Appl Health Econ Health Policy DOI 10.1007/s40258-013-0078-1
SYSTEMATIC REVIEW
A Systematic Review of Osteoporosis Medication Adherence and Osteoporosis-Related Fracture Costs in Men Yeshi Mikyas • Irene Agodoa • Nicole Yurgin
Ó Springer International Publishing Switzerland 2014
Abstract Background and objective Male osteoporosis is an increasingly important public health concern. Although several medications are approved for the treatment of osteoporosis, medication non-adherence and the associated consequences are not well documented in male populations. Our objective was to identify and summarize the current knowledge related to osteoporotic medication adherence, the potential implications of non-adherence to the medication, and the cost of osteoporosis-related fractures and health-resource utilization in men. Methods Two separate systematic searches were conducted concurrently: one to identify literature reporting male-specific adherence to anti-osteoporotic medication and the clinical consequence of non-adherence in men, and the other to identify literature reporting the cost and resource burden of osteoporosis-related fractures in men. The PubMed, MEDLINE, EMBASE, and Cochrane databases were searched using a date range of 1 January 1998 to 30 June 2012, and citations were screened based on pre-defined criteria. Results The percentage of males adherent to bisphosphonates [medication possession ratio (MPR)[0.8] over a 1-year
Electronic supplementary material The online version of this article (doi:10.1007/s40258-013-0078-1) contains supplementary material, which is available to authorized users. Y. Mikyas I. Agodoa (&) N. Yurgin Amgen Inc, One Amgen Center Drive, MS 28-3-A, Thousand Oaks, CA 91320, US e-mail: [email protected] Y. Mikyas e-mail: [email protected] N. Yurgin e-mail: [email protected]
period ranged from 32 % to 64 %. The data imply worse clinical outcomes with treatment non-adherence. Costs and resource use associated with osteoporosis-related fractures in men are high, with hip fractures generating the most cost. Conclusions One-third to two-thirds of men are not adherent to bisphosphonates. Non-adherence is associated with increased fracture risk. Estimates of direct and indirect osteoporosis-related fracture costs are also substantial in men, and may even be more costly than in women. More robust data would better inform disease management initiatives that could improve adherence to medication and outcomes in men with osteoporosis. Key Points for Decision Makers As in women, bisphosphonates are the most common osteoporosis therapy in men, and one-third to twothirds of men are non-adherent (i.e. taking fewer than 80 % of doses as prescribed) in 1 year on therapy. The limited data available suggest that low adherence is associated with greater fracture risk in males. Direct and indirect costs of osteoporosis-related fractures are substantial, and the cost per osteoporosisrelated fracture may even be higher in men than in women.
1 Introduction Osteoporosis is a chronic, asymptomatic disease that leads to decreased bone mineral density (BMD) and increased disposition to fractures from low impact forces that would not normally cause injury [1]. Fractures associated with
Y. Mikyas et al.
osteoporosis incur high medical cost, resource utilization, and societal burden [2]. Osteoporosis is more common in post-menopausal women than men, and women are more likely to be diagnosed with the disease than men [3]. However, male osteoporosis is becoming an increasingly important public health concern. The National Osteoporosis Foundation estimated that approximately 23 % (2.8 million) of individuals with osteoporosis in the US in 2010 were men, [1] and this number is expected to rise to over 3 million men by 2020. While osteoporotic fractures occur more commonly in women, and women have twice as high a risk of sustaining any fracture compared with men [4], men have worse outcomes following fracture; morbidity and mortality risk after a hip fracture is substantially higher in men than in women [5–7]. Furthermore, studies have shown that there is a low uptake of treatment and awareness of the disease in men, with fewer men than women being prescribed treatment upon discharge following a hip fracture [8]. Several therapies are available to treat osteoporosis, and treatment efficacy has been demonstrated in clinical trials through an increase in BMD and/or a reduction in fracture risk [9–12]. Current medications approved for use in men include antiresorptives and anabolics. However, adherence to most of these therapies in the clinical setting outside of trials is recognized to be low [13] and is associated with reduced anti-fracture treatment efficacy [14] as adherence to
Fig. 1 Selection of studies for the adherence analysis
therapy is required to gain the full benefits of treatment. These consequences of non-adherence have mostly been assessed for post-menopausal women and mixed-gender populations [14, 15]. The objective of this systematic review was to identify and summarize the current knowledge related to the adherence to osteoporotic medication in male populations, the potential implications of non-adherence to the medication, and the medical cost of osteoporosis-related fractures and health resource utilization in men.
2 Methods Due to the potential link between medication adherence or non-adherence and associated costly consequences (i.e. fracture), we chose to assess these together to provide a more comprehensive view of the burden of osteoporosis. Two searches were therefore conducted for this review. The first search was to identify literature reporting malespecific adherence to anti-osteoporotic medication, while the second search was to identify literature reporting the resource burden of osteoporosis in men. The PubMed database was searched for English-language studies published from 1 January 1998 to 30 June 2012 (the search date). The searches were conducted using comprehensive search strategies utilizing keywords (‘osteoporosis’, ‘patient persistence’, ‘medication adherence’, ‘bone fracture’, ‘cost’, ‘utilization’) and related medical subject
Osteoporosis-Related Fractures in Men
Fig. 2 Selection of studies for the cost and health resource utilization
headings (MeSH) [Figs. 1 and 2]. To ensure capture of key economic studies, the cost and resource utilization search was also conducted using Ovid to search MEDLINE, EMBASE, and the Cochrane Library Database. Retrospective or prospective observational studies conducted in men or in mixed populations reporting malespecific subgroup data were included in both searches. Included studies had to report the following outcomes: adherence, and consequences associated with adherence in the literature search for adherence analysis; and costs or resource utilization associated with male patients with osteoporosis-related fractures for cost-associated analysis. For the adherence analysis, all medications used to treat osteoporosis were included in the review. Adherence for the purpose of this review includes related terms, such as persistence and compliance; however, no restriction was placed on the definition since no universal standard definition exists; selection of only one definition would have resulted in the omission of potentially relevant data. For the cost analysis, all costs were reported in the original currency and in the 2012 US dollar (US$) equivalent. Conversions were computed using the World Bank’s
Purchasing Power Parity factor for the base country and year, and inflated to 2012 using country-specific annual consumer price inflation rates [16, 17]. Where no cost assessment year was specifically stated, the cost year was assumed to be the final cutoff year of the study analysis. Randomized clinical trials were excluded from the search as they do not necessarily reflect the patient population or adherence and costs in real world settings. The literature identified in the searches was screened in two stages. The first stage was a screen of the abstracts. Where abstracts were not available or could not be positively excluded according to the eligibility criteria, full-text copies of the citations were obtained and reviewed against the same eligibility criteria, and any articles that did not include male-specific information were excluded. In addition, the reference lists of retrieved publications were examined for likely candidates for inclusion in the systematic review. The initial search and abstraction of data was conducted by YM. Reference cross-check, data verification, and resolution of decision was conducted by IA and NY. The data that were extracted for each review are presented in Table 1.
