Palopegteriparatide for Adults with Chronic Hypoparathyroidism: Skeletal Dynamics Through 3 yr of the Phase 2 paTH Forward Trial

Hypoparathyroidism is an endocrine disease caused by insufficient levels of PTH, which acts directly on bone and kidney and indirectly on the intestine to regulate calcium and phosphate balance. In clinical trials, palopegteriparatide (TransCon PTH) treatment enabled independence from conventional therapy (no active vitamin D, <= 600 mg/d calcium) and maintained serum biochemistries within normal ranges. The current analyses describe patterns of change in BMD, serum bone turnover markers, and serum and urine calcium in adults with chronic hypoparathyroidism treated with palopegteriparatide through 3 years of the PaTH Forward trial. Baseline BMD Z-scores for the LS, TH, FN, and 1/3 distal radius were above zero, indicating bone mass exceeding age-adjusted normative values. BMD decreased from these elevated baseline levels with palopegteriparatide treatment, with larger reductions during the first 26 weeks and modest declines thereafter. Mean BMD Z-scores at week 162 remained above zero for all 4 sites. Participants with lower baseline BMD (Z-scores below -1 and T-scores below -2.5) generally exhibited lesser declines in BMD versus those with higher baseline BMD. Palopegteriparatide treatment was associated with early increases in bone resorption (serum C-terminal telopeptide of type I collagen, CTx) and bone formation (serum procollagen type 1 N-terminal propeptide, P1NP) that peaked at weeks 12 and 26, respectively, followed by declines to levels moderately higher than baseline at week 162. Mean CTx and P1NP in the overall population and the subgroup of postmenopausal women were below their upper limits of normal from weeks 58-162. At week 162, mean serum and median urine calcium remained within normal ranges and 91% of participants were independent from conventional therapy. These results suggest that long-term palopegteriparatide therapy in adults with chronic hypoparathyroidism gradually returns the skeleton toward its natural state thereby enhancing the skeleton's contribution to calcium homeostasis.Chronic hypoparathyroidism is caused by inadequate PTH levels and results in dysregulated calcium/phosphate balance in the body. Hypoparathyroidism can lead to bone abnormalities, such as lower bone turnover and higher BMD than people of similar age and sex without hypoparathyroidism. Conventional therapy (active vitamin D and calcium) is used to manage hypoparathyroidism and avoid low blood calcium but does not replace the missing functions of PTH. Palopegteriparatide is a new treatment for chronic hypoparathyroidism administered by injection once daily and designed to provide PTH levels in the physiological range for 24 hours/day. In the PaTH Forward trial, treatment with palopegteriparatide allowed 91% of participants to stop taking conventional therapy (no active vitamin D and <= 500 mg/d calcium) and kept blood calcium levels in the normal range over 26 weeks. Treatment with palopegteriparatide showed an initial increase in bone turnover, followed by stabilization through week 162. BMD decreased with palopegteriparatide treatment, mostly during the first 26 weeks, with slower subsequent decreases to levels that on average remained above normal at week 162. These results suggest palopegteriparatide helps to maintain normal calcium levels in chronic hypoparathyroidism in part by reactivating bone remodeling and returning BMD toward normal levels.