This study aimed to evaluate the 24-week effects of a high-intensity aquatic exercise program on bone remodeling markers and bone mass of postmenopausal women. In this randomized, controlled trial we studied 108 women (58.8 ± 6.4 years), randomized into Aquatic Exercise Group (AEG), n = 64, performing 24 weeks of aquatic exercises, and Control Group (CG), n = 44, sedentary. They had their fasting morning blood sample collected for the measures of intact parathyroid hormone (iPTH), procollagen type 1 amino-terminal propeptide (P1NP) and carboxy-terminal cross-linking telopeptide of type I collagen (CTx). Bone mass was measured by dual-energy X-ray absorptiometry before and after the intervention. Participants of both groups received a daily supplementation of 500 mg of elementary calcium and 1,000 IU of vitamin D (cholecalciferol). Results showed an augment in bone formation marker (P1NP) only in the AEG (15.8 %; p = 0.001), and although both groups experienced significant enhancements in bone resorption marker (CTx), this increase was less considerable in the AEG (15 % in the AEG and 29 % in the CG). IPTH was increased by 19 % in the CG (p = 0.003) at the end. The femoral trochanter BMD presented a 1.2 % reduction in the CG (p = 0.009), whereas in the AEG no change was observed (p = 0.069). The proposed aquatic exercise program was efficient in attenuating bone resorption raise and enhancing bone formation, which prevented the participants in the AEG from reducing the femoral trochanter BMD, as happened in the CG.

We studied the effect of acute oral phosphate loading on parathyroid hormone (PTH) secretion and action. Eighteen adults were studied before and after ingestion of 1 g elemental phosphorus as neutral sodium-potassium phosphate in grape juice or in water and 1.7 g NaCl in juice was used as a control. Five subjects were studied after ingesting 1.5 g P in juice. Blood was drawn every 15 min from -45 to +300 min for measurement of serum ionized calcium (Ca++), P, total Ca, creatinine, and immunoreactive PTH (iPTH); urine was collected hourly. Serum P declined after NaCl ingestion but rose significantly after ingestion of 1 g P in juice or in water. There were no significant changes in serum Ca++, iPTH, or urinary cyclic AMP excretion. Acute ingestion of 1-1.5 g P, which exceeds the P content of a normal meal, does not decrease serum Ca++ or increase iPTH secretion or renal action in normal adults.

Authors analyze their experience of parathyroid autotransplantation during total thyroidectomy, with the purpose of seeing whether this practice influenced the rate of postoperative hypocalcemia and/or hypoparathyroidism. We identified three groups of patients: group A, consisting of 57 patients, underwent parathyroid autotransplantation during total thyroidectomy; group B consisting of 87 patients not submitted to intraoperative autotransplantation in whom, as an incidental finding, a parathyroid gland was detected in the surgical specimen; group C consisted of 100 patients who did not undergo autotransplantation and whose surgical specimens were not found to contain parathyroid glands. The three groups were compared for sex and age as well as for a series of clinical and laboratory parameters on the first three postoperative days and at six months after surgery. The rate of permanent hypoparathyroidism was 3.5% in Group A, 3.45% in Group B, and 1% in Group C. Multivariate analysis revealed that all three groups showed postoperative recovery of calcium levels, although the rate and extent of this recovery differed between them. The control group showed a more rapid and more complete recovery of serum calcium values compared with Groups A and B. Calcium recovery in Groups A and B was comparable, in terms of both rate and extent. The same pattern of results emerged for the iPTH values. The analysis of the data showed that there were no significant differences in the analyzed parameters between Groups A and B. This suggests that parathyroid autotransplantation does not influence the rate of postoperative hypocalcemia and/or hypoparathyroidism.

BACKGROUND

Although some studies have reported that preoperative vitamin D deficiency (VDD) is a risk factor for hypocalcemia after total thyroidectomy (TT) in patients with nontoxic multinodular goiter or Graves' disease, the association between VDD and postoperative hypocalcemia in thyroid cancer patients undergoing TT plus central compartment neck dissection (CCND) remains unclear. This study evaluated whether preoperative VDD was associated with postoperative symptomatic hypocalcemia.

METHODS

Data were collected prospectively between September 2012 and May 2013. A total of 267 consecutive thyroid cancer patients who underwent TT with CCND were analyzed. Patients were divided into two groups--VDD or non-VDD--by preoperative vitamin D level of <10 or ≥10 ng/mL. Symptomatic hypocalcemia was defined as serum calcium <8.2 mg/dL and symptoms or signs of hypocalcemia. The rates of postoperative symptomatic hypocalcemia and clinicopathological features were compared between the two patient groups.