Y. Mikyas et al. Table 1 Study characteristics and outcomes extracted in the adherence and cost systematic reviews in male osteoporosis Adherence review
Cost review
Study characteristics Study design, size of sample population, the size of the male population, and male-specific population characteristics or outcomes Outcomes Adherence, compliance, persistence, adherence threshold, factors associated with adherence. Osteoporotic outcomes associated with non-adherence such as fracture risk, BMD and risk of hospitalization
Costs of osteoporosis, cost of resource utilization including cost of hospitalization, rehabilitation/nursing home care/long-term care, fracture-preventive drug therapy, other osteoporosis-related direct costs
BMD bone mineral density
Table 2 Summary of treatment adherence findings in male osteoporosis Reported measure
Country/location
Treatment(s) studied
Reported values
Percent of men adherent during 12-month follow-up
USA [25, 34]
Oral and IV BP
39.2 %
Alendronate
59 %
Norway [23]
Alendronate
45 %
Turkey [21]
Oral weekly BP
49.4 %
Netherlands [29]
Oral osteoporosis medications
39.7 %
Czech Republic [33]
Alendronate, risedronate, calcitonin, strontium ranelate
52–64 %
Percent of men adherent during 24-month follow-up
USA [25]
Alendronate
54 %
Percent of men adherent during 36-month follow-up
Turkey [21]
Oral weekly BP
17.9 %
Mean MPR
USA [34]
Oral and IV BP
0.56
Persistence at 12 months
Taiwan [28]
Alendronate
0.56
USA [20]
Oral BP
0.4 weekly BP; 0.7 for monthly/weekly BP
Turkey [21]
Oral weekly BP
0.77
Germany [31]
Oral weekly alendronate
54 % for alendronate and 100 % for IV zoledronic acid
IV zoledronic acid UK [18]
Teriparatide
81.4 % for teriparatide
Persistence at 18 months
UK [18]
Teriparatide
74.3 % for teriparatide
Persistence at 3 years
Turkey [21]
Oral weekly BP
0.38
Percent of men compliant during first year on therapy
Taiwan [28]
Alendronate
32.2 %
BP bisphosphonates, IV intravenous, MPR medication possession ratio
3 Results 3.1 Adherence and Clinical Consequences of Non-Adherence Eighteen studies were included in the adherence analysis [18–35] [Table 2; electronic supplementary material (ESM) Supplemental Table 1]. Fifteen studies were retrospective analyses of databases from the US and Europe, including hospital and clinic administrative records, claims databases, and inpatient surveys [18–22, 24, 25,
28–35]. Three were prospective studies of patients being treated in clinical settings [23, 26, 27]. Five studies were conducted exclusively in male populations [18, 21, 25, 31, 33] (Table 2; ESM Supplemental Table 1). In general, male populations were numerically small or proportionally smaller than the women population in the same studies. In male-only studies, the sample sizes ranged from 92 to 198; in mixed-gender studies, the proportion of males ranged from 2 to 47 %. The majority of the studies assessed adherence to bisphosphonates [19–35].
Osteoporosis-Related Fractures in Men
The definition and measure of medication adherence varied among studies. The terms adherence [19, 20, 23, 25, 34], persistence [18, 21, 24, 29–32, 34, 35], compliance [21, 24, 27–30] (including self-reported compliance [26]), and consumption rates [33] were used to assess the adherence to medication. ‘Adherence’ was measured in terms of medication possession ratio (MPR) in most studies that reported adherence. MPR computation was not consistent across all the studies; however, in all the studies that reported MPR as a measure of adherence, a patient was considered adherent if the MPR was C0.8 (or [0.8). For these studies, the percentage of men adherent to medication ranged from 39 % (US) to 64 % (Czech Republic) over a 1-year period [20, 23, 25, 33, 34]. In two large US studies, mean MPRs (adherence) for men were \0.8 [20, 34]. The term ‘persistence’ to medication had the most varied definition in the studies included in this review. While some studies did not indicate how persistence was measured, others defined persistence as one of the following: the length of time without a considerable gap in treatment, or as the number of medications taken relative to the number of medications prescribed, or as a repeat prescription of the drug without switching, or calculated as an MPR. Acknowledging these differences in the definition of persistence, the percentage of men persistent to medication as reported ranged between 40 % (The Netherlands) and 100 % (Germany) over a 1-year period [18, 29, 31]. It should be noted that the one study with 100 % persistence was in a population receiving zoledronic acid (given annually) [31], and the one study with 81 % persistence was in a population receiving off-label teriparatide treatment (for men), where the study required specific patient monitoring (UK) [18]. Excluding these two studies, 40–77 % of men were persistent with their medication at 1 year. For studies that used compliance as a measure of adherence to medication, compliance was often described in terms of MPR. Again, as in the adherence assessment, the way MPRs were computed differed among studies; however, in general, patients were considered compliant if the MPR was C0.8. The percentage of men compliant to medication ranged between 32 % (Taiwan) and 49 % (Turkey) over a 1-year period [21, 28]. Mean reported MPRs (compliance) for men were also \0.8 (Taiwan) [28]. A few studies reported adherence for treatment beyond the first year [18, 21, 25]. In all cases, the percentage of men adherent to medication decreased. Cevikoi et al. [21] showed that the percentage of Turkish men compliant to oral bisphosphonates fell from 49 % in the first year to 18 % at the 3-year follow-up. In a US study by Hansen et al. [25], the percentage of men adherent to alendronate decreased from 59 % over 1 year to 54 % over the 2-year study period; 28 % of men had completely stopped treatment by the end of the second year of the study.
Results comparing adherence to medication in men versus women were mixed. Roerholt et al. [32] and Briesacher et al. [19] showed that patient gender had little or no influence on the persistence or adherence to treatment. Gallagher et al. [24], on the other hand, indicated that men were more persistent and compliant to bisphosphonates, while Kamatari et al. [26] indicated compliance in men was lower than in women. Three studies discussed outcomes of adherence/nonadherence to medication specifically in male populations [25, 30, 31]. These studies suggest that non-adherence in men resulted in worse outcomes, while adherence to medication improves outcomes. In Germany, Ringe et al. [31] suggested that lower persistence to weekly alendronate contributed to lower treatment efficacy, while in the US, Hansen et al. [25] reported that bone biopsy results from non-adherent men indicate that they had smaller lumbar spine mass improvements than men who were adherent to medication. Modelling analyses of UK data by Rietbrock et al. [30] showed that increased persistence and compliance to bisphosphonates (alendronate and risedronate) resulted in the prevention of additional hip fractures. 3.2 Costs and Health Resource Utilization Thirty-seven studies reported male-specific health resource utilization or costs associated with osteoporosis and osteoporosis-related fracture (Table 3; ESM Supplemental Tables 2–4). Five studies estimated the societal cost of osteoporosis or fractures by measuring both direct and indirect costs [36–40]. Thirteen studies estimated direct medical costs, including both inpatient and outpatient services [2, 41–52]. However, the cost components used to compute direct medical costs varied from study to study and from country to country. Seventeen studies took a more narrow perspective of costs and resource utilization and focused on hospital or other institutions [53–69]. Except for one study [48] all the studies assessing costs and health resource utilization were conducted in mixed populations; in almost all cases (except for Bass et al. [41] and Levy et al. [48]) the male population was significantly smaller than the female population. In terms of societal costs, estimating both direct and indirect costs of osteoporosis and osteoporosis-related fractures for men, one study found the total first year cost of incident fractures in men to be SEK944 million (2012 US$993 million) in Sweden in 2005 [36]. Another study focused on hip fractures in men and estimated the cost to be €646 million (2012 US$713 million) in Germany in 2002 [38]. Indirect costs as a proportion of total cost in men varied widely, and depended on which indirect cost components were used in the study. For instance, one study that measured indirect costs from productivity loss due to
Y. Mikyas et al. Table 3 Costs in male osteoporosis (2012 US$) Reported measure
Country/location
Range of reported valuesa
Germany [38]
Hip fracture: 713 million
Sweden [36]
All fractures: 993 million
Societal costs (direct and indirect) Total 1-year cost
California, USA [39]
Total osteoporosis cost: 897 million Total direct osteoporosis cost: 893 million Total indirect osteoporosis cost: 3.7 million
Annual long-term cost
Sweden [36]
Mean annual costs per patient
Sweden [37]
Hip fracture: 750 million Direct: 142,593 Total: 153,177
Per patient-month
Belgium [40]
Direct: 58.0 Indirect: 258.1
Direct medical costs Incremental first-year cost post-trauma fracture
Olmsted County, USA [49]
0.15 million for pelvis to 157.6 million for hip
Total 1-year costs of fracture
West Virginia, USA [51]
All osteoporotic fractures: 4.8 million
Florida, USA [43]
All osteoporotic fractures: 388 million (2000) to 660 million (2025)
5 states, USA [46]
All fractures: 1,062 million
USA [2]
All incident fractures: 4.1 billion
USA [70]
Projections
Adjusted
NHNV fracture: 177–239 million Vertebral fracture: 86–99 million Hip fracture: 21 63–97 million
France [48]
All fracture (total direct): 243 million Inpatient costs: 120.2 million Physician visits: 4.8 million
Total inpatient costs at national level
West Virginia, USA [51]
Range: 265,170 for other sites to 3.1 million for hip
5 states, USA [46]
Range: 72.5 million for NHNV to 941.5 million for hip
USA [2]
Range: 186 million for wrist to 3.2 billion for hip
Switzerland [64]
Osteoporotic fractures: 150–208 million
Europe [56]
Vertebral fractures: 66,171 (Luxembourg) to 74.6 million (Germany) Hip fractures: 5.8 million (Luxembourg) to 1.7 billion (Germany)
Austria [61]
Hip fractures: 141 million
USA [2, 41, 50]
Range: 736 for other sites to 42,972 for hip
Costs per patient Mean 1-year fracture cost
Hip fractures: 86,603 First year: 13,221 (all), 4,180 for wrist/forearm to 29,234 for hip USA [70]
NHNV fracture: 24,879–31,571
Adjusted
Vertebral fracture: 23,401–46,499
Canada [69]
30,877
Mean incremental 1-year post-fracture cost
USA [70]
10,472–34,391
Median incremental healthcare costs
Canada [47]
Hip fracture: 17,688 Wrist fracture: 764
Hip fracture: 21,682–54,747
Humerus fracture: 3,566 Other fracture: 2,621 Mean post-hospitalization costs
Sweden [52]
Months 13–18 for hip: 39,906
Osteoporosis-Related Fractures in Men Table 3 continued Reported measure
Country/location
Range of reported valuesa
France [48]
5,168 (all fractures); 2,874 for vertebral/pelvic to 7,250 for hip
Cost per inpatient admission Mean cost per inpatient admission
Saudi Arabia [54]
165,380 for proximal femoral fractures
China [55]
58,385 for all fractures
USA [58]
29,168 (1993) to 40,182 (2003) for hip fractures
Europe [56]
14,409 (Spain) to 31,822 (Denmark) for vertebral fractures 3,714 (Ireland) to 15,433 (Austria) for hip fractures
Switzerland [63]
22,920 for osteoporosis-related fractures
USA [59]
25,942 for hip fracture
Austria [61]
125,520 for hip fracture
Singapore [62]
20,323
14,192 for vertebral fracture Median cost per inpatient admission NHNV non-hip non-vertebral a
Adjusted for Purchasing Power Parity
mortality from fractures estimated that indirect costs accounted for \1 % of total costs in men [39]. Another study that included indirect costs from productivity loss due to mortality, early retirement, and absenteeism estimated that indirect costs accounted for 17 % of total costs in men [42]. In all studies that reported indirect and direct costs by gender, indirect costs accounted for a higher percentage of costs for men compared with women [37– 40]. Aggregate 1-year direct costs related to fracture in men were substantial. At the national level, first-year estimates of fracture costs in men (Table 3) were as follows: US, US$4.1 billion in 2005 (2012 US$4.8 billion) [2]; Germany, €929 million (2012 US$988 million) in 2003 [45]; and France, €197.5 million (2012 US$243 million) in 1999 [48]. Estimated aggregate costs at more regional levels (i.e. state level) for 1 year were US$4.2 million (2006) in West Virginia (2012 US$4.8 million) [51], and US$311 million (2000) in Florida (2012 US$388 million) [43]. Hospital costs were similarly high (Table 3). The total annual cost of hospitalization for osteoporotic fracture has been estimated at CHF82 million (2012 US$148 million) in Switzerland (2000) [63], and €97.6 million (2012 US$120.2 million) in France (1999) [48]. One European Union study reported annual national hospitalization costs ranging from €55,037 (2012 US$66,161) in Luxembourg to €64.6 million (2012 US$74.6 million) in Germany in 2001 for vertebral fractures, and from €4.7 million (2012 US$5.9 million) in Ireland to €1.5 billion (2012 US$1.7 billion) in Germany for hip fractures [56]. Hip fractures in men were associated with the highest per fracture costs compared to other types of fractures.
Direct per-fracture medical costs in the first year post-hip fractures in men (Table 3) were reported as CAN$29,702 (median cost; 2012 US$49,071) in Canada (2006) [47]; US$86,603 (average annual cost for a Veterans’ Affairs (VA) subset of Medicare from 1999–2003) [41], US $36,562 (average annual cost in 2005; 2012 US$42,972) [2] and US$23,423 [50] (average annual costs in 2003; 2012 US$29,234). Hospital costs provide a useful measure of medical cost burden in the absence of total medical costs. Studies that measured only the hospital and/or other institution costs estimated these costs for hip fractures in men to be (mean costs): US$32,195 (2012 US$40,182) [58], US$18,119 (2012 US$25,942) [58], and US$18,349 (2012 US$29,168) [58] in the US in 2003, 1997 and 1993, respectively; SG$13,748 (2012 US$20,323) in Singapore in 2001 [62]; €5,886 (2012 US$7,250) in France in 1999 [48]; and 9,107 shilling (2012 US$125,520) in Austria in 1995 [61]. In the US in 2008, national 1-year incremental direct costs for men who experienced a second fracture were projected to range from 63 million (2012 US$67 million) in commercially insured men with a prior hip fracture to 224 million (2012 US$239 million) among commerciallyinsured men with a prior non-hip, non-vertebral fracture. In men with Medicare insurance coverage, the projected costs ranged from 91 million (2012 US$97 million) among men with a prior vertebral fracture to 166 million (2012 US$177 million) among men with a prior non-hip, non-vertebral fracture [70]. Within male populations, the mean hospital length of stay (LOS) following an osteoporotic fracture varied by fracture type and the longest LOS tended to be for hip
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fracture. For hip fractures, there was significant variation in the LOS by country. For example, several studies showed a LOS of approximately 7 days for hip fractures [41, 58, 59, 71] in the US, 11 days in Turkey [60], 18 days in Switzerland and Saudi Arabia [54, 63], 19 days in Singapore [62], and 34 days in China [55]. Hospital costs, LOS, and/ or resource utilization tended to be higher in men than in women [57, 59, 62] and tended to be higher in older men compared with younger men [15, 59]. In comparison to women, the overall cost burden associated with osteoporosis-related fractures in men are significantly lower, accounting for less than one-third of the cost for the entire population, an observation consistent with that reported by Strom et al. [4]. However, at a perfracture level, a few studies indicate that medical, hospital, resource utilization, and indirect costs are more for men than for women [40, 42, 44, 59]. In addition, costs associated with osteoporosis-related fractures in men in both Europe and the US are expected to continue increasing [38, 43, 46], and may even outpace those of women over the next few decades [38, 46]. Konnopka et al. [38] predicted that in Germany by 2050, osteoporosis-related hip fracture costs for men would increase by about 190 % from 2002. Men C75 years of age had the highest medical costs associated with osteoporosis-related fractures compared with other age groups [36, 37, 49, 52]. One study indicated that men C65 years accounted for 81 % of osteoporosisrelated fracture costs attributable to men [2].
