Elevated Plasma Parathyroid Hormone Research Articles

Characterization of Rickets Type II Model Rats to Reveal Functions of Vitamin D and Vitamin D Receptor.

Vitamin D has been known to exert a wide range of physiological effects, including calcemic, osteogenic, anticancer, and immune responses. We previously generated genetically modified (GM) rats and performed a comparative analysis of their physiological properties to elucidate the roles of vitamin D and vitamin D receptor (VDR). In this study, our primary goal was to investigate the manifestations of type II rickets in rats with the VDR(H301Q) mutation, analogous to the human VDR(H305Q). Additionally, we created a double-mutant rat with the VDR(R270L/H301Q) mutation, resulting in almost no affinity for 1,25-dihydroxy-vitamin D3 (1,25D3) or 25-hydroxy-vitamin D3 (25D3). Notably, the plasma calcium concentration in Vdr(R270L/H301Q) rats was significantly lower than in wild-type (WT) rats. Meanwhile, Vdr(H301Q) rats had calcium concentrations falling between those of Vdr(R270L/H301Q) and WT rats. GM rats exhibited markedly elevated plasma parathyroid hormone and 1,25D3 levels compared to those of WT rats. An analysis of bone mineral density in the cortical bone of the femur in both GM rats revealed significantly lower values than in WT rats. Conversely, the bone mineral density in the trabecular bone was notably higher, indicating abnormal bone formation. This abnormal bone formation was more pronounced in Vdr(R270L/H301Q) rats than in Vdr(H301Q) rats, highlighting the critical role of the VDR-dependent function of 1,25D3 in bone formation. In contrast, neither Vdr(H301Q) nor Vdr(R270L/H301Q) rats exhibited symptoms of alopecia or cyst formation in the skin, which were observed in the Vdr-KO rats. These findings strongly suggest that unliganded VDR is crucial for maintaining the hair cycle and normal skin. Our GM rats hold significant promise for comprehensive analyses of vitamin D and VDR functions in future research.

Real-world assessment: effectiveness and safety of extended-release calcifediol and other vitamin D therapies for secondary hyperparathyroidism in CKD patients

IntroductionExtended-release calcifediol (ERC), active vitamin D hormones and analogs (AVD) and nutritional vitamin D (NVD) are commonly used therapies for treating secondary hyperparathyroidism (SHPT) in adults with stage 3–4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI). Their effectiveness for increasing serum total 25-hydroxyvitamin D (25D) and reducing elevated plasma parathyroid hormone (PTH), the latter of which is associated with increased morbidity and mortality, has varied across controlled clinical trials. This study aimed to assess real-world experience of ERC and other vitamin D therapies in reducing PTH and increasing 25D.MethodsMedical records of 376 adult patients with stage 3–4 CKD and a history of SHPT and VDI from 15 United States (US) nephrology clinics were reviewed for up to 1 year pre- and post-ERC, NVD or AVD initiation. Key study variables included patient demographics, concomitant usage of medications and laboratory data. The mean age of the study population was 69.5 years, with gender and racial distributions representative of the US CKD population. Enrolled patients were grouped by treatment into three cohorts: ERC (n = 174), AVD (n = 55) and NVD (n = 147), and mean baseline levels were similar for serum 25D (18.8–23.5 ng/mL), calcium (Ca: 9.1–9.3 mg/dL), phosphorus (P: 3.7–3.8 mg/dL) and estimated glomerular filtration rate (eGFR: 30.3–35.7 mL/min/1.73m2). Mean baseline PTH was 181.4 pg/mL for the ERC cohort versus 156.9 for the AVD cohort and 134.8 pg/mL (p < 0.001) for the NVD cohort. Mean follow-up during treatment ranged from 20.0 to 28.8 weeks.ResultsSerum 25D rose in all cohorts (p < 0.001) during treatment. ERC yielded the highest increase (p < 0.001) of 23.7 ± 1.6 ng/mL versus 9.7 ± 1.5 and 5.5 ± 1.3 ng/mL for NVD and AVD, respectively. PTH declined with ERC treatment by 34.1 ± 6.6 pg/mL (p < 0.001) but remained unchanged in the other two cohorts. Serum Ca increased 0.2 ± 0.1 pg/mL (p < 0.001) with AVD but remained otherwise stable. Serum alkaline phosphatase remained unchanged.ConclusionsReal-world clinical effectiveness and safety varied across the therapies under investigation, but only ERC effectively raised mean 25D (to well above 30 ng/mL) and reduced mean PTH levels without causing hypercalcemia.

