals.org J Clin Endocrinol Metab, September 2011, 96(9):2762 2770

J Clin Endocrinol Metab, September 2011, 96(9):2762 2770 jcem.endojournals.org 2763 ating bisphosphonates receive only a fraction of this benefit due to nonadherence. Approximately 50% of subjects discontinue therapy within 1 2 yr (3), and studies examining the relation between osteoporosis medication adherence and effectiveness have consistently documented reduced benefits in nonadherent patients (4, 5). Innovations in osteoporosis treatment are likely to improve adherence. Observational studies suggest that less frequent bisphosphonate dosing is associated with improved adherence, with 12 27% higher adherence at 1 yr among patients prescribed weekly vs. daily bisphosphonates (6) and some (7) but not all (6, 8) studies reporting further improvements associated with monthly vs. weekly dosing. Recently approved iv formulations of the bisphosphonates ibandronate and zoledronic acid, as well as new agents such as denosumab, which is administered by sc injection, are administered on a quarterly to annual basis. Beyond therapeutic innovation, several recent studies have investigated behavioral interventions to improve adherence (9). Although effectiveness varied considerably by intervention, two studies found that patient counseling by nurses was associated with improved adherence. The behavior change technique of motivational interviewing, used in one of these studies and in several other disease areas, is being tested in an ongoing osteoporosis intervention study, in which trained health educators deliver a counseling-based intervention over the telephone on an approximately monthly basis (10). As new therapeutic options and behavioral interventions are considered, questions regarding their cost-effectiveness will arise. Accurately capturing adherence patterns and the effect of adherence on clinical benefit will be particularly important in analyses of such interventions. Methods for assessing the long-term clinical and economic consequences of osteoporosis treatments are well developed (11), and numerous studies have evaluated the costeffectiveness of targeting various patient groups for osteoporosis screening and treatment (12). However, these studies have largely missed the opportunity to examine the impact of nonadherence or incorporated it at a population level in a sensitivity analysis only. More recently, work has focused on methods for using microsimulation to model subject-level adherence patterns in models of osteoporosis treatment (13), and applied studies have assessed the effect of nonadherence on the cost-effectiveness of screening and various treatment regimens (14, 15). These models have not yet been used to evaluate the economics of adherence improvement interventions and are limited in that they have considered a limited range of possible relations between adherence and effectiveness. In this paper, we describe the development and validation of a model to simulate osteoporosis medication adherence patterns, clinical outcomes, and costs over a lifetime horizon from a U.S. societal perspective. Using this model, we estimate the cost-effectiveness of a hypothetical intervention to improve medication adherence among patients initiating bisphosphonate treatment and the sensitivity of our findings to various model assumptions. Materials and Methods We constructed a state transition model and used simulation at a patient level (microsimulation) to simulate patient-level medication adherence patterns, fracture outcomes, and osteoporosisrelated costs among community-dwelling patients initiating bisphosphonates. This model (Fig. 1) simulates the progression of patients as they move through a series of states describing health status (healthy, after hip fracture, after distal forearm fracture, after clinical vertebral fracture, after morphological vertebral fracture, after other fracture, and dead) and bisphosphonate treatment (on or off treatment). Movement between these states is governed by a series of parameters describing probabilities of fractures, mortality, and treatment discontinuation and reinitiation. Transitions are modeled as occurring at the end of each 3-month cycle. The model produces estimates of life expectancy, qualityadjusted life expectancy expressed in quality-adjusted life years (QALY), and osteoporosis-related costs over a lifetime horizon. By simulating a cohort of patients initiating bisphosphonates under two different scenarios, for example, an intervention to improve bisphosphonate adherence vs. usual care, it is possible to compare outcomes under