Khan, Aliya

ABSTRACT 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 μg/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. © 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). Abstract TransCon PTH is an investigational once-daily prodrug providing sustained release of active PTH designed to maintain stable PTH levels in the physiological range for 24 hours/day. The PaTHway trial met all primary and key secondary endpoints with statistically significant differences from placebo. Most adverse events (AEs) were mild/moderate. Injection-site reactions and headaches were the most common treatment-related AEs.

ABSTRACT This clinical practice guideline addresses the prevention, diagnosis, and management of hypoparathyroidism (HypoPT) and provides evidence-based recommendations. The HypoPT task forces included four teams with a total of 50 international experts including representatives from the sponsoring societies. A methodologist (GG) and his team supported the taskforces and conducted the systematic reviews. A formal process following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology and the systematic reviews provided the structure for seven of the guideline recommendations. The task force used a less structured approach based on narrative reviews for 20 non-GRADEd recommendations. Clinicians may consider postsurgical HypoPT permanent if it persists for >12 months after surgery. To predict which patients will not develop permanent postsurgical HypoPT, we recommend evaluating serum PTH within 12 to 24 hours post total thyroidectomy (strong recommendation, moderate quality evidence). PTH > 10 pg/mL (1.05 pmol/L) virtually excludes long-term HypoPT. In individuals with nonsurgical HypoPT, genetic testing may be helpful in the presence of a positive family history of nonsurgical HypoPT, in the presence of syndromic features, or in individuals younger than 40 years. HypoPT can be associated with complications, including nephrocalcinosis, nephrolithiasis, renal insufficiency, cataracts, seizures, cardiac arrhythmias, ischemic heart disease, depression, and an increased risk of infection. Minimizing complications of HypoPT requires careful evaluation and close monitoring of laboratory indices. In patients with chronic HypoPT, the panel suggests conventional therapy with calcium and active vitamin D metabolites as first-line therapy (weak recommendation, low-quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers the use of PTH. © 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).

ABSTRACT To develop guidelines for hypoparathyroidism and primary hyperparathyroidism, the panel assembled a panel of experts in parathyroid disorders, general endocrinologists, representatives of the Hypoparathyroidism Association, and systematic review and guideline methodologists. The guideline panel referred to a formal process following the Recommendations, Assessment, Development, and Evaluation Working Group (GRADE) methodology to issue GRADEd recommendations. In this approach, panelists and methodologists formatted the questions, conducted systematic reviews, evaluated risk of bias, assessed certainty of evidence, and presented a summary of findings in a transparent fashion. For most recommendations, the task forces used a less structured approach largely based on narrative reviews to issue non-GRADEd recommendations. The panel issued Eight GRADEd recommendations (seven for hypoparathyroidism and one for hyperparathyroidism). Each GRADEd recommendation is linked to the underlying body of evidence and judgments regarding the certainty of evidence and strength of recommendations, values and preferences, and costs, feasibility, acceptability and equity. This article summarizes the methodology for issuing GRADEd and non-GRADEd recommendations for patients with hypoparathyroidism or hyperparathyroidism. © 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).

ABSTRACT Both medical and surgical therapy represent potential management options for patients with asymptomatic primary hyperparathyroidism (PHPT). Because uncertainty remains regarding both medical and surgical therapy, this systematic review addresses the efficacy and safety of medical therapy in asymptomatic patients or symptomatic patients who decline surgery and surgery in asymptomatic patients. We searched Medline, Embase, Cochrane Central Register of Controlled Trials, and PubMed from inception to December 2020, and included randomized controlled trials in patients with PHPT that compared nonsurgical management with medical therapy versus without medical therapy and surgery versus no surgery in patients with asymptomatic PHPT. For surgical complications we included observational studies. Paired reviewers addressed eligibility, assessed risk of bias, and abstracted data for patient-important outcomes. We conducted random-effects meta-analyses to pool relative risks and mean differences with 95% confidence intervals and used Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to assess quality of evidence for each outcome. For medical therapy, 11 trials reported in 12 publications including 438 patients proved eligible: three addressed alendronate, one denosumab, three cinacalcet, two vitamin D, and two estrogen therapy. Alendronate, denosumab, vitamin D, and estrogen therapy all increased bone density. Cinacalcet probably reduced serum calcium and parathyroid hormone (PTH) levels. Cinacalcet and vitamin D may have a small or no increase in overall adverse events. Very-low-quality evidence raised the possibility of an increase in serious adverse events with alendronate and denosumab. The trials also provided low-quality evidence for increased bleeding and mastalgia with estrogen therapy. For surgery, six trials presented in 12 reports including 441 patients proved eligible. Surgery achieved biochemical cure in 96.1% (high quality). We found no convincing evidence supporting an impact of surgery on fracture, quality of life, occurrence of kidney stones, and renal function, but the evidence proved low or very low quality. Surgery was associated with an increase in bone mineral density. For patients with symptomatic and asymptomatic PHPT, who are not candidates for parathyroid surgery, cinacalcet probably reduced serum calcium and PTH levels; anti-resorptives increased bone density. For patients with asymptomatic PHPT, surgery usually achieves biochemical cure. These results can help to inform patients and clinicians regarding use of medical therapy and surgery in PHPT. © 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).