Vitamin D Insufficiency Prior to Paediatric Liver Transplantation Is Associated with Early T-Cell Mediated Rejection.

Objectives: T-cell mediated rejection (TCMR) can compromise long-term liver allograft survival. The immunomodulatory properties of vitamin D are increasingly recognized. We investigated whether perturbations in vitamin D metabolism prior to LT may predispose to TCMR in a representative cohort of paediatric LT recipients. Methods: In this retrospective single-center study of children who underwent liver transplantation between 2005 and 2017, we collected serum 25(OH) vitamin D levels and other parameters related to vitamin D metabolism. Post-transplant variables were collected from medical records during the first year following LT. Results: Eighty-two patients were included. Twenty-six (32%) developed TCMR, 52 (65%) presented at least one event of 25(OH) D insufficiency during the year before the transplant, while 23 (32%) had at least one documented elevated plasma parathyroid hormone level. Forty-six patients benefited from nutritional support (56%). The development of TCMR was associated with vitamin D insufficiency pre-LT (p = 0.01). No significant correlations were identified between PTH levels and incidence of TCMR. The association was stronger in patients transplanted for cholestatic diseases (p = 0.004). Conclusions: Vitamin D insufficiency before a liver transplant may be associated with TCMR during the first year post-LT. These findings warrant further investigation.

Parathyroid hormone may play a role in the pathophysiology of primary hypertension.

Parathyroid hormone has been related with the risk of hypertension, but the matter remains controversial. We examined the association of parathyroid hormone with central blood pressure and its determinants in 622 normotensive or never-treated hypertensive subjects aged 19–72 years without diabetes, cardiovascular or renal disease, or cardiovascular medications. The methods were whole-body impedance cardiography and analyses of pulse wave and heart rate variability. Cardiovascular function was examined in sex-specific tertiles of plasma parathyroid hormone (mean concentrations 3.0, 4.3 and 6.5 pmol/L, respectively) during head-up tilt. Explanatory factors for haemodynamics were further investigated using linear regression analyses. Mean age was 45.0 (s.d. 11.7) years, BMI 26.8 (4.4) kg/m2, seated office blood pressure 141/90 (21/12) mmHg, and 309 subjects (49.7%) were male. Only five participants had elevated plasma parathyroid hormone and calcium concentrations. Highest tertile of parathyroid hormone presented with higher supine and upright aortic diastolic blood pressure (P < 0.01) and augmentation index (P < 0.01), and higher upright systemic vascular resistance (P < 0.05) than the lowest tertile. The tertiles did not present with differences in pulse wave velocity, cardiac output, or measures of heart rate variability. In linear regression analyses, parathyroid hormone was an independent explanatory factor for aortic systolic (P = 0.005) and diastolic (P = 0.002) blood pressure, augmentation index (P = 0.002), and systemic vascular resistance (P = 0.031). To conclude, parathyroid hormone was directly related to central blood pressure, wave reflection, and systemic vascular resistance in subjects without cardiovascular comorbidities and medications. Thus, parathyroid hormone may play a role in the pathophysiology of primary hypertension.

Secondary hyperparathyroidism is associated with postpartum blood pressure in preeclamptic women and normal pregnancies.

