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1.  The Effects in the Rat of Varying Intakes of Dietary Calcium, Phosphorus, and Hydrogen Ion on Hyperparathyroidism Due to Chronic Renal Failure 
Journal of Clinical Investigation  1974;53(1):256-269.
Renal failure of 4 wk duration in rats led to parathyroid enlargement, increased bone resorption, and decreased tubular reabsorption of phosphate by the remnant kidney. The degree of hyperparathyroidism was influenced by each of the three dietary factors investigated. In the first study increasing calcium intake reduced the size of the parathyroids by increasing calcium and reducing phosphate absorption. In the second study phosphate intake was linearly related to parathyroid gland size in the uremic animals and associated with rising plasma phosphate levels. In the last study acidosis led directly to increased bone resorption but small parathyroid glands associated with elevated ionized calcium levels. Alkalosis lowered the serum ionized calcium and led to parathyroid enlargement and the expected associated findings. It was shown that parathyroid weight reflected both metabolic activity as judged by amino acid uptake, and the content of immunoassayable parathyroid hormone. In all studies gland weight was inversely related to serum ionized calcium.
PMCID: PMC301461  PMID: 4808640
2.  Fasting Plasma Glucose Levels Are Related to Bone Mineral Density in Postmenopausal Women with Primary Hyperparathyroidism 
How glucose levels affect bone in patients with primary hyperparathyroidism is unknown, although the prevalence of impaired glucose metabolism is higher in patients with primary hyperparathyroidism. The present study was performed to examine the relationships between fasting plasma glucose (FPG) and various indices in 93 postmenopausal women with primary hyperparathyroidism. Bone mineral density (BMD) and body composition were measured by dual-energy Xray absorptiometry. Body weight, body mass index (BMI), fat mass and % fat were positively related to FPG. Serum levels of calcium and parathyroid hormone (PTH) as well as bone metabolic indices were not related to FPG and immunoreactive insulin levels. As for BMD, FPG was positively related to the Z scores of BMD at the lumbar spine and femoral neck, although it was not significantly related to the Z-score of BMD at the radius. On the other hand, immunoreactive insulin levels were not significantly related to BMD parameters at any sites. In multiple regression analysis, FPG was significantly related to BMD (Z score) at the lumbar spine and femoral neck, when body weight, BMI, immunoreactive insulin, PTH, and bone resorption indices were considered; however, these relationships at the lumbar spine were not significant when fat mass was considered. In conclusion, the present study indicated that FPG levels were positively related to BMD at the lumbar spine and femoral neck in postmenopausal women with primary hyperparathyroidism.
PMCID: PMC2596330  PMID: 19079676
Primary hyperparathyroidism; glucose; bone mineral density; body composition
3.  Parathyroid-specific interaction of the calcium-sensing receptor and Gaq 
Kidney international  2008;74(12):1548-1556.
The calcium-sensing receptor regulates various parathyroid gland functions, including hormone secretion, gene transcription, and chief cell hyperplasia through Gαq- and Gαi-dependent signaling pathways. To determine the specific function of Gαq in these processes, we generated transgenic mice using the human parathyroid hormone promoter to drive overexpression of a dominant negative Gαqloop minigene to selectively disrupt Gαq function in the parathyroid gland. The Gαqloop mRNA was highly expressed in the parathyroid gland but not in other tissues of these transgenic mice. Gross appearance, body weight, bone mineral density, and survival of the transgenic mice were indistinguishable from those of their wild-type littermates. Adult transgenic mice, however, exhibited an increase in parathyroid hormone mRNA and in its basal serum level as well as in gland size. The response of the parathyroid gland to hypocalcemia was found to be reduced in sensitivity in the transgenic mice when compared to their wild-type controls. Abnormalities of the parathyroid gland function in these transgenic mice were similar to those of heterozygous Gαq+/− and calcium sensing receptor+/− mice. These studies demonstrate the feasibility of selectively targeting the parathyroid gland to investigate signaling mechanisms downstream of the calcium receptor.
PMCID: PMC2760404  PMID: 18813283
calcium-sensing receptor; G-protein; parathyroid gland
4.  Kidney cadmium levels and associations with urinary calcium and bone mineral density: a cross-sectional study in Sweden 
Environmental Health  2013;12:22.
Cadmium (Cd) can cause renal damage and osteoporosis after high-level exposure. Recently such effects, including increased urinary excretion of calcium, have been shown also at low-level exposure, as measured by Cd in blood or urine. However, associations with kidney Cd have not been examined. The aim of this study was to explore the relation between kidney Cd and urinary calcium excretion, or bone mineral density.
Cd was determined in kidney cortex biopsies from 109 living kidney donors. Serum was analyzed for ionized calcium, parathyroid hormone and vitamin D. Calcium was analyzed in overnight and 24-hour urine samples. Bone mineral density was measured in a subgroup of 67 donors. Associations between single variables were assessed by Spearman and Pearson correlation coefficients. Differences between independent groups were compared using Student’s t-test. For related samples, paired t-test was applied. Associations between urinary calcium and kidney Cd, ionized serum calcium, serum parathyroid hormone, inactive and active vitamin D and background variables were assessed using multiple linear regression and logistic regression.
