Role of magnesium metabolism and the effects of fluoride therapy in Paget's disease of bone.
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Biomedical subjects
Publications and source records attributed to L V Avioli.
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Proline-(14)C was administered to five adult rhesus monkeys, and the degradation of collagen was followed by the excretion of hydroxyproline-(14)C. The results suggested the presence of at least three separate pools of collagen with half-lives of 1 to 2, 2 to 3, and 50 to 70 days. The monkeys were killed after 44 days; at that time the specific activity of the hydroxyproline-(14)C in urine was found to be four to five times that of the hydroxyproline in soluble collagen and 81 to 93% that of hydroxyproline in insoluble collagen. The relationships between urinary hydroxyproline and the degradation of collagen were similar to those previously demonstrated in rats. Parathyroid hormone was administered daily to two of the monkeys from the 27th to the 44th day of the study. The parathyroid hormone increased the amount of hydroxyproline-(14)C excreted, but there was no significant change in the specific activity of the urinary hydroxyproline-(14)C. Since under the conditions of the experiment insoluble collagen was the only possible source of hydroxyproline-(14)C of relatively high specific activity, the results indicated that parathyroid hormone directly or indirectly increased the degradation of insoluble collagen. The results also suggested that parathyroid hormone increased the degradation of soluble collagen, but the relative magnitude of this effect was not clearly established.
Vitamin D(3)-(3)H has been administered intravenously to seven normal subjects, three patients with biliary fistulas, and four patients with cirrhosis. Plasma D(3)-(3)H half-times normally ranged from 20 to 30 hours. in vivo evidence that a metabolic transformation of vitamin D occurs was obtained, and a polar biologically active vitamin D metabolite was isolated from plasma. Urinary radioactivity averaged 2.4% of the administered dose for the 48-hour period after infusion, and all the excreted radioactivity represented chemically altered metabolites of vitamin D. The metabolites in urine were mainly water-soluble, with 26% in conjugated form. From 3 to 6% of the injected radioactivity was excreted in the bile of subjects with T-tube drainage and 5% in the feces of patients having no T-tube. The pattern of fecal and biliary radioactivity suggested that the passage of vitamin D and its metabolites from bile into the intestine represents an essential stage for the fecal excretion of vitamin D metabolites in man. Abnormally slow plasma disappearance of vitamin D(3)-(3)H in patients with cirrhosis was associated with a significant decrease in the quantity and rate of glucuronide metabolite excretion in the urine.
The fate of an intravenous dose of tritiated vitamin D(3) was studied in seven normal subjects, four children with vitamin D-resistant rickets, and four adults with a familial history of vitamin D-resistant rickets and persistent hypophosphatemia. An abnormal metabolism of vitamin D in vitamin D-resistant rickets was defined and characterized by a decrease in the plasma fractional turnover rate, a marked increase in plasma water-soluble metabolites, and a relative decrease in the conversion of vitamin D to a polar, biologically active metabolite. Alterations in vitamin D metabolism in the adults with persistent hypophosphatemia were similar but less severe than those of affected children with vitamin D-resistant rickets. It is tentatively concluded that the abnormalities in vitamin D metabolism documented in patients with vitamin D-resistant rickets and familial hypophosphatemia may account for the observed osseous and biochemical changes.
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Evidence is rapidly accumulating that implicates calcium intake and genetic factors as important determinants of the variations in bone mass in many geographical areas as well as the loss of bone following the accumulation of peak bone mass. However, it has also been well established that the postmenopausal component of bone loss is one of the predominant factors contributing to increases in the ratio of the female/male risk of skeletal fractures after the sixth decade of life, and that vertebral bone loss can result from relatively mild changes in estrogen production and metabolism before the clinical menopause begins. Although estrogen use during early menopause prevents bone loss in the axial and appendicular skeleton in the majority of females, those estrogen-dependent mechanism(s) that initiate and perpetuate alterations in osteoclast-osteoblast interactions and bone remodeling are still ill-defined. Until the specific pathophysiological mechanisms have been defined, the informed physician should attempt to identify those peri- and postmenopausal patients at risk for more active bone turnover and rapid bone loss syndromes utilizing well-established and FDA-approved therapeutic interventional procedures to prevent the loss of skeletal tissue.