4 Discussion This review was conducted to summarize the available evidence related to adherence to osteoporosis medication, and costs associated with osteoporosis-related fractures in men. Overall, the available studies investigating medication adherence and medical costs overwhelmingly focus on female populations, so male-specific data are not as robust as those available for women. In addition, the data available varied considerably in terms of source (both country and database used), cost components, and analysis methodologies, which make it more challenging to make conclusive statements. Even so, some general observations can be made from the available information. One-year adherence to bisphosphonates, which were predominately the medication of choice in the majority of studies included in this analysis, was between 32 % and 64 %, indicating that up to approximately one-third to twothirds of men are non-adherent (MPR \0.8) to the prescribed treatment. These data are consistent with those available for women showing that the majority of women on osteoporosis medication do not take their medication as directed [14, 72, 73].
At this point, only a small number of studies have documented an increased risk of fracture in men who were not adherent to their anti-osteoporotic medication compared with men who were adherent. However, the association between non-adherence to anti-osteoporotic medication and fracture incidence is well documented in women with post-menopausal osteoporosis receiving medication. Siris et al. [72] suggested a refill compliance (based on MPR) of up to 50 % yields only marginal benefits in women. As compliance increases, so do the benefits from treatment. Persistence to bisphosphonate therapy in post-menopausal women with osteoporosis has also been shown to be associated with lower fracture risk [74]. Without appropriate screening, identification of individuals who could benefit from osteoporosis disease management initiatives, as well as ongoing monitoring and support, fracture incidence will continue increasing among men as the prevalence of osteoporosis increases. Although health resource use and costs varied considerably among studies, the available data indicate that these osteoporosisrelated fractures in men are costly to both the individual and to society overall, and that these costs continue to mount well after an initial fracture occurs. Direct medical costs following fracture account for the largest portion of osteoporosis-related costs in men, and these costs continue to accumulate for at least 1 year following the fracture event. The published cost data also show that while women consume a larger portion of total osteoporosis fracturerelated costs due to larger numbers of fracture events, the average cost per fracture appears to be higher among men than among women. On the whole, these data suggest that there are a number of opportunities for improving the management of and outcomes associated with osteoporosis in men globally. A comprehensive disease management approach would likely include educating healthcare providers (generalists and specialists) and improving patient awareness, as well as initiatives designed to facilitate the diagnosis of this condition, identify appropriate interventions for each patient, and support patients in implementing and adhering with the recommended interventions. The Geisinger Health System Osteoporosis Disease Management Program, the Kaiser Southern California Healthy Bones Program, and the University of Wisconsin’s Osteoporosis Care Service are examples of this broad programmatic approach, while the Fracture Liaison Service in the UK is an example of a focused program designed for secondary fracture prevention among individuals with prior osteoporotic fracture [75–78]. Support of medication adherence is often a cornerstone of disease management for post-menopausal osteoporosis, and may also be an important element of disease management for osteoporosis in men. The literature, as noted
Osteoporosis-Related Fractures in Men
above, suggests that the suboptimal medication adherence that commonly occurs among men in North America, Europe, Asia, and Australia who have been identified for osteoporosis treatment can significantly mitigate the therapeutic benefits of prescribed osteoporosis treatments. Improvements in adherence to medication may therefore provide an avenue for fracture risk reduction in men, as it has in post-menopausal women. Despite the value of data relating to male osteoporosis, the interpretation of the data presented here are limited by several factors. The ability to draw strong conclusions is hindered by the lack of robust male-specific data, which reduces the ability to synthesize the evidence and compare between studies. The studies included here also used heterogeneous methods of defining, evaluating, and reporting adherence, persistence, and compliance, which again makes it difficult to interpret and compare data. Furthermore, most adherence studies are conducted in large databases (such as claims databases or similar datasets) and only use pharmacy records. Thus, it is uncertain whether patients actually took the drugs dispensed, which adds uncertainty to the adherence estimates reported in the studies included in this review. In considering the cost analysis in this systematic review, there may be studies included where the specific countries subsidize healthcare costs for their population; these costs may or may not have been included in the cost assessments in the specific studies. In addition, differences in healthcare systems and cost assessment year, and the heterogeneity of the data, make it difficult to compare costs between studies and/or regions (i.e. make judgment on whether the burden of osteoporosis is relatively more or less in one region than another).
5 Conclusion Data on medication adherence and osteoporosis-related fracture cost for male populations are significantly more limited than that for women. In addition, differences in analytical definitions and methods make it more difficult to draw broad conclusions. However, the data suggest that one-third to two-thirds of men are not adherent to prescribed bisphosphonates and non-adherence is implicated with increased risk in fracture. Osteoporosis-related fractures in men are costly both in terms of indirect and direct costs, and may even be more costly per event in men than in women. More robust data in male populations are needed to allow better understanding of the implications of non-adherence to medication and costs related to osteoporosis-related fractures. With an aging population and an increase in the number of at-risk men, it is important to plan for effective disease management that could improve
adherence to medication and result in better outcomes for men with osteoporosis. Acknowledgments and Conflicts of Interest This study was funded by Amgen Inc. The authors wish to thank Seema Patel (previously at HERON Evidence Development Ltd, UK) for providing assistance for the initial literature search for this analysis. We would also like to thank Sally Wade for her assistance in incorporating revisions to this manuscript. Nicole Yurgin and Irene Agodoa are employees of Amgen, and Yeshi Mikyas was previously employed by Amgen. A summary of the adherence and cost reviews has previously been presented in poster format at the American Society of Bone Mineral Research (ASBMR) 2011 Annual Meeting (San Diego, CA, USA; presentation no. SU0442) and the IOF-ECCEO 2012 Meeting (Bordeaux, France; presentation no. P523 and P524). All authors contributed to the conception and design of this study, as well as to the interpretation of the results. Yeshi Mikyas conducted the primary literature search, summarized the data, and drafted the manuscript. All authors provided critical revisions and final approval of the manuscript prior to journal submission. Nicole Yurgin is the guarantor for the overall content of this paper.
