Impact of gastrointestinal events on patient-reported outcomes in Asia-Pacific women with osteoporosis: baseline results of the MUSIC OS-AP study

The incidence of osteoporotic hip fracture has risen 2–3-fold in Asia over the past few decades [1]. It is now recognized that the prevalence of osteoporosis in older women (i.e., aged ≥50) living in Asia-Pacific countries is comparable to that in European and North American populations [2]. A scarcity of diagnostic instruments (e.g., dual-energy x-ray absorptiometers) and lack of epidemiologic and economic data have prevented many of these countries from developing official guidelines for diagnosis and treatment of osteoporosis and raising public awareness of the disease [1]. As a result, the burden of osteoporosis in the Asia-Pacific region is not well documented.

In particular, the gastrointestinal (GI) events that are common among users of osteoporosis therapy in US [3] and European [4, 5] populations are virtually uncharacterized in patients in the Asia-Pacific region. Such events, or use of medications suggesting their occurrence, have been shown to be associated with reduced adherence (both compliance and persistence) to treatment [6‐11] and low treatment satisfaction [12‐14]. Increased health care resource use has also been documented among patients with osteoporosis treatment-related GI events [15, 16]. However, such associations have not been assessed in Asian or Australian populations.

The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study in the Asia-Pacific Region (MUSIC OS-AP) was designed to address this information gap. The primary objectives of MUSIC OS-AP were (i) to describe the frequency of GI events among postmenopausal women receiving pharmacologic treatment for osteoporosis and (ii) to assess the association between GI events and adherence, treatment satisfaction, health-related quality of life, and health care resource utilization.

This baseline assessment of the MUSIC OS-AP population showed that GI events decreased adherence to treatment, treatment satisfaction, and quality of life, as reported by Asia-Pacific women receiving pharmacologic treatment for postmenopausal osteoporosis. GI events did not affect osteoporosis-related resource use.

There is little information on the effect of GI events on adherence to osteoporosis therapy in the Asia-Pacific region. In a study of 208 Japanese osteoporosis patients (1.5% male), patient-reported side effects were the primary driver of non-compliance with alendronate or risedronate [25]. Another study of 1307 Japanese patients (15.1% male) receiving their first bisphosphonate at a university hospital found that switching therapies because of adverse effects was associated with reduced persistence and that discontinuation of the first drug due to adverse effects was associated with higher rates of discontinuation of the second drug for the same reason (hazard ratio 4.2, 95% CI 2.1–8.4) [26]. However, neither of these studies limited the analysis of adverse events to GI events. Previous US studies have reported the effects of GI events on adherence among osteoporosis patients; however, these studies did not assess the effect of GI events on adherence using the ADEOS questionnaire [6, 10, 11, 13]. Among these US studies, the Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE) study is best suited for comparison to MUSIC OS [13]. In the US cohort of POSSIBLE, women reporting GI side effects were more likely to discontinue therapy at both 6 and 12 months [13]. However, discontinuation is not directly comparable to the medication-taking behaviors assessed by the ADEOS questionnaire. Such behaviors were assessed using ADEOS by the MUSIC OS study in Europe and Canada (MUSIC OS-EU), which found that treated osteoporosis patients with GI events had lower ADEOS scores than those without GI events (adjusted least squares mean difference −0.43; P < 0.001) [27]. This result is consistent with the findings of the MUSIC OS-AP study (adjusted least squares mean difference −0.348). The MUSIC OS-AP study is unique in that it directly assesses the association of GI events with adherence to oral osteoporosis therapies in the Asia-Pacific region using ADEOS scores.

The relationship of GI events to treatment satisfaction was assessed with the OPSAT questionnaire in a study of 4220 Korean women taking oral bisphosphonates [28]. The mean composite OPSAT score was 75.3 in non-users of acid-related medications versus 70.8 in users of such medications. Taking acid-related medication use as a proxy for GI symptoms, these data are quite similar to ours. In MUSIC OS-AP, the mean composite OPSAT score at baseline was 79.1 among treated patients, and GI events were shown to reduce this score by 6.9 points. We identified only one other study from Asia reporting the effects of GI symptoms on treatment satisfaction. Chung et al. used a crossover design to assess patient preferences for monthly ibandronate versus weekly risedronate in 365 Korean women [29]. In this study, less stomach discomfort and more tolerable side effects were among the patient-reported reasons for a preference for the ibandronate regimen. In the MUSIC OS-EU study, covariate-adjusted OPSAT scores of experienced users of treatment for osteoporosis were 5.68 points lower in those with versus without GI events [27], a decrement comparable to that seen in experienced users in the current study (−5.24). In the POSSIBLE-US cohort, women experiencing a GI side effect at month 6 had lower global treatment satisfaction scores (assessed by the Treatment Satisfaction Questionnaire for Medication) than those without GI side effects [13].

