Adherence With Bisphosphonate Therapy in US
Veterans With Rheumatoid Arthritis
J. STEUART RICHARDS,1GRANT W. CANNON,2CANDACE L. HAYDEN,2RICHARD L. AMDUR,1
DEANA LAZARO,3TED R. MIKULS,4ANDREAS M. REIMOLD,5LIRON CAPLAN,6
DANNETTE S. JOHNSON,7PASCALE SCHWAB,8BOGDAN N. CHERASCU,9AND GAIL S. KERR10
Objective. Pharmacy Benefits Management program data for patients enrolled in the Veterans Affairs Rheumatoid
Arthritis (VARA) registry were linked with clinical data to determine bisphosphonate adherence and persistence among
US veterans with rheumatoid arthritis (RA) and to determine factors associated with adherence.
Methods. The primary outcome measures were the duration of bisphosphonate therapy and the medication possession
ratio (MPR). Patients with an MPR <0.80 were classified as nonadherent. Potential covariates considered in the analysis
included patient demographics, RA disease activity and severity parameters, and factors associated with osteoporosis
risk. Associations of patient factors with duration of therapy and adherence were examined using multivariable
Results. Bisphosphonates were prescribed to 573 (41.5%) of 1,382 VARA subjects. The mean ? SD duration of therapy
for bisphosphonates was 39.2 ? 31.4 months. A longer duration of therapy correlated with older age, more years of
education, and dual x-ray absorptiometry testing. The mean ? SD MPR of VARA subjects for bisphosphonate therapy was
0.69 ? 0.28; 302 (52.7%) were nonadherent. In multivariate analyses, nonadherence with bisphosphonate therapy was
associated with a longer duration of RA disease (odds ratio [OR] 1.02, 95% confidence interval [95% CI] 1.00–1.04) and
duration of bisphosphonate therapy >32 months (OR 1.63, 95% CI 1.04–2.57). Whites were less likely to have a low MPR
compared with nonwhites (OR 0.52, 95% CI 0.30–0.88).
Conclusion. Nonadherence with bisphosphonates was common in this cohort of RA patients and was associated with
nonwhite ethnicity, a longer duration of RA disease, and a greater duration of bisphosphonate therapy.
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 re-
ported 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, His-
panic, 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 bis-
phosphonates are among the most common pharmacologic
agents prescribed. Randomized controlled clinical trials
have demonstrated the efficacy of alendronate, risedro-
Supported by a VA Health Services Research and Devel-
opment grant (SHP 08-172).
1J. Steuart Richards, MBBS, Richard L. Amdur, PhD: VA
Medical Center and Georgetown University, Washington,
George E. Whalen VA Medical Center and University of
Utah, Salt Lake City;
New York, New York;4Ted R. Mikuls, MD, MSPH: Omaha
VA Medical Center and University of Nebraska Medical
Center and University of Texas Southwestern, Dallas;6Liron
Caplan, MD, PhD: Denver VA Medical Center, Denver, and
University of Colorado, Aurora;7Dannette S. Johnson, DO:
G. V. “Sonny” Montgomery VA Medical Center and Univer-
sity of Mississippi, Jackson;8Pascale Schwab, MD: Portland
VA, Portland, Oregon;9Bogdan N. Cherascu, MD: Iowa City
VA, Iowa City, Iowa;10Gail S. Kerr, MD: VA Medical Center,
Georgetown University, and Howard University, Washing-
2Grant W. Cannon, MD, Candace L. Hayden, MSPH:
3Deana Lazaro, MD: Brooklyn VA,
5Andreas M. Reimold, MD: VA Medical
Address correspondence to J. Steuart Richards, MBBS,
Washington, DC VA Medical Center, 50 Irving Street NW,
Washington, DC 20422. E-mail: email@example.com.
Submitted for publication February 13, 2012; accepted in
revised form June 15, 2012.
