Treatment of Hypoparathyroidism by Re-Establishing the Effects of Parathyroid Hormone.

The conventional treatment of hypoparathyroidism (HypoPT) includes active vitamin D and calcium. Despite normalization of calcium levels, the conventional treatment is associated with fluctuations in calcium levels, hypercalciuria, renal impairment, and decreased quality of life (QoL). Replacement therapy with parathyroid hormone (PTH)(1-84) is an option in some countries. However, convincing beneficial effects have not been demonstrated, which may be due to the short duration of action of this treatment. Recently, palopegteriparatide (also known as TransCon PTH) has been marketed in Europe and is expected also to be approved in other countries. Palopegteriparatide is a prodrug with sustained release of PTH(1-34) designed to provide stable physiological PTH levels for 24 hours/day. A phase 3 study demonstrated maintenance of normocalcemia in patients with chronic HypoPT, with no need for conventional therapy. Furthermore, this treatment lowers urinary calcium and improves QoL. Another long-acting PTH analog with effects on the parathyroid hormone receptor (eneboparatide) is currently being tested in a phase 3 trial. Furthermore, the treatment of autosomal dominant hypocalcemia type 1 with a calcilytic (encaleret) is also being tested. All in all, improved treatment options are on the way that will likely take the treatment of HypoPT to the next level.

A delicate balance: the challenges of hypoparathyroidism.

A 38-yr-old woman with chronic non-surgical hypoparathyroidism, managed elsewhere, presented to our practice with symptomatic hypocalcemia. At the age of 17, she began to suffer from muscle cramps, paresthesia, and ongoing diffuse pain. It took years before she was correctly diagnosed with hypoparathyroidism. Her symptoms were severe enough that she required emergency room visits several times a year. After she was properly diagnosed and started on calcium and calcitriol therapy, she continued to experience frequent episodes of severe hypocalcemia. She saw multiple healthcare providers who each introduced a new regimen. In addition, poor communication led to her discontinuing her medications altogether. As a result, her calcium levels remained consistently low, and she lost confidence in her prospect for better health. At the time of her visit to our clinic, she had discontinued calcitriol, was taking a large amount of oral calcium daily all at once, and had hypocalcemia. We addressed her concerns, and the challenges she faces with adherence to her medication regimen. We provided her with detailed information about the disease and the reasoning behind her treatment plan. Treatment was initiated with calcium carbonate 600 mg 3 times daily and calcitriol 0.5 mcg once daily. One week after treatment initiation, her test results showed improvement in her albumin-adjusted calcium, phosphorus, and 24-h urine calcium which were all within target range.

Rare cause of recurrent hypocalcaemia and functional hypoparathyroidism due to hypomagnesaemia caused by TRPM6 gene mutation.

Magnesium is essential for the functioning and release of parathyroid hormone. Therefore, its deficiency can present as functional hypoparathyroidism. This case report describes a rare inherited disorder called congenital hypomagnesaemia with secondary hypocalcaemia due to TRPM6 gene mutation. This disease clinically and biochemically mimics hypoparathyroidism. However, unlike hypoparathyroidism, it can be treated only by long-term oral magnesium supplements. The patient presented to us with recurrent hypocalcaemic convulsions. The laboratory picture in each admission was similar to that of hypoparathyroidism. However, the hypocalcaemia persisted, and it was noticed to be associated with persistent hypomagnesaemia. A defect in the tubular magnesium reabsorption was postulated and a genetic analysis of the patient was done, which revealed a TRPM6 mutation causing hypomagnesaemia by excessive renal excretion of magnesium. The child responded well to oral magnesium supplements and is currently developmentally appropriate for her age and thriving well.

Extended Treatment With Recombinant Human Parathyroid Hormone (1-84) in Adult Patients With Chronic Hypoparathyroidism.