In spite of relatively low kidney Cd levels (median 13 μg/g, range 1.5-55 μg/g) kidney Cd and urinary calcium were positively associated, mainly caused by an association in women. Donors with kidney Cd above the median (subgroup mean 23 μg/g) had significantly higher excretion of urinary calcium normalized for creatinine than those below the median (subgroup mean 7.3 μg/g). In women, also the excretion of Ca per hour was higher in those with high kidney Cd (24 hour sample mean 0.21 vs. 0.15 mmol/h; overnight sample 0.16 vs. 0.11 mmol/h). There were negative associations between kidney Cd and bone mineral density, most of which, however, disappeared in multivariate analyses.
This study provides support for an association between kidney Cd levels and urinary calcium excretion in women, but not in men. The results strengthen the case for preventive measures against Cd pollution.
PMCID: PMC3627629  PMID: 23497059
Bone; Bone mineral density; Cadmium; Kidney; Urinary calcium; Kidney donor
5.  Preliminary investigation of plasma levels of sex hormones and human growth factor(s), and P300 latency as correlates to cognitive decline as a function of gender 
BMC Research Notes  2009;2:126.
Aging is marked by declines in levels of many sex hormones and growth factors, as well as in cognitive function. The P300 event-related potential has been established as a predictor of cognitive decline. We decided to determine if this measure, as well as 2 standard tests of memory and attention, may be correlated with serum levels of sex hormones and growth factors, and if there are any generalizations that could be made based on these parameters and the aging process.
In this large clinically based preliminary study several sex-stratified associations between hormone levels and cognition were observed, including (1) for males aged 30 to 49, both IGF-1 and IGFBP-3 significantly associated negatively with prolonged P300 latency; (2) for males aged 30 to 49, the spearman correlation between prolonged P300 latency and low free testosterone was significant; (3) for males aged 60 to 69, there was a significant negative correlation between P300 latency and DHEA levels; (4) for females aged 50 to 59 IGFBP-3 significantly associated negatively with prolonged P300 latency; (5) for females at all age periods, estrogen and progesterone were uncorrelated with P300 latency; and (6) for females aged 40 to 69, there was significant negative correlation between DHEA levels and P300 latency. Moreover there were no statistically significant correlations between any hormone and Wechsler Memory Scale-III (WMS-111). However, in females, there was a significant positive correlation between estrogen levels and the number of Attention Deficit Disorder (ADD) complaints.
Given certain caveats including confounding factors involving psychiatric and other chronic diseases as well as medications, the results may still have important value. If these results could be confirmed in a more rigorously controlled investigation, it may have important value in the diagnosis, prevention and treatment of cognitive impairments and decline.
PMCID: PMC2717101  PMID: 19583872
6.  Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats 
Journal of Clinical Investigation  2000;105(11):1595-1604.
Parathyroid hormone (PTH) is an effective bone anabolic agent, but it must be administered parenterally. An orally active anabolic agent would provide a valuable alternative for treating osteoporosis. NPS 2143 is a novel, selective antagonist (a “calcilytic”) of the parathyroid cell Ca2+ receptor. Daily oral administration of NPS 2143 to osteopenic ovariectomized (OVX) rats caused a sustained increase in plasma PTH levels, provoking a dramatic increase in bone turnover but no net change in bone mineral density. Concurrent oral administration of NPS 2143 and subcutaneous infusion of 17β-estradiol also resulted in increased bone turnover. However, the antiresorptive action of estrogen decreased the extent of bone resorption stimulated by the elevated PTH levels, leading to an increase in bone mass compared with OVX controls or to either treatment alone. Despite the sustained stimulation to the parathyroid gland, parathyroid cells did not undergo hyperplasia. These data demonstrate that an increase in endogenous PTH secretion, induced by antagonism of the parathyroid cell Ca2+ receptor with a small molecule, leads to a dramatic increase in bone turnover, and they suggest a novel approach to the treatment of osteoporosis.
PMCID: PMC300853  PMID: 10841518
7.  Short-term effects of synthetic human parathyroid hormone-(1--34) administration on bone mineral metabolism in osteoporotic patients. 
Journal of Clinical Investigation  1981;68(5):1261-1271.
Since studies in animals and humans have shown that parathyroid hormone can stimulate bone formation and increase trabecular bone, and patients with primary and secondary hyperparathyroidism may exhibit osteosclerosis, we evaluated the effect of short-term administration of human parathyroid hormone, hPTH-(1--34), in patients with osteoporosis. Six patients with osteoporosis underwent detailed studies including blood and urinary measurements of calcium, phosphate, and magnesium; 47Ca kinetic studies; and 18-d balance studies before and during the short-term administration (3--4 wk) of a daily subcutaneous injection of hPTH fragment 1--34 given as 450 or 750 U/dose. The mean fasting plasma calcium values rose slightly after hPTH-(1--34) administration, primarily in the high-dose group. There was no difference in the mean fasting plasma inorganic phosphate levels. The mean daily urinary excretion of calcium and phosphate was significantly increased in patients given the higher dose. In patients given 750 U, net intestinal calcium absorption increased, phosphate absorption increased, calcium balance improved, and phosphate balance improved. In patients given 450 U, calcium balance and phosphate balance worsened. 47Ca kinetic studies showed a minimal increase in bone accretion rate, a decrease in the mean transit time of calcium in the exchangeable pools, and a decrease in the exchangeable-pool size. In all six patients there was an increased renal clearance of 47Ca as a result of hPTH-(1--34) administration. These studies indicate that low doses of parathyroid hormone may promote bone formation, whereas higher doses clearly have an adverse effect on the skeleton.
