We investigated the vitamin D status and the effect of vitamin D supplementation in Korean breast-fed infants. The healthy term newborns were divided into 3 groups; A, formula-fed; B, breast-fed only; S, breast-fed with vitamin D supplementation. We measured serum concentrations of vitamin D (25OHD3), calcium (Ca), phosphorus (P), alkaline phosphatase (AP), intact parathyroid hormone (iPTH) and bone mineral density (BMD) at 6 and 12 months of age. Using questionnaires, average duration of sun-light exposure and dietary intake of vitamin D, Ca and P were obtained. At 6 and 12 months of age, 25OHD3 was significantly higher in group S than in group B (P<0.001). iPTH was significantly lower in group S than in group B at 6 months (P=0.001), but did not differ at 12 months. Regardless of vitamin D supplementation, BMD was lower in group B and S than in group A (P<0.05). Total intake of vitamin D differed among 3 groups (P<0.001, A>S>B), but total intake of Ca and P were higher in group A than in group B and S (P<0.001). In conclusion, breast-fed infants show lower vitamin D status and bone mineralization than formula-fed infants. Vitamin D supplementation (200 IU/day) in breast-fed infants increases serum 25-OH vitamin D3, but not bone mineral density.
Vitamin D; Nutritional Status; Bone Density; Vitamin D Deficiency; Dietary Supplements; Breast feeding; Infant
Although several studies indicate a link between vitamin D status and blood pressure (BP), the results are inconsistent. The purpose of this study is to investigate whether in predominantly non-obese elderly people without vitamin D deficiency or very high intact parathyroid hormone (iPTH) levels serum 25-hydroxyvitamin D3 [25(OH)D3] and iPTH are independently associated with BP.
Cross-sectional data of 132 non-institutionalised subjects (90 women and 42 men, aged 66- 96 years) from Giessen, Germany, were analysed. Serum 25(OH)D3 and iPTH were measured by an electrochemiluminescence immunoassay and BP was determined with a sphygmomanometer. We performed univariate and multiple regression analyses to examine the influence of 25(OH)D3 and iPTH on BP with adjustments for age, body composition and lifestyle factors.
While iPTH had no impact on BP, 25(OH)D3 was negatively associated with systolic BP in men, but not in women. After splitting the cohort into antihypertensive medication users and non-users, 25(OH)D3 was a significant predictor for systolic and diastolic BP only in men not receiving antihypertensive medicine, even after multiple adjustment. Adjustment for 25(OH)D3 resulted in an inverse association of iPTH with diastolic BP also only in men without intake of antihypertensive medicine.
In elderly men without vitamin D deficiency and not taking antihypertensive medicine, 25(OH)D3 may be a negative determinant of BP, independent of iPTH, body composition and lifestyle factors. Furthermore, iPTH may be an independent negative determinant of diastolic BP in men not taking antihypertensive medicine.
25-Hydroxyvitamin D3; Parathyroid hormone; Blood pressure; Elderly
An inverse relationship between major depressive disorder (MDD) and bone mineral density (BMD) has been suggested, but prospective evaluation in premenopausal women is lacking.
Participants of this prospective study were 21 to 45 year-old premenopausal women with MDD (n = 92) and healthy controls (n = 44). We measured BMD at the anteroposterior lumbar spine, femoral neck, total hip, mid-distal radius, trochanter, and Ward's triangle, as well as serum intact parathyroid hormone (iPTH), ionized calcium, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-hour urinary-free cortisol levels at 0, 6, 12, 24, and 36 months. 25-hydroxyvitamin D was measured at baseline.
At baseline, BMD tended to be lower in women with MDD compared to controls and BMD remained stable over time in both groups. At baseline, 6, 12, and 24 months intact PTH levels were significantly higher in women with MDD vs. controls. At baseline, ionized calcium and 25-hydroxyvitamin D levels were significantly lower in women with MDD compared to controls. At baseline and 12 months, bone-specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD vs. controls. Plasma ACTH was also higher in women with MDD at baseline and 6 months. Serum osteocalcin, urinary N-telopeptide, serum cortisol, and urinary free cortisol levels were not different between the two groups throughout the study.
Women with MDD tended to have lower BMD than controls over time. Larger and longer studies are necessary to extend these observations with the possibility of prophylactic therapy for osteoporosis.
ClinicalTrials.gov NCT 00006180
Emerging evidence indicates that there is an association between vitamin D and obesity. The aim of this study was to investigate whether the level of serum 25-hydroxyvitamin D3 [25(OH)D3] in the elderly is influenced by parameters of anthropometry and body composition independent of potential confounding lifestyle factors and the level of serum intact parathyroid hormone (iPTH).
