Serum Calcitriol Concentrations Research Articles

Effects of calcitriol and alfacalcidol on an osteoporosis model in rats with hepatic failure

To predict the potential utility of calcitriol in human osteoporosis with hepatic dysfunction, we examined the effects of calcitriol and alfacalcidol in ovariectomized (OVX) aged-rats with CCl4-induced hepatic failure. In OVX+CCl4 rats, GOT, GTP, alkaline phosphatase and total bilirubin increased and hepatic enzyme activity (cytochrome b5 and P450) decreased. Repeated oral doses of calcitriol (0.1 and 0.2 microgram/kg) for 51 days inhibited a decrease in serum calcium concentration. This effect was more potent than that of alfacalcidol at the same dose. Both drugs tended to inhibit a decrease in femoral calcium contents. Calcitriol (0.2 microgram/kg) prevented a decrease in femoral bone density (dry and ash weight per volume), unlike alfacalcidol. Soft X-ray imaging analysis revealed that both drugs tended to inhibit the decrease in femoral bone density. There were no differences in the femoral bone strength between OVX+CCl4 and sham-operated rats. The serum calcitriol concentrations increased after the last doses of calcitriol, while they did not increase after the last dose of alfacalcidol. All these effects of calcitriol were related to the serum calcitriol levels. These results suggest that calcitriol, unlike alfacalcidol, may have a clinical therapeutic effect in osteoporosis with hepatic dysfunction.

Calcitriol and bone mass accumulation in females during puberty.

Adolescence is characterized by rapid skeletal development and high demands for bone minerals. Though the stimulative effect of calcitriol on intestinal calcium and phosphorus absorption is well understood, its effect on bone development is not completely clear. It may be directly involved in the facilitation of calcium economy during this critical phase of skeletal development. Therefore, we evaluated the serum concentrations of calcitriol in relation to skeletal development in a cross-sectional study of 178 healthy Caucasian females during different pubertal stages, extending from childhood to young adulthood. In addition, a subsample of 57 younger girls was followed for a 1-year period to evaluate the association among serum calcitriol, nutrition parameters (dietary calcium, phosphorus, and vitamin D), bone mass accumulation, and biochemical markers of bone turnover. The serum calcitriol concentration in a cross-sectional sample was the highest during pubertal growth spurt (sexual maturity index 3-4, age 11-13 years) (ANOVA; F = 2.4945; P = 0.0329). This correlated to the peak skeletal calcium accretion (g/year) and bone mass accumulation in total body and forearm. In a longitudinal sample, there was a positive association between annual change in TBBMC (P = 0.0255); TBBMD (P = 0.0168); proximal radius (1/3 distance from styloid process) BMC (P = 0.0096); BMD (P = 0.0541), and baseline calcitriol level in forward stepwise regression analyses. The results of the forward stepwise regression analyses with serum calcitriol as a dependent variable and different serum, urinary, and dietary parameters measured at baseline (age 11 years, n = 114) and after 1 year (age 12 years, n = 57) showed that osteocalcin was positively associated with calcitriol in both years; more so in a second year (P = 0.0514, P < 0.001, respectively). Dietary vitamin D and phosphorus showed negative association with serum calcitriol at age 11, and dietary Ca and P were selected at age 12. The results of this study show that calcitriol is a significant correlate of bone mass accumulation during pubertal growth, presumably in response to the high requirements for calcium during this critical phase of skeletal development.

Regulation of serum calcitriol by serum ionized calcium in rats during pregnancy and lactation.