RESULTS

The rate of postoperative symptomatic hypocalcemia was higher in the VDD group than in the non-VDD group (43.8% vs. 30.4%, p=0.043). By logistic regression analysis, predictive factors for postoperative symptomatic hypocalcemia included a preoperative vitamin D level of <10 ng/mL (p=0.007; odds ratio=3.00). In patients who had postoperative intact parathyroid hormone (iPTH) levels <15 pg/mL, symptomatic hypocalcemia was more common in the VDD group than in the non-VDD group (77.5% vs. 53.2%, p=0.008). The findings show that a preoperative vitamin D threshold level of >20 ng/mL reduced the risk of symptomatic hypocalcemia by 72% when compared with patients with VDD (p=0.003).

CONCLUSIONS

VDD is significantly associated with postoperative symptomatic hypocalcemia in thyroid cancer patients undergoing TT plus CCND. VDD was predictive for symptomatic hypocalcemia when patients had postoperative serum iPTH levels <15 pg/mL. Thus, preoperative supplementation with oral vitamin D should be considered to minimize postoperative symptomatic hypocalcemia.

Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis because 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 preosteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in preosteoblasts and blunted osteoblastic commitment, proliferation, differentiation, and life span, 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 crosstalk pathways may provide pharmacological targets for bone anabolism.

Serum undercarboxylated osteocalcin (ucOC)/intact osteocalcin (iOC) ratio increased >1.0 in the patients undergoing hemodialysis, particularly in those with high bone turnover state. Consequently, serum ucOC/iOC ratio might lose its significance as a bone metabolic marker to indicate vitamin K deficiency in hemodialysis patients.

BACKGROUND

Serum intact osteocalcin (iOC), undercarboxylated OC (ucOC), and the ucOC/iOC ratio are considered clinically relevant indices in pre-dialysis chronic kidney disease (CKD) and hemodialysis (HD) patients, despite their accumulation in uremic serum.

METHODS

Serum iOC and ucOC were measured along with serum intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase (TRACP)-5b in 89 pre-dialysis CKD and 189 HD patients.

RESULTS

Serum iOC and ucOC showed significantly negative correlations with estimated glomerular filtration rate in pre-dialysis CKD patients, although serum ucOC/iOC ratio did not correlate. Serum ucOC was significantly greater in HD patients than in pre-dialysis CKD patients, while serum iOC did not differ significantly, resulting in serum ucOC/iOC ratio >1.0 in 135 (71.4%) out of 189 HD patients. HD patients with high serum ucOC/iOC ratio (>1.0) had a significantly younger age and significantly higher values of body mass index, serum creatinine, albumin, phosphate, iPTH, and TRACP-5b than those with low ucOC/iOC ratio (≤ 1.0). The baseline iPTH and P1NP correlated with the changes of the ucOC/iOC ratio during the 2 days of the inter-dialytic period. Multivariate analysis showed that log [ucOC/iOC] in HD patients was significantly associated with log [iPTH], log [BAP], or log [TRACP-5b].

CONCLUSIONS

Serum ucOC/iOC ratio >1.0 was observed in as high as 71.4% of HD patients, preferentially with high bone turnover state, in comparison with pre-dialysis CKD patients. These data suggested that serum ucOC/iOC ratio might lose its significance as a bone metabolic marker to indicate vitamin K deficiency in HD patients.