Preeclampsia has been associated with features of secondary hyperparathyroidism. In this study, we examine the relationships of calcium metabolism with blood pressure (BP) in preeclamptic women and in a control group of normal (NORM) pregnancies in the postpartum. Sixty-three consecutive preeclamptic women (age 35 ± 6 years) were studied 4 weeks after delivery. We collected clinical and lab information on pregnancy and neonates and measured plasma and urinary calcium and phosphate, plasma parathyroid hormone (PTH) and 25-hydroxy vitamin D [25(OH)D], and performed 24-h ambulatory BP monitoring. BP and calcium metabolism of 51 preeclamptic were compared with 17 NORM pregnant women that matched for age, race, and postpartum BMI. 25(OH)D deficiency (<10 ng/ml) was found in 3% of preeclamptic women, insufficiency (10-30 ng/ml) in 67%, and NORM values (31-100 ng/ml) in the remaining 30%. Elevated plasma PTH (≥79 pg/ml) was found in 24% of preeclamptic women who had 25(OH)D plasma levels of 21.4 ± 8.3 ng/ml. In these women, PTH levels was independently associated with 24-h SBP and DBP and daytime and night-time DBP. Prevalence of nondippers and reverse dippers was elevated (75% and 33%, respectively). No associations between calcium metabolism and neonates' characteristics of preeclamptic women were observed. Prevalence of vitamin D deficiency and insufficiency and of elevated plasma PTH levels were comparable in matched groups. Considering preeclamptic women and matched controls as a whole group, office SBP and DBP levels were associated with PTH independently of preeclampsia and other confounders. Features of secondary hyperparathyroidism are common in the postpartum. Preeclampsia and increased PTH levels were both independent factors associated with increased BP after delivery, and both might affect the future cardiovascular risk of these women.

Studies of mice deleted for Sox3 and uc482: relevance to X-linked hypoparathyroidism.

Hypoparathyroidism is genetically heterogeneous and characterized by low plasma calcium and parathyroid hormone (PTH) concentrations. X-linked hypoparathyroidism (XLHPT) in two American families is associated with interstitial deletion-insertions involving deletions of chromosome Xq27.1 downstream of SOX3 and insertions of predominantly non-coding DNA from chromosome 2p25.3. These could result in loss, gain, or movement of regulatory elements, which include ultraconserved element uc482, which could alter SOX3 expression. To investigate this, we analysed SOX3 expression in EBV-transformed lymphoblastoid cells from three affected males, three unaffected males, and four carrier females from one XLHPT family. SOX3 expression was similar in all individuals, indicating that the spatiotemporal effect of the interstitial deletion-insertion on SOX3 expression postulated to occur in developing parathyroids did not manifest in lymphoblastoids. Expression of SNTG2, which is duplicated and inserted into the X chromosome, and ATP11C, which is moved telomerically, were also similarly expressed in all individuals. Investigation of male hemizygous (Sox3−/Y and uc482−/Y) and female heterozygous (Sox3+/− and uc482+/−) knockout mice, together with wild-type littermates (male Sox3+/Y and uc482+/Y, and female Sox3+/+ and uc482+/+), revealed Sox3−/Y, Sox3+/−, uc482−/Y, and uc482+/− mice to have normal plasma biochemistry, compared to their respective wild-type littermates. When challenged with a low calcium diet, all mice had hypocalcaemia, and elevated plasma PTH concentrations and alkaline phosphatase activities, and Sox3−/Y, Sox3+/−, uc482−/Y, and uc482+/− mice had similar plasma biochemistry, compared to wild-type littermates. Thus, these results indicate that absence of Sox3 or uc482 does not cause hypoparathyroidism and that XLHPT likely reflects a more complex mechanism.

Parathyromatosis: A Rare Case of Recurrent Hyperparathyroidism Localized by Four-Dimensional Computed Tomography

To present a rare case of parathyromatosis. We present the clinical, laboratory, and imaging findings, along with a review of the literature. A 33-year-old man with a history of right upper parathyroid adenoma removal 5 years prior due to hyperparathyroidism was admitted for severe hypercalcemia (15.6 mg/dL; normal, 8.5 to 10.5 mg/dL) with elevated plasma parathyroid hormone (PTH) (882 pg/mL; normal, 15 to 65 pg/mL). Ultrasound, computed tomography (CT), sestamibi, and positron emission tomography scans were unremarkable; however, a four-dimensional CT (4DCT) of the neck showed an area of increased signal enhancement and hypervascularity without discrete nodule in the posterior right thyroid region. The patient underwent parathyroid surgical exploration with right hemithyroidectomy and compartment neck dissection to remove the affected tissue. PTH levels dropped to 208 pg/mL postoperatively; calcium decreased but remained elevated at 12.7 mg/dL. Pathology revealed the presence of several small nodular foci of atypical hyperplastic parathyroid tissue in the right thyroid and soft tissue in the left central neck compartment consistent with parathyromatosis. This case report represents the first-time use of 4DCT to localize parathyromatosis. Parathyromatosis is a rare but problematic cause of recurrent hyperparathyroidism. Ultrasound and 4DCT may represent the best imaging modalities for identification and perioperative management to remove all affected tissue without reseeding.

