Introduction
Osteoporosis is a major public health concern that results in considerable fracture-related morbidity and mortality [
1‐
3]. In Canada, oral bisphosphonates (alendronate, etidronate, and risedronate) are the most commonly prescribed agents for treating osteoporosis and preventing fractures [
3,
4]. However, persistence with therapy is suboptimal and linked to reduced drug effectiveness [
5‐
8]. Prior systematic reviews document that fewer than half of patients persist with osteoporosis treatment for a full year [
5,
9,
10], with estimates ranging between 18% and 78% for bisphosphonates [
11,
12]. An underreported finding is that many patients who discontinue bisphosphonate therapy reinitiate treatment after an extended gap [
13]. To further explore this issue, we studied all new users of oral bisphosphonates among older adults in Ontario from April 1996 to March 2009. We hypothesized that the majority of patients would discontinue treatment, yet a significant proportion would return to therapy after an extended gap in therapy. We also hypothesized that many patients would experience more than one extended gap in therapy, yet cumulative exposure to oral bisphosphonates would exceed 1 full year of therapy in most patients.
Discussion
Our results are consistent with prior reports that indicate that persistence with bisphosphonate therapy is suboptimal [
10‐
12]. Recent evidence suggests that uninterrupted bisphosphonate therapy for a minimum of 3–5 years is important to reduce fracture risk [
24‐
27]. However, our results show that fewer than half of patients persist with therapy for 2 years, and only 25% persist with therapy for 5 years. Even when a more lenient permissible gap of 120 days was used to identify non-persistence, our findings identify that only 40% of patients persisted with therapy for 5 years. We also note that extending the permissible gap length from 60 to 120 days changed our estimates of persistence from 63% to 77% at 1 year, and from 25% to 43% at 5 years. These findings highlight the impact of length of follow-up and permissible gap on persistence measurement. Given the observed variation in persistence rates with different permissible gap lengths, we recommend that methodology be explicitly reported to facilitate study comparisons [
13].
Regardless of the permissible gap length used to determine length of treatment persistence, our findings identify that extended gaps in oral bisphosphonate therapy are common, and the majority of patients experience more than one extended gap between bisphosphonate prescriptions. Although it is encouraging that many patients are returning to therapy, the clinical impact of the time off drug remains unknown, and requires further investigation. In fact, experiencing a fracture after stopping osteoporosis treatment has been found to be a significant predictor of reinitiating osteoporosis medication [
20].
Our results also indicate that the longer the length of follow-up, the more likely it is that a patient will switch treatments. Over the entire study period of up to 12.8 years, 37% of all users (51% of etidronate users) switched to a different oral bisphosphonate. In Ontario, etidronate has been available without restriction through the ODB program since 1996, thus permitting greater opportunity for patients to initiate etidronate and switch to another bisphosphonate over time. Although second generation bisphosphonates have been available since 1996 (daily alendronate), the initial listing status for both alendronate and risedronate required a trial of, or documented allergy to etidronate (2000–2003), or two of the following: (i) BMD T-score ≤3.0 SD, (ii) aged 75 or more years, (iii) prior osteoporosis-related fracture (2003–2007). Since 2007, all three agents have been covered without restrictions. Given that clinical trial data demonstrate reductions in non-vertebral fracture risk compared to placebo with use of alendronate and risedronate, but not etidronate [
2,
28], it is not surprising that patients were observed to have switched from etidronate to alendronate or risedronate after treatment failure, or once access to these drugs through the ODB program became less restrictive. We identified that less than 10% of alendronate/risedronate users switched to a different bisphosphonate over follow-up, compared to 51% of etidronate users. Switching rates between bisphosphonates may be lower in regions such as the United States, where etidronate is not available.
Despite the decline in etidronate prescribing over time and the noted increase in the number of males being treated, we found little change over time in the percent of new users having had a BMD test or fracture. The slight increase in BMD testing seen between April 1996–March 2000 and April 2000–March 2003 is likely attributable to the switch from DPA to DXA technology in 1998 and the increased number of DXA machines, from 95 in 1997 to 213 in 1998 [
29]. Similarly, the slight increase in the proportion with hip, humerus or radius/ulna fracture within the year prior to index is likely related to the change in coding from ICD-9-CM to ICD-10-CA that occurred in 2002. While ICD-10-CA includes greater specification, previous studies have found sensitivity of 95% or higher for the identification of fractures using ICD-9-CM [
30], and ICD-10-CA coding [
17]. Our results therefore suggest little change in the importance of BMD testing or fracture history in guiding bisphosphonate therapy over our study period.
