Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's disease.

Thirteen patients with severe Paget's disease of bone [mean serum alkaline phosphatase (SAP) level 17 times the upper limit of normal] were treated with 30 mg oral risedronate daily for 8 weeks. Patients were followed for 16 weeks without treatment. The change from baseline SAP was the primary end point. Those patients whose SAP levels did not reach the normal range were retreated with 30 mg for another 8 weeks. There was a mean percent decrease in SAP of 77% after the first course of risedronate treatment and 87% after the second course of treatment. All patients who completed the study had a decrease in SAP of at least 77% from the baseline. The urinary hydroxyproline/creatinine level was decreased by 64% and 79%, respectively, during the first and second treatment courses. There were transient asymptomatic decreases in serum calcium and phosphorus levels. The urinary calcium/creatinine ratio also decreased in these patients. Serum intact PTH and 1,25-dihydroxyvitamin D levels increased transiently during risedronate treatment. Oral risedronate was well tolerated by the patients. Only one patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.

Effect of UVB phototherapy and oral calcitriol (1,25-dihydroxyvitamin D3) on vitamin D photosynthesis in patients with psoriasis.

BACKGROUND: Phototherapy and activated froms of vitamin D help clear psoriasis. OBJECTIVE: The influence of UVB phototherapy and oral calcitriol (1,25-dihydroxyvitamin D3) on vitamin D photosynthesis was assessed in 16 patients. METHODS: Patients were randomly selected to receive orally either placebo or calcitriol (0.5 to 2 micrograms daily) for the duration of the 8-week study; all patients received approximately 21 UVB treatments. Before and after treatment, serum levels of 25-hydroxyvitamin D and calcitriol were measured by high-pressure liquid chromatography. RESULTS: Although calcitriol had no additive effect on phototherapy as a treatment modality, a significant increase in serum 25-hydroxyvitamin D levels occurred in both groups; in three patients extraordinarily high levels developed (> 120 ng/ml). Oral calcitriol significantly increased calcitriol serum levels. Increased serum calcitriol did not inhibit cutaneous synthesis of vitamin D or its hepatic conversion to serum 25-hydroxyvitamin D. CONCLUSION: UVB induces high levels of vitamin D photosynthesis. Because oral or topical calcitriol alone helps clear psoriasis, studies to explore the possible influence of UVB phototherapy on its production should be considered. If UVB phototherapy induces cutaneous calcitriol synthesis this could explain the lack of added benefit to treatment when oral calcitriol is administered with phototherapy.

Parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor and its messenger ribonucleic acid in rat aortic vascular smooth muscle cells and UMR osteoblast-like cells: cell-specific regulation by angiotensin-II and PTHrP.

PTH-related protein (PTHrP) is produced in vascular smooth muscle, where it is believed to act as a local vasorelaxant by activating either the classical PTH or a unique PTHrP receptor. We used a newly cloned complementary DNA encoding the rat PTH/PTHrP receptor to study the expression of its messenger RNA (mRNA) in primary aortic vascular smooth muscle cells (VSMC) and in UMR-106 osteoblast-like cells under basal conditions and in response to treatment with agonists. Both cell types expressed a 2.4-kilobase PTH/PTHrP receptor mRNA transcript and exhibited hormone-induced desensitization of PTHrP-(1-34)NH2-stimulated cAMP. In VSMC, angiotensin-II, which induces PTHrP expression, also rapidly (30 min) desensitized the cAMP response and down-regulated (75-90%) receptor mRNA within 1 h. Treatment of cells with phorbol 12-myristate 13-acetate (0.1 microM) mimicked these effects, whereas neither PTHrP-(1-34)NH2, forskolin, nor (Bu)2cAMP altered receptor mRNA expression. By contrast, in UMR-106 cells, PTHrP-(1-34)NH2 induced time- and dose-dependent decreases in receptor mRNA that were preceded by pronounced desensitization (cAMP and ligand binding) of cell surface receptors. These effects were mimicked by (Bu)2cAMP and forskolin, but not by phorbol 12-myristate 13-acetate, suggesting that both receptor mRNA down-regulation and receptor desensitization in UMR cells were mediated through a protein kinase-A pathway. We suggest that VSMC and UMR cells express a common receptor, which is subject to cell-specific regulation. Such diversity in the PTH/PTHrP receptor regulatory mechanisms provides a means for restricting the length and duration of the cellular response to hormone in a cell/tissue-specific manner.

