The PaTHway clinical trial demonstrated sustained efficacy, safety, and tolerability of daily palopegteriparatide in the treatment of adults with hypoparathyroidism. Palopegteriparatide treatment was also associated with improvements in estimated glomerular filtration rate (eGFR) over 52 wk in a post hoc analysis, prompting further exploration of palopegteriparatide in the preservation of renal function. The current post hoc analysis evaluated the impact of palopegteriparatide treatment on renal function in adults with hypoparathyroidism through Week 104; as with prior analysis, changes in renal function were assessed using eGFR. At Week 104, 93% (76/82) of participants remained in the open-label extension. Of those, 82% had albumin-adjusted serum calcium levels in the normal range (8.3-10.6 mg/dL), 97% were independent from conventional therapy (≤600 mg/d of elemental calcium and no active vitamin D). Mean (SD) serum phosphate (3.5 (0.7) mg/dL) and albumin-adjusted calcium × phosphate product (30.7(5.1) mg2/dL2) levels were also within normal ranges. Palopegteriparatide treatment resulted in a mean (SD) increase in eGFR of 8.9 (11.0) mL/min/1.73m2 (p < .0001) from baseline to Week 52, which was sustained through Week 104, where it was 77.8 (14.8) mL/min/1.73 m2 with a mean (SD) change from baseline of 9.0 (10.3) mL/min/1.73 m2 (p < .0001). By Week 104, 45% and 34% of participants had an increase in eGFR of ≥5 mL/min/1.73 m2 and ≥10 mL/min/1.73 m2, respectively. Palopegteriparatide treatment normalized mean (SD) 24-h urine calcium within 26 wk and maintained levels below 250 mg/d through Week 104 (158.8 (90.5) mg/24 h). Most treatment-emergent adverse events were mild or moderate; no new safety signals or cases of treatment-related nephrolithiasis were reported. These findings demonstrate sustained renal safety of palopegteriparatide and suggest that PTH replacement therapy with palopegteriparatide preserves and may improve renal function in adults with chronic hypoparathyroidism after 104 wk of treatment.

We describe a family with 11 members affected by oral, facial and digital findings, as well as adult-onset multiple long bone insufficiency fractures mimicking atypical femur fractures (AFF) on radiographs. The analysis of the pedigree of this family suggested an X-linked dominant inheritance. We performed whole-exome sequencing in this family. A rare novel variant, p.Ala642Asp (NM_003611, c.1925C>A, hg19) of the OFD1 gene was the only candidate on the X chromosome segregating with the phenotype within the family. The OFD1 gene targeted sequencing was carried out on 49 patients with AFF and 100 healthy controls. We detected another rare variant, p.Lys668Asn (NM_003611, c.2004G>C, hg19) of the OFD1 gene, in a woman with AFF. The structure of OFD1 protein has been predicted by AlphaFold 3 (AF3). According to the AF3 model of OFD1, the destabilization of the dimerization of OFD1 by the p.Ala642Asp variant and the breaking of ionic bond by the p.Lys668Asn variant could be pathogenic. This family demonstrates that such insufficiency fractures of long bones may occur in patients with oral-facial-digital syndrome and provides novel insight into the pathophysiology of these fractures and their association with dental and facial hypoplasia.

Strategies to reduce weight in people living with obesity (PwO) include calorie restriction, metabolic and bariatric surgery (MBS), and anti-obesity drugs, including glucagon-like peptide-1 receptor agonists (GLP-1Ra). Although weight loss in PwO has many health benefits, it can result in increased bone loss and fracture risk. Indeed, the consequences of weight loss interventions are well known: (1) significant weight loss induced by caloric restriction and MBS results in high turnover bone loss and (2) unlike calorie restriction, PwO experience a substantial deterioration in bone microarchitecture and strength associated with an increased risk of fracture after MBS, especially malabsorptive procedures. GLP-1 may enhance bone metabolism and improve bone quality, and liraglutide appears to have a positive effect on bone health despite significant weight loss in several rodent models. However, most of the positive effects on bone have been observed at concentrations much higher than those approved for obesity care in humans. The effects of GLP-1Ra on bone health in PwO are still limited; however, significant weight loss induced by GLP-1Ra may also result in accelerated bone turnover and bone loss, and semaglutide could lead to an increased risk of fractures in the at-risk population. The mechanisms responsible for the adverse skeletal effects of MBS are not yet fully understood, and there are insufficient human studies supporting pathophysiological hypotheses. However, data suggest that multiple mechanisms are involved, including nutritional factors, mechanical unloading, hormonal factors, adipokines, and alterations in the gut microbiome. Recommendations for the prevention and treatment of osteoporosis secondary to MBS are now available, and the efficacy of anti-osteoporosis medications in preventing bone loss has been evaluated in two randomized controlled trials. Priorities for future research include the development of effective approaches to reduce fracture risk in PwO following MBS and investigation of the effects of anti-obesity drugs on bone health.

