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Background The role of vitamin D on muscle health is debated. Methods An individual participant metanalysis of 4 randomized placebo-controlled trials, investigating short-term (3-9months) effects of vitamin D3 in moderate (2800 IU) to high (7000 IU) daily oral doses on muscle health and quality of life (QoL). Inclusion criteria were either obesity (n = 52), newly diagnosed primary hyperparathyroidism (n = 41), Graves’ disease (n = 86), or secondary hyperparathyroidism (n = 81). Results Overall (n = 260) as well as in a subgroup analysis including only vitamin D insufficient [25(OH)D 30 kg/m2, vitamin D supplementation had divergent effects on isometric muscle strength, with beneficial effects in obese individuals (n = 93) at knee flexion 90° (P = 0.04), and adverse effects in nonobese individuals (n = 167) at handgrip (P = 0.02), knee extension 60° (P = 0.03) and knee flexion 60° (P Conclusion Overall, short-term treatment with moderate to high daily doses of vitamin D did not affect muscle health or QoL. A potential beneficial effect was present on muscle strength in severely obese individuals and on QoL in vitamin D deficient individuals. Subgroup analyses, however, suggested negative effects of large relative increases in p-25(OH)D.

Context The calcium-sensing receptor (CaSR) is essential to maintain a stable calcium concentration in serum. Spermatozoa are exposed to immense changes in concentrations of CaSR ligands such as calcium, magnesium, and spermine during epididymal maturation, in the ejaculate, and in the female reproductive environment. However, the role of CaSR in human spermatozoa is unknown. Objective This work aimed to investigate the role of CaSR in human spermatozoa. Methods We identified CaSR in human spermatozoa and characterized the response to CaSR agonists on intracellular calcium, acrosome reaction, and 3′,5′-cyclic adenosine 5′-monophosphate (cAMP) in spermatozoa from men with either loss-of-function or gain-of-function mutations in CASR and healthy donors. Results CaSR is expressed in human spermatozoa and is essential for sensing extracellular free ionized calcium (Ca2+) and Mg2+. Activators of CaSR augmented the effect of sperm-activating signals such as the response to HCO3– and the acrosome reaction, whereas spermatozoa from men with a loss-of-function mutation in CASR had a diminished response to HCO3–, lower progesterone-mediated calcium influx, and were less likely to undergo the acrosome reaction in response to progesterone or Ca2+. CaSR activation increased cAMP through soluble adenylyl cyclase (sAC) activity and increased calcium influx through CatSper. Moreover, external Ca2+ or Mg2+ was indispensable for HCO3– activation of sAC. Two male patients with a CASR loss-of-function mutation in exon 3 presented with normal sperm counts and motility, whereas a patient with a loss-of-function mutation in exon 7 had low sperm count, motility, and morphology. Conclusion CaSR is important for the sensing of Ca2+, Mg2+, and HCO3– in spermatozoa, and loss-of-function may impair male sperm function.

