Effects of parathyroid hormone rhPTH(1-84) on phosphate homeostasis and vitamin D metabolism in hypoparathyroidism: REPLACE phase 3 study.
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SUBMITTER: Clarke BL
PROVIDER: S-EPMC5225224 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
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Effects of parathyroid hormone rhPTH(1-84) on phosphate homeostasis and vitamin D metabolism in hypoparathyroidism: REPLACE phase 3 study.
Clarke Bart L BL Vokes Tamara J TJ Bilezikian John P JP Shoback Dolores M DM Lagast Hjalmar H Mannstadt Michael M
Endocrine 20161012 1
In hypoparathyroidism, inappropriately low levels of parathyroid hormone lead to unbalanced mineral homeostasis. The objective of this study was to determine the effect of recombinant human parathyroid hormone, rhPTH(1-84), on phosphate and vitamin D metabolite levels in patients with hypoparathyroidism. Following pretreatment optimization of calcium and vitamin D doses, 124 patients in a phase III, 24-week, randomized, double-blind, placebo-controlled study of adults with hypoparathyroidism rec ...[more]
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Project description:IntroductionGain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism. Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism. The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion.MethodsIn this case series, we describe the use of recombinant human parathyroid hormone (rhPTH)1-84 to treat subjects with ADH1, with improved control of serum and urinary calcium levels.ResultsWe describe two children and one adult with ADH1 due to heterozygous CASR mutations who were treated with rhPTH(1-84). Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year. Calcitriol and calcium supplementation were discontinued after titration of rhPTH(1-84). Case 2 was a 9.5-year-old male whose 24-h urinary calcium decreased from 11.7 to 1.7 mg/kg at 1 year, and calcitriol was also discontinued. Case 3 was a 24-year-old female whose treatment was switched from multi-dose teriparatide to daily rhPTH(1-84). All three subjects achieved or maintained target serum levels of calcium and normal or improved urinary calcium levels with daily rhPTH(1-84) monotherapy.ConclusionsWe have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol.
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Project description:G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and cytoplasmic interactors may modulate their signaling, trafficking, and function. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, modulates PTHR activity. Scribble is a crucial regulator for establishing and developing tissue architecture, and its dysregulation is involved in various disease conditions, including tumor expansion and viral infections. Scribble co-localizes with PTHR at basal and lateral surfaces in polarized cells. Using X-ray crystallography, we show that colocalization is mediated by engaging a short sequence motif at the PTHR C-terminus using Scribble PDZ1 and PDZ3 domain, with binding affinities of 31.7 and 13.4 μM, respectively. Since PTHR controls metabolic functions by actions on renal proximal tubules, we engineered mice to selectively knockout Scribble in proximal tubules. The loss of Scribble impacted serum phosphate and vitamin D levels and caused significant plasma phosphate elevation and increased aggregate vitamin D3 levels, whereas blood glucose levels remained unchanged. Collectively these results identify Scribble as a vital regulator of PTHR-mediated signaling and function. Our findings reveal an unexpected link between renal metabolism and cell polarity signaling.
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Project description:Hypoparathyroidism is a rare disorder that is associated with abnormal bone properties. Recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] in short-term studies has beneficial skeletal effects. Although rhPTH(1-84) will likely be used indefinitely, long-term effects on skeletal microstructure are unknown. We therefore studied histomorphometric changes with transiliac crest bone biopsies before and after 8.3 ± 1 years of rhPTH(1-84) in 13 hypoparathyroid subjects compared with 45 controls. Before institution of rhPTH(1-84), skeletal remodeling indices were markedly suppressed. With long-term treatment, indices of bone remodeling increased. Mineralizing surface increased by 26-fold (0.3 ± 1 to 7.9 ± 7%, p = 0.003), bone formation rate increased by 15-fold (0.003 ± 0.01 to 0.047 ± 0.05 μm2 /μm/day, p = 0.007), osteoid width doubled (1.9 ± 1 to 4.3 ± 1 lamellae, p = 0.017), and osteoid surface tripled (3.3 ± 3 to 10.8 ± 6%, p = 0.011). Bone resorption as measured by eroded surface increased (4.6 ± 2 to 7.5 ± 3%, p = 0.021). Structural changes demonstrated intratrabecular tunneling, with increases in cancellous bone volume (19.6 ± 5 to 29.1 ± 11%, p = 0.017) and trabecular number (1.8 ± 1 to 2.5 ± 1 #/mm, p = 0.025). Cortical porosity tended to increase (6.3 ± 5 to 9.5 ± 3%, p = 0.07). Mineralizing surface, osteoid surface, and eroded surface surpassed control levels, as did cancellous bone volume, trabecular number, and cortical porosity. These data, the first to reflect such long exposure of any PTH for any disease, illustrate that PTH establishes and maintains a new skeletal state for at least 8 years in hypoparathyroidism. © 2018 American Society for Bone and Mineral Research.