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

The guideline panel, comprising international experts in X-linked hypophosphatemia (XLH), patient partners from the XLH patient population, and guideline methodologists, held 18 teleconferences between January 2023 and July 2024 to develop comprehensive guidelines for the diagnosis and management of XLH in children and adults. For a subset of our questions, we utilized the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, assessed the certainty of evidence and formulated GRADEd recommendations. For these questions, the panelists and methodologists collaboratively framed PICO (Population, Intervention, Control, and Outcomes) questions and conducted four systematic reviews assessing the impact of medical therapy—using either burosumab or phosphate and active vitamin D—on patient-important outcomes in the XLH population as well as the impact of medical intervention compared to no treatment. We assessed the risk of bias and transparently generated summary of findings tables using MAGICApp. The panel developed three GRADEd treatment recommendations for adults and two for children. Each GRADEd recommendation was linked to an underlying body of evidence, reflecting judgments on the certainty of evidence, recommendation strength, values, preferences, and considerations of costs, feasibility, acceptability, and equity. Due to the paucity of evidence, the panel developed very low-quality GRADEd recommendations on monitoring patients with XLH based on an expert clinical practice survey. Using a rigorous narrative literature review, the panel developed non-GRADEd recommendations including guidance for pregnant women, patients with dental complications, and other areas where evidence is limited. This article summarizes the methodology utilized for the development of both GRADEd and non-GRADEd recommendations for patients with XLH.

This report provides recommendations for X-linked hypophosphatemia (XLH) monitoring based on current monitoring practices of experts in the management of XLH in children (<18 years) and adults. We surveyed 43 international experts in XLH to determine their monitoring practices for children and adults with XLH, including pregnant and lactating women. In the initial evaluation of children and adults with XLH, experts consistently obtain a family history of XLH or hypophosphatemia, a history of fractures and dental infections, and assess pain through age-appropriate clinical interviews or caregiver reports. They measure height, weight, and blood pressure and conduct DNA analysis of multiple genes associated with hypophosphatemia including the PHEX gene. For children follow-up, experts arrange follow-up every 3 to 6 months assessing height, weight, and blood pressure and examining for skeletal deformities. Laboratory tests in children include serum phosphorus, corrected total/ionized calcium, alkaline phosphatase, renal function, and PTH and spot morning urine for calcium, creatinine, and phosphorus. During adult follow-up, experts assess patients every 6 to 12 months, with a clinical examination focused on skeletal deformities and joint involvement. The laboratory profile is completed at least once a year. In the presence of bone pain, experts conduct X-rays both in children and adults to evaluate for fractures or joint damage. With respect to nephrocalcinosis, renal ultrasound is suggested on an annual basis or less frequently when monitoring children and adults with XLH. Experts conduct a dental assessment at baseline and then every 6 to 12 months for all patients with XLH. The findings of the survey inform practice for assessing new patients with XLH, monitoring existing patients, and identifying areas for future research. All recommendations based on these practices are weak with very low-quality evidence.

CONTEXT:An International Working Group (IWG) developed new guidelines on the diagnosis, evaluation, management, and monitoring of X-linked hypophosphatemia (XLH) in children. Over the past 5 years, important advances have occurred in our understanding of the presentation, complications, and treatment of XLH. METHODS:A group of 50 international experts in XLH from Canada, the United States, Europe, Asia, and South America, along with methodology experts and a patient partner, held 18 teleconference meetings in 2023-2024. These meetings addressed key issues regarding diagnosing, evaluating, managing, and monitoring XLH in children. Two systematic reviews were conducted to examine the impact of burosumab compared to conventional therapy (phosphate salts and active vitamin D) or no therapy, and to assess the impact of conventional therapy vs no therapy on patient-important outcomes. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Additionally, narrative reviews were completed on XLH diagnosis and the role of genetic testing, and an expert clinical practice survey informed the monitoring recommendations. OUTCOMES:An approach to establishing the diagnosis of XLH is presented. GRADEd recommendations were developed on treatment strategies for XLH in children. Monitoring recommendations, GRADEd as weak with very low certainty, were based on clinical practice survey of the IWG experts. The guidelines also addressed dental complications and proposed potential strategies to mitigate them. CONCLUSION:These clinical practice guidelines provide an update of the current evidence on the diagnosis and management of XLH and provide a comprehensive guidance for multidisciplinary healthcare professionals involved in the care of children with XLH.