ABSTRACT The last international guidelines on the evaluation and management of primary hyperparathyroidism (PHPT) were published in 2014. Research since that time has led to new insights into epidemiology, pathophysiology, diagnosis, measurements, genetics, outcomes, presentations, new imaging modalities, target and other organ systems, pregnancy, evaluation, and management. Advances in all these areas are demonstrated by the reference list in which the majority of listings were published after the last set of guidelines. It was thus, timely to convene an international group of over 50 experts to review these advances in our knowledge. Four Task Forces considered: 1. Epidemiology, Pathophysiology, and Genetics; 2. Classical and Nonclassical Features; 3. Surgical Aspects; and 4. Management. For Task Force 4 on the Management of PHPT, Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology addressed surgical management of asymptomatic PHPT and non-surgical medical management of PHPT. The findings of this systematic review that applied GRADE methods to randomized trials are published as part of this series. Task Force 4 also reviewed a much larger body of new knowledge from observations studies that did not specifically fit the criteria of GRADE methodology. The full reports of these 4 Task Forces immediately follow this summary statement. Distilling the essence of all deliberations of all Task Force reports and Methodological reviews, we offer, in this summary statement, evidence-based recommendations and guidelines for the evaluation and management of PHPT. Different from the conclusions of the last workshop, these deliberations have led to revisions of renal guidelines and more evidence for the other recommendations. The accompanying papers present an in-depth discussion of topics summarized in this report. © 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).

ABSTRACT The efficacy and safety of parathyroid hormone (PTH) therapy for managing long-term hypoparathyroidism is being evaluated in ongoing clinical trials. We undertook a systematic review and meta-analysis of currently available randomized controlled trials to investigate the benefits and harms of PTH therapy and conventional therapy in the management of patients with chronic hypoparathyroidism. To identify eligible studies, published in English, we searched Embase, PubMed, and Cochrane CENTRAL from inception to May 2022. Two reviewers independently extracted data and assessed the risk of bias. We defined patients' important outcomes and used grading of recommendations, assessment, development, and evaluation (GRADE) to provide the structure for quantifying absolute effects and rating the quality of evidence. Seven randomized trials of 12 publications that enrolled a total of 386 patients proved eligible. The follow-up duration ranged from 1 to 36 months. Compared with conventional therapy, PTH therapy probably achieves a small improvement in physical health-related quality of life (mean difference [MD] 3.4, 95% confidence interval [CI] 1.5–5.3, minimally important difference 3.0, moderate certainty). PTH therapy results in more patients reaching 50% or greater reduction in the dose of active vitamin D and calcium (relative risk [RR] = 6.5, 95% CI 2.5–16.4, 385 more per 1000 patients, high certainty). PTH therapy may increase hypercalcemia (RR =2.4, 95% CI 1.2–5.04, low certainty). The findings may support the use of PTH therapy in patients with chronic hypoparathyroidism. Because of limitations of short duration and small sample size, evidence from randomized trials is limited regarding important benefits of PTH therapy compared with conventional therapy. Establishing such benefits will require further studies. © 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).

ABSTRACT The complications and symptoms of hypoparathyroidism remain incompletely defined. Measuring serum parathyroid hormone (PTH) and calcium levels early after total thyroidectomy may predict the development of chronic hypoparathyroidism. The study aimed (i) to identify symptoms and complications associated with chronic hypoparathyroidism and determine the prevalence of those symptoms and complications (Part I), and (ii) to examine the utility of early postoperative measurements of PTH and calcium in predicting chronic hypoparathyroidism (Part II). We searched Medline, Medline In-Process, EMBASE, and Cochrane CENTRAL to identify complications and symptoms associated with chronic hypoparathyroidism. We used two predefined criteria (at least three studies reported the complication and symptom and had statistically significantly greater pooled relative estimates). To estimate prevalence, we used the median and interquartile range (IQR) of the studies reporting complications and symptoms. For testing the predictive values of early postoperative measurements of PTH and calcium, we used a bivariate model to perform diagnostic test meta-analysis. In Part I, the 93 eligible studies enrolled a total of 18,973 patients and reported on 170 complications and symptoms. We identified nine most common complications or symptoms probably associated with chronic hypoparathyroidism. The complications or symptoms and the prevalence are as follows: nephrocalcinosis/nephrolithiasis (median prevalence among all studies 15%), renal insufficiency (12%), cataract (17%), seizures (11%), arrhythmia (7%), ischemic heart disease (7%), depression (9%), infection (11%), and all-cause mortality (6%). In Part II, 18 studies with 4325 patients proved eligible. For PTH measurement, regarding the posttest probability, PTH values above 10 pg/mL 12–24 hours postsurgery virtually exclude chronic hypoparathyroidism irrespective of pretest probability (100%). When PTH values are below 10 pg/mL, posttest probabilities range from 3% to 64%. Nine complications and symptoms are probably associated with chronic hypoparathyroidism. A PTH value above a threshold of 10 pg/mL 12–24 hours after total thyroidectomy is a strong predictor that the patients will not develop chronic hypoparathyroidism. Patients with PTH values below the threshold need careful monitoring as some will develop chronic hypoparathyroidism. © 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).

Abstract Context Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. Objective This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. Methods This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day). Results By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 μg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events. Conclusion TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

Abstract 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.