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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Osteoporosis is common in both women and men and predisposes to fragility fractures primarily of the hip, spine, or distal forearm. The lifetime fracture risk is reported to be nearly 40% for white women ages >50 years, but only 13% for white men of a similar age (1). Ethnic minorities have a smaller although still significant lifetime risk for osteoporotic fracture. A report from the California Hospital Discharge Data revealed a rate of hip fractures for non-Hispanic white women of 140.7/100,000 compared to rates of 49.7, 57.3, and 85.4 for African American, Hispanic, and Asian women, respectively (2). Men have a worse outcome following hip fractures, with mortality rates twice that of women in the first and second years following hip fractures (3).
Effective therapies for the prevention of both primary and secondary fragility fractures are available, and bisphosphonates are among the most common pharmacologic agents prescribed. Randomized controlled clinical trials have demonstrated the efficacy of alendronate, risedronate, ibandronate, and zoledronic acid in increasing bone mineral density (BMD) and reducing fractures (4–7).
Adherence with bisphosphonate therapy is associated with a measurable reduction in fractures compared with nonadherence (8). Most reports on bisphosphonate adherence have focused on women with postmenopausal osteoporosis, including African Americans and populations of European ancestry (9–12). In these prior studies, determinants of poor adherence with bisphosphonate treatment were found to include older age, daily versus weekly bisphosphonate dosing, number of comorbid conditions, male sex, the absence of BMD testing, side effects, and poor physical health status (10–13). It is unclear if these findings can be extrapolated to other groups, particularly men with rheumatoid arthritis (RA).
RA is associated with marginal joint erosions, periarticular osteopenia, and generalized bone loss or osteoporosis. Synovial cytokines, including macrophage colony-stimulating factor and RANKL, promote osteoclast differentiation and subsequent bone erosion (14). The mechanisms for generalized osteopenia distant from synovial inflammation remain controversial. Histomorphometric analysis of bone biopsies reveals decreased bone formation in these areas, but increased bone turnover is a factor (15). Other clinical factors that are contributory include the use of glucocorticoids and decreased mobility (16).
The purpose of this study was to examine adherence with oral bisphosphonate therapy in a cohort of RA patients utilizing data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry and the Veterans Affairs (VA) Pharmacy Benefits Management (PBM), and to determine factors associated with nonadherence.
Significance & Innovations
A longer duration of bisphosphonate therapy is associated with greater years of education, older age, and receiving a dual x-ray absorptiometry test.
Poor adherence with bisphosphonate therapy is associated with nonwhite ethnicity.
Poor bisphosphonate adherence is associated with a longer duration of rheumatoid arthritis disease and a greater duration of bisphosphonate therapy.
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
There were 1,382 subjects enrolled in the VARA at the 6 VA sites that had data available for analysis. Five hundred seventy-three subjects (41.5%) were dispensed at least 1 prescription for an oral bisphosphonate and served as the cohort for analysis. These patients were mostly men (89.9%), with a mean age of 68.7 years. The majority of subjects were white (81.7%), with African Americans and Hispanics accounting for 12.8% and 3.5% of the cohort, respectively. DXA testing was available in 258 subjects (45.0%), 66 (25.6%) of whom had a densitometric diagnosis of osteoporosis. Three hundred ninety-two individuals (68.4%) were prescribed prednisone. Apart from being more likely to have osteoporosis compared with non–bisphosphonate users, bisphosphonate users were more likely to be older, be white, have a DXA scan performed, receive prednisone, have higher Charlson-Deyo scores, have higher mean MDHAQ and mean DAS28 scores, and have a longer duration of RA (Table 1).
