Intermittent parathyroid hormone (iPTH) treatment stimulates T-cell production of the osteogenic Wnt ligand Wnt10b, a factor required for iPTH to activate Wnt signaling in osteoblasts and stimulate bone formation. However, it is unknown whether iPTH induces Wnt10b production and bone anabolism through direct activation of the parathyroid hormone (PTH)/PTH-related protein receptor (PPR) in T cells. Here, we show that conditional silencing of PPR in T cells blunts the capacity of iPTH to induce T-cell production of Wnt10b; activate Wnt signaling in osteoblasts; expand the osteoblastic pool; and increase bone turnover, bone mineral density, and trabecular bone volume. These findings demonstrate that direct PPR signaling in T cells plays an important role in PTH-induced bone anabolism by promoting T-cell production of Wnt10b and suggest that T cells may provide pharmacological targets for bone anabolism.

The vitamin D status was determined on one to four occasions either after summer (September-October) or after winter (March-April) in 175 male adolescents (13-17 years), resulting in 394 measurements of serum 25-hydroxyvitamin D (25(OH)D) and intact parathyroid hormone (iPTH). The subjects lived in a rural area to the north of Paris (49 degrees N). After summer the 25(OH)D concentration was 58.5 +/- 18.0 nmol/l (mean +/- SD), while after winter it had fallen to 20.6 +/-6.0 nmol/l (p = 0.0001). Meanwhile the iPTH concentration was 2.76 +/- 0.97 pmol/l (mean +/- SD) after summer and increased to 4.20 +/- 1.21 pmol/l after winter (p = 0. 0001). All the results were pooled and a nonlinear population model with random parameters was used to describe the relationship between serum iPTH and 25(OH)D. When the concentration of 25(OH)D was higher than 83 nmol/l, an iPTH mean 'plateau' level at 2.48 pmol/l was reached. When 25(OH)D concentrations fell below 83 nmol/l, the increase in iPTH concentration accelerates, and when the mean 25(OH)D concentration was equal to or lower than 10 nmol/l the mean iPTH level (4.97 pmol/l) was twice as high as the 'plateau' value.

BACKGROUND

Cinacalcet hydrochloride (KRN1493) acts on the parathyroid calcium receptors to suppress parathyroid hormone (PTH) secretion, and is already in wide use in the United States and the European countries. In this study, we examined the efficacy and safety of cinacalcet in Japanese patients on maintenance haemodialysis.

METHODS

One hundred forty-four patients with serum intact PTH (iPTH) levels>>or=300 pg/ml were enrolled and randomly allocated to two groups assigned to receive either cinacalcet or placebo for 14 weeks. Cinacalcet was started at the dose of 25 mg/day and titrated up to 100 mg/day to achieve the target iPTH level of <250 pg/ml.

RESULTS

Cinacalcet significantly decreased the median iPTH level from 606.5 pg/ml to 241.0 pg/ml, despite the mean dialysis vintage being 2.4 times longer (14.3+/-7.1 years) and the proportion of patients receiving vitamin D sterols being higher, than in the phase 3 studies conducted in the US/EU. The target iPTH level was achieved in 51.4% of the patients in the cinacalcet group, in sharp contrast to only 2.8% in the placebo group. Furthermore, the percentage of patients with both the serum calcium and phosphorus levels within the target range in the K/DOQI guidelines increased from 4.2% to 26.4% by cinacalcet.

CONCLUSIONS

These results suggest that lower dose levels of cinacalcet, as compared to those in US/EU studies, may be sufficient effectively suppress the serum iPTH levels and allow favourable management of the serum calcium and phosphorus levels in Japanese patients, having a longer average dialysis vintage.

The effect of vitamin D supplementation on bone mineral augmentation in 212 adolescent girls with adequate calcium intake was studied in a randomized placebo-controlled setting. Bone mineral augmentation determined by DXA increased with supplementation both in the femur and the lumbar vertebrae in a dose-responsive manner. Supplementation decreased the urinary excretion of resorption markers, but had no impact on formation markers.

BACKGROUND

Adequate vitamin D intake protects the elderly against osteoporosis, but there exists no indisputable evidence that vitamin D supplementation would benefit bone mineral augmentation. The aim of this 1-year study was to determine in a randomized double-blinded trial the effect of 5 and 10 microg vitamin D3 supplementation on bone mineral augmentation in adolescent girls with adequate dietary calcium intake.

METHODS

Altogether, 228 girls (mean age, 11.4 +/- 0.4 years) participated. Their BMC was measured by DXA from the femur and lumbar spine. Serum 25-hydroxyvitamin D [S-25(OH)D], intact PTH (S-iPTH), osteocalcin (S-OC), and urinary pyridinoline (U-Pyr) and deoxypyridinoline (U-Dpyr) were measured. Statistical analysis was performed both with the intention-to-treat (IT) and compliance-based (CB) method.

RESULTS

In the CB analysis, vitamin D supplementation increased femoral BMC augmentation by 14.3% with 5 microg and by 17.2% with 10 microg compared with the placebo group (ANCOVA, p = 0.012). A dose-response effect was observed in the vertebrae (ANCOVA, p = 0.039), although only with the highest dose. The mean concentration of S-25(OH)D increased (p < 0.001) in the 5-microg group by 5.7 +/- 15.7 nM and in the 10-microg group by 12.4 +/- 13.7 nM, whereas it decreased by 6.7 +/- 11.3 nM in the placebo group. Supplementation had no effect on S-iPTH or S-OC, but it decreased U-DPyr (p = 0.042).

