OBJECTIVE

To investigate the influence of the pancreas lipase inhibitor orlistat (OLS) on calcium metabolism, bone turnover, bone mass, bone density and body composition when given for obesity as adjuvant to an energy- and fat-restricted diet.

METHODS

Randomized controlled double-blinded trial of treatment with OLS 120 mg three times daily or placebo for 1 y.

METHODS

Thirty obese subjects with a mean body mass index (BMI) of 36.9+/-3.7 kg/m(2) and a mean age of 41+/-11 y. Sixteen patients were assigned to OLS and 14 to placebo.

METHODS

Dual energy X-ray absorptiometry (DXA) measurements of bone mineral and body composition included total bone mineral content (TBMC), total bone mineral density (TBMD), lumbar spine BMC and BMD, forearm BMC and BMD, fat mass (FM), fat free-mass (FFM), percentage fat mass (FM%) as well as a DXA estimate of the body weight. Body composition (FM, FFM and FM%) was estimated by total body potassium (TBK). Indices of calcium metabolism and bone turnover included serum values of ionized calcium (Ca(++)), iPTH (parathyroid hormone), alkaline phosphatase, 25(OH)-vitamin D, 1,25(OH)(2) vitamin D and osteocalcin as well as fasting urinary ratios of hydroxyproline/creatinine and Ca/creatinine (fU-OHpr/creat, fUCa/creat).

RESULTS

There were no significant differences between OLS and placebo groups as to any of the body composition variables (FFM, FM, FM%) at baseline or after 1 y treatment. Weight loss was of 11.2+/-7.5 kg in the OLS group and 8.1+/-7.5 kg in the placebo group (NS). The changes in FM and FM% were significant in both groups determined by DXA as well as by TBK, but the group differences between these changes were not significant. The composition of the weight loss was approximately 80% fat in both groups. FFM only changed significantly by DXA in the OLS group (-1.3 kg), but the difference from the placebo group was not significant. Forearm BMD in both groups, forearm BMC in the OLS group and TBMD in the placebo group fell discretely but significantly, but there were no significant group differences between the OLS and the placebo-treated group. All biochemical variables except s-osteocalcin changed significantly after 1 y in the OLS group, disclosing a pattern of an incipient negative vitamin D balance, a secondary increase in PTH-secretion, and an increase in bone turnover with the emphasis on an increase in resorption parameters (fU-OHpr/creat, fUCa/creat). In the placebo group, only s-25(OH)vitamin D and fU-OHpr/creat changed significantly, but the pattern was also that of a deteriorated vitamin D status and an increase in PTH levels and bone turnover. The only biochemical variable which was significantly different between OLS and placebo groups after one year was the fU-OHpr/creat ratio, which increased from 12.0 to 20.1 in the OLS group but only from 10.9 to 1 3.2 in the placebo group.

CONCLUSIONS

One year's treatment with OLS induces a lipid malabsorption which enhances a dietary weight loss without any significant deleterious effects on body composition. OLS induces a relative increase in bone turnover in favour of resorption, possibly due to malabsorption of vitamin D and/or calcium. However, no changes in bone mass or density are seen after 1 y of OLS treatment apart from those explained by the weight loss itself. Thus 1 y of OLS treatment seems safe from a 'bone preserving' point of view. A vitamin D and calcium supplement should be taken during the treatment.

OBJECTIVE

This 1-year double-blind, placebo-controlled, multicenter study evaluated the long-term safety and efficacy of cinacalcet for the treatment of secondary hyperparathyroidism in patients receiving hemodialysis.

METHODS

Patients were randomly assigned in a 1:1 ratio to cinacalcet or control treatment groups. The initial dose of cinacalcet (or matching placebo) was 30 mg. Doses were titrated every 3 or 4 weeks based on the intact parathyroid hormone (iPTH) response and safety profile. Sequential doses included 30, 60, 90, 120 and 180 mg/d. Phosphate binders and vitamin D sterols were adjusted per protocol as needed to control levels of calcium and phosphorus. Efficacy and safety were compared between treatment groups among patients who completed the study (52 total weeks of treatment). Reasons for withdrawal are presented for patients who did not complete the study.

RESULTS

A total of 210 patients completed 52 weeks of double-blinded treatment with cinacalcet (n = 99) or placebo (n = 111). Over the last 6 months of the study, a greater proportion of patients in the cinacalcet group than the control group achieved an iPTH level < or = 250 pg/ml (61.6 vs. 9.9%, p < 0.001) or a>> or = 30% decrease in iPTH from baseline (81.8 vs. 21.6%, p < 0.001). Mean iPTH levels decreased by -47.8% in the cinacalcet group and increased by +12.9% in the control group. Mean percentage changes in other laboratory values in the cinacalcet and control groups included the following: serum calcium -6.5 vs. +0.9% (p < 0.001), serum phosphorus -3.6 vs. -1.1% (p = 0.465), and Ca x P -9.9 vs. -0.3% (p = 0.006). The most commonly reported adverse events related to study drug by the investigators included nausea (13% cinacalcet, 5% control), investigator-reported hypocalcemia (11% cinacalcet, 1% control), vomiting (9% cinacalcet, 2% control), dyspepsia (5% cinacalcet, 4% control), and diarrhea (5% cinacalcet, 2% control).