In MUSIC OS-AP, both general and osteoporosis-specific quality of life were reduced by GI events. Least-squares mean differences associated with GI events were −0.092 for the EQ-5D utility score and −3.663 for the OPAQ physical function score. Although both values were statistically significant, only the former met the threshold of the minimal clinically important difference (see the “Methods” section). Previous studies of the relationship of GI events and quality of life are few. In one of the Korean studies described above, osteoporosis-specific quality of life was reduced in patients using acid-related medications (a proxy for GI events); the quality of life domain scores on the OPSAT questionnaire were 62.7 in users and 66.8 in non-users of acid-related medications (P < 0.001) [28]. Similar to the results reported in MUSIC OS-AP, EQ-5D and OPAQ-SV physical function scores were significantly reduced in patients with versus without GI events in the MUSIC OS-EU study [27]. In contrast, in POSSIBLE-US, EQ-5D utility scores measured at month 6 were not significantly different between patients with and without GI side effects [13].

The MUSIC OS-AP study included untreated patients at the baseline assessment, 18% of whom had a history of osteoporotic fracture. This fracture rate is somewhat lower than the expected lifetime fracture risk of 30 to 40% for older women [30‐32]. The GI event rate in this population (61%) is consistent with previous reports that GI symptoms are common in Asian adults, regardless of osteoporosis treatment [33‐36]. The EQ-5D-3L utility and VAS scores in untreated osteoporosis patients in MUSIC OS-AP (0.70 and 66.8, respectively) were lower than those in the published population norms for women in Australia (0.87 utility) [37], New Zealand (0.85 and 81.2, respectively) [38], Taiwan (74.3 VAS) [39], and Korea (0.89 and 78.7, respectively) [38]. GI event rates, quality of life scores, and resource use were numerically similar in untreated and treated women.

The results of the current MUSIC OS-AP analysis improve upon previous studies in several ways. First, MUSIC OS-AP assessed quality of life and treatment satisfaction separately in patients with or without GI events, a design element missing from earlier studies of this question [12, 14]. Second, our analyses were adjusted for demographic and clinical covariates, such that the results indicate an effect of GI events on adherence, quality of life, and treatment satisfaction independent of confounder variables. Finally, to our knowledge, MUSIC OS-AP is the first study to assess directly the association of GI events with adherence, quality of life, and treatment satisfaction in osteoporosis patients from the Asia-Pacific region.

Despite these strengths, the current analysis is subject to several important limitations. First, due to the design of the study as a patient survey, the accuracy of the findings is limited by patient recall and potentially affected by reporting bias. Second, the least-squares mean differences were not adjusted for adherence, so some patients may have had GI events not associated with treatment. Third, patients were not required to report the severity of the GI events; in fact, GI events typically considered severe (e.g., those involving bleeding or perforation) were not included in the patient questionnaire. Thus, our results reflect primarily the experience of patients with mild to moderate GI symptoms. Fourth, the lack of statistical comparisons of untreated and treated patients precludes drawing conclusions regarding the relationship between treatment and GI event rates and quality of life. Fifth, the data were pooled from culturally and demographically different countries and therefore reflect the average effect within potentially disparate data. Finally, lack of information about the minimal clinically important difference on the ADEOS and OPSAT questionnaires prevents assessment of the clinical relevance of the effect sizes reported here, and some of the observed differences in quality of life, although statistically significant, may not have been clinically important.

In conclusion, the baseline assessment of MUSIC OS-AP showed that GI events were common in postmenopausal women with osteoporosis in the Asia-Pacific region, occurring in approximately 60% of both treated and untreated patients. Among women treated for osteoporosis, GI events were associated with decreased adherence, lower treatment satisfaction, and worse quality of life. Treatment satisfaction was affected to a greater extent in new users of osteoporosis treatment versus experienced users. These results suggest that GI events should be given consideration during the clinical management of osteoporotic women in the Asia-Pacific region.