CONCLUSIONS

Bone mineral augmentation in the femur was 14.3% and 17.2% higher in the groups receiving 5 and 10 microg of vitamin D, respectively, compared with the placebo group, but only 10 mug increased lumbar spine BMC augmentation significantly. Vitamin D supplementation decreased the concentration of bone resorption markers, but had no impact on bone formation markers, thus explaining increased bone mineral augmentation. However, the positive effects were noted with the CB method but not with IT.

BACKGROUND

Secondary hyperparathyroidism is observed in patients with early chronic kidney disease (CKD). This study investigated the safety and efficacy of cinacalcet for secondary hyperparathyroidism in participants with CKD not receiving dialysis.

METHODS

Double-blind, randomized, 32-week, phase 3 study.

METHODS

404 participants with stage 3 or 4 CKD from 73 centers in 9 countries.

METHODS

Cinacalcet:placebo (3:1 ratio).

METHODS

Proportion of participants with a mean decrease of 30% or greater in intact parathyroid hormone (iPTH) level, proportion with iPTH level of 70 or less or 110 or less pg/mL (stage 3 and 4 CKD, respectively), and mean percentage of iPTH change from baseline, all during the efficacy-assessment phase.

RESULTS

A greater proportion of cinacalcet than placebo participants achieved a 30% or greater decrease in iPTH level (74% versus 28%; P < 0.001), corresponding to a 43.1% decrease in iPTH level from baseline (cinacalcet) compared with a 1.1% increase (placebo). At week 32, serum calcium levels were 8.9 +/- 0.8 mg/dL (-8.9%; cinacalcet) and 9.9 +/- 0.6 mg/dL (+0.8%; placebo), phosphorus levels were 4.5 +/- 1.0 mg/dL (+21.4%) and 4.0 +/- 0.7 mg/dL (+6.8%), and calcium-phosphorus product values were 40.1 +/- 8.3 mg(2)/dL(2) (+18.9%) and 38.9 +/- 6.9 mg(2)/dL(2) (+17.1%), respectively. During the study course, 62% (cinacalcet) and 1% (placebo) of participants experienced 2 consecutive serum calcium concentrations less than 8.4 mg/dL. They generally were asymptomatic and without significant clinical consequences. Treatment generally was well tolerated, and most adverse events were mild to moderate in severity.

CONCLUSIONS

The study was not designed to assess the effects of cinacalcet on vascular calcification, bone histomorphometric parameters, or other clinical outcomes. It is not known whether the observed differences in changes in iPTH levels are clinically more important than observed differences in changes in serum calcium or phosphorus levels or dosages of vitamin D sterols and phosphate binders.

CONCLUSIONS

These data show that cinacalcet treatment in patients with CKD not receiving dialysis can decrease plasma iPTH levels, but with frequent (albeit generally asymptomatic) serum calcium levels less than 8.4 mg/dL and increases in serum phosphorus levels.

OBJECTIVE

Intraoperative parathyroid hormone assay (IOPTH) has been used during minimally invasive parathyroidectomy (MIP) to predict operative success. However, the applied criteria are not equivalent in detection of multiglandular disease (MGD) and predicting cure. The purpose of this study was to evaluate the most commonly applied criteria of IOPTH in patients undergoing MIP in a tertiary referral center.

METHODS

A retrospective review of 260 patients with sporadic primary hyperparathyroidism and concordant results of sestamibi scanning and ultrasound of the neck undergoing MIP (135 video-assisted and 125 open) between Dec 2002 and May 2008, with a 6-month postoperative follow-up of intact parathyroid hormone and serum calcium levels, was performed. The main outcome measures included evaluation of predictive values of Halle, Miami, Rome, and Vienna IOPTH interpretation criteria.

RESULTS

The following overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive values were found, respectively: 65%, 62.9%, 100%, 100%, and 14.2% for Halle criterion; 97.3%, 97.6%, 93.3%, 99.6%, and 70% for Miami criterion; 83.8%, 82,9%, 100%, 100%, and 26.3% for Rome criterion; and 92.3%, 92.2%, 93.3%, 99.6%, and 60.9% for Vienna criterion.

CONCLUSIONS

Miami criterion followed by Vienna criterion was found to be the best balanced among other criteria, with the highest accuracy in intraoperative prediction of cure. However, Rome criterion followed by Halle criterion was found to be the most useful in intraoperative detection of MGD. Nevertheless, their application in patients qualified for MIP with concordant results of sestamibi scanning and ultrasound of the neck would result in a significantly higher number of negative conversions to bilateral neck explorations and only a marginal improvement in the success rate of primary operations.

Established bone turnover markers do not reflect fracture risk in idiopathic male and premenopausal osteoporosis and the role of microRNAs (miRNAs) in these patients is currently unclear. miRNAs are a class of small non-coding RNAs that regulate gene expression and bone tissue homeostasis. They are considered a new class of endocrine regulators with promising potential as biomarkers.