Arthritis Care & Research
Vol. 64, No. 12, December 2012, pp 1864–1870
© 2012, American College of Rheumatology
nate, 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 adher-
ence have focused on women with postmenopausal osteo-
porosis, including African Americans and populations of
European ancestry (9–12). In these prior studies, determi-
nants of poor adherence with bisphosphonate treatment
were found to include older age, daily versus weekly bis-
phosphonate 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, periartic-
ular osteopenia, and generalized bone loss or osteoporosis.
Synovial cytokines, including macrophage colony-stimu-
lating factor and RANKL, promote osteoclast differentia-
tion and subsequent bone erosion (14). The mechanisms
for generalized osteopenia distant from synovial inflam-
mation 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 pa-
tients 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.
PATIENTS AND METHODS
Patients. The VARA registry is a longitudinal multi-
center chronic disease cohort of US veterans who fulfill
the 1987 American College of Rheumatology criteria for
the classification of RA, and is described in detail else-
where (17–19). In summary, the registry began in 2003 and
currently enrolls patients from 11 VA medical centers. The
registry database includes patient demographics, longitu-
dinal markers of RA disease activity and severity, comor-
bid diseases, and BMD results for those undergoing dual
x-ray absorptiometry (DXA) as part of their routine care.
VARA subjects eligible for this analysis were required to
have received at least 1 prescription for an oral bisphos-
Bisphosphonate therapy. The PBM database contains
detailed information on every prescription filled within
the VA Health Care System since 1999 and includes med-
ication name, dose of tablet, date dispensed, number of
tablets dispensed, expected duration of therapy, and pre-
scribing directions (20,21). At the time of the analysis,
PBM data on VARA patients were available for 6 VA
medical centers (Dallas, Denver, Jackson, Omaha, Salt
Lake City, and Washington, DC). The PBM data were an-
alyzed for the bisphosphonates alendronate, risedronate,
etidronate, and ibandronate, which included all doses dis-
pensed within the VA for these medications. Dosing regi-
mens used for Paget’s disease and parenteral preparations
were not included for this study. For each dispensed pre-
scription, an expected duration of therapy was calculated.
The dispensing date and expected duration were used to
calculate the end date for each prescription. Differences
between the expected end of a prescription and the dis-
pensing date of the subsequent medication refill were con-
sidered gaps in therapy. A patient was defined as receiving
a course of bisphosphonate therapy if there was a ?90-day
gap between refills for a specific bisphosphonate. A course
ended when a 90-day gap occurred as defined above or the
medication was discontinued. The duration of the course
was defined from the date of the first bisphosphonate
prescription dispensed until the expected end date for the
last prescription before a 90-day gap or the end of the
observation period. The duration of therapy was measured
from the date of the initial prescription until the last ex-
pected refill date of the final prescription, and therefore
included the duration of all courses plus gaps for each
Bisphosphonate adherence. Medication adherence was
assessed by calculating the medication possession ratio
(MPR), defined as the proportion of treatment time that a
patient had an available drug (22). The MPR was deter-
mined for the duration of therapy by calculating the time
that the patient had medication available divided by the
time from the date the medication was initially dispensed
until the last expected refill date of the final prescription.
The details of the extraction of medication courses from
PBM were recently described for methotrexate; we used
similar methodology for bisphosphonates (23). Current
data indicate that fracture risk decreases as medication
adherence increases, from 50% to 80%, but with no fur-
ther reduction beyond 80% (24). Therefore, for this analy-
sis, subjects were deemed adherent with bisphosphonate
therapy if the MPR was ?0.80 and nonadherent if the MPR
Primary outcome measures and patient characteristics.
Duration of bisphosphonate therapy and an MPR ?0.80
were the primary outcome measures. To examine factors
potentially contributing to the outcomes, we analyzed co-
variates, including sex, age (?70 versus ?70 years), race/
ethnicity (nonwhite versus white), education (?12 versus
?12 years), current smoking status, comorbidity measured
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.
Bisphosphonate Adherence and Persistence in US Veterans With RA 1865
by the Charlson-Deyo Comorbidity Index (25), disease ac-
tivity as measured by the mean Disease Activity Score in
28 joints (DAS28) (26), the mean Multidimensional Health
Assessment Questionnaire (MDHAQ) score (27,28), dura-
tion of RA, use of prednisone during VARA enrollment,
duration of bisphosphonate therapy (for an MPR ?0.80),
and whether patients had DXA performed or a densitomet-
ric diagnosis of osteoporosis.