Cross-sectional data of 131 independently living participants (90 women, 41 men; aged 66–96 years) of the longitudinal study on nutrition and health status in senior citizens of Giessen, Germany were analysed. Concentrations of 25(OH)D3 and iPTH were ascertained by an electrochemiluminescence immunoassay. Body composition was measured by a bioelectrical impedance analysis. We performed univariate and multiple regression analyses to examine the influence of body composition on 25(OH)D3 with adjustments for age, iPTH and lifestyle factors.
In univariate regression analyses, 25(OH)D3 was associated with body mass index (BMI), hip circumference and total body fat (TBF) in women, but not in men. Using multiple regression analyses, TBF was shown to be a negative predictor of 25(OH)D3 levels in women even after controlling for age, lifestyle and iPTH (ß = −0.247; P = 0.016), whereas the associations between BMI, hip circumference and 25(OH)D3 lost statistical significance after adjusting for iPTH. In men, 25(OH)D3 was not affected by anthropometric or body composition variables.
The results indicate that 25(OH)D3 levels are affected by TBF, especially in elderly women, independent of lifestyle factors and iPTH.
25-Hydroxyvitamin D3; Body composition; Fat mass; Elderly
Objective: To evaluate the effect of strenuous exercise on bone metabolism and related hormones in elderly subjects.
Methods: Twenty one active elderly subjects (11 men and 10 women; mean age 73.3 years) showing a mean theoretical Vo2max of 151.4% participated. Concentrations of plasma ionised calcium (iCa), serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25(OH)D), and 1.25-dihydroxy-vitamin D3 (1.25(OH)2D3), as well as the bone biochemical markers type I collagen C-telopeptide for bone resorption and osteocalcin and bone alkaline phosphatase for bone formation, were analysed before and after a maximal incremental exercise test.
Results: At basal level, iPTH was positively correlated with age (r = 0.56, p<0.01) and negatively correlated with 25(OH)D (r = –0.50; p<0.01) and 1.25(OH)2D3 (r = –0.47; p<0.05). Moreover, 25(OH)D and 1.25(OH)2D3 levels were negatively correlated with age (r = –0.50, p<0.01 and r = –0.53, p<0.01, respectively). After exercise, iCa and 25(OH)D decreased (p<0.001 and p = 0.01, respectively) while iPTH increased (p<0.001). The levels of 1.25(OH)2D3, bone biochemical markers, haematocrit, and haemoglobin were unchanged. The variations in iCa and 25(OH)D were not related to age and/or sex. The iPTH variation was directly related to basal iPTH levels (p<0.01) and indirectly related to age.
Conclusions: In active elderly subjects, strenuous exercise disturbed calcium homeostasis and bone related hormones without immediate measurable effect on bone turnover. Although an increase in iPTH could have an anabolic action on bone tissue, our findings from our short term study did not allow us to conclude that such action occurred.
Twenty-seven unselected patients were investigated three to eight years after jejunoileal bypass for morbid obesity. The serum levels of calcium, magnesium, and phosphorus, and the renal excretions of calcium and magnesium were reduced. The serum alkaline phosphatase levels were increased. The serum levels of the two vitamin D metabolites 25-hydroxyvitamin D (25-OHD) and 1.25-dihydroxyvitamin D (1.25-(OHD)2D) were reduced and inversely related to the increased serum levels of immunoreactive parathyroid hormones (iPTH). Serum 1.25-(OH)2D correlated positively and serum iPTH inversely with serum concentrations and renal excretion rates of calcium. Iliac crest bone biopsies after in vivo tetracycline double-labelling showed a reduced bone turnover with an increased amount of osteoid due to an increase in both surface extent and mean width of osteoid seams. The increased volume of osteoid was caused by a decreased osteoblastic function with a longer life-span of bone-forming sites and a prolongation of the mineralisation lag time. The amount of trabecular bone was normal. The results indicate an impaired vitamin D metabolism with osteomalacia and secondary hyperparathyroidism.
The effect of magnesium chloride or magnesium sulfate infusion on circulating levels of immunoreactive calcitonin (iCT) was evaluated on nine occasions in three patients with metastatic medullary carcinoma of the thyroid. One patient was normocalcemic and had normal circulating levels of immunoreactive parathyroid hormone (iPTH), one patient was hypocalcemic and had surgical hypoparathyroidism, and one patient had mild to moderate hypercalcemia associated with bone metastases. The basal serum iPTH levels were undetectable in the latter two patients. In every instance magnesium administration produced a rapid and striking fall in circulating iCT and usually a detectable fall in serum calcium. During the hypermagnesemic state, serum iPTH fell from normal to undetectable in the patient with normal parathyroid function, while serum iPTH levels remained undetectable in the hypoparathyroid patient and in the patient with hypercalcemia associated with bone metastases. The results of these studies indicate that: (a) contrary to what has been reported in normal experimental animals, magnesium administration lowers circulating iCT in human subjects with thyroid medullary carcinoma and (b) the calcium-lowering effect produced by magnesium in patients with medullary carcinoma may, in part at least, be due to a redistribution of body calcium that is not mediated by the actions of either parathyroid hormone or clacitonin.
