Clarke, B.L.

Abstract 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.

Abstract The sections in this article are: Molecular Actions of Thyroid Hormone Thyroid Hormone Regulation of Growth and Development Extrahypothalamic Thyrotropin‐Releasing Hormone Metabolic Actions of Islet Cell Hormones Insulin Glucagon Amylin Calcitonin Gene‐Related Peptide Somatostatin Pancreatic Polypeptide Thyroid Hormone Regulation of Insulin Metabolic Actions Euthyroidism Hyperthyroidism Hypothyroidism Thyroid Hormone Regulation of Glucagon Metabolic Actions Hyperthyroidism Hypothyroidism Thyroid Hormone Regulation of Somatostatin Metabolic Actions Hyperthyroidism Hypothyroidism Thyroid Hormone Regulation of Pancreatic Polypeptide Metabolic Actions Summary and Conclusions

Abstract Disclosure: A.A. Khan: Alexion Pharmaceuticals, Inc., Amgen Inc, Amolyt Pharma, Ascendis Pharma. B.L. Clarke: Amolyt Pharma, Ascendis Pharma, EnteraBio, Extend Bio, Takeda. M.R. Rubin: Ascendis Pharma, MBX Biosciences. P.E. Schwarz: Aventis Pharmaceuticals, Genmab, Novo Nordisk. D.M. Shoback: Ascendis Pharma. C. Gagnon: Amgen Inc, Ascendis Pharma, Novo Nordisk, Shire, Takeda. A. Palermo: None. L.G. Abbott: Abbott Laboratories, Ascendis Pharma, Clarus, Shire, Takeda. L. Kohlmeier: Amgen Inc, Ascendis Pharma, Radius Health, Inc. E. Tsourdi: Alexion Pharmaceuticals, Inc., Ascendis Pharma, Kyowa Kirin, Takeda, UCB. F. Cetani: None. R. Jain: Amgen Inc, Ascendis Pharma. C. Zhao: Ascendis Pharma. B. Lai: Ascendis Pharma. M.A. Makara: Ascendis Pharma. J. Ukena: Ascendis Pharma. C.T. Sibley: Ascendis Pharma. A.D. Shu: Ascendis Pharma. L. Rejnmark: Amolyt Pharma, Ascendis Pharma, BridgeBio, Kyowa Kirin, Takeda. Background: Hypoparathyroidism is an endocrine disease caused by insufficient levels of parathyroid hormone (PTH) and is associated with reduced quality of life and a high comorbidity burden. Conventional therapy for hypoparathyroidism (active vitamin D and elemental calcium) aims to alleviate hypocalcemia but does not address insufficient PTH and may increase the risk of renal complications. Palopegteriparatide is a prodrug of PTH(1-34), administered subcutaneously once daily, designed to provide active PTH within the physiological range for 24 hours/day. It is approved by the Food and Drug Administration, European Commission, and Medicines and Healthcare products Regulatory Agency. This analysis evaluated the long-term efficacy and safety of palopegteriparatide in adults with chronic hypoparathyroidism through week 156 of the PaTHway trial. Methods: PaTHway is a phase 3 trial with a 26-week randomized, double-blind, placebo-controlled period followed by an ongoing open-label extension period. Serum biochemistries were assessed at baseline and regular intervals. Renal function was assessed by estimated glomerular filtration rate (eGFR). Safety assessments included 24-hour urine calcium and treatment-emergent adverse events (TEAEs). Results: At week 156, 89% (73/82) of participants remained in the trial; of those, 96% were independent from conventional therapy (no active vitamin D and ≤600 mg/day elemental calcium) and 88% had normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL) with a mean (SD) of 8.9 (0.6) mg/dL. Mean (SD) serum phosphate (3.4 [0.6] mg/dL) and calcium x phosphate product (30.6 [5.4] mg2/dL2) levels remained within normal ranges through week 156. Mean (SD) eGFR at week 156 was 78.0 (14.5) mL/min/1.73 m2, reflecting a mean (SD) increase of 8.8 (11.9) mL/min/1.73 m2 from baseline (P<0.0001); 59% and 43% of participants had an increase in eGFR of ≥5 mL/min/1.73 m2 and ≥10 mL/min/1.73 m2, respectively. Among participants with baseline eGFR <60 mL/min/1.73 m2 (n=23), the mean (SD) increase in eGFR was 14.0 (8.9) mL/min/1.73 m2 from baseline to week 156. Mean (SD) 24-hour urine calcium levels normalized with palopegteriparatide treatment, remaining below the upper limit of normal (≤250 mg/day) through week 156 (162.1 [117.8] mg/day). TEAEs were mostly grade 1 or 2, with no new safety signals identified. Conclusion: Through year 3 of the PaTHway trial, retention rate was high and palopegteriparatide demonstrated consistent longer-term safety and efficacy, which included the maintenance of serum and urine biochemistries within normal levels and sustained improvement in renal function. Presentation: Saturday, July 12, 2025

