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.
| S-EPMC7853300 | biostudies-literature
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: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.
| S-EPMC6977408 | biostudies-literature
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).
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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 ?-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.
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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.
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Project description:Abstract RACE is an open-label study that assessed the long-term safety and efficacy of recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) for the treatment of hypoparathyroidism in adults (ClinicalTrials.gov identifier NCT01297309). Patients initially received 25 or 50 µg/day of rhPTH(1-84) subcutaneously, once daily, with stepwise dose adjustments of 25 µg (up or down) to a maximum of 100 µg/day. rhPTH(1-84) could be titrated and oral calcium (Ca) and calcitriol doses adjusted at any time during the study to maintain albumin-corrected serum Ca levels in the target range of 8.0-9.0 mg/dL. A composite efficacy endpoint was the proportion of patients who achieved at least a 50% reduction from baseline (BL) in oral Ca dose (or Ca ≤500 mg/day) and at least a 50% reduction from BL in calcitriol dose (or calcitriol ≤0.25 µg/day), while normalizing or maintaining albumin-corrected serum Ca compared with BL value and not exceeding the upper limit of normal for the central laboratory. Here, we present 6-year safety and efficacy data with descriptive summary statistics (mean ± SD). The study cohort consisted of 49 patients enrolled at 12 US centers (mean age, 48.1±9.78 years; 81.6% female); data from 34 patients (69.4%) who completed 72 months (M72) of treatment with rhPTH(1-84) as of July 17, 2018 are presented here. Oral Ca and calcitriol doses were reduced by 40.4% and 72.2% at M72, respectively, and albumin-corrected serum Ca levels were maintained within the target range (BL, 8.4±0.70 mg/dL; M72, 8.4±0.68 mg/dL). At M72, 22 of 34 patients (64.7%) achieved the composite efficacy endpoint. Urinary Ca excretion declined from above-normal at BL to within the normal range (BL, 356.7±200.37 mg/24 h; M72, 213.2±128.82 mg/24 h). Mean serum creatinine levels remained stable (BL, 1.0±0.21 mg/dL; M72, 0.9±0.21 mg/dL), as did estimated glomerular filtration rate (eGFR; BL, 77.7±17.67 mL/min/1.73 m2; M72, 79.4±18.39 mL/min/1.73 m2). Serum phosphorus levels declined from above-normal at BL to within normal range (BL, 4.8±0.58 mg/dL; M72, 4.0±0.62 mg/dL); calcium-phosphorus product levels also declined (BL, 42.1±6.35 mg2/dL2; M72, 33.7±5.01 mg2/dL2). Treatment-emergent adverse events and treatment-emergent serious adverse events were reported in 98.0% and 26.5% of patients, respectively; no new safety concerns were identified. Continuous use of rhPTH(1-84) over 6 years resulted in a favorable safety profile, was effective, and improved key measurements of mineral homeostasis, notably normalization of urinary calcium. Disclosures: All of the authors disclose a relationship with Shire: advisory board member, JPB, MAL, MM, DMS, TJV; consultant, JPB, BLC, MAL, MM, DMS, TJV; grant recipient, JPB, DD, MM, MP, DMS, MLW; employee, H-ML, NS; research investigator, JPB, HB, JR, DMS, TJV, MLW, NBW; speaker, JPB, HB, MLW, NBW. Funding: Shire
| S-EPMC6554941 | biostudies-literature
Project description:IntroductionHigher concentrations of serum 25-hydroxyvitamin D (25(OH)D) and lower concentrations of parathyroid hormone (PTH) are associated with lower insulin resistance and incident diabetes in non-Hispanic White and Hispanic Americans. Results are mixed in other populations, with no observational studies in a large multiethnic cohort. The association of serum 25(OH)D with diabetes may vary by adiposity level.Research design and methodsAmong 5611 participants in the Multi-Ethnic Study of Atherosclerosis without diabetes at baseline, cross-sectional associations of serum 25(OH)D with homeostasis model assessment of insulin resistance (HOMA-IR) and HOMA-β were examined using linear regressions. The association of 25(OH)D with incident diabetes over 9 years was examined using Cox proportional hazard regression.ResultsBlack Americans had the highest proportion of individuals with 25(OH)D<20 ng/mL (61%) and White Americans had the least (17%). Serum 25(OH)D was inversely associated with HOMA-IR in fully adjusted models (-0.34% difference in HOMA-IR per ng/mL higher 25(OH)D, p<0.0001). Longitudinally, a 1 ng/mL higher serum 25(OH)D was associated with 2% lower risk of incident diabetes (HR 0.982, CI 0.974 to 0.991), and a 1 pg/mL higher serum PTH was associated with 1% higher risk of incident diabetes (HR 1.007, CI 1.004 to 1.010), both prior to adjustment for waist circumference. After adjusting for waist circumference, a 1 ng/mL higher 25(OH)D was associated with 1% lower risk of incident diabetes (HR 0.991, CI 0.983 to 1.000). The magnitude of association of serum 25(OH)D with incident diabetes was largest at lower waist circumference (p for interaction=0.025). There was no heterogeneity by race/ethnicity (p=0.317).ConclusionsSerum 25(OH)D is inversely associated with insulin resistance and incident diabetes in a diverse cohort, including non-Hispanic White, Black, Hispanic and Chinese Americans. Future research should explore mechanisms for the interaction between serum 25(OH)D and adiposity in this relationship.
| S-EPMC9516211 | biostudies-literature
Project description:BackgroundSmall cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies.MethodsClinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN).ResultsA total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate-standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting.ConclusionsHyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.
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Project description:The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.
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