Hypoparathyroidism, a disorder characterized by low parathyroid hormone (PTH), is generally treated with oral calcium and vitamin D supplementation. We investigated the effects of PTH(1–84) treatment in 30 hypoparathyroid subjects for 24 months. PTH(1–84) treatment in hypoparathyroidism significantly reduced supplemental calcium and 1,25-dihydroxyvitamin D requirements without generally altering serum and urinary calcium levels.
Hypoparathyroidism, a disorder characterized by low PTH, is associated with hypocalcemia, hypercalciuria, and increased bone mineral density (BMD). Conventional therapy with calcium and 1,25-dihydroxyvitamin D can maintain the serum calcium concentration, but doses are high, and control is variable. We investigated the effects of human PTH(1–84) treatment in hypoparathyroidism.
Thirty subjects with hypoparathyroidism were treated in an open-label study of PTH(1–84) 100 μg every other day by subcutaneous injection for 24 months, with monitoring of calcium and vitamin D supplementation requirements, serum and 24 h urinary calcium excretion, and BMD by dual energy X-ray absorptiometry.
Requirements for supplemental calcium decreased significantly (3,030±2,325 to 1,661±1,267 mg/day (mean± SD); p<0.05), as did requirements for supplemental 1,25-dihydroxyvitamin D (0.68±0.5 to 0.40±0.5 μg/day; p< 0.05). Serum calcium levels and 24 h urinary calcium excretion were mostly unchanged at 24 months. BMD increased at the lumbar spine by 2.9±4% from baseline (p<0.05), while femoral neck BMD remained unchanged and distal one third radial BMD decreased by 2.4±4% (p<0.05).
PTH(1–84) treatment in hypoparathyroidism significantly reduces supplemental calcium and 1,25-dihydroxyvitamin D requirements without generally altering serum and urinary calcium levels.
Calcium; Hypoparathyroidism; PTH(1–84)
A new radioimmunoassay for human parathyroid hormone (PTH) in serum, which can measure the hormone present in 94% of the normal sera tested, is described. It is based on the ability of human PTH to compete with 131I-labeled bovine PTH for binding to an antiserum directed against porcine PTH. This antiserum distinguishes between human PTH extracted from parathyroid adenomata and that present in hyperparathyroid sera. Evidence is given to suggest that this is due to immunochemical changes in the hormone extracted from adenomata and not to immunochemical heterogeneity of the hormone present in serum.
Physiologic data supporting the validity and specificity of the assay are presented. Induced episodes of hypercalcemia and hypocalcemia resulted in appropriate responses in serum immunoreactive PTH (IPTH) in normal subjects and in patients with Paget's disease of bone. In normals, there was a progressive increase in serum IPTH in the late afternoon and evening, suggesting a diurnal secretory rhythm. A negative correlation was found between the serum calcium and serum IPTH over the normal range of serum calcium values; a positive correlation was found between these variables in patients with primary hyperparathyroidism. There was apparent overlap between serum IPTH values in normal subjects and patients with primary hyperparathyroidism, but formal discriminate analysis of values for serum calcium and IPTH demonstrated separation of these two groups, without overlap.
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that is secreted from bone and serum level increases as renal function declines. Higher levels of FGF23 are associated with increased mortality in hemodialysis-patients and in patients with chronic kidney disease (CKD) stage 2-4. The use of active vitamin D and phosphate binders as recommended in international guidelines, may affect the level of FGF23 and thereby clinical outcome. We investigated the effects of a phosphate binder and active vitamin D on the serum levels of intact FGF23 (iFGF23) and intact parathyroid hormone (iPTH) in patients with CKD stage 3b (glomerular filtration rate (GFR) 30–44 ml/min/1.73 m2).
Seven women and 14 men were included, mean age 65.6 ± 12.2 years. They were randomized in a 1:1 ratio to receive one of two treatment sequences. Group-1 (the alphacalcidol-sevelamer carbonate group): alphacalcidol 0.25 μg once daily for two weeks followed by sevelamer carbonate 800 mg TID with meals for two weeks after a two-week washout period. Group-2 (the sevelamer carbonate-alphacalcidol group): vice versa. Nineteen patients completed the study. The 25-hydroxyvitamin D level at baseline was 97.6 ± 25.0 nmol/l.