CONCLUSIONS

Treatment with cinacalcet is a safe and effective therapy for long-term control of secondary hyperparathyroidism. 1-year therapy with cinacalcet was associated with sustained, clinically significant reductions in calcium, Ca x P and iPTH which allowed a greater percentage of patients to achieve NKF-KDOQI target goals for PTH and Ca x P.

Hemodialysis patients with secondary hyperparathyroidism (SHP) suffer from excessive oxidative stress and inflammation. Vitamin D analogues are currently the first line therapy for SHP, but the influence of vitamin D treatment on inflammation and oxidative stress remains unknown. This study investigated the influence of vitamin D therapy on oxidative stress and inflammatory markers in hemodialysis patients with SHP. Twenty-five patients (mean age 58 ± 12 years, 13 males and 12 females) were enrolled in the study to receive calcitriol treatment for 16 weeks. We evaluated changes in the serum biochemical parameters, inflammatory markers [C-reactive protein (CRP) and interleukin-6 (IL-6) levels], serum oxidative stress condition [total antioxidant status (TAS)], and CD4(+) T-lymphocyte intracellular cytokines [interferon γ (IFN-γ) and interleukin-4 (IL-4)] before and at the end of the 16-week calcitriol treatment. Correlations between each of these factors were also studied. All patients with SHP had low serum 1,25-dihydroxyvitamin D(3) levels and elevated serum levels of intact parathyroid hormone (iPTH), CRP and IL-6. Twenty patients (10 males and 10 females) responded to the calcitriol therapy, with significant decrements in serum iPTH. Our results showed that calcitriol can effectively suppress iPTH secretion, reduce inflammatory markers (CRP and IL-6) and oxidative stress. It can also effectively reduce inflammatory cytokine (CD4(+) IFN-γ) and increase anti-inflammatory cytokine (CD4(+) IL-4). Interestingly, significant correlations between CD4(+) IFN-γ levels and serum iPTH levels, as well as between TAS and iPTH levels were noted. Overall, our study has demonstrated calcitriol treatment significantly attenuates inflammation and oxidative stress in hemodialysis patients with SHP.

The precursor of the active form of vitamin D, 25-hydroxyvitamin D (25(OH)D), is recognized as the optimal indicator of vitamin D status. Vitamin D3 undergoes conversion through a multitude of enzymatic reactions described within the paper, and vitamin D levels are dependent on many factors including the vitamin D binding protein (DBP). The free hormone hypothesis postulates that protein-bound hormones are not biologically available and that unbound hormones are biologically active. The majority of circulating 25(OH)D and 1,25-dihydroxyvitamin D is tightly bound to DBP and albumin, with less than 1% circulating in an unbound form. As a result, factors affecting DBP alter the interpretation of 25(OH)D levels. The aim of this review is to assess the current methodology used to measure total and free 25(OH)D, and DBP. Additionally, we analyze the effects of other endocrine hormones and disease processes on DBP levels and subsequently, the interpretation of 25(OH)D levels.

BACKGROUND

CF = cystic fibrosis DBP = vitamin D binding protein ELISA = enzyme-linked immunosorbent assay ESLD = end-stage liver disease HC = hormone contraceptives iPTH = intact parathyroid hormone LC-MS = liquid chromatography-mass spectrometry MS = multiple sclerosis 25(OH)D = 25-hydroxyvitamin D PHPT = primary hyperparathyroidism RIA = radioimmunoassay.