these two scenarios. Incremental cost-effectiveness ratios (ICERs) for the adherence intervention vs. usual care are calculated as a difference in lifetime costs divided by a difference in lifetime QALY. The model is designed to conduct analyses from a societal perspective such that all costs are included regardless of payer. Future costs and life years are discounted at an annual rate of 3% to reflect the greater value placed on current vs. future resources, as recommended by the Panel on Cost-Effectiveness in Health and Medicine (16). The discount rate was varied from 0 5% in sensitivity analyses. All analyses were conducted with Data TreeAge Pro (TreeAge, Williamstown, MA). Model inputs Rates of treatment discontinuation and reinitiation were derived from an analysis of claims data, as described below. Remaining model inputs were derived from the published literature. Fracture rates Rates of fracture as a function of age, sex, and clinical site, adjusted to reflect rates among community-dwelling elderly, were calculated using data from the Rochester Epidemiology Project Study (17) and previously described methods (18), briefly summarized here. Other fracture rates were calculated based on rates of proximal forearm, humerus, distal femur, pelvis, proximal tibia/fibula, clavicle, scapula, and sternum fractures. The fracture rates for community-dwelling seniors were further adjusted using published methods (18) to reflect the greater prevalence of risk factors such as previous fracture and osteo-

2764 Patrick et al. Osteoporosis and Economics of Adherence J Clin Endocrinol Metab, September 2011, 96(9):2762 2770 Treatment Strategies Usual Care M Intervention M Health States On Treatment No prior Fx Prior Distal Forearm Fx Prior Clinical Vertebral Fx Prior Morphological Vertebral Fx Prior Hip Fx Prior Other Fx Prior Hip and Clin. Vertebral Fx Dead Off Treatment M No Prior Fx Prior Distal Forearm Fx Prior Clinical Vertebral Fx Prior Morphological Vertebral Fx Prior Hip Fx Prior Other Fx Prior Hip and Clin. Vertebral Fx Dead Clinical Events During Cycle No event Distal Forearm Fx Morphological Vertebral Fx Clinical Vertebral Fx Fatal Hip Fx Non-fatal Other Fx Death (other causes) porosis among the target population for this study, patients initiating osteoporosis medications. The site-specific fracture incidence rates derived from the Rochester Epidemiology Project study were calculated among patients who had not experienced a previous fracture at that specific anatomical site. To capture the increased risk of repeat fractures after an incident fracture, we assumed that a previous vertebral fracture was associated with a 4-fold increase in a repeat vertebral fracture (19), a previous hip fracture with a 1.7- fold increased risk of a subsequent hip fracture (20), a previous distal forearm fracture with a 2.1-fold increased risk of a subsequent distal forearm fracture (21). These increased risks were assumed to persist for 10 yr after the initial fracture. Prevalence of osteoporosis and previous fracture among patients initiating bisphosphonates Age group and sex-specific estimates of the prevalence of osteoporosis and previous fracture were derived by combining two study populations: 163 patients who completed a baseline survey as part of OPTIMA (10), a trial to assess the efficacy of a telephonic intervention to improve osteoporosis medication adherence among patients 65 yr or older, and 590 patients aged 65 yr or older who participated in a study on predictors of medication persistence and compliance (22). Effectofbisphosphonatetreatmentonfractureoutcomes Based on a Cochrane Collaboration metaanalysis of randomized controlled trials of alendronate in women, bisphosphonate therapy was assumed to reduce the rate of vertebral fracture by 45%, hip fracture by 53%, and nonvertebral, nonhip fracture by 23% for women under full adherence (23). A 64% vertebral fracture rate reduction and 27% nonvertebral rate reduction were assumed for men based on data from the two published randomized controlled trial of alendronate in men (24). The fracture reduction benefit was assumed to begin after 3 months of } } } Medication Events During Cycle Remain on / Re-intiate tx Remain off / Discontinue tx Legend Decision node Chance node M Markov node Terminal node FIG. 1. Model structure. Patients enter the model distributed between the on-treatment health states, excluding dead. In each simulated 3-month cycle, patients may experience no clinical event, a fracture, or death. Patients who remain alive and have been on treatment can remain on treatment or discontinue