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Objective: To estimate the impact of medication adherence on the cost–effectiveness of mass-screening by bone densitometry followed by alendronate therapy for women diagnosed with osteoporosis.
Methods: A validated Markov microsimulation model with a Belgian health-care payer perspective and a lifetime horizon was used to assess the cost per quality-adjusted life year (QALY) gained of the screening/treatment strategy compared with no intervention. Real-world adherence to alendronate therapy and full adherence over 5 years were both investigated. The real-world adherence scenario employed adherence data from published observational studies, and medication adherence was divided into persistence, compliance, and primary adherence. Uncertainty was investigated using one-way and probabilistic sensitivity analyses.
Results: At 65 years of age, the costs per QALY gained because of the screening/treatment strategy versus no intervention are €32,008 and €16,918 in the real-world adherence and full adherence scenarios, respectively. The equivalent values are €80,836 and €40,462 at the age of 55 years, and they decrease to €10,600 and €1229 at the age of 75 years. Sensitivity analyses show that the presence of the upfront cost of case finding has a substantial role in the impact of medication adherence on cost–effectiveness.
Conclusion: This study indicates that nonadherence with osteoporosis medications substantially increases the incremental cost–effectiveness ratio of osteoporosis screening strategies. All aspects of medication adherence (i.e., compliance, persistence, and primary adherence) should therefore be reported and included in pharmacoeconomic analyses, and especially in the presence of the upfront cost of case finding (such as screening cost).
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Medication nonadherence is a widespread public health problem, especially in chronic diseases such as osteoporosis. Approximately 75% of women who initiated osteoporosis drug therapy were shown to be nonadherent with treatment within 1 year, and almost 50% discontinued therapy by this time . Poor adherence to drug therapy is associated with adverse outcomes, and nonadherent patients have a significantly greater risk of fractures [2,3]. Such behavior may have a substantial impact on the cost–effectiveness of interventions [4,5] and, in particular, for screening strategies which include the upfront cost of case finding.
Screening for osteoporosis has been widely recommended for identifying patients at high risk before any fracture occurs . The cost–effectiveness of screening strategies is of obvious importance, and many studies have been reported in the literature . These studies have mainly investigated the cost–effectiveness of bone densitometry combined with therapy [8–10], of pre-screening strategies for bone densitometry (e.g. quantitative ultrasound or clinical risk factors) [11,12], and of strategies assessing absolute fracture risk combining clinical risk factors with bone densitometry [13–17].
Poor adherence to osteoporosis drug therapy was not routinely included by these studies despite its potential impact. Moreover, when adherence was included, a lack of methodological rigor and consistency in definitions reduced the impact of medication nonadherence. Some studies did provide realistic assumptions with respect to persistence with drug therapy [8,10], but additional adherence effects (such as inappropriate use of drug therapy or primary nonadherence) were largely neglected. These problems may result in the overestimation of the cost–effectiveness of osteoporosis screening .
In light of these limitations, this study aimed to evaluate the impact of all aspects of medication nonadherence (i.e., non-compliance, nonpersistence, and primary nonadherence) on the cost–effectiveness of osteoporosis screening. Using our validated Markov microsimulation model, recently published in Value in Health, we estimated the cost per quality-adjusted life year (QALY) gained of bone densitometry combined with alendronate therapy for those who have osteoporosis, compared with no intervention. We also assessed the impact of the upfront cost of case finding on the effect of medication adherence on cost–effectiveness. Bone densitometry is the most widely used and recommended instrument to establish or confirm a diagnosis of osteoporosis . Despite the new World Health Organization paradigm of treating osteoporosis based on absolute fracture risk rather than bone density alone , bone densitometry remains a vital component in the diagnosis and management of osteoporosis . In Belgium, the reference country for the analysis, as in many other European countries, drug therapy is actually only reimbursed for patients with a bone mineral density (BMD) t-score ≤ −2.5, defined by bone densitometry, or in the presence of one or more fragility fracture.
