Context Individuals with hypoparathyroidism experience a range of physical and cognitive symptoms and reduced quality of life (QoL) despite management with conventional therapy (active vitamin D and calcium). Objective This analysis investigated the long-term impact of parathyroid hormone (PTH) replacement therapy with palopegteriparatide (YORVIPATH®) on symptoms, daily functioning, and well-being in adults with chronic hypoparathyroidism. Associations between patient characteristics and changes in patient-reported outcomes (PROs) were also analyzed. Methods PaTH Forward was a phase 2 clinical trial of palopegteriparatide with a 4-week randomized, double-blind, placebo-controlled period followed by an open-label extension period lasting through trial week 266. PRO measures were collected at baseline, weeks 4, 12, 26, 58, and annually thereafter through the end of the trial. The Hypoparathyroidism Patient Experience Scales (HPES) assess disease-specific symptoms and impacts on functioning and well-being. The Short Form Health Survey (SF-36v2) measures general health-related QoL. Data were analyzed using descriptive statistics and Mixed Models for Repeated Measures. Results Palopegteriparatide treatment demonstrated significant improvements from baseline in disease-specific symptoms and impacts on daily functioning and well-being at week 12, which were sustained through week 110. Mean changes in PROs met thresholds for clinically meaningful within-patient improvement. Significant improvements in general health-related QoL were also shown in SF-36v2 scores. Results were generally similar across demographics and patient characteristics. Conclusion Through week 110 of the PaTH Forward trial, PTH replacement therapy with palopegteriparatide was associated with significant improvements in disease-specific symptoms and impacts on daily functioning and well-being, as well as general health-related QoL.

BACKGROUND & AIMS:Vitamin D affects immune function and is associated with lower COVID-19 risk in observational studies. However, randomized clinical trials vary in whether they find vitamin D supplementation affects COVID-19 risk. The objective of this trial was to determine whether moderate or high dose vitamin D (4000 or 10,000 IU/day) versus low dose vitamin D (400 IU/day) affects COVID-19 risk. METHODS:We conducted a double-blind, parallel-group randomized trial (clinicaltrials.gov, NCT0486890) enrolling participants from December 5, 2020 to May 23, 2023 who chose between study branches comparing moderate versus low dose or high versus low dose vitamin D for up to 9 months and were randomized between the doses in their chosen branch. Recruitment occurred at UChicago Medicine or Rush University Medical Center. Eligibility criteria excluded persons with increased risk from vitamin D supplementation. Recruitment concluded March 30, 2023, with 955 participants randomized, and 923 continuing their participation until receipt of study vitamin D, including 324 high-versus-low branch participants. The primary outcome was time from randomization to COVID-19 infection. RESULTS:COVID-19 risk was not lower for pooled moderate or high versus low dose (10.9% (50/461) versus 14.7% (68/462), aHR:0.73; 95%-CI:0.51-1.06; P = 0.10). In prespecified secondary analyses, COVID-19 risk was lower for moderate versus low dose (aHR:0.62; 95%-CI:0.39-0.99; P = 0.045) but not high versus low dose (aHR:0.99; 95%-CI:0.53-1.86; P = 0.98). Prespecified time-varying analyses controlling for post-randomization 25(OH)D levels found similar treatment effects, with no effects of 25(OH)D levels on risk. In a final prespecified analysis, among 130 seroconverting participants, COVID-19 was not reported less for pooled moderate or high versus low dose (aOR:0.62; 95%-CI:0.27-1.41; P = 0.25) and moderate versus low dose (aOR:0.37; 95%-CI:0.13-1.04; P = 0.06). CONCLUSION:Moderate or high versus low dose vitamin D supplementation did not decrease COVID-19 risk, but effects may vary by dose. Further study is warranted of the effects of higher doses and 25(OH)D levels on COVID-19 and other viral respiratory tract infections, and whether these infections become clinically evident. TRIAL REGISTRATION:clinicaltrials.gov, NCT04868903, https://clinicaltrials.gov/study/NCT04868903.

