JBMRORIGINAL ARTICLE

The Relationship Between Bisphosphonate Adherence
and Fracture: Is It the Behavior or the Medication?
Results From the Placebo Arm of the FractureIntervention Trial
Jeffrey R Curtis, 1,2 Elizabeth Delzell, 2 Lang Chen, 1 Dennis Black, 3 Kristine Ensrud, 4,5 Suzanne Judd, 6
Monika M Safford , 7 Ann V Schwartz , 3 and Douglas C Bauer8
1

Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
3
Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA
4
Department of Medicine and Epidemiology, University of Minnesota, Minneapolis, MN, USA
5
Department of Medicine, Minneapolis Veterans Administration Medical Center, Minneapolis, MN, USA
6
Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL. USA
7
Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
8
Departments of Medicine and Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA
2

ABSTRACT
Medication compliance may be a surrogate for factors that improve health outcomes such as fractures. Little is known about the size of
this potential ‘‘healthy adherer’’ effect. We evaluated the hypothesis that compliance with placebo is associated inversely with bone loss
and fractures among women participating in the Fracture Intervention Trial (FIT). Compliance with placebo and alendronate was
evaluated using daily medication diaries. Women were defined as having high compliance if they took 80% or more of dispensed study
medication. Change in bone mineral density (BMD) was assessed using mixed models comparing women with high versus lower
compliance with placebo. Cox proportional-hazards models analyzed the association between placebo compliance and various types offractures. Among 3169 women randomized to placebo, 82% had high compliance. Compared with women with lower placebo
compliance, bone loss at the total hip was lower in compliant placebo-treated women (0.43%/year versus 0.58%/year, p ¼ .04).
Among placebo-treated women, there were 46 hip, 110 wrist, 77 clinical vertebral, and 492 total clinical fractures. Compared with womenwith lower placebo compliance, women with high placebo compliance had a nonsignificant reduced risk for hip fracture [adjusted
hazard ratio (HR) ¼ 0.67, 95% confidence interval (CI) 0.30–1.45]. This trend was not observed for other fractures. Medication compliance
may be a proxy for factors that confers benefit on reducing hip fracture (but not other types of fractures) independent of the effect of the
medication itself. Nonrandomized studies of interventions designed to maintain or improve bone density and/or hip fracture may needto consider medication compliance as a confounder to better estimate true intervention effects. ß 2011 American Society for Bone andMineral Research.
KEY WORDS: COMPLIANCE; ADHERENCE; HIP FRACTURE; VERTEBRAL FRACTURE; ALENDRONATE; BISPHOSPHONATEIntroduction

S

everal studies have reported a strong inverse relation
between high compliance with oral bisphosphonates andfracture risk.(1–5) A recent review has summarized many ofthese studies and shown that long-term compliance with oral
osteoporosis medications generally is low and that women withhigh compliance who took at least 80% of prescribed medication
had a substantially lower risk for fracture than less compliant
women.(6) However, concerns have been raised that medication
compliance itself is associated with factors that may have afavorable impact on outcomes. This finding, sometimes called
the ‘‘healthy adherer effect,’’ is a potential source of confoundingthat is not always accounted for in analyses. Data supporting theReceived in original form May 4, 2010; revised form August 17, 2010; accepted October 1, 2010. Published online October 11, 2010.
Address correspondence to: Jeffrey R Curtis, MD, MS, MPH, Center for Education and Research on Therapeutics of Musculoskeletal Diseases (CERTs), Arthritis ClinicalIntervention Program (ACIP), University of Alabama at Birmingham, FOT 805, 1530 3rd Avenue South, Birmingham, AL 35249, USA. E-mail: jcurtis@uab.edu
For a Commentary on this article, please see Silverman and Gold (J Bone Miner Res. 2011;26:681–682. DOI: 10.1002/jbmr 384).
Journal of Bone and Mineral Research, Vol. 26, No. 4, April 2011, pp 683–688
DOI: 10.1002/jbmr.274
ß 2011 American Society for Bone and Mineral Research683

