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

Abstract Context Type 2 diabetes (T2D) increases fragility fracture risk despite normal/elevated aBMD, attributed to compromised bone microarchitecture. However, evidence guiding pharmacologic management of diabetic bone disease remains limited. Objective To evaluate interim effects of zoledronate, denosumab, or teriparatide on bone microarchitecture in postmenopausal women with T2D at high fracture risk. Design 72-week, randomized, open-label, blinded-endpoint (PROBE) pilot clinical trial (CTRI/2022/02/039978). Setting Single tertiary care center in India. Patients Total of 129 postmenopausal women with T2D>5 years and high fracture risk (prior fragility fracture and/or T-score<-2.5 (corrected for T2D) with elevated FRAX®). Interventions Participants were randomized in 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. Main Outcome Measure Pre-specified 24-week interim exploratory analysis focusing on changes in bone microarchitecture assessed by second-generation HR-pQCT at 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 vBMD (tibia/radius), trabecular number (Tb.N), BV/TV (tibia), and trabecular thickness (radius). Denosumab improved tibial trabecular vBMD and Tb.N. Zoledronate improved only tibial total vBMD. Micro finite element analysis-derived strength parameters were unchanged, except for modest increase in tibial stiffness with denosumab. BTMs decreased with anti-resorptives, increased with teriparatide and showed an anabolic window by 6 weeks. Conclusions Teriparatide demonstrated early improvements in bone microarchitecture in postmenopausal women with T2D while denosumab showed a modest increase in bone stiffness at distal tibia. Larger, adequately powered studies are needed to clarify the relative effects of anabolic and anti-resorptive therapies in this population.