Exogenous calciferol (vitamin D) and vitamin D endocrine status among elderly nursing home residents in the New York City area.

OBJECTIVE: To determine the role and relative importance of sources of exogenous calciferol (vitamin D) in maintaining vitamin D endocrine status in the mid-winter and early spring in a representative sample of institutionalized elderly persons in the New York City area. DESIGN: Cross-sectional survey. SETTING: A privately-run urban nursing home and the long-term care unit of a suburban public hospital. PARTICIPANTS: Residents aged 60 years and older scheduled for a routine annual physical examination and an additional group of individuals ascertained by random sampling. Those with a history of anti-convulsant or glucocorticoid use, liver disease, chronic renal disease (or serum creatinine > 1.5 mg/dL), parathyroid disease, Paget's disease, gastric surgery, or pharmacological vitamin D use were excluded. Of 301 sampled individuals, 221 were found eligible to participate, and 109 were successfully enrolled. RESULTS: The average vitamin D intake was 379 IU/day (range 55-1006 IU/day) and total vitamin D intake was below the Recommended Dietary Allowance in 16% of subjects. Fifty percent of total vitamin D intake came from fortified milk, and 26% came from vitamin supplements. Vitamin supplement use was not associated with low dietary intake. Among subjects taking a supplement containing 400 IU/day, none had serum calcidiol levels below 15 ng/mL, while among subjects with vitamin D intake between 200 and 400 IU/day, 46% had serum calcidiol levels below 15 ng/mL and 14% had calcidiol levels below 10 ng/mL. Vitamin D intake from non-supplement sources (but not from supplements) appeared to have a negative association with serum calcitriol levels. CONCLUSIONS: Many nursing home residents may require vitamin supplements in order to achieve optimal levels of calciferol replacement. The choice of a vehicle for calciferol replacement may affect calcitriol levels.

Vitamin D supplementation in elderly nursing home residents increases 25(OH)D but not 1,25(OH)2D.

Vitamin D metabolism in elderly individuals can be compromised by several mechanisms. We previously described reduced concentrations of 1,25-dihydroxyvitamin D [1,25(OH)2D] in 30% of elderly nursing home residents. The present study assesses the effect of vitamin D supplementation on 25-hydroxyvitamin D [25(OH)D] and 1,25(OH)2D. We performed a double-blind study in which 30 elderly nursing home residents were randomly given either 50 micrograms vitamin D or a placebo daily for 6 wk. Vitamin D metabolites, immunometrically assayed parathyroid hormone (IRMA-PTH), ionized calcium, and bone Gla hormone (BGP) were measured in serum at baseline and biweekly for 6 wk. Serum 25(OH)D concentrations increased significantly (P less than 0.0001) over the 6 wk in the treatment group but were unchanged in the placebo group. Serum 1,25(OH)2D, ionized calcium, BGP, and PTH were not significantly altered by the supplement. We conclude that vitamin D supplementation results in an increase in circulating 25(OH)D but not 1,25(OH)2D; however, the long-term effect on bone mineral metabolism remains unclear.

Nephrolithiasis and bone involvement in primary hyperparathyroidism.