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The lifetime costs, QALYs, and the ICER for the screening/treatment strategy versus no intervention are shown in Table 1, according to age and medication adherence. In the case of real-world adherence, the QALY gains of the screening/treatment strategy compared with no intervention were estimated at 0.0152, 0.0208, and 0.0163 at the ages of 55, 65, and 75 years, respectively. These values represented only 30.2%, 32.1%, and 34.2% of the one estimated with full adherence assumption. The cost per QALY gained for the screening/treatment strategy was shown to progressively decrease with increasing age of screening and to be highly sensitive to medication adherence. At the ages of 55 and 65 years, the ICERs of the screening/treatment strategy were approximately doubled under real-world adherence when compared with full adherence.
Table 1. Lifetime costs, QALYs, and ICER (cost in € per QALY gained) of the screening/treatment strategy versus no intervention, according to screening age and medication adherence
| ||No intervention||Screening/treatment strategy|
|Real-world adherence||Full adherence|
|Aged 55 years|| || || |
| Costs (€)||10,288.0||11,515.0||12,326.4|
| ICER, €/QALY|| ||80,836||40,462|
|Aged 65 years|| || || |
| Costs (€)||11,561.6||12,227.4||12,656.2|
| ICER, €/QALY|| ||32,008||16,918|
|Aged 75 years|| || || |
| Costs (€)||11,120.0||11,291.7||11,178.3|
| ICER, €/QALY|| ||10,600||1,229|
Assuming a 20% increase in adherence rates reduced the cost per QALY gained of the screening/treatment strategy at €63,482, €25,416, and €6379 at the ages of 55, 65, and 75 years, respectively (Fig. 2). The equivalent values decreased to €54,000, €22,723, and €4258 when assuming an increase of 40%. If we assumed the cost of generic alendronate, the ICER of the screening/treatment strategy at 65 years of age was €20,055 and €6322 in the real-world adherence and full adherence scenarios, respectively (Fig. 3). The equivalent values were €65,236 and €28,505 at the age of 55 years, and the screening/treatment strategy was cost-saving (i.e., lower cost and higher effectiveness) at the age of 75 years, even in the case of real-world adherence.
Figure 2. Impact of medication adherence on the incremental cost–effectiveness ratio (cost in € per QALY gained) of the screening/treatment strategy versus no intervention. Ad., adherence; QALY, quality-adjusted life year; RW, real-world.
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Figure 3. Incremental cost–effectiveness ratio (cost in € per QALY gained) of the screening/treatment strategy versus no intervention, assuming the cost of generic alendronate. QALY, quality-adjusted ife year.
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The impact of additional one-way sensitivity analyses on the ICER were conducted at the age of 65 years (Table 2). Each aspect of medication adherence was specifically assessed. The ICER was markedly reduced when assuming full persistence and no changes in compliance and primary nonadherence rates; while the cost–effectiveness was less sensitive to changes in compliance or in primary adherence. The increase in fracture rates for poorly compliant women had a limited impact on the results. Other one-way sensitivity analyses showed moderate increases in the cost per QALY gained with assumed lower fracture disutility, lower fracture costs and more marked increases with higher discount rates, lower fracture risk, higher therapy cost, and lower treatment efficacy (Table 2). Although model parameters and treatment specificities had an impact on the ICER of the screening/treatment strategy, they did not significantly influence the relative difference between real-world and full adherence.