importance of the healthy adherer effect come from several
sources, including a meta-analysis of eight clinical trials showingthat high compliance with placebo was associated with a 44%
lower rate of death.(7) High compliance also has been associatedwith health-seeking behavior, use of preventive services (eg,immunization and cancer screening tests), and a lower rate oftraumatic accidents.(8,9) However, the existence and magnitudeof the healthy adherer effect has not been examined previouslywith respect to fracture outcomes.
The Fracture Intervention Trial (FIT) was a trial that was
conducted in 11 US communities in the 1990 s, included over
6000 women, and tested the efficacy of alendronate in
improving bone mineral density (BMD) and reducing fracturerisk.(10–12) We used data from the FIT to evaluate the hypothesisthat high compliance with placebo was associated with lower
rates of bone loss and fracture. We also evaluated changes incompliance following a fracture, hypothesizing that women
would be more likely to be noncompliant following a fracture.

Methods

proportional-hazards models were used to estimate theassociation between high compliance and hip, clinical vertebral,
and wrist fractures. Change in BMD, reported as annualized
percent change, was assessed between study annual visits andwas analyzed in relation to compliance during this same interval
using mixed models. Each patient could contribute multiple
observations to the BMD analysis. Factors hypothesized topotentially affect the association between compliance andfractures (eg, age, fracture history, self-reported health status)and baseline BMD were adjusted for in both the survival models
and the mixed models.
To better understand the dynamic nature of compliance in thesetting of an acute fracture, compliance was reported among
patients with hip, clinical vertebral, and wrist fracture, comparing
compliance before fracture (ie, from the beginning of the study
until the fracture date) with compliance after fracture (ie, fromthe fracture date until the end of the study). Agreement between
pre- and postfracture compliance was quantified using Cohen’s
kappa statistic with 95% confidence intervals (CIs). All analyses
were conducted using SAS 9.2 (SAS Institute, Cary, NC, USA).

Study population
The FIT was a placebo-controlled, double-blind trial of 6469
women randomized to alendronate versus placebo.(10,11) The FITI and FIT-II cohorts included women with low bone mass (defined
as a T-score of less than 1.6 at the femoral neck) with andwithout existing vertebral fracture at baseline, respectively. Data
from both groups of women were pooled for this analysis given
comparable compliance to study medication in the two cohorts.
Daily calcium intake was estimated by food-frequency questionnaire, and participants in both groups who had calcium
intakes of less than 1000 mg were given a daily supplement
providing 500 mg of elemental calcium (as the carbonate salt)
and 250 IU of cholecalciferol (vitamin D). About 82% ofparticipants received the supplement at the randomization visit.

Ascertainment of compliance and fracture outcomes
Compliance in FIT was evaluated using daily patient diaries andpill counts returned at annual study visits, which had excellent
agreement with one another. Although compliance therefore
was defined as a continuous variable ranging from 0% to 100%,
women were defined as having high compliance in this analysis
if they took 80% or more of dispensed medication, following
prior conventions.(6) Fractures were confirmed centrally throughreview of medical records, as per the FIT protocol.

Results
A total of 3169 women participating in FIT were randomized toplacebo. Compliance with the placebo study medication washigh over the course of FIT, with 80% to 85% of women having
high compliance over the 4 years of the study (Fig. 1). Stratifying
these women into high versus lower compliance at the end of
FIT, Table 1 describes their characteristics. Women with lower
compliance were more likely than highly compliant women tohave fair/poor self-reported health and to be current or former
smokers.
The association between compliance with placebo orcompliance with alendronate and change in BMD is shownin Table 2. As shown, women with high compliance withalendronate had a significantly greater increase in BMD at allsites than those with lower compliance with alendronate orplacebo-treated women. Women with high compliance withplacebo had significantly less BMD loss at the total hip than thosewith lower compliance with placebo. A similar pattern wasobserved at the femoral neck but not the lumbar spine.