Serum calcitriol concentrations in rats follow a biphasic pattern during reproduction, with elevated levels during late pregnancy, a decline after parturition, and a rise to even higher levels during peak lactation. We have previously shown that serum calcitriol in rats at peak lactation correlates significantly with, and appears to be regulated by, serum ionized Ca (Ca2+), with parathyroid hormone (PTH) serving a permissive role. We have extended this study by determining if serum calcitriol also correlates with serum Ca2+ during late pregnancy, when calcitriol levels are clearly elevated, and during early lactation, when only modest increases in serum calcitriol are observed. Analyses of data combined from nonmated, 21-day pregnant (P), and 1-day lactating rats (L) revealed a significant regression (p < 0.001) of calcitriol on Ca2+, but a nonsignificant regression (p = 0.34) of calcitriol on serum PTH. An even stronger correlation (p < 0.001) between calcitriol and Ca2+ was found for the combined data for 5-, 8-, and 14-day L rats. The partial correlation coefficient for calcitriol versus Ca2+, with PTH as the independent variable, was highly significant (p < 0.01) for the data from both combined groups. However, the coefficient for calcitriol versus PTH, with Ca2+ as the independent variable, was not significant (p > 0.05). Fetal weights (uterus and contents) correlated significantly with both maternal calcitriol and Ca2+ concentrations (p < 0.01), but not with maternal PTH levels. Litter weights for 14-day-old pups likewise correlated significantly with maternal calcitriol and Ca2+ (p < 0.001). We conclude that hypocalcemia, induced by the demands for Ca for fetal calcification and milk production, appears to be a controlling factor in serum calcitriol elevation in late pregnancy and throughout lactation, whereas PTH may be important for calcitriol synthesis without playing a direct regulatory role.

Relations between calcium intake, calcitriol, polymorphisms of the vitamin D receptor gene, and calcium absorption in premenopausal women

The relations between calcium absorption, dietary calcium intake, 1,25-dihydroxyvitamin D3 (calcitriol), and vitamin D receptor (VDR) gene polymorphisms were evaluated in 99 healthy women who were approaching menopause (mean age: 47 y, range: 43-53 y). Dietary calcium was assessed by food-frequency questionnaire and calcium absorption was measured by a single-isotope radiocalcium test. VDR alleles were classified according to the presence (b, t, a) or absence (B, T, A) of the BsmI, TaqI, and ApaI restriction enzyme cutting sites. Radiocalcium absorption was positively related to serum calcitriol (r = 0.23, P < 0.05) and inversely related to dietary calcium intake (r = -0.26, P < 0.01). There was, however, no significant relation (r = 0.10) between serum calcitriol concentrations and dietary calcium. Radiocalcium absorption was higher in the bbaaTT haplotype (P < 0.05) and the aa genotype (P < 0.05), polymorphisms said to be associated with a higher bone density. We conclude that serum calcitriol and dietary calcium are independent determinants of calcium absorption in premenopausal women and that VDR gene polymorphisms influence calcium absorption.

Measurement of vitamin D and its metabolites (calcidiol and calcitriol) and their clinical significance

The serum concentration of vitamin D will only give information about the recent exposure to either nutritional vitamin D or to recent vitamin D production in the skin. Within hours vitamin D is removed from the circulation and reappears again a few hours later as 25(OH)D. Measurements of vitamin D therefore are not useful to judge the vitamin D status of man. Plasma concentrations of 25-hydroxyvitamin D (25(OH)D) are the best markers of imminent or existing vitamin D deficiency. Suboptimal vitamin D supply (or 25(OH)D plasma concentrations) are observed in most European countries and North America from November to April. Vitamin D substitution is recommended to persons with a serum concentration of 25(OH)D below 50 nmol/L (20 üg/L). Plasma concentrations of 1,25(OH)2D3 (calcitriol) depend mainly on renal function, concentrations of intact PTH and the supply of the organism with calcium and phosphate. High PTH, low calcium and low phosphate supply are the main stimulators of the production of calcitriol. Vitamin D substitution, or if necessary, therapy with active vitamin D metabolites or analogs, e.g. calcitriol or alfacalcidol, are often necessary in hypercalcemic persons with low serum concentrations of calcitriol, e.g. in patients with renal failure. Disorders with low or high vitamin D metabolite concentrations in serum are described in this paper.