OBJECTIVE: Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is efficacious in patients with hypoparathyroidism but additional data supporting its prolonged use are needed. We evaluated whether efficacy, safety, and tolerability are maintained during long-term rhPTH(1-84) treatment of patients with chronic hypoparathyroidism. METHODS: This was a phase 4, single-center, open-label, single-arm, 3-year extension (NCT02910466) of the phase 3 Hypo Extended (HEXT) study (NCT01199614). Patients self-administered rhPTH(1-84) once daily by subcutaneous injection, with doses individualized based on clinical parameters. Albumin-adjusted serum calcium levels (primary outcome measure), other disease biomarkers, health-related quality of life, and safety of rhPTH(1-84) were assessed using descriptive statistics. RESULTS: All patients (n = 39) had been exposed to rhPTH(1-84) (mean exposure [SD] 8.5 [3.5] years) before the start of the study, resulting in a mean exposure of 10.8 years including the present study. Mean patient age was 51.9 years, 79.5% were female, and 97.4% were White. Mean albumin-adjusted serum calcium concentrations were within the target range, and mean serum phosphate, serum calcium-phosphate product, and 24-hour urinary calcium excretion levels were within reference ranges at end of treatment. Mean doses of supplemental calcium and active vitamin D were maintained throughout the study. Bone turnover marker levels were maintained from baseline to end of treatment. No clinically relevant changes in bone mineral density were observed. Patient-reported health-related quality-of-life scores were generally maintained throughout the study. Four adverse events were considered treatment related and no new safety signals were identified. CONCLUSION: The effects of rhPTH(1-84) on biochemical, skeletal, and health-related quality-of-life parameters did not wane with extended use.

The effects of adequate dietary calcium intake in patients with hypoparathyroidism non-adherent to treatment: a prospective randomized controlled trial.

OBJECTIVE: A significant problem that compels clinicians in the conventional treatment of hypoparathyroidism is patients' non-adherence to treatment. This study aimed to evaluate the effects of adequate Ca intake with dietary recommendations among hypoparathyroidism patients who persistently use Ca supplementation irregularly on plasma Ca and phosphate levels. METHODS: This prospective, randomized, controlled study was conducted on patients diagnosed with chronic hypoparathyroidism who persistently interrupt Ca supplementation therapy and therefore have a hypocalcemic course. Patients with a total daily Ca intake below 800 mg were randomized. All patients were advised to keep the doses of active vitamin D and Ca supplements they were currently using. The patients in the study group (n=32) were advised to consume 1,000-1,200 mg of Ca daily, and the patients in the control group (n=35) were advised to continue their diet according to their daily habits. After 12 weeks of follow-up, the patients' laboratory values were compared between groups to assess treatment goals. RESULTS: The mean of the total Ca level was 8.56±0.36 mg/dL in the study group and was found to be significantly higher than that in the control group, which was 7.67±0.48 mg/dL (p<0.001). The mean serum phosphate and serum Ca-P product levels were significantly higher in the study group (p<0.001) but did not exceed the safe upper limits in any patient. CONCLUSION: A suitable increase in dietary Ca intake could effectively control hypocalcemia in patients with hypoparathyroidism who persistently interrupt the recommended calcium supplementation.

Management of hypoparathyroidism: a Position Statement of the Expert Group of the Polish Society of Endocrinology.

