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1.
J Clin Endocrinol Metab ; 98(11): 4285-90, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24037886

ABSTRACT

CONTEXT: Transient and permanent postoperative hypoparathyroidism are recognized complications of neck surgery. Postoperative hypoparathyroidism is usually considered permanent when it persists for 6 months; in rare cases, recovery of hypoparathyroidism through 1 year has been described. Recovery of hypoparathyroidism years after diagnosis has not previously been reported. OBJECTIVE: We report four patients being treated with PTH(1-84) in a research protocol who recovered from postoperative hypoparathyroidism many years after onset. METHODS: Recovery from hypoparathyroidism was established by: 1) serum calcium and PTH levels within the normal range off PTH(1-84) treatment for at least 1 week; 2) requirement for daily calcium supplementation reduced to ≤1 g; and 3) no supplemental active vitamin D therapy. RESULTS: Hypoparathyroidism developed in three subjects after repeated neck surgery for primary hyperparathyroidism and in one subject after total thyroidectomy for Graves' disease. Parathyroid tissue autotransplant was performed in two of the four subjects. Two had undetectable PTH levels at study entry, whereas the other two subjects had detectable, although low, PTH levels. Hypoparathyroidism had been present for at least 8 years, and in one case for 16 years. The recovery of parathyroid function followed treatment with PTH(1-84) for 36 to 63 months. CONCLUSIONS: Although it remains relatively rare, this report documents recovery of long-term postoperative hypoparathyroidism many years after the initial diagnosis. A potential role for exogenous PTH is intriguing with several plausible mechanisms.


Subject(s)
Hyperparathyroidism/surgery , Hypoparathyroidism/metabolism , Parathyroid Hormone/metabolism , Postoperative Complications/metabolism , Recovery of Function/physiology , Adult , Aged , Female , Graves Disease/surgery , Humans , Middle Aged , Parathyroid Glands/metabolism , Parathyroid Glands/transplantation , Parathyroidectomy/adverse effects , Thyroidectomy/adverse effects , Transplantation, Autologous
2.
J Clin Endocrinol Metab ; 98(6): 2356-61, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23596139

ABSTRACT

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.


Subject(s)
Hypoparathyroidism/drug therapy , Parathyroid Hormone/therapeutic use , Quality of Life , Adolescent , Adult , Aged , Female , Humans , Hypoparathyroidism/psychology , Male , Middle Aged , Recombinant Proteins/therapeutic use
3.
Endocrine ; 44(1): 237-46, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23099796

ABSTRACT

Most studies of combination therapy with teriparatide and a bisphosphonate have not shown greater efficacy over monotherapy. The bisphosphonate risedronate, has not been studied in this context. The purpose of this proof-of-concept study was to assess whether combination risedronate and teriparatide increases bone mineral density (BMD) more than monotherapy with either drug alone. This was a randomized, double-blinded study of risedronate (35 mg weekly plus placebo injection), teriparatide (20 µg subcutaneously daily plus placebo tablet), or both risedronate plus teriparatide (combination) for 18 months in 29 men with low BMD. The primary endpoint was percentage change in lumbar spine (LS) BMD at 18 months. Secondary outcomes included changes in bone markers and BMD at other sites and interim time-points. All therapies increased LS BMD as compared with baseline (p < 0.05), but there were no between-group differences at 18 months. Total hip (TH) BMD increased to a greater extent in the combination group (mean ± SEM, 3.86 ± 1.1 %) versus teriparatide (0.29 ± 0.95 %) or risedronate (0.82 ± 0.95 %; p < 0.05 for both). Femoral neck (FN) BMD also increased more in the combination group (8.45 ± 1.8 %) versus risedronate (0.50 ± 1.7 %; p = 0.002), but was not different from teriparatide alone. In the combination group, P1NP and CTX increased rapidly, mirroring the teriparatide-alone arm. There were no between-group differences in adverse events. Combination teriparatide and risedronate increased BMD at the LS, TH as well as the FN and provided greater BMD increases at the TH than monotherapy. The results suggest combination risedronate and teriparatide therapy holds promise as a treatment for osteoporosis.


Subject(s)
Bone Density Conservation Agents/administration & dosage , Etidronic Acid/analogs & derivatives , Osteoporosis/drug therapy , Teriparatide/administration & dosage , Adult , Aged , Aged, 80 and over , Bone Density/drug effects , Double-Blind Method , Drug Therapy, Combination , Etidronic Acid/administration & dosage , Femur Neck , Humans , Injections, Subcutaneous , Lumbar Vertebrae , Male , Middle Aged , Placebos , Risedronic Acid
4.
J Clin Endocrinol Metab ; 98(1): 137-44, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23162103

ABSTRACT

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.


Subject(s)
Hypoparathyroidism/drug therapy , Parathyroid Hormone/adverse effects , Parathyroid Hormone/therapeutic use , Adult , Aged , Calcium/administration & dosage , Female , Follow-Up Studies , Hormone Replacement Therapy/adverse effects , Humans , Male , Middle Aged , Parathyroid Hormone/administration & dosage , Prospective Studies , Time Factors , Treatment Outcome , Vitamin D/administration & dosage , Vitamin D/analogs & derivatives
5.
Endocrine ; 41(3): 410-4, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22311174

ABSTRACT

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.