We evaluated the effects of hydrochlorothiazide administration in relation to Ca balance, the PTH and vitamin D endocrine systems, acid-base balance, and bone. We studied six healthy men fed constant diets providing only 5.1 +/- 0.7 SD mmoles Ca/day. Three of the men were also given calcitriol, 0.5 microgram 6-hrly throughout their studies. All subjects were observed during 18 control days and then during 18 days of hydrochlorothiazide (HTZ) administration, 25 mg 12-hrly. Observations during control days 11 through 16 were compared to those during days 7 through 18 of HTZ administration, inclusively. Directional changes during HTZ did not differ among subjects not given or given calcitriol. For all six subjects, control net intestinal Ca absorption, serum 1,25-(OH)2-D concentrations, serum iPTH concentrations, and daily urine cAMP excretion averaged 0.5 +/- 2.2 mmoles/day, 162 +/- 51 pM, 4.3 +/- 2.2 microliter Eq/ml and 4.2 +/- 0.9 mumoles/day, respectively; none changed during HTZ. As expected, HTZ administration was accompanied by a fall in urinary Ca excretion, averaging -1.4 +/- 0.8 mmoles/day; P less than 0.01. HTZ administration was also accompanied by less negative Ca balances, averaging +1.6 +/- 1.0 mmoles/day; P less than 0.025, and by a fall in daily urinary hydroxyproline excretion averaging -0.13 +/- 0.09 mmoles/day; P less than 0.025. We interpret these data to indicate that HTZ administration is accompanied by an inhibition of bone resorption. HTZ administration also raised serum HCO3 concentrations by +2.7 +/- 0.5 mEq/liter; P less than 0.001 and blood pH by + 0.05 +/- 0.02 units; P less than 0.005.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma FGF-23 concentrations and its relationship with calcium-phosphate homeostasis were evaluated in 48 perimenopausal obese women and in 29 nonobese controls. Serum parathyroid hormone, 25-hydroxyvitamin D(3), CTX1, osteocalcin, total calcium, phosphorus, creatinine, and plasma intact FGF-23 concentrations were assessed. DXA of lumbar spine and femoral neck was performed to determine bone mineral density (BMD). Plasma iFGF-23 concentration was significantly higher in obese patients (by 42%) and correlated with age and BMD of proximal femur (R = -0.346; R = 0.285, resp.) but not with markers of bone turnover. However, serum phosphorus level in obese subjects was significantly lower. iFGF-23 concentration correlated significantly with body mass index (R = 0.292) and fat content (R = 0.259) in all study subjects. Moreover, a significant correlation between iFGF-23 and iPTH (R = 0.254) was found. No correlation between serum phosphorus or eGFR and plasma iFGF-23 and between eGFR and serum phosphorus was found. Elevated serum iFGF-23 concentration may partially explain lower phosphorus levels in the obese and seems not to reflect bone turnover.

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 D(3), but not bone mineral density.

Recently identified soluble circulating osteoprotegerin (OPG), a member of tumor necrosis factor receptor family, is the osteoclastogenesis inhibitory factor (OCIF). It acts as a "decoy" receptor for receptor activator of NF-kappaB ligand (RANKL) and antagonises RANKL/RANK activity. This way OPG exerts the protective effect on bone, which is also important in hyperparathyroidism. The studies measuring OPG levels in secondary hyperparathyroidism have shown contradictory results and inconsistent conclusions. The aim of our work was to evaluate OPG levels in hemodialysis patients and their correlation with the intensity of bone turnover, bone formation and bone resorption. Serum OPG levels, bone alkaline phosphatase activity (bALP) and beta-CrossLaps (CTx) were measured in a control group (n = 20, age 30+/-6.7 years) and in two groups of dialysis patients: the first group with serum intact parathyroid hormone (iPTH) concentration below 200 pg/ml (n = 28, age 62.6+/-14.8 years) and the second group with iPTH concentration above 200 pg/ml (n = 16, age 63.7+/-14.8 years). Compared to controls, serum OPG levels were 6.4-fold higher in dialysis patients. OPG levels in patients with high PTH were approximately 1.2-fold higher than in the low-PTH group. OPG correlated weakly with bALP (r = 0.277, p = 0.153), as well as with CTx (r = 0.018, p = 0.929) in the low-PTH group, and there was an insignificant negative correlation in the high-PTH group (r = -0.145, p = 0.593 and r = -0.219, p = 0.416, respectively). In conclusion, 6.4-fold increase in OPG might protect bone against intensive bone loss in hemodialysis patients, but this increase is probably not mediated by the increased bone formation; rather, it seems to be the consequence of the imbalance of bone kinetics in renal disease. The precise role of OPG in the pathogenesis of renal osteodystrophy remains unknown and establishing it requires further studies.