There were no treatment effects on the iFGF23 and iPTH levels overall. In group-1 the iFGF23 level was higher after treatment with alphacalcidol compared with sevelamer carbonate (mean 105.8 ± 41.6 vs. 79.1 ± 36.5 pg/ml, p = 0.047 (CI: 0.4-52.9), and the iPTH level was lower (median: 26.5, range: 14.6-55.2 vs. median 36.1, range 13.4-106.9 pg/ml, p = 0.011). In group-2 the iFGF23 level increased non-significantly after treatment with sevelamer carbonate and throughout the washout period.
In this crossover trial with alphacalcidol and sevelamer carbonate in patients with CKD stage 3b, the levels of iFGF23 were not significantly different after the two treatments. However, in the group of patients initiating therapy with sevelamer carbonate the iFGF23 levels seemed to increase while this response was mitigated in the group of patients given alphacalcidol followed by sevelamer carbonate. This may have therapeutic implications on choice of first line therapy. The number of patients is small and this conclusion is in part based on subgroup analysis. It is therefore important that these results are confirmed in larger studies.
Trial Registration Number: European Clinical Trial Database (EudraCT) 2010-020415-36 and Clinical Trials.gov NCT01231438
Active vitamin D; Chronic kidney disease; Fibroblast growth factor 23; FGF23; Phosphate-binder; Parathyroid hormone; PTH; Sevelamer carbonate
Corticosteroid-induced osteoporosis is the most common secondary cause of osteoporosis. We conducted a 12-mo, randomized clinical trial of human parathyroid hormone 1-34 (hPTH 1-34) in postmenopausal women (mean age was 63 yr) with osteoporosis who were taking corticosteroids and hormone replacement therapy. Response to the treatment was assessed with bone mineral density (BMD) measurements of the lumbar spine by quantitative computed tomography (QCT); BMD measurements of the lumbar spine, hip, and forearm by dual-energy x-ray absorptiometry (DXA); and biochemical markers of bone turnover. The mean (+/-SE) changes in BMD of the lumbar spine by QCT and DXA in the PTH group were 35+/-5.5% and 11+/-1.4%, respectively, compared with a relatively small change of 1.7+/-1.8% and 0+/-0.9% in the estrogen-only group. The differences in mean percentage between the groups at 1 yr were 33.5% for the lumbar spine by QCT (P < 0.001) and 9.8% for the lumbar spine by DXA (P < 0.001). The changes in the hip and forearm were not significantly different between or within the groups. During the first 3 mo of PTH treatment, markers of bone formation increased to nearly 150%, whereas markers of bone resorption increased only 100%, suggesting an early uncoupling of bone turnover in favor of formation. These results suggest that parathyroid hormone dramatically increases bone mass in the central skeleton of postmenopausal women with corticosteroid- induced osteoporosis who are taking hormone replacement.
Optimal vitamin D status for the prevention of osteoporosis has been inferred from examinations of the serum 25-hydroxyvitamin D [25(OH)D] concentration below which there is an increase in serum parathyroid hormone (PTH).
The objectives of the study were to ascertain whether a threshold for serum 25(OH)D exists below which serum PTH increases and whether persons with 25(OH)D above this threshold have lower rates of bone loss than do persons with 25(OH)D below the threshold.
The relation of serum 25(OH)D to serum PTH was analyzed in 208 African American women studied longitudinally for 3 y. These healthy women in midlife were randomly assigned to receive placebo or 800 IU vitamin D3/d; after 2 y, the vitamin D3 supplementation was increased to 2000 IU/d. Both groups received calcium supplements to ensure an adequate calcium intake. A systematic literature review found a wide range of threshold values in part due to varied calcium intake.
A Loess plot suggested a breakpoint between 40 and 50 nmol/L for serum 25(OH)D. A line-line model was fitted to the data, and it showed a spline knot at 44 nmol/L. A heuristic approach verified that PTH does not decline as rapidly when the serum concentration of 25(OH)D is >40 nmol/L as when it is <40 nmol/L. We found no significant difference in rates of bone loss between persons with 25(OH)D concentrations above and below 40 nmol/L.
Although a threshold for 25(OH)D can be identified, we suggest that it should not be used to recommend optimal vitamin D status.
African Americans; vitamin D; parathyroid hormone; PTH; osteoporosis; calcium intake; secondary hyperparathyroidism
Two major species of serum immunoreactive parathyroid hormone (iPTH) were measured in 47 untreated patients with primary osteoporosis by using two highly specific radioimmunoassays. Mean iPTH was normal with one antiserum but was lower than normal (P < 0.001) with the other, iPTH values did not correlate with biochemical parameters or with the proportion of bone-resorbing surfaces in iliac crest bone biopsy specimens. These data suggest that the increased bone resorption is not due to increased parathyroid function in most osteoporotic patients. However, seven of our patients (15%) appear to represent a separate population because they had increased values with one or the other of the antisera.
Recent systematic reviews have cast doubt on the association between vitamin D and cardiovascular disease. No prior studies have investigated the association between 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2D) and intact parathyroid hormone (iPTH) and cardiovascular disease mortality in a temperate climate.