Association of Nonoxidized Parathyroid Hormone with Cardiovascular and Kidney Disease Outcomes in Chronic Kidney Disease.

In patients with CKD, elevated plasma parathyroid hormone (PTH) levels are associated with greater cardiovascular morbidity and mortality. However, the reference method for PTH measurement is disputed. It has been argued that measurement of nonoxidized PTH better reflects biologically active PTH than measurements with conventional assays. PTH and nonoxidized PTH levels were measured at study baseline in 535 patients with CKD with an eGFR range between 89 and 15 ml/min per 1.73 m2. Patients were followed over 5.1 years for the occurrence of acute heart failure, atherosclerotic events, CKD progression (doubling of serum creatinine or initiation of RRT), or all-cause death. Atherosclerotic events, acute heart failure, CKD progression, and deaths from any cause occurred in 116, 58, 73, and 85 patients, respectively. In Kaplan-Meier analyses, patients at the highest PTH and nonoxidized-PTH tertile (79-543 and 12-172 pg/ml, respectively) showed a higher rate of atherosclerotic events, acute heart failure, CKD progression, and death from any cause. After adjustment for eGFR and albuminuria, nonoxidized PTH was no longer associated with atherosclerotic events (hazard ratio third versus first tertile, 1.04 [95% confidence intervals, 0.62-1.75]), acute heart failure (hazard ratio third versus first tertile, 1.24 [95% confidence intervals, 0.59-2.62]), CKD progression (hazard ratio third versus first tertile, 0.93 [95% confidence intervals, 0.46-1.90]), and death from any cause (hazard ratio third versus first tertile, 1.23 [95% confidence intervals, 0.66-2.31]), and PTH lost its association with atherosclerotic events (hazard ratio third versus first tertile, 0.80 [95% confidence intervals, 0.46-1.38]) and CKD progression (hazard ratio third versus first tertile, 0.99 [95% confidence intervals, 0.46-2.10]), although it remained associated with acute heart failure (hazard ratio third versus first tertile, 2.76 [95% confidence intervals, 1.11-6.89]) and all-cause death (hazard ratio third versus first tertile, 2.35 [95% confidence intervals, 1.13-4.89]). After further adjustment for cardiovascular and kidney risk factors, PTH remained associated with all-cause death (hazard ratio third versus first tertile, 2.79 [95% confidence intervals, 1.32-5.89]), but with no other end point. In a cohort of patients with CKD, PTH was associated with all-cause mortality; there was no association of nonoxidized PTH with any of the clinical outcomes examined.

Bone Canopies in Pediatric Renal Osteodystrophy.

Pediatric renal osteodystrophy (ROD) is characterized by changes in bone turnover, mineralization, and volume that are brought about by alterations in bone resorption and formation. The resorptive and formative surfaces on the cancellous bone are separated from the marrow cavity by canopies consisting of a layer of flat osteoblastic cells. These canopies have been suggested to play a key role in the recruitment of osteoprogenitors during the process of bone remodeling. This study was performed to address the characteristics of the canopies above bone formation and resorption sites and their association with biochemical and bone histomorphometric parameters in 106 pediatric chronic kidney disease (CKD) patients (stage 2–5) across the spectrum of ROD. Canopies in CKD patients often appeared as thickened multilayered canopies, similar to previous reports in patients with primary hyperparathyroidism. This finding contrasts with the thin appearance reported in healthy individuals with normal kidney function. Furthermore, canopies in pediatric CKD patients showed immunoreactivity to the PTH receptor (PTHR1) as well as to the receptor activator of nuclear factor kappa-B ligand (RANKL). The number of surfaces with visible canopy coverage was associated with plasma parathyroid hormone (PTH) levels, bone formation rate, and the extent of remodeling surfaces. Collectively, these data support the conclusion that canopies respond to the elevated PTH levels in CKD and that they possess the molecular machinery necessary to respond to PTH signaling.