Over the past few years, there have been significant advances in our understanding of hypoparathyroidism (HypoPT) in terms of its epidemiology, clinical presentation, etiology, and skeletal and renal complications. Moreover, the available treatment options for HypoPT have changed. This position statement of the Expert Group of the Polish Society of Endocrinology summarizes the current state of knowledge and provides recommendations for optimal management to assist clinicians in the diagnosis, treatment, and monitoring of HypoPT in Poland. The specific aspects of HypoPT management in children, pregnant and lactating women, and patients with chronic kidney disease are also discussed. HypoPT is a rare disorder characterized by hypocalcemia and the lack or deficiency of parathyroid hormone (PTH). Hypoparathyroidism can be associated with complications, including nephrocalcinosis, nephrolithiasis, renal insufficiency, cataract, seizures, cardiac arrhythmia, depression, and an increased risk of infection. Minimizing complications of HypoPT requires careful evaluation and close monitoring of laboratory parameters. Conventional management of HypoPT has focused on maintaining serum calcium levels using oral calcium and active vitamin D. However, this approach is limited because it does not restore normal PTH function, is often associated with inadequate biochemical control, and raises concerns as to long-term side effects. HypoPT is the only classic endocrine insufficiency that is not commonly treated with the substitution of the missing hormone. Recently, recombinant human PTH(1-84) has become available, offering hope that the use of the missing hormone in the treatment of HypoPT will help achieve better control and reduce the risk of complications. However, this treatment is currently unavailable in Poland.

New directions in the treatment of hypoparathyroidism.

Treatment of chronic hypoparathyroidism remains a therapeutic challenge. In three quarters of cases, this endocrine disorder arises as a consequence of neck surgery, but it can also present in other disease settings, for example, in rare genetic disorders. Conventional standard of care treatment is based on oral administration of calcium and vitamin D. However, a significant proportion of patients remain uncontrolled biochemically under this treatment, with persistent clinical symptoms that affect quality of life. Administration of parathyroid hormone (PTH) in more recent times has encountered the problem of the short half-life of the hormone, which necessitates multiple daily injections or continuous subcutaneous administration controlled by a pump. Recently, progress in understanding the pathophysiology of hypoparathyroidism has opened the possibility of new therapeutic approaches using longer-acting forms of PTH, PTH receptor analogs or, more recently, calcilytic agents. These are the subjects of current clinical trials, with encouraging results. However, their possible future use will depend on their long-term impacts on bone metabolism and renal function, which remain to be determined.

Continuous subcutaneous rhPTH infusion for managing difficult chronic hypoparathyroidism. A systematic review.

PURPOSE: Standard treatment for chronic hypoparathyroidism is represented by long-life per os supplementation of calcium and vitamin D. Since 90s, exogenous PTH is also available, but a not negligible number of patients experience a poor control. Starting from the experience with pumps in diabetes, it has been hypothesized that the infusion of PTH through pump might result in a better disease control. The aim of this systematic review is to summarize the published data about continuous subcutaneous PTH infusion in chronic hypoPTH patients and achieve conclusions for clinical practice. METHODS: A comprehensive computer literature search of the PubMed/MEDLINE, Embase, and Scopus databases was conducted by two authors independently (last search on November 30, 2022). All findings were summarized and critically discussed. RESULTS: We included 14 of the 103 retrieved articles, 2 RCTs, 8 case reports, and 4 case series, published between 2008 and 2022. Of the total 40 patients, 17 were adults, and 23 pediatric. The etiology was postsurgical in 50% of cases and genetic in the other 50%. All had a failure of standard care and a rapid improvement of clinical and biochemical parameters on PTH pump therapy, without severe adverse events. CONCLUSIONS: Based on literature, pump PTH infusion may represent an effective, safe, and feasible option for patients with chronic hypoparathyroidism refractory to standard therapy. From a clinical perspective, careful patient selection, a skilled healthcare team, the assessment of the local setting and the collaboration with pump suppliers are essential.

Evaluation of an early detection protocol, intensive treatment and control of post-surgical hypoparathyroidism in the first month after total thyroidectomy.