treatment; patients who have been off treatment can remain off treatment or reinitiate treatment. Patients begin the next cycle in a state determined by their clinical event history and most recent medication events. The process is repeated until all patients are dead. treatment, persist through the fifth year of treatment, and then decline linearly to no effect at 10 yr (11, 13). For patients discontinuing treatment before the end of 5 yr, we assumed that the length of the treatment offset period was equal to the duration of treatment, based on data suggesting that the rate of bone loss after treatment discontinuation is dependent on the duration of therapy (25). Because the residual clinical benefit after treatment discontinuation is poorly understood, we conducted a series of sensitivity analyses around the duration of the treatment offset period (maximum of 1 vs. 5 yr), the way in which residual benefit declines over time (linearly vs. logarithmically), and the minimum duration of treatment required to obtain a residual benefit after discontinuation. Patterns of bisphosphonate use Probabilities of bisphosphonate discontinuation and reinitiation under usual care were estimated from a cohort of patients aged 65 yr or older dually enrolled in Medicare and a Pennsylvania pharmaceutical benefit program for the elderly [Pennsylvania Pharmaceutical Assistance Contract for the Elderly (PACE)]. Treatment discontinuation was defined as having a 30-d gap during which no bisphosphonate supply was available. Because the average proportion of days covered during treated intervals was 94%, with 93% of patients having proportion of days covered of 80 100%, we assumed full bisphosphonate efficacy during treated intervals. Our approach closely mirrors recently published recommendations (13) for the incorporation of adherence into osteoporosis models with two exceptions. First, because the target population is patients who have filled an initial prescription, we did not incorporate primary nonadherence. Second, we included treatment reinitiation because the intervention may affect reinitiation rates and because reinitiation appears to be a common occurrence among elderly patients receiving osteoporosis medications. Estimates of bisphosphonate persistence derived from PACE are similar to those reported in the literature for patients initiating bisphosphonate treatment (26). Mortality rates Background mortality rates by age and sex were obtained from 2006 U.S. life tables. Mortality during the 6 months after a hip fracture was assumed to be 6.28 times the background rate (27). In the primary analysis, no excess mortality was assumed beyond 6 months or after fractures at other anatomic sites (27, 28). Because there is controversy surrounding the effect of fractures on mortality, we conducted sensitivity analyses where we included a 23% (29) and 90% (30) increased risk of mortality in remaining years of life after vertebral and hip fractures, respectively. In addition, we varied the short-term increase in mortality after hip fracture from a 4.9-fold to 6.7-fold increase (31). Costs We used the Red Book average wholesale price to estimate the cost of bisphosphonate treatment (32). In our base case analysis,

J Clin Endocrinol Metab, September 2011, 96(9):2762 2770 jcem.endojournals.org 2765 TABLE 1. Model parameter estimates Base case value Range Source Transition probabilities Mortality All-cause mortality rate, per 100 person-years a 1.15 NA U.S. life tables Increase in mortality during 6 months after hip 6.28 times all-case mortality 4.9 6.7 Tosteson et al. (27) fracture rate Fracture rates plus drug effect Fracture rate, per 100 person-years NA Melton et al. (17) Hip fracture a,b 0.207 Clinical vertebral fracture a,b 0.237 Morphological vertebral fracture Distal forearm fracture a,b 0.816 Other fracture a,b 0.915 Effect of bisphosphonates on fracture rates Vertebral fracture, men 0.36 0.17 0.77 Sawka et al. (24) Nonvertebral fracture, men 0.73 0.32 1.67 Sawka et al. (24) Vertebral fracture, women 0.55 0.43 0.69 Wells et al. (23) Hip fracture, women 0.47 0.26 0.85 Wells et al. (23) Nonvertebral, nonhip fracture, women 0.77 0.64 0.92 Wells et al. (23) Adherence Probability of bisphosphonate discontinuation, per 90-d interval 32% 1st 90 d after initiation, PACE data (see text) declining to 9% after 2 yr Probability of bisphosphonate reinitiation, per 38% 1st 90 d after PACE data (see text) 90-d interval discontinuation, declining to 2% after 2 yr Costs Bisphosphonate treatment, per quarter $266 $107 304 Red book, Drugstore.com (36) Acute event costs a 25% Hip fracture $51,296 Burge et al. (1) Clinical vertebral fracture $1,792 Burge et al. (1) Morphological vertebral fracture $0 Assumption Distal forearm $1,008 Burge et al. (1) Other fracture $4,362 Burge et al. (1) Ongoing, postfracture costs a 25% Hip fracture $4,405 Burge et al. (1) Vertebral, distal forearm, other fractures $0 Assumption Quality of life weights (utilities) No previous fracture a 0.86 Disutilities associated with previous fracture Morphological vertebral fracture, 1st year 0.126 Oleksik et al. (37) yr 1 6 0.06 Oleksik et al. (37) yr 6 0 Oleksik et al. (37) Distal forearm fracture, 1st year 0.06 Borgstrom et al. (38) Subsequent years 0.001 Borgstrom et al. (38) Other fracture 0.073 Kanis et al. (39) Subsequent years 0.023 Kanis et al. (39) Clinical vertebral fracture 0.23 Borgstrom et al. (38) Subsequent years 0.064 Borgstrom et al. (38) Hip fracture 0.17 Borgstrom et al. (38) Subsequent years 0.131 Borgstrom et al. (38) Clinical vertebral and hip fracture, 1st year 0.36 Tosteson et al. (40) Subsequent years 0.2 Tosteson et al. (40) NA, Not available. a Vary by age and sex. Values presented are those for 65-yr-old women. b Fracture rates are adjusted for presence or absence of previous fracture and osteoporosis. we assumed that treatment would consist of 70 mg alendronate taken on a weekly basis. The direct medical costs associated with fractures by age and clinical site were obtained from a recent study of fracture-related costs in the United States (1). For hip fractures, ongoing costs associated with nursing home placement were included. In our primary analysis, we excluded medical costs arising in added years of life; these were included in a sensitivity analysis. All costs are expressed in 2010 U.S. dollar values. Where necessary, older estimates were inflated to current dollar values using the Medical Care Component of the Consumer Price Index.

2766 Patrick et al. Osteoporosis and Economics of Adherence J Clin Endocrinol Metab, September 2011, 96(9):2762 2770 Quality of life adjustment (utilities) Utility values for postfracture states (Table 1) were derived from the published literature. Model validation Fracture risk Model-based projections of 10-yr and lifetime fracture risks by age and anatomic site were compared with estimates from the published literature to assess the model s external validity (33, 34). These projections were made for the general U.S. population. Bisphosphonate adherence Model-based projections of prescription drug use patterns over time were also validated. Specifically, the model was used to calculate the percentage of patients on bisphosphonate treatment (including patients who had restarted treatment after quitting) and the percentage of patients persistent with bisphosphonate treatment (excluding patients who had restarted after quitting) for each 3-month interval since initiation. These estimates were compared with estimates derived directly from the PACE data that had been used to calculate probabilities of transitioning on and off treatment. Analyses of hypothetical interventions to improve adherence Our base case analysis focused on an intervention costing $250 and reducing treatment discontinuation by 30% among women aged 65. The 30% relative reduction in discontinuation rates was selected based on a review of interventions to improve adherence to osteoporosis medications (15). We evaluated a variety of possible interventions by varying the intervention cost from $100 500 and the relative reduction in treatment discontinuation from 10 50%. In a series of one-way sensitivity analyses, we varied the intervention cost, intervention effectiveness, bisphosphonate cost, and assumptions surrounding the treatment onset and offset periods. To assess the joint effects of patient age, intervention cost, and intervention effectiveness, we conducted two-way analyses of treatment cost and effectiveness within women aged 65, 75, and 85. Analyses were conducted as first-order Monte-Carlo simulations. Results Model validation Model-based predictions of lifetime fracture risks for an unselected population (i.e. not restricted to bisphosphonate initiators) under the assumption of no treatment were consistent with estimates reported in the literature (34). For a 50-yr-old female, predicted lifetime risks of hip (19%), clinical vertebral (19%), distal forearm (17.5%), and any clinical fracture (52%) were extremely close to the values of 17.5, 15.6, 16, and 50%, respectively, reported in the literature. For males, the model yielded estimates of 6% for hip fracture, 6% for vertebral fracture, 2% for distal forearm