Evaluation of circulating miRNA signatures in male and female subjects with idiopathic and postmenopausal osteoporotic low-traumatic fractures.

This was a case-control study of cross-sectional design of 36 patients with prevalent low-traumatic fractures and 39 control subjects Main Outcome Measures: One hundred eighty-seven miRNAs were quantified in serum by qPCR, compared between groups and correlated with established bone turnover markers.

Significant differences in serum levels of circulating miRNAs were identified in all three subgroups (46 in premenopausal, 52 in postmenopausal, 55 in male). A set of 19 miRNAs was consistently regulated in all three subgroups. Eight miRNAs [miR-152-3p, miR-30e-5p, miR-140-5p, miR-324-3p, miR-19b-3p, miR-335-5p, miR-19a-3p, miR-550a-3p] were excellent discriminators of patients with low-traumatic fractures, regardless of age and sex, with area under the curve values>> 0.9. The 11 remaining miRNAs showed area under the curve values between 0.81 and 0.89. Correlation analysis identified significant correlations between miR-29b-3p and P1NP, and miR-365-5p and iPTH, TRAP5b, P1NP and Osteocalcin, as well as BMDL1-L4 and miR-19b-3p, miR-324-3p, miR-532-5p, and miR-93-5p.

Specific serum miRNA profiles are strongly related to bone pathologies. Therefore miRNAs might be directly linked to bone tissue homeostasis. In particular, miR-29b-3p has previously been reported as regulator of osteogenic differentiation and could serve as a novel marker of bone turnover in osteoporotic patients as a member of a miRNA signature.

OBJECTIVE

This study investigated the prevalence of vitamin D deficiency, its association with nutrition-related parameters, and the effects of ergocalciferol supplementation in stage 5 chronic kidney disease (CKD). Measures of interest included serum albumin, glycosylated hemoglobin (HgA1c), hemoglobin, phosphorus, corrected calcium, parathyroid hormone (iPTH), equilibrated normalized protein catabolic rate (enPCR), and quality-of life-survey physical component score (SF-36 PCS).

METHODS

This retrospective study was conducted at five dialysis centers in western Massachusetts. Patient records were examined for a 6-month period in 2006, after initiation of a protocol to assess serum 25(OH)D and implement treatment with ergocalciferol if the level of serum 25(OH)D were <40 ng/mL.

RESULTS

Over 90% (i.e., 92.4%) of patients had vitamin D levels of less than 40 ng/mL; 80% had vitamin D levels at 31 ng/mL or less. Ergocalciferol supplementation (50,000 IU/week x 24) was associated with significant improvements in serum 25(OH)D from baseline (18.4 +/- 9.0 ng/mL; mean +/- SD) to 6 months (42.0 +/- 24.7 ng/mL) (P < .0005). The level of glycosylated hemoglobin decreased from 6.9% +/- 1.9% at baseline to 6.4% +/- 1.5% at 6 months (P < .0005), while hemoglobin improved from 12.1 +/- 1.6 g/dL to 12.3 +/- 1.4 g/dL (P < .0005). Corrected calcium decreased from 8.7 +/- 0.8 mg/dL to 8.5 +/- 0.9 mg/dL at 6 months (P = .002). Phosphorus and iPTH exhibited a downward trend, though not significantly. Albumin remained stable, while enPCR increased (0.91 +/- 0.23 at baseline, vs. 0.98 +/- 0.32 at 6 months) (P = .01). The SF-36 PCS scores did not differ significantly from baseline (35.4 +/- 11.8) at 6 months (35.0 +/- 11.1).

CONCLUSIONS

Vitamin D [25(OH)D] deficiency appears to be widely prevalent in stage 5 CKD. Repletion with ergocalciferol may assist in improving glycemic control in the management of diabetes. Additional research is needed to confirm these results and determine the optimal levels of serum 25(OH)D.