PMCID: PMC370921  PMID: 7298851
8.  Substernal oxyphil parathyroid adenoma producing PTHrP with hypercalcemia and normal PTH level 
Parathyroid adenoma is the most common cause of primary hyperparathyroidism. Preoperative serum calcium and intact-parathyroid hormone levels are the most useful diagnostic parameters that allow differentiating primary hyperparathyroidism from non-parathyroid-dependent hypercalcemia. Parathyroidectomy is the definitive treatment for primary hyperparathyroidism. Approximately 5% of patients who underwent parathyroidectomy present with persistent or recurrent hyperparathyroidism due to ectopic localization of the adenoma. Functioning oxyphil parathyroid adenoma is an uncommon histological form, seldom causing primary hyperparathyroidism. Parathyroid adenoma with hypercalcemia exhibiting normal parathyroid hormone level is rare. An incidence of 5% to 33% has been documented in the literature; no etiologic explanation has been given. In 1987, parathyroid-hormone-related peptide was isolated as a causative factor of humeral hypercalcemia of malignancy. The presence of parathyroid-hormone-related peptide in parathyroid tissue under normal and pathological conditions has been described in the literature; however, its role in causing hyperparathyroidism has not yet been defined.
Case presentation
We present a case of persistent hypercalcemia with a normal level of intact-parathyroid hormone due to a substernal parathyroid adenoma, treated with radioguided parathyroidectomy. The final histological diagnosis was oxyphil adenoma, positive for parathyroid-hormone-related peptide antigens.
In clinical practice, this atypical biochemical presentation of primary hyperparathyroidism should be considered in the differential diagnosis of hypercalcemia. The parathyroid-hormone-related peptide should be considered not only in the presence of malignancy.
PMCID: PMC2279131  PMID: 18291038
9.  Parathyroid hormone related protein and hypercalcaemia in breast cancer. 
BMJ : British Medical Journal  1991;303(6816):1506-1509.
OBJECTIVE--To see whether parathyroid hormone related protein has a humoral role in breast cancer. DESIGN--Plasma concentrations and tumour expression of parathyroid hormone related protein were determined (by two site immunoradiometric assay and immunohistochemistry respectively) in women with breast cancer and related to the presence of bone metastases and serum calcium concentrations. SUBJECTS--Plasma concentrations of parathyroid hormone related protein were measured in 57 women with early breast cancer without apparent bone metastases, 28 women with bone metastases, and 13 women with bone metastases and hypercalcaemia. Tissue positivity for parathyroid hormone related protein was determined retrospectively in 106 primary breast tumours from women without apparent bone metastases and 72 tumours from women with bone metastases, 25 of whom subsequently developed hypercalcaemia. RESULTS--Plasma parathyroid hormone related protein concentrations were detectable (greater than 0.23 pmol/l) in 12 (92%) of the 13 hypercalcaemic patients with bone metastases compared with 10 (36%) of the 28 normocalcaemic patients with bone metastases and five (9%) of the 57 normocalcaemic patients without bone metastases. Parathyroid hormone related protein concentrations were significantly higher in hypercalcaemic than normocalcaemic patients with bone metastases. Tumour staining was positive for parathyroid hormone related protein in 22 (88%) of the 25 primary breast cancers from patients with bone metastases. Tumour staining was positive for parathyroid hormone related protein in 22 (88%) of the 25 primary breast cancers from patients with bone metastases who later developed hypercalcaemia compared with 25 (53%) of the 47 from women in this group who remained normocalcaemic and 55 (52%) of the 106 early breast cancers from women without known metastases. CONCLUSION--Tumour derived parathyroid hormone related protein may have an important humoral role in hypercalcaemia associated with metastatic breast cancer.
PMCID: PMC1671803  PMID: 1782489
10.  Cytochemical bioassay of parathyroid hormone in maternal and cord blood. 
Archives of Disease in Childhood  1985;60(2):110-115.
Parathyroid hormone and calcium were measured in plasma taken from pregnant women at term and from the umbilical veins of their infants at birth. Three assays were used to measure parathyroid hormone, a cytochemical bioassay of bioactivity and two immunoradiometric assays, one specific for the amino terminus, the other specific for the carboxy terminus of the parathyroid hormone molecule. Plasma calcium was significantly higher in the infants than in the mothers. Maternal parathyroid hormone bioactivity and the amino terminus were both slightly raised, but the carboxy terminus value was normal; these findings supported the view that late pregnancy is a time of mild physiological hyperparathyroidism. In the infants, the amino terminus was undetectable and the carboxy terminus was either undetectable or towards the lower end of the normal range: bioactivity of parathyroid hormone was considerably raised and was related to the gradient of calcium across the placenta. This suggests that the parathyroid glands are not suppressed during fetal life and that they may play an important part in the maintenance of high fetal plasma calcium concentrations.
PMCID: PMC1777137  PMID: 3977382
11.  Hepatic osteodystrophy and liver cirrhosis 
AIM: To investigate the correlation between hepatic osteodystrophy and osteoporosis in patients with liver cirrhosis.
METHODS: Bone mineral density of the patients (n = 55) and that of the control group (n = 30) were measured by dual-energy X-ray absorptiometry. All the women in the study were premenopausal. Deoxypyridinoline, pyridinoline and urinary Ca2+ were measured as bone destruction markers, while alkaline phosphatase (ALP), osteocalcin and insulin-like growth factor-1 (IGF-1) were measured as bone formation markers. Furthermore, interleukin-1 (IL-1), IL-6, tumor necrosis factor α (TNF-α), vitamin D3, direct bilirubin, albumin, cortisol and parathyroid hormone (PTH) levels were measured. The independent Student t test and χ2 test were employed in comparing both groups, and the Pearson correlation test was used to determine associations.