Statistical analysis. Adherent and nonadherent pa-
tients were compared using chi-square tests for categorical
variables and univariate one-way analysis of variance for
continuous variables. Multivariate associations with non-
adherence were examined using logistic regression analy-
sis. Odds ratios (ORs) and their 95% confidence intervals
(95% CIs) were calculated. Mean duration of therapy was
measured and the SD was calculated. Multivariate associ-
ations of patient factors with duration of therapy were
examined using linear regression analysis. Covariates with
P values greater than 0.1 in the univariate analyses were
not included in the multivariate analyses for both duration
of bisphosphonate therapy and an MPR ?0.80.
Human subjects review. The VARA registry received
Institutional Review Board approval at each site and all
enrollees provided written informed consent. This study
was approved by the Scientific and Ethics Advisory Com-
mittee for the VARA registry.
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 diagno-
sis 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).
Four hundred ninety-seven patients (86.7%) received
alendronate as their only bisphosphonate and 17 (3.0%)
received risedronate; 59 patients (10.3%) received pre-
scriptions 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 prepa-
ration, and 1 of the 76 subjects prescribed risedronate
received a once daily prescription. Three subjects received
a prescription for etidronate and no subjects were pre-
scribed ibandronate. These subjects given either etidronate
or daily bisphosphonate therapy were excluded from fur-
ther 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 intra-
venous zoledronic acid and 6 were switched to teripa-
ratide. The univariate and multivariate associations of
Table 1. Characteristics of bisphosphonate users and nonusers among Veterans Affairs
Rheumatoid Arthritis enrollees*
(n ? 1,372)
Subjects ever used
(n ? 573)
Subjects never used
(n ? 799)
Age, mean ? SD years†
Women, no. (%)
Ethnicity, no. (%)†
Education, mean ? SD years
Smoking (current), no. (%)
Charlson-Deyo Index, mean ? SD‡
Prednisone use, no. (%)†
DXA testing, no. (%)†
Osteoporosis, no. (%)†
Duration of RA, mean ? SD years†
MDHAQ score, mean ? SD§
DAS28, mean ? SD§
66.3 ? 11.5
68.7 ? 10.3
64.6 ? 12.0
12.8 ? 2.6
1.8 ? 2.2
16.6 ? 12.3
1.0 ? 0.5
3.63 ? 1.18
12.8 ? 2.6
1.99 ? 2.08
19.1 ? 12.6
1.05 ? 0.49
3.74 ? 1.18
12.9 ? 2.7
1.72 ? 2.25
14.9 ? 11.8
0.96 ? 0.51
3.54 ? 1.17
* DXA ? dual x-ray absorptiometry; RA ? rheumatoid arthritis; MDHAQ ? Multidimensional Health Assessment
Questionnaire; DAS28 ? Disease Activity Score in 28 joints.
† P ? 0.001 (bisphosphonate users vs. nonusers).
‡ P ? 0.05 (bisphosphonate users vs. nonusers).
§ P ? 0.01 (bisphosphonate users vs. nonusers).
1866 Richards et al
treatment duration are shown in Table 2. In the multivar-
iate analysis, a longer duration of therapy was associated
with age ?70 years (OR 1.79, 95% CI 1.04–3.08), educa-
tion past twelfth grade (OR 2.12, 95% CI 1.09–4.14), and
receiving DXA (OR 1.74, 95% CI 1.05–2.89).
The mean ? SD MPR of VARA subjects receiving bis-
phosphonate 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, giv-
ing 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 bis-
phosphonate 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 bis-
phosphonate therapy prescribed for ?32 months (OR 1.63,
95% CI 1.04–2.57). The univariate and multivariate ana-
lyses for MPR are shown in Table 3.
