Reduced binding of [3H]1,25-dihydroxyvitamin D3 in the parathyroid glands of patients with renal failure

This study examined the hypothesis that altered binding of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) to parathyroid receptors might be involved in the pathogenesis of secondary hyperparathyroidism associated with chronic renal failure. The binding of [3H]1,25-(OH)2D3 to hyperplastic parathyroid glands obtained from seven patients with chronic renal failure was measured. These values were compared with those for binding to hyperplastic parathyroid tissue obtained from six patients who had received renal transplants and for binding to parathyroid adenomas removed from five patients who had primary hyperparathyroidism. We found that Nmax (an estimate of the concentration of 1,25-(OH)2D3 receptors) was reduced (42 +/- 15 fmol per milligram of protein) in patients with chronic renal failure as compared with patients with transplanted kidneys (78 +/- 24 fmol per milligram of protein) and patients with primary hyperparathyroidism (114 +/- 30). Nmax correlated inversely with the severity of renal dysfunction, the serum level of phosphorus, and the logarithm of the serum level of immunoreactive parathyroid hormone. These observations suggest that 1,25-(OH)2D3 binding by parathyroid tissue is reduced in chronic renal failure. This may contribute to the pathogenesis of secondary hyperparathyroidism by reducing the inhibition by 1,25-(OH)2D of parathyroid hormone secretion. The low serum levels of 1,25-(OH)2D in chronic renal failure may accentuate this effect.     

Effect of sunlight exposure on circulating 1,25-dihydroxyvitamin D in hemodialyzed patients and of exogenous parathyroid hormone in anephric patients

Sunshine exposure increased the serum concentration of 25-hydroxyvitamin D (25-OHD) in 9 hemodialyzed patients. Mean 1,25-dihydroxyvitamin D (1,25-(OH)2D) was unchanged, but in two patients with low initial 25-OHD values this increase was accompanied by a rise in circulating 1,25-(OH)2D, although not to normal levels. One hemodialyzed patient developed liver insufficiency with a resultant reduction of serum 25-OHD concentration accompanied by a decrease in serum 1,25-(OH)2D concentration. The results indicate that the circulating levels of 1,25-(OH)2D in patients with end-stage renal failure are to some extent regulated by the serum 25-OHD concentrations. Injection of parathyroid hormone (PTH) induced minor increases in serum concentrations of 1,25-(OH)2D in patients with end-stage renal failure and even in anephric patients, suggesting the existence of an extrarenal PTH-sensitive 1-alpha-hydroxylase. However, the enzyme was stimulated by supraphysiological concentrations of PTH, and therefore not necessarily of importance in the normal regulation of calcium metabolism.     

Effects of metabolic acidosis on PTH and 1,25(OH)2D3 response to low calcium diet

To study the effects of chronic metabolic acidosis on the metabolism of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] rats were given either a low calcium diet (LCD) (0.002% calcium) or chow (1.2% calcium); ammonium chloride (NH4Cl) was added (1 or 1.5%) to the drinking water of some rats eating LCD or chow while others served as nonacidotic controls. LCD increased circulating 1,25(OH)2D3 levels from 46 +/- 14 to 204 +/- 24 pg/ml (P less than 0.001) in the absence of NH4Cl; 1.5% NH4Cl prevented the increase in 1,25(OH)2D3 (25 +/- 6 vs. 27 +/- 8 pg/ml (P, NS) but 1% NH4Cl did not (50 +/- 12 vs. 161 +/- 23 pg/ml; P less than 0.001). Acidosis suppressed neither serum immunoreactive parathyroid hormone (PTH) nor urine cAMP response to LCD. Although total serum calcium and phosphorus showed no regular changes with NH4Cl, acidosis raised blood ionized calcium in rats fed either chow or LCD, and serum 1,25(OH)2D3 levels were inversely correlated with ionized calcium (r = 0.714; P less than 0.001) during LCD. Chronic NH4Cl acidosis prevented serum 1,25(OH)2D3 from rising during LCD, independent of changes in PTH secretion, cAMP generation, or serum phosphorus. The absence of a 1,25(OH)2D3 response may be due to increased ionized calcium produced by acidosis.     

Parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentration in elderly patients

Summary In 50 patients of a geriatric hospital (33 women, aged 65–96 years, mean age 80 years, and 17 men, aged 68–91, mean age 78.3 years) calcium, albumin, phosphate, urea, creatinine, parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were determined. Forty patients with serum creatinine levels up to 1.4 mg/dl (124 mol/l) and 10 patients with creatinine concentrations 1.5 mg/dl (132mol/l) were evaluated. In patients with normal creatinine, a positive correlation was found between parathyroid hormone and age (r=0.41;P<0.01). In patients with elevated creatinine, negative correlations were found in 1,25-dihydroxyvitamin D and calcium (r=–0.724;P<0.05), 1,25dihydroxyvitamin D and creatinine (r=–0.79;P<0.01) and 1,25-dihydroxyvitamin D and phosphate (r=–0.87;P< 0.002). The best correlation was observed in patients with elevated serum creatinine for 1,25-dihydroxyvitamin D and phosphate (r=–0.91;P< 0.001). The results suggest that low levels of calcium and phosphate stimulate the 1-hydroxylation of 25-hydroxyvitamin D even in advanced age and that the calcium metabolism of these patients is frequently disturbed. Nineteen patients had low levels of 25-hydroxyvitamin D, indicating an insufficient supply of vitamin D or rare exposure to sunlight. In 49 of 50 patients, one ore more of the parameters of calcium metabolism were outside the normal range.Abbreviations 25-OH-D 25-hydroxyvitamin D - 1,25(OH)₂D 1,25-dihydroxyvitamin D - PTH parathyroid hormone Supported by the Deutsche Forschungsgemeinschaft (Schm 405–407)     

Vitamin D deficiency and low osteocalcin concentrations in anorexia nervosa.

The calcium, vitamin D, and osteocalcin concentrations were investigated in 17 patients with anorexia nervosa. Serum 25-hydroxyvitamin D (25 OHD) concentrations below normal were observed in 15 (88%); only two patients has serum 1,25 dihydroxycholecalciferol (1,25(OH)2D) concentrations below normal. Serum parathyroid hormone (PTH) concentration was also normal in all except these two patients. Serum osteocalcin concentration was below normal in seven of 14 patients. Although a low concentration of serum 25 OHD is common in patients with anorexia nervosa in the United Kingdom, 1,25(OH)2D concentrations are usually normal. Hypovitaminosis D with secondary hyperparathyroidism is relatively uncommon. The subnormal osteocalcin concentrations observed in these patients probably reflect diminished osteoblastic activity, which may contribute to their osteopenia.     

Selective deficiency of 1,25-dihydroxycholecalciferol. A cause of isolated skeletal resistance to parathyroid hormone.

To investigate the role of vitamin D metabolites in the pathogenesis of pseudohypoparathyroidism, we studied an elderly man with a unique variant of the disease, which was characterized by hypocalcemia, elevated serum parathyroid hormone (513 +/- 13 pg per milliliter, mean +/- S.E.M., normal, less than 450) but normal renal responses (phosphate and cyclic AMP) to exogenous parathyroid extract. Treatment with parathyroid extract did not produce a calcemic effect, suggesting an isolated skeletal hyporesponsiveness to parathyroid hormone. Although 25-hydroxyvitamin D levels were not reduced, levels of 1,25-dihydroxycholecalciferol were extremely low (0.52 ng per deciliter; normal 3.3 +/- 0.06, S.D.). Treatment with 1,25-dihydroxycholecalciferol (1 microgram by mouth per day for four days) increased circulating levels to normal (4.60 ng per deciliter) and restored to normal the calcemic response to parathyroid (change in calcium 3.0 mg per deciliter). These data suggest that 1,25-dihydroxycholecalciferol deficiency may explain the skeletal resistance, but not the renal resistance, often present in classic pseudohypoparathyroidism.     