Statistical analysis
Descriptive statistics were used to summarize demographics,
comorbidities, and BMD data comparing women with highcompliance versus others; for purposes of this analysis, allwomen who did not meet criteria for high compliance werecategorized as having lower compliance (< 80%). Compliance
was measured in a time-varying manner and measured
as average compliance since the beginning of the study.
Compliance with placebo was the primary independent variableof interest; outcomes associated with compliance with alendronate also were evaluated for comparative purposes. Cox

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Journal of Bone and Mineral Research

Fig. 1. Compliance over the course of FIT. Data shown are the percent of
women compliant at each time point.

CURTIS ET AL.

Table 1. Baseline Characteristics of FIT Participants Randomized to Placebo (n ¼ 3169)
Variable
Age, %< 65 years
65–74 years
75–81 years
Mean (SD) age in years
Femoral neck, SDs below peak, %>2.5
2.0–2.5
1.5–2.0
Mean (SD) BMD in g/cm2
Femoral neck
Posteroanterior spine
History of fractures  45 years, %Vertebral fractures at baseline, %Body mass index, mean (SD), kg/m2
Self-rated health status, %Very good/excellent
Good
Fair/poor
Baseline height, mean (SD), cm
Dietary calcium intake, mean (SD), mg/d
Smoking, %Current
FormerNever

High compliancea

Lower compliancea

51.7%
29.8%
18.5%
68.2 (6.10)

51.0%
28.1%
20.8%
68.6 (6.2)

42.7%
26.1%
31.1%

42.5%
27.1%
30.4%

0.58 (0.06)
0.83 (0.14)
41.9%
9.0%
25.2 (4.1)

0.58 (0.07)
0.82 (0.13)
43.5%
9.9%
25.4 (4.3)

66.0%
29.6%
4.5%
1601 (61)629 (395)

54.5%
36.4%
9.1%
1599 (62)649 (399)

10.6%
34.0%
55.4%

13.3%
37.2%
49.5%

p Value
.49

.12
.90

.26
.54
.49
.53
.26
< .001

.64
.77
.03

Note: For this table, compliance was assessed at the end of the study. All other compliance analyses were time-varying. Data were analyzed using chisquare tests for nominal groups and t tests for continuous data.
aHigh compliance defined as 80% or greater; lower compliance defined as less than 80%.

lower risk for hip and clinical vertebral fracture among womenwith high compliance with alendronate than among those withlower compliance with alendronate.
Table 4 shows the adjusted risk of fracture comparing
alendronate versus placebo among those with both lower andhigh compliance. Among women with lower compliance withplacebo or alendronate, there were no significant differences
between the two groups in the rates of any fracture type.
In contrast, among women with high alendronate compliance,
there was an adjusted and significant 45% lower risk for hip
fracture, a 59% lower risk for clinical vertebral fracture, and a 20%

Table 3 shows the adjusted association between compliancewith placebo and fracture. Women with high compliance withplacebo had proportionately fewer hip fractures than those withlower compliance with placebo. The adjusted rate of hip fracture
among women with high placebo compliance was 33% lower
than among women with lower placebo compliance, butthere were few events, and the results did not reach statisticalsignificance. There was no suggestion of an association between
high compliance with placebo and a reduced risk for any othertype of fracture. Comparing women with lower versus highcompliance with alendronate, there was an approximately 50%

Table 2. Annualized Percent Change in BMD of High and Lower Compliance With Placebo and Alendronate
PlaceboLower complianceTotal hipFemoral neck
Spine

a,b

0.58
0.30a,c
0.49a,c

Alendronate
High compliancea0.43
0.16a0.48a

Lower complianceHigh compliance

a

0.30
0.05a
0.79a

0.99
1.15
2.33

Note: Results are adjusted for age, baseline BMD, height, BMI, self-reported health, smoking status, calcium intake, calcium supplement use, having a
broken bone after age 45, and having a vertebral fracture at baseline.
ap < .0001 compared with alendronate high-compliance group.
ab
p ¼ .04 compared with placebo high-compliance group.
bc
p ¼ NS compared with placebo high-compliance group.