RESULTS: Comparing cirrhosis and control groups, lumbar total T-score (-1.6 ± 1.2 g/cm2 vs -0.25 ± 1.3 g/cm2, P < 0.001), lumbar total Z-score (-1.2 ± 1.23 g/cm2 vs -0.6 ± 1.3 g/cm2, P < 0.001), total femur T-score (-0.05 ± 1 g/cm2 vs -0.6 ± 0.9 g/cm2, P = 0.003) and total femur Z-score (-0.08 ± 1.5 g/cm2 vs 0.7 ± 0.9 g/cm2, P = 0.003) showed significantly lower values in the cirrhosis group. Blood ALP level (109.2 ± 57 U/L vs 62.6 ± 32.5 U/L, P < 0.001), IL-6 level (27.9 ± 51.6 pg/mL vs 3.3 ± 3.1 pg/mL, P = 0.01), TNF-α level (42.6 ± 33.2 pg/mL vs 25.3 ± 12.3 pg/mL, P = 0.007) and direct bilirubin level (0.9 ± 0.7 mg/dL vs 0.3 ± 0.2 mg/dL, P < 0.001) were significantly higher in the cirrhosis group. IGF-1 level (47.7 ± 26.2 ng/mL vs 143.4 ± 53.2 ng/mL, P < 0.001), osteocalcin level (1.05 ± 2.5 ng/mL vs 7.0 ± 13 ng/mL, P = 0.002) and 24 h urinary Ca2+ (169.6 ± 227.2 mg/dL vs 287 ± 168.6 mg/dL, P = 0.003) were significantly lower in the cirrhosis group. Urinary deoxypyridinoline/creatinine (9.4 ± 9.9 pmol/μmol vs 8.1 ± 5.3 pmol/μmol, P = 0.51), urinary pyridinoline/creatinine (51.3 ± 66.6 pmol/μmol vs 29 ± 25.8 pmol/μmol, P = 0.08), blood IL-1 level (3.4 ± 8.8 pg/mL vs 1.6 ± 3.5 pg/mL, P = 0.29), vitamin D3 level (18.6 ± 13.3 μg/L vs 18.4 ± 8.9 μg/L, P = 0.95), cortisol level (11.1 ± 4.8 μg/dL vs 12.6 ± 4.3 μg/dL, P = 0.15) and PTH level (42.7 ± 38 μg/dL vs 34.8 ± 10.9 μg/dL, P = 0.27) were not significantly different.
CONCLUSION: Hepatic osteodystrophy is an important complication encountered in patients with liver cirrhosis and all patients should be monitored for hepatic osteodystrophy.
PMCID: PMC2848372  PMID: 20355242
Liver cirrhosis; Osteoporosis; Hepatic osteodystrophy
12.  The Role of Mast Cells in Parathyroid Bone Disease 
Journal of Bone and Mineral Research  2010;25(7):1637-1649.
Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT. In rats, mature mast cells were preferentially located at sites undergoing bone turnover, and the number of mast cells at the bone–bone marrow interface was greatly increased following treatment with PTH. Time-course studies and studies employing parathyroid hormone–related peptide (PTHrP), as well as inhibitors of platelet-derived growth factor-A (PDGF-A, trapidil), kit (gleevec), and PI3K (wortmannin) signaling revealed that mature mast cell redistribution from bone marrow to bone surfaces precedes and is associated with osteitis fibrosa, a hallmark of parathyroid bone disease. Importantly, mature mast cells were not observed in the bone marrow of mice. Mice, in turn, were resistant to the development of PTH-induced bone marrow fibrosis. These findings suggest that the mast cell may be a novel target for treatment of metabolic bone disease. © 2010 American Society for Bone and Mineral Research.
PMCID: PMC3154003  PMID: 20200965
hyperparathyroidism; iliac crest bone biopsy; PDGF; PI3K; stem cell factor
13.  Plasma Calcitonin in Renal Osteodystrophy 
Canadian Medical Association Journal  1971;104(12):1098-1091.
Whether calcitonin plays a significant role in the pathogenesis of renal osteodystrophy is not known. Plasma calcitonin-like activity (CLA) was measured by means of an extraction procedure and bioassay in 17 patients with chronic renal failure. Recent bone biopsy data were available for 11 patients. Plasma CLA was found to be in the normal range in the patients studied. There was a positive and strong correlation between plasma calcium and plasma CLA. Chronic dialysis and renal transplantation had no significant effect on plasma CLA. The severity and type of bone lesions did not correlate with plasma CLA. Although plasma calcitonin in chronic renal failure does not appear to be directly related to renal osteodystrophy, normal mobilization of calcitonin may protect the skeleton to some degree from the high levels of parathyroid hormone usually present in such patients.
PMCID: PMC1931030  PMID: 4931771
14.  Primary hyperparathyroidism with classic and severe skeletal involvement 
BMJ Case Reports  2010;2010:bcr0420102929.