Abstract Disclosure: D.S. Ali: None. Z. Chung: None. L. Kamel: None. S. Björnsdottir: Shire. B.L. Clarke: Shire, Takeda, Ascendis, Calcilytix. S. Hahner: None. L.C. Hofbauer: Amgen Inc, Ascendis, UCB, Ascendis, Amolyte. P. Houillier: None. S.W. Ing: Amgen Inc, Radius Health, Inc, Takeda, AscendAlexion, Amolyt, Ascendis, Calcilytix, Kyowa Kirin. M.A. Levine: Takeda, Amolyt, Calcilytix. M. Mannstadt: Takeda, Amolyt, Calcilytix. L. Rejnmark: Takeda, Amolyt, Ascendis, Calcilytix. D.M. Shoback: Amolyt, Ascendis, member of the advisory board (PARADIGHM). M. Brandi: Takeda, Eli Lilly & Company, Calcilytix, Kyowa Kirin, UCB, Abiogen, Alexion, Amolyt, Amorphical, Bruno Farmaceutici, CoGeDi, Echolight. A.A. Khan: Takeda, Amgen Inc, Alexion, Ascendis, Amolyt, Calcilytix. Background: Hypoparathyroidism (HypoPT) is a rare endocrine disorder that requires close evaluation and follow up during pregnancy to minimize maternal and fetal complications. The primary objectives of this study are to evaluate the use of rhPTH (1-84) during pregnancy by analyzing data from the PARADIGHM disease registry, and to compare maternal and neonatal outcomes among patients who continued PTH therapy during pregnancy versus those on conventional therapy (CT). Methods: We performed a retrospective analysis of data in the PARADIGHM registry. Maternal and neonatal outcomes in women treated with rhPTH (1-84) were compared to women who received CT. Results: We analyzed 39 pregnancies of 32 women. Of those, 4 women (6 pregnancies) used rhPTH (1-84) either before or during pregnancy and 28 women (33 pregnancies) continued CT during pregnancy. The mean (SD) maternal age at enrollment was 31.7 (5.6) years. Postsurgical HypoPT was the most common etiology (68.8%). The mean gestational age at delivery was 36 (2.4) weeks (PTH-treated) vs 38.3 (3.3) weeks (CT) (p=0.162). Preterm delivery rates were higher in the PTH-treated group (50% vs. 27%, p=0.591), but this was not statistically significant. Two women had pre-eclampsia, one in each group (PTH-treated and CT). In the PTH-treated group, one pregnancy resulted in a stillbirth, and one infant was born with congenital anomalies (16.7% each). Conclusions: The safety of rhPTH (1-84) use in pregnancy cannot be determined at this time. The PTH-treated group exhibited trends towards higher rates of preterm delivery, but the rates of stillbirth, and congenital anomalies were low and comparable in both groups of women. Larger studies are necessary to determine the optimal approach to manage women with HypoPT during pregnancy. Presentation: Sunday, July 13, 2025

Abstract Context Data on cardiovascular outcomes in patients with chronic hypoparathyroidism (hypoPT) are limited. Objective To investigate the risk of cardiovascular outcomes, acute myocardial infarction, atrial fibrillation/flutter, heart failure, valvular heart disease, peripheral artery disease, and stroke/transient ischemic attack (TIA) in patients with chronic hypoPT. Design The Swedish National Patient Registry, the Swedish Prescribed Drug Registry, and the Total Population Registry, 1997-2018. Settings Population-based cohort study in Sweden. Patients National registries were used to identify patients with chronic hypoPT and matched controls. Results A total of 1982 with chronic hypoPT and 19 499 controls were included. After adjustment for cardiovascular risk factors, patients with chronic hypoPT had higher risk of valvular heart disease [hazard ratio (HR) 2.08; 95% confidence interval (CI) 1.67-2.60], peripheral artery disease (HR 1.78; 95% CI 1.41-2.26), heart failure (HR 1.66; 95% CI 1.44-1.90), atrial fibrillation/flutter (HR 1.58; 95% CI 1.38-1.81), acute myocardial infarction (HR 1.31; 95% CI 1.05-1.64), and fatal cardiovascular disease (HR 1.59; 95% CI 1.40-1.80) compared to matched controls. No significant difference in risk of stroke/TIA was observed. Cardiovascular outcomes did not differ between patients with surgical and nonsurgical chronic hypoPT. Females with hypoPT had a significantly increased risk of valvular heart disease, peripheral artery disease, heart failure, atrial fibrillation, myocardial infarction, and fatal cardiovascular disease compared to female controls. There were no differences in any cardiovascular outcomes between males with hypoPT and male controls. Conclusion The risk of cardiovascular diseases was increased in patients with chronic hypoPT, particularly among women. These findings highlight the need for close monitoring and preventive management of cardiovascular risk factors, especially in women.