BACKGROUND AND OBJECTIVE: Hypoparathyroidism is the most common complication of total thyroidectomy and usually requires monitoring of calcaemia, whereby it is one of the factors that most contributes to hospital stay. The objective of the study is to evaluate the clinical usefulness of the application of our protocol for early detection, intensive treatment and control of hypoparathyroidism in the first month after thyroidectomy. PATIENTS AND METHOD: Retrospective observational cross-sectional study of 79 patients who underwent total thyroidectomy in whom parathormone (PTH) and calcemia determinations were performed at 6-8 h and 18-24 h post-surgery. When the PTH value was lower than inferior limit of the reference (15 pg/ml), oral treatment was started with 1000 mg of calcium and 0.25 µg of calcitriol every 8 h followed by calcemia controls. RESULTS: Twenty-six cases (32.9%) of normocalcemic hypoparathyroidism were detected in whom treatment prevented their progression to hypocalcaemia, except for 3 cases that had an episode of mild asymptomatic hypocalcaemia. There were no cases of moderate/severe hypocalcaemia and only one case of asymptomatic mild hypercalcaemia. There were no readmissions due to calcium abnormalities. No case with PTH > 15 pg/ml had hypocalcaemia. The protocol allowed a hospital stay of 24 h. The prevalence of permanent hypoparathyroidism was 5.1%. CONCLUSIONS: The application of our protocol during the first month after thyroidectomy is very useful because it avoids the appearance of moderate/severe hypocalcaemia and hypercalcaemia, allows a short hospital stay and is associated with a low prevalence of permanent hypoparathyroidism.

Vitamin D in hypoparathyroidism: insight into pathophysiology and perspectives in clinical practice.

Hypoparathyroidism (HypoPT) is a rare endocrine disorder characterized by the absence or insufficient parathyroid hormone production resulting in chronic hypocalcemia. Complications of HypoPT include perturbation of several target organs. The conventional treatment consists of the administration of active vitamin D, namely calcitriol. Regarding vitamin D status, few data are available, mostly in HypoPT subjects supplemented with parent vitamin D. In addition, perturbation of vitamin D metabolism has been poorly investigated, as well as the contribution of altered vitamin D status on the clinical expression of the disease. The most recent consensus on the management of chronic HypoPT suggests the baseline evaluation of serum 25-hydroxy-vitamin D [25(OH)D] and supplementation with parent vitamin D with the aim to achieve and maintain serum 25(OH)D levels in the range of 30-50 ng/mL. The rationale for using supplementation with parent vitamin D (either ergocalciferol or cholecalciferol) in HypoPT would be to provide sufficient 25(OH)D substrate to the residual 1-α-hydroxylase activity, thus ensuring its conversion to active vitamin D in renal and extra-renal tissues. More data from experimental and clinical studies are needed for better assessing how these mechanisms may significantly influence metabolic control in HypoPT and eventually skeletal and extra-skeletal manifestation of the disease. Finally, future data will clarify how the currently available parent vitamin D compounds (ergocalciferol, cholecalciferol, calcifediol) would perform in addressing these specific issues.

Presentation and management of hypoparathyroidism in a paediatric patient - a case report.

Hypoparathyroidism occurs due to insufficient parathyroid gland activity leading to abnormal calcium and phosphate levels. The presentation of hypoparathyroidism is rare in adults and mostly encountered in the paediatric population. We present a case of a 3.5-month-old male infant with the presenting complaint of an episode of afebrile generalized tonic-clonic seizure. Haematological, urinary, cerebro-spinal fluid and radiological investigations were unremarkable but a biochemical profile revealed hypocalcaemia, hyperphosphataemia and lowered vitamin D3 levels. Parathyroid hormone profile showed a decreased level, confirming diagnosis of hypoparathyroidism. Intravenous administration of calcium and magnesium in combination with oral activated vitamin D3 and phosphate binders managed to resolve symptoms and maintain normal levels. The rationale of this case is to confirm the necessity of early diagnosis to prevent irreversible sequelae of hypocalcaemia and regular monitoring of treatment to avoid side-effects of medication.

The Clinical and Skeletal Effects of Long-Term Therapy of Hypoparathyroidism With rhPTH(1-84).