Background Hypoparathyroidism is a rare disease characterized by deficiency of parathyroid hormone (PTH), resulting in abnormal mineral homeostasis. Conventional therapy (active vitamin D and calcium) targets short-term symptoms, but fails to restore normal PTH physiology, and may lead to complications such as nephrolithiasis, nephrocalcinosis, and renal insufficiency. TransCon PTH is an investigational long-acting prodrug of PTH(1-34) dosed once-daily for the treatment of adults with hypoparathyroidism. In the phase 2 PaTH Forward trial of TransCon PTH, 82% of participants achieved independence from conventional therapy at Week 4, a trend observed through Week 26 and 58. Here we report the Week 84 results from PaTH Forward trial. Methods The phase 2 PaTH Forward trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 4-week clinical trial with an open-label extension (OLE) period planned through Week 214. Participants received 4 weeks fixed dose of TransCon PTH (15, 18, or 21 mcg/d) or placebo co-administered with conventional therapy, followed by an OLE period during which TransCon PTH dose was titrated to maintain normocalcemia. Efficacy assessments at Week 84 included levels of 24-hour urine calcium (uCa) and sCa and independence from conventional therapy (defined as taking no active vitamin D and ≤600 mg calcium). After Week 58, a subset of 12 participants had frequent blood and urine sampling over 24 hours for evaluation of pharmacodynamic effect on sCa and uCa level and active PTH pharmacokinetic assessment (PD/PK substudy). Results Fifty-eight of 59 participants continued in the trial through Week 84. The average dose of TransCon PTH at Week 84 was 22.8 mcg/d. Fifty-four of 58 participants (93%) at Week 84 achieved independence from conventional therapy. Baseline mean 24-hour uCa was above normal (428 mg/24-hour) but normalized at Week 26 (173 mg/24-hour), and sustained through Week 58 (144 mg/24-hour), and Week 84 (131 mg/24-hour). Average values for sCa baseline were 8.8 mg/dL and remained in normal range at Weeks 26 (8.9 mg/dL), 58 (8.5 mg/dL) and 84 (8.5 mg/dL). The majority of adverse events (AE) were mild and unrelated to study drug; no serious AEs were reported. No AEs led to discontinuation of the study drug, nor from the trial. In the PD/PK substudy, mean sCa and uCa levels were stable in the normal range at all time points. Active PTH levels reflected steady physiologic exposure throughout the 24-hour period. Conclusion Week 84 results from the PaTH Forward trial investigating TransCon PTH for adults with hypoparathyroidism showed continued independence from conventional therapy for 93% of participants and maintenance of normal sCa and 24-hour uCa. Results from the PD/PK substudy demonstrated 24-hour stability of sCa and uCa levels and confirm infusion-like PK profile in a population of adults with hypoparathyroidism. TransCon PTH was generally well-tolerated through Week 84. Presentation: Monday, June 13, 2022 11:00 a.m. - 11:15 a.m.

Background: Hypoparathyroidism (HP) is caused by a deficiency in parathyroid hormone (PTH), which leads to hypocalcemia and hyperphosphatemia. Standard of care (SoC), i.e. large doses of calcium (Ca) and active vitamin D, worsens hypercalciuria and increases the serum Ca (sCa) x serum phosphate (sP) product. Studies have shown that continuous subcutaneous infusion of PTH(1-34) normalizes sCa, sP, serum magnesium, urine Ca (uCa) and bone turnover better than SoC or once- or twice-daily injections of PTH in HP patients. TransCon PTH, an investigational long-acting prodrug of PTH (1-34) transiently bound to an inert carrier via a linker, is under development as a potential once-daily replacement therapy for HP. Under physiological conditions, linker auto-cleavage occurs, releasing active PTH at a controlled rate with ~60 hour half-life. Phase 1 trial results demonstrated that once-daily TransCon PTH provided a flat, infusion like profile within the normal range of PTH 24 hours per day, increasing sCa while controlling uCa and decreasing sP, with no evidence of bone anabolic activity. Phase 2 Design: PaTH Forward is a global phase 2 trial evaluating the safety, tolerability, and efficacy of TransCon PTH in adult subjects with HP. Patients with HP treated with SoC were randomized at sites worldwide to daily TransCon PTH 15, 18 or 21 µg PTH(1-34) or daily blinded placebo via pen-injector for 4 weeks. The primary composite endpoint requires 1) normal albumin-adjusted sCa, and 2) normal Fractional Excretion of Ca (or ≥50% decrease from baseline), and 3) not taking active D, and 4) taking ≤1000 mg/d of Ca. After four weeks, all subjects enter an open-label extension period with the opportunity to receive TransCon PTH individually optimized to doses of 6 to 30 µg daily to evaluate long-term safety and efficacy. Other endpoints include the impact of treatment on patient experience, CaxP product, bone turnover markers, and bone mass by DXA and TBS to confirm the lack of anabolic effect. Preliminary Results: Approximately 55 subjects are expected to be randomized and dosed. Preliminary diary data on the initial 8 subjects completing 4 weeks of follow-up in the extension trial shows that all have discontinued SoC. Additional information will be presented at ENDO 2020. The Phase 2 trial is designed to inform the starting dose for a global pivotal phase 3 trial and evaluate TransCon PTH as a “true” PTH replacement therapy.