By the time patients require dialysis replacement therapy, nearly all chronic kidney diseases (CKD) patients are affected with uremic bone diseases. High-turnover osteodystrophy can be prevented; patients with CKD should be monitored for imbalances in calcidiol (25 OH vitamin D), calcium, and phosphate homeostasis. We aimed to determine the effect of a monthly oral 300,000 IU vitamin D(3) (cholecalciferol) supplementation on the uremic bone diseases (UBD) markers such as iPTH and alkaline phosphatase in CKD patients. Among a total of 70 patients under treatment in the nephrology unit, 40 predialysis CKD patients (mean age of 49 +/- 14, male/female 20/20) were included the study. The patients were randomly divided into two groups. Treatment group included 20 patients (mean age of 51 +/- 14, male/female 9/11), and the control group comprised 20 patients (mean age of 47 +/- 14, male/female 9/11). Treatment group patients were given a single dose of Devit3 ampoule (300,000 U cholecalciferol) per month orally way. Patients in the control group did not take any vitamin D for a month. The level of calcidiol was lower than normal range in two groups. After a month, treatment group patient's calcidiol increased statistically significant (6.8 +/- 3.5 to 17.8 +/- 21.4 ng/mL, p < 0.001). After a month, iPTH level decreased in the treatment group statistically significantly (368 +/- 274 to 279 +/- 179 pg/ml, p < 0.001). At the 30(th) day of the treatment, in 9/20 of the treatment group patients (45%), the iPTH value decreased at least 30% (p < 0.001). We suggest that oral depot cholecalciferol treatment causes a statistically significant decrease of serum iPTH level but does not cause a statistically significant change in Ca, P, ratio of Ca x P, or urinary calcium creatinine rate in UBD predialysis CKD. This treatment can be used safely for the predialysis CKD patients, along with the cautious control of serum calcium and phosphor.

Due to little outdoor activity and low dietary intake of vitamin D (VD), Bangladeshi low-income women are at risk for osteoporosis at an early age. The present study assessed the effect of VD, Ca and multiple micronutrient supplementation on VD and bone status in Bangladeshi young female garment factory workers. This placebo-controlled 1-year intervention randomly assigned 200 apparently healthy subjects (aged 16-36 years) to four groups: VD group, daily 10 microg VD; VD and Ca (VD-Ca) group, daily 10 microg VD+600 mg Ca; multiple micronutrient and Ca (MMN-Ca) group, 10 microg VD and other micronutrients+600 mg Ca; a placebo group. Serum 25-hydroxyvitamin D (S-25OHD), intact parathyroid hormone (S-iPTH), Ca, phosphate and alkaline phosphatase were measured. Bone mineral density and bone mineral content were measured by dual-energy X-ray absorptiometry. All measurements were made at baseline and at 12 months. Significantly (P < 0.001) higher S-25OHD concentrations were observed in the supplemented groups than in the placebo group after the intervention. Supplementation had an effect (P < 0.001) on S-iPTH in the VD-Ca and MMN-Ca groups compared with the placebo group. Bone mineral augmentation increased at the femur in the supplemented groups. Supplementation with VD-Ca should be recommended as a strategic option to reduce the risk of osteomalacia and osteoporosis in these subjects. MMN-Ca may have analogous positive health implications with additional non-skeletal benefits.

BACKGROUND

Vascular calcification and low bone turnover with a relatively low parathyroid hormone (PTH) often coexist in diabetic patients undergoing haemodialysis. Since calcium salts (CaS) are used extensively as primary phosphate binders and have been associated with progressive vascular calcification, we studied the effects of CaS on coronary arteries and parathyroid activity in incident haemodialysis diabetic patients.

METHODS

We measured the change in coronary artery calcium scores (CACS) with sequential electron beam computed tomography (EBCT) in 64 diabetic and 45 non-diabetic patients, randomized to CaS or sevelamer within 90 days of starting haemodialysis. CACS measurements were repeated after 6, 12 and 18 months. Serum intact PTH (iPTH), calcium and phosphorus were serially tested.

RESULTS

During the study period, serum phosphate was similar in diabetic and non-diabetic patients. Serum calcium levels were similar at baseline (2.3+/-0.25 mmol/l for both) and increased significantly with CaS treatment (P<0.05) both in diabetic and non-diabetic patients but not with sevelamer. Diabetic patients treated with CaS showed a significantly greater CACS progression than sevelamer-treated patients (median increase 177 vs 27; P=0.05). During follow-up, diabetic patients receiving CaS were significantly more likely to develop serum iPTH values<16 pmol/l than diabetic patients treated with sevelamer (33% vs 6%, P=0.005) and had a lower mean iPTH level (24+/-16 vs 31+/-14 pmol/l; P=0.038).

CONCLUSIONS

The management of hyperphosphataemia with CaS in haemodialysis diabetic patients is associated with a significantly greater progression of CACS than with sevelamer. These effects are accompanied by iPTH changes suggestive of low bone turnover.

Chronic kidney disease (CKD) leads to reduced bone mineral density (BMD) in pre-dialysis and dialysis patients. A few studies have used dual-energy x-ray absorptiometry (DEXA) to assess BMD in pre-dialysis CKD patients and have shown low BMD to be highly prevalent. Until now there have been no studies reporting the histological features of low BMD in pre-dialysis CKD patients.

OBJECTIVE

To determine the prevalence and histological features of low BMD in pre-dialysis CKD patients.