Serum calcidiol and calcitriol concentrations in elderly people: variations with age, sex, season and disease

The influence of age, sex, seasonal variations and vitamin D supplementation on serum concentrations (s-conc.) of calcidiol and calcitriol were studied in 311 hospitalized and 106 home-living people aged 70 years and over, residing at 60° latitude. The serum calcidiol conc. (meanSD, nmol/L) was reduced in the hospital group compared to the home-living group (males: 40.6 ± 23.2 compared to 59.6 ± 28.9; females: 37.3 ± 22.6 compared to 48.5 ± 20.3) and showed no seasonal variation. The homeliving group showed highest levels in August-September (62.2 ± 26), and lowest levels in January–March (42.9 ± 21). Serum calcidiol declined with age, most prominent in the home group (males: r = −0.13, P = 0.036;females: r = −0.33, P = 0.001). A positive correlation was shown between s-calcitriol and s-calcidiol conc. ( r = 0.26, P > 0.001). An increased s-conc. of calcidol was present in those with vitamin supplementation (home: 59.9 ± 26; hospital: 43.4 ± 22) compared to those without supplementation (home: 46.6 ± 22; hospital: 36.2 ± 22), but s-calcidiol conc. did not correlate to nutritional vitamin D intake. Vitamin D deficiency (s-calcidiol conc. < 30 nmol/L) was more common in old people recently admitted to hospital, compared to those living at home. Only the home-living group had the benefit of sunlight exposure, but both groups may benefit from vitamin supplementation.

Bone Density and Mineral Metabolism in Thyroidectomized Patients Treated with Long-Term l-Thyroxine

1. A decreased bone mass has been reported in patients with endogenous hyperthyroidism, but the effect on bone density and mineral metabolism of thyroxine administration in thyroidectomized patients is still controversial. To further contribute to this debate, we studied 25 women thyroidectomized for thyroid cancer on long-term treatment with thyroid-stimulating hormone-suppressive doses of L-thyroxine. Twenty-one sex- and age-matched normal subjects were also studied as a control group. 2. The bone density of the spine and serum calcitonin, calcitriol and parathyroid hormone concentrations were not different when the whole patient group was compared with the control subjects, nor when the patients and control subjects were compared according to their menopausal status. However, post-menopausal thyroidectomized patients showed significantly lower bone mass (P < 0.001) than premenopausal patients. 3. L-Thyroxine-treated patients showed significantly higher levels of bone alkaline phosphatase and urine hydroxyproline excretion than control subjects (P < 0.003 and P < 0.001, respectively). These differences were still present when patients and control subjects were analysed according to their menopausal status. However, bone alkaline phosphatase was significantly higher in postmenopausal than in premenopausal women only in L-thyroxine-treated patients (P < 0.05). In postmenopausal L-thyroxine-treated patients a negative correlation between time since menopause and bone mass (P < 0.05) and a positive correlation between bone alkaline phosphatase and hydroxyproline excretion (P < 0.03) were also found.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium Kinetics in the Hyperprostaglandin E Syndrome

Metabolic investigations, including the use of stable isotopes of calcium, were used to study calcium kinetics in three children with the hyperprostaglandin E syndrome. The studies were performed both during indomethacin treatment and in the absence of therapy. Off therapy, each child had hypercalciuria (mean urinary calcium excretion 0.478 mM/kg/d), hyperprostaglandinuria, and elevated serum calcitriol concentration. All had diminished bone density and were euparathyroid. Indomethacin treatment was associated with a marked reduction in serum calcitriol concentration, as well as decreased prostaglandin E excretion. Mean urinary calcium excretion fell to 0.135 mM/kg/d. The stable isotope studies defined two components to the hypercalciuria of this disease: an indomethacin-sensitive dietary contribution and a relatively indomethacin-resistant bone resorptive element. Bone densitometry confirmed the presence of the resorptive element by demonstrating skeletal demineralization.

Prophylactic Efficacy and Bone Toxicity Associated with Phosphonoformate Therapy against Retrovirus Infection