Table 1. Characteristics of bisphosphonate users and nonusers among Veterans Affairs Rheumatoid Arthritis enrollees*
| ||Total sample (n = 1,372)||Subjects ever used bisphosphonates (n = 573)||Subjects never used bisphosphonates (n = 799)|
|Age, mean ± SD years†||66.3 ± 11.5||68.7 ± 10.3||64.6 ± 12.0|
|Women, no. (%)||127 (9.3)||58 (10.1)||69 (8.6)|
|Ethnicity, no. (%)†|| || || |
| White||1,053 (76.7)||468 (81.7)||585 (73.2)|
| Nonwhite||304 (22.2)||100 (17.5)||204 (25.5)|
|Education, mean ± SD years||12.8 ± 2.6||12.8 ± 2.6||12.9 ± 2.7|
|Smoking (current), no. (%)||367 (26.8)||146 (25.5)||221 (27.7)|
|Charlson-Deyo Index, mean ± SD‡||1.8 ± 2.2||1.99 ± 2.08||1.72 ± 2.25|
|Prednisone use, no. (%)†||828 (60.4)||392 (68.4)||43 (5.4)|
|DXA testing, no. (%)†||495 (36.1)||258 (45.0)||237 (29.7)|
|Osteoporosis, no. (%)†||79 (16)||66 (25.6)||13 (5.5)|
|Duration of RA, mean ± SD years†||16.6 ± 12.3||19.1 ± 12.6||14.9 ± 11.8|
|MDHAQ score, mean ± SD§||1.0 ± 0.5||1.05 ± 0.49||0.96 ± 0.51|
|DAS28, mean ± SD§||3.63 ± 1.18||3.74 ± 1.18||3.54 ± 1.17|
Four hundred ninety-seven patients (86.7%) received alendronate as their only bisphosphonate and 17 (3.0%) received risedronate; 59 patients (10.3%) received prescriptions for both of these bisphosphonates at some point during the period of observation. Seven of the 556 subjects prescribed alendronate received only a once daily preparation, and 1 of the 76 subjects prescribed risedronate received a once daily prescription. Three subjects received a prescription for etidronate and no subjects were prescribed ibandronate. These subjects given either etidronate or daily bisphosphonate therapy were excluded from further analysis, given the likely influence of this dosing schedule on adherence and the low number of subjects. Subjects received a mean ± SD of 2.3 ± 1.6 courses of therapy and 240 subjects (42%) were only dispensed a single course (range 1–11 courses).
The mean ± SD duration of oral bisphosphonate therapy was 39.2 ± 31.4 months. Thirty-five patients receiving once weekly oral bisphosphonates were switched to intravenous zoledronic acid and 6 were switched to teriparatide. The univariate and multivariate associations of treatment duration are shown in Table 2. In the multivariate analysis, a longer duration of therapy was associated with age ≥70 years (OR 1.79, 95% CI 1.04–3.08), education past twelfth grade (OR 2.12, 95% CI 1.09–4.14), and receiving DXA (OR 1.74, 95% CI 1.05–2.89).
Table 2. Predictors of prescribed duration of bisphosphonate therapy of >32 months for Veterans Affairs Rheumatoid Arthritis subjects*
| ||Univariate OR (95% CI)||Adjusted OR (95% CI)†|
|Age ≥70 years||1.70 (1.22–2.37)‡||1.79 (1.04–3.08)§|
|Female sex||0.73 (0.42–1.26)||0.74 (0.33–1.66)|
|Nonwhite||1.32 (0.85–2.03)||1.32 (0.70–2.48)|
|Education ≥12th grade||1.29 (0.78–2.13)||2.12 (1.09–4.14)§|
|Smoking (current)||0.57 (0.39–0.83)‡||0.64 (0.36–1.15)|
|Charlson-Deyo Index||0.98 (0.95–1.01)||1.03 (0.99–1.03)|
|Prednisone use||0.86 (0.60–1.23)||0.73 (0.41–1.29)|
|DXA||1.16 (0.83–1.61)||1.74 (1.05–2.89)§|
|Osteoporosis¶||1.04 (0.59–1.82)|| |
|Duration of RA||0.98 (0.96–0.99)‡||1.01 (0.99–1.03)|
|MDHAQ score, mean||1.04 (0.74–1.46)||1.26 (0.72–2.19)|
|DAS28, mean||1.03 (0.89–1.19)||0.87 (0.68–1.11)|
The mean ± SD MPR of VARA subjects receiving bisphosphonate therapy was 0.69 ± 0.28. Approximately half (302 [52.7%]) were nonadherent (MPR <0.80). If gaps >90 days were removed from the duration of therapy and the MPR calculated for each course the patient received, giving more weight to longer courses, the mean ± SD MPR would be 0.90 ± 0.13; this MPR was not used for further analyses. In univariate analyses, nonadherence with bisphosphonate therapy was associated with <12 years of education (OR 1.67, 95% CI 1.00–2.79), a longer duration of RA (OR 1.02, 95% CI 1.01–1.04), a higher mean DAS28 score (OR 1.17, 95% CI 1.01–1.35), and a duration of bisphosphonate therapy ≥32 months (OR 1.98, 95% CI 1.42–2.77). In the multivariate analysis, whites were less likely to be nonadherent (OR 0.52, 95% CI 0.30–0.88). The MPR <0.80 for bisphosphonates was associated with the duration of RA (OR 1.02, 95% CI 1.00–1.04) and bisphosphonate therapy prescribed for ≥32 months (OR 1.63, 95% CI 1.04–2.57). The univariate and multivariate analyses for MPR are shown in Table 3.