To test the hypothesis that muscle weakness associated with aging is in part due to low serum levels of vitamin D, we investigated the relationship between muscle strength and serum levels of vitamin D metabolites in ambulatory elderly people who were not receiving vitamin D supplementation. We enrolled 319 ambulatory elderly subjects (103 women: mean age 74.2, age range 65-86; 216 men: mean age 76.6, age range 66-95) between April and August 1995. The study design was cross-sectional. Muscle strength was measured as leg extension power in watts (LEP). Mean 25-hydroxyvitamin D serum concentrations were higher in male participants at 36.2 ng/ml (range 3.0-85.0) versus 27.4 ng/ml (range 5.0-88.0) in female subjects (p = 0.008). We found 12 percent of female and 18 percent of male subjects with 25-hydroxyvitamin D values below the lower threshold (< 12 ng/ml). Mean 1,25-dihydroxyvitamin D levels were similar in both sexes: 39.8 pg/ml (range 15.0-73.0) in women and 37.9 pg/ml (range 13.0-69.0) in men. LEP declined with age in women and men (f: r = -0.35, p = 0.001; m: r = -0.48, p < 0.0001). Men were significantly stronger than women (p < 0.0001). In men both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D showed pairwise correlation with LEP (r = 0.24; p = 0.0004/r = 0.14; p = 0.045). In women only 1,25-hydroxyvitamin D was significantly correlated with LEP (r = 0.22; p = 0.03). In ANCOVA, including all participants, explaining LEP by sex (p < 0.0001), age (p < 0.0001), BMI (p = 0.013), 1,25-dihydroxyvitamin D (p = 0.02), 25-hydroxyvitamin D (p = 0.18) and iPTH (p = 0.82), all factors showed significant effects except 25-hydoxyvitamin D and iPTH (r2 of the whole model: 0.41). In conclusion our results support the view that, in concert with other factors, deficiency of both 25-hydroxyvitamin D and 1,25-hydroxyvitamin D contributes to the age-related decline in muscle strength. Modest, but significant relationships between 1,25-dihydroxyvitamin D and muscle strength in both sexes, and 25-hydroxyvitamin D in male participants could be documented. Whether the impact of vitamin D on calcium homeostasis and bone mineral density or directly on the muscle tissue level is more important for prevention of hip fractures remains unclear. Further prospective and comparative treatment studies should be performed, in order to evaluate whether and in which dose requirements, vitamin D supplementation can improve muscle strength in the elderly.

Nonclassic actions of vitamin D include potential regulation of immune function and glucose homeostasis. The bone-metabolism loop has recently been expanded to include osteocalcin, which appears to play a more direct role in pancreatic beta cell function and energy metabolism. We hypothesized that both vitamin D and osteocalcin would correlate negatively with indices of adiposity-related comorbidity risk in periadolescents, varying by ethnic group. We analyzed anthropometric, metabolic, and inflammatory markers from a multiethnic population of 106 school children 11 to 14 years of age studied as part of the Reduce Obesity and Diabetes (ROAD) consortium. As expected, 25-hydroxyvitamin D (25-OH vitamin D) was inversely correlated with intact parathyroid hormone (iPTH); total osteocalcin (OCN) and uncarboxylated osteocalcin (uOCN) were directly correlated with each other. OCN and uOCN concentrations correlated inversely with age. Vitamin D deficiency was most prevalent among East Asians (EA) and African Americans (AA). The highest lipid risk scores and homeostatic model for assessment of insulin resistance (HOMA-IR) values were seen in the South Asian (SA) group. Overall, adiposity measures were inversely correlated with OCN and iPTH, whereas such relationships were not observed for vitamin D. Acute insulin response to glucose challenge correlated negatively with uOCN in all subjects; however, lipid risk score correlated negatively with uOCN only in whites. The relationships between markers of calcium metabolism and body composition, glucose homeostasis, lipids, and inflammation all showed racial and ethnic differences. No consistent relationship was found between vitamin D and adiposity or vitamin D and glucose metabolism; instead vitamin D levels varied by race and ethnicity in this school-based group. These findings are consistent with the hypothesis that markers of calcium and bone metabolism may reflect risk for adiposity-related comorbidities in children.

BACKGROUND

Vascular calcification and arterial stiffening are cardiovascular risk factors among chronic kidney disease patients. Elevated aortic pulse wave velocity (AoPWV) is an independent predictor of increased cardiovascular morbidity and mortality.

OBJECTIVE

The aim of the study was to analyze the relationships between inflammatory and vascular calcification parameters and arterial wall stiffness in chronic kidney disease (CKD) patients treated by peritoneal dialysis.

METHODS

The study included 57 patients (27 women and 30 men) aged from 19 to 75 years (mean age 53 ± 13), treated by peritoneal dialysis during 4-100 months (mean 30.4 months). The concentrations of albumin, lipids, interleukin-6 (IL-6), IL-18, high-sensitive C-reactive protein, transforming growth factor-β1 (TGF-β1), osteocalcin, osteoprotegerin (OPG), fibroblast growth factor 23, fetuin A, parathyroid hormone (iPTH), total calcium (Ca), and phosphates (Pi) were measured. AoPWV was performed using a tonometric method, common carotid artery intima-media thickness (CCA-IMT) by ultrasonography evaluation, and calcium scoring (CaSc) with multirow spiral computed tomography (MSCT).

