A cross-sectional study of 232 healthy children, with about equal numbers of boys and girls and blacks and whites, aged 4 to 16 yr, was conducted to investigate the racial differences in bone mineral. Bone mineral content (BMC) by dual x-ray absorptiometry was found to be similar between blacks and whites at the spine after controlling for age and Tanner stage. However, total body BMC was higher in blacks, compared with whites of the same age and Tanner stage. Height and weight alone reduced the racial difference in BMC from 152 g to 66 g in girls and from 163 g to 105 g in boys, in whom the difference was further reduced to 66 g after accounting for lean and fat body mass and subscapular skinfold. The only significant sex hormone was androstenedione, which explained another 4-5 g of the racial difference in total body BMC for both boys and girls. Among the biochemical variables, only 25OH vitamin D reduced the residual racial difference in total body BMC to 39 g in girls, whereas serum PTH, urine free deoxypyridinoline ratio, and 1,25(OH)(2) vitamin D reduced the residual difference to 25 g in boys. The residual racial differences in bone mass were not statistically significant.

Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.

NO is synthesized from l-arginine by at least three isoforms of nitric oxide synthase (NOS) and is known to function as a vasodilator and neurotransmitter. NO is produced by bone cells but its function in bone biology is, as yet, unclear. We hypothesized that NOS mediates bone formation in remodeling regions of the skeleton. We studied the effects of two NOS inhibitors: NG-nitro-l-arginine methyl ester (l-NAME), which is a general inhibitor of NOS activity and is known to inhibit the vasodilatory effects of the endothelial NOS (eNOS) isoform; and aminoguanidine, which is a selective inhibitor of the inducible NOS (iNOS) isoform. Our hypothesis was tested by treating rats with NOS inhibitors and measuring bone formation rates in the tibial epiphysis and diaphysis. Bone formation indices were measured using standard bone histomorphometry. l-NAME treatment significantly raised mean arterial blood pressure (MAP). This effect was partially reversed by addition of l-arginine. Aminoguanidine had no significant effect on MAP, indicating that it did not block eNOS. The treatments also had substantial effects on bone formation in remodeling trabecular bone. l-NAME did not significantly change trabecular bone formation rate, whereas aminoguanidine reduced bone formation rate in the tibial epiphysis by 79% compared with control. This reduction was completely reversed by l-arginine, suggesting that bone formation during remodeling is, in part, mediated through l-arginine metabolism. No effect of aminoguanidine on bone formation was seen in the tibial diaphysis, a site that undergoes minimal bone remodeling. This finding suggests that the l-arginine-NO pathway is important in bone remodeling.

. We hypothesized that fluoride partly acts by changing the levels of circulating calcium-regulating hormones and skeletal growth factors. The effects of oral fluoride on 24 female, Dutch-Belted, young adult rabbits were studied. The rabbits were divided into two study groups, one control and the other receiving about 16 mg fluoride/rabbit/day in their drinking water. After 6 months of fluoride dosing, all rabbits were euthanized and bone and blood samples were taken for analyses. Fluoride treatment increased serum and bone fluoride levels by over an order of magnitude ( P < 0.001), but did not affect body weight or the following serum biochemical variables: urea, creatinine, phosphorus, total protein, albumin, bilirubin, SGOT, or total alkaline phosphatase. No skeletal fluorosis or osteomalacia was observed histologically, nor did fluoride affect serum PTH or Vitamin D metabolites ( P > 0.4). BAP was increased 37% ( P < 0.05) by fluoride; serum TRAP was increased 42% ( P < 0.05); serum IGF-1 was increased 40% ( P < 0.05). Fluoride increased the vertebral BV/TV by 35% ( P < 0.05) and tibial ash weight by 10% ( P < 0.05). However, the increases in bone mass and bone formation were not reflected in improved bone strength. Fluoride decreased bone strength by about 19% in the L5 vertebra ( P < 0.01) and 25% in the femoral neck ( P < 0.05). X-ray diffraction showed altered mineral crystal thickness in fluoride-treated bones ( P < 0.001), and there was a negative association between crystal width and fracture stress of the femur ( P < 0.02). In conclusion, fluoride's effects on bone mass and bone turnover were not mediated by PTH. IGF-1 was increased by fluoride and was associated with increased bone turnover, but was not correlated with bone formation markers. High-dose fluoride treatment did not improve, but decreased, bone strength in rabbits, even in the absence of impaired mineralization.

Studies were carried out with rat epididymal fat pads first to compare the effects of the synthetic N-terminal 1-34 peptide of bovine parathyroid hormone and of the native hormone to determine whether this portion of the molecule is responsible for the lipolytic action of the hormone and second to determine whether this biologic action of parathyroid hormone is mediated by cyclic adenosine 3',5'-monophosphate. The N-terminal polypeptide was as effective as the native hormone in stimulating lipolysis in the concentration range between 10(-8) M and 10(-6) M. Parathyroid hormone stimulated lipolysis by isolated fat cells. The concentration of cyclic adenosine 3',5'-monophosphate in the fat pads was significantly increased by the hormone (10(-6)M). Lipolytic stimulation by parathyroid hormone (10(-6)M) was diminished by insulin (100 muU/ml) and prostaglandin E1 (1 mug/ml), both of which are known inhibitors of lipolysis. The findings indicate that the amino-terminal 1-34 peptide portion of parathyroid hormone is responsible for the lipolytic action and that this effect is mediated through cyclic adenosine 3',5'-monophosphate.