Subject(s)
Hypoparathyroidism/drug therapy , Bone Density , Bone Density Conservation Agents/therapeutic use , Bone Remodeling , Hormone Replacement Therapy , Humans , Hypoparathyroidism/diagnosis , Hypoparathyroidism/diet therapy , Hypoparathyroidism/physiopathology , Parathyroid Hormone/therapeutic use , Peptide Fragments/therapeutic use , Recombinant Proteins/therapeutic use , Teriparatide/therapeutic use
6.
J Clin Endocrinol Metab ; 96(12): 3804-10, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21937621

ABSTRACT

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.


Subject(s)
Bone Morphogenetic Proteins/blood , Parathyroid Diseases/blood , Parathyroid Glands/physiopathology , Adaptor Proteins, Signal Transducing , Adult , Aged , Bone Density/physiology , Cross-Sectional Studies , Female , Genetic Markers , Humans , Male , Middle Aged , Parathyroid Diseases/physiopathology , Parathyroid Glands/metabolism
7.
J Bone Miner Res ; 26(11): 2727-36, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21735476

ABSTRACT

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.


Subject(s)
Bone Remodeling/physiology , Hypoparathyroidism/drug therapy , Hypoparathyroidism/physiopathology , Parathyroid Hormone/administration & dosage , Parathyroid Hormone/therapeutic use , Adolescent , Adult , Aged , Biomarkers/metabolism , Biopsy , Bone Remodeling/drug effects , Bone and Bones/drug effects , Bone and Bones/pathology , Bone and Bones/physiopathology , Case-Control Studies , Cohort Studies , Female , Humans , Ilium/drug effects , Ilium/pathology , Ilium/physiopathology , Longitudinal Studies , Male , Middle Aged , Parathyroid Hormone/pharmacology , Young Adult
8.
Bone ; 46(1): 190-5, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19782782

ABSTRACT

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.


Subject(s)
Bone and Bones/pathology , Hypoparathyroidism/pathology , Imaging, Three-Dimensional/methods , Adult , Aged , Aged, 80 and over , Bone and Bones/metabolism , Female , Humans , Hypoparathyroidism/metabolism , Male , Middle Aged , Parathyroid Hormone/metabolism , X-Ray Microtomography
9.
J Bone Miner Res ; 23(12): 2018-24, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18684087

ABSTRACT

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 microm, p = 0.03), and cortical width (Ct.Wi: 923.4 +/- 420 versus 753.5 +/- 246 microm, 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 microm(3)/microm(2)/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.


Subject(s)
Bone Density , Bone and Bones/metabolism , Hypoparathyroidism/pathology , Adult , Animals , Biopsy , Bone and Bones/pathology , Case-Control Studies , Cohort Studies , Densitometry/methods , Female , Humans , Male , Middle Aged , Postmenopause , Premenopause
10.
Clin Chem ; 53(8): 1470-6, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17599957

ABSTRACT

BACKGROUND: A new parathyroid hormone (PTH) species, the N-terminal PTH form (N-PTH), is distinct from intact human PTH of 84 amino acid residues [hPTH(1-84)] and is recognized in a 3rd-generation assay of "whole" PTH (wPTH; the 1-2 epitope) but not in a 2nd-generation assay of "total" PTH (tPTH; the 12-18 epitope). N-PTH usually represents <15% of wPTH but can be overproduced in severe primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism. We investigated whether N-PTH is also overproduced in parathyroid cancer and whether N-PTH concentration is influenced by calcimimetic therapy. METHODS: We studied 8 patients with parathyroid carcinoma before and at week 16 of cinacalcet therapy, 6 patients with PHPT, and 6 control individuals. We fractionated sera with HPLC and analyzed fractions with the 2 assays to quantify hPTH(1-84), N-PTH, and non-(1-84) PTH fragments. RESULTS: Half of parathyroid carcinoma patients had an increased wPTH:tPTH ratio [mean (SD), 1.35 (0.29)]; the others had a typical ratio [0.72 (0.12)]. HPLC fractionation of sera from 2 high-ratio patients confirmed N-PTH overproduction [65% (12%) of wPTH]. The N-PTH fraction was <15% of wPTH in PHPT and healthy individuals. Calcimimetic therapy appreciably reduced calcium concentrations in parathyroid carcinoma patients but had little influence on PTH concentration, the wPTH:tPTH ratio, or the PTH HPLC profile. CONCLUSION: N-PTH is overproduced in some parathyroid cancer patients, but calcimimetic therapy does not influence its production. The clinical implications of this finding in parathyroid carcinoma await additional studies with an emphasis on N-PTH's biological activity and with larger numbers of patients.


Subject(s)
Biomarkers, Tumor/biosynthesis , Parathyroid Hormone/biosynthesis , Parathyroid Neoplasms/metabolism , Peptide Fragments/biosynthesis , Adult , Aged , Chromatography, High Pressure Liquid , Cinacalcet , Female , Humans , Hyperparathyroidism, Primary/drug therapy , Hyperparathyroidism, Primary/metabolism , Male , Middle Aged , Naphthalenes/therapeutic use , Parathyroid Hormone/blood , Parathyroid Neoplasms/drug therapy , Peptide Fragments/blood
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