Hypoparathyroidism is an endocrine disease caused by insufficient levels of parathyroid hormone (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, ≤500 mg/d calcium) and maintained serum biochemistries within normal ranges. The current analyses describe patterns of change in bone mineral density (BMD), serum bone turnover markers, and serum and urine calcium in adults with chronic hypoparathyroidism treated with palopegteriparatide through 3 yr of the PaTH Forward trial. Baseline BMD Z-scores for the lumbar spine, total hip, femoral neck, 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 wk 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.

FRAX is poorly validated in Black and Hispanic people in the United States. We recently demonstrated that FRAX underestimated fractures in Black and Hispanic patients with diabetes (DM), but it is not known if this is a diabetes-specific issue. We sought to compare the performance of the original FRAX (oFRAX) without BMD and a hypothetical race-neutral FRAX (rn-FRAX) in a retrospective multiethnic cohort of patients with DM and control patients with hypertension (HTN). We specifically sought to compare performance across race. Patients were included if they were followed for DM or HTN in the health system and averaged at least 1 visit per year. Incident major osteoporotic fractures (MOFs) and FRAX inputs were collected using diagnosis codes or medication data. A rn-FRAX was created using U.S. census data. Performance was compared using measures of discrimination (area under the curve, AUC) and calibration (observed-to-predicted ratios, O/P). There were 17,400 Black (45.4% DM), 9,865 White (35.3% DM), and 1,196 Hispanic (57.9% DM) patients included. Discrimination was similar for oFRAX and rn-FRAX (AUC 0.72-0.73). In DM patients, the O/P was 1.4 for oFRAX and 1.0 for rn-FRAX. By race, we found good performance for both calculators in White patients (O/P 0.8-1.2). In Black patients, oFRAX underestimated risk (O/P 1.3-2.3). Conversely, rn-FRAX overestimated risk in Black women (O/P 0.7-0.8) but performed well in Black men (O/P 0.9-1.1). In Hispanic patients, oFRAX substantially underestimated fractures (O/P 1.8-2.4), and this was only partially alleviated by rn-FRAX (O/P 1.2-1.6). In conclusion, we found that the current FRAX without BMD significantly underestimated major osteoporotic fractures in Black and Hispanic patients, while a hypothetical race-neutral FRAX improved performance overall. Our findings suggest the current adjustments for race in U.S. FRAX may not be necessary or, if maintained, need to be updated.

Objective: Black patients fracture less often than White patients at any given bone mineral density (BMD). This may be related to superior bone structure; however, bone structure is challenging to measure in clinical practice. Advances in 3-dimensional (3D) modeling have allowed for the measurement of trabecular and cortical parameters from dual-energy x-ray absorptiometry (DXA). This technology, known as 3D-DXA, may provide a way to assess hitherto unexplained differences in bone structure between Black and White patients. Methods: This is a secondary analysis of 775 women (368 Black and 407 White) previously recruited from an osteoporosis clinic. All women had undergone DXA and vertebral fracture assessment, and 3D-DXA was run retrospectively on the proximal femur BMD scan. Participants were classified as having a prior fracture if there was a fracture on vertebral fracture assessment or a self-reported history of fragility fracture. Results: Black women had generally superior 3D-DXA parameters, with the largest differences in cortical thickness of the femoral neck (FN) and buckling ratio of the FN. There were substantial differences in associations between fracture and 3D-DXA parameters in Black women compared with White women. After adjusting for age, glucocorticoids, and areal BMD T-score, cortical thickness of the FN was significantly associated with prior fracture (odds ratio, 1.4 per standard deviation decline; 95% CI, 1.0-1.9; P 1/4 .04) in Black women but not White women. Conclusion: 3D-DXA parameters were superior in Black women than in White women, and cortical thickness of the FN was associated with fractures only in Black women. 3D-DXA may improve fracture risk assessment in Black patients. (c) 2024 AACE. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