Hypoparathyroidism (HypoPT) is a disorder characterized by hypocalcemia, low or absent parathyroid hormone (PTH) levels, reduced bone remodeling, and high areal bone mineral density (aBMD). PTH is a therapeutic option, yet data on the prolonged clinical and skeletal effects of PTH treatment are limited. We tracked annual daily doses of calcium and active vitamin D supplements, calciotropic biochemistries, estimated glomerular filtration rate (eGFR), and aBMD measurements in 27 HypoPT patients (16 postsurgical, 11 nonsurgical) who were treated with recombinant human PTH(1-84) [rhPTH(1-84)] for at least 8 (n = 27) and up to 12 (n = 14) years. We also performed high-resolution-peripheral quantitative computed tomography (HRpQCT) imaging and report results at baseline, 5, 8, and 12 years of rhPTH(1-84) treatment. With prolonged use of rhPTH, reductions in the need for supplemental calcium and active vitamin D were maintained. The eGFR did not decline. Serum calcium was maintained within the lower limit of the normal range. aBMD by dual-energy X-ray absorptiometry (DXA) showed an increase at the lumbar spine and a decrease at the distal 1/3 radius. By HRpQCT, cortical volumetric BMD (vBMD) at the tibia decreased at year 5: -20.0% ± 1.5%. The magnitude of this reduction was mitigated in year 8: -8.5% ± 1.6% and in year 12: -10.3% ± 2.2% but all were significantly below the mean baseline value (p < 0.001). A similar pattern of decline was observed at the radius. Cortical porosity progressively increased at the tibia in year 5: 17.4% ± 10% (p < 0.05), year 8: 55.2% ± 11% (p < 0.001), and year 12: 83.5% ± 14% (p < 0.001). A similar pattern of increase was observed at the radius. Failure load, which was higher than normal at baseline, decreased but remained above normal at year 12. This is the longest experience, to date, with PTH therapy in HypoPT. These results demonstrate sustained biochemical stability but overall decreases in bone mass. © 2023 American Society for Bone and Mineral Research (ASBMR).

Subtotal Parathyroidectomy Successfully Controls Calcium Levels of Patients with Neonatal Severe Hyperparathyroidism Carrying a Novel CASR Mutation.

INTRODUCTION: Inactivating mutations of the calcium-sensing receptor (CASR) gene result in neonatal severe hyperparathyroidism (NSHPT). Total parathyroidectomy is an effective way to control life-threatening hypercalcemia in NSHPT but leads to permanent hypoparathyroidism. An alternative surgical option is subtotal parathyroidectomy. However, few cases were reported in the literature. Here, we report two unrelated NSHPT patients, one with a novel homozygous mutation (c.1817T>C; p.Leu606Pro) in CASRand the other with heterozygous for the same mutation who also carried two rare intronic variants in CASR. The outcomes of subtotal parathyroidectomy in these patients are also described. CASE PRESENTATION: Two infants presented with an alteration of consciousness, respiratory distress, and bradycardia. Severe hypercalcemia, hypophosphatemia, and markedly elevated parathyroid hormone levels were identified, suggesting NSHPT. Cinacalcet was unable to control calcium (Ca) levels of both patients. A novel heterozygous and homozygous missense mutation c.1817T>C; p.Leu606Pro was identified in patients 1 and 2, respectively. Based on the model prediction, proline substitution at Leu606 is likely to disrupt conversion between the active and inactive conformations at the extracellular to transmembrane domain interface of CASR. In addition, two extremely rare intronic variants in CASR (chr3:g.122180314A>G and chr3:g.122251601G>A, based on GRCh38) were identified in patient 1 and his mother. These variants might have contributed to the clinical manifestations of patient 1 who was heterozygous for the c.1817T>C; p.Leu606Pro variant. Subtotal parathyroidectomy was performed by removing three and a half parathyroid glands. So far, patient 1 has been in normocalcemia for 5 years. Patient 2 was in normocalcemia for 16 months after surgery and subsequently developed mild hypoparathyroidism which required only low-dose calcitriol treatment. CONCLUSION: We report a novel heterozygous and homozygous missense variant (c.1817T>C; p.Leu606Pro) in CASR in two NSHPT patients. The mutation likely disrupts conformational changes of CASR and results in cinacalcet unresponsiveness. Intronic variants in CASR identified in the patient with heterozygous variant might have contributed to the clinical manifestations of the patient. Although total parathyroidectomy is widely accepted as a standard treatment for NSHPT, we demonstrate that subtotal parathyroidectomy is also an effective procedure to normalize Ca levels and allow these patients to be in normocalcemia or mild hypoparathyroidism, which is simply controlled by low-dose calcitriol treatment. Subtotal parathyroidectomy appeared to be an effective treatment for NSHPT regardless of the molecular etiologies.