Phosphonoformate (PFA) is a simple pyrophosphate analogue which is a topical and parenteral treatment for human herpes virus infections and is currently undergoing evaluation for treatment of human immunodeficiency virus (HIV) and cytomegalovirus infections associated with (AIDS). In this study, antiretroviral activity of PFA was demonstrated by two separate treatment regimens. In the first, an inoculum of feline leukaemia virus (FeLV) in plasma from viraemic cats was treated with 1024 μM PFA prior to intravenous inoculation into susceptible animals. Three of four cats given the PFA treated inoculum were protected from viraemia by the PFA treatment, while 2 of 2 challenge controls receiving sham treated inoculum and 6 of 6 untreated challenge controls became viraemic. In the second regimen, a long-term continuous intravenous infusion of PFA (1000 mg kg−1day−1) was administered to 6 young cats beginning 1–2 days prior to and extending 4 weeks following intravenous inoculation with FeLV. Five of the six PFA-treated cats also received heparin intravenously and acetyl salicylic acid (aspirin) orally to reduce risk of thrombosis. Six cats (heparin controls) received only heparin and aspirin and were inoculated with FeLV in an identical manner. Six cats served as untreated challenge controls. Four of 6 PFA-treated cats were protected from FeLV antigenaemia. In contrast, all 6 heparin-control animals and all 6 challenge-control animals became persistently viraemic as evidenced by continuous expression of FeLV p27 antigen. All challenged cats including the 4 protected by PFA treatment developed antibody to FeLV, indicating that PFA did not prevent primary virus infection. Significant toxic effects of PFA treatment were reduced weight-gain and rickets-like bone lesions in the cats receiving the 4 week treatment. Additionally, decreased serum alkaline phosphatase, phosphorus, and calcitriol concentrations, presumably related to the bone lesions, were observed. Results of this study suggest that the antiviral effect of PFA involves an immediate and direct mechanism targeted at cell-free virus and that long-term continuous intravenous infusion of PFA has significant anti-retroviral activity in vivo.

Effects of conjugated estrogen on the calcitriol response to parathyroid hormone in postmenopausal women.

We evaluated the effects of estrogen on the calcitriol response to the active peptide, human PTH(1-34), in postmenopausal women. Fifteen women were studied before and again after at least 1 month of treatment with conjugated equine estrogens, 1.25 mg/day. Six women received two series of four graded peptide infusions, each with the sequence 200, 400, 800, and 1600 USP U hPTH(1-34). Nine women received only one dose of peptide, either 200 or 800 U, before and while taking estrogen. Baseline values and the incremental and percent changes in circulating calcitriol 24 h after the 20-min infusions were evaluated. Estrogen treatment resulted in significant reductions in blood levels of calcium (2.26 +/- 0.03 mmol/L vs. 2.16 +/- 0.02, P less than 0.05) and phosphorus (1.23 +/- .05 mmol/L vs. 1.14 +/- 0.03, P less than 0.005), a rise in serum calcitriol concentrations (42.2 +/- 3.9 pg/mL vs. 28.6 +/- 3.1, P less than 0.005), and no change in circulating PTH. The rise in calcitriol after 200 U hPTH(1-34) was significantly greater on estrogen (17.6 +/- 2.0 pg/mL vs. 9.5 +/- 1.8, P less than 0.01), but estrogen did not alter incremental responses to larger doses. When results were normalized for differences in baseline values, the estrogen-related change in response to 200 U was no longer significant. hPTH(1-34) acutely increased urinary clearance of cAMP and phosphorus, but estrogen did not affect this response. We conclude that exogenous estrogen does not increase renal sensitivity to PTH in postmenopausal women.

Serum concentrations of calcitriol and PTH in hemo-dialysis patients on treatment with calcium carbonate.

The effects of calcium carbonate and aluminium hydroxide as phosphate binders were investigated in nine patients on chronic hemodialysis. Aluminium hydroxide, 1 g X 3, was given during four weeks followed by a period of four weeks without any phosphate binders and after this calcium carbonate, 2.5 g X 3, was introduced for four weeks. Calcium carbonate resulted in lowering of bioactive PTH in serum from 22.4 to 16.4 pM and a rise of serum calcitriol from 8.0 to 11.5 pg/ml with maintained control of phosphate and without significant difference in the calcium-phosphate product. Calcium in serum rose from 2.27 to 2.57 mM and mild hypercalcemia (less than 3.0 mM) in five of the patients could be controlled by dose reduction of calcium carbonate without losing control of serum phosphate levels. We conclude that calcium carbonate offers advantages as a phosphate binder compared to aluminium hydroxide in that it offers equal control of serum phosphate and elevates serum calcium which helps to control the hyperparathyroidism secondary to uremia.

