Interim Effects of Zoledronate, Denosumab, or Teriparatide on Bone Microarchitecture in Type 2 Diabetes: A Pilot Trial

CONTEXT: Type 2 diabetes (T2D) increases fragility fracture risk despite normal/elevated areal bone mineral density (aBMD), attributed to compromised bone microarchitecture. However, evidence guiding pharmacologic management of diabetic bone disease remains limited. OBJECTIVE: We aimed to evaluate interim effects of zoledronate, denosumab, or teriparatide on bone microarchitecture in postmenopausal women with T2D at high fracture risk. METHODS: A 72-week, randomized, open-label, blinded-end point (PROBE) pilot clinical trial (CTRI/2022/02/039978) was conducted at a single tertiary care center in India. Participants included 129 postmenopausal women with T2D for more than 5 years and high fracture risk (prior fragility fracture and/or T-score < -2.5 [corrected for T2D] with elevated FRAX®). Participants were randomly assigned in a 1:1:1:1 ratio to receive zoledronate 5 mg annually, denosumab 60 mg every 6 months, teriparatide 20 µg daily, or only standard of care (calcium/cholecalciferol) for 72 weeks. The outcome measure included a prespecified 24-week interim exploratory analysis focusing on changes in bone microarchitecture assessed by second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal tibia and radius. Bone turnover markers (BTMs) were also evaluated. RESULTS: Baseline demographic, biochemical, aBMD, and HR-pQCT parameters were comparable across groups. Teriparatide significantly improved total and trabecular volumetric BMD (vBMD) (at tibia and radius), trabecular number (Tb.N), trabecular bone volume fraction (BV/TV) (at tibia), and trabecular thickness (Tb.Th) (at radius). Denosumab improved tibial trabecular vBMD and Tb.N. Zoledronate improved only tibial total vBMD. Microfinite element analysis-derived strength parameters were unchanged, except for a modest increase in tibial stiffness with denosumab. BTMs decreased with antiresorptives, increased with teriparatide, and showed an anabolic window by 6 weeks. CONCLUSION: Teriparatide demonstrated early improvements in bone microarchitecture in postmenopausal women with T2D while denosumab showed a modest increase in bone stiffness at the distal tibia. Larger, adequately powered studies are needed to clarify the relative effects of anabolic and antiresorptive therapies in this population.