Table 2. One-way sensitivity analyses of incremental cost-effectiveness ratio (cost in € per quality-adjusted life-year gained) of the screening/treatment strategy versus no intervention, for women aged 65 years
|Parameter||Real-world adherence||Full adherence|
|Adherence|| || |
| Full primary adherence*||30,040||—|
| Full compliance*||30,542||—|
| Full persistence*||20,794||—|
| A 17% increase in fracture rates for poor compliance*||31,246||—|
| A 35% increase in fracture rates for poor compliance*||32,491||—|
|Model parameters|| || |
| Discount rates 3% (costs and effects)||38,424||19,308|
| Discount rates 5% (costs and effects)||54,921||28,771|
| 0.75 times base-case fracture risk||52,014||29,958|
| 1.25 times base-case fracture risk||20,320||8,982|
| 0.75 times base-case fracture disutility||39,529||20,863|
| 1.25 times base-case fracture disutility||25,546||14,672|
| 0.75 times base-case fracture cost||37,042||20,156|
| 1.25 times base-case fracture cost||26,250||11,827|
| 0.75 times base-case therapy cost||22,122||8,317|
| 1.25 times base-case therapy cost||40,375||22,301|
| 0.75 times base-case treatment efficacy||52,838||30,614|
| 1.25 times base-case treatment efficacy||20,589||8,888|
| 0.50 times base-case offset time||41,893||22,165|
| 1.50 times base-case offset time||26,923||10,874|
Screening cost had a large impact on the effect of medication adherence on the ICER of the screening/treatment strategy (Fig. 4). At the screening age of 65 years, the ratio between real-world and full adherence, estimated at 1.89 (= 32,008/16,918), in the base-case analysis, decreased to 1.62 if screening cost was reduced by 50% and increased to 2.09 for a 50% increase of screening cost. When assuming no upfront fixed cost of case-finding, the ratio decreased to 1.35.
Figure 4. Incremental cost–effectiveness ratio (cost in € per QALY gained) of the screening/treatment strategy versus no intervention according to screening cost, for women aged 65 years. QALY, quality-adjusted life year.
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The probability that the screening/treatment strategy was cost-effective compared with no intervention increased with increasing age of screening and with improving medication adherence (Fig. 5). At a willingness to pay of €40,000, the screening/treatment strategy had a probability of being cost–effective respectively of 79.3%, 59.3%, and 2.7% at the ages of 75, 65, and 55 years in the case of real-world adherence. The equivalent probabilities were 88.7%, 90.7%, and 40.7% under full adherence assumption. The probabilities that the screening/treatment strategy was cost-saving were 15.3% and 42.7% at the age of 75 years, respectively, in the case of real-world and full adherence.
Figure 5. Cost–effectiveness acceptability curves of the screening/treatment strategy versus no intervention, according to age and medication adherence. RW, real-world; QALY, quality-adjusted life year.
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Medication nonadherence has important negative consequences for clinical outcomes as well as for cost–effectiveness, and, in particular, for screening strategies which include the upfront cost of case-finding. The present study shows that poor adherence with drug therapy significantly reduces the clinical and economic outcomes of osteoporosis screening strategy. The QALY gain in the case of real-world adherence represents only 30–35% to that estimated with full adherence and the cost per QALY gained of screening strategy versus no intervention was approximately doubled when assuming real-world adherence compared with full adherence. Sensitivity analyses showed that the presence of the upfront cost of case-finding has a substantial role on the effect of medication nonadherence on ICER; hence, making ICER, in this study, highly sensitive to medication adherence through the cost of screening.
The impact of medication nonadherence on the cost–effectiveness of osteoporosis screening strategy was greater than those reported by prior studies. For example, a Swiss-based study  showed that the ICER of a screening strategy was CHF (Swiss franc)45,545 and CHF55,533 for women aged 65 years under full and realistic persistence assumption, respectively. For US men aged 80 years , the cost per QALY gained of bone densitometry and treatment strategy was $33,128 and $45,587 with full and realistic adherence assumption. This is because prior studies have not taken into account all aspects of medication adherence, rather than because of unusual medication adherence rates in the present analysis. Most of the prior studies assumed a significant level of medication nonpersistence , but additional adherence effects (such as imperfect use of drug therapy or primary nonadherence) were largely neglected. Our study assessed all aspects of medication adherence (i.e., persistence, compliance, and primary adherence). Although persistence was shown to have the greater impact on cost–effectiveness, compliance and primary adherence have also a substantial impact on ICER and should be reported and incorporated into health economic analyses.
