Among this cohort of older U.S. patients with osteoporosis based upon the occurrence of a recent fracture, we observed that high medication adherence to bisphosphonates significantly decreased fracture risk. Consistent with known adverse effects of SSRIs on bone and fracture risk(14
), high adherence to SSRIs significantly increased fracture risk, suggesting that if there was any healthy adherer bias present, it did not meaningfully impair our ability to detect the previously-described significant association between SSRI use and increased fracture risk. Finally, as was hypothesized in the absence of a healthy adherer effect, there was no association between adherence to ACE/CCBs and fractures; in fact, fracture rates were as high or slightly higher among patients with ACE/CCB MPRs >=80% than among those with MPRs <50%, although this difference was not statistically significant. As these medications have no known effect on bone or fracture risk, the lack of a protective association between high adherence to these medications and fracture provides reassurance that there was not an important healthy adherer bias present in this population.
Although some RCTs have suggested the existence of a healthy adherer bias for medications provided by a clinical trial (5
), this was not observed in this observational analysis of real-world data. While many factors are different between a trial setting and routine clinical care, patients’ and physicians’ knowledge of the indication for the medication might produce adherence patterns different from those seen for a medication provided in a blinded fashion and in accordance with a study protocol. Moreover, patients participating in trials may have different demographics, motivations, and comorbidities that limit the generalizability of results from trials to the real world. Finally, the duration of follow-up in the trials that have suggested a healthy adherer effect may be important if potential confounders could not be adjusted for in a time-varying fashion. The mean follow-up time in this analysis was relatively short, approximately 1 year, which limits the potential problem of misclassifying baseline confounders that could change over time.
The association between high medication adherence and other important factors and outcomes has been examined in a number of observational studies. High adherence to bisphosphonates has been shown to have a strong association with high adherence to other long term medications (20
). High medication adherence also appears to be associated with a greater proclivity for health-seeking behaviors such as vaccination and cancer screening(25
). Providing some support for the existence of a healthy adherer bias, adherence to statin therapy has been shown to be associated with a lower likelihood of workplace accidents, motor vehicle crashes, and other effects unlikely to be attributable to statins (26
). However, evidence for a healthy adherer bias is not consistent in the literature. A study of patients that survived myocardial infarction found a mortality benefit among patients who adhered to statins and beta-blockers but not calcium channel blockers (28
), suggesting the benefit of adherence was drug class specific and not an epiphenomenon of behaviors or other factors associated with adherence. Likewise, an osteoporosis-focused study found that high adherence with calcitonin and raloxifene did not confer any non-vertebral fracture benefit (29
). Given that these medications have not been shown even in RCTs to provide meaningful non-vertebral fracture benefit, this result provides some reassurance for lack of an important healthy adherer bias in that population.
It was perhaps surprising that except for medication adherence, there were not strong associations between the risk factors that were examined and fracture. This was noted both in the similarity between the crude and adjusted hazard ratios for each multivariable model, as well as by the lack of significance of most risk factors as shown in . Indeed, aside from diabetes, income, and trends for older age, there were few additional risk factors for fracture. Although speculative, this may be due to the fact that the people in this age group (age 65+) with the major fractures required for eligibility in this analysis were relatively similar to one another in terms of frailty and other conditions, such that there were few other important fracture risk factors identifiable after controlling for medication adherence.
The strengths of our study include a large number of patients with osteoporosis defined by the occurrence of a recent fracture rather than on the basis of an administrative diagnosis code for osteoporosis, or even a bone mineral density test result. Our study design allowed us to assess adherence with three different medications that were expected to have favorable effects on fracture risk reduction (bisphosphonates), unfavorable effects on bone (SSRIs), and ACEI/CCBs that are not known to have important effects on bone. The benefit of examining the latter two medication groups is that we could evaluate adherence behaviors and associated factors with presumably less fracture-related channeling and confounding expected if only osteoporosis medications were able to be studied.
Despite these strengths, administrative data lack detailed clinical information on some risk factors for fracture including bone mineral density results, markers of frailty, and fall risk. However, administrative data have been shown to predict fracture risk comparably with clinical risk factors and the World Health Organization’s Fracture Risk Assessment Tool, FRAX®(30
). Our population of patients included only individuals age >= 65, perhaps limiting the generalizability of our results to older patients. The number of fracture events was modest, especially for hip fractures; consequently, some analyses yielded wide confidence intervals. Finally, the cutpoints for categories of adherence selected from the literature may not have been optimal to discriminate between the fracture benefits of adherence with MPR of 50-<80% versus >=80%, as many of the patients in the 50-<80% category had MPR at the upper end of this range. Moreover, the dataset used did not capture patients who were prescribed but failed to ever fill the medications that were studied, so called ‘primary non-adherence’.
In conclusion, in this observational analysis of individuals enrolled in Medicare, we did not find strong evidence of a healthy adherer effect that suggested that medication adherence behaviors and associated factors conferred fracture benefit. Based upon this result, observational analyses evaluating the association between osteoporosis medication adherence and fracture risk in older patients may not be meaningfully confounded by a healthy adherer bias.