PURPOSE: The purpose of this study was to compare patients with primary hyperparathyroidism with and without nephrolithiasis with regard to (1) biochemical profile, and (2) presence and extent of bone involvement. PATIENTS AND METHODS: Of 70 unselected patients enrolled in a longitudinal study on the natural history of primary hyperparathyroidism, 62 who underwent complete bone densitometry evaluation were considered. The patients had mild hypercalcemia (2.77 +/- 0.02 mmol/L), as well as elevated parathyroid hormone levels by mid-molecule, N-terminal, and immunoradiometric assays. Bone densitometry was assessed by dual-photon absorptiometry of the lumbar spine and femoral neck, and single-photon absorptiometry of the forearm. RESULTS: Eleven of the 62 patients (18%) had nephrolithiasis. There was no difference in serum parathyroid hormone levels, calcium, phosphorus, serum 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D3 between those with and without kidney stones. Total daily urinary calcium excretion was higher among those who formed stones (8.2 +/- 1.0 mmol versus 6.1 +/- 0.4 mmol, p less than 0.05), but not when expressed per mmol of creatinine (0.72 +/- 0.07 versus 0.69 +/- 0.04). Urinary hydroxyproline was also higher in patients who formed stones (58 +/- 11 mg/24 hours versus 37 +/- 2 mg/24 hours; p less than 0.05). Hypercalciuria occurred in 39% of the entire cohort (n = 24), and in 33% (n = 17) of those without stones. Only 29% (n = 7) of those with hypercalciuria had nephrolithiasis. Calcium excretion correlated positively with serum 1,25-dihydroxyvitamin D3 (r = +0.32, p less than 0.05), and negatively with forearm bone mineral density (all patients: r = -0.34, p less than 0.05; hypercalciuric patients: r = -0.53, p less than 0.05). Circulating 1,25-dihydroxyvitamin D3 levels were elevated in a similar proportion of (1) all patients (31%, n = 19); (2) those with nephrolithiasis (27%); and (3) those without stones (31%). Bone mineral density was less than 80% of normal in 61% of patients, but forearm, femoral neck, and lumbar spine density were indistinguishable among those with and without stones. CONCLUSIONS: Cortical bone demineralization occurs to the same extent and frequency in patients with and without nephrolithiasis, and these two subgroups share similar biochemical and bone densitometric profiles. The pathophysiologic events leading to renal and skeletal involvement in primary hyperparathyroidism may be less selective than previously believed, as evidenced by: (1) increased urinary hydroxyproline in patients with nephrolithiasis, and (2) documentation that urinary calcium excretion reflects not only vitamin D status, but bone resorption was well.

Tissue-specific regulation of avian vitamin D-dependent calcium-binding protein 28-kDa mRNA by 1,25-dihydroxyvitamin D3.

We have studied the regulation, by 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), of vitamin D-dependent calcium-binding protein (28-kDa CaBP) mRNA in chick tissues in vivo. Northern analysis of poly(A)+ RNA was carried out using, as hybridization probes, synthetic oligonucleotides complementary to chick 28-kDa CaBP mRNA. In vitamin D-deficient chicks, 28-kDa CaBP mRNA was virtually undetectable in intestine, was clearly detectable in kidney, and present at the highest levels in cerebellum. After a single intravenous dose of 500 ng of 1,25-(OH)2D3, intestinal 28-kDa CaBP mRNA levels were increased 50-fold, kidney levels were increased 4-fold, and cerebellum levels were unchanged. Increased levels of 28-kDa CaBP mRNA were appreciated 2 h after induction and were maximal at 12 h. Pretreatment of vitamin D-deficient chicks with actinomycin D had little effect on the acute phase of the 1,25-(OH)2D3 induction of 28-kDa CaBP mRNA in intestine but blunted the induction in kidney. Pretreatment with cycloheximide caused a delayed response to 1,25-(OH)2D3 in the intestine, although control (noninhibition) levels of 28-kDa CaBP mRNA were present 12 h after hormone administration. By contrast, in the kidney, cycloheximide pretreatment resulted in an increased steady-state (vitamin D-deficient) level of 28-kDa CaBP mRNA, but completely abolished the induction of 1,25-(OH)2D3. Our studies indicate that, whereas 1,25-(OH)2D3 does not regulate 28-kDa CaBP mRNA levels in the brain, the hormone modulates 28-kDa CaBP gene expression in intestine and kidney in a tissue-specific manner, by acting through both transcriptional and post-transcriptional mechanisms.

Animal model of primary hyperparathyroidism.