Rapid Loss of Vertebral Mineral Density after Renal Transplantation

Osteopenia is a major complication of renal transplantation. Immunosuppressive regimens including cyclosporine, which permit the use of lower doses of glucocorticoids, may reduce glucocorticoid-induced osteopenia. We prospectively studied the magnitude, distribution, and mechanism of bone loss in 20 adults who received renal allografts from living related donors, who had good renal function, and who were treated with azathioprine, cyclosporine, and low doses of prednisone. We measured serum biochemical markers of bone metabolism, determined the bone mineral density of the second, third, and fourth lumbar vertebrae and the shaft of the radius, and analyzed the histomorphometric features of iliac bone at the time of transplantation and six months later. Measurements of vertebral mineral density were repeated 18 months after transplantation in 17 of the patients. After transplantation, the mean serum concentrations of parathyroid hormone, phosphorus, and alkaline phosphatase decreased and the serum calcitriol concentration increased. The mean (+/- SD) bone mineral density of the vertebrae had decreased 6.8 +/- 5.6 percent 6 months after transplantation (P less than 0.05) and 8.8 +/- 7.0 percent 18 months after transplantation. In contrast, the bone mineral density of the radius had increased six months after transplantation (P less than 0.05). The histomorphometric studies showed that the rate of bone formation decreased from 50.5 +/- 44.8 to 23.1 +/- 13.8 microns3 per square micrometer per year (P less than 0.05), and the formation period lengthened from 70 +/- 42 to 146 +/- 144 days (P less than 0.05). Consequently, the amount of bone replaced during a remodeling cycle diminished. Osteopenia associated with renal transplantation remains a problem in the cyclosporine era. The loss of vertebral bone in our subjects was due to an imbalance in bone remodeling consistent with a toxic effect of glucocorticoids.

Calcium absorption in normal and osteoporotic postmenopausal women

Hourly fractional absorption of radiocalcium (alpha), serum calcitriol, and a number of other variables were measured in 152 normal and 148 osteoporotic postmenopausal women. Alpha, body weight, and serum albumin were all significantly lower in the osteoporotic than in the normal women, and plasma alkaline phosphatase, fasting urinary calcium, sodium, and hydroxyproline were all significantly higher in the osteoporotic than in the normal group. The most significant determinant of alpha in each group was the serum calcitriol concentration, but calcium absorption relative to serum calcitriol was significantly lower in the osteoporotic than in the normal women. The serum calcitriol level was slightly but not significantly lower in the osteoporotic than in the normal group and accounted for only 20% of the difference in alpha between them. The implied "resistance" to calcitriol in the osteoporotic group was significantly related to serum albumin and body weight but independent of age. Urinary hydroxyproline was an inverse function of alpha and a positive function of fasting urinary calcium in the osteoporotic group.

Pharmacokinetics of Calcitriol in Continuous Ambulatory and Cycling Peritoneal Dialysis Patients

Oral calcitriol is commonly used for the treatment of secondary hyperparathyroidism in patients undergoing long-term dialysis, but it has been suggested that intravenous (IV) or intraperitoneal (IP) administration enhances the therapeutic efficacy of the sterol. To examine potential mechanisms for this difference, the bioavailability of calcitriol was evaluated after single oral (PO), IV, and IP doses of 60 ng/kg in each of six adolescent patients with osteitis fibrosa undergoing continuous ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis (CCPD). Serum calcitriol levels were 3.6 +/- 4.3, 8.2 +/- 7.5, and 2.5 +/- 3.0 pg/mL, respectively, before IV, PO, and IP doses of the sterol; these values increased to similar levels at 24 hours: 55.6 +/- 14.6 pg/mL after PO, 56.4 +/- 17.6 pg/mL after IV, and 53.8 +/- 20.1 pg/mL after IP. Serum calcitriol levels were higher 1, 3, and 6 hours after IV injections than after PO or IP doses; values thereafter did not differ among groups. The bioavailability of calcitriol, determined from the 24-hour area under the curve (AUC0-24) for the increase in serum calcitriol concentration above baseline values was 50% to 60% greater after IV, 2,340 +/- 523 pg.mL-1.h-1, than after PO, 1,442 +/- 467 pg.mL-1.h-1, or IP, 1,562 +/- 477 pg.mL-1.h1, dosages, P less than 0.05. These differences were due to higher values for AUC during the first 6 hours after calcitriol administration. Although IP calcitriol did not increase sterol bioavailability, radioisotope tracer studies indicated that 35% to 40% of the hormone adheres to plastic components of the peritoneal dialysate delivery system.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis and Management of Bone Disorders in Chronic Renal Failure and Dialyzed Patients