RESULTS

In univariate analysis, AoPWV correlated negatively with osteocalcin (R = -0.37; P = 0.005) and positively with OPG (R = 0.41; P = 0.002). Additionally, AoPWV was significantly positively associated with inflammatory parameters: IL-6 (R = 0.35; P = 0.009), TGF-β1 (R = 0.27; P = 0.047), and white blood cell (WBC) count (R = 0.33; P = 0.01). There were also positive correlations between AoPWV and imaging data: CCA-IMT (R = 0.32; P = 0.02) and CaSc (R = 0.38; P = 0.004). AoPWV did not correlate with calcium, phosphate, Ca × Pi index, or iPTH concentration. After multiple adjustments, osteocalcin was the only significant predictor of AoPWV. In logistic regression adjusted for age, hypertension, and mean arterial pressure at AoPWV evaluation, only osteocalcin was significantly associated with high (above median) AoPWV values [odds ratio 0.96 (0.92-0.99) per unit increase in osteocalcin].

CONCLUSIONS

OPG concentration and some inflammatory markers (WBC count, IL-6, TGF-β1) influenced the severity of arterial wall stiffness in CKD patients. Measurement of osteocalcin seems to be the best predictor of AoPWV.

OBJECTIVE

Posttransplant bone disease and bone metabolism markers were investigated in primary kidney transplant recipients receiving calcineurin inhibitor (CNI) based triple immunosuppression. We examined the safety profile and independent potential of CNIs on bone formation and bone resorption. The study also attempted to correct for modifiable and nonmodifiable factors that impact on posttransplantation bone metabolism, such as age, renal function, rejection, steroid dosage, and secondary hyperparathyroidism.

METHODS

Serum alkaline phosphatase and osteocalcin were used as indices of bone formation and urinary deoxypyridinoline as a marker for bone resorption. Bone mineral density (BMD) data were assessed in all patients. Osteocalcin and deoxypyridinoline data were correlated with BMD scores to predict the clinical utility and sensitivity of these tests. Sixty-six patients among 300 kidney transplant recipients were enrolled as eligible candidates based upon more than 12 months' posttransplantation follow-up excellent graft function (GFR values >60 mL/min), and intact parathormone levels <100 pg/mL.

RESULTS

Mean follow-up was 1395.3 +/- 179.3 days and 1488.9 +/- 225.1 days for cyclosporine (CsA) and FK506 groups, respectively. Mean values for alkaline phosphatase and osteocalcin were 108.8 +/- 6.0 versus 98.4 +/- 9.7 U/L and 10.1 +/- 1.2 versus 9.8 +/- 1.5 ng/mL for the CsA and FK506 groups, respectively. Both CsA and FK506 caused mild osteoblastic proliferation and matrix mineralization activity, as reflected by increased osteocalcin and alkaline phosphatase levels in 22.6% and 12.5% of patients, respectively. This bone formation activity was counterbalanced by a three-fold increase in urine deoxypyridinoline levels in both groups. Mean deoxypyridinoline levels were, respectively, 13.8 +/- 4.4 versus 11.3 +/- 2.1 nM/mMCr in the CsA and FK506 groups. Thirty-four (68%) patients in the CsA and 10 (62.5%) in the FK506 groups had elevated deoxypyridinoline levels. A strong correlation existed between deoxypyridinoline levels and BMD scores for the CsA group (P < .0001). Despite the presence of relatively greater elevations in deoxypyridinoline and BMD values among CsA-treated patients, there was no significant difference in terms of bone resorption potential of both groups. No correlation existed between iPTH values (<65 pg/mL or among 65 to 98.2 pg/mL) at any time versus osteocalcin, alkaline phosphatase, deoxypyridinoline, or BMD levels. The symptomatic bone disease and fracture rates were 0% in this series.

CONCLUSIONS

Calcineurin inhibitor-based immunosuppression with low maintenance doses of glucocorticoids induces slight bone formation but relatively potent, clinically relevant bone resorption.

BACKGROUND

Cognitive impairment was frequently reported in uremic patients with dialysis, but improvements of cognition after parathyroidectomy for symptomatic secondary hyperparathyroidism have never been reported before.

METHODS

Thirty-nine patients, who were successfully operated on with total parathyroidectomy plus autotransplantation were enrolled. Twenty-three dialysis patients, age >50 years, who had a serum level of intact parathyroid hormone (iPTH) greater than 650 pg/ml, and who did not undergo parathyroidectomy were selected as the control group. The mini-mental state examination (MMSE) and the clinical dementia rating (CDR) test were administered to all patients. Before the operation, educational level, symptoms of bone pain, skin itching, general weakness and insomnia were recorded and serum levels of calcium, phosphorus, alkaline phosphatase (Alk-ptase), iPTH, aluminum, and hemoglobin were measured in the study and control groups. At 12-week postoperatively, serum levels of calcium, phosphorus, Alk-ptase, iPTH, and aluminum were measured again and at 16-week postoperatively, the MMSE and the CDR test were administered again. In the control group, both MMSE and CDR test were administered again after the period or 16-week.