An experimental model of hyperparathyroidism was developed in the rat to simulate primary hyperparathyroidism in humans. In this model thyroparathyroidectomized (TPTX) or parathyroidectomized (PTX) animals were infused for 6 days with an amount of bovine synthetic parathyroid hormone (PTH)-(1-34) fragment to restore plasma calcium levels to normal (0.7 U X h-1) or with PTH at twofold (1.4 U X h-1) or threefold (2.1 U X h-1) this basal level. Animals infused with 2.1 U X h-1 of bovine PTH-(1-34) exhibited hypercalcemia, hypophosphatemia, a reduction in theoretical renal threshold for phosphate and an increase in 1,25-dihydroxyvitamin D plasma levels that were approximately threefold the control value. In addition, these animals demonstrated nephrocalcinosis and changes of bone histology that were typical of the findings in patients with primary hyperparathyroidism. In contrast, in animals infused at 1.4 U X h-1, plasma calcium, phosphate, and theoretical renal threshold for phosphate remained within normal limits, but plasma 1,25-dihydroxyvitamin D was increased above control, suggesting that increased activity of 1 alpha-hydroxylase may be the most sensitive index of increased PTH levels. This animal model permits sustained elevation of PTH plasma levels at basal or pathologically elevated levels and should provide an effective means by which to evaluate the consequences of chronic hyperparathyroidism on epithelial function, bone, and other organ systems.

1,25-Dihydroxyvitamin D3 induces the synthesis of vitamin D-dependent calcium-binding protein in cultured chick kidney cells.

A 28,000 mol wt vitamin D-dependent calcium-binding protein (CaBP), first isolated from avian intestine, has recently been shown to exist in kidney and other tissues. To study the mechanism regulating the production of renal CaBP, we used primary cultures of chick kidney cells as an in vitro model. Renal cortical tubules isolated from vitamin D-deficient chicks were grown in serum-free, hormone-supplemented medium. Confluent cells were epithelioid and expressed CaBP, as demonstrated by immunocytochemistry and a specific RIA. 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] increased cellular CaBP content in a dose-dependent manner (10(-10)-10(-7) M) from basal concentrations of 50-240 ng/mg protein to maximal concentrations of 600-1200 ng/mg protein 48 h after dosing. Cycloheximide (2 microM) inhibited 1,25-(OH)2D3 induction of CaBP, indicating that the mechanism requires new protein synthesis. Western blotting of cell extracts confirmed the identity of the inducible protein as the 28,000 mol wt CaBP. 25-Hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 were effective but somewhat less potent inducers of CaBP, whereas vitamin D3 was without significant effect. The activities of 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 are attributed to their rapid conversion by kidney cells to 1 alpha-hydroxylated metabolites. The dose-response profiles for two additional bioresponses in these cells, namely induction of 24-hydroxylase and inhibition of 1 alpha-hydroxylase activity, were comparable to those for CaBP induction. To our knowledge, this is the first description of a cell culture system that exhibits 1,25-(OH)2D3-inducible CaBP in vitro. This model should permit the study of certain aspects of the physiology of 1,25-(OH)2D3 and CaBP in kidney that are not possible in vivo.

Neoplastic hypercalcemia: physiologic response to intravenous etidronate disodium.

Following a four-day control period during which an elevated serum calcium level either stabilized or continued to rise despite maximally tolerated saline diuresis, 12 patients with neoplastic hypercalcemia were treated with intravenous etidronate disodium (etidronate) 7.5 mg/kg/day for up to seven days. Serum calcium reverted to normal levels in all patients, with the mean pretreatment serum calcium level of 12.5 +/- 0.4 mg/dl dropping to 9.2 +/- 0.2 mg/dl (p less than 0.01) by Day 7. Elevated urinary calcium (1,107 +/- 134 mg/g creatinine) and hydroxyproline levels (154 +/- 16 mg/g creatinine) declined to 245 +/- 52 mg/g creatinine and 75 +/- 14 mg/g creatinine, respectively, suggesting a marked reduction in bone resorption following treatment. Serum phosphorus levels were unchanged, but urinary phosphorus levels dropped rapidly from 1,181 +/- 125 mg/g creatinine before treatment to 723 +/- 94 mg/g creatinine after two days. Serum parathyroid hormone levels (mid-molecule assay) were suppressed before treatment (64 +/- 16 pg/ml), but rose rapidly to 223 +/- 68 pg/ml by Day 7 of treatment. The value of serum 1,25-dihydroxyvitamin D was initially below normal (16 +/- 3 pg/ml), but rose rapidly with treatment to 42 +/- 12 pg/ml by Day 7. Symptoms of hypercalcemia and bone pain improved with treatment, and no serious adverse reactions to treatment were encountered. Intravenous etidronate is apparently an effective and safe treatment for neoplastic hypercalcemia.