Improving adherence with osteoporosis medications is therefore needed to improve the cost–effectiveness of osteoporosis screening strategy. However, this is a complex and challenging issue . No clear trends regarding successful interventions have been identified  and interventions that improve adherence are rarely cost-free. New formulations and dosages schemes (i.e., monthly oral medication, or quarterly, twice-yearly or yearly intravenous infusion) have been recently developed, which in principle can improve adherence . Less frequent dosing regimens have been frequently associated with better adherence . The recent introduction of generic alendronate, by decreasing the financial burden placed on the payer, may also contribute to improve the cost–effectiveness of the screening/treatment strategy, if the clinical efficacy, safety, and adherence of generic alendronate will match those of branded alendronate.
The methodology to incorporate adherence into modeling was conceptually close to the one suggested by Ström et al. , with some remarkable difference. In modeling compliance, patients were classified as compliant (MPR ≥ 80%) and poorly compliant (MPR < 80%). The proportions of these groups were derived for any given year  and poorly compliant patients were assumed to be associated with an increased risk of fractures [2,45]. Drug cost was also reduced for the poorly compliant group.
Our results should be analyzed in the light of these limitations, including assumptions on medication adherence. First, patients were assumed to be poorly compliant if their MPR was below 80%. This group will be, by definition, diverse in their levels of compliance, which would influence the effect of therapy on fracture risk and the cost of therapy. A vast majority of poorly compliant patients had an MPR between 50% and 80%  and were therefore not divided into smaller intervals. Second, drug cost was assumed to be 100% and 80% of full price for compliant and poorly compliant women, respectively. However, it is likely that some patients in both groups will not bear all these costs. Because the mean MPR was not available in these groups, we conservatively assumed high drug cost. Third, no further treatment was assumed for patients who discontinued therapy. A refill gap period of 5 weeks was used in the observational study to assess persistence , which is among the longest refill gap periods used in previous studies . However, we cannot exclude that some patients would return to therapy after this period. A recent study identified particular patients who return from temporary interruptions in therapy . Such patients may affect the results but are difficult to include in modeling because the effectiveness of oral bisphosphonates used in an intermittent regimen is unknown. Finally, differences in methodology and in patients demographics incorporated in the available studies resulted in wide variations in reported adherence data . Country-specific data are therefore required because many determinants affected by local conditions may influence adherence rates .
Our study was constructed in line with the actual reimbursement of osteoporosis drug therapy in Belgium as well as in many European countries (i.e., women with a BMD T-score ≤ −2.5 or in the presence of prior fragility fracture). The screening/treatment strategy was close to that recently reported by Schwenkglenks et al.  and Schousboe et al. . Our results were entirely consistent with these studies and with the recommendations of the National Osteoporosis Foundation recommending the prescription of bone densitometry in all women over age 65 .
Potential limitations may, however, be related to the study design. First, the prevalence of osteoporosis in the target population (i.e., women without fracture) was assumed to be the same than in the general women population. However, particularly in those aged 75, a substantial proportion of women with early-onset osteoporosis will already have fractured or will be treated, and the remaining population may differ with respect to osteoporosis prevalence. Although the impact may not be huge, it will be higher at an older age and the cost–effectiveness differences between screening ages may be overestimated. Second, treatment length was restricted to a 5-year period, corresponding to the duration of most clinical trials. Effectiveness and adherence over a longer period is uncertain and should be assessed in clinical trials. Finally, many other screening programs are currently available. Among those, the new World Health Organization algorithm (FRAX) recommends to guide treatment decision based on absolute fracture risk combined bone densitometry with clinical risk factors, rather than bone density alone . In the context of this paradigm, bone densitometry may have a more restricted role, but is nonetheless likely to be important for some subsets of the population  and remains a vital component in the diagnosis and management of osteoporosis . Further cost–effectiveness modeling studies will be useful in defining the most cost–effective way bone densitometry can be used to identify patient who are likely to benefit from therapy . Such analyses should definitely take into account of medication adherence, given their potential impact.