Intensive care of the pregnant mother with diabetes has dramatically decreased the incidence of diabetic fetopathy. The persistently high rate of fetal and neonatal mortality in diabetic pregnancies is nowadays mainly due to the increased incidence of serious congenital malformations. However, attempts to elucidate the precise teratogenic mechanisms have been sparse, presumably because of a lack of relevant animal models. In the present study we recorded the incidence and types of skeletal malformations in live offspring of normal rats and in rats made diabetic with the B-cytotoxic agent streptozotocin (SZ) at least 2 wk before conception. In some of the diabetic animals insulin treatment was begun 1 wk after the SZ injection and continued throughout pregnancy. In addition, the fetal development was followed by assessing the calcification of the skeleton on gestational days 20 and 22 with the aid of Alazarin Red S staining. Manifest diabetes in the pregnant rat induced a decrease in fetal weight and viability and marked retardation of skeletal maturation. In addition, about 20% of 135 viable fetuses showed skeletal malformations comprising either micrognathia or caudal dysgenesis. These defects were not found in 314 offspring of the control rats. Only two cases of caudal dysgenesis and none of micrognathia were detected among 233 offspring of the insulin-treated rats. The present data underscore the importance of a strict differentiation in the offspring of the diabetic rat between transient development retardations and true malformations. They also demonstrate that correction of the maternal glucose intolerance is crucial for preventing the fetus from developing skeletal malformations. Altogether the data suggest that fetal malformations in the diabetic rat are attributable either to the hyperglycemia as such or to some accompanying metabolic consequence of insulin deficiency.
Intestinal disease might contribute to osteopenia. Measurements of IgA antibodies to gliadin have been established as an accepted screening procedure for detection of coeliac disease. When we applied these measurements to 92 patients with verified osteoporosis, 11 subjects (12%) were found to have elevated levels. This is markedly higher than the incidence in healthy subjects (3%). However, the patients with raised levels of IgA antibodies displayed no clinical symptoms and no laboratory evidence of calcium malabsorption. Thus their values for serum calcium, phosphate, parathyroid hormone (PTH), alkaline phosphatase and osteocalcin, as well as the fasting urinary excretion of hydroxyproline and calcium, were similar to those found in other patients with osteoporosis. Intestinal biopsy verified coeliac disease in three patients and was normal in another three. This gives an incidence of verified coeliac disease in this patient group that is approximately tenfold higher than that in the healthy population. Subclinical coeliac disease appears to be unusually over-represented among patients with idiopathic osteoporosis, and screening for gliadin antibodies might therefore be a valuable addition to the routine assessment of the osteopenic patient. The mechanisms underlying the relationship are not clear, but calcium malabsorption is not evident.
A placebo-controlled, double-blind study was carried out over 4 months to evaluate two doses of synthetic human calcitonin (0.25 and 0.125 mg) given s.c. three times per week. Enrolled were 60 women, aged 56-82 years, who had experienced a vertebral fracture due to low-energy trauma within the preceding year. During active treatment there was within the first month a dose-dependent decrease of the indices of bone resorption (fasting urinary calcium and hydroxyproline excretions), whereas only the higher dose and a treatment period of 4 months produced a reduction of bone formation (serum osteocalcin). The bone mineral content (BMC) of the nondominant forearm was unchanged. Treatment with calcitonin also had significant, dose-dependent, analgetic effects. The amelioration of pain was, in multivariate analyses, related to a reduction in parameters felt to be markers for bone resorption. In the placebo group there was a significant reduction of the BMC of the forearm but no changes of any of the biochemical markers for bone turnover and no improvement of pain. In conclusion, treatment with two low doses of calcitonin induced changes of the biochemical markers of bone turnover in a dose-dependent manner. The analgetic properties of calcitonin were also of salient clinical importance. The knowledge derived from this study could be adapted to the dosage schedule in long-term trials in osteoporosis.
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