Growth hormone modulates cholecalciferol metabolism with moderate effects on intestinal mineral absorption and specific effects on bone formation in growing dogs raised on balanced food.

The aim of the study was to investigate the influence of growth hormone (GH) on Vitamin D3 metabolism and the subsequent effects on calcium (Ca) homeostasis and skeletal growth in growing dogs. A group of Miniature Poodles received supraphysiological doses of GH (GH group; n = 6; 0.5 IU GH per kg body per day) from 12 to 21 weeks of age and was compared with a control placebo-treated group (n = 8). Biologic activity of GH in the GH compared to the control group was indicated by (a) the 2.5- to 3.5-fold increase in the plasma concentrations of insulin-like growth factor I (IGF-I), (b) the increased production of 1,25-dihydroxycholecalciferol as indicated by the significantly increased plasma 1,25-dihydroxycholecalciferol concentrations and the 12.9-fold increase in renal 1alpha-hydroxylase gene expression, and (c) the inhibited production of 24,25-dihydroxycholecalciferol as indicated by the significantly lower plasma 24,25-dihydroxycholecalciferol concentrations and the similar levels of renal 24-hydroxylase gene expression. Despite the distinct effects on Vitamin D(3) metabolism in the GH group, there were only moderate effects on the intestine, i.e. at 20 weeks of age there was a significant increase of 14.4 and 5.6% in fractional absorption of Ca and phosphate (Pi), respectively, compared to the control group. GH administration resulted in significantly elevated glomerular filtration rate, with no differences in Pi urine excretion as a result of a concomitant increase in the tubular reabsorption of Pi. GH had only limited disturbing effects on endochondral ossification as indicated by the maintenance of the regularity of the growth plates. However, GH had specific anabolic effects on bone formation without concomitant effect on bone resorption that may result in disorders of skeletal remodeling and manifestation of enostosis.

Hormonal regulation of calcium homeostasis in two breeds of dogs during growth at different rates.

Growing giant-breed dogs are more susceptible to developing skeletal disorders than small-breed dogs when raised on diets with deficient or excessive Ca content. Differential hormonal regulation of Ca homeostasis in dogs with different growth rates was investigated in Great Danes (GD, n = 9) and Miniature Poodles (MP, n = 8). All animals were raised on the same balanced diet and under identical conditions. Calciotropic and growth-regulating hormones were measured. Production and clearance of 1,25-dihydroxycholecalciferol (1,25[OH]2D3) were investigated with the aid of [3H]-1,25(OH)2D3 and renal messenger RNA abundance of 1 alpha-hydroxylase and 24-hydroxylase. Intestinal, renal, and skeletal Ca handling were evaluated with the aid of 45Ca balance studies. Skeletal development was evaluated by radiology and histomorphometry. Great Danes had greater (P < 0.001) growth rates than MP, as indicated by the 17-fold greater body weight gain, by increased longitudinal growth reflected in the increased (P < 0.05) gain in length of the radius and ulna, and by increased (P < 0.001) growth plate thickness. These findings were accompanied in GD by greater (P < 0.05) plasma GH and IGF-I concentrations. Effects were observed for vitamin D3 metabolism, such as greater (P < 0.01) plasma 1,25(OH)2D3 concentrations due to decreased (P < 0.01) clearance rather than increased production of 1,25(OH)2D3, and decreased (P < 0.01) plasma 24,25-dihydroxycholecalciferol (24,25[OH]2D3) concentrations likely due to competitive inhibition of the production of 24,25(OH)2D3. These findings were accompanied in both breeds by a limited hormonal regulation of Ca and P absorption at the intestinal level, and in GD by increased (P < 0.05) renal reabsorption of inorganic P (Pi) compared with MP, resulting in greater (P < 0.01) Pi retention and greater (P < 0.01) plasma Pi concentrations. Bone turnover, resorption, and formation were greater (P < 0.01) in GD than in MP. In addition, GD had more irregular (P < 0.01) growth plates than MP, accompanied by disorders of endochondral ossification. It is suggested that in GD, increased calcitonin levels and/or a relative deficiency in 24,25(OH)2D3 at the growth-plate level may both be responsible for the retarded maturation of chondrocytes, resulting in retained cartilage cones and osteochondrosis, and this may be a pathophysiological factor for the increased susceptibility of large breed dogs to developing skeletal disorders.

Dietary 135-fold cholecalciferol supplementation severely disturbs the endochondral ossification in growing dogs.

The effects of excessive non-toxic dietary Vitamin D(3) supplementation on Ca homeostasis with specific effects on endochondral ossification and skeletal remodeling were investigated in a group of growing Great Dane dogs supplemented with cholecalciferol (Vitamin D(3); HVitD) versus a control group (CVitD) (1350 microg versus 11.4 microg Vitamin D(3) per kilogram diet) from 6 to 21 weeks of age. There were no differences between groups in plasma concentrations of total Ca, inorganic phosphate, growth hormone, and insulin-like growth factor I and no signs of Vitamin D(3) intoxication in HVitD. For the duration of the study in HVitD compared to CVitD, plasma levels of parathyroid hormone (PTH) decreased, calcitonin (CT) increased, 25-hydroxycholecalciferol [25(OH)D(3)] increased 30- to 75-fold, 24,25-dihydroxycholecalciferol [24,25(OH)(2)D(3)] increased 12- to 16-fold, and 1,25-dihydroxycholecalciferol [1,25(OH)(2)D(3)] decreased by approximately 40%. The latter was attributed to the two-fold increased metabolic clearance rate in the HVitD versus CVitD accompanied by the absence of the anabolic effect of PTH on the production of 1,25(OH)(2)D(3). Fractional Ca absorption (alpha) did not differ between groups at 8 and 14 weeks of age, whereas at 20 weeks of age alpha increased by only 16.4% in HVitD compared to CVitD. Excessive non-toxic Vitamin D(3) supplementation resulted in decreased bone remodeling and focal enlargement of the growth plate with morphology resembling those induced by administration of CT. Hypercalcitoninemia and the imbalanced relationship between 1,25(OH)(2)D(3) and 24,25(OH)(2)D(3) are potent candidates for the disturbed endochondral ossification.