1073 community-dwelling older adults were evaluated in 1997-99; serum levels of 25(OH)D (mean 42ng/mL), 1,25(OH)2D (median 29pg/mL) and iPTH (median 46pg/mL) were measured; mean estimated glomerular filtration rate (eGFR) was 74mL/min/1.73m2. Participants were followed up to 10.4 (mean 6.4) years with 111 cardiovascular disease deaths.
In unadjusted Cox proportional hazards models, higher levels of 1,25(OH)2D were protective against cardiovascular mortality, while higher levels of iPTH predicted increased risk of cardiovascular death. After adjusting for age alone or multiple covariates, there was no significant association between 25(OH)D, 1,25(OH)2D or iPTH and cardiovascular mortality; results did not differ by eGFR≥60mL/min/1.73m2 or <60mL/min/1.73m2.
In this prospective study of Caucasian, middle-income, community-dwelling older adults living in sunny southern California, serum levels of 25(OH)D, 1,25(OH)2D, or iPTH were not independently associated with cardiovascular mortality.
aging; cardiovascular mortality; chronic kidney disease; parathyroid hormone; vitamin D
Elevated serum phosphorus (P) levels have been linked to increased morbidity and mortality in dialysis patients with secondary hyperparathyroidism (SHPT) but may be difficult to control if parathyroid hormone (PTH) is persistently elevated. We conducted a post hoc analysis of data from an earlier interventional study (OPTIMA) to explore the relationship between PTH control and serum P.
The OPTIMA study randomized dialysis patients with intact PTH (iPTH) 300–799 pg/mL to receive conventional care alone (vitamin D and/or phosphate binders [PB]; n = 184) or a cinacalcet-based regimen (n = 368). For patients randomized to conventional care, investigators were allowed flexibility in using a non-cinacalcet regimen (with no specific criteria for vitamin D analogue dosage) to attain KDOQI™ targets for iPTH, P, Ca and Ca x P. For those assigned to the cinacalcet-based regimen, dosages of cinacalcet, vitamin D sterols, and PB were optimized over the first 16 weeks of the study, using a predefined treatment algorithm. The present analysis examined achievement of serum P targets (≤4.5 and ≤5.5 mg/dL) in relation to achievement of iPTH ≤300 pg/mL during the efficacy assessment phase (EAP; weeks 17–23).
Patients who achieved iPTH ≤ 300 pg/mL (or a reduction of ≥30% from baseline) were more likely to achieve serum P targets than those who did not, regardless of treatment group. Of those who did achieve iPTH ≤ 300 pg/mL, 43% achieved P ≤4.5 mg/dL and 70% achieved P ≤5.5 mg/dL, versus 21% and 46% of those who did not achieve iPTH ≤ 300 pg/mL. Doses of PB tended to be higher in patients not achieving serum P targets. Patients receiving cinacalcet were more likely to achieve iPTH ≤300 pg/mL than those receiving conventional care (73% vs 23% of patients). Logistic regression analysis identified lower baseline P, no PB use at baseline and cinacalcet treatment to be predictors of achieving P ≤4.5 mg/dL during EAP in patients above this threshold at baseline.
This post hoc analysis found that control of serum P in dialysis patients was better when serum PTH levels were lowered effectively, regardless of treatment received.
Clinicaltrials.gov identifier NCT00110890
Serum immunoreactive parathyroid hormone (IPTH) was measured by radioimmunoassay in 54 patients with primary hyperparathyroidism and in 18 consecutive patients with ectopic hyperparathyroidism due to nonparathyroid cancer without apparent skeletal metastasis. Although serum calcium concentration was higher in the group with ectopic hyperparathyroidism, serum IPTH was lower (rank sum test, P < 0.001) and was undetectable in eight. A second anti-PTH antiserum also differentiated between IPTH in the two groups, although IPTH was undetectable in only 1 of 14 sera. When IPTH values in serial dilutions were plotted, slopes for the two patients with ectopic hyperparathyroidism who had relatively high IPTH were less (P < 0.001) than slopes for standard hyperparathyroid sera. By using differences in either IPTH rank or slope of the dilutional curve of sera, primary hyperparathyroidism could be excluded as a cause of the hypercalcemia in 16 of the 18 patients with ectopic hyperparathyroidism. The data are interpreted as indicating that PTH-like material in the serum of these patients with ectopic hyperparathyroidism is immunologically different from the PTH in the serum of patients with primary hyperparathyroidism.