Introduction Palopegteriparatide is a prodrug of PTH(1-34), administered once daily, designed to provide active PTH within the physiological range for 24hours/day. It is approved in the US, EU, and several other countries. This analysis evaluated the long-term efficacy and safety of palopegteriparatide in adults with chronic hypoparathyroidism through week 156 of PaTHway, a phase 3 trial with a 26-week randomized, double-blind, placebo-controlled period, followed by an open-label extension. 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≤600mg/day elemental calcium) and 88% had normal albumin-adjusted serum calcium (2.07–2.64mmol/L) with a mean (SD) of (2.2 [0.2] mmol/L). Mean (SD) serum phosphate (1.1 [0.2] mmol/L) and calcium×phosphate product (2.5 [0.4] mmol2/L2) remained within normal ranges. Mean (SD) eGFR was 78.0 (14.5) mL/min/1.73m2, reflecting a mean (SD) increase of 8.8 (11.9) mL/min/1.73m2 from baseline (P<0.0001); 59% and 43% of participants had an increase in eGFR of≥5mL/min/1.73m2 and≥10mL/min/1.73m2, respectively. Mean (SD) 24-hour urine calcium levels normalized with palopegteriparatide treatment, remaining below the upper limit of normal (≤250mg/day) through week 156 (162.1 [117.8] mg/day). TEAEs were mostly grade 1 or 2, with no new safety signals identified. Discussion 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.

Obesity and diabetes are interlinked diseases, but it was unclear how obesity vs. diabetes modifies the risk and severity of gut bacterial infection. We aimed to determine how obesity or hyperglycemia, indicative of diabetes, altered metabolic endotoxemia and severity of enteric infection. Metabolic endotoxemia was determined using TLR4 activity reporter assay in serum from humans with obesity or diabetes, and from hyperglycemic Akita+/- mice and genetically obese ob/ob mice. Diarrhea severity during Escherichia coli infection was determined in humans during a previous community outbreak. The enteropathogen Citrobacter rodentium was used to define the mechanisms of action that altered the severity of enteric infection in ob/ob and Akita+/- mice. We found that elevated blood glucose, indicative of diabetes, was associated with increased occurrence and severity of diarrhea during an E. coli outbreak in humans. Metabolic endotoxemia occurred in a separate cohort of people with obesity who were normoglycemic or hyperglycemic, and in mice with either obesity or hyperglycemia. Hyperglycemia, not obesity, increased mortality during infection with the diarrhea-causing pathogen C. rodentium in mouse models of type 1 and type 2 diabetes. Common indicators of poor prognosis, such as gut pathology, systemic bacteraemia, or metabolic endotoxemia, did not predict worse outcomes during enteric infection in diabetic mice. Hyperglycemia activated intestinal Wnt/β-catenin and increased mortality, which could be reversed by blocking Wnt/β-catenin, lowering blood glucose, or restoring fluid balance during infection. The increased severity of infection via overactivation of intestinal Wnt/β-catenin during hyperglycemia may be a potential target for therapeutics.NEW & NOTEWORTHY We show that elevated blood glucose is associated with worse diarrhea during an Escherichia coli outbreak in humans. Obesity or hyperglycemia was sufficient to promote metabolic endotoxemia in humans and mice. Hyperglycemia promotes worse enteric infection outcomes independent of obesity. Finally, we showed that blocking of Wnt/β-catenin, lowering blood glucose, or restoring fluids improved enteric infection outcomes in hyperglycemic mice.

