Eneboparatide Restores Calcium Homeostasis Without Compromising Bone Microarchitecture: A Comparative Study in a Rat Model of Hypoparathyroidism

Background Hypoparathyroidism (HypoPT) is characterized by parathyroid hormone (PTH) deficiency and hypocalcemia and is often caused by damage/removal of parathyroid glands during neck surgery. Conventional treatments with oral calcium and 1,25(OH) 2 vitamin D can lead to blood calcium fluctuations, hypercalciuria, and renal complications. PTH-replacement strategies can potentially restore reduced bone remodeling in HypoPT. Eneboparatide (AZP-3601/LA-PTH), a PTH1 receptor (PTH1R) agonist, induces prolonged calcemic responses and shows promise in clinical trials as a potential treatment for HypoPT, but its effects on bone are uncertain. Objectives Determine optimal doses of eneboparatide and PTH(1-34) for normalizing serum calcium in thyroparathyroidectomized (TPTX) rats and evaluate the effects on bone microarchitecture and bone turnover markers. Methods This dose-range analysis in TPTX rats compared effects of daily subcutaneous injections of eneboparatide or PTH(1-34) or continuous PTH(1-34) infusion on serum calcium, bone microarchitecture, and bone turnover markers. Male Sprague-Dawley TPTX rats (∼8 per group) were treated for 16 days with eneboparatide daily subcutaneous injection (1.0, 2.0, or 4.0 nmol/kg), PTH(1-34) continuous infusion (1.5, 2.0, or 3.0 nmol/kg daily), or PTH(1-34) daily subcutaneous injection (50 nmol/kg). Blood ionized calcium and serum total calcium were measured at various timepoints. On day 16 (24 hours after last injection), serum was analyzed for P1NP, CTX-1, and TRAP-5b and femur bone microarchitecture was analyzed using microcomputed tomography. Results Optimal doses for normalizing serum calcium were PTH(1-34) 50 nmol/kg daily subcutaneous injection, PTH(1-34) 3.0 nmol/kg daily continuous infusion, and eneboparatide 1.0 nmol/kg daily subcutaneous injection; higher eneboparatide doses (2.0 and 4.0 nmol/kg) caused hypercalcemia. ​At optimal doses, eneboparatide produced minimal changes in bone turnover markers and microarchitecture; ​PTH(1-34) daily subcutaneous injection showed anabolic effects on bone, and PTH(1-34) continuous infusion exerted catabolic effects. Conclusions Eneboparatide normalized serum calcium in TPTX rats without compromising bone microarchitecture, supporting potential therapeutic use for HypoPT.