Fracture risk and healthcare resource utilization and costs among osteoporosis patients with type 2 diabetes mellitus and without diabetes mellitus in Japan: retrospective analysis of a hospital claims database

Osteoporosis and its resultant fractures are significant and expanding health burdens, impacting markedly on patient mortality, morbidity, and quality of life [1]. Given the prevalence of osteoporosis among the elderly, an enormous rise in its incidence has been predicted in Asia, where a 7.6-fold increase in the elderly population is expected [2]. By 2050, it is projected that 50% of all hip fractures will occur in Asia [2]. Japan currently has one of the world’s highest proportions of aged adults and this proportion is increasing; by 2050, 32% of the population is expected to be aged over 70 years [3]. The accompanying rise in the number of patients with osteoporosis is likely to have a major impact on healthcare resource utilization and costs. In Japan, treatment of hip fractures alone requires an average of 38.2 days in hospital and treatment costs per year are estimated to be 4.9 billion US dollars [3].

Effective management of osteoporotic fractures requires careful evaluation not only of osteoporosis but also of the increasing number of comorbidities that are thought to influence the risk of fractures [4]. Diabetes is emerging as one of the most important comorbidities in terms of its impact on fractures, as suggested by studies in the USA and in Europe [5, 6]. The presence of diabetes is independently associated with an increased risk of fracture, due in part to alterations in bone structure and strength [7]; the risk of hip fracture is almost twice as high for patients with diabetes than for those without diabetes [8]. The prevalence of diabetes, particularly type 2 diabetes mellitus (T2DM), in Japan is one of the highest in the world and has been increasing markedly, especially among the elderly [9, 10]. The rising prevalence of both osteoporosis and T2DM in the elderly Japanese population is likely to lead to greater numbers of patients with osteoporosis who also have TD2M.

Osteoporosis comorbid with T2DM may require a re-evaluation of diagnostic criteria or planned treatment; skeletal fragility due to T2DM can result even without a noticeable reduction in bone mineral density (BMD), which has traditionally been used to diagnose osteoporosis [7, 11]. Although not completely understood, this increased fragility has been proposed to be due to a deterioration of bone quality rather than bone mass [6, 7], and osteoporosis treatments that are able to address this deterioration may be preferred for patients with T2DM. In a subgroup analysis of the Multiple Outcomes of Raloxifene Evaluation study, for a small number of patients, Johnell and coauthors reported that the osteoporosis drug raloxifene showed higher efficacy in women with osteoporosis and diabetes than in women with osteoporosis [12]. A number of studies have suggested that raloxifene may prevent the deterioration of bone quality by reducing the formation of detrimental collagen cross-links [13] or by reducing inhibition of the Wnt/β-catenin signalling pathway, leading to bone formation and turnover [14, 15]. However, relatively little is known about whether raloxifene treatment has an impact on the incidence of fractures in osteoporosis patients with and without T2DM. There is a need for increased awareness of the potential impact of T2DM on osteoporotic fractures and how treatment costs, treatment patterns, and healthcare resource utilization in patients with osteoporosis may change depending on the presence or absence of T2DM. This information can help physicians optimize the treatment and management of patients with osteoporosis and T2DM.

The aim of this claims database study was to describe the real-world effect of T2DM comorbidity on the incidence of fracture, costs, and healthcare resource utilization in patients with osteoporosis in Japan. Furthermore, this study also aimed to describe the effect of raloxifene treatment on the incidence of fractures in patients with T2DM compared with patients without diabetes mellitus (DM).

To our knowledge, this is the first study to examine the real-world impact of T2DM on the incidence of fracture, cost, and healthcare resource utilization in patients with osteoporosis in Japan. As might be expected, at baseline, patients with T2DM incurred greater costs, utilized proportionally greater healthcare resources, and were in poorer health than patients without DM (Table 1). This is consistent with studies highlighting the considerable financial cost and resources required to adequately manage patients with T2DM, independent of osteoporosis [16, 17]. A similar pattern of differences in fracture characteristics and healthcare resource utilization was observed between the two groups following initiation of osteoporosis medication (during the follow-up period), even after 1:1 exact matching of baseline characteristics (Table 2). Although a proportion of patients in both the T2DM and non-DM groups developed clinical fractures during the follow-up period, the proportion in the T2DM group was significantly larger than in the non-DM group (12.7% vs 9.9%; P < 0.001; Table 2). This difference reflects the additional fracture risk posed by T2DM (independent of osteoporosis), as has been observed in previous studies [4, 5, 8]. These findings suggest that both physicians and patients need to carefully consider the potential impact of T2DM on the treatment and management of osteoporosis in order to achieve the best clinical outcome and to ensure the most efficient use of healthcare resources.