fracture, and 26% for any clinical fracture, consistent with literature-based estimates of 6, 5, 2.5, and 25%. Ten-year probabilities of hip fracture predicted by the model were also consistent with estimates from the literature (33). For females, the risk increased from 1.7% at age 60 to 13.2% at age 80, consistent with estimates of 1.8 and 14.2%. For men, model-based projections increased from 0.1% at age 60 to 5% at age 80 compared with the values reported in the literature at 1.1 and 6.2%, respectively. Model-based projections of the percentage of patients on bisphosphonate treatment and persistent with bisphosphonate treatment under usual care were consistent with estimates from the PACE population (Fig. 2, A and B). Effects of an intervention to improve adherence on clinical and economic outcomes Under usual care, a population of 65-yr-old women initiating bisphosphonates had a 10-yr hip fracture risk of 8.4% and clinical fracture risk of 31.7%; these were reduced to 7.9 and 30.7% by an intervention that reduced bisphosphonate stopping rates by 30%. For 85-yr-old women, the 10-yr fracture risks of hip fracture and any clinical fracture under usual care were 17.9 and 40.3% and were reduced to 17.1 and 39.1% by a comparable intervention. A population of 65-yr-old women initiating bisphosphonate treatment under usual care had a quality-adjusted life expectancy of 9.273 QALY and osteoporosis-related costs of $25,149. An intervention costing $250 and re- A % on treatment B % persistent 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 empirical data model projection 2 4 6 8 10 12 14 16 18 20 90-day interval empirical data model projection 2 4 6 8 10 12 14 16 18 20 22 90-day interval FIG. 2. Validation of model-based projections against data on bisphosphonate use under usual care. Percentage of patients on treatment (A) and persistent with treatment (B) by 90-d interval since bisphosphonate initiation under usual care. Persistence is defined as continuous bisphosphonate use without a gap in use of at least 30 d.

J Clin Endocrinol Metab, September 2011, 96(9):2762 2770 jcem.endojournals.org 2767 Patient Characteristics Patient age (65 years)* Patient sex (female) Intervention Characteristics Intervention cost ($250) Intervention efficacy, % reduction in stopping (30%) Duration of intervention effect (5 years) Bisphosphonate Effectiveness Bisphosphonate effectiveness** Treatment onset period, months (3) Treatment offset period -- maximum years (5)*** Treatment offset period -- duration dependence*** Costs and Discounting Fracture costs (multiples of base case) Bisphosphonate cost per 3 month supply ($266) Discount rate, annual % (3) 85 Female base case value 65 0 $40K $80K $120K $160K Incremental Cost-Effectiveness ($/QALY) ducing bisphosphonate stopping rates by 30% increased quality-adjusted life expectancy to 9.285 QALY at an additional cost of $358. The ICER for this intervention vs. usual care is estimated at $29,571 per QALY. Among 65-yr-old men initiating bisphosphonates, a comparable intervention increased quality-adjusted life expectancy from 8.465 to 8.47 QALY and increased osteoporosisrelated costs from $13,694 to $14,332, yielding an ICER of $119,161 per QALY. Sensitivity analysis Figure 3 depicts a series of one-way sensitivity analyses. The cost-effectiveness of the intervention was sensitive to both intervention cost and intervention effectiveness. Reducing the cost to $100 reduced the ICER to $17,099 per QALY; increasing it to $500 increased the ICER to $49,754 per QALY. Increasing the effectiveness to a 50% reduction in stopping rates reduced the ICER to $20,692; reducing it to a 10% reduction in stopping rates increased the ICER to $71,566. Reducing the duration of the intervention effect from 5 to 1 yr increased the ICER to $136,870. The treatment offset period was another influential parameter. In the base case analysis, the offset period was assumed to be dependent on treatment duration with a maximum value of 5 yr. Reducing this maximum to 1 yr increased the ICER to $67,006; changing it to be independent of treatment duration and fixing at 5 yr increased the ICER to $93,663. Assumptions surrounding Male $100 $500 50% 10% 5 1 3 9 5 1 Yes 1.5 0.5 $107 $303 0% 5% *Intervention is cost-saving in 85 year-old women **Base case values were point estimates of hazard rate ratios from a recent meta-analysis. The lower and upper 95% confidence limits for these estimates were associated with the reported minimum and maximum ICER, respectively. ***In the base case, the treatment offset period was assumed to be equal to treatment duration, to a maximum of 5 years. FIG. 3. One-way sensitivity analyses. Each bar represents the incremental cost-effectiveness ratio of the adherence intervention for different assumptions concerning the parameter listed. The vertical line depicts the incremental cost-effectiveness ratio when all parameters are set at their base case values (listed in parentheses beside the parameter name). No the cost and effectiveness of bisphosphonate treatment were also important. At a 90-d drug cost of $107, the intervention had an ICER of $4215 per QALY; at a cost of $304, the ICER increased to $36,733. Figure 4 depicts the approximate cost-effectiveness of a variety of possible interventions to improve adherence as a function of their cost and effectiveness as well as the age group in which they are implemented. Among women age 65 initiating bisphosphonate treatment, the ICER for an adherence intervention was less than $100,000 per QALY for most possible interventions evaluated, excluding those where the reduction in treatment discontinuation was only 10% and the cost of the intervention was $400 or more. The ICER was less than $50,000 per QALY for interventions resulting in a 30% or greater reduction in stopping or for those with a cost below $300 and smaller reductions in treatment discontinuation. Among women age 75, the ICER is less than $100,000 per QALY for all interventions evaluated; the ICER is less than $50,000 per QALY for interventions with a cost of $300 or less or a reduction in treatment discontinuation of 20% or greater. Among 85-yr-old women, all interventions with a cost of $300 or less or a reduction in treatment discontinuation of 20% or greater had an ICER less than $50,000 per QALY. Discussion Poor adherence to osteoporosis treatment is a well-documented problem (3). Although new medications requiring less frequent dosing and the implementation of interventions designed to improve adherence show promise in reducing nonadherence, questions arise regarding the cost-effectiveness of such therapies and behavioral interventions to improve adherence. These questions are best answered through the use of a simulation model, such as the one described and validated in this manuscript, which accurately projects clinical outcomes and treatment adherence patterns and simulates the health and economic consequences of improvements in adherence. Using our model, we found that a hypothetical intervention to improve bisphosphonate adherence can be cost-effective for a wide range of intervention cost and

2768 Patrick et al. Osteoporosis and Economics of Adherence J Clin Endocrinol Metab, September 2011, 96(9):2762 2770 a 65 year- old women Effectiveness -- Relative Reduction in Treatment Discontinuation Cost 0.1 0.2 0.3 0.4 0.5 $100 $200 $300 $400 $500 b 75 year-old women Effectiveness -- Relative Reduction in Treatment Discontinuation Cost 0.1 0.2 0.3 0.4 0.5 $100 $200 $300 $400 $500 c 85 year-old women Effectiveness -- Relative Reduction in Treatment Discontinuation Cost 0.1 0.2 0.3 0.4 0.5 $100 $200 $300 $400 $500 Legend ICER < $50,00 / QALY ICER $50,00 - $100,000 / QALY ICER > $100,000 / QALY FIG. 4. Two-way analysis on intervention cost and intervention effectiveness. Each block represents a possible intervention characterized by its cost and effectiveness. The color coding denotes the cost-effectiveness of the intervention. effectiveness values. Among 65-yr-old women initiating bisphosphonates, for example, an intervention reducing treatment discontinuation by 20% had an ICER less than $100,000 per QALY at any cost up to and including $500. Among 75- and 85-yr-old women, the ICER was below $50,000 per QALY for the majority of cost and effectiveness values evaluated. Several previous papers have evaluated the consequences of improving osteoporosis medication adherence, although none are directly comparable to the current analysis. A U.S.-based study (35) of women age 50 yr or older with osteoporosis and a prevalent vertebral fracture reported an ICER for monthly vs. weekly bisphosphonate therapy of $9476, assuming the same price for both bisphosphonate formulations. An analysis conducted using Swedish data (13) reported that a hypothetical drug costing 200 more than standard therapy and conferring full adherence was associated with an incremental cost effectiveness ratio of 18,809 per QALY in 70-yr-old women with osteoporosis and was cost saving among 80-yr-old women with osteoporosis. The results were most sensitive to assumptions surrounding drug effect, drug price, and fracture risk, similar to our own findings. Other studies have evaluated the