Abnormalities in parathyroid hormone secretion and 1,25-dihydroxyvitamin D3 formation in women with osteoporosis

We investigated the parathyroid hormone-1,25-dihydroxyvitamin D3 (1,25(OH)2D) axis in osteoporosis by administering phosphate to 8 postmenopausal women with osteoporosis (49 to 78 years old) and to 10 normal women matched for age (50 to 74 years). All subjects responded with a similar increase in the serum phosphorus concentration (women with osteoporosis, 1.15 +/- 0.06 to 1.79 +/- 0.09 mmol per liter; controls, 1.14 +/- 0.05 to 1.73 +/- 0.08 mmol per liter) and a fall in the ionized calcium concentration (women with osteoporosis, 1.12 +/- 0.03 to 1.06 +/- 0.03 mmol per liter; controls, 1.17 +/- 0.01 to 1.11 +/- 0.02 mmol per liter). Parathyroid hormone levels rose 2.5-fold in the control group (15.4 +/- 2.2 to 37.9 +/- 6.1 pg per milliliter) but increased by only 43 percent in the group with osteoporosis (14.8 +/- 2.8 to 21.2 +/- 4.1 pg per milliliter), an increase similar to that previously reported in young normal subjects (53 percent). In healthy older and younger subjects, the levels of 1,25(OH)2D did not change; in the subjects with osteoporosis, however, they decreased significantly (50 percent). We conclude that older women require a greater parathyroid hormone stimulus than younger women to maintain vitamin D homeostasis, because of an age-related decline in the formation of 1,25(OH)2D in response to parathyroid hormone, and that in osteoporosis the age-appropriate parathyroid hormone response to the same hypocalcemic signal is diminished. Our results are consistent with the presence of an abnormality in parathyroid hormone secretory function in osteoporosis in addition to the universal decline in 1,25(OH)2D responsiveness associated with aging.     

Effects of 1,25-(OH)2D3 administered in vivo on phosphate uptake by isolated chick renal cells

Renal cells from Vitamin D-deficient and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-repleted chicks were isolated by a collagenase-hyaluronidase procedure. Exclusion of trypan blue and respiratory measurements indicate that the cells were functionally intact and metabolically active. The uptakes of phosphate and alpha-methylglucoside were stimulated markedly by Na+ in the extracellular medium. Phosphate uptake in the presence of Na+ was saturable with respect to phosphate concentration; half-maximal activity was obtained with approximately 0.2 mM. Three hours after 1,25-(OH)2D3 was injected into vitamin D-deficient chicks the Na+-dependent phosphate uptake by the isolated cells had increased about 40%, i.e., 2.00 compared with 1.44 nmol.min-1.mg protein-1. Phosphate uptake in the presence of K+ in the extracellular medium and alpha-methylglucoside uptake in the presence or absence of Na+ were unchanged. In a secondary response found 17 h after 1,25-(OH)2D3 injection, Na+-dependent phosphate uptake decreased. Serum concentrations of phosphorus and calcium were not measurably changed in the 3-h repleted bird, but both levels were increased 17 h after treatment. Administration of phosphate into vitamin D-deficient chicks, so that the serum concentration of phosphorus was raised to that of the 17-h 1,25-(OH)2D3 repleted animal, effected a comparable decrease in phosphate uptake. Serum calcium levels were not altered by this treatment. The actions of parathyroid hormone in stimulating adenylate cyclase and in inhibiting phosphate uptake were notably blunted in the vitamin D-deficient chick. Sensitivity to parathyroid hormone was not restored until several days after 1,25-(OH)2D3 repletion. These findings suggest that the initial response to 1,25-(OH)2D3, to increase renal phosphate uptake, and the secondary response, to decrease phosphate uptake, were by parathyroid hormone-independent processes. The results also indicate that the isolated renal cell represents an excellent model for studying the mechanism by which 1,25-(OH)2D3 regulates phosphate transport in the kidney.     

Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women

Vitamin D intake should be sufficient to maintain calcium absorption and prevent increased parathyroid secretion throughout the year. To determine the level of intake that achieved the latter in elderly women, we studied the interrelations among vitamin D intake, serum 25-hydroxyvitamin D (25(OH)D) levels, and parathyroid hormone concentrations in a cross-sectional study of 333 healthy, white, postmenopausal women with low median calcium (408 mg a day) and vitamin D (112 IU a day) intakes who lived in Massachusetts. The overall inverse relation between serum parathyroid hormone and 25(OH)D levels was found to be dependent on vitamin D intake. In women whose estimated intake of vitamin D was less than or equal to 220 IU a day, the mean (+/- SD) serum parathyroid hormone values were lowest in those studied between August and October (30 +/- 11 ng per liter; n = 72) and highest in those studied between March and May (37 +/- 16 ng per liter; n = 54); the respective serum 25(OH)D levels were 93 +/- 32 and 63 +/- 21 nmol per liter. At vitamin D intakes of more than 220 IU a day, the mean serum parathyroid hormone and 25(OH)D levels did not vary with the season. The correlation between vitamin D intake and serum 25(OH)D concentration, although significant in all women (r = 0.29; P less than 0.001), was highest in those studied between March and May (r = 0.65; P less than 0.001) and lowest in those studied between August and October (r = 0.13; P greater than 0.10). The estimated serum 25(OH)D level associated with a vitamin D intake of 220 IU a day between March and May was 95 nmol per liter. Mean serum calcium values were similar at all times in both groups. We conclude that the dietary intake of more than 220 IU of vitamin D a day by postmenopausal women in Massachusetts may be sufficient to maintain constant serum 25(OH)D and parathyroid hormone concentrations throughout the year. Such an intake prevents a seasonal increase in parathyroid hormone secretion, with its possible deleterious skeletal effects.     

Serum 25-hydroxyvitamin D levels in early and advanced breast cancer

BACKGROUND: Laboratory and epidemiological studies have implicated vitamin D deficiency in the pathogenesis of breast cancer. 1,25-Dihydroxyvitamin D (1,25(OH)(2)D) promotes differentiation and apoptosis, and potently inhibits proliferation of malignant breast epithelial cells in culture. Serum levels of 1,25(OH)(2)D are higher in normal women than in patients with primary breast cancer. AIM: To clarify the role of vitamin D in breast cancer progression by comparing the levels of serum vitamin D in patients with early and in those with advanced breast cancer. METHODS: Circulating levels of 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and calcium were measured prospectively in 279 Caucasian women with invasive breast cancer, 204 women with early-stage disease and 75 women with locally advanced or metastatic disease. RESULTS: Patients with early-stage breast cancer had significantly higher circulating levels of 25(OH)D (p<0.005) and significantly lower PTH (p<0.001) levels than those with advanced disease. Calcium levels did not differ significantly (p = 0.74). CONCLUSION: Serum levels of 25(OH)D are significantly higher in patients with early-stage breast cancer than in those with locally advanced or metastatic disease.     

Inappropriate phosphate excretion in idiopathic hypercalciuria: the key to a common cause and future treatment?