PLACEBO ADHERENCE, BMD, AND FRACTURE

Journal of Bone and Mineral Research

685

Table 3. Risk of Hip, Clinical Vertebral, Wrist, and All Clinical Fractures Comparing High Versus Lower Compliance With Placebo and
Alendronate
Placebo
Fracture typeHip, nCrude ratea
Crude HR
Adjustedb HR
Clinical vertebral, n
Crude ratea
Crude HR
Adjustedb HR
Wrist, n
Crude ratea
Crude HR
Adjustedb HR
Any clinical fracture, n
Crude ratea
Crude HR
Adjustedb HR

Alendronate

Lower complianceHigh compliance

Lower complianceHigh compliance85.0
1.0 (referent)
1.0 (referent)
10
6.3
1.0 (referent)
1.0 (referent)
11
7.0
1.0 (referent)
1.0 (referent)57
39.0
1.0 (referent)
1.0 (referent)

38
3.6
0.67 (0.3–1.45)
0.67 (0.30–1.45)
67
6.4
0.99 (0.51–1.94)
1.05 (0.53–2.06)
99
9.5
1.34 (0.72–2.50)
1.18 (0.63–2.23)
435
44.5
1.11 (0.84–1.47)
1.06 (0.80–1.41)

10
6.3
1.0 (referent)
1.0 (referent)
11
6.9
1.0 (referent)
1.0 (referent)
14
8.6
1.0 (referent)
1.0 (referent)64
43.2
1.0 (referent)
1.0 (referent)20
1.9
0.30 (0.14–0.63)
0.46 (0.19–1.10)31
2.9
0.43 (0.22–0.87)
0.51 (0.24–1.09)
91
8.7
0.94 (0.53–1.65)
1.05 (0.57–1.93)
349
35.1
0.80 (0.61–1.04)
0.87 (0.65–1.15)

HR ¼ hazard ratio.
a
Per 1000 person-years.
b
Adjusted for age, baseline BMD, height, BMI, self-reported health, smoking status, dietary calcium intake, calcium/vitamin D supplement provided bystudy, having a broken bone after age 45, and having a vertebral fracture at baseline.

before and after fracture, women were more likely to change
from having high compliance before fracture to lower
compliance after fracture. For hip fractures, for example, 12
women who had high compliance prior to the hip fracture had
lower compliance following the fracture. No women with lower
compliance prior to hip fracture became highly compliant after

lower risk for all clinical fractures than among women with highplacebo compliance.
Compliance with study medication (placebo or alendronate)
before and after hip, clinical vertebral, and wrist fracture among
patients who fractured during the course of FIT is shown in
Table 5. Although most women had high compliance both

Table 4. Risk of Hip, Clinical Vertebral, Wrist, and All Clinical Fractures Comparing Lower Compliance With Placebo Versus Alendronate
and High Compliance With Placebo Versus Alendronate
Lower compliance
Fracture typeHip, nCrude ratea
Crude HR
Adjustedb HR
Clinical vertebral, n
Crude ratea
Crude HR
Adjustedb HR
Wrist, n
Crude ratea
Crude HR
Adjustedb HR
Any clinical fracture, n
Crude ratea
Crude HR
Adjustedb HR

High compliance

Placebo

Alendronate

Placebo

Alendronate8
5.0
1.0 (referent)
1.0 (referent)
10
6.3
1.0 (referent)
1.0 (referent)
11
7.0
1.0 (referent)
1.0 (referent)57
39.0
1.0 (referent)
1.0 (referent)

10
6.3
1.26 (0.50–3.18)
0.86 (0.31–2.37)
11
6.9
1.11 (0.47–2.60)
0.87 (0.35–2.14)
14
8.6
1.27 (0.57–2.79)
1.03 (0.45–2.33)
64
43.2
1.11 (0.78–1.58)
0.97 (0.67–1.41)38
3.6
1.0 (referent)
1.0 (referent)
67
6.4
1.0 (referent)
1.0 (referent)99
9.5
1.0 (referent)
1.0 (referent)
435
44.5
1.0 (referent)
1.0 (referent)