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SYSTEMATIC REVIEW
A Systematic Review of Osteoporosis Medication Adherence and Osteoporosis-Related Fracture Costs in Men Yeshi Mikyas • Irene Agodoa • Nicole Yurgin
Ó Springer International Publishing Switzerland 2014
Abstract Background and objective Male osteoporosis is an increasingly important public health concern. Although several medications are approved for the treatment of osteoporosis, medication non-adherence and the associated consequences are not well documented in male populations. Our objective was to identify and summarize the current knowledge related to osteoporotic medication adherence, the potential implications of non-adherence to the medication, and the cost of osteoporosis-related fractures and health-resource utilization in men. Methods Two separate systematic searches were conducted concurrently: one to identify literature reporting male-specific adherence to anti-osteoporotic medication and the clinical consequence of non-adherence in men, and the other to identify literature reporting the cost and resource burden of osteoporosis-related fractures in men. The PubMed, MEDLINE, EMBASE, and Cochrane databases were searched using a date range of 1 January 1998 to 30 June 2012, and citations were screened based on pre-defined criteria. Results The percentage of males adherent to bisphosphonates [medication possession ratio (MPR)[0.8] over a 1-year
Electronic supplementary material The online version of this article (doi:10.1007/s40258-013-0078-1) contains supplementary material, which is available to authorized users. Y. Mikyas I. Agodoa (&) N. Yurgin Amgen Inc, One Amgen Center Drive, MS 28-3-A, Thousand Oaks, CA 91320, US e-mail: [email protected] Y. Mikyas e-mail: [email protected] N. Yurgin e-mail: [email protected]
period ranged from 32 % to 64 %. The data imply worse clinical outcomes with treatment non-adherence. Costs and resource use associated with osteoporosis-related fractures in men are high, with hip fractures generating the most cost. Conclusions One-third to two-thirds of men are not adherent to bisphosphonates. Non-adherence is associated with increased fracture risk. Estimates of direct and indirect osteoporosis-related fracture costs are also substantial in men, and may even be more costly than in women. More robust data would better inform disease management initiatives that could improve adherence to medication and outcomes in men with osteoporosis. Key Points for Decision Makers As in women, bisphosphonates are the most common osteoporosis therapy in men, and one-third to twothirds of men are non-adherent (i.e. taking fewer than 80 % of doses as prescribed) in 1 year on therapy. The limited data available suggest that low adherence is associated with greater fracture risk in males. Direct and indirect costs of osteoporosis-related fractures are substantial, and the cost per osteoporosisrelated fracture may even be higher in men than in women.
1 Introduction Osteoporosis is a chronic, asymptomatic disease that leads to decreased bone mineral density (BMD) and increased disposition to fractures from low impact forces that would not normally cause injury [1]. Fractures associated with
Y. Mikyas et al.
osteoporosis incur high medical cost, resource utilization, and societal burden [2]. Osteoporosis is more common in post-menopausal women than men, and women are more likely to be diagnosed with the disease than men [3]. However, male osteoporosis is becoming an increasingly important public health concern. The National Osteoporosis Foundation estimated that approximately 23 % (2.8 million) of individuals with osteoporosis in the US in 2010 were men, [1] and this number is expected to rise to over 3 million men by 2020. While osteoporotic fractures occur more commonly in women, and women have twice as high a risk of sustaining any fracture compared with men [4], men have worse outcomes following fracture; morbidity and mortality risk after a hip fracture is substantially higher in men than in women [5–7]. Furthermore, studies have shown that there is a low uptake of treatment and awareness of the disease in men, with fewer men than women being prescribed treatment upon discharge following a hip fracture [8]. Several therapies are available to treat osteoporosis, and treatment efficacy has been demonstrated in clinical trials through an increase in BMD and/or a reduction in fracture risk [9–12]. Current medications approved for use in men include antiresorptives and anabolics. However, adherence to most of these therapies in the clinical setting outside of trials is recognized to be low [13] and is associated with reduced anti-fracture treatment efficacy [14] as adherence to
Fig. 1 Selection of studies for the adherence analysis
therapy is required to gain the full benefits of treatment. These consequences of non-adherence have mostly been assessed for post-menopausal women and mixed-gender populations [14, 15]. The objective of this systematic review was to identify and summarize the current knowledge related to the adherence to osteoporotic medication in male populations, the potential implications of non-adherence to the medication, and the medical cost of osteoporosis-related fractures and health resource utilization in men.
2 Methods Due to the potential link between medication adherence or non-adherence and associated costly consequences (i.e. fracture), we chose to assess these together to provide a more comprehensive view of the burden of osteoporosis. Two searches were therefore conducted for this review. The first search was to identify literature reporting malespecific adherence to anti-osteoporotic medication, while the second search was to identify literature reporting the resource burden of osteoporosis in men. The PubMed database was searched for English-language studies published from 1 January 1998 to 30 June 2012 (the search date). The searches were conducted using comprehensive search strategies utilizing keywords (‘osteoporosis’, ‘patient persistence’, ‘medication adherence’, ‘bone fracture’, ‘cost’, ‘utilization’) and related medical subject
Osteoporosis-Related Fractures in Men
Fig. 2 Selection of studies for the cost and health resource utilization
headings (MeSH) [Figs. 1 and 2]. To ensure capture of key economic studies, the cost and resource utilization search was also conducted using Ovid to search MEDLINE, EMBASE, and the Cochrane Library Database. Retrospective or prospective observational studies conducted in men or in mixed populations reporting malespecific subgroup data were included in both searches. Included studies had to report the following outcomes: adherence, and consequences associated with adherence in the literature search for adherence analysis; and costs or resource utilization associated with male patients with osteoporosis-related fractures for cost-associated analysis. For the adherence analysis, all medications used to treat osteoporosis were included in the review. Adherence for the purpose of this review includes related terms, such as persistence and compliance; however, no restriction was placed on the definition since no universal standard definition exists; selection of only one definition would have resulted in the omission of potentially relevant data. For the cost analysis, all costs were reported in the original currency and in the 2012 US dollar (US$) equivalent. Conversions were computed using the World Bank’s
Purchasing Power Parity factor for the base country and year, and inflated to 2012 using country-specific annual consumer price inflation rates [16, 17]. Where no cost assessment year was specifically stated, the cost year was assumed to be the final cutoff year of the study analysis. Randomized clinical trials were excluded from the search as they do not necessarily reflect the patient population or adherence and costs in real world settings. The literature identified in the searches was screened in two stages. The first stage was a screen of the abstracts. Where abstracts were not available or could not be positively excluded according to the eligibility criteria, full-text copies of the citations were obtained and reviewed against the same eligibility criteria, and any articles that did not include male-specific information were excluded. In addition, the reference lists of retrieved publications were examined for likely candidates for inclusion in the systematic review. The initial search and abstraction of data was conducted by YM. Reference cross-check, data verification, and resolution of decision was conducted by IA and NY. The data that were extracted for each review are presented in Table 1.