METHODS

Pre-dialysis CKD patients (n = 103, 46 females/57 males), median creatinine clearance of 29 (10 - 78) ml/min/ 1.73 m2, were evaluated using biochemical analysis and DEXA. Bone biopsies were obtained from those with low BMD.

RESULTS

Fifty (48.5%) out of the 103 patients had low BMD (LBD group) and 53 (51.5%) had normal BMD (NBD group). The risk for low BMD was increased in those patients with alkaline phosphatase levels above 190 U/l and intact-PTH (iPTH) below 70 pg/ml (p < 0.05). Demographic and biochemical parameters from both groups were comparable, except for lower body mass index (BMI) in LBD subjects (p = 0.04). Women who had been post-menopausal for at least 1 year comprised 65% (13/20) and 50% (13/26) of the LBD and NBD groups, respectively (p = NS). In 40 LBD patients, bone histomorphometry revealed adynamic bone disease (ABD, 52.5%), osteomalacia (OM, 42.5%) and mixed bone disease (MBD, 5%). Trabecular bone volume (BV/TV) was lower in ABD and OM patients. A nearly significant association was found between ABD and iPTH < or = 150 pg/ml (p = 0.056), whereas higher values of iPTH were associated with OM. Total alkaline phosphatase < or = 190 U/l was significantly associated with ABD, whereas higher values were associated with OM. No correlation was observed between BV/TV and BMD.

CONCLUSIONS

Low BMD is frequent in pre-dialysis CKD patients, and low turnover bone disease, manifesting as ABD and OM, was the hallmark of this bone loss.

Osteopenia is a major complication of orthotopic liver transplantation (OLT). However, no effective therapy for bone disease has been defined. We have studied vertebral bone mineral density (VMD) and fasting serum markers of bone formation [bone gla protein (BGP), procollagen I carboxyterminal peptide (PICP)] and metabolism (serum Ca, P, intact parathyroid hormone (iPTH), 25OHD3 and 1,25(OH)2D3) in 120 patents after OLT. VMD was measured by dual-energy X-ray absorptiometry (DXA) using a Hologic QDR 1000 densitometer on two occasions, 12 months apart. Patients with OLT had a VBD significantly lower compared with age- and sexed-matched Spanish controls (P < 0.05). Prevalence of osteoporosis (Z score below -2 SD) was 35.8%. Serum BGP (8.6 +/- 0.7 ng/ml) and PICP (222.9 +/- 81.9 ng/dl) were higher than those of controls. However, serum calcium, phosphorus, iPTH, 25OHD3, and 1,25(OH)2D3 were within normal range. Patients with osteoporosis were randomly treated with 40 IU/day of calcitonin i.m. (Diatin, Ferrer Int. Laboratories) (n = 17) or 400 mg p.o., 15 days every 3 months, of sodium ethiodronate (Difosfen, Rubio Laboratories) (n = 23). All patients received 500 mg/12 hours of elemental calcium p.o. After 12 months of treatment, a significant increment of vertebral mineral density (VMD) was observed (6.4% and 8.2%, respectively). Serum BGP and PICP values remained elevated without a difference between the two drugs. Our results indicate that antiresorptive drugs may be of benefit in the high turnover osteoporosis of OLT recipients.

The effect of oestrogen administration (4-6 weeks) on the response of human calcitonin (hCT) secretion to 5 min calcium infusions was studied in ten elderly women. There was no significant difference in mean basal plasma hCT levels before and after oestrogen administration. However, the mean increment in plasma hCT in response to calcium infusion (delta hCT) increased significantly (P < 0.001) from 21.9 +/- 6.6 (mean +/- SE) before treatment, to 79.6 +/- 15.5 ng/l after oestrogen administration. Mean serum calcium levels decreased significantly (P < 0.001) from 2.42 +/- 0.06 before to 2.19 +/- 0.07 mmol/l after oestrogen treatment. Mean plasma immunoreactive PTH (iPTH) levels increased significantly (P < 0.05) from 521 +/- 41 before to 696 +/- 96 ng/l after oestrogen treatment. To exclude out the possibility that the decreased serum calcium level itself might have influenced delta hCT, 1 alpha-hydroxycholecalciferol (1 alpha-OH-D3) was administered with oestrogens. While this resulted in a slight increase in serum calcium level, there was no significant difference in delta hCT in response to calcium infusion following oestrogen treatment alone, and after combination therapy of oestrogen and 1 alpha-OH-D3. The primary action of administered oestrogen may be in stimulating hCT secretion which results in a decrease in plasma calcium concentration and an increase in plasma iPTH level.

OBJECTIVE

To study the prevalence of hypovitaminosis D [serum 25(OH)D < or = 37 nmol L-1)] in Finnish medical in- and outpatients in a cross-sectional study.