Clinical studies show that use of oral bisphosphonates
reduces the risk of osteoporotic fractures. However, adher-
ence 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 dem-
onstrated a lower adherence in nonwhite patients and
patients with a longer duration of RA or in whom bisphos-
phonates 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 predom-
inantly women and reported 43–70.5% of subjects to be
adherent with oral bisphosphonates (8,29,30). We in-
cluded all gaps in the duration of therapy when calculat-
ing the MPR; if we removed gaps of ?90 days and calcu-
lated 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 stud-
ies could have obscured any racial differences. Economic
factors are unlikely to have accounted for the racial differ-
ences 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 asso-
ciated with older age, more comorbid conditions, more
nonosteoporosis medications, and institutionalization in a
nursing home (9). Our data set did not include nonosteo-
porosis or non-RA medications, but the burden of comor-
bidity measured by the Charlson-Deyo Index was not
Table 2. Predictors of prescribed duration of bisphosphonate therapy of >32 months for
Veterans Affairs Rheumatoid Arthritis subjects*
Age ?70 years
Education ?12th grade
Duration of RA
MDHAQ score, mean
* OR ? odds ratio; 95% CI ? 95% confidence interval; DXA ? dual x-ray absorptiometry; RA ?
rheumatoid arthritis; MDHAQ ? Multidimensional Health Assessment Questionnaire; DAS28 ? Disease
Activity Score in 28 joints.
† Adjusted for age ?70 years, female sex, enrollment site, number of bisphosphonate courses, education
?12 years, DAS28 (mean), Charlson-Deyo Index, prednisone use, and DXA.
‡ P ? 0.01.
§ P ? 0.05.
¶ Not included in the multivariate model because P ? 0.10.
Bisphosphonate Adherence and Persistence in US Veterans With RA 1867
associated with adherence in either univariate or multivar-
A retrospective review of male veterans in Wisconsin
found nonadherence with bisphosphonates to be associ-
ated with tobacco use and side effects related to the bis-
phosphonates, whereas men undergoing bone density test-
ing 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 bis-
phosphonate therapy, and the results of repeat DXA were
not routinely entered in the VARA registry. This pre-
cluded 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 educa-
tion, 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 De-
partment of VA data set (31). In our cohort, a duration of
bisphosphonate therapy of more than 32 months was as-
sociated 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 re-
ported 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 repre-
sentative of all patients with RA, since our patients are
mostly men and older. Second, adherence may be overes-
Table 3. Univariate and multivariate associations between demographic and clinical variables and MPR*
MPR <0.80MPR >0.80
MPR <0.80, OR (95% CI)
Charlson-Deyo Index, mean ? SD
Duration of RA, mean ? SD years
MDHAQ score, mean ? SD
DAS28, mean ? SD
Duration of bisphosphonate, months
1.11 (0.80–1.54)1.36 (0.86–2.23)
0.82 (0.48–1.41)0.74 (0.37–1.47)
0.51 (0.33–0.81)‡0.52 (0.30–0.88)§
1.67 (1.00–2.79)§1.64 (0.92–2.93)
2.18 ? 2.22
1.78 ? 1.89
1.16 (0.80–1.66)1.25 (0.77–2.04)
0.97 (0.69–1.34) 1.03 (0.66–1.60)
20.6 ? 13.0
1.07 ? 0.53
3.84 ? 1.21
17.4 ? 12.0
1.04 ? 0.44
3.63 ? 1.13
1.98 (1.42–2.77)#1.63 (1.04–2.57)§
* Values are the number (percentage) unless otherwise indicated. MPR ? medication possession ratio; OR ? odds ratio; 95%
CI ? 95% confidence interval; DXA ? dual x-ray absorptiometry; RA ? rheumatoid arthritis; MDHAQ ? Multidimensional
Health Assessment Questionnaire; DAS28 ? Disease Activity Score in 28 joints.
† Adjusted for age ?70 years, female sex, white ethnicity, enrollment site, DXA, education ?12 years, smoking (current),
Charlson-Deyo Index, prednisone use, DXA, duration of RA, MDHAQ score (mean), DAS28 (mean), and duration of bisphos-
‡ P ? 0.01.
