22-oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure.
BACKGROUND: Calcitriol therapy suppresses serum levels of parathyroid hormone (PTH) in patients with renal failure but has several drawbacks, including hypercalcemia and/or marked suppression of bone turnover, which may lead to adynamic bone disease. A new vitamin D analogue, 22-oxacalcitriol (OCT), has been shown to have promising characteristics. This study was undertaken to determine the effects of OCT on serum PTH levels and bone turnover in states of normal or impaired renal function. METHODS: Sixty dogs were either nephrectomized (Nx, N = 38) or sham-operated (Sham, N = 22). The animals received supplemental phosphate to enhance PTH secretion. Fourteen weeks after the start of phosphate supplementation, half of the Nx and Sham dogs received doses of OCT (three times per week); the other half were given vehicle for 60 weeks. Thereafter, the treatment modalities for a subset of animals were crossed over for an additional eight months. Biochemical and hormonal indices of calcium and bone metabolism were measured throughout the study, and bone biopsies were done at baseline, 60 weeks after OCT or vehicle treatment, and at the end of the crossover period. RESULTS: In Nx dogs, OCT significantly decreased serum PTH levels soon after the induction of renal insufficiency. In long-standing secondary hyperparathyroidism, OCT (0.03 microg/kg) stabilized serum PTH levels during the first months. Serum PTH levels rose thereafter, but the rise was less pronounced compared with baseline than the rise seen in Nx control. These effects were accompanied by episodes of hypercalcemia and hyperphosphatemia. In animals with normal renal function, OCT induced a transient decrease in serum PTH levels at a dose of 0.1 microg/kg, which was not sustained with lowering of the doses. In Nx dogs, OCT reversed abnormal bone formation, such as woven osteoid and fibrosis, but did not significantly alter the level of bone turnover. In addition, OCT improved mineralization lag time, (that is, the rate at which osteoid mineralizes) in both Nx and Sham dogs. CONCLUSIONS: These results indicate that even though OCT does not completely prevent the occurrence of hypercalcemia in experimental dogs with renal insufficiency, it may be of use in the management of secondary hyperparathyroidism because it does not induce low bone turnover and, therefore, does not increase the risk of adynamic bone disease. (+info)
The elevated serum alkaline phosphatase--the chase that led to two endocrinopathies and one possible unifying diagnosis.
A 39-year-old Chinese man with hypertension being evaluated for elevated serum alkaline phosphatase (SAP) levels was found to have an incidental right adrenal mass. The radiological features were characteristic of a large adrenal myelolipoma. This mass was resected and the diagnosis confirmed pathologically. His blood pressure normalised after removal of the myelolipoma, suggesting that the frequently observed association between myelolipomas and hypertension may not be entirely coincidental. Persistent elevation of the SAP levels and the discovery of hypercalcaemia after surgery led to further investigations which confirmed primary hyperparathyroidism due to a parathyroid adenoma. The patient's serum biochemistry normalised after removal of the adenoma. The association of adrenal myelolipoma with primary hyperparathyroidism has been reported in the literature only once previously. Although unconfirmed by genetic studies this association may possibly represent an unusual variation of the multiple endocrine neoplasia type 1 syndrome. (+info)
Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group.