METHODS

The subjects were 106 consecutive medical inpatients (57 females, 49 males with mean ages of 65 and 58 years) from the Peijas Hospital, Vantaa, Finland, and 99 ambulatory patients (48 females, 51 males with mean ages of 42 and 46 years) contacting a private outpatient centre in Helsinki, Finland. Serum 25(OH)D, vitamin D binding protein (DBP), free vitamin D index (FDI), intact PTH (iPTH), and albumin-corrected calcium were measured.

RESULTS

Serum 25-hydroxyvitamin D [25(OH)D] was 37 nmol L(-1) or less in 70% of female and in 61% of male inpatients and in 44% of female and in 37% of male outpatients. In the whole population, a statistically significant inverse association (P < 0.0001) was detected between iPTH and 25(OH)D levels; the iPTH concentration appeared to start increasing when 25(OH)D concentration was 50 nmol L(-1) or less. The association remained the same (P < 0.0001) when FDI was used instead of 25(OH)D in the calculations. When the sexes were analysed separately, the statistically significant association was found only in females (P < 0.0001 for iPTH versus 25(OH)D; P < 0.0001 for iPTH versus FDI) but not in males.

CONCLUSIONS

Hypovitaminosis D is very common amongst Finnish in- and outpatients in both sexes, causing secondary hyperparathyroidism in females. More extensive studies are warranted to elucidate the vitamin D status of the Finnish population.

Primary hyperparathyroidism (HPTH) is frequently associated with hypertension. To date, the relationship between these two conditions is still not clear. We have studied 34 consecutive patients with primary HPTH due to a parathyroid adenoma. The diagnosis was later surgically confirmed in 32 cases. Ten of thirty-four HPTH patients were hypertensive. Before adenomectomy (PTHX) and 1-2 months after PTHX, we measured the following parameters in all patients: circulating levels of total and ionized Ca, intact immunoreactive parathormone (iPTH) (1-84), plasma renin activity (PRA), aldosterone, and daily total urinary catecholamine excretion. Moreover, 10 hypertensive HPTH patients, 10 normotensive HPTH patients, compared to 10 to 10 sex- and age-matched healthy normotensive subjects, underwent an acute norepinephrine test to assess vascular reactivity to a pressor agent. Before PTHX, no significant difference was observed between normotensive and hypertensive patients in all the above-mentioned variables, except for PRA and plasma aldosterone levels which were higher in hypertensive patients. Furthermore, the pressor response to the norepinephrine test was significantly greater in hypertensive HPTH patients than in the other 2 groups. After PTXH, serum Ca and intact iPHT (1-84) levels were reduced to normal values in all patients, while blood pressure, PRA and plasma aldosterone levels became normal in 8 of 10 hypertensive patients. The pressor response to the norepinephrine test was similar in the 2 groups. These results are consistent with the hypothesis of a direct effect of PTH on renin secretion which could contribute to the pathogenesis of hypertension and to the vessels sensitization to pressor agents.

BACKGROUND

Parathyroidectomy has a success rate of greater than 95% in the hands of experienced surgeons. To maintain this result in a more cost-effective way, intraoperative monitoring of intact parathyroid hormone (iPTH) has been used to decrease operative times. This technique signals when all hyperfunctioning tissue has been excised or when further dissection is necessary.

METHODS

Eighty-nine consecutive patients with hyperparathyroidism had plasma samples measured for iPTH levels during parathyroidectomy. Nine patients had previous neck explorations. Perioperative iPTH measurements using immunochemiluminescent assays with a turnaround time of 10 minutes were done after excision of each suspected abnormal parathyroid gland.

RESULTS

All patients except one returned to and maintained normal calcium levels during the follow-up period of 8 months (range, 1 to 25 months). Prediction of postoperative calcium levels by means of quick immunochemiluminescent assay has a sensitivity of 97%, specificity of 100%, and an overall accuracy of 97%. Specific influence on surgical judgment was noted in four patients with multiglandular disease, in seven with difficult localization problems, and in one patient in whom the hyperfunctioning parathyroid tissue was not recognized. Monitoring the plasma iPTH levels during parathyroidectomy directly aided the surgeon's operative approach in these 12 patients.

CONCLUSIONS

Intraoperative iPTH assay is useful with predictive accuracy of 97%. It influenced or changed the operative approach in 13% of patients.