It is now generally accepted that estrogen status, exercise and adequate calcium intake are the singularly most important factors which guarantee the assumption of genetically programmed peak bone mass. Physicians also recognize that estrogen replacement therapy is not only essential to prevent bone loss in the early postmenopausal female, but also for the long-term preservation of bone mineral density. The efficacy of either continuous or intermittent calmon calcitonin administration in preventing further bone loss and in some instances decreasing fracture incidences in established osteoporotic syndromes is currently well established. As noted during a variety of controlled investigations performed both in the United States and abroad, and in the Physician's Resource Manual on Osteoporosis published by the United States National Osteoporosis Foundation, salmon calcitonin is also effective in early postmenopausal women who are not candidates for estrogen replacement therapy in addition to those patients with established osteoporosis. The practicing physician should acknowledge that of all the anti-resorptive agents recommended for therapy in osteoporotic syndromes, estrogens and salmon calcitonin are currently the only two drugs recommended by the U.S. Food and Drug Administration (USFDA) as safe and effective as treatment modalities in osteoporosis.
Calcium deficiency contributes to age-related bone loss; consequently, any preventive approach to osteoporosis should include dietary Ca adjustment or supplementation. The ideal Ca supplement would yield the greatest bioavailability. Studies in animals have shown that dietary supplements with certain amino acids, particularly L-lysine, can increase Ca absorption. Therefore, we examined the potential effect of this essential amino acid on Ca metabolism in humans. In one study, the acute effects of an oral Ca load (3 g as CaCl2) administered with or without 400 mg of L-lysine were compared in 15 healthy and 15 osteoporotic women. In all cases, the oral Ca load determined a progressive increase in serum total Ca and Ca2+ and a concomitant decrease in neophrogenous cAMP. As expected, a progressive increase in urinary Ca excretion was also observed, except in the L-lysine-treated healthy subjects, who exhibited a blunted calciuric response to the Ca load. In a second study, the effects of a short-term dietary supplementation with either L-lysine, L-valine, or L-tryptophan (800 mg/day) on 47Ca fraction absorption were compared in 45 osteoporotic patients. L-Lysine but not L-valine or L-tryptophan significantly increased the intestinal absorption of the mineral. Our results suggest that L-lysine can both enhance intestinal Ca absorption and improve the renal conservation of the absorbed Ca. The combined effects may contribute to a positive Ca balance, thus suggesting a potential usefulness of L-lysine supplements for both preventive and therapeutic interventions in osteoporosis.
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The authors examine the effects of different drugs used in osteoporosis therapy for the primary and secondary prevention of fractures. They base their review on prospective randomized studies; retrospective studies are included only if a consistent number of subjects has been examined. Their methodological characteristics are illustrated, and results with significant levels and 95% confidence intervals are reported. Only hormone replacement therapy and salmon calcitonin have been demonstrated as able to prevent vertebral and non-vertebral fractures. Vitamin D and its analogues seem to be effective only in elderly patients, although conclusive data are lacking. With regard to bisphosphonates, only data on vertebral fractures are presently available. Results from fluoride studies are still very inconclusive, and, in fact, lead to the hypothesis of a fracture-promoting effect. At present, no data on ipriflavone are available. Considerably more research is necessary to define the efficacy of different treatment protocols for fracture prevention. Each therapeutic proposal for osteoporosis should be supported by data on its efficacy in reducing the incidence of fractures. Not always, in fact, is an absolute increase of bone mass followed by the effective prevention of fractures. At this time, only estrogens and calcitonin have been demonstrated as able to reduce fracture incidence.