Dataset Information

The Effects of Long-term Administration of rhPTH(1-84) in Hypoparathyroidism by Bone Histomorphometry.

ABSTRACT: 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??m2 /?m/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.

SUBMITTER: Rubin MR

PROVIDER: S-EPMC6546298 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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The Effects of Long-term Administration of rhPTH(1-84) in Hypoparathyroidism by Bone Histomorphometry.

Rubin Mishaela R MR Zhou Hua H Cusano Natalie E NE Majeed Rukshana R Omeragic Beatriz B Gomez Maximo M Nickolas Thomas L TL Dempster David W DW Bilezikian John P JP

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20180816 11

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 ...[more]

PMID: 29972871

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Project description:Dynamic bone histomorphometry is the standard method for measuring bone remodeling at the level of individual events. Although dynamic bone histomorphometry is an invaluable tool for understanding osteoporosis and other metabolic bone diseases, the technique's two-dimensional nature requires the use of stereology and prevents measures of individual remodeling event number and size. Here, we used a novel three-dimensional fluorescence imaging technique to achieve measures of individual resorption cavities and formation events. We performed this three-dimensional histomorphometry approach using a common model of postmenopausal osteoporosis, the ovariectomized rat. The three-dimensional images demonstrated the spatial relationship between resorption cavities and formation events consistent with the hemiosteonal model of cancellous bone remodeling. Established ovariectomy was associated with significant increases in the number of resorption cavities per unit bone surface (2.38 ± 0.24 mm⁻² sham surgery versus 3.86 ± 0.35 mm⁻² bilateral ovariectomy [OVX], mean ± SD, p < 0.05) and total volume occupied by cavities per unit bone volume (0.38% ± 0.06% sham versus 1.12% ± 0.18% OVX, p < 0.001), but there was no difference in surface area per resorption cavity, maximum cavity depth, or cavity volume. In addition, we found that established ovariectomy is associated with increased size of bone formation events because of the merging of formation events (23,700 ± 6,890 µm² sham verusus 33,300 ± 7,950 µm² OVX). No differences in mineral apposition rate (determined in 3D) were associated with established ovariectomy. That established estrogen depletion is associated with increased number of remodeling events with only subtle changes in remodeling event size suggests that circulating estrogens may have their primary effect on the origination of new basic multicellular units with relatively little effect on the progression and termination of active remodeling events.

Project description:Background and objectivesOver the past decade, the management of CKD-mineral and bone disorder has changed substantially, altering the pattern of bone disease in CKD. We aimed to evaluate the natural history of kidney bone disease in contemporary kidney transplant recipients and patients on dialysis.Design, settings, participants, & measurementsSixty one patients on dialysis who were referred to kidney transplantation participated in this prospective cohort study during November 2009 and December 2010. We performed baseline bone biopsies while the patients were on dialysis and repeated the procedure in 56 patients at 2 years after kidney transplantation or 2 years after baseline if transplantation was not performed. Measurements of mineral metabolism and bone turnover, as well as dual energy x-ray absorptiometry scans, were obtained concurrently.ResultsA total of 37 out of 56 participants received a kidney transplant, of which 27 underwent successful repeat bone biopsy. The proportion of patients with high bone turnover declined from 63% at baseline to 19% at 2 years after kidney transplantation, whereas the proportion of those with low bone turnover increased from 26% to 52%. Of 19 participants remaining on dialysis after 2 years, 13 underwent successful repeat biopsy. The proportion of patients remaining on dialysis with high bone turnover decreased from 69% to 31%, and low bone turnover increased from 8% to 38%. Abnormal bone mineralization increased in transplant recipients from 33% to 44%, but decreased in patients remaining on dialysis from 46% to 15%. Trabecular bone volume showed little change after transplantation, but low bone volume increased in patients remaining on dialysis. Bone mineral density did not correlate with histomorphometric findings.ConclusionsBone turnover decreased over time both in patients remaining on dialysis and in kidney transplant recipients. Bone mineral density and bone biomarkers were not associated with bone metabolism changes detected in bone biopsy specimens.

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.

Dataset Information

The Effects of Long-term Administration of rhPTH(1-84) in Hypoparathyroidism by Bone Histomorphometry.

Publications

The Effects of Long-term Administration of rhPTH(1-84) in Hypoparathyroidism by Bone Histomorphometry.

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