RESULTS

Serum calcium level was only significant difference (p = 0.002), whereas clinical symptoms, gender, etiologies of secondary hyperparathyroidism, duration of dialysis, educational level, age, and serum levels of phosphorus, Alk-ptase, iPTH, aluminum, and hemoglobin were not significantly different between the two groups. The educational level was the only factor affecting MMSE scores (p = 0.003). In the study group, at 12-week postoperatively, symptoms improved significantly, serum levels of calcium, phosphorus, Alk-ptase, iPTH, and aluminum decreased significantly, and at 16-week postoperatively, MMSE scores increased from 25 +/- 5 (mean +/- SD) to 26 +/- 5 (p < 0.001) and CDR scales decreased significantly (p < 0.001). Neither MMSE scores nor CDR scales of the control group changed significantly after the 16-week period.

CONCLUSIONS

Parathyroidectomy for symptomatic secondary hyperparathyroidism can improve cognition.

Vitamin D insufficiency is prevalent in chronic kidney disease (CKD) and associated with secondary hyperparathyroidism (SHPT) and increased risk of bone and vascular disease. Unfortunately, supplementation of stage 3 or 4 CKD patients with currently recommended vitamin D2 or D3 regimens does not reliably restore serum total 25-hydroxyvitamin D to adequacy (≥30ng/mL) or effectively control SHPT. Preclinical and clinical studies were conducted to evaluate whether the effectiveness of vitamin D repletion depends, at least in part, on the rate of repletion. A modified-release (MR) oral formulation of calcifediol (25-hydroxyvitamin D3) was developed which raised serum 25-hydroxyvitamin D3 and calcitriol levels gradually. Single doses of either bolus intravenous (IV) or oral MR calcifediol were administered to vitamin D deficient rats. Bolus IV calcifediol produced rapid increases in serum 25-hydroxyvitamin D3, calcitriol and FGF23, along with significant induction of CYP24A1 in both kidney and parathyroid gland. In contrast, oral MR calcifediol produced gradual increases in serum 25-hydroxyvitamin D3 and calcitriol and achieved similar hormonal exposure, yet neither CYP24A1 nor FGF23 were induced. A 10-fold greater exposure to bolus IV than oral MR calcifediol was required to similarly lower intact parathyroid hormone (iPTH). Single doses of oral MR (450 or 900μg) or bolus IV (450μg) calcifediol were administered to patients with stage 3 or 4 CKD, SHPT and vitamin D insufficiency. Changes in serum 25-hydroxyvitamin D3 and calcitriol and in plasma iPTH were determined at multiple time-points over the following 42 days. IV calcifediol produced abrupt and pronounced increases in serum 25-hydroxyvitamin D3 and calcitriol, but little change in plasma iPTH. As in animals, these surges triggered increased vitamin D catabolism, as evidenced by elevated production of 24,25-dihydroxyvitamin D3. In contrast, MR calcifediol raised serum 25-hydroxyvitamin D3 and calcitriol gradually, and meaningfully lowered plasma iPTH levels. Taken together, these studies indicate that rapid increases in 25-hydroxyvitamin D3 trigger CYP24A1 and FGF23 induction, limiting effective exposure to calcitriol and iPTH reduction in SHPT. They also support further investigation of gradual vitamin D repletion for improved clinical effectiveness. This article is part of a Special Issue entitled "17th Vitamin D Workshop".

Data on peak bone mineral density (BMD) and its determinants in Asian Indians are limited. We studied the peak BMD and its determinants in Asian Indians. A total of 1137 young (age: 25--35yr) healthy volunteers of either sex (558 men and 579 women) were recruited for dietary evaluation, analyses of serum calcium, inorganic phosphorus, alkaline phosphatase, 25-hydroxyvitamin D [25(OH)D], and intact parathyroid hormone (iPTH) levels, and measurement of BMD with dual-energy X-ray absorptiometry. In men and women, peak bone mass (PBM) at the femoral neck, femoral trochanter, total femur, and lumbar spine was achieved between 25 and 30yr of age, whereas PBM at the femoral intertrochanter occurred between 30 and 35yr of age. Peak BMD was lower than that of Caucasians by 15.2--21.1% in men and 14.4--20.6% in women. On stepwise multiple regression, height and weight were the most consistent predictors of BMD at all sites in both groups. In men, 25(OH)D positively predicted BMD at the hip, whereas in women, serum iPTH negatively predicted BMD at the femoral trochanter and total femur. The study concluded that Asian Indians have significantly lower peak BMD than Caucasians and that weight and height are the most consistent predictors of BMD at all sites in both men and women.