We used 1:1 exact matching to adjust for differences between the T2DM and non-DM groups, which resulted in the removal of most of the significant baseline differences between the two groups, indicating reduction of some of the existing bias. However, during the follow-up period, matching did little to change the pattern of significant differences observed between the two groups, indicating that these differences were likely to be real. Of note was the fact that the proportion of patients in the T2DM group who underwent BMD tests was significantly smaller than that in the non-DM group; this pattern was observed during follow-up (38.8% vs 44.5%; P < 0.001). This difference may be partly explained by the fact that BMD measurements have been suggested to be of limited use in predicting fracture risk in patients with chronic kidney disease (CKD), particularly in the later stages of CKD [18]. In fact, the 2009 Kidney Disease Improving Global Outcomes CKD-Mineral and Bone Disorder (CKD-MBD) Work Group does not recommend routine BMD testing to estimate fracture risk in patients with stage 3-5D CKD with evidence of CKD-MBD [19]. As the T2DM group had more patients with CKD, a lower rate of BMD testing amongst patients with CKD may have contributed to the significantly smaller proportion of patients undergoing BMD tests in the T2DM group compared with the non-DM group. Another explanation for the difference in BMD tests between the two groups may be that given the seriousness of the comorbidities and complications associated with diabetes (eg, nephropathy and retinopathy), patients diagnosed with T2DM may have prioritized management of T2DM in favor of osteoporosis [7], leading to fewer BMD tests being carried out. In Japan, patients with diabetes are often treated by endocrinologists, diabetologists, or internists, whereas patients with osteoporosis are often treated by orthopedic surgeons. This difference in medical care can lead to different treatment priorities, which may mean that patients with osteoporosis comorbid with diabetes may not receive optimal treatment for the increased fracture risk. The findings of this study highlight the need to educate both patients and physicians about the impact of diabetes on fracture risk so that screening and treatment of osteoporosis can be modified appropriately.

Compared with the overall study group, similar patterns in fracture characteristics and healthcare resource utilization were observed in the raloxifene subgroup, before matching (Table 3). However, in contrast to the overall study group, there were no statistically significant differences in any of the fracture characteristics between the T2DM and non-DM groups in the raloxifene subgroup during the 30 months of the follow-up period; this was observed in both unadjusted (clinical fracture: 14.4% vs 13.3%; P = 0.568) and matched groups (clinical fracture: 12.1% vs 13.4% P = 0.681). Following matching, there were even fewer significant differences between the two groups in terms of healthcare resource utilization. Taken together, these results may indicate that comorbid diabetes had a lower impact on fractures and healthcare resource utilization in patients who were prescribed raloxifene. Based on its mechanism of action, raloxifene has been proposed to affect diabetes-related fracture risk in a number of ways. Raloxifene may decrease the accumulation of advanced glycation endproducts, which are thought to reduce bone quality [11, 20]. Raloxifene has also been suggested to improve bone quality by increasing the formation of enzymatic cross-links in bone [13] and by improving collagen spacing [21] and bone toughness [22]. It is important to note that we cannot confirm that raloxifene alone is responsible for the beneficial effects observed or that these effects may not be mediated by other osteoporosis treatments. Furthermore, a recent study has suggested that the efficacy of bisphosophonates and raloxifene in reducing fracture risk is not affected by the presence of diabetes [23]. Nevertheless, our results indicate that further testing of raloxifene in this clinical setting, particularly in comparison with other osteoporosis medications, may be warranted.

In addition to considerations surrounding the efficacy of different osteoporosis treatments in patients with T2DM, physicians may also have to consider the safety profile of certain osteoporosis treatments in the context of diabetes. For instance, a retrospective analysis by Khamaisi and coauthors suggested that patients with diabetes may be at increased risk of developing osteonecrosis of the jaw when treated with bisphosphonates [24]. Conversely, physicians should also consider the effects of treatments for T2DM on osteoporosis. A meta-analysis of 10 randomized controlled trials suggested that long-term thiazolidinedione use doubles the risk of fractures among women with T2DM [25]. It is clear that comorbidity with T2DM adds further complexity to clinical decision-making during the treatment of osteoporosis.

The strengths of this study include the large number of patients and the fact that the analyses were performed on an extensive medical claims database, which reflects real-world clinical practice in more than 100 hospitals in Japan. Given that the data are drawn from a claims database, there are several inherent limitations, which include a reliance on ICD-10 codes being applied accurately and the fact that outcomes cannot be directly measured but must be inferred from available data. Although an exact matching method was used to minimize the differences between the T2DM and non-DM groups, there may have been additional unobserved confounding factors that were not considered during the matching process, which may have introduced bias into the comparisons. Additional limitations include the relatively short follow-up period, which may underestimate the incidence of fractures. Patients who were diagnosed with T2DM during the baseline period were not distinguished from those who were diagnosed during the follow-up period. The severity of osteoporosis in each patient was also not known; disproportionate numbers of patients with severe osteoporosis in each group may have introduced bias into the study. Patients may have also received their prescriptions from sources other than hospitals, which would not have been captured by the database utilized. Varying levels of adherence to and persistence with osteoporosis medications may have also affected the incidence of fractures observed. These limitations should be considered when interpreting the findings of this study and it should also be noted that no causative effects can be identified from this analysis.

This study is one of the first to highlight the impact of T2DM on osteoporosis in real-world clinical practice in Japan. Patients with osteoporosis and T2DM had a higher incidence of fractures, utilized proportionally greater healthcare resources, and incurred proportionally higher healthcare costs, than matched patients without DM. This has important implications for clinical practice, as greater education of both patients and physicians may increase awareness of the substantial impact of diabetes on fracture risk in osteoporosis. In particular, physicians have to consider not only the increased fracture risk but the appropriateness of treatments for both osteoporosis and T2DM. Our analysis of study patients treated with raloxifene indicates that further assessment of this treatment in the context of T2DM may be warranted. Given the sizeable impact of osteoporosis on the economy and healthcare system of the “super-aging” society in Japan [26], strategies to offset the additional burden of T2DM on osteoporotic fractures may be of substantial value.