§ P ? 0.05.
¶ Osteoporosis was not included in the multivariate analysis due to the small numbers.
# P ? 0.0001.
1868 Richards et al
timated in the current study, since we calculated the ad-
herence 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 analy-
sis 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 adher-
ence 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 bis-
phosphonate therapy were the major risk factors for
nonadherence; poor physical function and higher disease
activity of RA did not explain bisphosphonate nonadher-
In summary, in a cohort of veterans with RA, oral bis-
phosphonate adherence is subpar, and our findings pro-
vide baseline data to permit a targeted approach for im-
provement in fracture prevention interventions. Our
findings provide useful baseline information for the devel-
opment of initiatives for an improved risk management
approach for the prevention of osteoporotic fractures in
VA patients with RA.
The authors wish to thank Jeffrey Huang for his assistance
in collating the data for analysis.
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors ap-
proved 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,
1. Melton L, Chrischilles EA, Cooper C, Lane AW, Riggs BL.
Perspective: how many women have osteoporosis? J Bone
Miner Res 1992;7:105–10.
2. Silverman SL, Madison RE. Decreased incidence of hip frac-
ture in Hispanics, Asians, and blacks: California Hospital
Discharge Data. Am J Public Health 1988;78:1482–3.
3. Wehren LE, Hawkes WG, Orwig DL, Hebrel JR, Zimmerman
SI, Magaziner J. Gender differences in mortality after hip
fracture: the role of infection. J Bone Miner Res 2003;18:
4. Cummings SR, Black DM, Thompson DE, Applegate WB,
Barrett-Conner E, Musliner TA, et al. Effect of alendronate on
risk of fracture in women with low bone density but without
vertebral fractures: results from the Fracture Intervention
Trial. JAMA 1988;280:2077–82.
5. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG,
Roux C, et al. Effect of risedronate on risk of hip fracture in
elderly women. N Engl J Med 2001;344:333–40.
6. Delmas PD, Recker RR, Chestnut CH III, Skag A, Stakkestad
JA, Emkey R, et al. Daily and intermittent oral ibandronate
normalize bone turnover and provide significant reduction in
vertebral fracture risk: results from the BONE study. Osteo-
porsis Int 2004;15:792–8.
7. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley
JA, et al. Once yearly zoledronic acid for the treatment of
postmenopausal osteoporosis. N Engl J Med 2007;356:1809–
8. Siris ES, Harris ST, Rosen CJ, Barr CE, Arvesen JN, Abbott TA,
et al. Adherence to bisphosphonate therapy and fracture rates
in osteoporotic women: relationship to vertebral and nonver-
tebral fractures from 2 US claims databases. Mayo Clin Proc
9. Solomon DH, Avorn J, Katz JN, Finkelstein JS, Arnold M,
Polinski JM, et al. Compliance with osteoporosis medications.
Arch Int Med 2005;165:2414–9.
10. Roerholt C, Eiken P, Abrahamsen B. Initiation of anti-osteo-
porotic therapy in patients with recent fractures: a nationwide
analysis of prescription rates and persistence. Osteoporosis
11. Tosteson AN, Do TP, Wade SW, Anthony MS, Downs RW.
Persistence and switching patterns among women with varied
osteoporosis medication histories: 12-month results from
POSSIBLE US. Osteoporos Int 2010;21:1769–80.
12. Hansen KE, Senson ED, Baltz B, Shuna AA, Jones AN, Elliott
ME. Adherence to alendronate in male veterans. Osteoporosis
13. Grazio S, Babic-Naglic D, Kehler T, Curkovic B. Persistence of
weekly alendronate: a real-world study in Croatia. Clin Rheu-
14. Gravallese EM, Harada Y, Wang JT, Gorn AH, Thornhill TS,
Goldring SR. Identification of cell types responsible for bone
resorption in rheumatoid arthritis and juvenile rheumatoid
arthritis. Am J Pathol 1998;152:943–51.
15. Gough A, Sambrook P, Devlin J, Huissoon A, Njeh C, Robbins
S, et al. Osteoclastic activation is the principal mechanism
leading to secondary osteoporosis in rheumatoid arthritis.