Research and management of XLH have concentrated on the disease in childhood, and the natural history and morbidity of XLH in adult life are thus poorly understood. We have studied 22 adults (6 men) with XLH to clarify these aspects of this most common inherited form of rickets and osteomalacia. Most study participants had presented with rickets in early childhood and had undergone tibial osteotomies on at least 1 occasion. Seventeen individuals had genu varum, 1 had genu valgum, and 4 had straight legs, attributable to successful osteotomies in 2. Five subjects reported increasing lower limb deformity in the late teens or subsequently. Eight subjects complained of bone pain, 6 of whom had radiologic evidence of pseudofractures; pseudofractures were found in 4 additional asymptomatic individuals. None of 16 subjects who underwent transiliac bone biopsy had normal double tetracycline labeling; accordingly, all were considered to have osteomalacia. Bone pain was associated with a relative osteoid volume in excess of 25%. Relative osteoid volume was inversely related to serum 1,25(OH)2D concentration (r = -0.74, p less than 0.02), but unrelated to serum concentrations of calcium and phosphate or their product. Eighteen participants complained of joint pain, predominantly in the knees and ankles. The severity of joint pain correlated with the degree of lower limb deformity (p = 0.011) which, in turn, was related to fasting serum phosphate concentration (r = -0.56, p less than 0.025) and TmP/GFR (r = -0.70, p less than 0.005). Enthesopathy affected 33% of those younger than 30 years, and all those above this age. Nineteen individuals had experienced significant dental problems, most commonly abscess formation. Eight had required complete dental clearance. Twelve women from the group had a total of 22 live births. Fifteen of these were by cesarean section, although radiologic evidence of pelvic narrowing was not found in any subject. Serum ALP was elevated in all but 3 of the 18 untreated subjects. Levels correlated with those of other indices of bone turnover (BGP r = 0.82, p less than 0.005; urine total HP r = 0.60, p less than 0.025; urine free HPr = 0.78, p less than 0.005), but were not related to the degree of osteomalacia found on bone biopsy. Serum levels of iPTH, 25(OH)D, 1,25(OH)2D, and thyroid hormones were generally normal in the untreated patients. We conclude that adults with untreated XLH have osteomalacia that is frequently symptomatic. Even greater morbidity is caused by degenerative joint disease arising from lower limb deformities.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of an acute elevation of the serum magnesium concentration on the concentrations of serum immunoreactive parathyroid hormone (IPTH) were studied in hypocalcemic hypomagnesemic patients, hyperparathyroid patients, and normal individuals. Basal serum IPTH concentrations in the hypomagnesemic patients ranged from undetectable to 3 times the upper limit of normal. All hypomagnesemic patients were observed to have an immediate rise in the serum IPTH concentration after magnesium administration regardless of the basal IPTH concentration. In contrast, normal individuals and patients with primary and secondary hyperparathyroidism responded to magnesium administration with either a decrease or little change in the serum IPTH concentration. These date indicate that an acute stimulation of PTH secretion induced by magnesium is characteristic of the magnesium-deficient state. The consistency of this response suggests that impaired PTH secretion is a significant factor contributing to the hypocalcemia of magnesium deficiency.

In an earlier 8-day study, we showed increased immunoreactive PTH (iPTH) levels in young adults fed high phosphorus (P), low calcium (Ca) diets assembled from common grocery foods, a dietary pattern characteristic of teens and young adults. Because animals fed high P, low Ca diets developed secondary hyperparathyroidism and, ultimately, osteopenia, perhaps the typical teen diet may reduce peak bone mass and contribute to osteoporotic fracture later in life. To determine if the elevation in iPTH levels and action persists with chronic intake of this typical diet, we studied the 24-h mineral and hormone responses of 15 young women (18-25 yr of age) to either high P, low Ca or control diets. Each subject served as her own control, first consuming a basal diet (800 mg Ca, 900 mg P) for 28 days; 10 women were then switched to the high P, low Ca test diet (400 mg Ca, 1700 mg P) for 28 days, while the remaining 5 women in the control group continued eating the basal diet. On days 28 and 56, all subjects were studied as inpatients for 24 h, with blood drawn every 4 h and collection of fasting and 24-h urine. Serum iPTH (midregion) and serum intact PTH (2-site immunoradiometric assay) increased significantly [maximal increases of 26% (P less than 0.002) and 36% (P less than 0.004), respectively] after 4 weeks of consuming the test diet, and there was no change in the control group. In contrast to our 8-day study, plasma levels of 1,25-dihydroxyvitamin D did not change in either group. Our findings suggest that this common dietary pattern in young adult women causes persistent alterations in calcium-regulating hormones that could be unfavorable to achieving maximal positive bone balance.

In 29 women with postmenopausal osteoporosis, the proportion of total bone surface undergoing resorption or formation was evaluated by microradiography of iliac crest biopsy samples before and after short-term (2(1/2)-4 months) and long-term (26-42 months for estrogen and 9-15 months for anabolic hormone) treatment. After estrogen administration, values for bone-resorbing surfaces decreased, although less prominently after long-term than after short-term therapy. The magnitude of this decrease was positively correlated with the pretreatment value for bone-resorbing surfaces (P < 0.001). When the pretreatment value for bone-resorbing surfaces was used as a covariable, estrogen and anabolic hormone appeared to be equally effective. For bone-forming surfaces, short-term therapy with either hormone had no effect but long-term therapy significantly decreased the values. Serum immunoreactive parathyroid hormone (IPTH) increased significantly after estrogen therapy; the change in IPTH was inversely related to the change in serum calcium (P < 0.001, sign test). We conclude that the primary effect of sex hormones in postmenopausal osteoporosis is to decrease the increased level of bone resorption, perhaps by decreasing the responsiveness of bone to endogenous parathyroid hormone. However, this favorable effect, at least in part, is negated after long-term treatment by a secondary decrease in bone formation. Our data are consistent with the concept that the maximal benefit that can be derived from sex hormone therapy in postmenopausal osteoporosis is arrest or slowing of the progession of bone loss.