Elevated parathyroid hormone (PTH) is a risk factor for increased morbidity and mortality. PTH levels increase with adiposity in older adults but the basis for this association is unclear. The objective of this study was to examine the association of percent body fat (%Fat) with serum PTH in 307 older men and women and to determine the extent to which it may be explained by vitamin D status, bone turnover, calcium metabolism, and glucose homeostasis. The data are from the baseline visit of a clinical trial of calcium and vitamin D to prevent bone loss. %Fat was measured by dual-energy X-ray absorptiometry and fasting blood and urine samples were collected. Serum PTH levels increased by about 0.4 pmol/l per 10 unit increase in percent body fat (P = 0.003). The variables that we examined, including plasma 25-hydroxyvitamin D and serum osteocalcin, calcium, phosphorus, and insulin explained only a small proportion of this association (18%). Further work is needed to identify the mediators of the higher PTH levels in subjects with greater adiposity. This is important in view of worldwide increases in overweight and obesity and the potential contribution of elevated PTH to morbidity and mortality.
Body fat; Parathyroid hormone; Bone turnover; Calcium binding; Insulin; Glucose
Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis as it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells, and induces these lymphocytes to activate canonical Wnt-signaling in pre-osteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in pre-osteoblasts and blunted osteoblastic commitment, proliferation, differentiation and lifespan which result in decreased trabecular bone anabolism and no increase in strength. Demonstrating the specific role of lymphocytic Wnt10b, iPTH has no anabolic activity in mice lacking T cell produced Wnt10b. Therefore, T cell mediated activation of Wnt signaling in osteoblastic cells plays a key permissive role in the mechanism by which iPTH increases bone strength, suggesting that T cell osteoblast cross-talk pathways may provide pharmacological targets for bone anabolism.
Background and aims: Vitamin D deficiency is common in patients with small intestinal resection and may lead to secondary hypersecretion of parathyroid hormone (PTH), which in turn may result in increased bone turnover rate and loss of bone mineral. The aims of this study were to investigate the prevalence of vitamin D deficiency, as assessed by low serum concentrations of 25-hydroxyvitamin D (25(OH)D) in patients with small intestinal resection and to explore the relation of 25(OH)D to PTH, markers of bone turnover rate, and bone mineral density (BMD) in these patients.
Patients: Forty two patients with small intestinal resection, a faecal energy excretion of more than 2.0 MJ/day, and a mean length of the remaining small intestine of 199 cm were included. Diagnoses were Crohn’s disease (n=35) and other (n=7).
Methods: 25(OH)D was analysed by radioimmunoassay and bone turnover rate was assessed by measurement of serum osteocalcin, serum alkaline phosphatase, urine pyridinoline, and urine deoxypyridinoline. BMD was measured by dual energy x ray absorptiometry.
Results: Mean 25(OH)D concentration was 13.4 (SD 9.7) ng/ml, which was significantly below the reference mean of 26.4 (SD 13.2) ng/ml (p<0.001). Vitamin D deficiency (25(OH)D concentration ≤8 ng/ml) was found in 38.1% of patients and was accompanied by raised concentrations of PTH and significantly increased markers of bone resorption (p<0.05). Low 25(OH)D concentrations correlated significantly with lower BMD z scores of the spine (r=0.38; p=0.02) and hip (r=0.33; p=0.04).
Conclusions: We found reduced 25(OH)D concentrations in patients with small intestinal resection, and showed that a deficient 25(OH)D concentration is associated with significantly increased markers of bone resorption and decreased BMD values.
vitamin D; bone metabolism; small intestinal resection
The combination of transfusion and chelation therapy has dramatically extended the life expectancy of thalassemic patients. The main objective of this study is to determine the prevalence of prominent thalassemia complications.
Two hundred twenty patients entered the study. Physicians collected demographic and anthropometric data and the history of therapies as well as menstrual histories. Patients have been examined to determine their pubertal status. Serum levels of 25(OH) D, calcium, phosphate, iPTH were measured. Thyroid function was assessed by T3, T4 and TSH. Zinc and copper in serum were determined by flame atomic absorption spectrophotometry. Bone mineral density (BMD) measurements at lumbar and femoral regions have been done using dual x-ray absorptiometry. The dietary calcium, zinc and copper intakes were estimated by food-frequency questionnaires.
Short stature was seen in 39.3% of our patients. Hypogonadism was seen in 22.9% of boys and 12.2% of girls. Hypoparathyroidism and primary hypothyroidism was present in 7.6% and 7.7% of the patients. About 13 % of patients had more than one endocrine complication with mean serum ferritin of 1678 ± 955 micrograms/lit. Prevalence of lumbar osteoporosis and osteopenia were 50.7% and 39.4%. Femoral osteoporosis and osteopenia were present in 10.8% and 36.9% of the patients. Lumbar BMD abnormalities were associated with duration of chelation therapy. Low serum zinc and copper was observed in 79.6% and 68% of the study population respectively. Serum zinc showed significant association with lumbar but not femoral BMD. In 37.2% of patients serum levels of 25(OH) D below 23 nmol/l were detected.