PARADIGHM is an actively recruiting, prospective, observational registry (NCT01922440/EUPAS16927). The primary objective is to evaluate the safety and effectiveness of recombinant human parathyroid hormone, rhPTH(1-84), treatment in patients with chronic hypoparathyroidism (HypoPT) under routine clinical care. The secondary objective is to characterize the clinical course of chronic HypoPT under conditions of routine clinical practice. At enrollment, registry inclusion criteria are patients having a HypoPT diagnosis >6 months and receiving conventional therapy (CT; eg, calcium supplements and active vitamin D), rhPTH(1-84) plus CT, or rhPTH(1-84). We present baseline characteristics of patients as of a June 30 2019 data cut. Baseline was defined as the value entered at the time of enrollment (Visit 1). Baseline symptom data exclude patients who initiated rhPTH(1-84) prior to enrollment (n=68) and are herein presented as two groups: those subsequently prescribed with rhPTH(1-84) after enrollment or those treated with CT. All data are summarized descriptively. Patient data from 64 centers in Europe and North America were analyzed. In the analysis population (n=737), 587 patients (79.6%) were female, 620 (84.1%) were white, and the mean (SD) age was 49.1 (16.45) years. The mean (SD) BMI was 19.3 (5.73) kg/m2 and 30.0 (7.72) kg/m2 in patients aged

Context Some patients with primary hyperparathyroidism (PHPT) develop renal calcifications. Investigation of urinary and nonurinary risk factors are essential. Objective We aimed to study the prevalence and potential biochemical predictors of renal calcifications. Design Nested case-control study. Setting University hospital. Participants We identified 792 patients with PHPT from 2005 to 2015. We used biochemical data to validate the diagnosis of PHPT. Main Outcome Measures The prevalence of renal calcifications defined as nephrolithiasis or nephrocalcinosis assessed by a routine CT scan at the time of diagnosis. Results A total of 792 patients with PHPT were identified among whom 617 patients (78%) had a CT scan preformed. We found a prevalence of renal calcifications of 23%, equally frequent between sexes. A total of 76 patients (12%) had nephrolithiasis and 75 patients (12%) had nephrocalcinosis where 7 patients (1%) had both nephrolithiasis and nephrocalcinosis. Compared with patients without renal calcifications, patients with renal calcifications had significantly higher levels of ionized calcium, parathyroid hormone, and 24-hour calcium excretion (Pall < 0.01). Patients with nephrocalcinosis had higher plasma levels of phosphate and a higher calcium-phosphate product compared with patients with nephrolithiasis (Pall < 0.05). Impaired renal function (estimated glomerular filtration rate Conclusion Renal calcifications are frequent in patients with PHPT and are associated with the severity of the disease. Impaired renal function is also common in PHPT, but renal function was not associated with renal calcifications.

Chronic hypoparathyroidism (HypoPT) is associated with impaired renal function.1 This study evaluated change in estimated glomerular filtration rate (eGFR) over a 5-yr period in adult patients (pts) with chronic HypoPT treated with or without recombinant human parathyroid hormone (1–84), rhPTH(1–84). The rhPTH(1–84)-treated pt cohort was derived from NCT01297309 (RACE) and NCT01199614 (HEXT) clinical trials. A historical control pt cohort with HypoPT who did not receive rhPTH(1–84) or rhPTH(1–34) were from the large national US Explorys electronic medical record database (Jan 2007−Aug 2019) using criteria similar to the trial enrollment criteria. The index date was the day after treatment initiation for the rhPTH(1–84) cohort and the day after the first calcitriol prescription for the control. The analysis included pts with eGFR ≥60 mL/min/1.73 m2 at the closest eGFR measurement during the 6 months before index date, ≥2 eGFR measurements ≥3 months apart during the 5 yrs on or after the index date and ≥1 eGFR measurement at 5 yrs (±6 months). For pts from RACE, baseline and study visit data after rhPTH(1–84) initiation were collected from the antecedent trials. Changes in eGFR were assessed in linear mixed and multivariable models (adjusted for age/sex/race, baseline eGFR value, history of hypercalciuria/hypertension/type 2 diabetes (T2D)/acute HypoPT manifestations/cardiovascular condition). There were 72 pts in the rhPTH(1–84) cohort and 174 in the control cohort. Before the index date, pts in the rhPTH(1–84) cohort, compared with the control, were younger (mean±SD, 47.5±11.0 vs 53.9±15.5 yrs; P