Serum iPTH was measured in a large series of normal and osteoporotic women as a function of age, with radioimmunoassays using three antisera: GP-1M, which recognizes primarily a region within the 44--68 amino acid sequence of PTH; CH-12M, which appears to recognize primarily intact hormone; and CH-14M, which recognizes primarily a region within the 1--34 amino acid sequence of PTH. In normal women 20 to 90 years of age, serum iPTH increased significantly with age (p less than 0.001); the proportional increase was greater when measured with antiserum GP-1M (80%) than when measured with antiserum CH-12M (30%), which suggests that the increase in circulating carboxyl fragments of PTH was greater than the increase in circulating intact PTH. In 40 patients with postmenopausal osteoporosis, the mean value for serum iPTH assayed by antiserum GP-1M did not differ significantly from that for age-matched normal women; however, three osteoporotic patients had elevated values and thus appear to represent a separate population. When these subjects were excluded, mean serum iPTH assayed by antiserum GP-1M also was lower than normal (p less than 0.001). The mean value for serum iPTH was lower in osteoporotic patients than in normal subjects when assayed by either antiserum CH-12M (p less than 0.001) or antiserum CH-14M (p less than 0.001). Values for serum phosphate and renal tubular phosphate resorption, both indices of PTH function, were increased (p less than 0.005) in the osteoporotic subjects. Although creatinine clearance decreased with age in both normal and osteoporotic subjects, partial correlations with age held constant showed no relationship between creatinine clearance and serum iPTH. This suggests that a decrease in renal function was not the major factor accounting for the rise in serum iPTH with age. We conclude that serum iPTH increases with aging but that for any given age, it is either normal or low in patients with postmenopausal osteoporosis.

Abnormalities in mineral metabolism have been linked to mortality in hemodialysis (HD) patients. We postulated that these abnormalities would have a particularly large deleterious impact on deaths due to cardiovascular causes in Japan. This study describes the recent status of abnormal mineral metabolism, significant predictors, and potential consequences in the Dialysis Outcomes and Practice Patterns Study (DOPPS), Phases 1 and 2, in Japan. Major predictor variables were patient demographics, comorbidities, and laboratory markers of mineral metabolism such as albumin-adjusted serum calcium (calciumAlb), phosphorus, and intact PTH (iPTH). In a cross section of 3973 Japanese HD patients in DOPPS I and II, a large faction had laboratory values outside of the recommended Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline range for serum concentrations of phosphorus (51% of patients above upper target range), calciumAlb (43.7% above), calcium-phosphorus (Ca x P) product (41.1% above), and iPTH (18.6% above). All-cause mortality was significantly and independently associated with calciumAlb (relative risk [RR]=1.22 per 1 mg/dL, p=0.0005) and iPTH (RR=1.04 per 100 pg/mL, p=0.04). Cardiovascular mortality was significantly associated with calciumAlb (RR=1.28, p=0.02), phosphorus (RR=1.13 per 1 mg/dL, p=0.008), Ca x P product (RR=1.07 per 2 mg(2)/dL(2), p=0.002), and PTH (RR=1.08, p=0.0001). This study expands our understanding of the relationship between altered mineral metabolism and mortality outcomes, showing slightly stronger associations with cardiovascular causes than observed for all-cause mortality. These findings have important therapeutic implications for Japanese HD patients.

The first part of this study consisted of an 18 month follow-up of the vitamin D status and parathyroid function in a group of 54 French male adolescents, aged from 13 to 16 years old and all pupils of a jockey training school. During the 18 month period four samplings were made, one every 6 months. The first was during September of the first year, the second and third during March and October of the second year, and the last in March of the third year. Therefore we had two main periods: summer and winter. The summer 25-hydroxyvitamin D (25(OH)D) concentrations were higher (71.6 +/- 19.9 and 52.4 +/- 16.5 nmol/l) than the winter ones (20.4 +/- 6.9 and 21.4 +/- 6.1 nmol/l). Conversely, the winter intact parathyroid hormone (iPTH) serum levels (4.18 +/- 1.18 and 4.11 +/- 1.35 pmol/l) were higher than the summer ones (2.44 +/- 0.82 and 2.71 +/- 0.71 pmol/l). At the two winter time points the 25(OH)D concentrations were lower than 25 nmol/l (10 ng/ml) in 72% (2nd year) and 68% (3rd year) of the adolescents. In the second part of the study we tried a vitamin D3 supplementation procedure designed to maintain the 25(OH)D and iPTH postsummer serum levels throughout the winter. Pairs of male adolescents matched for height, weight and Tanner pubertal stage were randomly assigned to either vitamin D3 supplementation (2.5 mg, i.e., 100,000 IU) administered orally at three specific periods (end of September, November and January) or no vitamin D3 treatment (control subjects). Blood was collected just before the first intake of vitamin D3 and 2 months after the last intake (March). The control subjects had blood drawn at the same time points. In the vitamin D3-treated subjects, the concentrations of 25 (OH)D (55.3 +/- 11.5 nmol/l) and of iPTH (3.09 +/- 1.16 pmol/l) in March and September (53.8 +/- 12.3 nmol/l and 2.75 +/- 1.26 pmol/l) were not significantly different. In the control subjects, March 25(OH)D levels (21.0 +/- nmol/l were low, with values below 25 nmol/l in 78% of subjects, and iPTH concentrations (3.97 +/- 1.08 pmol/l) were significantly (p<0.001) higher than in September (2.91 +/- 0.81 pmol/l). The constant vitamin D wintertime deficiency and wintertime rise in iPTH in adolescent French males throughout puberty has been demonstrated. In adolescents with low dairy calcium intakes, the vitamin D3 treatment was sufficient to maintain 25(OH)D concentrations at their summer levels throughout winter and to prevent an excessive wintertime rise in iPTH levels.