OBJECTIVE:To describe clinical and biochemical characteristics, including health-related quality of life (HRQoL), in patients with chronic hypoparathyroidism (cHypoPT) who were receiving conventional therapy (calcium and active vitamin D), and to compare baseline HRQoL between patients who subsequently received recombinant human parathyroid hormone (1-84) (rhPTH [1-84]) and those who did not. DESIGN:Cross-sectional analysis of data recorded at enrollment (baseline) from patients with cHypoPT in the PARADIGHM registry before May 31, 2022. METHODS:Eligible patients were aged ≥18 years and receiving conventional therapy at enrollment. Health-related quality of life was measured using the 36-Item Short-Form Health Survey version 2 (SF-36v2), Work Productivity and Activity Impairment Specific Health Problem (WPAI:SHP) questionnaire, and the Hypoparathyroidism Symptom Diary (HypoPT-SD). RESULTS:Eligible patients (N = 1070) were mostly female (80.7%) and White (86.0%). Surgery was the most common cause of cHypoPT (82.2%). Mean serum albumin-adjusted calcium, phosphate, and calcium-phosphate product levels were within the target ranges. Mean (standard deviation [SD]) SF-36v2 physical and mental component scores were 46.3 (10.2) and 47.6 (11.5), respectively (normative scores: 50). Patients who went on to receive rhPTH (1-84) (n = 102) had significantly worse baseline HRQoL scores than patients in the conventional therapy group (n = 968) for all SF-36v2 and HypoPT-SD parameters and most WPAI parameters. There were no meaningful differences in biochemical parameters between the groups. CONCLUSIONS:Thirty-six-Item Short-Form Health Survey version 2 scores in patients with cHypoPT were lower than the normalized values reported previously for the US population. Patients who were subsequently prescribed rhPTH (1-84) had worse baseline HRQoL scores than those in the conventional therapy group.

OBJECTIVE:To assess the impact of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] compared with placebo, in combination with conventional therapy with vitamin D and/or calcium supplements, on health-related quality of life (HRQoL) in patients with symptomatic chronic hypoparathyroidism (cHypoPT). DESIGN:Randomized, double-blind, placebo-controlled, phase 3b-4 study (ClinicalTrials.gov ID: NCT03324880). METHODS:Eligible patients with symptomatic cHypoPT were randomized to receive subcutaneous rhPTH(1-84) 25-100 µg/day or placebo. The primary endpoint was the change from baseline to week 26 in Hypoparathyroidism Symptom Diary (HypoPT-SD) symptom subscale score. Key secondary endpoints were changes from baseline to week 26 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and in 36-item Short Form Health Survey physical component summary (SF-36v2 PCS). RESULTS:In total, 93 patients were randomized to receive treatment: 45 received rhPTH(1-84) and 48 received placebo. Change from baseline to week 26 in HypoPT-SD symptom subscale score was significantly greater (improved) in the rhPTH(1-84) group than in the placebo group (difference in least-squares mean changes, -0.53; 95% confidence interval, -0.90 to -0.15, P = .003). Key secondary endpoints, changes between baseline and week 26 in the FACIT-Fatigue and SF-36v2 PCS scores were also significantly greater (improved) in the rhPTH(1-84) group than in the placebo group. The safety profile of rhPTH(1-84) was consistent with previous findings, and no new safety signals were identified. CONCLUSIONS:rhPTH(1-84) alongside conventional therapy improved symptom burden (as measured by the HypoPT-SD) and HRQoL to a greater extent than conventional therapy alone in patients with symptomatic cHypoPT.

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.

Purpose Black patients fracture less than White patients at any given BMD. This may be related to superior bone structure; however, bone structure is challenging to measure in clinical practice. Advances in 3D modeling have allowed for the measurement of trabecular and cortical parameters from DXA. This technology, known as 3D-DXA, may provide a way to assess hitherto unexplained differences in bone structure between Black and White patients. Methods This is a secondary analysis of 775 women (368 Black, 407 White) previously recruited from an osteoporosis clinic. All women had undergone DXA and VFA, and 3D-DXA was run retrospectively on the proximal femur BMD scan. Participants were classified as having a prior fracture if there was a fracture on VFA or a self-reported history of fragility fracture. Results Black women had generally superior 3D-DXA parameters, with the largest differences in cortical thickness of the femoral neck (FN) and buckling ratio of the FN. There were substantial differences in associations between fracture and 3D-DXA parameters in Black as compared to White women. After adjusting for age, glucocorticoids, and areal BMD T-score, cortical thickness of the FN was significantly associated with prior fracture (OR 1.4 per standard deviation decline, 95% CI 1.0-1.9, p=0.04) in Black but not White women. Conclusion 3D-DXA parameters were superior in Black than White women, and cortical thickness of the femoral neck was associated with fractures only in Black women. 3D-DXA may improve fracture risk assessment in Black patients.