Three important study limitations are worth noting. First, we were unable to study patterns of bisphosphonate therapy among persons younger than 66 years. It is possible that prescribing patterns have changed over time in ways that we were unable to observed, such as prescribing pharmacotherapy at younger ages and prior to 66 years. It is also possible that some of the identified “new users” were prevalent users with private drug coverage that switched to coverage under the ODB program once these agents were covered by the public plan. However, recent data suggest good agreement between self-report and ODB pharmacy data for bisphosphonate use among older women (kappa statistic = 0.81, 95% CI = 0.77–0.85 [
18]), and few seniors in Ontario do not access medications through the ODB program [
14].
Second, we restricted our study to oral bisphosphonates, and thus it is possible that some users classified as non-persistent with therapy may have switched to non-oral bisphosphonate therapy, such as calcitonin, raloxifene, teriparatide, or zoledronic acid. However, we expect this to have occurred in only a few patients, as calcitonin and teriparatide are not listed on the ODB formulary, and raloxifene and zoledronic acid are only available under restricted conditions. For example, zoledronic acid is only available among men and women unable to take oral medications. In addition, prior research has identified that those who return to osteoporosis therapy after an extended gap tend to return to the same drug class [
20]. Thus, while we recognize that switching between osteoporosis therapies may be more common in regions with better access to non-bisphosphonate therapy, we expect this to be minimal in our sample. Further research using large claims databases in other regions will help clarify switching patterns.
Third, we recognize that some of our observed non-persistence may have been physician directed due to the experience of, or concern for adverse drug events. Although oral bisphosphonates are generally well tolerated, upper gastrointestinal complaints are commonly reported in new users [
31]. In addition, with recent concerns for possible increased risk for femoral shaft fractures after long-term bisphosphonate use [
32], a physician directed drug holiday may be reasonable for those patients with more than 5 years of bisphosphonate use, and could account for some of the non-persistence seen beyond 5 years. While the median exposure was only 2.2 years, 25% of patients had 5 years of uninterrupted therapy, and 12% had 9 years of uninterrupted therapy.
Despite these limitations, our study has several strengths. We followed more than 450,000 new users of oral bisphosphonates for up to 12.8 years. This provided ample follow-up to characterize both drug switching and treatment reinitiation patterns. Our results indicate that most patients discontinue bisphosphonate therapy within 2 years and many experience more than one extended gap in bisphosphonate use. Although emerging evidence suggests that after 3–5 years of uninterrupted therapy a physician-directed drug holiday may be appropriate for many patients [
24‐
26], further research is needed to clarify for which patients this may be suitable. In addition, we document that the majority of patients are not exposed to bisphosphonate therapy long enough to be considered for a physician-directed drug holiday, with a median length of exposure of only 2 years, and the majority experiencing one or more extended gaps in therapy.
Osteoporosis is a major public health concern that results in debilitating fractures. Oral bisphosphonates are first-line therapy for osteoporosis, and are effective in reducing fracture risk. Although other therapies are available, including nasal calcitonin, raloxifene, teriparatide, zoledronic acid, and most recently, denosumab; these agents are reserved as second or third line treatment options. Our results not only confirm findings from other countries by identifying sub-optimal rates of persistence with oral bisphosphonate, but our findings add to the literature by identifying the frequency of extended gaps and rate of return to therapy. We identify that many patients return to therapy following an extended gap; however, the clinical impact of this time away from therapy remains unknown. Further research is needed to identify predictors of non-persistence and to clarify when and among which patients a physician-directed drug holiday may be appropriate. Results may then be used to develop effective interventions that aim to improve the length of persistence and reduce the frequency of gaps in bisphosphonate therapy. It is through improved treatment rates among patients at high risk for fracture that we will we reduce the public impact of osteoporotic fractures.
Acknowledgements
This research was supported by research grants from the Canadian Institutes of Health Research (CIHR) and the Ontario Ministry of Research Innovation (OMRI). Dr Cadarette holds a CIHR New Investigator Award in the Area of Aging and Osteoporosis and an OMRI Early Researcher Award. Andrea Burden holds the Graduate Department of Pharmaceutical Sciences 2010 Wyeth Pharmaceutical Fellowship in Health Outcomes Research and the 2010–2011 University of Toronto Bone and Mineral Group Scholarship (Clinical). Dr. Solomon receives salary support from Amgen for work on rheumatoid arthritis as well as support from the Arthritis Foundation, AHRQ, and the NIH (AR 055989, AR 047782) on osteoporosis and adherence. Dr. Mamdani has received honoraria for unrelated work from Pfizer, Eli Lilly, and Amgen within the past 3 years. Authors acknowledge Dr. M. Alan Brookhart for insightful discussions, Brogan Inc. for providing access to drug identification numbers used to identify eligible drugs, and Jin Luo at the Institute for Clinical Evaluative Sciences (ICES) for assistance with statistical analyses. ICES is a non-profit research corporation funded by the Ontario Ministry of Health and Long-Term Care. The opinions, results and conclusions are those of the authors and are independent from the funding sources. No endorsement by CIHR, ICES, OMRI or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred.