Abstract
ABSTRACTType 2 diabetes mellitus (T2DM) increases fracture risk despite normal or increased BMD. Abaloparatide reduces fracture risk in patients with postmenopausal osteoporosis (PMO); however, its efficacy in women with T2DM is unknown. This post hoc analysis evaluated the efficacy and safety of abaloparatide in patients with T2DM. The analysis included patients with T2DM from the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE), a phase 3, double‐blind, randomized, placebo‐ and active‐controlled trial. In ACTIVE, participants were randomized 1:1:1 to daily s.c. injections of placebo, abaloparatide (80 μg), or open‐label teriparatide (20 μg) for 18 months. A total of 198 women with PMO and T2DM from 21 centers in 10 countries were identified from ACTIVE through review of their medical records. The main outcomes measured included effect of abaloparatide versus placebo on BMD and trabecular bone score (TBS), with secondary outcomes of fracture risk and safety, in patients from ACTIVE with T2DM. Significant (p < 0.001) improvements in BMD at total hip (mean change 3.0% versus −0.4%), femoral neck (2.6% versus −0.2%), and lumbar spine (8.9% versus 1.3%) and TBS at lumbar spine (3.72% versus −0.56%) were observed with abaloparatide versus placebo at 18 months. Fracture events were fewer with abaloparatide treatment in patients with T2DM, and differences were not significant between groups except nonvertebral fractures in the abaloparatide versus placebo groups (p = 0.04). Safety was consistent with the ACTIVE population. In conclusion, in women with PMO and T2DM, abaloparatide treatment resulted in significant improvements in BMD and TBS versus placebo, consistent with the overall ACTIVE population © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
Osteoporosis significantly increases the risk of fragility fractures, which can substantially impact affected individuals and their families because of increased mortality, morbidity, and loss of independence and, thereby, imposes a high economic burden on society.[1,2,3] Osteoporosis and type 2 diabetes mellitus (T2DM) are frequently comorbid conditions, both of which increase in prevalence with age.[4,5] Compared with the general population, patients with T2DM have a greater risk of major osteoporotic fractures including hip fractures.[6,7,8] T2DM
Existing evidence suggests that the increased fracture risk seen in patients with T2DM may occur in the presence of normal or higher than expected BMD and is a consequence of multiple mechanisms, including altered bone metabolism and compromised bone microarchitecture.[16,17] T2DM has been associated with decreased bone turnover, reduced parathyroid hormone levels, and a decrease in circulating markers of bone formation.[15,16,17,25] Abaloparatide acts through the parathyroid 1 receptor (PTH1R) to stimulate bone formation and improve bone microarchitecture, suggesting it may be beneficial for the reduction of fracture risk in patients with T2DM.[27,31,32,33]
In light of the evidence that compromised bone microarchitecture contributes to an increased fracture risk in the T2DM population, we examined the impact of abaloparatide on Trabecular bone score (TBS), which is correlated with and may be a surrogate measure for bone microarchitecture
Summary
Osteoporosis significantly increases the risk of fragility fractures, which can substantially impact affected individuals and their families because of increased mortality, morbidity, and loss of independence and, thereby, imposes a high economic burden on society.[1,2,3] Osteoporosis and type 2 diabetes mellitus (T2DM) are frequently comorbid conditions, both of which increase in prevalence with age.[4,5] Compared with the general population, patients with T2DM have a greater risk of major osteoporotic fractures including hip fractures.[6,7,8] T2DM is a risk factor for delayed healing and increased mortality following a hip fracture.[9,10] Because of these issues, effective fracture prevention strategies are needed for patients with T2DM.[11]The increased risk of fracture in patients with T2DM is somewhat paradoxical, as these individuals often exhibit normal or increased BMD.[12,13,14] Evidence suggests that fracture risk in patients with T2DM is associated with bone fragility caused by deterioration in bone quality.[15,16,17] Trabecular bone score (TBS)is strongly correlated with microarchitectural parameters that reflect bone strength and is lower in patients with T2DM, 1n those with poor glycemic control (HbA1c >7.5%) compared with the general population.[18,19,20] Recent guidelines support the use of TBS to help predict fracture risk in combination with other fracture risk assessment strategies, including in patients with T2DM.[21]Several potential consequences of hyperglycemia have been postulated to contribute to altered bone metabolism, including accumulation of advanced glycation end products in collagen, increased IL-6 production leading to stimulation of osteoclasts, osmotic-induced damage to osteoblasts, suppression of gene expression involved with osteoblast maturation, and potential effects of microvascular disease on bone.[17,22,23,24] In particular, T2DM is characterized by decreased bone turnover, reduced PTH levels, lower circulating levels of bone formation markers, increased circulating sclerostin, and increased cortical pore volume.[15,16,25,26]In summary, bone in T2DM appears to be characterized by relatively preserved BMD with deficits in other aspects of bone quality. Abaloparatide is a selective activator of the parathyroid 1 receptor (PTH1R) signaling pathway that favors the stimulation of bone formation.[27] In preclinical and clinical studies, abaloparatide increased BMD.[28,29,30,31,32] improved bone microarchitecture,(31–33) and increased bone strength.[28,31] In ACTIVE (Abaloparatide Comparator Trial In Vertebral Endpoints), the pivotal phase 3 study for abaloparatide in women with postmenopausal osteoporosis, abaloparatide significantly increased BMD and decreased the risk of new vertebral, nonvertebral, clinical, and major osteoporotic fractures versus placebo, and decreased risk of major osteoporotic fractures versus teriparatide.[30] In this post hoc analysis, we evaluated the efficacy and safety of abaloparatide in the subgroup of ACTIVE patients with T2DM.
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