J Rheumatol 1998;25:1282–9.
16. Sambrook P, Nguyen T. Vertebral osteoporosis in rheumatoid
arthritis patients: effect of low dose prednisone therapy [let-
ter]. Br J Rheumatol 1992;31:573–4.
17. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF,
Cooper NS, et al. The American Rheumatism Association
1987 revised criteria for the classification of rheumatoid ar-
thritis. Arthritis Rheum 1988;31:315–24.
18. Mikuls TR, Fay BT, Michaud K, Sayles H, Thiele GM, Caplan
L, et al. Associations of disease activity and treatments with
mortality in men with rheumatoid arthritis: results from the
VARA registry. Rheumatology (Oxford) 2011;50:101–9.
19. Mikuls TR, Kazi S, Cipher D, Hooker R, Kerr GS, Richards JS,
et al. The association of race and ethnicity with disease ex-
pression in male US veterans with rheumatoid arthritis.
J Rheumatol 2007;34:1480–4.
20. Department of Veterans Affairs. Pharmacy Benefits Manage-
ment services. URL: http://www.pbm.va.gov/Default.aspx.
21. Sales MM, Cunningham FE, Glassman PA, Valentino MA,
Good CB. Pharmacy benefits management in the Veterans
Administration: 1995 to 2003. Am J Manage Care 2005;11:
22. Andrade SE, Kahler KH, Frech F, Chan KA. Methods for
evaluation of medication adherence and persistence using
automated databases. Pharmacoepidemiol Drug Saf 2006;15:
Bisphosphonate Adherence and Persistence in US Veterans With RA 1869
23. Cannon GW, Mikuls TR, Hayden CL, Ying J, Curtis JR, Rei- Download full-text
mold AM, et al. Merging Veterans Affairs Rheumatoid Arthri-
tis registry and pharmacy data to access methotrexate adher-
ence and disease activity in clinical practice. Arthritis Care
Res (Hoboken) 2011;63:1680–90.
24. Caro JJ, Ishak KJ, Huybrechts KF, Raggio G, Naujoks C. The
impact of compliance with osteoporosis therapy on fracture
rates in actual practice. Osteoporos Int 2004;15:1003–8.
25. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comor-
bidity index for use with ICD-9-CM administrative databases.
J Clin Epidemiol 1992;45:613–9.
26. Prevoo ML, van ’t Hof MA, Kuper HH, van Leeuwen MA, van
de Putte LB, van Riel PL. Modified disease activity scores that
include twenty-eight–joint counts: development and valida-
tion in a prospective longitudinal study of patients with rheu-
matoid arthritis. Arthritis Rheum 1995;38:44–8.
27. Pincus T, Sokka T, Kautiainen H. Further development of a
physical function scale on a MDHAQ [corrected] for standard
care of patients with rheumatic diseases. J Rheumatol 2005;
28. Pincus T, Swearingen C, Wolfe F. Toward a Multidimensional
Health Assessment Questionnaire (MDHAQ): assessment of
advanced activities of daily living and psychological status in
the patient-friendly Health Assessment Questionnaire format.
Arthritis Rheum 1999;42:2220–30.
29. Curtis JR, Westfall AO, Cheng H, Lyles K, Saag KG, Delzell E.
Benefit of adherence with bisphosphonates depends on age
and fracture type: results from an analysis of 101,038 new
bisphosphonate users. J Bone Miner Res 2008;23:1435–41.
30. Rabenda V, Mertens R, Fabri V, Vanoverloop J, Sumkay F,
Vannecke C, et al. Adherence to bisphosphonate therapy and
hip fracture risk in women. Osteoporosis Int 2008;19:811–8.
31. Roughead EE, Ramsay E, Priess K, Barratt J, Ryan P, Gilbert
AL. Medication adherence, first episode duration, overall du-
ration and time without therapy: the example of bisphospho-
nates. Pharmacoepidemiol Drug Saf 2009;18:69–75.
1870 Richards et al