PURPOSE:An international working group (IWG) consisting of experts in X-linked hypophosphatemia (XLH) developed global guidelines providing a comprehensive, evidence-based approach to XLH diagnosis, management, and monitoring. METHODS:The IWG, consisting of 43 members as well as methodologists and a patient partner, conducted 2 systematic reviews (SRs) and narrative reviews to address key areas. The SRs addressed the impact of burosumab compared to conventional therapy (phosphate and active vitamin D) or no therapy on patient-important outcomes in adults. They also evaluated conventional therapy compared to no therapy. GRADE methodology was applied to evaluate the certainty of evidence. Non-GRADED recommendations were made in the presence of insufficient evidence to conduct SRs. These guidelines have been reviewed and endorsed by several medical and patient societies and organizations. RESULTS:The diagnosis of XLH is based on integrating clinical evaluation, laboratory findings confirming renal phosphate wasting (following exclusion of conditions mimicking XLH), and skeletal imaging. Fibroblast growth factor 23 measurement and DNA analysis are of value in the diagnosis, if available. Pathogenic or likely pathogenic variants in the PHEX gene are confirmatory but not necessary for the diagnosis. Management requires a multidisciplinary team knowledgeable and experienced in XLH. Effective medical therapy with burosumab can improve fracture and pseudofracture healing. MAIN CONCLUSION:In adults with XLH and fractures or pseudofractures, burosumab is recommended over no therapy (strong recommendation, GRADEd). Additionally, burosumab is suggested as the preferred treatment compared to conventional therapy (conditional recommendation, GRADEd) in the absence of fractures or pseudofractures. If burosumab is not available, symptomatic adults should be treated with conventional therapy (Non-GRADEd recommendation).

OBJECTIVES:Real-world data on diabetes management among a heterogenous aging population remain limited. This study aims to provide an overview of technology use and factors associated to its use, diabetes management, and psychosocial aspects experienced by adults aged 50 and over living with type 1 diabetes or latent autoimmune diabetes in adults. METHODS:This cross-sectional study analyzed data from the Canadian BETTER registry, mostly based on self-reported outcomes from individuals living with type 1 diabetes or latent autoimmune diabetes in adults. Comparative analyses were conducted across 3 age groups: 50-59, 60-69, and ≥ 70. RESULTS:Participants (n = 674) were predominantly Caucasian (97% to 98% across groups) and residing in Quebec, Canada (71% to 79%). Insulin pump use was similar across age groups (36% to 39%, P = .822), while continuous glucose monitoring was lower among those aged ≥ 70 years (85% for both 50-59 and 60-69 vs 73% for ≥ 70 years, P = .020). Among other factors, having private insurance and living outside of Quebec were positively associated with both insulin pump and continuous glucose monitoring use. A high proportion (80% to 86%) of participants achieved an HbA1c ≤ 8% across all groups. Level 2 hypoglycemia events in the last month were more frequent among participants aged 50-59 years compared to those aged ≥70 years (6.9 vs 3.4, P = .001). Level 3 hypoglycemia, social and professional support were similar between groups. Interestingly, diabetes-related distress was lower in older age groups. CONCLUSIONS:Most individuals in this cohort adopted technology use but in lower proportion among the group aged ≥70. Overall, diabetes management was good and similar between age groups.

L-lactate participates in metabolism, including the Cori cycle, but less is known about D-lactate. We found that circulating D-lactate was higher in humans and mice with obesity. D-lactate increased hepatic glycogen, triglycerides, and blood glucose more than equimolar L-lactate in mice. Stable isotope analyses showed that D-lactate is metabolized in mice and in hepatocytes to pyruvate, TCA intermediates, lipids, and glucose. The gut microbiota is the main source of blood D-lactate. Colonization of mice with a bacterial strain that produced D-lactate elevated blood glucose more than an L-lactate producer. Oral delivery of a biocompatible polymer that traps gut D-lactate, forcing fecal excretion, lowered blood glucose and insulin resistance in obese mice in a polymer length- and dose-dependent manner. This D-lactate trap lowered hepatic inflammation and fibrosis in mice with metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatohepatitis (MASH). Therefore, microbial-derived D-lactate contributes to host glucose and lipid metabolism and can be trapped to improve metabolic disease during obesity.