Effect of calcitriol and calcium on basal ganglia calcification in hypoparathyroidism: experimental models.

Basal ganglia calcification (BGC) is a common complication in hypoparathyroid patients, linked to hyperphosphatemia and altered vitamin-D and calcium homeostasis following conventional therapy. The pathogenesis of BGC in hypoparathyroidism is not clear. Recently, we developed an ex vivo model of BGC using rat-striatal cell culture in 10.0 mmol/L of ß-glycerophosphate (31.8 mg/dL phosphate). However, the effect of 1,25(OH)2 D, calcium, and milder phosphate excess on BGC in hypoparathyroidism is not known. This study describes two modified ex vivo models investigating pathogenesis of BGC in 'drug-naïve' and 'conventionally treated' hypoparathyroid state. The first modification involved striatal cells cultured in low concentration 1,25(OH)2D (16.0 pg/mL), ionized calcium(0.99 mmol/L), hPTH(1-34) (6.0 pg/mL), and 2.68 mmol/L (8.3 mg/dL) of phosphate akin to 'drug-naïve' state for 24 days. In second modification, striatal cells were exposed to 46.0 pg/mL of 1,25(OH)2D, normal ionized calcium of 1.17 mmol/L, and 2.20 mmol/L (6.8 mg/dL) of phosphate akin to 'conventionally treated' state. Striatal cell culture under 'drug-naïve' state showed that even 16.0 pg/mL of 1,25(OH)2D enhanced the calcification. In 'conventionally treated' model, striatal cell calcification was enhanced in 54% cases over 'drug-naïve' state. Calcification in 'conventionally treated' state further increased on increasing phosphate to 8.3 mg/dL, suggesting importance of phosphatemic control in hypoparathyroid patients. Striatal cells in 'drug-naïve' state showed increased mRNA expression of pro-osteogenic Wnt3a, Cd133,Vglut-1-neuronal phosphate-transporters, calcium-ion channel-Trvp2,Alp, and Collagen-1α and decreased expression of Ca-II. These models suggest that in 'drug-naïve' state, 1,25(OH)2D along with moderately elevated phosphate increases the expression of pro-osteogenic molecules to induce BGC. Although normalization of calcium in 'conventionally treated' state increased the expression of Opg, Osterix, Alp, and Cav2, calcification increased only in a subset, akin to variation in progression of BGC in hypoparathyroid patients on conventional therapy.

Is parathyroid allotransplantation a viable option in the treatment of permanent hypoparathyroidism? A review of the literature.

BACKGROUND: The standard clinical treatment for hypoparathyroidism, replacement of calcium and vitamin metabolites (calcitriol), has been used for decades; however, evidence points to its inefficiency in acting on the pathophysiology of the disease, which may precipitate or aggravate conditions already related to hypoparathyroidism. Therapies based on recombinant human parathyroid hormone have emerged in recent years but still have low availability due to their high cost. Parathyroid allotransplantation (Pt-a) has been reported as a strategy for treating more severe cases. METHODS: This narrative review highlights relevant aspects of conventional permanent hypoparathyroidism treatment and provides a comprehensive and critical review of the reports of applications of Pt-a, especially those carried out in recent years. Particular focus is placed on the following key points: parathyroid immunogenicity, immunosuppression regimens (short-term or chronic), techniques to reduce the expression of immunogenic molecules, follow-up time, and reductions in calcium and vitamin D supplementation. CONCLUSION: Pt-a has been considered a safe and relatively low-cost therapy and is believed to have the potential to cure the disease, in addition to treating symptoms. However, there is considerable heterogeneity in treatment protocols; therefore, more studies are required to improve the standardization of the procedure and thus improve the consistency of outcomes.

