James Sliney

Dynamic and Structural Properties of the Skeleton in Hypoparathyroidism

Hypoparathyroidism, a disorder in which PTH is absent, is associated with BMD that is above average. We studied associated structural and dynamic properties of the skeleton in hypoparathyroidism. Thirty‐three subjects with hypoparathyroidism and 33 age‐ and sex‐matched control subjects with no known metabolic diseases underwent percutaneous iliac crest bone biopsies after double‐labeling with tetracycline. The main outcome was histomorphometric assessment of structural and dynamic skeletal parameters. Subjects with hypoparathyroidism had greater cancellous bone volume (mean ± SD; BV/TV: 23.5 ± 8 versus 19.7 ± 5%, p = 0.02), trabecular width (Tb.Wi: 136.1 ± 37 versus 119.3 ± 21 μm, p = 0.03), and cortical width (Ct.Wi: 923.4 ± 420 versus 753.5 ± 246 μm, p = 0.05) than control subjects. Dynamic skeletal indices, including mineralizing surface (MS: 0.85 ± 1.58 versus 4.27 ± 3.32%, p < 0.0001) and bone formation rate (BFR/BS: 0.006 ± 0.014 versus 0.032 ± 0.028 μm3/μm2/d, p < 0.0001), were profoundly suppressed in the hypoparathyroid subjects. We conclude that hypoparathyroidism is characterized by markedly unusual structural and dynamic properties of bone.

Therapy of Hypoparathyroidism with PTH(1–84): A Prospective Four-Year Investigation of Efficacy and Safety

CONTEXT PTH may be an effective treatment option for hypoparathyroidism, but long-term data are not available. OBJECTIVE We studied the effect of 4 yr of PTH(1-84) treatment in hypoparathyroidism. DESIGN Twenty-seven subjects were treated with PTH(1-84) for 4 yr, with prospective monitoring of calcium and vitamin D requirements, serum and urinary calcium, serum phosphorus, bone turnover markers, and bone mineral density (BMD). RESULTS Treatment with PTH(1-84) reduced supplemental calcium requirements by 37% (P = 0.006) and 1,25-dihydroxyvitamin D requirements by 45% (P = 0.008). Seven subjects (26%) were able to stop 1,25-dihydroxyvitamin D completely. Serum calcium concentration remained stable, and urinary calcium and phosphorus excretion fell. Lumbar spine BMD increased by 5.5 ± 9% at 4 yr (P < 0.0001). Femoral neck and total hip BMD remained stable. At 4 yr, distal radius BMD was not different from baseline. Bone turnover markers increased significantly, reaching a 3-fold peak from baseline values at 6-12 months (P < 0.05 for all), subsequently declining to steady-state levels at 30 months. Hypercalcemia was uncommon (11 episodes in eight subjects over 4 yr; 1.9% of all values), with most episodes occurring within the first 6 months and resolving with adjustment of supplemental calcium and vitamin D. CONCLUSIONS PTH(1-84) treatment of hypoparathyroidism for up to 4 yr maintains the serum calcium concentration, while significantly reducing supplemental calcium and 1,25-dihydroxyvitamin D requirements. Lumbar spine BMD increases without significant changes at other sites. These data provide support for the safety and efficacy of PTH(1-84) therapy in hypoparathyroidism for up to 4 yr.

PTH(1–84) administration reverses abnormal bone‐remodeling dynamics and structure in hypoparathyroidism

Hypoparathyroidism is associated with abnormal structural and dynamic skeletal properties. We hypothesized that parathyroid hormone(1–84) [PTH(1–84)] treatment would restore skeletal properties toward normal in hypoparathyroidism. Sixty‐four subjects with hypoparathyroidism were treated with PTH(1–84) for 2 years. All subjects underwent histomorphometric assessment with percutaneous iliac crest bone biopsies. Biopsies were performed at baseline and at 1 or 2 years. Another group of subjects had a single biopsy at 3 months, having received tetracycline before beginning PTH(1–84) and prior to the biopsy (quadruple‐label protocol). Measurement of biochemical bone turnover markers was performed. Structural changes after PTH(1–84) included reduced trabecular width (144 ± 34 µm to 128 ± 34 µm, p = 0.03) and increases in trabecular number (1.74 ± 0.34/mm to 2.07 ± 0.50/mm, p = 0.02) at 2 years. Cortical porosity increased at 2 years (7.4% ± 3.2% to 9.2% ± 2.4%, p = 0.03). Histomorphometrically measured dynamic parameters, including mineralizing surface, increased significantly at 3 months, peaking at 1 year (0.7% ± 0.6% to 7.1% ± 6.0%, p = 0.001) and persisting at 2 years. Biochemical measurements of bone turnover increased significantly, peaking at 5 to 9 months of therapy and persisting for 24 months. It is concluded that PTH(1–84) treatment of hypoparathyroidism is associated with increases in histomorphometric and biochemical indices of skeletal dynamics. Structural changes are consistent with an increased remodeling rate in both trabecular and cortical compartments with tunneling resorption in the former. These changes suggest that PTH(1–84) improves abnormal skeletal properties in hypoparathyroidism and restores bone metabolism toward normal euparathyroid levels.