| S-EPMC6546298 | biostudies-literature
Project description: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).
| S-EPMC10101915 | biostudies-literature
Project description:ContextChronic 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.ObjectiveTo assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment.MethodsThis 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.ResultsThirty-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.Conclusion6 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.
| S-EPMC10119703 | biostudies-literature
Project description:ContextConventional treatment of hypoparathyroidism is associated with decreased renal function and increased bone mineral density (BMD).ObjectiveTo evaluate the effects of 8 years of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] therapy on key biochemical and densitometric indices.DesignProspective open-label trial.SettingTertiary medical center.ParticipantsTwenty-four subjects with hypoparathyroidism.InterventionTreatment with rhPTH(1-84) for 8 years.Main outcome measuresSupplemental calcium and vitamin D requirements, serum calcium and phosphorus levels, calcium-phosphate product, urinary calcium excretion, estimated glomerular filtration rate (eGFR) and BMD.ResultsPTH therapy was associated with progressive reduction in supplemental calcium (57%; P < 0.01) and active vitamin D (76%; P < 0.001) requirements over 8 years. Serum calcium concentration was stable; urinary calcium excretion declined 38% (P < 0.01). eGFR remained stable and was related to baseline eGFR and serum calcium levels. Calcium-phosphate product was below the recommended limit; serum phosphorus remained within normal range. Lumbar spine and total hip BMD increased, peaking at 4 (mean ± SE, 4.6% ± 1.5%; P = 0.01) and 8 years (2.6% ± 1.1%; P = 0.02), whereas femoral neck BMD did not change and one-third radius BMD decreased (mean ± SE, -3.5% ± 1.1%; P = 0.001). BMD at all sites was higher throughout the 8 years than in the age- and sex-matched reference population. Hypercalcemia and hypocalcemia were uncommon.ConclusionrhPTH(1-84) is a safe and effective treatment for hypoparathyroidism for 8 years. Long-term reductions in supplemental requirements and biochemical improvements with stable renal function are maintained.
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Project description:Chronic hypoparathyroidism (HypoPT) is conventionally managed with oral calcium and active vitamin D. Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is a therapy targeting the pathophysiology of HypoPT by replacing parathyroid hormone. To compare changes in the estimated glomerular filtration rate (eGFR) in patients with chronic HypoPT receiving or not receiving rhPTH(1-84) during a 5-year period. A retrospective analysis of patients with chronic HypoPT treated with or without rhPTH(1-84). Sixty-nine patients with chronic HypoPT from 4 open-label, long-term trials (NCT00732615, NCT01268098, NCT01297309, and NCT02910466) composed the rhPTH(1-84) cohort and 53 patients with chronic HypoPT not receiving rhPTH(1-84) from the Geisinger Healthcare Database (01/2004-06/2016) composed the historical control cohort. The rhPTH(1-84) cohort (N = 69) received rhPTH(1-84) therapy; the historical control cohort (N = 53) did not receive rhPTH(1-84). Changes in eGFR from baseline during a 5-year follow-up were examined in multivariate regression analyses. At baseline, demographic characteristics and eGFR were similar between cohorts, though the proportions with diabetes and cardiac disorders were lower in the rhPTH(1-84) cohort. At the end of follow-up, mean eGFR increased by 2.8 mL/min/1.73 m2 in the rhPTH(1-84) cohort, while mean eGFR fell by 8.0 mL/min/1.73 m2 in the control cohort. In the adjusted model, the difference in the annual eGFR change between the rhPTH(1-84) cohort and the control cohort was 1.7 mL/min/1.73 m2 per year (P = 0.009). Estimated glomerular filtration rate was preserved for over 5 years among patients with chronic HypoPT receiving rhPTH(1-84) treatment, contrasting with an eGFR decline among those not receiving rhPTH(1-84).