PURPOSE: To assess whether pamidronate can reduce the frequency of skeletal morbidity in women with lytic bone metastases from breast cancer treated with hormone therapy. PATIENTS AND METHODS: Three hundred seventy-two women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy were randomized to receive 90 mg of pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 weeks for 24 cycles. Patients were evaluated for skeletal complications: pathologic fractures, spinal cord compression, irradiation of or surgery on bone, or hypercalcemia. The skeletal morbidity rate (the ratio of the number of skeletal complications to the time on trial) was the primary efficacy variable. Bone pain, use of analgesics, quality of life, performance status, bone tumor response, and biochemical parameters were also evaluated. RESULTS: One hundred eighty-two patients who received pamidronate and 189 who received placebo were assessable. The skeletal morbidity rate was significantly reduced at 12, 18, and 24 cycles in patients treated with 90 mg of pamidronate (P = .028, .023, and .008, respectively). At 24 cycles, the proportion of patients having had any skeletal complication was 56% in the pamidronate group and 67% in the placebo group (P = .027). The time to the first skeletal complication was longer for patients receiving pamidronate than for those given placebo (P = .049). There was no statistical difference in survival or in objective bone response rate. Pamidronate was well tolerated. CONCLUSION: Treatment with 90 mg of pamidronate as a 2-hour intravenous infusion every 4 weeks in addition to hormonal therapy significantly reduces skeletal morbidity from osteolytic metastases. (+info)
Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23-dihydroxyvitamin D (calcitriol) and EB1089.
The steroid hormone 1,25-dihydroxyvitamin D [1,25(OH)2D, also known as calcitriol] is known to inhibit the proliferation and to promote the differentiation of human prostate cancer cells. Additionally, we showed that 1,25(OH)2D markedly inhibits the invasiveness of human prostate cancer cells in vitro (G. G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997). These properties support the use of 1,25(OH)2D as differentiation therapy in prostate cancer. However, the use of 1,25(OH)2D in vivo is limited by the risk of hypercalcemia. We therefore compared the effects of 1,25(OH)2D and of EB1089, an analogue of 1,25(OH)2D with reduced calcemic effects, in an in vivo model of androgen-insensitive metastatic prostate cancer, the rat Dunning MAT LyLu prostate cancer model. Tumor growth and metastasis were studied using Copenhagen rats given s.c. injections of MAT LyLu cells. Fifty male rats were divided into five groups of 10 rats each. Four experimental groups received i.p. injections of low and high doses of 1,25(OH)2D and EB1089 (0.5 and 1.0 microg/kg, low and high, respectively). A control group received injections of vehicle only. Tumor volumes were measured three times per week. Rats were weighed weekly. The number of metastases to the lungs and the extent of hypercalcemia were evaluated. Compared with controls, tumor volumes were significantly smaller in all experimental groups. Similarly, the number of lung metastases (number of foci/lung) was reduced markedly by both 1,25(OH)2D and EB1089. Control rats developed 22.7 (+/- 1.98 SE) tumor foci per lung. Rats treated with 1,25(OH)2D and with EB1089 (1.0 microg/kg) developed 10.4 (+/- 2.81) and 7.70 (+/- 1.29) tumor foci, respectively (P < 0.001 and P < 0.0001, respectively; drug versus control). Compared with controls (10.79 +/- 0.1 mg/dl), serum calcium levels were significantly elevated in both 1,25(OH)2D and EB1089-treated rats (P < 0.01). However, EB1089 was significantly less calcemic than 1,25(OH)2D (12.59 +/- 0.21 mg/dl versus 14.47 +/- 0.46 mg/dl; 1.0 microg/kg; P < 0.001). Rats treated with 1,25(OH)2D showed marked weight loss: 20.0 +/- 1.9% and 26.3 +/- 1.7% of their initial weight (low and high doses, respectively, P < 0.001). Weight loss was significantly lower in rats treated with EB1089 at the high dose 8.4 (+/- 2.9) %. Moreover, rats treated with low-dose EB1089 gained 5.2 (+/- 3.7) % of their initial weight. In conclusion, 1,25(OH)2D and EB1089 showed marked and equivalent inhibition of prostate cancer metastasis in vivo. EB1089 was significantly less calcemic than 1,25(OH)2D and did not induce severe weight loss. This is the first report of a vitamin D analogue that significantly inhibits prostate cancer metastasis in vivo and that does so without producing cachexia or unacceptable hypercalcemia. (+info)
Renal biopsy in the milk-alkali syndrome.
In milk-alkali syndrome the degree of renal impairment varies greatly. Few reports have been published describing structural changes on renal biopsy. In three illustrative cases, impairment of renal function was related to morphological changes shown on percutaneous biopsy. Milk-alkali syndrome should be considered as a cause of renal dysfunction in patients with a long history of dyspensia. (+info)
A large intrathoracic parathyroid adenoma.
