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Therapy of Hypoparathyroidism With rhPTH(1-84): A Prospective, 8-Year Investigation of Efficacy and Safety.

ABSTRACT: CONTEXT:Conventional treatment of hypoparathyroidism is associated with decreased renal function and increased bone mineral density (BMD). OBJECTIVE:To evaluate the effects of 8 years of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] therapy on key biochemical and densitometric indices. DESIGN:Prospective open-label trial. SETTING:Tertiary medical center. PARTICIPANTS:Twenty-four subjects with hypoparathyroidism. INTERVENTION:Treatment with rhPTH(1-84) for 8 years. MAIN OUTCOME MEASURES:Supplemental calcium and vitamin D requirements, serum calcium and phosphorus levels, calcium-phosphate product, urinary calcium excretion, estimated glomerular filtration rate (eGFR) and BMD. RESULTS:PTH 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. CONCLUSION:rhPTH(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.

SUBMITTER: Tay YD

PROVIDER: S-EPMC6977408 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Therapy of Hypoparathyroidism With rhPTH(1-84): A Prospective, 8-Year Investigation of Efficacy and Safety.

Tay Yu-Kwang Donovan YD Tabacco Gaia G Cusano Natalie E NE Williams John J Omeragic Beatriz B Majeed Rukshana R Gomez Almonte Maximo M Bilezikian John P JP Rubin Mishaela R MR

The Journal of clinical endocrinology and metabolism 20191101 11

<h4>Context</h4>Conventional treatment of hypoparathyroidism is associated with decreased renal function and increased bone mineral density (BMD).<h4>Objective</h4>To evaluate the effects of 8 years of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] therapy on key biochemical and densitometric indices.<h4>Design</h4>Prospective open-label trial.<h4>Setting</h4>Tertiary medical center.<h4>Participants</h4>Twenty-four subjects with hypoparathyroidism.<h4>Intervention</h4>Treatment with ...[more]

PMID: 31310310

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Project description:Human recombinant (rh)PTH(1-84) was recently approved for the treatment of refractory hypoparathyroidism, based upon a short-term phase 3 clinical trial. Long-term data are needed, because no time limit was placed on the treatment period.We studied the effect of long-term rhPTH(1-84) treatment in hypoparathyroidism for up to 6 years.Prospective open-label study.Referral center.A total of 33 subjects with hypoparathyroidism.rhPTH(1-84) treatment was initiated at a starting dose of 100 ?g every other day for 6 years. Due to the availability of new dosages during the 6-year time period of the study, the dose could be and was adjusted for most patients to a daily dosing regimen.Supplemental calcium and vitamin D requirements, serum and urinary calcium (monthly for 6 mo and then biannually), serum phosphorus, bone turnover markers, and bone mineral density (BMD) biannually.Treatment with rhPTH(1-84) progressively reduced supplemental calcium requirements over 6 years by 53% (P < .0001) and 1,25-dihydroxyvitamin D requirements by 67% (P < .0001). Sixteen subjects (48%) were able to eliminate 1,25-dihydroxyvitamin D supplementation completely. Serum calcium concentration remained stable, and urinary calcium excretion fell. Lumbar spine BMD increased (3.8 ± 1%, P = .004) as did total hip BMD (2.4 ± 1%, P = .02), whereas femoral neck BMD remained stable and the distal one third radius decreased (-4.4 ±1%, P < .0001). Bone turnover markers increased significantly, reaching a 3-fold peak above baseline values at 1 year and subsequently declining but remaining higher than pretreatment values. Hypercalcemia was uncommon (12 episodes over 6 y; 2.5% of all values).Long-term, continuous therapy of hypoparathyroidism for 6 years with rhPTH(1-84) is associated with reductions in supplemental calcium and calcitriol requirements, stable serum calcium concentration, and reduced urinary calcium excretion. The safety profile remains good. These data represent the longest experience with the therapeutic use of PTH for any condition and demonstrate its long-term efficacy and safety in hypoparathyroidism.

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.

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

Dataset Information

Therapy of Hypoparathyroidism With rhPTH(1-84): A Prospective, 8-Year Investigation of Efficacy and Safety.

Publications

Therapy of Hypoparathyroidism With rhPTH(1-84): A Prospective, 8-Year Investigation of Efficacy and Safety.

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