effect of nonadherence on the costeffectiveness of screening and treatment (14) and the effects of improved adherence on predicted fracture incidence in France (15). Our study suffers from several limitations of the published data. There is substantial uncertainty regarding several aspects of bisphosphonate therapy. Both the treatment onset and offset periods, the amount of time a bisphosphonate must be taken before its effects are manifest and the amount of time after treatment discontinuation until its effects are extinguished, are unknown. Furthermore, the pattern of effectiveness decay during the offset period is also unclear. Although we attempted to consider this uncertainty through sensitivity analyses, we have not captured all possible relationships between usage patterns and drug benefit in the current analyses. Our findings do suggest that the cost-effectiveness of improving osteoporosis medication adherence is sensitive to assumptions regarding the offset period, highlighting the need for further research in this area. The societal cost of bisphosphonate treatment is also unclear. Our results varied substantially depending on the specific bisphosphonate cost estimate used. In keeping with convention, we used the average wholesale price in our base case analysis; however, given the substantial discounts available to health plans and to patients through online pharmacies (such as drugstore.com), this may be an overestimate. On the other hand, if patients discontinuing an initial prescription tend to reinitiate a more expensive medication, the average wholesale price for generic alendronate may be an underestimate of medication cost. Finally, because the data we used in estimating bisphosphonate adherence patterns predate the widespread use of zoledronic acid for the treatment of osteoporosis, we were not able to include yearly zolendronate as a treatment option in our analysis. Our hypothetical study population consisted of women initiating bisphosphonate treatment. We estimated the prevalence of previous fracture and osteoporosis among this population using data from two surveys. However, the number of patients included in these surveys is relatively small, and the clinical composition of the populations initiating bisphosphonate treatment is likely to reflect the local practices at the two study sites. Variability between practices, health plans, and geographic regions will influence the cost-effectiveness of intervening on patients initiating bisphosphonates. In addition, we conducted our analysis using fracture rates from a Caucasian population. Compared with Caucasians, it has been estimated that African American, Asian, and Hispanic women have fracture rates that are 57%, 50%, and 47% lower, suggesting that our findings may not generalize to non-caucasian populations.

J Clin Endocrinol Metab, September 2011, 96(9):2762 2770 jcem.endojournals.org 2769 In conclusion, we developed and validated a model simulating medication adherence patterns, fracture outcomes, and osteoporosis-related costs among community-dwelling women initiating bisphosphonates. The model allows us to estimate the ICER for a variety of hypothetical interventions, such as reminders and counseling interventions, aimed at improving medication adherence. Our simulations suggest favorable ICER for the majority of intervention effectiveness and cost assumptions, especially for older women. One potential implication is that some patients currently being prescribed drugs with a less frequent dosing interval could instead be given medications requiring more frequent dosing coupled with an adherence intervention. Given the growing interest in reducing nonadherence to medications through behavioral interventions and the development of new therapies, the incorporation of adherence into decision analytic models is an important area of research. Acknowledgments We thank Joe Melton for sharing unpublished data on first fracture rates. Address all correspondence and requests for reprints to: Amanda Patrick, Brigham and Women s Hospital Division of Pharmacoepidemiology, 1620 Tremont Street, Suite 3030, Boston, Massachusetts 02120. E-mail: arpatrick@partners.org. This work was supported by a grant from the National Institutes of Health (NIH P60 AR047782). The work of D.H.S. on this project is also supported by a mentoring grant from the NIH (K24 AR055989). Disclosure Summary: D.H.S. receives research support from Amgen and Abbott on work unrelated to osteoporosis. The remaining authors have nothing to disclose. References 1. 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