Background: Maple syrup, a minimally transformed sweetener rich in polyphenols, can exert a action and improve metabolic parameters in animal models. However, no randomized clinical trial has investigated this. Objectives: This study aims to determine whether replacing refined sugars with an equivalent quantity of maple syrup could decrease key cardiometabolic risk factors in individuals with mild metabolic alterations. Methods: In a randomized, double-blind, controlled crossover trial with 42 overweight adults with mild cardiometabolic alterations, participants were instructed to substitute 5% of their total caloric intake from added sugars with either maple syrup or an artificially flavored sucrose syrup for 8 wk. The primary outcome included changes in glucose homeostasis, whereas secondary outcomes were changes in other cardiometabolic risk factors such as blood pressure, anthropometric indices, and blood lipid profiles. Exploratory outcomes involved analyzing changes in gut microbiota composition. Results: Replacing refined sugars with maple syrup over 8 wk decreased the glucose area under the curve when compared with substituting refined sugars with sucrose syrup, as determined during the oral glucose tolerance test, leading to a significant difference between the intervention arms (-50.59 +/- 201.92 compared with 29.93 +/- 154.90; P < 0.047). Substituting refined sugar with maple syrup also significantly decreased android fat mass (-7.83 +/- 175.05 g compared with 67.61 +/- 206.71 g; P = 0.02) and systolic blood pressure (-2.72 +/- 8.73 mm Hg compared with 0.87 +/- 8.99 mm Hg; P = 0.03). No changes in the blood lipid profile were observed. As an exploratory outcome, we further observed that substituting refined sugars with maple syrup promoted selective taxonomic changes in the gut microbiota such as a significant reduction in the abundance of Klebsiella species and decreased microbial functions associated with bacterial-induced cytokine response, when compared with substitution with sucrose syrup. Conclusions: Substituting refined sugars with maple syrup in individuals with mild metabolic alterations result in a significantly greater reduction of key cardiometabolic risk factors compared with substitution with sucrose syrup, in association with specific changes in gut microbiota. The role of the gut microbiota in these effects remains to be further explored.

Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism. PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR < 60 or ≥ 60 mL/min/1.73 m2. At week 52, over 95

Context: Conventional therapy for hypoparathyroidism aims to alleviate symptoms of hypocalcemia but does not address insufficient parathyroid hormone (PTH) levels. Objective: Assess the long-term efficacy and safety of TransCon PTH (palopegteriparatide) for hypoparathyroidism. Design: Phase 3 trial with a 26-week, double-blind, placebo-controlled period followed by a 156-week, open-label extension (OLE). Setting: Twenty-one sites across North America and Europe. Participants: A total of 82 adults with hypoparathyroidism were randomized and received study drug and 78 completed week 52. Intervention(s): All OLE participants received TransCon PTH administered once daily. Main Outcome Measure(s): Multicomponent efficacy endpoint: proportion of participants at week 52 who achieved normal serum calcium (8.310.6 mg/dL) and independence from conventional therapy (<= 600 mg/day of elemental calcium and no active vitamin D). Other efficacy endpoints included patient-reported outcomes and bone mineral density. Safety was assessed by 24-hour urine calcium and treatment-emergent adverse events. Results: At week 52, 81% (63/78) met the multicomponent efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. Patient-reported outcomes showed sustained improvements in quality of life, physical functioning, and wellbeing. Mean bone mineral density Z-scores decreased toward age- and sex-matched norms from baseline to week 52. Mean (SD) 24-hour urine calcium excretion decreased from 376 (168) mg/day at baseline to 195 (114) mg/day at week 52. Most treatment-emergent adverse events were mild or moderate and none led to trial discontinuation during the OLE. Conclusion: At week 52 of the PaTHway trial, TransCon PTH showed sustained efficacy, safety, and tolerability in adults with hypoparathyroidism.

Context: Renin-angiotensin-aldosterone system (RAAS) activation is closely linked to obesity; however, the sex-specific associations between RAAS activity and body composition among individuals without obesity are not well understood. Objective: To investigate the associations of aldosterone and renin with body composition according to sex in the general population. Design: Population-based cohort study. Setting: Qu & eacute;bec (Canada). Participants: Adults aged 40 to 69 years enrolled in CARTaGENE between 2009 and 2010 (N = 3687). Exposures: Plasma aldosterone and renin concentrations. Main Outcome: Measures Body composition assessed via anthropometrics (waist circumference and waist-to-hip ratio), bioelectrical impedance (lean body mass, fat mass, and muscle mass), and cardiac magnetic resonance imaging (epicardial and pericardial adipose tissue volumes). Results: The mean (SD) age and body mass index were 55 (8) years and 27.3 (4.8) kg/m(2), respectively. Among males, higher aldosterone and renin were associated with increased waist circumference, increased waist-to-hip ratio, increased fat mass, decreased lean body mass, and decreased muscle mass (P < .05). Aldosterone (P = .02), but not renin (P = .43), was associated with increased ectopic cardiac adiposity in males. In contrast, higher renin (P < .05), but not aldosterone (P >= .05), was associated with increased waist circumference, increased waist-to-hip ratio, and increased cardiac adiposity in females. Among females, higher renin and aldosterone were associated with increased fat mass (P < .05) but were not associated with lean body mass or muscle mass (P >= .05). All aforementioned associations were independent of body weight. Conclusion: Independent of body weight, increased RAAS activity is associated with unfavorable differences in body composition; however, the strength and pattern of association varies by sex.