Normocalcemic primary hyperparathyroidism: a survey in a small village of Southern Italy

We investigated the prevalence of normocalcemic primary hyperparathyroidism (NPHPT) in the adult population living in a village in Southern Italy. All residents in 2010 (n=2045) were invited by calls and 1046 individuals accepted to participate. Medical history, calcium intake, calcium, albumin, creatinine, parathyroid hormone (PTH) and 25OHD were evaluated. NPHPT was defined by normal albumin-adjusted serum calcium, elevated plasma PTH, and exclusion of common causes of secondary hyperparathyroidism (SHPT) (serum 25OHD <30 ng/ml, estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2 and thiazide diuretics use), overt gastrointestinal and metabolic bone diseases. Complete data were available for 685 of 1046 subjects. Twenty subjects did not meet the inclusion criteria and 341 could not be evaluated because of thawing of plasma samples. Classical PHPT was diagnosed in four women (0.58%). For diagnosing NPHPT the upper normal limit of PTH was established in the sample of the population (n=100) who had 25OHD ≥30 ng/ml and eGFR ≥60 ml/min per 1.73 m2 and was set at the mean+3s.d. Three males (0.44%) met the diagnostic criteria of NPHPT. These subjects were younger and with lower BMI than those with classical PHPT. Our data suggest, in line with previous studies, that NPHPT might be a distinct clinical entity, being either an early phenotype of asymptomatic PHPT or a distinct variant of it. However, we cannot exclude that NPHPT might also represent an early phase of non-classical SHPT, since other variables, in addition to those currently taken into account for the diagnosis of NPHPT, might cumulate in a normocalcemic subject to increase PTH secretion.

Calcium and phosphate homeostasis in hyperthyroid cats – associations with development of azotaemia and survival time

To evaluate calcium and phosphate homeostasis in hyperthyroid cats and determine if plasma parathyroid hormone and fibroblast growth factor-23 are associated with the presence of -azotaemic chronic kidney disease and/or have prognostic significance. Retrospective cohort study. Logistic regression analysis and Cox regression analysis were performed to identify if parathyroid hormone and fibroblast growth factor-23 were predictors of development of azotaemia following treatment and survival time, respectively. Two hundred and seven hyperthyroid cats were included. Elevated plasma parathyroid hormone concentrations, hyperphosphataemia, decreased plasma fibroblast growth factor-23 concentrations and hypocalcaemia were documented; however, all parameters returned to reference intervals following treatment of hyperthyroid cats without azotaemic chronic kidney disease. After adjustment for plasma creatinine concentration, baseline plasma parathyroid hormone and fibroblast growth factor-23 concentrations were not predictors of the development of azotaemia following treatment. Baseline plasma fibroblast growth factor-23 concentrations were associated with all-cause mortality; however, this association was not maintained after adjustment for packed cell volume. Changes in plasma parathyroid hormone and fibroblast growth factor-23 concentrations which occur in hyperthyroid cats are not mediators of progression of chronic kidney disease; however, fibroblast growth factor-23 would appear to have some prognostic significance in hyperthyroidism.

Familial hypocalciuric hypercalcaemia

Hypercalcaemia is a potentially life-threatening condition. Familial hypocalciuric hypercalcaemia (FHH) is a rare, lifelong, benign condition. It is important to separate this condition from other hypercalcaemic states such as hypercalcaemia of malignancy and primary hyperparathyroidism (PHPT). FHH is caused by inactivating mutations in the calcium sensing receptor (CASR) gene leading to a general calcium-hyposensitivity, compensatory hypercalcaemia and hypocalciuria. The inheritance of FHH is autosomal dominant. Similar to PHPT, FHH is characterized by hypercalcaemia, unsuppressed or elevated plasma parathyroid hormone, and typically normal renal function. The phenotype is normal, and hypercalcaemic symptoms are generally absent. The hallmark is a relatively low urine calcium excretion in contrast to PHPT, in which urine calcium excretion is increased. The vitamin D status as measured by plasma 25-hydroxyvitamin D has been reported to be normal with normal seasonal variations, whereas plasma 1,25-dihydroxyvitamin D has been found slightly increased compared to normal. Bone mineral density Z-scores are normal in spite of a slightly increased bone turnover. Differential diagnoses include mainly PHPT, but in some cases also hypercalcaemia of malignancy and use of thiazide diuretics. In general, FHH does not require treatment. We recommend a two-step diagnostic procedure. First, the calcium/creatinine clearance ratio is measured from a 24-h urine. Second, all patients with calcium/creatinine clearance ratio of 0.020 or less are tested for mutations in the CASR gene. The diagnostic sensitivity of this setup is 98%.