This prospective study was aimed at evaluating risk factors for symptomatic stress fractures among 179 Finnish male military recruits, aged 18 to 20 years. The subjects were studied in the very beginning of the military service of 6 to 12 months in summer. Bone mineral content (BMC) and density (BMD) were measured by dual energy X-ray absorptiometry (DXA) at the lumbar spine and at the hip and heel ultrasound investigation was performed. Blood was sampled for determination of serum total and free testosterone, total and free estradiol, sex hormone-binding globulin (SHBG), procollagen type I N propeptide, total and carboxylated osteocalcin, tartrate-resistant acid phosphatase 5b, 25-hydroxyvitamin D (25-OHD), and intact parathyroid hormone (iPTH), as well as for studying the XbaI and PvuII polymorphisms of the estrogen receptor gene and the CAG repeat polymorphism of the androgen receptor gene. Urine was collected for the determination of N-terminal cross-linking telopeptide of type I collagen. Muscle strength was measured and Cooper's test was performed. Current exercise, smoking, calcium intake, and alcohol consumption were recorded using a questionnaire. During military service, 15 men experienced a stress fracture, diagnosed with X-ray in 14 and with nuclear magnetic resonance in one man. Those who experienced a fracture were taller than those who did not (P = 0.047). The result of Cooper's test was worse in the fracture group than in the non-fracture group (P = 0.026). Femoral neck and total hip BMC and BMD, adjusted for age, weight, height, exercise, smoking, and alcohol and calcium intake were lower (P = 0.021-0.041) for the fracture group. Stress fractures associated with higher iPTH levels (P = 0.022) but not with lower 25-OHD levels. Bone turnover markers as well as sex hormone and SHBG levels were similar for men with and without stress fracture. There was no difference in the genetic analyses between the groups. In conclusion, tall height, poor physical conditioning, low hip BMC and BMD, as well as high serum PTH level are risk factors for stress fractures in male Finnish military recruits. Given the poor vitamin D status of young Finnish men, intervention studies of vitamin D supplementation to lower serum PTH levels and to possibly reduce the incidence of stress fractures are warranted.

We assessed whether modification of vitamin D nutritional status during the last trimester of pregnancy affects maternal and neonatal calcium homeostasis. At the end of the first trimester, 40 pregnant women were randomly assigned to either of two groups, and blood taken to assess the basal values of Ca, Pi, Mg, iPTH, 25-OHD, and 1,25(OH)2D. From the sixth month on, group 1 (+D) received 1000 IU vitamin D3 daily; group 2 (-D) served as control. At the time of delivery, maternal serum 25-OHD was higher in the +D group (P less than 0.0005). Ca, Pi, iPTH, and 1,25(OH)2D were not affected. At term, venous cord 25-OHD levels were also higher in the +D group (P less than 0.0005), and 1,25(OH)2D levels slightly lower (P less than 0.05), but neither Ca, Pi, nor iPTH differed between the two groups. Serum CaT dropped significantly (P less than 0.002) at 4 days of age in the infants from both groups, although to a lesser extent in these from the +D group (P less than 0.05). Circulating iPTH increased in both groups. Serum 25-OHD remained low in the -D group, and dropped slightly in the +D group; 1,25(OH)2D remained stable during the first 4 days of life in the -D group, and increased in the +D group (P less than 0.001). Our data demonstrate the importance of providing adequate maternal vitamin D stores to ensure better perinatal handling of calcium. This is of particular importance for populations at risk for hypovitaminosis D.

Parathyroid hormone release and end-organ responsiveness to parathyroid extract (PTE) were evaluated in a 25-year-old woman with magnesium deficiency associated with hypocalcemia and inappropriately low levels of serum immunoreactive parathyroid hormone (iPTH). End-organ responsiveness to PTE was demonstrated by increases in serum calcium and in urinary phosphorus, cyclic AMP, and hydroxyproline. When the serum calcium was increased from a baseline of 6.9 mg/100 ml to levels of 8.0 mg/100 ml and higher by calcium infusion, the serum iPTH decreased from the low normal range to below the limits of detectability. The intravenous administration of 3 mg/kg of body weight of magnesium led to an abrupt and striking increase in circulating iPTH with a 2-fold increase in one minute, a 6-fold increase in two minutes, and an 8-fold increase in five minutes. The very rapid increase in serum iPTH produced by magnesium infusion in this study suggests an effect of magnesium on hormone secretion rather than an effect on hormone synthesis. The evidence provided by this investigation indicates that the release of parathyroid hormone is impaired in magnesium deficiency and that the level of circulating calcium required for the suppression of parathyroid hormone secretion is lower than that in normal subjects.

OBJECTIVE

To evaluate whether the combined application of preoperative localization and intraoperative monitoring of intact parathyroid hormone (iPTH) levels could facilitate safe outpatient parathyroidectomy.

METHODS

Consecutive patients, who had no antecedent social or medical conditions mandating hospitalization, were prospectively offered ambulatory parathyroidectomy with a mean follow-up of 7 months (range, 1-25 months).