Table 3. Univariate and multivariate associations between demographic and clinical variables and MPR*
| ||MPR <0.80||MPR ≥0.80||MPR <0.80, OR (95% CI)|
|Age, years|| || || || |
| ≥70||137 (45.4)||130 (48.0)||Referent||Referent|
| <70||165 (54.6)||141 (52.0)||1.11 (0.80–1.54)||1.36 (0.86–2.23)|
|Sex|| || || || |
| Male||274 (90.7)||241 (88.9)||Referent||Referent|
| Female||28 (9.3)||30 (11.1)||0.82 (0.48–1.41)||0.74 (0.37–1.47)|
|Ethnicity|| || || || |
| Nonwhite||66 (22.0)||34 (12.7)||Referent||Referent|
| White||234 (78.0)||234 (87.3)||0.51 (0.33–0.81)‡||0.52 (0.30–0.88)§|
|Education, years|| || || || |
| ≥12||172 (78.2)||168 (85.7)||Referent||Referent|
| <12||48 (21.8)||28 (14.3)||1.67 (1.00–2.79)§||1.64 (0.92–2.93)|
|Smoking|| || || || |
| No||217 (73.6)||196 (74.2)||Referent||Referent|
| Yes||78 (26.4)||68 (25.8)||1.04 (0.71–1.51)||1.20 (0.72–1.99)|
|Charlson-Deyo Index, mean ± SD||2.18 ± 2.22||1.78 ± 1.89||1.01 (0.98–1.04)||1.03 (0.99–1.08)|
|Prednisone use|| || || || |
| No||82 (28.2)||83 (31.2)||Referent||Referent|
| Yes||209 (71.8)||183 (68.8)||1.16 (0.80–1.66)||1.25 (0.77–2.04)|
|DXA|| || || || |
| Never||166 (55.1)||146 (54.3)||Referent||Referent|
| Ever||135 (44.9)||123 (45.7)||0.97 (0.69–1.34)||1.03 (0.66–1.60)|
|Osteoporosis¶|| || || || |
| No||98 (72.6)||94 (76.4)||Referent|| |
| Yes||37 (27.4)||29 (23.6)||1.22 (0.70–2.15)|| |
|Duration of RA, mean ± SD years||20.6 ± 13.0||17.4 ± 12.0||1.02 (1.01–1.04)‡||1.02 (1.00–1.04)§|
|MDHAQ score, mean ± SD||1.07 ± 0.53||1.04 ± 0.44||1.12 (0.80–1.58)||1.01 (0.63–1.63)|
|DAS28, mean ± SD||3.84 ± 1.21||3.63 ± 1.13||1.17 (1.01–1.35)§||1.15 (0.93–1.42)|
|Duration of bisphosphonate, months|| || || || |
| <32||126 (41.7)||159 (58.7)||Referent||Referent|
| ≥32||176 (58.3)||112 (41.3)||1.98 (1.42–2.77)#||1.63 (1.04–2.57)§|
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Clinical studies show that use of oral bisphosphonates reduces the risk of osteoporotic fractures. However, adherence to therapy is required for improved outcomes and appears to represent a major treatment obstacle in US veteran patients with RA. In our VARA cohort, we demonstrated a lower adherence in nonwhite patients and patients with a longer duration of RA or in whom bisphosphonates were prescribed for a longer period of time.
Much of the literature pertaining to adherence with bisphosphonate therapy is from randomized clinical trials enrolling primarily women, which may not reflect clinical practice, or from studies utilizing prescription benefit claims, which lack clinical data. A major strength of the current study is the merging of electronic databases, i.e., clinical data from the VARA registry with the detailed dispensing data from the PBM. The mean MPR of 0.69 was comparable to that of other studies that included predominantly women and reported 43–70.5% of subjects to be adherent with oral bisphosphonates (8, 29, 30). We included all gaps in the duration of therapy when calculating the MPR; if we removed gaps of >90 days and calculated the MPR for each course, giving more weight to longer courses, the mean ± SD MPR would be 0.90 ± 0.13. We believe the method used for calculating the MPR in our analysis was more appropriate, since bisphosphonates are used for long-term prophylaxis against fractures; therefore, long-term adherence is more important.