Y. Mikyas et al. Table 1 Study characteristics and outcomes extracted in the adherence and cost systematic reviews in male osteoporosis Adherence review
Cost review
Study characteristics Study design, size of sample population, the size of the male population, and male-specific population characteristics or outcomes Outcomes Adherence, compliance, persistence, adherence threshold, factors associated with adherence. Osteoporotic outcomes associated with non-adherence such as fracture risk, BMD and risk of hospitalization
Costs of osteoporosis, cost of resource utilization including cost of hospitalization, rehabilitation/nursing home care/long-term care, fracture-preventive drug therapy, other osteoporosis-related direct costs
BMD bone mineral density
Table 2 Summary of treatment adherence findings in male osteoporosis Reported measure
Country/location
Treatment(s) studied
Reported values
Percent of men adherent during 12-month follow-up
USA [25, 34]
Oral and IV BP
39.2 %
Alendronate
59 %
Norway [23]
Alendronate
45 %
Turkey [21]
Oral weekly BP
49.4 %
Netherlands [29]
Oral osteoporosis medications
39.7 %
Czech Republic [33]
Alendronate, risedronate, calcitonin, strontium ranelate
52–64 %
Percent of men adherent during 24-month follow-up
USA [25]
Alendronate
54 %
Percent of men adherent during 36-month follow-up
Turkey [21]
Oral weekly BP
17.9 %
Mean MPR
USA [34]
Oral and IV BP
0.56
Persistence at 12 months
Taiwan [28]
Alendronate
0.56
USA [20]
Oral BP
0.4 weekly BP; 0.7 for monthly/weekly BP
Turkey [21]
Oral weekly BP
0.77
Germany [31]
Oral weekly alendronate
54 % for alendronate and 100 % for IV zoledronic acid
IV zoledronic acid UK [18]
Teriparatide
81.4 % for teriparatide
Persistence at 18 months
UK [18]
Teriparatide
74.3 % for teriparatide
Persistence at 3 years
Turkey [21]
Oral weekly BP
0.38
Percent of men compliant during first year on therapy
Taiwan [28]
Alendronate
32.2 %
BP bisphosphonates, IV intravenous, MPR medication possession ratio
3 Results 3.1 Adherence and Clinical Consequences of Non-Adherence Eighteen studies were included in the adherence analysis [18–35] [Table 2; electronic supplementary material (ESM) Supplemental Table 1]. Fifteen studies were retrospective analyses of databases from the US and Europe, including hospital and clinic administrative records, claims databases, and inpatient surveys [18–22, 24, 25,
28–35]. Three were prospective studies of patients being treated in clinical settings [23, 26, 27]. Five studies were conducted exclusively in male populations [18, 21, 25, 31, 33] (Table 2; ESM Supplemental Table 1). In general, male populations were numerically small or proportionally smaller than the women population in the same studies. In male-only studies, the sample sizes ranged from 92 to 198; in mixed-gender studies, the proportion of males ranged from 2 to 47 %. The majority of the studies assessed adherence to bisphosphonates [19–35].
Osteoporosis-Related Fractures in Men
The definition and measure of medication adherence varied among studies. The terms adherence [19, 20, 23, 25, 34], persistence [18, 21, 24, 29–32, 34, 35], compliance [21, 24, 27–30] (including self-reported compliance [26]), and consumption rates [33] were used to assess the adherence to medication. ‘Adherence’ was measured in terms of medication possession ratio (MPR) in most studies that reported adherence. MPR computation was not consistent across all the studies; however, in all the studies that reported MPR as a measure of adherence, a patient was considered adherent if the MPR was C0.8 (or [0.8). For these studies, the percentage of men adherent to medication ranged from 39 % (US) to 64 % (Czech Republic) over a 1-year period [20, 23, 25, 33, 34]. In two large US studies, mean MPRs (adherence) for men were \0.8 [20, 34]. The term ‘persistence’ to medication had the most varied definition in the studies included in this review. While some studies did not indicate how persistence was measured, others defined persistence as one of the following: the length of time without a considerable gap in treatment, or as the number of medications taken relative to the number of medications prescribed, or as a repeat prescription of the drug without switching, or calculated as an MPR. Acknowledging these differences in the definition of persistence, the percentage of men persistent to medication as reported ranged between 40 % (The Netherlands) and 100 % (Germany) over a 1-year period [18, 29, 31]. It should be noted that the one study with 100 % persistence was in a population receiving zoledronic acid (given annually) [31], and the one study with 81 % persistence was in a population receiving off-label teriparatide treatment (for men), where the study required specific patient monitoring (UK) [18]. Excluding these two studies, 40–77 % of men were persistent with their medication at 1 year. For studies that used compliance as a measure of adherence to medication, compliance was often described in terms of MPR. Again, as in the adherence assessment, the way MPRs were computed differed among studies; however, in general, patients were considered compliant if the MPR was C0.8. The percentage of men compliant to medication ranged between 32 % (Taiwan) and 49 % (Turkey) over a 1-year period [21, 28]. Mean reported MPRs (compliance) for men were also \0.8 (Taiwan) [28]. A few studies reported adherence for treatment beyond the first year [18, 21, 25]. In all cases, the percentage of men adherent to medication decreased. Cevikoi et al. [21] showed that the percentage of Turkish men compliant to oral bisphosphonates fell from 49 % in the first year to 18 % at the 3-year follow-up. In a US study by Hansen et al. [25], the percentage of men adherent to alendronate decreased from 59 % over 1 year to 54 % over the 2-year study period; 28 % of men had completely stopped treatment by the end of the second year of the study.