Renal osteodystrophy is multifactorial. Decreased calcium absorption from the GI tract, secondary to low calcitriol levels; hyperphosphatemia; skeletal resistance to the action of parathormone; and aluminum deposition on the surface of the bones are its main pathogenetic mechanisms. Its biochemical features include abnormalities in serum calcium, phosphate, alkaline phosphatase, parathormone, calcitriol, and aluminum concentration. Radiographic methods are of little use in the characterization of the type of osteodystrophy present, but they may be of help in assessing mineral loss from the skeleton. Clinical manifestations are from bones (pain, deformities, fractures) or from metastatic calcifications. Bone biopsy is the definitive means of diagnosis. The main histologic types of osteodystrophy include osteitis fibrosa, osteomalacia, mixed form (with features of both osteitis fibrosa and osteomalacia), and aluminum osteodystrophy (presenting as either osteomalacia or aplastic lesion). The management of renal osteodystrophy should address all the pathogenetic mechanisms. Correction of the abnormalities in calcium and phosphate metabolism and prevention of aluminum osteodystrophy are the cardinal rules of management. Specific measures (parathyroidectomy, chelation of aluminum) have clear-cut indications and usually require a bone biopsy.

Dietary potassium influences kidney maintenance of serum phosphorus concentration

In studying the metabolic effects of diet potassium (K+) variation in normal humans, we noted that varying diet K+ within its normal range influenced inorganic phosphorus (Pi) homeostasis and serum calcitriol (1,25-dihydroxyvitamin D) levels. In six men who ingested a constant whole-foods diet containing (per 70 kg body wt) 27 mmol/day Pi and 52 mEq/day K+, we increased diet K+ to 156 mmol/day with supplements first of potassium bicarbonate (KHCO3) alone and then of potassium chloride (KCL) alone, each for eight days interrupted by an eight-day recovery period of no K+ supplement. Urine Pi decreased promptly with either K(+)-salt, each inducing a persisting retention of 7 to 10 mmoles Pi, which was dumped during recovery. Fasting serum [Pi] increased with either K+ supplement (P = 0.022, repeated measures analysis of variance); the composite mean serum [Pi] for the two K(+)-supplement periods exceeded that for the two periods without supplements (P less than 0.01, paired t-test). Conversely, the concentrations of serum calcitriol decreased with either K+ supplement (P = 0.020). Among subjects, the diet K(+)-induced increases in serum [Pi] correlated with those in plasma [K+] (r = 0.64, P = 0.027); the decreases in serum calcitriol concentration correlated with the increases in serum [Pi] (r = -0.69, P = 0.014). There were no significant differences among periods in serum parathyroid hormone, ionized calcium, urine cyclic AMP excretion, plasma renin activity, body weight, serum albumin, or creatinine clearance; plasma volume decreased slightly during KCL but not during KHCO3 periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin D metabolism in myeloma.

We measured serum concentrations of vitamin D metabolites in 27 patients with myeloma, 16 of whom were hypercalcaemic. Serum values were compared with values from normal controls. Serum concentrations of calcitriol (1.25-dihydroxyvitamin D; 1.25(OH)2D3) were decreased in both hyper- and normocalcaemic patients, but more markedly so in hypercalcaemia. These findings were not solely due to impaired renal function nor due to an inadequate supply of 25-hydroxyvitamin D, and in hypercalcaemic patients were reversed by diphosphonate treatment. We conclude that hypercalcaemia in myeloma is not mediated by abnormalities in vitamin D metabolism. Decreased serum concentrations of 1.25(OH)2D3 may adversely affect both skeletal and tumour metabolism.