Forearm Bone Mineral Density in Familial Hypocalciuric Hypercalcemia and Primary Hyperparathyroidism: A Comparative Study

Studies have shown that cancellous bone is relatively preserved in primary hyperparathyroidism (PHPT), whereas bone loss is seen in cortical bone. Familial hypocalciuric hypercalcemia (FHH) patients seem to preserve bone mineral in spite of hypercalcemia and often elevated plasma parathyroid hormone (PTH). The objective of this study was to compare total and regional forearm bone mineral density (BMD) in patients with PHPT and FHH and to examine if differences can be used to separate the two disorders. We included 63 FHH, and 121 PHPT patients in a cross-sectional study. We performed dual-energy X-ray absorptiometry scans of the forearm, hip and lumbar spine and measured a number of biochemical variables. PTH patients had significantly lower Z-scores in all parts of the forearm compared to FHH. This was also the case after adjustment for body mass index. When stratifying for age, gender and PTH, T-scores were still significantly lower in PHPT patients than in FHH patients at the total, the mid and the ultradistal forearm, but not at the proximal 1/3 forearm. In a multiple regression analysis BMD Z-score was lower in PHPT compared to FHH at the total forearm, the mid forearm and the ultradistal forearm but not the proximal forearm when adjusting for biochemical variables including PTH, 1,25(OH)(2)D and Ca(2+). These observations support that inactivating mutations in the CASR gene in bone cells in FHH may protect against forearm bone loss. Differences between the two groups in total or regional forearm BMD were inferior to the calcium/creatinine clearance ratio as a diagnostic tool to separate FHH from PHPT.

Impact of renal failure on metabolic bone parameters in a vitamin D-deficient patient cohort

Chronic renal failure is associated with major changes in bone metabolism, but studies evaluating bone metabolism with mild or moderate renal failure are rare. Moreover, the study populations were often heterogenous and/or patients were pretreated with calcium and vitamin-D preparations. Therefore, we prospectively evaluated metabolic bone parameters in patients with renal insufficiency (Stage 1 - 4) on their first visit to outpatient nephrologists. 285 patients were prospectively evaluated regarding renal function, serum phosphorous, plasma parathyroid hormone (PTH), serum 25-OH-vitamin-D and serum bone specific alkaline phosphatase (BAP) concentrations. Patients were subdivided according to the stages of chronic kidney disease. Hypocalcemia occurred in only 10% of patients in Stage 4, whereas serum phosphorous was elevated at the same stage in 40% of the patients. PTH increased from Stage 1 to 4 continually with a high prevalence of elevated PTH levels (> 65 pg/ml) in Stage 1: 44%; Stage 4: 84%. Serum 25-OH-vitamin-D levels were very low irrespective of renal function: < 15 ng/dl, i.e., 37.5 nmol/l in 70% of all patients. 25-OH-D was negatively correlated with PTH (r = 0.3, p < 0.0002). BAP was within the normal range in all stages but with a high prevalence of BAP values < 7.5 ng/ml in up to 25% in Stage 4. Only 6.5% of patients had features of classical renal hyperparathyroidism. Nearly 20% had low BAP levels in the presence of normal (9.5%) or increased (9.6%) PTH levels. This study demonstrates a high prevalence of hyperphosphatemia in patients with moderate renal failure. Hyperparathyroidism was present even in earlier stages and was aggravated by a high prevalence of vitamin D deficiency. However, also in the presence of elevated PTH levels, there is indication of low bone turnover as evidenced by low BAP levels, suggesting adynamic bone disease.