Background: Chronic hypoparathyroidism (HypoPT) managed with conventional therapy (i.e., oral calcium and active vitamin D) may increase the risk of nephrolithiasis and nephrocalcinosis. This study evaluated whether HypoPT is associated with increased risk of these conditions. Methods: A retrospective cohort study was conducted to compare the risk of nephrolithiasis and nephrocalcinosis between chronic HypoPT patients (excluding those receiving parathyroid hormone) and randomly selected non-HypoPT patients over 5 years of follow-up using a large US commercial claims database (Q1 2007 - Q2 2017). The first date of follow up (i.e., index date) for HypoPT patients was the earliest HypoPT diagnosis date at least 6 months after the initial HypoPT diagnosis and for non-HypoPT patients was the date of a randomly selected medical claim. Patient characteristics at baseline (the 6 months prior to index date) were compared between cohorts. The risk of nephrolithiasis (identified by diagnosis and procedure codes) was compared between cohorts using Kaplan-Meier analysis and adjusted Cox proportional hazards models. Adjusting parameters included demographic (age, sex, race, region, and index year) and clinical (nephrolithiasis, gout, hypercalciuria, hypertension, diabetes, and thiazide diuretic use) characteristics at baseline. Similar analyses were conducted for nephrocalcinosis, among those without the condition at baseline. Adjusting parameters included demographic information and hypercalciuria. A sensitivity analysis for nephrocalcinosis was conducted among those with study period kidney imaging. Results: A total of 8,097 chronic HypoPT patients and 40,485 non-HypoPT patients were included. Compared to non-HypoPT patients, HypoPT patients were older (58.6 vs. 47.3 years), a higher proportion were female (76.2 vs. 54.4%), and higher proportions had nephrolithiasis (3.3 vs. 1.3%), nephrocalcinosis (0.6 vs.

Background: Chronic hypoparathyroidism (HypoPT) managed with conventional therapy (i.e., oral calcium and active vitamin D) may potentially increase the risk of cardiovascular (CV) conditions. This study evaluated whether chronic HypoPT is associated with increased risk of various CV conditions. Methods: A retrospective cohort study was conducted to compare the risk of CV conditions between chronic HypoPT patients (excluding those receiving parathyroid hormone) and randomly selected non-HypoPT patients over 5 years of follow-up using a large US commercial claims database (Q1 2007 - Q2 2017). CV conditions in this analysis included atrial fibrillation (AF), cerebrovascular disease, coronary artery disease (CAD), heart failure (HF), peripheral vascular disease (PVD), tachyarrhythmia, and a composite endpoint of related pathophysiology (i.e., cerebrovascular disease, CAD, HF, and PVD). The first date of follow-up (i.e., index date) for HypoPT patients was the earliest HypoPT diagnosis date at least 6 months after the initial HypoPT diagnosis and for non-HypoPT patients was the date of a randomly selected medical claim. Patient characteristics at baseline (the 6 months prior to index date) were compared between cohorts. Among those free of each CV condition at baseline, the risks of first occurrence of each condition during the study period were compared using Kaplan-Meier analysis and adjusted Cox proportional hazards models. Adjusting parameters included demographic (age, sex, race, region, and index year) and clinical (other comorbid CV conditions, chronic kidney disease, hypertension, and diabetes) characteristics at baseline. Results: A total of 8,097 HypoPT and 40,485 non-HypoPT patients were included. Overall, HypoPT patients were older (58.6 vs. 47.3 years), a higher proportion were female (76.2 vs. 54.4%), and a higher proportion had AF (6.0 vs. 2.7%), cerebrovascular disease (6.0 vs. 3.0%), CAD (9.6 vs. 5.3%), HF (5.9 vs. 2.4%), PVD (7.4 vs. 2.8%), and tachyarrhythmia (0.7 vs. 0.4%) at baseline. Kaplan-Meier analyses showed that HypoPT patients had increased risk of new occurrence of each CV condition and the composite CV endpoint compared to non-HypoPT patients (all p