Evaluation of management of patients with postoperative permanent hypoparathyroidism. How close are we to the targets?

BACKGROUND: Postoperative hypoparathyroidism (PO-HypoPT) is a complication usually seen after thyroid surgery. PO-HypoPT, which lasts longer than 6 months is defined permanently. The aim of this study was to evaluate how close permanent PO-HypoPT patients can approach target values. METHODS: One hundred seven patients who were followed-up with permanent diagnosis of PO-HypoPT between 2016-2020 were included in the study. The study protocol includes serum albumin corrected total calcium (Alb-sCa), phosphate (P), Ca-P product, and 24 h urine calcium measurements. Laboratory measurements of the patients include the values recorded in 4-year visits and in the last visit. In addition, radiological reports of renal/abdominal ultrasound and cranial tomography examinations performed in our hospital for any reason during this period were also reviewed. RESULTS: When looking at the total measurements in the 4-year period, the Alb-sCa level was below the target in most of the measurements (68.1%). P level was higher than normal in 296 (46.2%) measurements. Twenty-four h urine ca excretion was measured 185 times in total visits, and 81 (43.7%) of these measurements showed hypercalciuric values. The patient's latest visit measurements were evaluated on 4 targets (Alb-sCa, P, Ca-P product and 24 h urine Ca excretion). The number of patients meeting all four targets was only 21 (19.6%). Six (7.5%) patients had kidney stones or nephrocalcinosis. Three (0.09%) patients with imaging had calcification in the basal ganglia. CONCLUSIONS: Our study shows that the management of the patients with PO-HypoPT is suboptimal with active vitamin D and cholecalciferol treatment.

The risk of chronic kidney disease development in adult patients with chronic hypoparathyroidism treated with rhPTH(1-84): A retrospective cohort study.

OBJECTIVE: This study assessed the risk of developing chronic kidney disease (CKD) and decline in estimated glomerular filtration rate (eGFR) over a period of up to 5 years in adult patients with chronic hypoparathyroidism treated with recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) compared with a historical control cohort of patients not treated with rhPTH(1-84). DESIGN: Retrospective cohort study of patients with chronic hypoparathyroidism treated with rhPTH(1-84) derived from the REPLACE (NCT00732615), RELAY (NCT01268098), RACE (NCT01297309) and HEXT (NCT01199614, and its continuation study NCT02910466) clinical trials and a historical control cohort who did not receive PTH selected from an electronic medical record database. PATIENTS: One hundred and eighteen patients treated with rhPTH(1-84) and 497 patient controls. MEASUREMENTS: Incident CKD was defined as ≥2 eGFR measurements <60 ml/min/1.73 m2 ≥3 months apart during the study and a sustained eGFR decline of ≥30% from baseline. RESULTS: Over the 5-year period, Kaplan-Meier analyses showed that rhPTH(1-84)-treated patients had a significantly lower risk of developing CKD (log-rank p = .002) and a lower risk for a sustained eGFR decline ≥30% from baseline (log-rank p < .001) compared with patients in the control cohort. In adjusted analyses, patients in the rhPTH(1-84)-treated cohort had a 53% lower risk of developing CKD (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.25-0.87) and a 65% lower risk for sustained eGFR decline ≥30% from baseline (HR, 0.35; 95% CI, 0.13-0.89) compared with controls. CONCLUSIONS: Patients with chronic hypoparathyroidism treated with rhPTH(1-84) in long-term clinical trials had a significantly lower risk of developing CKD compared with patients in a historical control cohort not treated with rhPTH(1-84).