The trend toward limited exploration for primary hyperparathyroidism (1 degrees HPT) has stemmed from advances in sestamibi scanning, gamma probe technology, and intraoperative parathyroid hormone monitoring (iPTH). Prior to widespread application, directed parathyroidectomy must be shown to meet the high standards of conventional cervical exploration. In this prospective, nonrandomized trial, results of parathyroidectomy utilizing the gamma probe, iPTH, or neither technique were evaluated. Altogether, 150 patients underwent parathyroidectomy utilizing the gamma probe (n = 50), iPTH (n = 50), or neither technique (n = 50). Each group was evaluated for operating time, length of hospitalization, cure rate, morbidity, mortality, and cost. A telephone survey was conducted with 25 patients in each group (n = 75) to address patient satisfaction. The gamma probe localized the abnormal gland in 66% of patients and confirmed cure intraoperatively in 84%. In the iPTH group, a more than 50% decrease from baseline occurred in 98%. The mean operating times were 76, 84, and 90 minutes, respectively (p = 0.16); and the mean length of hospitalization was 1 day. The biochemical cure rates were 98%, 100%, and 96%, respectively (p = 0.17). Total costs were $4476, $3918, and $3905, respectively. A total of 96% of patients in all three groups were "very satisfied" with their surgical procedure. Directed parathyroidectomy utilizing the gamma probe or iPTH assay does not significantly alter the operating time, length of hospitalization, cure rate, morbidity, mortality, or patient satisfaction when compared to conventional exploration in our practice. The probe is more expensive and was not a consistently reliable tool for localizing parathyroid pathology. PTH monitoring reliably predicts cure intraoperatively.

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 effects of acute and chronic metabolic acidosis on serum immunoreactive parathyroid hormone (iPTH) were studied. Acute metabolic acidosis induced by administration of ammonium chloride (NH4Cl) produced a barely detectable increase in serum iPTH. Chronic NH4Cl administration produced a marked elevation of serum iPTH that was well correlated with the magnitude of acid-induced hypercalciuria but not with the degree of acidosis. Acetazolamide administration produced an equivalent degree of acidosis, but hypercalciuria was minimal and iPTH increased only marginally. Methionine administration caused moderate hypercalciuria and a significant but moderate increase in iPTH. Chronic NH4Cl-induced acidosis produced no hypercalciuria when dietary sodium intake was rigidly restricted, and under these conditions serum iPTH remained normal. When sodium intake was suddenly increased while maintaining the acid load, hypercalciuria appeared and was followed by progressive rise in serum iPTH equivalent to that observed during chronic NH4Cl-induced acidosis in subjects consuming salt ad lib. These results indicate that chronic acidosis elevates iPTH mainly by producing hypercalciuria and that acidosis itself is not a primary stimulus to PTH secretion.

We evaluated the turnover of the plasma 25-OH-vitamin D pool, acid, and mineral balances in paired balance studies of 6 normal subjects during normal acid base conditions and during stable chronic metabolic acidosis induced by NH4Cl. Positive acid balances and negative Ca balances due to hypercalciuria were observed as previously reported. Plasma 25-OH-D pool turnover averaged 6.1+/-0.4 nmol/day during control and did not change during acidosis (6.5 +/- 0.5 nmol/day) nor were any significant increments in net intestinal absorption of Ca, PO4, or Mg, the physiological expression of vitamin D action, observed during acidosis. In 3 other subjects, repetitive measurements of serum iPTH during 7 control days and 24 days of stable NH4Cl acidosis showed no changes. We interpret the data to support the hypothesis that neither PTH nor vitamin D and its metabolites mediates the increase in net bone resorption that must accompany chronic metabolic acidosis.

Studies were carried out to evaluate whether skeletal resistance to acute increments in endogenous parathyroid hormone exists in patients with mild to moderate renal insufficiency. Hypocalcemia was induced with the infusion of ethyl-enediamine-tetra-acetate (EDTA) in 10 normal subjects and 13 patients with mild renal failure. After the induction of hypocalcemia, the concentration of serum calcium increased gradually and reached preinfusion levels by 22 h in the normal subjects; in contrast, the levels of serum calcium in patients with mild renal insufficiency were significantly lower than the preinfusion values even at the end of 26 h following the EDTA infusion. This delayed recovery occurred despite significantly higher levels of serum immunoreactive parathyroid hormone (IPTH) in the patients than in the normal subjects. The increase in the levels of IPTH reflect elevations in the concentrations of biologically active hormone since urinary cyclic AMP increased significantly. Urinary calcium excretion following the EDTA infusion was not different in both groups and, therefore, could not account for the delayed recovery of serum calcium values in the patients with renal insufficiency. These results indicate that secondary hyperparathyroidism exists early in patients with renal failure and such patients have exaggerated parathyroid hormone secretion in response to acute hypocalcemia. The data are consistent with the concept that skeletal resistance to increments in endogenous parathyroid hormone is present in such patients. This abnormality is, at least partly, responsible for the hypocalcemia and secondary hyperparathyroidism of renal insufficiency.