Calcitriol deficiency with retained synthetic reserve in chronic renal failure

Serum calcitriol and the free calcitriol index together with factors considered to regulate calcitriol production were measured in eleven patients with moderate chronic renal failure (MCRF) and eleven age- and sex-matched normal subjects. Although the serum dialysable calcium levels were similar in the two groups, there was depression of calcitriol levels and an elevation of PTH and nephrogenous cyclic AMP (NcAMP) levels in the MCRF patients. Furthermore, plasma phosphate levels were higher and the renal phosphate threshold was depressed in this patient group. When all subjects were grouped together calcitriol was positively correlated with GFR. When calcitriol levels were factored for GFR, to permit an assessment of calcitriol production per unit functioning renal mass, there was no significant difference between normal and MCRF subjects. To determine whether reserve for calcitriol production existed, six of the MCRF patients and six of the age- and sex-matched normal subjects received a low calcium diet for one week supplemented by cellulose phosphate to bind calcium within the gut. In both groups there was a significant rise in calcitriol, although the absolute levels were much lower in the MCRF patients than the normal subjects. These results suggest that calcitriol deficiency is a major feature of MCRF despite marked hyperparathyroidism. The rise in calcitriol levels in MCRF suggests persistent reserve secretory capacity in this condition. Therefore, the low serum calcitriol concentration may be due not only to structural renal damage, but also to suppression of calcitriol formation perhaps due to altered renal phosphate handling.

Bone and Mineral Metabolism and Chronic Alcohol Abuse

Studies of bone and mineral metabolism were made in 22 patients with chronic alcohol abuse and varying degrees of liver damage. None of the patients had clinical evidence of metabolic bone disease, but quantitative bone histology showed that six had osteoporosis, three osteomalacia, and two osteoporosis and osteomalacia combined. Trabecular bone volume (TBV) tended to be reduced in relation to age, and there was histological evidence of reduced bone formation particularly among the patients with osteoporosis. Multivariate analysis of the relevant variables showed that the major determinants of age-adjusted trabecular bone volume were the serum concentration of albumin and the dietary calcium. The presence of osteoporosis was related to the state of liver function and the type of alcohol habitually consumed, and was a particular feature of patients with severe liver disease and those who only drank spirits. Six patients (five with osteoporosis) had biochemical evidence of hyperparathyroidism, but none showed histological evidence of increased bone resorption or of osteitis fibrosa. In four patients the development of hyperparathyroidism was probably related to underlying magnesium deficiency. Serum calcidiol tended to be reduced and was directly related to the state of liver function; four patients had reduced or low normal serum concentrations of calcitriol. In only three patients could the development of osteomalacia be related to vitamin D deficiency; in two patients the cause of the osteomalacia was obscure. Significant changes in bone structure and mass appear to be common among heavy drinkers even in the absence of clinical metabolic bone disease. These skeletal abnormalities are likely to be relevant to the increased fracture risk associated with heavy drinking.

Families of Children With Idiopathic Hypercalciuria: Evidence for the Hormonal Basis of Familial Hypercalciuria

• Six children with idiopathic hypercalciuria and their families were examined with an oral calcium loading test. Family members were divided into two clinical categories: group 1 consisted of the six index children and their parents and siblings with urolithiasis or unexplained hematuria; group 2 comprised the remaining parents and siblings without signs or symptoms associated with hypercalciuria. The results revealed that fasting urinary excretion of calcium was similar in both groups, but group 1 displayed a greater calciuric response to an oral calcium load. Serum concentrations of calcitriol (1,25-dihydroxyvitamin D 3 ) and calcium were higher in group 1 than in group 2, while parathyroid activity was lower in group 1 patients. Urinary excretion of sodium, phosphorus, and magnesium, urine pH, serum levels of calcifediol (25-hydroxyvitamin D 3 ) and phosphorus, and the renal tubular threshold for phosphate were not significantly different in the two groups. These findings suggest that idiopathic hypercalciuria may arise from a disturbance in the regulation of vitamin D metabolism that mediates enhanced intestinal absorption of calcium. ( AJDC 1985;139:621-624)