AIMS: To present experimental evidence in support of a proposed common cause for absorptive hypercalciuria, renal hypercalciuria, renal phosphate leak and enhancement of 1,25-(OH)2-vitamin D concentrations in patients presenting with renal stone disease; and to suggest further investigation with a view to new management. METHODS: An oral calcium loading test was administered to 15 patients with renal stones and 10 normal controls in the fasting state: urine and blood were collected hourly. After the second urine sample, 400 mg calcium dissolved in water was administered orally. Serum calcium, albumin, parathyroid hormone (PTH), and phosphate were measured together with urine calcium clearance and urinary phosphate from which the TmPO4/glomerular filtration rate (GFR) ratio was calculated. Serum 1,25-(OH)2-vitamin D was measured in the first serum sample. In addition, 24 hour urine calcium results were collected retrospectively from the patients' case notes over the previous 18 months. RESULTS: In the basal state, renal stone patients had an overall greater phosphaturia (lower TmPO4/GFR: median 1.72 compared with 2.10 in controls) and increased calcium clearance. Serum corrected calcium and PTH concentrations did not differ between the groups. After calcium loading, serum calcium and urine calcium clearance rose in both groups, with patients with renal stones experiencing a greater percentage fall in phosphaturia. In both groups TmPO4/GFR fell (greater phosphaturia) with increased serum corrected calcium, with the patients showing notably greater phosphaturia for any given calcium concentration. Patients also had notably greater phosphaturia compared with the serum calcium concentration for any given PTH value. Serum 1,25-(OH)2-vitamin D was higher in patients than controls and for any 1,25-(OH)2-vitamin D concentration phosphaturia measured against serum calcium was greater in patients than controls. 1,25-(OH)2-vitamin D did not correlate with phosphaturia relative to serum calcium concentrations within the patient and control groups. CONCLUSIONS: It is proposed that patients with idiopathic hypercalciuria have an "inappropriately' high phosphate excretion for any given serum calcium concentration. Loss of phosphate may induce increased activation of 1,25-(OH)2-vitamin D. Some of the commonly described causes of stone formation may be manifestations of a single mechanism.     

Disturbed calcium metabolism in subjects with elevated diastolic blood pressure

Summary Essential hypertension has been associated with disturbed calcium metabolism, but the available data are controversial. We measured parameters of calcium metabolism in groups of untreated male subjects (n = 78) with elevated diastolic blood pressure (101 ± 6 mmHg, mean ± SD) and age-matched male subjects (n=79) with low diastolic blood pressure (62 ± 4 mmHg). The participants of the study were drawn from a random population sample. Subjects with high diastolic blood pressure had significantly higher carboxy-terminal parathyroid hormone (PTH) plasma concentrations than controls with low diastolic blood pressure (median 114 vs. 43 pmol/l, P < 0.01). The 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations were comparable in both groups. Individuals with high diastolic blood pressure had significantly lower total serum calcium (2.41 ± 0.10 vs. 2.47 ± 0.10 mmol/l, mean ± SD; P < 0.01). PTH concentrations were correlated with diastolic pressure (r = –0.39, P < 0.001). The data are compatible with increased parathyroid activity despite unchanged concentrations of vitamin D metabolites in human hypertension.Abbreviations PTH parathyroid hormone - C-PTH carboxy-terminal parathyroid hormone - 1,25(OH)₂D 1,25-di-hydroxyvitamin D - 25(OH)D 25-hydroxyvitamin D     

Regulation and function of the FGF23/klotho endocrine pathways

Calcium (Ca(2+)) and phosphate (PO(4)(3-)) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca(2+) levels by increasing Ca(2+) reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] production by the kidney, enhancing Ca(2+) and PO(4)(3-) intestinal absorption and increasing Ca(2+) and PO(4)(3-) efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)(2)D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)(2)D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO(4)(3-) handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.     

Ultrastructural evaluation of the effects of 1,25-dihydroxyvitamin D3 on bone of thyroparathyroidectomized rats fed a low-calcium diet

Thyroparathyroidectomized rats fed a low-calcium-normal-phosphorus diet were administered 1 or 5 units of 1,25-dihydroxyvitamin D3-(1,25-[OH]2D3) or placebo daily for 7 days. 1,25-(OH)2D3 elevated serum and urine calcium and decreased serum phosphorus. Rats given 1 unit of 1,25-(OH)2D3 had increased numbers of osteoclasts in metaphyseal trabeculae, Ultrastructurally, osteoclasts, osteoblasts, and osteocytes in rats given 1 unit of 1,25-(OH)2D3, were similar to those in rats given placebo. In rats given 5 units of 1,25-(OH)2D3, osteoclasis was markedly increased. Osteoblasts were more numerous and interpreted to be active in matrix production and mineralization. Lamellated electron-dense bodies were observed adjacent to the plasma membranes of less active osteoblasts and were interpreted to be modified matrix. Most osteocytes in rats given 5 units of 1,25-(OH)2D3 were indistinguishable from osteocytes in rats given placebo. However,the pericellular space of some osteocytes in rats given 5 units of 1,25-(OH)2D3 contained electron-dense granular deposits that were interpreted to be calcium phosphate. It is concluded that 1,25-(OH)2D3 is able to significantly elevate serum calcium independent of dietary calcium, parathyroid hormone, and calcitonin primarily by increasing ostoeclasis with minimal dependence on osteocytic osteolysis.     