High prevalence of vitamin D deficiency in the sunny Eastern region of Saudi Arabia: a hospital-based study

This study evaluated the vitamin D status of a cohort of healthy young Saudi Arabians in the Eastern region of Saudi Arabia. A sample of 139 blood donors (87 males and 52 females) answered a questionnaire about their clinical history, including intake of vitamin D supplements and calcium-rich foods and exposure to sunshine. Blood samples were taken for routine biochemistry, serum 25-hydroxyvitamin D [25(OH)3] and plasma parathyroid hormone (PTH) levels. Serum 25(OH)D levels did not differ significantly between males and females, although the levels were low [10.1 (SD 4.6) ng/mL and 9.9 (SD 4.5) ng/mL respectively]. When subjects with elevated PTH levels were excluded, serum 25(OH)3 levels were still in the deficiency range. There was a high prevalence of a vitamin D deficiency in this sample of Saudi Arabians despite > 65% of participants having adequate exposure to sunlight and > 90% reporting adequate intake of dairy products.

Acute Pseudogout Following Intravenous Neridronate for Osteoporosis

To the Editor: An 84-year-old woman with a history of surgical menopause at the age of 37 years, gastroesophageal reflux disease, and prolonged corticosteroid use (prescribed by her general pratictioner for osteoarthritis-related pain), sustained a low-trauma vertebral fracture at L3 level. Radiographs showed previous L2 fracture. Other investigations were unremarkable, except for low 25-OH vitamin D levels (22.1 ng/ml) and elevated plasma parathyroid hormone (144 pg/ml). She was then diagnosed with osteoporosis, supplemented with 300,000 IU of oral cholecalciferol, and started therapy with neridronic acid (NA), 100 mg intravenously1. Corticosteroids had been tapered before starting NA. The day after her first NA dose, she noticed polyarthralgia, myalgia, and fever (to 38°C). Over the subsequent 5 days, symptoms eased, but she experienced progressive pain and swelling … Address correspondence to Dr. S. Carda, Physical and Rehabilitative Medicine Department, AUO Maggiore della Carità, v. le Piazza d’Armi 1, 28100 Novara, Italy. E-mail: stefano.carda{at}virgilio.it

Plasma Parathyroid Hormone and the Risk of Cardiovascular Mortality in the Community

Diseases with elevated levels of parathyroid hormone (PTH) such as primary and secondary hyperparathyroidism are associated with increased incidence of cardiovascular disease and death. However, data on the prospective association between circulating PTH levels and cardiovascular mortality in the community are lacking. The Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men (mean age, 71 years; n=958), was used to investigate the association between plasma PTH and cardiovascular mortality. During follow-up (median, 9.7 years), 117 participants died of cardiovascular causes. In Cox proportional-hazards models adjusted for established cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease), higher plasma PTH was associated with higher risk for cardiovascular mortality (hazard ratio for 1-SD increase in PTH, 1.38; 95% confidence interval, 1.18 to 1.60; P<0.001). This association remained essentially unaltered in participants without previous cardiovascular disease and in participants with normal PTH (<6.8 pmol/L) with no other signs of a disturbed mineral metabolism (normal serum calcium, 2.2 to 2.6 mmol/L; normal glomerular filtration rate, >50 mL . min(-1) . 1.73 m(-2) and without vitamin D deficiency, plasma 25-OH vitamin D >37.5 nmol/L). Interestingly, elevated plasma PTH (>5.27 pmol/L) accounted for 20% (95% confidence interval, 10 to 26) of the population-attributable risk proportion for cardiovascular mortality. Plasma PTH levels predict cardiovascular mortality in the community, even in individuals with PTH within the normal range. Further studies are warranted to evaluate the clinical implications of measuring PTH in cardiovascular risk prediction and to elucidate whether PTH is a modifiable risk factor.

Ethnic differences in parathyroid hormone secretion and mineral metabolism in response to oral phosphate administration