A case is described in which an unusually large parathyroid adenoma was visible on the plain chest radiograph taken during the investigation of hypercalcaemia. This was diagnosed preoperatively and a scheme is suggested whereby such a disgnosis can now readily be made. The differential diagnosis is discussed ant the literature is reviewed. (+info)
Promoter structure of mouse RANKL/TRANCE/OPGL/ODF gene.
Receptor activator of NF-kappa B ligand (RANKL)/tumor necrosis factor-related activation induced cytokine (TRANCE)/osteoprotegerin ligand (OPGL)/osteoclast differentiation factor (ODF) is a membrane-bound signal transducer responsible for differentiation and maintenance of osteoclasts. To elucidate the mechanism regulating RANKL/TRANCE/OPGL/ODF gene expression, we cloned the 5'-flanking basic promoter region of the mouse RANKL/TRANCE/OPGL/ODF gene and characterized it by transient transfection studies and genomic Southern blot analysis. Inverted TATA- and CAAT-boxes and a putative Cbfa1/Osf2/AML3 binding domain constituted the basic promoter structure. The repeated half-sites for the vitamin D3 (VitD3) and glucocorticoid receptors were located at -935 and -640, respectively. Transient transfection studies revealed that short-term treatment with 1alpha,25(OH)2 VitD3 or dexamethasone increased luciferase activity up to 204% and 178%, respectively; on the other hand, treatment with dibutyryl cyclic AMP did not affect the promoter activity. Since the expression of Cbfa1/Osf2/AML3 is also regulated by VitD3, 1alpha,25(OH)2 VitD3 might affect RANKL/TRANCE/OPGL/ODF gene expression both directly and indirectly. CpG methylation was observed dominantly in mouse stromal cells, ST2, of a later passage which ceased to support in vitro osteoclastogenesis, suggesting that the methylation status of the CpG loci in the RANKL/TRANCE/OPGL/ODF gene promoter may be one of the influential cis-regulating factors. (+info)
Excessive Ca and P intake during early maturation in dogs alters Ca and P balance without long-term effects after dietary normalization.
Calcium (Ca) and phosphorus (P) balance is important for skeletal development. Although the effects of deficiencies are well known, reports on the effects of excessive Ca and P supply are relatively scarce. Epidemiologic data and a few controlled studies have shown that skeletal abnormalities may develop when Ca intake is excessive, particularly in periods of rapid growth. Changes in Ca and P balance during and/or after a high Ca intake are thought to underlie this phenomenon. In this study, the effects of excessive Ca (3.1 g/kg dry matter) or Ca and P (Ca 3.1 g/kg, P 2.8 g/kg) intake on Ca and P balance in young, rapidly growing dogs during (for the period from 3 to 17 wk of age) and after (for the period from 17 to 27 wk of age) high Ca and P intake were compared with findings in age-matched controls with normal Ca and P intakes (Ca 1.0 g/kg, P 0.8 g/kg). Dogs fed a high Ca diet developed hypercalcemia, and food intake and fractional absorption of Ca and P were significantly lower at 15 wk of age, whereas endogenous fecal and renal Ca excretion were significantly higher than in controls. This resulted in significantly higher Ca retention than in controls only at 9 wk of age, and in disproportionate absorption of Ca and P. In dogs fed a high Ca and P diet, normocalcemia was maintained, fractional absorption of Ca and P were significantly lower at 9 and 15 wk of age, but retention of both was significantly higher at 9 wk than in controls. The endogenous fecal Ca and renal P losses were significantly higher, but renal Ca excretion was not different from that in controls. After normalization of Ca and P intake, Ca and P balance did not differ among groups. In conclusion, excessive Ca and P intake during early maturation alters Ca and P balance, but does not influence Ca and P balance after dietary normalization. (+info)