Women were not more adherent than men in our cohort, but the relatively small number of women (10.1% of the cohort) limited the power of our calculations in examining sex-related differences. Nonwhites were less adherent in our study, an observation that was not found by others (9, 12); however, the predominance of whites in these studies could have obscured any racial differences. Economic factors are unlikely to have accounted for the racial differences in our study, given the small copayment (no more than $9 per month at the time of the study) for all veterans eligible for care in the VA Health Care System.
Poor bisphosphonate adherence is reported to be associated with older age, more comorbid conditions, more nonosteoporosis medications, and institutionalization in a nursing home (9). Our data set did not include nonosteoporosis or non-RA medications, but the burden of comorbidity measured by the Charlson-Deyo Index was not associated with adherence in either univariate or multivariate analyses.
A retrospective review of male veterans in Wisconsin found nonadherence with bisphosphonates to be associated with tobacco use and side effects related to the bisphosphonates, whereas men undergoing bone density testing were less likely to be nonadherent (13). This led us to postulate that patients with osteoporosis or DXA testing would be more adherent with bisphosphonate therapy. However, our data did not duplicate this finding. DXA was not systematically obtained prior to the initiation of bisphosphonate therapy, and the results of repeat DXA were not routinely entered in the VARA registry. This precluded analysis of the effect repeat DXA had on either duration of therapy or adherence.
Osteoporosis is typically an asymptomatic condition, and patients, particularly those with fewer years of education, as was seen in our cohort, may find it difficult to understand the risk of fracture and benefits of therapy. Other barriers to adherence with oral bisphosphonates include inconvenience and side effects, neither of which was included in our VARA data or analysis (12).
The mean duration of bisphosphonate therapy in VARA patients was 39.2 months, similar to the median duration of 3.27 years reported from a study of the Australian Department of VA data set (31). In our cohort, a duration of bisphosphonate therapy of more than 32 months was associated with older age, more years of education, and having a DXA scan performed. In contrast, a large study of 152,777 Danish patients with osteoporotic fractures reported that older subjects were more likely to discontinue or change treatments (10).
There are limitations to this retrospective cohort study. First, the subjects in the VARA cohort may not be representative of all patients with RA, since our patients are mostly men and older. Second, adherence may be overestimated in the current study, since we calculated the adherence based on medication dispensed to the patients and did not perform pill counts, although it may be logical to assume that patients are unlikely to refill medications they are not taking. Third, some patients may participate in dual care and may be receiving prescriptions from non-VA pharmacies, data that would not be captured in PBM. Another limitation of this study is the absence of fracture data, which could influence adherence; an analysis of 101,038 new bisphosphonate users found that the mean bisphosphonate adherence was 7% lower in the 6 months following a hip fracture compared to the 6 months preceding the hip fracture (29). Finally, our study did not measure side effects from bisphosphonates, which other studies have reported to be a major reason for poor adherence and persistence of bisphosphonate therapy (12).
Factors contributing to bisphosphonate nonadherence in patients with postmenopausal osteoporosis include lack of DXA testing, poor physical function, and older age, and may not apply to RA patients with secondary osteoporosis. Similar findings were demonstrated in our cohort, where nonwhite ethnicity, duration of RA, and duration of bisphosphonate therapy were the major risk factors for nonadherence; poor physical function and higher disease activity of RA did not explain bisphosphonate nonadherence.
In summary, in a cohort of veterans with RA, oral bisphosphonate adherence is subpar, and our findings provide baseline data to permit a targeted approach for improvement in fracture prevention interventions. Our findings provide useful baseline information for the development of initiatives for an improved risk management approach for the prevention of osteoporotic fractures in VA patients with RA.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Mr. Richards had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Richards, Cannon, Kerr.
Acquisition of data. Richards, Cannon, Hayden, Amdur, Lazaro, Mikuls, Reimold, Caplan, Johnson, Schwab, Cherascu, Kerr.
Analysis and interpretation of data. Richards, Cannon, Amdur, Kerr.