BACKGROUND

Vitamin D deficiency/insufficiency (VDDI) is common in CKD patients and may be associated with abnormal mineral metabolism. It is not clear whether the K/DOQI recommended doses of ergocalciferol are adequate for correction of VDDI and hyperparathyroidism.

METHODS

Retrospective study of 88 patients with CKD Stages 1 - 5 and baseline 25-hydroxyvitamin D level < 30 ng/ml (< 75 nmol/l). Patients treated with ergocalciferol as recommended by K/DOQI guidelines. Only 53 patients had elevated baseline PTH level for the CKD stage. Patients were excluded if they received vitamin D preparations other than ergocalciferol or phosphate binders. 25-hydroxyvitamin D level, intact PTH level (iPTH), and other parameters of mineral metabolism were measured at baseline and after completion of ergocalciferol course.

RESULTS

88 patients with CKD were treated with ergocalciferol. Mean age 56.8 +/- 9.5 years and 41% were males. The mean (+/- SD) GFR was 28.3 +/- 16.6 ml/min. At the end of the 6-month period of ergocalciferol treatment, the mean 25-hydroxyvitamin D level increased from 15.1 +/- 5.8 to 23.3 +/- 11.8 ng/ml (37.75 +/- 14.5 to 58.25 +/- 29.5 nmol/l) (p < 0.001). Treatment led to>> or = 5 ng/ml (12.5 nmol/l) increases in 25-hydroxyvitamin D level in 54% of treated patients, and only 25% achieved levels>> or = 30 ng/ml (75 nmol/l). Mean iPTH level decreased from 157.9 +/- 125.9 to 150.7 +/- 127.5 pg/ml (p = 0.5). Only 26% of patients had>> or = 30% decrease in their iPTH level after treatment with ergocalciferol.

CONCLUSIONS

Current K/DOQI guidelines are inadequate for correcting VDDI or secondary hyperparathyroidism in CKD patients. Future studies should examine the effects of higher or more frequent dosing of ergocalciferol on these clinical endpoints.

This cross sectional study was conducted to determine the prevalence and pattern of renal osteodystrophy (ROD) in patients on maintenance hemodialysis (HD) in Tripoli, Libya. A total of 103 randomly selected patients, of whom 53% were males, were investigated. Their mean age was 47.6 +/- 12.5 years. They were on dialysis for a mean duration of 6.2 +/- 4.3 years. Pre-dialysis serum levels of intact parathyroid hormone (iPTH), osteocalcin, alkaline phosphatase, albumin, total calcium and phosphate were measured in all the patients. Depending on serum iPTH levels, the patients were divided into three groups: hyperparathyroid bone disease (iPTH>> 450 pg/ml), adynamic bone disease (iPTH < 60 pg/ml), and a group with apparently normal bone (iPTH 60 pg/ml to 450 pg/ml). As a whole, the mean serum levels of iPTH, osteocalcin, alkaline phosphatase and corrected total calcium were high in all study patients (373.7 pg/ml, 251.3 ng/ml, 254.9 IU/l, and 9.9 mg/dl respectively). The prevalence of ROD among these patients was 55.3%. Of these, 29 (28.1%) had laboratory evidence of hyperparathyroid bone disease, while 28 patients (27.1%) had laboratory evidence of adynamic bone disease. In only 18 patients, (17.4%) the serum levels of iPTH were within the target range recommended by the K/DOQI guidelines (150-300 pg/ml). This cross sectional study, albeit in a limited number of patients, shows that the prevalence of ROD in our institution is high, possibly because of inadequate patient monitoring and lack of insight into ROD among both patients and physicians.

OBJECTIVE

Familial hypocalciuric hypercalcaemia (FHH) is clinically characterized by mild to moderate parathyroid hormone (PTH)-dependent hypercalcaemia, autosomal dominant pattern of inheritance, and normal to frankly reduced urinary calcium excretion in spite of a high serum calcium (clearance (Ca)/clearance (Cr)<0.01). FHH has a benign course and should be differentiated from primary hyperparathyroidism. It is usually caused by a heterozygous loss-of-function mutation in the calcium-sensing receptor gene (CASR).

METHODS

We report the case of a 16-year-old patient with hypercalcaemia and a mixed family history of parathyroid adenoma and mild hypercalcaemia. Serum calcium was 14 mg/dl with a serum iPTH of 253 pg/ml.