Results comparing adherence to medication in men versus women were mixed. Roerholt et al. [32] and Briesacher et al. [19] showed that patient gender had little or no influence on the persistence or adherence to treatment. Gallagher et al. [24], on the other hand, indicated that men were more persistent and compliant to bisphosphonates, while Kamatari et al. [26] indicated compliance in men was lower than in women. Three studies discussed outcomes of adherence/nonadherence to medication specifically in male populations [25, 30, 31]. These studies suggest that non-adherence in men resulted in worse outcomes, while adherence to medication improves outcomes. In Germany, Ringe et al. [31] suggested that lower persistence to weekly alendronate contributed to lower treatment efficacy, while in the US, Hansen et al. [25] reported that bone biopsy results from non-adherent men indicate that they had smaller lumbar spine mass improvements than men who were adherent to medication. Modelling analyses of UK data by Rietbrock et al. [30] showed that increased persistence and compliance to bisphosphonates (alendronate and risedronate) resulted in the prevention of additional hip fractures. 3.2 Costs and Health Resource Utilization Thirty-seven studies reported male-specific health resource utilization or costs associated with osteoporosis and osteoporosis-related fracture (Table 3; ESM Supplemental Tables 2–4). Five studies estimated the societal cost of osteoporosis or fractures by measuring both direct and indirect costs [36–40]. Thirteen studies estimated direct medical costs, including both inpatient and outpatient services [2, 41–52]. However, the cost components used to compute direct medical costs varied from study to study and from country to country. Seventeen studies took a more narrow perspective of costs and resource utilization and focused on hospital or other institutions [53–69]. Except for one study [48] all the studies assessing costs and health resource utilization were conducted in mixed populations; in almost all cases (except for Bass et al. [41] and Levy et al. [48]) the male population was significantly smaller than the female population. In terms of societal costs, estimating both direct and indirect costs of osteoporosis and osteoporosis-related fractures for men, one study found the total first year cost of incident fractures in men to be SEK944 million (2012 US$993 million) in Sweden in 2005 [36]. Another study focused on hip fractures in men and estimated the cost to be €646 million (2012 US$713 million) in Germany in 2002 [38]. Indirect costs as a proportion of total cost in men varied widely, and depended on which indirect cost components were used in the study. For instance, one study that measured indirect costs from productivity loss due to
Y. Mikyas et al. Table 3 Costs in male osteoporosis (2012 US$) Reported measure
Country/location
Range of reported valuesa
Germany [38]
Hip fracture: 713 million
Sweden [36]
All fractures: 993 million
Societal costs (direct and indirect) Total 1-year cost
California, USA [39]
Total osteoporosis cost: 897 million Total direct osteoporosis cost: 893 million Total indirect osteoporosis cost: 3.7 million
Annual long-term cost
Sweden [36]
Mean annual costs per patient
Sweden [37]
Hip fracture: 750 million Direct: 142,593 Total: 153,177
Per patient-month
Belgium [40]
Direct: 58.0 Indirect: 258.1
Direct medical costs Incremental first-year cost post-trauma fracture
Olmsted County, USA [49]
0.15 million for pelvis to 157.6 million for hip
Total 1-year costs of fracture
West Virginia, USA [51]
All osteoporotic fractures: 4.8 million
Florida, USA [43]
All osteoporotic fractures: 388 million (2000) to 660 million (2025)
5 states, USA [46]
All fractures: 1,062 million
USA [2]
All incident fractures: 4.1 billion
USA [70]
Projections
Adjusted
NHNV fracture: 177–239 million Vertebral fracture: 86–99 million Hip fracture: 21 63–97 million
France [48]
All fracture (total direct): 243 million Inpatient costs: 120.2 million Physician visits: 4.8 million
Total inpatient costs at national level
West Virginia, USA [51]
Range: 265,170 for other sites to 3.1 million for hip
5 states, USA [46]
Range: 72.5 million for NHNV to 941.5 million for hip
USA [2]
Range: 186 million for wrist to 3.2 billion for hip
Switzerland [64]
Osteoporotic fractures: 150–208 million
Europe [56]
Vertebral fractures: 66,171 (Luxembourg) to 74.6 million (Germany) Hip fractures: 5.8 million (Luxembourg) to 1.7 billion (Germany)
Austria [61]
Hip fractures: 141 million
USA [2, 41, 50]
Range: 736 for other sites to 42,972 for hip
Costs per patient Mean 1-year fracture cost
Hip fractures: 86,603 First year: 13,221 (all), 4,180 for wrist/forearm to 29,234 for hip USA [70]
NHNV fracture: 24,879–31,571
Adjusted
Vertebral fracture: 23,401–46,499
Canada [69]
30,877
Mean incremental 1-year post-fracture cost
USA [70]
10,472–34,391
Median incremental healthcare costs
Canada [47]
Hip fracture: 17,688 Wrist fracture: 764
Hip fracture: 21,682–54,747
Humerus fracture: 3,566 Other fracture: 2,621 Mean post-hospitalization costs
Sweden [52]
Months 13–18 for hip: 39,906
Osteoporosis-Related Fractures in Men Table 3 continued Reported measure
Country/location
Range of reported valuesa
France [48]
5,168 (all fractures); 2,874 for vertebral/pelvic to 7,250 for hip
Cost per inpatient admission Mean cost per inpatient admission
Saudi Arabia [54]
165,380 for proximal femoral fractures
China [55]
58,385 for all fractures
USA [58]
29,168 (1993) to 40,182 (2003) for hip fractures
Europe [56]
14,409 (Spain) to 31,822 (Denmark) for vertebral fractures 3,714 (Ireland) to 15,433 (Austria) for hip fractures
Switzerland [63]
22,920 for osteoporosis-related fractures
USA [59]
25,942 for hip fracture
Austria [61]
125,520 for hip fracture
Singapore [62]
20,323
14,192 for vertebral fracture Median cost per inpatient admission NHNV non-hip non-vertebral a
Adjusted for Purchasing Power Parity
mortality from fractures estimated that indirect costs accounted for \1 % of total costs in men [39]. Another study that included indirect costs from productivity loss due to mortality, early retirement, and absenteeism estimated that indirect costs accounted for 17 % of total costs in men [42]. In all studies that reported indirect and direct costs by gender, indirect costs accounted for a higher percentage of costs for men compared with women [37– 40]. Aggregate 1-year direct costs related to fracture in men were substantial. At the national level, first-year estimates of fracture costs in men (Table 3) were as follows: US, US$4.1 billion in 2005 (2012 US$4.8 billion) [2]; Germany, €929 million (2012 US$988 million) in 2003 [45]; and France, €197.5 million (2012 US$243 million) in 1999 [48]. Estimated aggregate costs at more regional levels (i.e. state level) for 1 year were US$4.2 million (2006) in West Virginia (2012 US$4.8 million) [51], and US$311 million (2000) in Florida (2012 US$388 million) [43]. Hospital costs were similarly high (Table 3). The total annual cost of hospitalization for osteoporotic fracture has been estimated at CHF82 million (2012 US$148 million) in Switzerland (2000) [63], and €97.6 million (2012 US$120.2 million) in France (1999) [48]. One European Union study reported annual national hospitalization costs ranging from €55,037 (2012 US$66,161) in Luxembourg to €64.6 million (2012 US$74.6 million) in Germany in 2001 for vertebral fractures, and from €4.7 million (2012 US$5.9 million) in Ireland to €1.5 billion (2012 US$1.7 billion) in Germany for hip fractures [56]. Hip fractures in men were associated with the highest per fracture costs compared to other types of fractures.
Direct per-fracture medical costs in the first year post-hip fractures in men (Table 3) were reported as CAN$29,702 (median cost; 2012 US$49,071) in Canada (2006) [47]; US$86,603 (average annual cost for a Veterans’ Affairs (VA) subset of Medicare from 1999–2003) [41], US $36,562 (average annual cost in 2005; 2012 US$42,972) [2] and US$23,423 [50] (average annual costs in 2003; 2012 US$29,234). Hospital costs provide a useful measure of medical cost burden in the absence of total medical costs. Studies that measured only the hospital and/or other institution costs estimated these costs for hip fractures in men to be (mean costs): US$32,195 (2012 US$40,182) [58], US$18,119 (2012 US$25,942) [58], and US$18,349 (2012 US$29,168) [58] in the US in 2003, 1997 and 1993, respectively; SG$13,748 (2012 US$20,323) in Singapore in 2001 [62]; €5,886 (2012 US$7,250) in France in 1999 [48]; and 9,107 shilling (2012 US$125,520) in Austria in 1995 [61]. In the US in 2008, national 1-year incremental direct costs for men who experienced a second fracture were projected to range from 63 million (2012 US$67 million) in commercially insured men with a prior hip fracture to 224 million (2012 US$239 million) among commerciallyinsured men with a prior non-hip, non-vertebral fracture. In men with Medicare insurance coverage, the projected costs ranged from 91 million (2012 US$97 million) among men with a prior vertebral fracture to 166 million (2012 US$177 million) among men with a prior non-hip, non-vertebral fracture [70]. Within male populations, the mean hospital length of stay (LOS) following an osteoporotic fracture varied by fracture type and the longest LOS tended to be for hip