A 63-year-old woman has had multiple repeated fractures. A diagnosis of primary hyperparathyroidism (PHPT) was made after she was found to be hypercalcaemic with an elevated level of intact parathyroid hormone (iPTH). Radiographs revealed classic and severe bone findings in PHPT, features which were common in the past but are thought to be rare at this modern age. She also had nephrolithiasis and osteoporosis. An enlarged parathyroid gland was seen on ultrasound and CT scan, and hyperfunction was demonstrated by scintigraphy. Parathyroidectomy was performed. Histopathologic analysis revealed a parathyroid adenoma. She developed the hungry-bone syndrome 7 days postoperatively, which resolved with with administration of calcium and calcitriol.
PMCID: PMC3028290  PMID: 22767476
15.  Bone density parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women. 
BMJ : British Medical Journal  1992;305(6848):273-277.
OBJECTIVE--To examine the relation between bone density and indices of calcium metabolism including parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women. DESIGN--A cross sectional study. SETTING AND SUBJECTS--138 women volunteers aged 45-65 with no known osteoporosis and unselected for disease status recruited for a dietary assessment study from the community using general practice registers. Volunteer rate was 20%. MAIN OUTCOME MEASURE--Bone mineral density measured with dual energy x ray absorptiometry. RESULTS--Bone density at the lumbar spine and neck and trochanteric regions of the femur was inversely related to serum intact parathyroid hormone concentrations and positively related to serum 25-hydroxyvitamin D concentrations. These associations were independent of possible confounding factors, including age, body mass index, cigarette smoking habit, menopausal status, and use of diuretics and postmenopausal hormone replacement therapy. These associations were apparent throughout the whole distribution of bone density and 25-hydroxyvitamin D and parathyroid hormone concentrations within the normal range, suggesting a physiological relation. CONCLUSIONS--The findings are consistent with the hypothesis that parathyroid hormone and 25-hydroxyvitamin D concentrations influence bone density in middle aged women. Findings from this study together with other work suggest that the role of vitamin D in osteoporosis should not be neglected. The associations with parathyroid hormone also indicate plausible biological mechanisms. The roughly 5-10% difference in bone density between top and bottom tertiles of serum 25-hydroxyvitamin D concentrations, though not large in magnitude, may have considerable public health implications in terms of prevention of osteoporosis and its sequelae, fractures.
PMCID: PMC1882724  PMID: 1392857
16.  Calcitriol, parathyroid hormone, and accumulation of aluminum in bone in dogs with renal failure. 
Journal of Clinical Investigation  1987;79(3):754-761.
Accumulation of aluminum in bone is a frequent finding in patients requiring chronic dialysis and is associated with considerable morbidity and/or mortality. Until now, evidence seemed to point to relatively low circulating levels of parathyroid hormone as a contributing factor, but because levels of parathyroid hormone and calcitriol are interrelated, calcitriol might be also involved. In this study we employed an animal model to evaluate the single and combined effects of parathyroid hormone and calcitriol on bone aluminum accumulation. The results show significantly less aluminum accumulation in calcitriol-replete dogs independent of the presence or absence of parathyroid hormone. These results indicate that low levels of calcitriol may play a role in the development of aluminum related bone disease. Further studies are needed to demonstrate whether administration of calcitriol in patients with renal insufficiency will prevent development of aluminum-related bone disease.
PMCID: PMC424190  PMID: 3818947
17.  May Long Term Oxcarbazepine Treatment Be Lead to Secondary Hyperparathyroidism? 
Background and Purpose
The adverse effects of newer antiepileptic drugs are not well-known. This study assessed the impact of oxcarbazepine (OXC) treatment on bone turnover.
Forty-four children with idiopathic focal (and/or secondarily generalized) epilepsy who had been treated with OXC for more than 1 year were compared with 33 healthy, age- and sex-matched children. Serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, osteocalcin, calcitonin, and 25-hydroxyvitamin D, and bone mineral density were measured to evaluate and compare bone mineralization between the two groups.
The serum levels of calcium, osteocalcin, 25-hydroxyvitamin D, and bone mineral density did not differ significantly between the study and control groups. However, serum levels of parathyroid hormone, alkaline phosphatase, phosphorus, and calcitonin differed significantly between the two groups.
These findings suggest that OXC treatment leads to secondary hyperparathyroidism with high-turnover bone disease and/or impaired intestinal calcium absorption.
PMCID: PMC3325434  PMID: 22523515
oxcarbazepine; bone mineralization; children
18.  No evidence of circulating autoantibodies against osteoprotegerin in patients with celiac disease 
AIM: To investigate risk factors for low bone mineral density (BMD) in celiac disease (CD) patients, focusing on circulating autoantibodies against osteoprotegerin (OPG).
METHODS: Seventy asymptomatic CD adult patients on gluten-free diet (GFD) and harbouring persistent negative CD-related serology were recruited. Conventional risk factors for osteoporosis (e.g., age, sex, menopausal status, history of fractures, smoke, and body mass index) were checked and BMD was assessed by dual energy X ray absorptiometry. Serum calcium and parathyroid hormone (PTH) levels were evaluated. Thirty-eight patients underwent repeat duodenal biopsy. Serum samples from a selected sub-group of 30 patients, who were also typed for human leukocyte antigen (HLA) DQ2 and DQ8 haplotype, were incubated with homodimeric recombinant human OPG and tested by western blotting with an anti-OPG antibody after immunoprecipitation.