High prevalence of complications among our thalassemics signifies the importance of more detailed studies along with therapeutic interventions.
Serum immunoreactive parathyroid hormone (iPTH) and plasma total calcium, ionized calcium, magnesium, and phosphorus levels were determined during the first 9 days of life in 137 normal term infants, 55 “sick” infants, and 43 hypocalcemic (Ca <7.5 mg/100 ml; Ca++<4.0 mg/100 ml) infants.
In the cord blood, elevated levels of plasma Ca++ and Ca were observed, while levels of serum iPTH were either undetectable or low. In normal newborns during the first 48 h of life there was a decrease in plasma Ca and Ca++, while the serum iPTH level in most samples remained undetectable or low; after 48 h there were parallel increases in plasma Ca and Ca++ and serum iPTH levels. Plasma Mg and P levels increased progressively after birth in normal infants.
In the sick infants, plasma Ca, Ca++ and P levels were significantly lower than in the normal newborns, while no significant differences were found in the plasma Mg levels. The general pattern of serum iPTH levels in the sick infants was similar to that observed in the normal group, though there was a tendency for the increase in serum iPTH to occur earlier and for the iPTH levels to be higher in the sick infants.
In the hypocalcemic infants, plasma Mg levels were consistently lower than in the normal infants after 24 h of age, while no significant differences were found in the plasma P levels. Hyperphosphatemia was uncommon and did not appear to be a contributing factor in the pathogenesis of hypocalcemia in most infants. Most of the hypocalcemic infants, including those older than 48 h, had inappropriately low serum iPTH levels.
Evidence obtained from these studies indicates that parathyroid secretion is normally low in the early new born period and impaired parathyroid function, characterized by undetectable or low serum iPTH, is present in most infants with neonatal hypocalcemia. Additional unknown factors appear to contribute to the lowering of plasma Ca in the neonatal period. The net effect of unknown plasma hypocalcemic factor(s) on the one hand and parathyroid activity on the other may account for differences in plasma Ca levels observed between normal, sick, and hypocalcemic infants. Depressed plasma Mg is frequently present in hypocalcemic infants. To what degree the hypomagnesemia reflects parathyroid insufficiency or the converse, to what degree parathyroid insufficiency and hypocalcemia are secondary to hypomagnesemia, is uncertain.
To investigate via the vitamin D status whether patients with peripheral arterial disease (PAD) tend to develop vitamin D deficiency that in turn influences their clinical symptoms.
PATIENTS AND PARTICIPANTS
Three hundred twenty-seven patients were evaluated; subjects with secondary causes of bone disease or bone active medication were excluded. One hundred sixty-one patients with either PAD stage II (n = 84) or stage IV (n = 77) were enrolled and compared to 45 age- and sex-matched healthy controls.
MEASUREMENTS AND MAIN RESULTS
All patients underwent determinations of serum chemistry, 25-hydroxyvitamin D (vitamin D3) intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and osteocalcin and were further stratified according to an individual restriction score into 3 groups: mildly, moderately, or severely restricted in daily life due to the underlying disease. Patients with PAD IV showed significantly lower vitamin D3 (P = .0001), and calcium (P = .0001) values and significantly higher iPTH (P = .0001), osteocalcin (P = .0001) and ALP (P = .02) levels as compared to patients with PAD II. Patients considering themselves as severely restricted due to the underlying disease showed lower vitamin D3 and higher iPTH levels than those who described only a moderate (vitamin D3: P < .001; iPTH: P < .01) or mild (vitamin D3: P < .001; iPTH: P < .001) restriction in daily life.
Patients with PAD IV, especially those who feel severely restricted due to the disease, are at high risk of developing vitamin D deficiency, secondary hyperparathyroidism, and ultimately osteomalacia due to immobilization and subsequent lack of exposure to sunlight, all of which in turn lead to further deterioration. Monitoring of vitamin D metabolism and vitamin D replacement therapy could be a simple, inexpensive approach to mitigating clinical symptoms and improving quality of life in patients with advanced PAD.