Information in the electronic health record (EHR), such as diagnoses, vital signs, utilization, medications, and laboratory values, may predict fractures well without the need to verbally ascertain risk factors. In our study, as a proof of concept, we developed and internally validated a fracture risk calculator using only information in the EHR. Fracture risk calculators, such as the Fracture Risk Assessment Tool, or FRAX, typically lie outside the clinician workflow. Conversely, the electronic health record (EHR) is at the center of the clinical workflow, and many variables in the EHR could predict fractures without having to verbally ascertain FRAX risk factors. We sought to evaluate the utility of EHR variables to predict fractures and, as a proof of concept, to create an EHR-based fracture risk model. Routine clinical data from 24,189 subjects presenting to primary care from 2010 to 2018 was utilized. Major osteoporotic fractures (MOFs) were captured by physician diagnosis codes. Data was split into training (n = 18,141) and test sets (n = 6048). We fit Cox regression models for candidate risk factors in the training set, and then created a global model using a backward stepwise approach. We then applied the model to the test set and compared the discrimination and calibration to FRAX. We found variables related to vital signs, utilization, diagnoses, medications, and laboratory values to be associated with incident MOF. Our final model included 19 variables, including age, BMI, Parkinson’s disease, chronic kidney disease, and albumin levels. When applied to the test set, we found the discrimination (AUC 0.73 vs. 0.70, p = 0.08) and calibration were comparable to FRAX. Routinely collected data in EHR systems can generate adequate fracture predictions without the need to verbally ascertain fracture risk factors. In the future, this could allow for automated fracture prediction at the point of care to improve osteoporosis screening and treatment rates.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Context Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled. Objective To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment. Methods This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices. Results Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 +/- 0.19 mmol/L at baseline (n = 49) to 1.3 +/- 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% +/- 113.6% and calcitriol by 74% +/- 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites. Conclusion 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.

Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 mu g/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and <= 600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. (c) 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

BackgroundOsteoporotic fracture prediction calculators are poorly utilized in primary care, leading to underdiagnosis and undertreatment of those at risk for fracture. The use of these calculators could be improved if predictions were automated using the electronic health record (EHR). However, this approach is not well validated in multi-ethnic populations, and it is not clear if the adjustments for race or ethnicity made by calculators are appropriate.ObjectiveTo investigate EHR-generated fracture predictions in a multi-ethnic population.DesignRetrospective cohort study using data from the EHR.SettingAn urban, academic medical center in Philadelphia, PA.Participants12,758 White, 7,844 Black, and 3,587 Hispanic patients seeking routine care from 2010 to 2018 with mean 3.8 years follow-up.InterventionsNone.MeasurementsFRAX and QFracture, two of the most used fracture prediction tools, were studied. Risk for major osteoporotic fracture (MOF) and hip fracture were calculated using data from the EHR at baseline and compared to the number of fractures that occurred during follow-up.ResultsMOF rates varied from 3.2 per 1000 patient-years in Black men to 7.6 in White women. FRAX and QFracture had similar discrimination for MOF prediction (area under the curve, AUC, 0.69 vs. 0.70, p=0.08) and for hip fracture prediction (AUC 0.77 vs 0.79, p=0.21) and were similar by race or ethnicity. FRAX had superior calibration than QFracture (calibration-in-the-large for FRAX 0.97 versus QFracture 2.02). The adjustment factors used in MOF prediction were generally accurate in Black women, but underestimated risk in Black men, Hispanic women, and Hispanic men.LimitationsSingle center design.ConclusionsFracture predictions using only EHR inputs can discriminate between high and low risk patients, even in Black and Hispanic patients, and could help primary care physicians identify patients who need screening or treatment. However, further refinements to the calculators may better adjust for race-ethnicity.