Three dimensional cancellous bone structure in hypoparathyroidism

By conventional 2-dimensional histomorphometric analysis, we have shown that cancellous bone architecture is markedly altered in hypoparathyroidism. We have now extended these observations to a 3-dimensional analysis using microcomputed tomography. Percutaneous iliac crest bone biopsies were analyzed by high-resolution microcomputed tomography from the following 25 subjects with hypoparathyroidism: 5 postmenopausal women, 13 premenopausal women and 7 men. Thirteen living premenopausal healthy controls and 12 cadaver subjects without bone disease served as matched controls. Hypoparathyroid subjects had significantly greater bone surface density (BS/TV: 5.74+/-4.7 vs. 3.73+/-1.01 mm(2)/mm(3) [mean+/-SD]; p=0.04), trabecular thickness (Tb.Th: 0.25+/-0.19 vs. 0.17+/-0.04 mm; p=0.04), trabecular number (Tb.N: 2.99+/-3.4 vs. 1.62+/-0.39 mm(-1); p=0.05) and connectivity density (Conn.D: 16.63+/-18.7 vs. 8.39+/-5.8 mm(3); p=0.04) in comparison to matched controls. When an additional 8 hypoparathyroid (total n=33) and 24 cadaver (total cadaver n=36) subjects were added to the groups for an unmatched analysis, hypoparathyroid subjects had significantly greater cancellous bone volume (BV/TV: 26.98+/-10 vs. 15.39+/-4%; p<0.001), while trabecular separation (Tb.Sp: 0.642+/-0.10 vs. 0.781+/-0.13 mm; p<0.001) and estimation of the plate-rod characteristic (SMI: -0.457+/-1.52 vs. 0.742+/-0.51; p<0.001) were significantly lower, the latter observation implying a more plate-like trabecular structure. Variables of cancellous bone structure in the hypoparathyroid subjects, as assessed by microcomputed tomography, were highly correlated with those assessed by conventional histomorphometry. We conclude that cancellous bone in hypoparathyroidism is abnormal, suggesting that parathyroid hormone is required to maintain normal trabecular structure. The effect of these structural changes on bone strength remains to be determined.

Circulating Sclerostin in Disorders of Parathyroid Gland Function

CONTEXT Sclerostin, a protein encoded by the SOST gene in osteocytes and an antagonist of the Wnt signaling pathway, is down-regulated by PTH administration. Disorders of parathyroid function are useful clinical settings to study this relationship. OBJECTIVE The objective of the study was to evaluate sclerostin in two different disorders of parathyroid function, primary hyperparathyroidism and hypoparathyroidism, and to analyze the relationship between sclerostin and PTH, bone markers, and bone mineral density. DESIGN This is a cross-sectional study. SETTING The study was conducted at a clinical research center. PATIENTS Twenty hypoparathyroid and 20 hyperparathyroid patients were studied and compared to a reference control group. RESULTS Serum sclerostin was significantly higher in hypoparathyroid subjects than in hyperparathyroid subjects (P < 0.0001) and controls (P < 0.0001). PTH was negatively associated with sclerostin, achieving statistical significance in hypoparathyroidism (r = -0.545; P = 0.02). The bone turnover markers, cross-linked C-telopeptide of type I collagen (CTX) and amino-terminal propeptide of type I collagen (P1NP), were differently associated with sclerostin according to the parathyroid disorder. In primary hyperparathyroidism, bone turnover markers were associated negatively with sclerostin (for P1NP, r = -0.490; P = 0.03). In hypoparathyroidism, bone turnover markers were associated positively with sclerostin (for CTX, r = +0.571; P = 0.01). Although there was no significant correlation between bone mineral density and sclerostin in either parathyroid disorder, there was a significant positive relationship between sclerostin and bone mineral content in hypoparathyroidism. CONCLUSIONS The results are consistent with the hypothesis that PTH is a regulator of sclerostin in human disorders of parathyroid function. In addition, the results suggest that bone mineral content may be another factor that influences sclerostin.

The Effect of PTH(1–84) on Quality of Life in Hypoparathyroidism

CONTEXT Complaints from hypoparathyroid patients often reflect a reduction in quality of life (QOL), yet few data exist characterizing these complaints or the potential effects of PTH therapy to ameliorate them. OBJECTIVE We tested the hypothesis that PTH(1-84) therapy improves QOL in hypoparathyroidism. DESIGN Fifty-four hypoparathyroid subjects received open-label recombinant human PTH(1-84). Before and during PTH(1-84), subjects completed the RAND 36-Item Health Survey, a measure of health-related QOL covering 8 domains of physical and mental health. RESULTS At baseline, subjects scored significantly lower than the normative reference range in all 8 domains (T-scores -1.35 to -0.78; P < 0.001 for all). With PTH(1-84), the total score improved as early as month 1 and remained higher through 1 year (400 ± 200 to 478 ± 230; P = 0.001). The overall mental component summary score improved (204 ± 110 to 247 ± 130; P = 0.001), as did 3 mental health domains (vitality, social functioning, and mental health), all within 1 month (T-scores improving from -1.3 to -0.7, -1.0 to -0.6, and -0.9 to -0.3, respectively; P < 0.05 for all). The overall physical component summary score also increased by 1 month and remained higher at 1 year (196 ± 110 to 231 ± 130; P = 0.003) as did 2 physical health domains (physical functioning and general health: T-scores improving from -0.8 to -0.4, -1.2 to -0.8, respectively; P < 0.01 for both). CONCLUSIONS These data suggest that hypoparathyroidism is associated with compromised QOL. Along with improved biochemical control, these results indicate that PTH(1-84) treatment of hypoparathyroidism improves physical and mental functioning.