vitamin D3; secondary hyperparathyroidism; osteomalacia; immobilization; peripheral arterial disease
Chronic cimetidine therapy has been shown to suppress circulating concentrations of immunoreactive parathyroid hormone (iPTH) in hemodialysis patients. To evaluate the long-term metabolic effects of cimetidine treatment, we studied seven chronically uremic dogs for 20 wk. The dogs were studied under metabolic conditions before, during, and after cimetidine therapy. iPTH fell progressively in the five treated dogs from 536±70 μleq/ml (mean±SE) (nl < 100 μleq/ml) before treatment to 291±25 μleq/ml at 12 wk (P < 0.001) and 157±32 μleq/ml at 20 wk (P < 0.001). The control dogs showed no consistent change in iPTH. The fall in iPTH was not associated with a change in serum ionized calcium. However, serum phosphorus decreased from 5.7±0.9 mg/dl to 3.4±0.2 mg/dl by the 20th wk (P < 0.05). By contrast, the serum concentration of 1,25-dihydroxycholecalciferol increased in all treated dogs from 33.4±4.3 pg/ml to 51.8±2.4 pg/ml during treatment (P < 0.01). Calcium balance was negative in all seven dogs before cimetidine (−347±84 mg/72 h) and remained so in the control dogs; it became positive in the five treated dogs after 12 wk (1,141±409 mg/72 h) (P < 0.05). Phosphorus balance, 24-h fractional phosphate excretion, and creatinine clearance remained unchanged. Pooled samples of serum obtained during the control and 20th wk of therapy were fractionated by gel filtration and the eluates assayed for immunoreactivity. The decrease in iPTH was associated with a decrease in all the immunoreactive species, indicating suppression of parathyroid gland secretion.
These observations indicate that cimetidine suppressed circulating concentration of biologically active parathyroid hormone. A probable net decrease in the loss of phosphorus from bone to blood ensued, resulting in a fall in serum phosphorus. This may have stimulated synthesis of 1,25-dihydroxycholecalciferol and led to a positive calcium balance, thereby maintaining the serum ionized calcium concentration. The maintenance of phosphate balance, despite suppression of iPTH by cimetidine, indicates that factors other than hyperparathyroidism relate to phosphate homeostasis in chronically uremic dogs.
Cinacalcet is effective for treating refractory secondary hyperparathyroidism (SHPT), but little is known about the response rates and clinical factors influencing the response.
Materials and Methods
A prospective, single-arm, multi-center study was performed for 24 weeks. Cinacalcet was administered to patients with intact parathyroid hormone (iPTH) level greater than 300 pg/mL. Cinacalcet was started at a dose of 25 mg daily and titrated until 100 mg to achieve a serum iPTH level <300 pg/mL (primary end point). Early response to cinacalcet was defined as a decrease of iPTH more than 50% within one month.
Fifty-seven patients were examined. Based on the magnitude of iPTH decrease, patients were divided into responder (n=47, 82.5%) and non-responder (n=10, 17.5%) groups. Among the responders, 38 achieved the primary end point, whereas 9 patients showed a reduction in serum iPTH of 30% or more, but did not reach the primary end point. Compared to non-responders, responders were significantly older (p=0.026), female (p=0.041), and diabetics (p<0.001). Additionally, early response was observed more frequently in the responders (30/47, 63.8%), of whom the majority (27/30, 90.0%) achieved the primary end point. Multivariate analysis showed that lower baseline iPTH levels [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.93-0.99], the presence of diabetes (OR 46.45, CI 1.92-1125.6) and early response (OR 21.54, CI 2.94-157.7) were significant clinical factors affecting achievement of iPTH target.
Cinacalcet was effective in most hemodialysis patients with refractory SHPT. The presence of an early response was closely associated with the achievement of target levels of iPTH.
Cinacalcet; end-stage renal disease; hemodialysis; parathyroid hormone; secondary hyperparathyroidism
Disorders in mineral metabolism are associated with risk for cardiovascular disease (CVD) events in patients with kidney disease as well as in the general population. This risk is thought to be mediated, in part, through the mechanism of stiffening of the arteries.
The objective of this study was to evaluate the relationships between serum calcium, phosphorus, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels and arterial pulse wave velocity (aPWV) among 2,229 community-dwelling elderly persons participating in the Health Aging and Body Composition (Health ABC) study.
The mean age of the participants was 72 years; 52% were woman, 39% were black, and 17% had chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2). In parallel unadjusted analyses, the following associations were observed: 2.86% greater aPWV per 12 ng/ml (s.d.) lower 25-hydroxyvitamin D (95% confidence interval −4.38%, −1.31%), 3.04% greater aPWV per 28 pg/ml (s.d.) higher iPTH (95% confidence interval 1.42–4.68%), and 2.37% lower aPWV per 0.5 mg/dl (s.d.) higher phosphorus (95% confidence interval −3.90% to − 0.81%). Except for phosphorus, these associations were attenuated and rendered no longer statistically significant after adjustment for demographic risk factors, clinical site, season, medications and other CVD risk factors. The results were similar in men and women and were not dependent on the presence of CKD.
Among well-functioning community-dwelling elderly persons, only serum phosphorus was associated with aPWV; and this association was in the opposite direction of the one hypothesized. Factors other than vascular stiffening may mediate the relationship between disordered mineral metabolism and CVD events in community-living elders.
arterial stiffness; blood pressure; cardiovascular disease; hypertension; kidney disease; mineral metabolism; PWV