20
1.9
0.52 (0.30–0.90)
0.55 (0.32–0.95)
31
2.9
0.46 (0.30–0.70)
0.41 (0.26–0.65)
91
8.7
0.92 (0.69–1.22)
0.92 (0.68–1.23)
349
35.1
0.79 (0.69–0.91)
0.80 (0.69–0.92)

HR ¼ hazard ratio.
aCompliance measured in a time-varying way.
b
Adjusted for age, baseline BMD, height, BMI, self-reported health, smoking status, dietary calcium intake, calcium/vitamin D supplement provided bystudy, having a broken bone after age 45, and having a vertebral fracture at baseline.

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Journal of Bone and Mineral Research

CURTIS ET AL.

Table 5. Comparison of Compliance With Study Medication (Alendronate or Placebo) Measured Before and After Fracture

Fracture type
Hip
Clinical vertebral
Wrist

Lower compliance Agreementa between highbefore, highHigh compliance Lower compliance High compliance before,
compliance at timecompliancelower compliance
before andbefore andof fracture versus
after fracture
after fracture
after fracture
after fracture
end of study
53
90
182

11
17
21

12
10
10

0
2
2

0.66 (0.47–0.85)
0.65 (0.49–0.81)
0.73 (0.60–0.86)

Note: High compliance was 80% or greater; lower compliance was less than 80%.
aReported as kappa (95% CI); kappas between 0.60 and 0.80 are generally considered as ‘‘good agreement’’ (Altman et al., 1991).(13)fracture. Agreement between compliance before and after
fracture for each of the three fracture types was good, withkappas in the 0.65 to 0.73 range.

Discussion
Among women participating in FIT who were randomized
to placebo, we did not find significant associations between
compliance with placebo and fractures. However, we found thathigh compliance with placebo was associated with reduced
total-hip bone loss, and a similar trend was observed for changes
in femoral neck BMD. Furthermore, compared with women withlower compliance with placebo, the risk of hip fracture was 33%
lower among women with high compliance with placebo; thisrelationship did not reach statistical significance and was notobserved for any other clinical fracture type. These findings
suggest that the effect of compliance with placebo on hip
BMD, and perhaps hip fracture risk, was not attributable toconfounding by the known fracture risk factors collected in FIT.
In total, our findings provide some support for the existence ofthe healthy adherer effect in this population and suggest that
medication compliance may be a proxy for behaviors and/or
other factors that confer hip BMD (and possibly hip fracture)benefit independent of the effect of the medication.
The possible protective effect on hip fracture may be
mediated at least in part by changes in BMD, recognizing thatthe correlation between change in BMD and fracture benefit is
only modest.(14) Comparing women with high versus lower
compliance with placebo, the annualized difference in change in
hip BMD between the two groups was 0.15%. To provide somecontext for this difference, these changes in BMD are comparablewith differences in BMD among depressed women comparedwith those without depressive symptoms(15) and with themagnitude of BMD loss among women using selective serotonin
reuptake inhibitors (SSRIs) compared with nonusers.(16)In analyses that evaluated the dynamic nature of compliance,
we observed that compliance varied before and after fractures.
At least in a randomized, controlled trial (RCT), the occurrence ofa clinical fracture would appear to affect subsequent adherencewith study medication, at least for some patients. This finding
also has been reported in observational data from a nonclinical
trial population.(1) These results support the conclusion thatanalyzing compliance in a manner that ignores the timedependent nature of adherence before and after fractures may
yield biased results.
PLACEBO ADHERENCE, BMD, AND FRACTURE