METHODS

Tertiary care referral center

METHODS

From 85 patients who had primary hyperparathyroidism with hypercalcemia and elevated iPTH levels, 57 were offered outpatient parathyroidectomy. Nineteen patients were asymptomatic, 3 had hypercalcemic crisis, and the others gave a history of renal stones or had complaints consistent with bone disease.

METHODS

Technetium Tc 99m sestamibi scintiscans were used for preoperative localization. Monitoring iPTH levels during parathyroidectomy quantitatively assured the surgeon (G.L.I. only) when all hyperfunctioning glands were excised.

METHODS

The number of patients without complications and with short operative times who were discharged without hospital admission or overnight stay.

RESULTS

The combination of preoperative localization of abnormal parathyroid glands and a decline in circulating iPTH levels predicting postoperative normocalcemia after excision of all hyperfunctioning glands resulted in successful parathyroidectomy in 84 of 85 patients. A decreased operative time (average, 52 minutes) with minimal neck dissection permitted outpatient parathyroidectomy in 42 of 57 eligible patients.

CONCLUSIONS

The combination of preoperative parathyroid scintiscan localization and iPTH level monitoring during surgery permitted successful parathyroidectomy in an ambulatory setting in half of a consecutive series of patients with primary hyperparathyroidism. The safety, success, and likely cost savings of this approach suggest wider application.

The serum levels of the three major vitamin D metabolites [25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyitamin D (1,25-(OH)2D), 24,25-dihydroxyvitamin D (24,25-(OH)2 D)] and immunoreactive parathyroid hormone (iPTH) were measured in 14 morbid obese patients, who later on were subjected to jejunoileal bypass surgery. The preoperative median values of 25-OHD and 24,25-(OH)2D were reduced compared with controls (P less than 0.001), whereas elevated concentrations were found of 1,25-(OH)2D (P less than 0.005). Median levels of iPTH in the obese group were significantly higher than those found in normal subjects (P less than 0.001). A decrease was observed in serum concentrations of all three vitamin D metabolites following jejunoileal bypass (P less than 0.005). An increase in the serum levels of iPTH and alkaline phosphatase was seen postoperatively (P less than 0.002), probably indicating a secondary hyperparathyroidism. The results show that the vitamin D metabolism is slightly abnormal in severely obese patients. Jejunoileal bypass is followed by severe disturbances of vitamin D metabolism.

A comparison was made of the biochemical and osseous effects of 25-hydroxyvitamin D3 [25(OH)D3], 1 alpha-25-hydroxyvitamin D3 [1 alpha, 25(OH)2D3], and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] in adult vitamin D-deficient man. Administration of 50 micrograms/d of 25(OH)D3 for 8 weeks led to a return of the mineralization front to normal associated with a return of TmPO4/GFR to normal, an increase in serum phosphate and calcium concentrations, a fall in serum IPTH, and a rise in serum alkaline phosphatase activity. Giving 2.5 micrograms/d of 1 alpha,25(OH)2D3 did not produce these effects. Administration of 1 alpha, 25 (OH)2D3 caused an increase in intestinal calcium absorption, and a rise in serum calcium associated with a fall in serum immunoreactive parathormone (IPTH) concentrations but no sustained rise in either alkaline phosphatase, serum phosphate concentration, nor in TmPO4/GFR. Its administration caused an increase in the extent of the osteoclastic bone resorption surface but the extent of the mineralization front remained subnormal. Administration of 20 micrograms/d of 24,25(OH)2D3 caused a fall in urinary calcium excretion and in serum IPTH, and a rise in serum alkaline phosphatase, but no change in TmPO4/GFR or serum phosphate, and only a slight increase in the extent of the mineralization front. Combined treatment with 1 alpha, 25(OH)2D3 and 24,25(OH)2D3 led to a return of the mineralization front of normal even though both TmPO4/GFR and serum phosphate concentration remained low. It is concluded that 1alpha,25(OH)2D3 is not the sole biologically active metabolite of vitamin D in man. It is apparent that either 25(OH)D3 or some as yet unidentified metabolite of 25(OH)D3 stimulates the renal tubular reabsorption of calcium and phosphate, and that the subsequent rise in serum phosphate concentrations along with the direct actions of 1 alpha-25(OH)2D3, 24,25(OH)2D3, and possibly 25(OH)D3 on bone cells all participate in the restoration of normal bone formation and bone mineralization in vitamin D-deficient man.