The relationship between endogenous oestradiol and vitamin D3 metabolites in serum and follicular fluid during ovarian stimulation for in-vitro fertilization and embryo transfer.

The present study was undertaken to examine the effect of circulating oestradiol on serum levels of 25-hydroxyvitamin D3 (25-OHD3), 24,25-dihydroxyvitamin D3[24,25-(OH)2D3], and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] during gonadotrophin-induced ovarian stimulation in 10 healthy women undergoing in-vitro fertilization and embryo transfer (IVF). The presence of these metabolites in the follicular fluid was also investigated. Plasma oestradiol increased from 25 +/- 3.2 (mean +/- SE) pg/ml before initiation of treatment to 2563 +/- 328 pg/ml on the day of injection of human chorionic gonadotrophin (HCG) and 1641 +/- 299 pg/ml on the day of ovum retrieval (P < 0.01). Serum levels of 1,25-(OH)2D3 increased from 32.0 +/- 1.9 (mean +/- SE) pg/ml to 46.6 +/- 8.1 and 48.5 +/- 7.7 pg/ml (P < 0.05) on the day of HCG and ovum retrieval, respectively. No changes in blood levels of 25-OHD3 and 24,25-(OH)2D3 were found. The presence of vitamin D metabolites in follicular fluid is documented herein for the first time. All three metabolites were present in the follicular fluid but were significantly lower than in the concurrent serum (P < 0.01). A highly significant correlation was found between serum and follicular fluid levels: r = 0.787, P < 0.001 for 1,25-(OH)2D3; r = 0.738, P < 0.01 for 25-OHD3; and r = 0.751, P < 0.01 for 24,25-(OH)2D3. Our results suggest that raised levels of circulating oestradiol during gonadotrophin-induced ovarian stimulation are associated with a significant increase of serum 1,25-(OH)2D3.     

Light- and electron-microscopic evaluation of the effects of 1,25-dihydroxyvitamin D3 on bone of thyroparathyroidectomized rats.

1,25-Dihydroxyvitamin D3 (1,25-[OH]2D3) was administered in doses of 1 (65 picomoles) or 5 (325 picomoles) units daily for 7 days to adult thyroparathyroidectomized rats fed a normal rodent diet. Both dose levels significantly increased serum calcium, decreased serum phosphorus, and increased urinary calcium and phosphorus concentrations. Numbers of osteoblasts were significantly increased in rats given 5 units 1,25-(OH)2D3. Ultrastructurally, these osteoblasts were larger and interpreted to be more active in bone matrix synthesis and mineralization, compared with osteoblasts in control rats. The number of osteoblasts in rats given 1 unit 1,25-(OH)2D3 was not increased, compared with controls, but they were morphologically similar to the osteoblasts in rats given 5 units 1,25-(OH)2D3. A granular electron-dense material, interpreted to be mineral, was present in the pericellular space of osteocytes in rats given 1 and 5 units 1,25-(OH)2D3. The size of osteocytes, organellar development, and contour of osteocytic lacunae were not affected by 1,25-(OH)2D3. The number of osteoclasts was not significantly elevated in 1,25-(OH)2D3-treated rats and their morphology was similar to that of osteoclasts in controls. It is concluded that in metaphyseal bone 1,25-(OH)2D3 increased the number and synthetic activity of osteoblasts without significantly enhancing osteoclasis or osteocytic osteolysis. This response was independent of parathyroid hormone and calcitonin in rats fed a normal diet.     