Vitamin D is suggested to have a role in the coupling of bone resorption and formation. Compared with women, men are believed to have more stable bone remodeling, and thus, are considered less susceptible to the seasonal variation of calcitropic hormones. We examined whether seasonal variation exists in calcitropic hormones, bone remodeling markers, and BMD in healthy men. Furthermore, we determined which vitamin D intake is required to prevent this variation. Subjects (N = 48) were healthy white men 21-49 yr of age from the Helsinki area with a mean habitual dietary intake of vitamin D of 6.6 +/- 5.1 (SD) microg/d. This was a 6-mo double-blinded vitamin D intervention study, in which subjects were allocated to three groups of 20 microg (800 IU), 10 microg (400 IU), or placebo. Fasting blood samplings were collected six times for analyses of serum (S-)25(OH)D, iPTH, bone-specific alkaline phosphatase (BALP), and TRACP. Radial volumetric BMD (vBMD) was measured at the beginning and end of the study with pQCT. Wintertime variation was noted in S-25(OH)D, S-PTH, and S-TRACP (p < 0.001, p = 0.012, and p < 0.05, respectively) but not in S-BALP or vBMD in the placebo group. Supplementation inhibited the winter elevation of PTH (p = 0.035), decreased the S-BALP concentration (p < 0.05), but benefited cortical BMD (p = 0.09) only slightly. Healthy men are exposed to wintertime decrease in vitamin D status that impacts PTH concentration. Vitamin D supplementation improved vitamin D status and inhibited the winter elevation of PTH and also decreased BALP concentration. The ratio of TRACP to BALP shows the coupling of bone remodeling in a robust way. A stable ratio was observed among those retaining a stable PTH throughout the study. A daily intake of vitamin D in the range of 17.5-20 microg (700-800 IU) seems to be required to prevent winter seasonal increases in PTH and maintain stable bone turnover in young, healthy white men.

OBJECTIVE

The pathogenesis of sporadic idiopathic hypoparathyroidism is unclear. The calcium sensing receptor (CaSR) plays a pivotal role in extracellular calcium homeostasis and is the candidate autoantigen in hypoparathyroidism associated with autoimmune polyglandular endocrinopathy syndrome. We therefore looked for antibodies (Ab) against the CaSR in patients with sporadic idiopathic hypoparathyroidism and their association, if any, with the major histocompatibility complex (MHC) class II human leukocyte antigen (HLA)-DR haplotypes.

METHODS

The subjects included 51 patients with sporadic idiopathic hypoparathyroidism and 45 healthy controls. Investigations included computerised tomography, serum calcium, phosphorus, thyroxine, TSH, cortisol, intact parathyroid hormone (iPTH), ACTH and thyroid peroxidase (TPO) and adrenal antibodies. The CaSRAb were assayed in patients' sera by Western blot. Genotyping of the HLA-DR locus was performed using PCR and sequence-specific oligonucleotide probes.

RESULTS

Intracranial calcification and cataract were present in 76.5% and 41.1% of the patients respectively and 62.7% had convulsions. Autoantibodies against the 168 kDa CaSR protein were demonstrated in the serum of 49.0% of the patients and in 13.3% of the controls (P<0.001). Pre-incubating serum samples from the CaSRAb-positive patients with parathyroid membrane produced a 90% decrease in the band intensity. HLA-DRB1*01 and DRB1*09 alleles were significantly associated with idiopathic hypoparathyroidism (relative risk of 7.8, P=0.001). The frequency of HLA-DRB1*09 and DRB1*10 alleles tended to be higher in patients positive for the CaSRAb. There was no significant difference in the frequency of occurrence of convulsions, cataract, intracranial calcification, calcium:phosphorus ratio, and iPTH levels between patients with and without CaSRAb.

CONCLUSIONS

49.0% of the patients studied had serological evidence of organ-specific autoimmunity against the CaSR protein. The occurrence of CaSRAb and the HLA-DR associations imply an autoimmune component to the disease, but the primary role of the CaSRAb in the pathogenesis of the disease needs to be assessed further.