RESULTS: Despite persistent negative CD-related serology and strict adherence to GFD, 49 out of the 70 (74%) patients displayed low BMD. Among these patients, 13 (24%) showed osteoporosis and 36 (76%) osteopenia. With the exception of age, conventional risk factors for osteoporosis did not differ between patients with normal and low BMD. Circulating serum calcium and PTH levels were normal in all patients. Duodenal mucosa healing was found in 31 (82%) out of 38 patients who underwent repeat duodenal biopsy with 20 (64%) still displaying low BMD. The remaining 7 patients had an incomplete normalization of duodenal mucosa with 6 (84%) showing low BMD. No evidence of circulating antibodies against OPG was found in the serum of 30 celiac patients who were tested for, independent of BMD, duodenal histology, and HLA status.
CONCLUSION: If any, the role of circulating autoantibodies against OPG in the pathogenesis of bone derangement in patients with CD is not a major one.
PMCID: PMC3325528  PMID: 22529691
Celiac disease; Osteoprotegerin; Bone mineral density; Gluten-free diet; Osteoporosis; Osteopenia
19.  An LRP5 Receptor with Internal Deletion in Hyperparathyroid Tumors with Implications for Deregulated WNT/β-Catenin Signaling 
PLoS Medicine  2007;4(11):e328.
Hyperparathyroidism (HPT) is a common endocrine disorder with incompletely understood etiology, characterized by enlarged hyperactive parathyroid glands and increased serum concentrations of parathyroid hormone and ionized calcium. We have recently reported activation of the Wnt signaling pathway by accumulation of β-catenin in all analyzed parathyroid tumors from patients with primary HPT (pHPT) and in hyperplastic parathyroid glands from patients with uremia secondary to HPT (sHPT). Mechanisms that may account for this activation have not been identified, except for a few cases of β-catenin (CTNNB1) stabilizing mutation in pHPT tumors.
Methods and Findings
Reverse transcription PCR and Western blot analysis showed expression of an aberrantly spliced internally truncated WNT coreceptor low-density lipoprotein receptor–related protein 5 (LRP5) in 32 out of 37 pHPT tumors (86%) and 20 out of 20 sHPT tumors (100%). Stabilizing mutation of CTNNB1 and expression of the internally truncated LRP5 receptor was mutually exclusive. Expression of the truncated LRP5 receptor was required to maintain the nonphosphorylated active β-catenin level, transcription activity of β-catenin, MYC expression, parathyroid cell growth in vitro, and parathyroid tumor growth in a xenograft severe combined immunodeficiency (SCID) mouse model. WNT3 ligand and the internally truncated LRP5 receptor strongly activated transcription, and the internally truncated LRP5 receptor was insensitive to inhibition by DKK1.
The internally truncated LRP5 receptor is strongly implicated in deregulated activation of the WNT/β-catenin signaling pathway in hyperparathyroid tumors, and presents a potential target for therapeutic intervention.
Gunnar Westin and colleagues report the expression of an aberrantly spliced LRP5 receptor in primary and spontaneous parathyroid tumors and implicate it in the deregulated activation of the Wnt/β-catenin signaling pathway.
Editors' Summary
The parathyroid glands—four rice-sized glands in the neck—maintain a normal calcium balance in the body, to maintain strong bones and essential cellular functions. The glands release parathyroid hormone as a response to a decrease in blood calcium level. By stimulating calcium release from bone and its absorption in the gut, parathyroid hormone restores the blood calcium level. However, 100,000 new individuals in the US develop hyperparathyroidism (HPT) annually, characterized by enlarged, overactive parathyroid glands and high blood levels of calcium. Primary HPT (pHPT) is usually caused by a benign tumor (a non-life-threatening growth) in one of the parathyroid glands. Secondary HPT (sHPT) occurs in response to calcium regulatory disturbances, linked to vitamin D deficiency, and more or less invariably develops in patients with uremic kidney disease.
Why Was This Study Done?
HPT is usually treated by surgical removal of the enlarged parathyroid glands, which is done with great efficiency. However, ideally, doctors would like to know what drives the overgrowth of the parathyroid glands to be able to develop drugs for treatment or disease prophylaxis. Researchers recently reported that the cells in enlarged parathyroid glands from patients with HPT contain high amounts of β-catenin. This protein is part of the Wnt signaling pathway, which has been found to be disrupted in many tumor entities in other organs. In the absence of Wnt proteins, a group of proteins called the β-catenin destruction complex marks β-catenin so that it is rapidly destroyed. When Wnt proteins bind to a cell-surface receptor called Frizzled and a coreceptor called LRP5, the destruction complex is inhibited and β-catenin accumulates. This accumulation induces the production of other proteins (in particular, c-Myc) that stimulate cell growth and division. The accumulation of β-catenin in the enlarged parathyroid glands of patients with HPT could, therefore, significantly contribute to the overgrowth of their glands—but what causes β-catenin accumulation? In this study, the researchers have investigated this question to try to identify a target for drugs to treat HPT.
What Did the Researchers Do and Find?
The researchers looked for genetic changes (mutations) in β-catenin that stabilize the protein and measured the expression of LRP5 in abnormal parathyroid gland tissue from 37 patients with pHPT and 20 with uremia and sHPT. All the samples contained high levels of β-catenin, but only four contained a β-catenin–stabilizing mutation. All the sHPT samples and 32 pHPT samples (but none of the samples containing the β-catenin stabilizing mutation) expressed a mutated LRP5, with the central region deleted. To investigate the functional consequences of this internally deleted LRP5 protein, the researchers used a technique called RNA interference to block its expression in a human parathyroid tumor cell line. They found that expression of the mutated, short LRP5 is required for accumulation of β-catenin, expression of c-Myc, and continued growth of the cell line in test tubes and in animals.