Vitamin D3 and calcium to prevent hip fractures in the elderly women.

BACKGROUND. Hypovitaminosis D and a low calcium intake contribute to increased parathyroid function in elderly persons. Calcium and vitamin D supplements reduce this secondary hyperparathyroidism, but whether such supplements reduce the risk of hip fractures among elderly people is not known. METHODS. We studied the effects of supplementation with vitamin D3 (cholecalciferol) and calcium on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women (mean [+/- SD] age, 84 +/- 6 years). Each day for 18 months, 1634 women received tricalcium phosphate (containing 1.2 g of elemental calcium) and 20 micrograms (800 IU) of vitamin D3, and 1636 women received a double placebo. We measured serial serum parathyroid hormone and 25-hydroxyvitamin D (25(OH)D) concentrations in 142 women and determined the femoral bone mineral density at base line and after 18 months in 56 women. RESULTS. Among the women who completed the 18-month study, the number of hip fractures was 43 percent lower (P = 0.043) and the total number of nonvertebral fractures was 32 percent lower (P = 0.015) among the women treated with vitamin D3 and calcium than among those who received placebo. The results of analyses according to active treatment and according to intention to treat were similar. In the vitamin D3-calcium group, the mean serum parathyroid hormone concentration had decreased by 44 percent from the base-line value at 18 months (P < 0.001) and the serum 25(OH)D concentration had increased by 162 percent over the base-line value (P < 0.001). The bone density of the proximal femur increased 2.7 percent in the vitamin D3-calcium group and decreased 4.6 percent in the placebo group (P < 0.001). CONCLUSIONS. Supplementation with vitamin D3 and calcium reduces the risk of hip fractures and other nonvertebral fractures among elderly women.     

Vitamin D deficiency after highly selective vagotomy

While bone disease is occasionally seen after gastrectomy, the influence of vagotomy on calcium and vitamin D metabolism is uncertain. We have, therefore, investigated 23 male patients who had undergone highly selective vagotomy for ulcer 4.3 +/- 1.2 years previously. The 25OHD concentrations were decreased (p less than 0.05), the 1,25(OH)2D concentrations elevated (p less than 0.05) and the immunoreactive parathyroid hormone concentrations normal. Local and total bone mass were normal compared to age-matched men, and there was no biochemical evidence of increased bone turnover. We suggest that the changes in calcium absorption, which are described in the literature after vagotomy, are mediated by 1,25(OH)2D. Although the changes in vitamin D metabolism do not lead to calcium-metabolic disturbances in selected patients, we believe that some will eventually develop vitamin D deficiency and that vitamin D supplementation should be considered.     

The effects of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sarcoidosis

Although corticosteroids are effective in the treatment of hypercalciuria and hypercalcemia in chronic sarcoidosis, complications of their long-term use frequently limit therapy. We studied the efficacy of chloroquine in two patients with sarcoidosis who were unable to tolerate the dosage of corticosteroids required to control hypercalciuria and prevent the formation of renal stones. Over a three-year period, each patient received a 6-month and a 10-month course of oral chloroquine phosphate (500 mg per day) while continuing to receive corticosteroids at a fixed dose. Chloroquine therapy was associated with a significant reduction in levels of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and urinary calcium. We observed a direct correlation between serum 1,25-(OH)2D levels and 24-hour urinary calcium excretion, supporting the hypothesis that excessive serum 1,25-(OH)2D is responsible for the hypercalciuria in sarcoidosis. Serum levels of 25-hydroxyvitamin D (25-(OH)D) did not change with therapy, suggesting that chloroquine may act by inhibiting the conversion of 25-(OH)D to 1,25-(OH)2D. Current dosage guidelines and ophthalmologic-surveillance techniques, which allow chloroquine to be administered with little risk of retinopathy, should permit an expanded role for this agent in the treatment of the calcium abnormalities of sarcoidosis.