Osteoprotegerin (OPG) has a profound inhibitory effect on osteoclast differentiation and bone resorption. Because high-turnover renal osteodystrophy (ROD) is characterized by increased osteoclast activity, serum OPG concentrations might be used to distinguish between forms of ROD. Twenty-six patients on maintenance hemodialysis therapy underwent a transiliac crest biopsy for evaluation of histopathologic characteristics and histomorphometric studies. ROD was diagnosed as type II (normal or low turnover) or type III (high turnover plus osteoidosis) disease. Bone mineralization density distribution (BMDD) was characterized by measuring the mean trabecular calcium concentration in the biopsy specimen with quantitative backscattered electron imaging. Patients underwent additional dual-energy x-ray absorptiometry (DEXA) of the spine and hip and measurement of such biochemical markers of bone turnover as OPG, intact parathyroid hormone (iPTH), osteocalcin, calcitonin, bone alkaline phosphatase, and cross-laps. OPG levels were significantly reduced in patients with ROD III compared with ROD II (118 +/- 38 versus 204 +/- 130 pg/mL; P < 0.05) and correlated with BMDD (r = 0.43; P < 0.05). Patients with ROD III showed significantly lower BMDD compared with healthy controls (21.42% +/- 0.12% versus 22.17% +/- 0.81% weight; P < 0.01). Besides iPTH, which showed significantly greater levels in patients with ROD III than ROD II (382 +/- 322 versus 136 +/- 156 pg/mL; P < 0.05), none of the serological markers or DEXA was useful in separation of the groups. Discriminant function analysis showed that a combination of OPG and iPTH correctly classifies ROD II in 72% and ROD III in 88% of patients. We conclude that OPG in combination with iPTH can be used as a marker for noninvasive diagnosis of ROD in hemodialysis patients. Furthermore, OPG serum levels might be used to estimate trabecular bone mineralization in these subjects.

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P: < 0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (<600, 600 to 1,200, and >1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P: < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

Previous studies often report lower responses to erythropoietin (EPO) therapy in pediatric patients on chronic dialysis than those of adults. Because of the greater capacity for hematopoiesis in the younger population, these studies may be confounded by poorly identified variables. Thus, we made parallel studies of pediatric and adult cohorts to explore the relationship between age, gender and other risk factors with EPO resistance. Thirty pediatric subjects (aged 8-20 years) and 66 adult subjects (aged 22-85 years) on chronic hemodialysis and EPO were enrolled. After stratification by 50th percentile of EPO response, the best predictive model was identified by backward elimination of the risk factors with the least contribution to the regression. Relationship between age, gender and EPO resistance was examined by analysis of covariance (ANCOVA). The most predictive model of EPO response for the pediatric cohort had, as the major variables, urea clearance x dialysis duration/total body water (Kt/V), urea reduction ratio (URR), intact parathyroid hormone (iPTH), blood loss, normalized protein catabolic rates (nPCR) and indices of malnutrition and inflammation, whereas adults had iron and folate deficiencies as the dominant variables. Although EPO resistance was more common in female subjects than in male subjects, relationship with neither age nor gender was significant. Furthermore, the prescription of a larger (initiating) EPO dose by pediatric physicians compared with adult nephrologists confounded the interaction between age and EPO resistance. In summary EPO resistance in the pediatric dialysis cohort was predicted by nutritional deficits, inflammation, poor dialysis, and hyperparathyroidism, while iron and folate deficits were the major determinants in adults. Although confounded by the pattern of EPO prescription, neither age nor gender was predictive of EPO resistance in the two study groups.

BACKGROUND

The geographical difference in presentation of primary hyperparathyroidism (PHPT) is known. However, there is sparse literature on the influence of age and gender on presentation of PHPT.

OBJECTIVE

To analyze the effect of age and gender on presentation of symptomatic primary hyperparathyroidism.

METHODS

This is a retrospective analysis of data from the primary hyperparathyroidism registry of a north Indian tertiary care teaching institute.

METHODS

Analysis of 184 histopathologically proven PHPT patients registered between March 1990 and March 2010 from a single centre of north India. PHPT patients were divided into three different age groups i.e. children and adolescents less than 25 years, adults 25-49 years, and ≥ 50 years. Clinical presentations, biochemical parameters and parathyroid weight were compared between different age groups and gender using appropriate statistical methods.

RESULTS

Mean age of patients was 38.5±13.8 years with female: male ratio of 7:3. Rickets as presenting manifestations were seen in one child and adolescent each. Prevalence of renal stones (P=0.03) and gall stones (P=0.02) was higher in the adult groups compared to the younger and older. There was no difference in bone pain (P=0.7), fracture (P=0.3), osteitis fibrosa cystica (P=0.2), fatigue (P=0.6) and other symptoms among different age groups. There was no difference in serum calcium, phosphate, parathyroid hormone (PTH) and 25 (OH) D levels among different age groups, however, as expected alkaline phosphatase was higher in adolescents compared to adults (P=0.03). Bone pain and muscle aches (P<0.001), fracture (P=0.04), osteitis fibrosa cystica (P=0.01), and gall stones (P=0.03) were more common among women while renal stones (P=0.05) and pancreatitis (P=0.02) were common in men. Serum calcium and phosphate levels were similar in either sex but parathyroid hormone (iPTH) level was higher among women (P=0.02). Parathyroid adenoma weight was higher in older compared to young but did not reach to a level of statistical significance.

CONCLUSIONS

Age and gender have substantial influence on presentation of PHPT. Bone pain and rickets were common in children and adolescents while renal stones in adults. Women have more severe disease as musculoskeletal manifestations are common and iPTH levels are also higher compared to men.