What Do These Findings Mean?
The accumulation of β-catenin in all the enlarged parathyroid glands examined so far strongly implicates abnormal Wnt/β-catenin signaling in the development of pHPT and sHPT. These new findings identify which part of the signaling pathway is altered. The expression data and functional data together suggest that an internally deleted LRP5 coreceptor is often responsible for the accumulation of β-catenin. The functional data also show that expression of shortened LRP5 is necessary for the abnormal growth of parathyroid tumor cells. Exactly how the internally deleted coreceptor activates β-catenin signaling in parathyroid gland cells, or why a shorter-than-normal LRP5 is made, are not yet known. However, because these findings indicate that internally deleted LRP5 has a fundamental role in activating Wnt signaling in HPT, drugs that inactivate this aberrant protein but leave the normal protein unscathed might provide a nonsurgical treatment for this common hormone disorder.
Additional Information.
Please access these Web sites via the online version of this summary at
edlinePlus has encyclopedia pages on hyperparathyroidism, primary hyperparathyroidism, and secondary hyperparathyroidim (in English and Spanish)
Information is available for patients from the US National Institute of Diabetes and Digestive and Kidney Diseases on hyperparathyroidism, which includes links to organizations that help people with hyperparathyroidism
Wikipedia maintains pages on Wnt signaling pathway and on β-catenin (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2082644  PMID: 18044981
20.  Primary hyperparathyroidism diagnosed after surgical ablation of a costal mass mistaken for giant-cell bone tumor: a case report 
Primary hyperparathyroidism is a common endocrine disorder characterized by elevated parathyroid hormone levels, which cause continuous osteoclastic bone resorption. Giant cell tumor of bone is an expansile osteolytic tumor that contains numerous osteoclast-like giant cells. There are many similarities in the radiological and histological features of giant cell tumor of bone and brown tumor. This is a rare benign focal osteolytic process most commonly caused by hyperparathyroidism.
Case presentation
We report the unusual case of a 40-year-old Caucasian woman in which primary hyperparathyroidism was diagnosed after surgical ablation of a costal mass. The mass was suspected of being neoplastic and histopathology was compatible with a giant cell tumor of bone. On the basis of the biochemical results (including serum calcium, phosphorous and intact parathyroid hormone levels) primary hyperparathyroidism was suspected and a brown tumor secondary to refractory hyperparathyroidism was diagnosed.
Since giant cell tumor is a bone neoplasm that has major implications for the patient, the standard laboratory tests in patients with bone lesions are important for a correct diagnosis.
PMCID: PMC3261225  PMID: 22204520
21.  Effects of Parathyroid Hormone on Skeletal Muscle Protein and Amino Acid Metabolism in the Rat 
Journal of Clinical Investigation  1983;71(6):1806-1821.
Because prominent skeletal muscle dysfunction and muscle wasting are seen in both chronic uremia and in primary hyperparathyroidism, and because markedly elevated parathyroid hormone levels occur in both disorders, potential effects of parathyroid hormone on skeletal muscle protein, amino acid, and cyclic nucleotide metabolism were studied in vitro using isolated intact rat epitrochlearis skeletal muscle preparations. Intact bovine parathyroid hormone and the synthetic 1-34 fragment of this hormone stimulated the release of alanine and glutamine from muscle of control but not from chronically uremic animals. This stimulation was dependent upon the concentration of parathyroid hormone added: At 105 ng/ml parathyroid hormone increased alanine release 84% and glutamine release 75%. Intracellular levels of alanine and glutamine were not altered by parathyroid hormone. Increasing concentrations of the 1-34 polypeptide decreased [3H]leucine incorporation into protein of muscles from both control and uremic animals. Using muscles from animals given a pulse-chase label of [guanido-14C]arginine in vivo, parathyroid hormone increased the rate of loss of 14C label from acid-precipitable protein during incubation and correspondingly increased the rate of appearance of this label in the incubation media. Parathyroid hormone increased muscle cAMP levels by 140% and cGMP levels by 185%, but had no effect on skeletal muscle cyclic nucleotide phosphodiesterase activities as assayed in vitro. Adenylyl cyclase activity in membrane preparations from control but not uremic rats was stimulated by parathyroid hormone in a concentration-dependent fashion. However, no stimulation of guanylyl cyclase activity was noted by parathyroid hormone, although stimulation by sodium azide was present. Incubation of muscles with added parathyroid hormone produced a diminished responsiveness towards epinephrine or serotonin regulation of amino acid release and cAMP formation in the presence compared to the absence of parathyroid hormone. In the absence of parathyroid hormone, detectable inhibition of alanine and glutamine release was produced by 10−9 M epinephrine, whereas in the presence of parathyroid hormone (1,000 ng/ml) inhibition of alanine and glutamine release required 10−6 M or greater epinephrine. Resistance to cyclic AMP action as well as inhibition of cyclic AMP formation by parathyroid hormone was found. Preincubation of rat sarcolemma with 1-34 parathyroid hormone produced a decreased activity of the isoproterenol-stimulable adenylyl cyclase activity but there was no apparent change in the concentration of isoproterenol required for one-half maximal and maximal stimulation of the enzyme.
These findings suggest that high levels of parathyroid hormone have direct effects on skeletal muscle protein, amino acid, and cyclic nucleotide metabolism in muscle of normal but not uremic animals. Treatment with these high levels of parathyroid hormone in vitro appears to reproduce in normal muscle, the metabolic deficits and loss of hormone responsiveness observed in muscle of chronically uremic animals. It is therefore possible that direct effects of parathyroid hormone on skeletal muscle may account in part for the muscle dysfunction and wasting of primary hyperparathyroidism and chronic uremia.