If the healthy adherer effect is generalizable to a nonclinical
trial setting, our findings may have implications for future comparative effectiveness research (CER) of osteoporosis medications, at least for hip fracture outcomes. Analyses studying therelative effectiveness of medications that require intravenous
administration (eg, zoledronic acid and denosumab) will need tocarefully consider how to choose the most valid comparatorgroups. For example, patients receiving parenteral osteoporosis
agents given by a health care provider consist of a mix of patients
who would have variable degrees of compliance with oral
bisphosphonates. Comparing these patients with patients whoare highly compliant with oral bisphosphonates could yieldbiased results because the compliant oral bisphosphonate users
may have better outcomes (including lower hip fracture risk) inpart owing to the healthy adherer effect. In contrast, a comparator group of patients starting oral bisphosphonates, without
considering whether they remained compliant, would be biased
given their lesser exposure to bisphosphonates. These studies
could, for example, consider compliance with other medications
to at least partially address these concerns. Future work evaluating healthy behaviors and factors that are associated withcompliance behavior are necessary to ensure unbiased resultsfrom observational comparative effectiveness analyses.
Although our results suggested a trend toward reduced hip
fracture risk associated with placebo compliance, we did notobserve similar trends for other fracture types, such as wrist or
clinical vertebral fractures. Risk factors for wrist fractures aredifferent from those for hip fractures,(17) and wrist fracturesgenerally occur in younger, healthier, and more active women.
Factors associated with medication adherence may be more
relevant for older, frailer patients at risk for hip fracture. Given
that our crude and fully adjusted results were similar for eachanalysis, it would seem that the risk factors controlled for within
this analysis are not important confounders of fracture risk
associated with medication adherence. Furthermore, studies thatshow a fracture benefit associated with medication compliance
may not be confounded if fracture types other than hip fractures
are being evaluated.
The strengths of our study include a large population of
women with median follow-up of more than 4 years. Fracture
outcomes were adjudicated through medical record review, andlongitudinal BMD data were available over the course of FIT.
Compliance was assessed with high precision through the use ofboth patient diaries and pill counts. Despite these strengths, ourresults must be interpreted in light of some limitations. Modest
numbers of outcome events and generally high compliance
Journal of Bone and Mineral Research687

within FIT required dichotomizing compliance and resulted inwide confidence intervals for some of our results. Additionally,
FIT was a clinical trial of women who were enrolled to study
fracture outcomes, and thus these results may not be generalizable to other settings and patient populations. Last, somefactors that may affect fracture risk were not collected in FIT,
such as exercise, falls, depression, comorbidities, and measuresof frailty. The association between compliance and smoking andpoorer health status reported in Table 1 suggest the possibility
that these two factors may be proxies for one or more of
unmeasured confounders.
Another potentially important factor that was not systematically measured in FIT was 25-hydroxyvitamin D. An ancillary
study to FIT that sampled 1000 women at baseline showed that
only a small proportion (2.3%) were deficient in vitamin D[25(OH)D  10 ng/mL) at baseline, and the response to alendronate was not affected by baseline 25(OH)D status.(18)
However, it is unknown whether low vitamin D at baseline or
throughout the study might be associated with low complianceand could have affected for our results.
In conclusion, based on these data from a randomized,
controlled trial, we found small but significant differences in thechange in hip BMD between women with high versus low
compliance with placebo. However, perhaps most important,studies reporting fracture risk reduction associated with highcompliance with bisphosphonates do not appear to be
confounded by healthy behaviors and factors associated withmedication compliance except possibly for hip fracture. Further
work is needed to assess the existence of a healthy adherer effectfor fracture outcomes in other populations and how best tocontrol for this potential confounder.

Disclosures
JC received research grants from Amgen, Novartis, Procter andGamble, Roche, and Merck and did consulting for Roche andAmgen. ED received research grants from Amgen. DB received
research grants from Novartis and Amgen and did consulting for
Merck and Amgen. All the other authors state that they have noconflicts of interest.

Acknowledgments
Some of the investigators received support from the National
Institutes of Health (AR053351 to JRC) and AHRQ
(1U18HS016956-01 to MMS). FIT was funded by Merck andcoordinated by the UCSF Coordinating Center.

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