| S-EPMC7470469 | biostudies-literature
Project description:Inorganic phosphate (Pi) is an abundant element in the body and is essential for a wide variety of key biological processes. It plays an essential role in cellular energy metabolism and cell signalling, e.g. adenosine and guanosine triphosphates (ATP, GTP), and in the composition of phospholipid membranes and bone, and is an integral part of DNA and RNA. It is an important buffer in blood and urine and contributes to normal acid-base balance. Given its widespread role in almost every molecular and cellular function, changes in serum Pi levels and balance can have important and untoward effects. Pi homoeostasis is maintained by a counterbalance between dietary Pi absorption by the gut, mobilisation from bone and renal excretion. Approximately 85% of total body Pi is present in bone and only 1% is present as free Pi in extracellular fluids. In humans, extracellular concentrations of inorganic Pi vary between 0.8 and 1.2 mM, and in plasma or serum Pi exists in both its monovalent and divalent forms (H2PO4- and HPO42-). In the intestine, approximately 30% of Pi absorption is vitamin D regulated and dependent. To help maintain Pi balance, reabsorption of filtered Pi along the renal proximal tubule (PT) is via the NaPi-IIa and NaPi-IIc Na+-coupled Pi cotransporters, with a smaller contribution from the PiT-2 transporters. Endocrine factors, including, vitamin D and parathyroid hormone (PTH), as well as newer factors such as fibroblast growth factor (FGF)-23 and its coreceptor α-klotho, are intimately involved in the control of Pi homeostasis. A tight regulation of Pi is critical, since hyperphosphataemia is associated with increased cardiovascular morbidity in chronic kidney disease (CKD) and hypophosphataemia with rickets and growth retardation. This short review considers the control of Pi balance by vitamin D, PTH and Pi itself, with an emphasis on the insights gained from human genetic disorders and genetically modified mouse models.
| S-EPMC6326012 | biostudies-literature
Project description:ObjectivesChronic hypoparathyroidism is treated conventionally with active vitamin D and high doses of calcium. Recombinant human parathyroid hormone (PTH) replacement is an attractive option for treating patients with hypoparathyroidism since it can replace the physiological action of native PTH. The aim of our study was to perform a comprehensive evaluation of the effects of PTH replacement on calcium homeostasis, bone metabolism, and daily requirement of calcium and active vitamin D.Materials and methodsRandomized controlled trials done in chronic hypoparathyroid patients were included in this meta-analysis. The PTH group included subjects receiving a subcutaneous injection of either PTH (1-84) or PTH (1-34) with oral calcium and/or active vitamin D. The control group included those receiving oral calcium and active vitamin D with/without subcutaneous placebo injection. The primary outcome of this meta-analysis was to compare serum calcium, 24-h urinary calcium, and severe adverse effects among PTH and control groups.ResultsIn this meta-analysis, we did not find any difference in serum calcium level between PTH and control groups [mean difference (MD) - 0.01; 95% confidence interval (CI) - 0.09, 0.06; P = 0.71]. Although there was a trend towards low 24-h urinary calcium in the PTH group, the difference was not statistically significant (MD - 1.43; 95% CI - 2.89, 0.03; P = 0.06). The incidence of serious adverse events was also similar in both groups (RR 1.35; 95% CI 0.58, 3.16; P = 0.49).ConclusionBoth PTH and active vitamin D therapies are associated with comparable serum and urine calcium levels with a similar incidence of serious adverse events in patients with chronic hypoparathyroidism.
| S-EPMC7333760 | biostudies-literature
Project description:IntroductionPatients with chronic hypoparathyroidism are at increased risk of cardiovascular disease. This study evaluated the risk of developing cardiovascular conditions over a period of 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).MethodsThis retrospective cohort study comprised patients with chronic hypoparathyroidism treated with rhPTH(1-84) in the REPLACE (NCT00732615), RELAY (NCT01268098), and RACE (NCT01297309) clinical trials, and controls selected from the IBM® Explorys electronic medical record database (January 2007-August 2019) who did not receive parathyroid hormone but who had enrollment criteria similar to those for the clinical trials. Cardiovascular outcomes were the first diagnosis of cerebrovascular, coronary artery, peripheral vascular disease, or heart failure during the study period.ResultsWe evaluated 113 adult patients with chronic hypoparathyroidism treated with rhPTH(1-84) and 618 control patients who did not receive rhPTH(1-84). Over the 5-year follow-up period, 3.5% of patients (n = 4) in the rhPTH(1-84) cohort had a cardiovascular event compared with 16.3% (n = 101) in the control cohort. Kaplan-Meier analysis demonstrated that patients in the rhPTH(1-84) cohort had lower risk of experiencing a cardiovascular event compared with patients in the control cohort (P = 0.005). Multivariable analyses adjusted for baseline variables showed that patients in the rhPTH(1-84) cohort had 75% lower risk for a cardiovascular event compared with patients in the control cohort (adjusted hazard ratio, 0.25 [95% CI 0.08-0.81]; P = 0.020).ConclusionLong-term treatment with rhPTH(1-84) was associated with a lower risk of incident cardiovascular conditions compared with conventional therapy in patients with chronic hypoparathyroidism. Previous studies demonstrated that mineral homeostasis was maintained with lower use of calcium and active vitamin D when rhPTH(1-84) was added to conventional therapy. Future studies are needed to understand whether improved regulation of mineral homeostasis conferred by rhPTH(1-84) may provide long-term cardiovascular benefits to patients with chronic hypoparathyroidism.
| S-EPMC9309129 | biostudies-literature