PMCID: PMC370386  PMID: 6306055
22.  The Serum Level of Fibroblast Growth Factor-23 and Calcium-Phosphate Homeostasis in Obese Perimenopausal Women 
Plasma FGF-23 concentrations and its relationship with calcium-phosphate homeostasis were evaluated in 48 perimenopausal obese women and in 29 nonobese controls. Serum parathyroid hormone, 25-hydroxyvitamin D3, CTX1, osteocalcin, total calcium, phosphorus, creatinine, and plasma intact FGF-23 concentrations were assessed. DXA of lumbar spine and femoral neck was performed to determine bone mineral density (BMD). Plasma iFGF-23 concentration was significantly higher in obese patients (by 42%) and correlated with age and BMD of proximal femur (R = −0.346; R = 0.285, resp.) but not with markers of bone turnover. However, serum phosphorus level in obese subjects was significantly lower. iFGF-23 concentration correlated significantly with body mass index (R = 0.292) and fat content (R = 0.259) in all study subjects. Moreover, a significant correlation between iFGF-23 and iPTH (R = 0.254) was found. No correlation between serum phosphorus or eGFR and plasma iFGF-23 and between eGFR and serum phosphorus was found. Elevated serum iFGF-23 concentration may partially explain lower phosphorus levels in the obese and seems not to reflect bone turnover.
PMCID: PMC3227462  PMID: 22164160
23.  Restoration of Parathyroid Responsiveness in Vitamin D—Deficient Rats by Parenteral Calcium or Dietary Lactose* 
Journal of Clinical Investigation  1967;46(10):1572-1578.
The effects of treatment with vitamin D, calcium, or lactose on the responsiveness of vitamin D—deficient rats to parathyroid hormone were compared. In the absence of vitamin D, parenteral calcium or dietary lactose administration resulted in increases in serum calcium concentration although not to the normal values obtained in animals given vitamin D. Dietary lactose also partially restored the low bone calcium content of vitamin D—deficient rats. Untreated vitamin D—deficient rats showed no significant changes in serum calcium concentration after parathyroidectomy or parathyroid extract administration. Vitamin D, lactose, and calcium all restored responsiveness to parathyroid hormone; serum calcium concentration decreased after parathyroidectomy and showed a dose-related increase in response to parathyroid extract. Hence, the unresponsiveness to parathyroid hormone in vitamin D deficiency may be due to a lack of calcium at a local site of action, presumably bone, rather than to the absence of vitamin D as a specific cofactor.
PMCID: PMC292905  PMID: 6061734
24.  Parathyroid hormone and 25-hydroxyvitamin D concentrations in sick and normal elderly people. 
Serum 25-hydroxyvitamin D and immunoreactive parathyroid hormone concentrations were measured in normal elderly subjects living at home and in sick elderly patients in hospital. Normal old people tended to have high 25-hydroxyvitamin D and low parathyroid hormone concentrations; in the sick elderly this pattern was reversed. The raised serum parathyroid hormone concentrations in the sick elderly were not due to poor renal function and may have been a response to vitamin D deficiency. A high serum parathyroid hormone concentration in an elderly patient must be interpreted in the light of the patient's general health and nutritional state. Caution is needed in diagnosing primary hyperparathyroidism in this age group.
PMCID: PMC1548439  PMID: 6411203
25.  Effects of sports training & nutrition on bone mineral density in young Indian healthy females 
Background & objectives:
Peak bone mass, a major determinant of osteoporosis is influenced by genetic, nutritional, lifestyle and hormonal factors. This study was designed to evaluate the impact of sports training on dietary intake and bone mineral and metabolic parameters in young healthy Indian females.
Healthy female college going students (N=186, sportswomen, 90; controls 96) in the age group of 18-21 yr, residing in New Delhi (India) were evaluated for anthropometry, biochemistry (serum total and ionic calcium, phosphorus, total alkaline phosphatase, 25-hydroxyvitamin D & parathyroid hormone), diet, physical activity and lifestyle. Bone mineral density (BMD) at hip, forearm and lumbar spine were studied using central DXA.
Sports related physical activity (3 vs. 0 h/day, P<0.001) and direct sunlight exposure (120 vs. 30 min/day, P<0.001) were significantly higher in sportswomen than in controls with sedentary lifestyle. Significantly higher intake of all macronutrients (energy, protein, carbohydrates and fat) and dietary calcium was noted in the diets of sportswomen. Mean serum 25(OH)D levels were significantly higher (53.0±18.9 vs. 12.9±7.7 nmol/l; P<0.001) while PTH (35.3±17.6 vs. 51.7±44.9 pg/ml; P<0.001) and ALP levels (194.0±51.0 vs. 222.1±51.4 IU/l; P<0.001) were significantly lower in sportswomen when compared to controls. No significant difference was found in ionized calcium and inorganic phosphorus in the two groups. Significantly higher (P<0.001) total BMD and BMD at all sites except femur neck were found in sportswomen than controls (P<0.001).
Interpretation & conclusions:
Physical activity, optimal nutrition and adequate sun exposure are vital for attaining peak bone mass.
PMCID: PMC3193711  PMID: 21985813
Bone mineral density; nutrition; physical activity; sun exposure; sportswomen

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