RESULTS

A neck 99mTc-sesta MIBI tomoscintigraphy showed a definite hyperactivity in the left upper quadrant. A surgical four-gland exploration confirmed a single parathyroid adenoma. After surgical resection of a left superior parathyroid adenoma, the patient's hypercalcemia improved but did not normalize, returning to a level typical of FHH. An inactivating mutation in exon 4 of the CASR gene, predicting a p.Glu297Lys amino acid substitution was found.

CONCLUSIONS

Thus, this 16-year old patient presented with the association of FHH and a single parathyroid adenoma. The young age of the patient and the association of parathyroid adenoma and FHH in his grandmother argue for a causal link between CASR mutation and parathyroid adenoma in this family. This case contributes to illustrate the expanding clinical spectrum of CASR loss-of-function mutations.

BACKGROUND

The success of parathyroid surgery depends on the identification and removal of all hyperactive parathyroid tissue. At this writing, bilateral cervical exploration and identification of all parathyroid glands represent the operative standard for primary hyperparathyroidism (pHPT). However, improved preoperative localization techniques and the availability of intraoperative parathyroid hormone monitoring prepare the way for minimally invasive procedures.

METHODS

Patients with pHPT and one unequivocally enlarged parathyroid gland on preoperative ultrasound and 99mTc-SestaMIBI scintigraphy underwent minimally invasive video-assisted parathyroidectomy by an anterior approach. Intraoperatively, a rapid chemiluminescense immunoassay was used to measure intact parathyroid hormone (iPTH) levels shortly before and then 5, 10, and 15 min after excision of the adenoma. The operation was considered successful when more than a 50% decrease in preexcision iPTH levels was observed after 5 min.

RESULTS

Between October 1999 and November 2001, 36 of 82 patients with pHPT were eligible for a minimally invasive approach. A conversion to open surgery became necessary in five patients because of technical problems. In three cases, intraoperative iPTH monitoring showed no sufficient decrease in iPTH values. In these cases, subsequent cervical exploration showed one double adenoma and two hyperplasias, respectively. In two patients we had difficulty interpreting intraoperative iPTH values, resulting in persistent pHPT.

CONCLUSIONS

Despite the use of high-resolution ultrasound and 99mTc-SestaMIBI scintigraphy, the presence of multiple glandular disease cannot be ruled out completely. Intraoperative iPTH monitoring to ensure operative success is indispensible for a minimally invasive approach. Despite our problems with iPTH monitoring in two patients, we believe that in selected cases, minimally invasive parathyroidectomy represents an attractive alternative to conventional surgery.

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.

Eighteen patients (17 women and 1 man) with primary osteoporosis were divided into two groups of 9 patients each. Group A received 2.0 to 2.5 g of calcium and 400 units of vitamin D per day orally and was studied before and after short-term (3 to 4 months) treatment; group B received 1.5 to 2.0 g of calcium per day and 50,000 units of vitamin D twice weekly and was studied before, after short-term, and after long-term (1 year) treatment. In group A there was a decrease (P is less than 0.01) in bone-resorbing surfaces (microradiography of bone biopsy samples) after short-term treatment. In group B there was a decrease (P is less than 0.01) in bone-forming and bone-resorbing surfaces after both short-tern and long-term treatment. Fasting-state (morning) serum immunoreactive parathyroid hormone (iPTH) concentrations decreased after short-term treatment (combined data of groups A and B) and after long-term treatment (group B). We conclude that the principal effect of the oral calcium and vitamin D therapy in primary osteoporosis is to decrease bone turnover. The most probable mechanism for this effect on bone is a partial inhibition of PTH secretion.

The bone loss that occurs during lactation in rats was aggravated by increasing the number of suckling pups and was further accentuated by feeding the rats a calcium (Ca)-deficient diet. The bone loss was evenly distributed along the whole length of the femur in severe cases. In less severe cases, the metaphyses were affected more than the midshaft. Mechanical properties of femurs, i.e., bone 'strength', 'stiffness', 'toughness' and 'ductility', were all affected in lactating rats suckling seven to eleven pups and fed the 0.1% Ca diet. The positive correlation between bone 'strength' and ash weight is consistent with the concept that when there is loss of bone, bone becomes more susceptible to fracture. The fall in serum ionized Ca and the rise in serum iPTH were closely related to the intensity of lactation and were profoundly affected by litter size and Ca concentration of the diet. We conclude that the change in Ca homeostasis in lactating rats is due to the large loss of Ca required for milk production and that the loss of Ca is associated with hyperfunction of the parathyroid gland. Furthermore, a Ca-deficient diet severely reduced bone mineral content and affected the mechanical properties of femurs of lactating rats adversely, especially those suckling large litters of pups.