Bone disease in hypoparathyroidism

Clarke, B.L.

doi:10.1590/0004-2730000003399

Cited by 22 publications

(16 citation statements)

References 24 publications

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“…Parathyroid hormone (PTH) signaling contributes via PTH-related protein (PTHrP)-derived peptides, to the mechanical loading-induced osteocyte-mediated adaptation of bone tissue composition ( 52 , 53 ). Inherited hypoparathyroidism is a rare disease that reduces bone turnover causing higher bone mineral density (BMD) and brittle bone ( 54 ). However, the osteocyte mechanotransduction-mediated bone adaptation in inherited hypoparathyroidism is still unknown.…”

Section: Introductionmentioning

confidence: 99%

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

2020

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Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases.

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Section: Introductionmentioning

confidence: 99%

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

2020

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“…It is well‐established that bone turnover levels are low, in association with structural skeletal alterations, including higher cancellous bone volume and trabecular thickness, but lower bone surface per volume . Increased bone mineral density (BMD) has been reported as compared to age‐ and sex‐matched controls and postmenopausal bone loss may also be attenuated . Noteworthy, Seeman and colleagues suggested that PTH deficiency might protect against age‐related bone loss; however, their study did not allow conclusions on the related mechanism (decelerated loss or higher peak bone mass).…”

Section: Introductionmentioning

confidence: 99%

PTH(1-84) Administration in Hypoparathyroidism Transiently Reduces Bone Matrix Mineralization

Misof

Roschger

Dempster

et al. 2015

Journal of Bone and Mineral Research

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Patients with hypoparathyroidism have low circulating parathyroid (PTH) levels and higher cancellous bone volume and trabecular thickness. Treatment with PTH(1-84) was shown to increase abnormally low bone remodeling dynamics. In this work, we studied the effect of 1yr or 2yr PTH(1-84) treatment on cancellous and cortical bone mineralization density distribution (Cn. and Ct.BMDD) based on quantitative backscattered electron imaging (qBEI) in paired transiliac bone biopsy samples. The study cohort comprised 30 adult hypoparathyroid patients (14 treated for 1yr/16 treated for 2yr). At baseline, Cn.BMDD was shifted to higher mineralization densities in both treatment groups (average degree of mineralization Cn.CaMean +3.9% and +2.7%, p<0.001) compared to reference BMDD. After 1yr PTH(1-84), Cn.CaMean was significantly lower than that at baseline (-6.3%, p<0.001), while in the 2yr PTH(1-84) group Cn.CaMean did not differ from baseline. Significant changes of Ct.BMDD were observed in the 1yr treatment group only. The change in histomorphometric bone formation (mineralizing surface) was predictive for Cn.BMDD outcomes in the 1yr PTH(1-84) group, but not in the 2yr PTH(1-84) group. Our findings suggest higher baseline bone matrix mineralization consistent with the decreased bone turnover in hypoparathyroidism. PTH(1-84) treatment caused differential effects dependent on treatment duration which were consistent with the histomorphometric bone formation outcomes. The greater increase in bone formation during the first yr of treatment was associated with a decrease in bone matrix mineralization, suggesting that PTH(1-84) exposure to the hypoparathyroid skeleton has the greatest effects on BMDD early in treatment.

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“…In hypoparathyroidism, the bone formation rate is markedly suppressed, with a significant reduction in remodeling activation frequency . The reduced remodeling properties are particularly evident in the trabecular compartment, where histomorphometric studies have shown the greatest reduction in formation rate . Different from what is seen in hypoparathyroid patients, skeletal turnover is normal in most cases of postmenopausal osteoporosis and mechanisms associated with bone loss are primarily caused by a negative remodeling balance .…”

Section: Discussionmentioning

confidence: 96%

Comparative Effect of rhPTH(1-84) on Bone Mineral Density and Trabecular Bone Score in Hypoparathyroidism and Postmenopausal Osteoporosis

Cipriani

Pepe

Silva

et al. 2018

Journal of Bone and Mineral Research

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Parathyroid hormone (PTH) (1-84) improves lumbar spine (LS) areal bone mineral density (aBMD) and trabecular bone score (TBS) in hypoparathyroidism over a 2-year treatment period. Studies in osteoporosis have shown that with PTH(1-34) there is a significant increase in LS aBMD and TBS. In this article, we provide new data comparing the effects of the same form of PTH, namely recombinant human PTH, rhPTH(1-84), on aBMD and TBS in hypoparathyroid and osteoporotic patients over an 18-month treatment period. We studied 19 premenopausal (mean age 45.8 ± 11.8 years) and 16 postmenopausal (71 ± 8.4 years) hypoparathyroid women and 38 women with postmenopausal osteoporosis (71 ± 8.3 years). DXA (hologic) at LS, femoral neck, total hip, and distal one-third radius was assessed. Site-matched LS TBS data were extracted from deidentified spine DXA scans using the TBS iNsight software (version 2.1; Medimaps, Geneva, Switzerland). We observed a significant increase in LS aBMD in premenopausal and postmenopausal hypoparathyroid (3 ± 1.1%, p < 0.02 and 3.1 ± 1.4%, p < 0.05, respectively) and osteoporosis (6.2 ± 1.1%, p < 0.0001) patients after 18 months. There was a significant increase (3 ± 1.5%, p = 0.05) in TBS in premenopausal hypoparathyroid patients. A change in TBS was not observed in either postmenopausal group. One-third radius aBMD significantly declined in postmenopausal hypoparathyroid (-3.6 ± 1.1%, p < 0.01) and osteoporosis (-8 ± 1.4%, p < 0.0001) patients. Overall, there was a significantly greater increase in TBS in premenopausal hypoparathyroid than in osteoporosis patients (p < 0.0001) after adjusting for baseline values, age, BMI, and average daily dose of rhPTH(1-84). Comparing only postmenopausal women, the LS aBMD increase was greater in osteoporotic than hypoparathyroid subjects (p < 0.01). Our results demonstrate that rhPTH(1-84) administered for 18 months increases trabecular aBMD in hypoparathyroidism and postmenopausal osteoporosis with greater gains observed in the subjects with osteoporosis. The data suggest different effects of PTH on bone depending on the baseline skeletal structure, skeletal dynamics, compartments, and menopausal status. © 2018 American Society for Bone and Mineral Research.

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Bone disease in hypoparathyroidism

Cited by 22 publications

References 24 publications

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

PTH(1-84) Administration in Hypoparathyroidism Transiently Reduces Bone Matrix Mineralization

Comparative Effect of rhPTH(1-84) on Bone Mineral Density and Trabecular Bone Score in Hypoparathyroidism and Postmenopausal Osteoporosis

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