Parathyroid Hormone Stimulates Circulating Osteogenic Cells in Hypoparathyroidism

CONTEXT The osteoanabolic properties of PTH may be due to increases in the number and maturity of circulating osteogenic cells. Hypoparathyroidism is a useful clinical model because this hypothesis can be tested by administering PTH. OBJECTIVE The objective of the study was to characterize circulating osteogenic cells in hypoparathyroid subjects during 12 months of PTH (1-84) administration. DESIGN Osteogenic cells were characterized using flow cytometry and antibodies against osteocalcin, an osteoblast-specific protein product, and stem cell markers CD34 and CD146. Changes in bone formation from biochemical markers and quadruple-labeled transiliac crest bone biopsies (0 and 3 month time points) were correlated with measurements of circulating osteogenic cells. SETTING The study was conducted at a clinical research center. PATIENTS Nineteen control and 19 hypoparathyroid patients were included in the study. INTERVENTION Intervention included the administration of PTH (1-84). RESULTS Osteocalcin-positive cells were lower in hypoparathyroid subjects than controls (0.7 ± 0.1 vs. 2.0 ± 0.1%; P < 0.0001), with greater coexpression of the early cell markers CD34 and CD146 among the osteocalcin-positive cells in the hypoparathyroid subjects (11.0 ± 1.0 vs. 5.6 ± 0.7%; P < 0.001). With PTH (1-84) administration, the number of osteogenic cells increased 3-fold (P < 0.0001), whereas the coexpression of the early cell markers CD34 and CD146 decreased. Increases in osteogenic cells correlated with circulating and histomorphometric indices of osteoblast function: N-terminal propeptide of type I procollagen (R(2) = 0.4, P ≤ 0.001), bone-specific alkaline phosphatase (R(2) = 0.3, P < 0.001), osteocalcin (R(2) = 0.4, P < 0.001), mineralized perimeter (R(2) = 0.5, P < 0.001), mineral apposition rate (R(2) = 0.4, P = 0.003), and bone formation rate (R(2) = 0.5, P < 0.001). CONCLUSIONS It is likely that PTH stimulates bone formation by stimulating osteoblast development and maturation. Correlations between circulating osteogenic cells and histomorphometric indices of bone formation establish that osteoblast activity is being identified by this methodology.

Mini-review: new therapeutic options in hypoparathyroidism.

Hypoparathyroidism is a disorder characterized by hypocalcemia and low or absent parathyroid hormone (PTH). While standard treatment of hypoparathyroidism consists of oral calcium and vitamin D supplementation, maintaining serum calcium levels can be a challenge, and concerns exist regarding hypercalciuria and ectopic calcifications that can be associated with such treatment. Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved treatment. This mini-review focuses on the use of PTH in the treatment of hypoparathyroidism. There are two available formulations of PTH: teriparatide [human PTH(1-34)] and the full-length molecule, PTH(1-84). Both PTH(1-34) and PTH(1-84) lower supplemental vitamin D requirements and increase markers of bone turnover. Densitometric and histomorphometric studies in some subjects treated with PTH(1-84) demonstrate improvement in abnormal bone-remodeling dynamics and return of bone metabolism toward normal euparathyroid levels. Further detailed examination of skeletal features following therapy with the different treatment regimens and data regarding the effect of PTH on quality of life measures are under active investigation.

Use of parathyroid hormone in hypoparathyroidism.

Hypoparathyroidism is a disorder characterized by hypocalcemia, deficient PTH, and abnormal bone remodeling. Standard treatment of hypoparathyroidism consists of oral calcium and vitamin D supplementation. However, maintaining serum calcium levels can be a challenge. In addition, concerns exist regarding hypercalciuria and ectopic calcifications that can be associated with such treatment. Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved treatment. This review focuses on the use of PTH in the treatment of hypoparathyroidism, in the form of teriparatide [PTH(1–34)] and the full-length molecule, PTH(1–84). Studies in hypoparathyroid subjects demonstrate that PTH(1–34) and PTH(1–84) lower or abolish supplemental calcium and vitamin D requirements as well as increase markers of bone turnover. Densitometric and histomorphometric studies in some subjects treated with PTH(1–34) and PTH(1–84) show an improvement in bone-remodeling dynamics and return of bone metabolism toward normal levels. Given the chronic nature of hypoparathyroidism, and the expectation that PTH will be used for extended periods of time in hypoparathyroidism, further studies are needed to determine the long-term safety of PTH therapy in this population.