Background: Hypoparathyroidism (HP) is characterized by insufficient levels of parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, hypercalciuria, and a reduced quality of life (QoL). PTH replacement therapy should restore physiologic levels of PTH and restore downstream physiologic levels of calcitriol, promoting independence from Ca and active vitamin D supplements and normalization of QoL. TransCon PTH is an investigational long-acting prodrug of PTH(1–34) for the treatment of HP. During the initial 4-week fixed-dose period of the PaTH Forward Trial, TransCon PTH enabled 82% of subjects to achieve independence from standard of care (SoC; no active vitamin D and Ca ≤ 500 mg/day) compared to 15% with placebo. Here, we report 6-month (Week 26) results from the open-label extension (OLE). Methods: PaTH Forward is a phase 2, double-blind, placebo-controlled trial evaluating TransCon PTH in adult HP patients treated with SoC. Subjects received fixed doses of TransCon PTH 15, 18, or 21 µg PTH(1–34)/day or placebo for 4 weeks, followed by an OLE period during which TransCon PTH dose was titrated (6–30 µg PTH[1–34]/day) per individual dosing requirement. Safety and efficacy endpoints were evaluated at predefined timepoints over the OLE. Endpoints were evaluated at Week 26 including 1) sCa, 2) 24-hour uCa, 3) independence from active vitamin D, and 4) independence from therapeutics doses of oral calcium. QoL was assessed by the SF-36 and the Hypoparathyroidism Patient Experience Scales (HPES). Results: All 59 subjects completed the initial 4-week period and continued in the OLE; 58 subjects continue in the OLE beyond 6 months (1 withdrew unrelated to safety or efficacy). TransCon PTH enabled independence from SoC (no active vitamin D and Ca ≤ 500 mg/day) in 91% of subjects and independence from all supplements (no active vitamin D and no Ca) in 76% of subjects by Week 26. Mean 24-hour uCa decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while maintaining sCa, and reducing sP and CaxP to fall within the normal range. The mean scores for all SF-36 summary and domains increased from below normal at baseline to within the normal range by Week 26. The HPES Symptom and Impact scores continuously improved through 26 weeks for TransCon PTH and placebo subjects switching to TransCon PTH. TransCon PTH continued to be well-tolerated with no treatment-related serious or severe adverse events. Conclusions: Results from the OLE of the PaTH Forward Trial demonstrated that TransCon PTH continued to enable independence from active vitamin D and Ca supplements for most subjects while maintaining normal sCa, sP, uCa, and demonstrating enhanced quality of life, supporting its potential as a hormone replacement therapy for patients with HP. TransCon PTH will be further evaluated in the phase 3 PaTHway Trial.

Patients (pts) with chronic hypoparathyroidism are at increased risk of renal complications. This study evaluated chronic kidney disease (CKD) outcomes over a period of up to 5 years in adult pts with chronic hypoparathyroidism treated with recombinant human parathyroid hormone (1–84), rhPTH(1–84), compared with a historical control cohort of pts who did not receive rhPTH(1–84). The cohort of pts with chronic hypoparathyroidism treated with rhPTH(1–84) was derived from the NCT00732615 (REPLACE), NCT01268098 (RELAY), NCT01297309 (RACE) and NCT01199614 (HEXT) clinical trials. The control cohort of adult pts who did not receive rhPTH(1–84) or rhPTH(1–34) was selected from the US Explorys electronic medical record database (Jan 2007−Aug 2019), using criteria similar to the enrollment criteria used in the trials. Index date was the day after treatment initiation for the rhPTH(1–84) cohort, and the day after the first calcitriol prescription for the control cohort. Pts with CKD at baseline (defined as estimated glomerular filtration rate [eGFR]