Objective: This post hoc analysis evaluated the efficacy of abaloparatide treatment in a subgroup of postmenopausal women from the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE; NCT01343004) study who met high fracture risk criteria (defined in several professional society guidelines). Methods: Women from ACTIVE meeting ≥1 of the following fracture risk criteria were included: fracture within the past 12 months or prevalent vertebral fracture, baseline T score of <−3.0 at any site, very high fracture risk probability by FRAX (ie, 10-yr major osteoporotic fracture >30% or hip fracture >4.5%), or multiple prior fractures at baseline since age ≥45 years. Results: A total of 2,026 participants met ≥1 fracture risk criteria defined in clinical guidelines (abaloparatide, n = 664; placebo, n = 677; teriparatide, n = 685). New vertebral fracture risk was reduced in participants receiving abaloparatide (4 [0.72%]) and teriparatide (6 [0.99%]) versus placebo (28 [4.77%]; both P < 0.0001). Estimated Kaplan-Meier cumulative incidence of nonvertebral fracture was 3.0%, 5.3%, and 3.0% in the abaloparatide, placebo, and teriparatide groups, respectively; 4.0%, 9.0%, 4.3% for clinical fracture; 1.6%, 6.8%, 3.0% for major osteoporotic fractures; and 1.1%, 2.1%, 2.1% for wrist fracture. Abaloparatide was associated with bone mineral density gains from baseline at the lumbar spine, total hip, and femoral neck at all time points (6, 12, and 18 mo; P < 0.0001 for all). Common adverse events reported in participants treated with abaloparatide were hypercalciuria (11.5%), dizziness (11.0%), and arthralgia (8.9%). Conclusions: Abaloparatide reduced fracture incidence and increased bone mineral density in participants at highest fracture risk, consistent with the overall ACTIVE study.

Abstract Context Tumor-induced osteomalacia (TIO), a paraneoplastic disorder characterized by renal phosphate wasting, is cured by surgical removal of the culprit tumor. Despite correct localization, some remain refractory to intervention, resulting in substantial long-term medical complications. Objective We aim to identify risk factors associated with a refractory outcome. Methods This is a retrospective cohort of 44 patients with TIO diagnosed from 1998 to 2023 who underwent targeted intervention following successfully localization. Cure was defined as maintenance of normophosphatemia without supplementation for ≥1 month, maintained at last follow-up. Results Twenty-nine patients achieved cure and 15 had a refractory outcome. On univariate Cox regression, the HR for predicting cure was 3.43 (95% CI 1.45-8.11, P = .005) for patients diagnosed after 2013 (compared to before), and that for a negative surgical tumor margin was 2.56 (95% CI 1.20-5.45, P = .015) compared to positive/unspecified margins. After adjustment for year of diagnosis, tumors originating from soft tissue (HR 2.72 vs bone, 95% CI 1.22-6.09, P = .015) or located outside the spine (HR 0.22 for spine vs nonspine, 95% CI 0.05-0.96, P = .043) had higher chances of cure. Size of tumor, age, gender, or baseline biochemistry including levels of fibroblast growth factor (FGF)23, phosphorus, 1,25-dihydroxyvitamin D, or alkaline phosphatase were not predictive of cure. Postprocedural FGF23 was the best biochemical marker of cure (area under curve 0.899, 95% CI 0.764-1.00, P &lt; .001). Conclusion Tumors diagnosed within the past decade with clear resection margins had more favorable prognoses. With regards to tumoral factors, baseline biochemistry was uninformative in predicting cure, while bone and/or spine localizations were associated with a refractory outcome.