Tumor-induced osteomalacia. Kinetics of calcium, phosphorus, and vitamin D metabolism and characteristics of bone histomorphometry.

A patient with a mesenchymal tumor and hypophosphatemic osteomalacia was studied before and after tumor excision. Initial laboratory values included normal serum calcium, decreased serum phosphorus and tubular reabsorption of phosphate, undetectable 1,25-dihydroxyvitamin D, and normal parathyroid hormone. Histomorphometry of a bone biopsy specimen showed evidence of increased osteoclastic bone resorption. By 16 hours after tumor removal, 1,25-dihydroxyvitamin D level had normalized, but serum phosphorus level was unchanged; at 28 hours, both serum phosphorus value and tubular reabsorption of phosphate were within normal limits. It is concluded that tumor removal is associated with rapid correction both of 1,25-dihydroxyvitamin D production and of renal phosphate wasting. Increased bone resorption suggests the production of an osteoclast activator by the tumor and may explain the typically normal serum calcium value in this disorder.

The effect of oral phosphate administration on major indices of skeletal metabolism in normal subjects.

The effect of brief periods of phosphate administration on indices of human skeletal metabolism was investigated. Thirteen subjects (8 women, 5 men; 19-36 years old) received 2 g of oral phosphate daily for 5 days. Serum phosphorus rose 26% (3.8 +/- 0.1 mg/dl to 4.8 +/- 0.1 mg/dl; p less than .01) while total calcium fell (9.3 +/- 0.1 mg/dl to 8.9 +/- 0.1 mg/dl; p less than .01). Parathyroid hormone levels increased by 50% (14.1 +/- 2.0 pg/ml to 21.5 +/- 1.7 pg/ml; p less than .05) although values remained within the normal range. A persistent phosphaturia (0.64 +/- 0.10 g/g Cr to 1.8 +/- 0.4 g/g Cr; p less than .05) and a 69% fall in urinary calcium (80.8 +/- 10.0 mg/g Cr to 24.6 +/- 6.0 mg/g Cr; p less than .001) were observed. 1,25-dihydroxyvitamin D3 and urinary hydroxyproline concentrations did not change significantly but the bone gamma-carboxyglutamic acid protein (BGP) concentration rose 41% by day 2 (9.6 +/- 1.3 mg/ml to 13.5 +/- 2.2 mg/ml; p less than .005) and remained elevated throughout the study period. These results support the possibility that brief periods of phosphate administration may be useful in the therapy of disorders associated with low bone turnover, such as osteoporosis.

End-organ resistance to 1,25-dihydroxycholecalciferol.

A 13-year-old girl with total alopecia who in infancy had rickets unresponsive to large doses of vitamin D2 is described. She had profound hypocalcaemia which was resistant to treatment with high doses of dihydrotachysterol, 1 alpha-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol. Serum concentrations of 25-hydroxyvitamin D were normal but those of 1,25-dihydroxycholecalciferol were markedly raised (674 and 745 pg/ml). In addition, 24,25-dihydroxyvitamin D was undetectable in serum. Administration of synthetic 24,25-dihydroxycholecalciferol was followed by normocalcaemia which persisted long after treatment was stopped. Her sister, who died at the age of 10 months, also had had total alopecia, rickets, and hypocalcaemia resistant to vitamin-D2 therapy. In this familial syndrome there seems to be end-organ resistance to the action of 1,25-dihydroxycholecalciferol, possibly as a result of changes at the receptor sites.