Ethnic differences in bone metabolism have been reported and it has been suggested that these may be partly due to prolonged exposure to an elevated plasma parathyroid hormone (PTH) concentration or a decreased sensitivity to PTH. We explored ethnic differences in bone and mineral metabolism by 5 days of oral phosphate (P) loading to stimulate PTH secretion. Healthy older people from UK (B), The Gambia (G) and China (C), 15 individuals from each sex and ethnic group, were studied. Blood and urine samples were collected before and 2 h after P dose on days 1, 4 and 5 and on a control day. The induced changes (%) in PTH and markers of mineral and bone metabolism after 2 h and over 5 days were examined.At baseline, PTH, 1,25(OH)2D and bone turnover markers were higher in Gambian subjects than in British and Chinese subjects (P≤0.01).2 h after P loading, ionized calcium (iCa) decreased and PTH and plasma P (P) increased in all groups (P≤0.01, n.s. between groups). Urinary P to creatinine ratio (uP/Cr) increased, the increase being greater in Chinese subjects than in British and Gambian subjects on days 4 and 5 (P≤0.01). By day 5, fasting iCa was decreased and P increased in British and Gambian (P≤0.01) but not in Chinese subjects. Fasting PTH and uP/Cr increased in all groups. There were ethnic differences in changes in bone markers, but the relationship with changes in PTH was comparable between groups.In conclusion, ethnic differences in mineral metabolism in response to 5-day P loading were found. Chinese subjects showed a more rapid renal clearance of P than British and Gambian counterparts and there were differences between the groups in the skeletal response to P loading, but no evidence was found for resistance to the resorbing effects of PTH.

Plasma 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone in familial hypocalciuric hypercalcemia and primary hyperparathyroidism

Familial hypocalciuric hypercalcemia (FHH) is a lifelong, benign, inherited condition caused by inactivating mutations in the calcium-sensing receptor (CASR) gene. Both FHH and primary hyperparathyroidism (PHPT) are characterized by elevated P-calcium, normal or elevated plasma-parathyroid hormone (P-PTH), and typically normal renal function. In PHPT, vitamin D metabolism is typically characterized by low plasma levels of 25-hydroxyvitamin D (25OHD), and high plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). In FHH, the vitamin D metabolism is not very well known. To compare and evaluate plasma 25OHD, 1,25(OH)(2)D, and PTH in FHH and PHPT. Cross-sectional study. About 66 FHH patients with mutations in the CASR gene, 147 patients with surgically verified PHPT, and 46 controls matched to FHH patients according to age (+/-5 years), sex, and season. All patients had a P-creatinine <140 micromol/l. We measured P-calcium, P-Ca(2)(+), P-albumin, P-creatinine, P-phosphate, P-magnesium, and P-PTH by standard laboratory methods. P-25OHD and P-1,25(OH)(2)D were measured by RIA or enzyme immunoassay. In FHH, all protein-coding exons in the CASR gene were sequenced and aligned to GenBank reference sequence NM_000388.2. PHPT patients had higher body mass index (2p<0.01), together with higher P-PTH (2p<0.01) and P-1,25(OH)(2)D (2p<0.01) compared with FHH patients. The groups had similar levels of P-Ca(2)(+) and of P-25OHD. The phenotypic expression of the CASR mutations (as determined by the degree of hypercalcemia) did not influence the levels of P-1,25(OH)(2)D. Even though P-calcium and P-25OHD were comparable, P-1,25(OH)(2)D and P-PTH differed between FHH and PHPT.

Relationship between Parathyroid Hormone and Cardiac Abnormalities in Chronic Dialysis Patients

It has been shown that parathyroid hormone (PTH) influences cardiac abnormalities in dialysis patients. The purpose of this study was to evaluate the relationship between the plasma PTH level and cardiac abnormalities in these patients without overt cardiac disease. A total of 81 of the 208 patients who received chronic dialysis treatment at our institution were included in this study. Plasma PTH level measurement, other blood examinations and echocardiography were performed in all patients. The subjects were divided into two groups based on plasma PTH level (<300 pg/ml: group A; > or =300 pg/ml: group B). There were no significant differences in echocardiographic parameters between group A and group B. The plasma PTH level was not significantly correlated with any echocardiographic parameter in any patient. In addition, we chose 10 patients with a plasma PTH level of more than 500 pg/ml from group B and 20 patients matched for various characteristics (excluding PTH level) from group A and compared the echocardiographic parameters between them. LVMI and intraventricular septum thickness (IVST) were significantly greater in patients with a plasma PTH level of greater than 500 pg/ml. PTH was not strongly associated with cardiac abnormalities such as LVH or decreased left ventricular function in the overall group of patients. PTH may not play a major role in the pathogenesis of cardiac abnormalities in these patients. However, PTH could influence LVH in patients with remarkably elevated plasma PTH levels.