Y. Mikyas et al.
fracture. For hip fractures, there was significant variation in the LOS by country. For example, several studies showed a LOS of approximately 7 days for hip fractures [41, 58, 59, 71] in the US, 11 days in Turkey [60], 18 days in Switzerland and Saudi Arabia [54, 63], 19 days in Singapore [62], and 34 days in China [55]. Hospital costs, LOS, and/ or resource utilization tended to be higher in men than in women [57, 59, 62] and tended to be higher in older men compared with younger men [15, 59]. In comparison to women, the overall cost burden associated with osteoporosis-related fractures in men are significantly lower, accounting for less than one-third of the cost for the entire population, an observation consistent with that reported by Strom et al. [4]. However, at a perfracture level, a few studies indicate that medical, hospital, resource utilization, and indirect costs are more for men than for women [40, 42, 44, 59]. In addition, costs associated with osteoporosis-related fractures in men in both Europe and the US are expected to continue increasing [38, 43, 46], and may even outpace those of women over the next few decades [38, 46]. Konnopka et al. [38] predicted that in Germany by 2050, osteoporosis-related hip fracture costs for men would increase by about 190 % from 2002. Men C75 years of age had the highest medical costs associated with osteoporosis-related fractures compared with other age groups [36, 37, 49, 52]. One study indicated that men C65 years accounted for 81 % of osteoporosisrelated fracture costs attributable to men [2].
4 Discussion This review was conducted to summarize the available evidence related to adherence to osteoporosis medication, and costs associated with osteoporosis-related fractures in men. Overall, the available studies investigating medication adherence and medical costs overwhelmingly focus on female populations, so male-specific data are not as robust as those available for women. In addition, the data available varied considerably in terms of source (both country and database used), cost components, and analysis methodologies, which make it more challenging to make conclusive statements. Even so, some general observations can be made from the available information. One-year adherence to bisphosphonates, which were predominately the medication of choice in the majority of studies included in this analysis, was between 32 % and 64 %, indicating that up to approximately one-third to twothirds of men are non-adherent (MPR \0.8) to the prescribed treatment. These data are consistent with those available for women showing that the majority of women on osteoporosis medication do not take their medication as directed [14, 72, 73].
At this point, only a small number of studies have documented an increased risk of fracture in men who were not adherent to their anti-osteoporotic medication compared with men who were adherent. However, the association between non-adherence to anti-osteoporotic medication and fracture incidence is well documented in women with post-menopausal osteoporosis receiving medication. Siris et al. [72] suggested a refill compliance (based on MPR) of up to 50 % yields only marginal benefits in women. As compliance increases, so do the benefits from treatment. Persistence to bisphosphonate therapy in post-menopausal women with osteoporosis has also been shown to be associated with lower fracture risk [74]. Without appropriate screening, identification of individuals who could benefit from osteoporosis disease management initiatives, as well as ongoing monitoring and support, fracture incidence will continue increasing among men as the prevalence of osteoporosis increases. Although health resource use and costs varied considerably among studies, the available data indicate that these osteoporosisrelated fractures in men are costly to both the individual and to society overall, and that these costs continue to mount well after an initial fracture occurs. Direct medical costs following fracture account for the largest portion of osteoporosis-related costs in men, and these costs continue to accumulate for at least 1 year following the fracture event. The published cost data also show that while women consume a larger portion of total osteoporosis fracturerelated costs due to larger numbers of fracture events, the average cost per fracture appears to be higher among men than among women. On the whole, these data suggest that there are a number of opportunities for improving the management of and outcomes associated with osteoporosis in men globally. A comprehensive disease management approach would likely include educating healthcare providers (generalists and specialists) and improving patient awareness, as well as initiatives designed to facilitate the diagnosis of this condition, identify appropriate interventions for each patient, and support patients in implementing and adhering with the recommended interventions. The Geisinger Health System Osteoporosis Disease Management Program, the Kaiser Southern California Healthy Bones Program, and the University of Wisconsin’s Osteoporosis Care Service are examples of this broad programmatic approach, while the Fracture Liaison Service in the UK is an example of a focused program designed for secondary fracture prevention among individuals with prior osteoporotic fracture [75–78]. Support of medication adherence is often a cornerstone of disease management for post-menopausal osteoporosis, and may also be an important element of disease management for osteoporosis in men. The literature, as noted
Osteoporosis-Related Fractures in Men
above, suggests that the suboptimal medication adherence that commonly occurs among men in North America, Europe, Asia, and Australia who have been identified for osteoporosis treatment can significantly mitigate the therapeutic benefits of prescribed osteoporosis treatments. Improvements in adherence to medication may therefore provide an avenue for fracture risk reduction in men, as it has in post-menopausal women. Despite the value of data relating to male osteoporosis, the interpretation of the data presented here are limited by several factors. The ability to draw strong conclusions is hindered by the lack of robust male-specific data, which reduces the ability to synthesize the evidence and compare between studies. The studies included here also used heterogeneous methods of defining, evaluating, and reporting adherence, persistence, and compliance, which again makes it difficult to interpret and compare data. Furthermore, most adherence studies are conducted in large databases (such as claims databases or similar datasets) and only use pharmacy records. Thus, it is uncertain whether patients actually took the drugs dispensed, which adds uncertainty to the adherence estimates reported in the studies included in this review. In considering the cost analysis in this systematic review, there may be studies included where the specific countries subsidize healthcare costs for their population; these costs may or may not have been included in the cost assessments in the specific studies. In addition, differences in healthcare systems and cost assessment year, and the heterogeneity of the data, make it difficult to compare costs between studies and/or regions (i.e. make judgment on whether the burden of osteoporosis is relatively more or less in one region than another).
5 Conclusion Data on medication adherence and osteoporosis-related fracture cost for male populations are significantly more limited than that for women. In addition, differences in analytical definitions and methods make it more difficult to draw broad conclusions. However, the data suggest that one-third to two-thirds of men are not adherent to prescribed bisphosphonates and non-adherence is implicated with increased risk in fracture. Osteoporosis-related fractures in men are costly both in terms of indirect and direct costs, and may even be more costly per event in men than in women. More robust data in male populations are needed to allow better understanding of the implications of non-adherence to medication and costs related to osteoporosis-related fractures. With an aging population and an increase in the number of at-risk men, it is important to plan for effective disease management that could improve
adherence to medication and result in better outcomes for men with osteoporosis. Acknowledgments and Conflicts of Interest This study was funded by Amgen Inc. The authors wish to thank Seema Patel (previously at HERON Evidence Development Ltd, UK) for providing assistance for the initial literature search for this analysis. We would also like to thank Sally Wade for her assistance in incorporating revisions to this manuscript. Nicole Yurgin and Irene Agodoa are employees of Amgen, and Yeshi Mikyas was previously employed by Amgen. A summary of the adherence and cost reviews has previously been presented in poster format at the American Society of Bone Mineral Research (ASBMR) 2011 Annual Meeting (San Diego, CA, USA; presentation no. SU0442) and the IOF-ECCEO 2012 Meeting (Bordeaux, France; presentation no. P523 and P524). All authors contributed to the conception and design of this study, as well as to the interpretation of the results. Yeshi Mikyas conducted the primary literature search, summarized the data, and drafted the manuscript. All authors provided critical revisions and final approval of the manuscript prior to journal submission. Nicole Yurgin is the guarantor for the overall content of this paper.
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