Little is known about the magnitude of vitamin D deficiency in patients with stage 5 chronic kidney disease (CKD-5) on hemodialysis (HD). In the present study, we examined the prevalence of vitamin D deficiency in patients with CKD-5 undergoing HD, evaluating the relationship between calcidiol levels with other parameters of mineral metabolism, nutrition/inflammation, functional capacity (FC), and sunlight exposure. Serum 25(OH) vitamin D levels were evaluated in 84 stable patients on chronic HD not receiving vitamin D supplements, with a mean age 58.9+/-16.6 years, during the month of September (end of winter in the southern hemisphere). 25(OH) vitamin D serum levels, intact PTH (iPTH), as well as serum albumin, calcium, phosphorus, and alkaline phosphatase were analyzed in fasting samples. Similarly, protein catabolic rate (PCR) and body mass index (BMI) were determined as nutritional parameters. Functional capacity according to the Karnofsky index, and sunlight exposure were also analyzed. In this study, we considered adequate vitamin D levels those above 30 ng/mL (U.S.A. National Kidney Foundation DOQI Guidelines), vitamin D insufficiency when levels were between 15 and 30 ng/mL, and vitamin D deficiency when levels were below 15 ng/mL. The mean 25(OH) D levels were significantly higher in men than in women (28.6 vs. 18.9 ng/mL; p=0.001). Vitamin D insufficiency was found in 53.5% of the patients (n=45) and vitamin D deficiency in 22.6% (n=19). In the univariate analysis, there were no correlations between 25(OH) D levels with age, iPTH, calcium, or phosphorus. There were positive correlations between serum 25(OH) D levels and degrees of sunlight exposure (R=0.55; p<0.0001), serum creatinine (r=0.38; p<0.001), serum albumin (r=0.22; p=0.04), and a negative correlation with BMI (r=-0.26; p=0.01). In the multiple regression analysis, only sunlight exposure (B=0.361), BMI (B=-0.23), and gender (B=-0.27) were significantly associated with 25(OH) D levels. Patients with FC 1 to FC 2 (n: 70%, 83.3%) had significantly higher 25(OH) D serum levels compared with FC 3 to FC 4 patients (n: 14%, 16.6%): 25.9 vs. 17.1 ng/mL (p=0.03). These results indicate that vitamin D insufficiency/deficiency is highly prevalent (76.1%) at the end of winter, in stage 5 CKD patients on HD, and lower values seem to be related to decreased sunlight exposure, female gender, increased BMI, and worse functional class.

BACKGROUND

The purpose of this study was to examine the relationships of vitamin D supplementation and serum concentrations of vitamin D metabolites and parathyroid hormone (PTH) with neuromuscular function and falls in older community-dwelling women.

METHODS

We examined these relationships using a 4-year prospective multi-center study among 9,526 community-dwelling women enrolled in the Study of Osteoporotic Fractures (median age: 70 years; interquartile range: 67-75) and a subset of 389 women (97%) out of 400 who were randomly selected from the entire cohort for serum measures. Measurements included: vitamin D supplementation, serum 25-hydroxyvitamin D(3) [25(OH)D(3)], serum 1,25-dihydroxyvitamin D(3) [1,25(OH) (2)D(3)], and serum intact parathyroid hormone (iPTH); grip and quadriceps strength, chair-stand time, walking speed, reaction time, and balance-walk time (including changes in grip strength, chair-stand time, walking speed and balance-walk time over approximately 3.7 years); and incident fall rates (number of falls/woman-years).

RESULTS

In 9,526 women, vitamin D supplementation was not associated with any measures of neuromuscular function, change in neuromuscular function, or fall rates (p>0.01 for all). In a subgroup of 389 women, there was a trend of higher 25(OH)D(3) concentration with slightly weaker grip strength (p=0.007), and women in the fourth quartile of 1,25(OH)(2)D(3) had a faster chair-stand time (p=0.017) than women in the first quartile; still, in general, concentrations of 25(OH)D(3), 1,25(OH)(2)D(3), and iPTH were not associated with either neuromuscular function or changes in neuromuscular function (p>0.05 for all). However, higher 1,25(OH)(2)D(3) concentration was associated with lower fall rates (p=0.039).

CONCLUSIONS

Higher 1,25(OH)(2)D(3) concentration is associated with a lower fall risk in older community-dwelling women, but vitamin D supplementation, and 25(OH)D(3) and iPTH concentrations are not associated with either neuromuscular function or falls.

BACKGROUND

Vitamin D deficiency is common following bariatric surgery and is due to a combination of baseline deficiency and postoperative malabsorption. There are few prospective studies evaluating the appropriate dose of vitamin D to prevent and treat vitamin D deficiency following bariatric surgery.

METHODS

We evaluated three doses of vitamin D3 (800, 2,000, and 5,000 IU/day) in a prospective, randomized pilot trial of 45 patients undergoing Roux-en-Y gastric bypass. Serum 25 hydroxy Vitamin D (25OHD), intact PTH (iPTH), calcium, and urine calcium/creatinine ratios were measured at 6, 12, and 24 months postoperatively. Due to a high dropout rate at 24 months, we focus on the 12-month data.

RESULTS

At 12 months, the 800-, 2,000-, and 5,000-IU groups had a mean +/- SD increase in 25OHD of 27.5 +/- 40.0, 60.2 +/- 37.4, and 66.1 +/- 42.2 nmol/L, respectively (p = 0.09) with a maximum increase in each group of 87.4, 114.8, and 129.8 nmol/L. Forty-four percent, 78%, and 70% achieved 25OHD levels>>or=75 nmol/L (p = 0.38). Results for the 6- and 24-month time points were similar to the 12-month results. Mean weight loss at 24 months of the study was not different among groups (p = 0.52). Serum calcium did not change significantly, and there were no cases of hypercalcemia or sustained hypercalciuria.

CONCLUSIONS

Higher doses of vitamin D supplementation trend towards higher levels of 25OHD. Vitamin D replacement as high as 5,000 IU /day is safe and necessary in many patients to treat vitamin D deficiency following Roux-en-Y gastric bypass yet is still suboptimal in others.