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Pyrophosphate and diphosphonates in skeletal metabolism. Physiological, clinical and therapeutic aspects.

Pyrophosphate and diphosphonates produce striking results on calcium metabolism in experimental animals and man. Compounds containing P-O-P- bonds (e.g. inorganic pyrophosphate [PP-ii1 or P-C-P bonds (diphosponates) inhibit both the formation and dissolution of calcium phosphate crystals in vitro. PP-i may have a physiological function in regulating calcification and bone turnover, and obnormalities in its metabolism may occur in some human diseases notably hypophosphatasia and pseudogout. Diphosphonates inhibit ectopic calcification, and slow down resorption and bone turnover in several experimental systems in vivo. They have helped in studies of various aspects of the regulation of calcium metabolism. The diphosphonate, disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) has been shown in clinical studies to be effective against ectopic calcification particularly in myositis ossificans progressiva and in disorders of increased bone resorption such as Paget's diseases and some types of osteoporosis. -99mTechnetium complexes of EHDP, PP-i and other polyphosphates have also recently been used successfully as bone scanning agents.

Animals↗

Rest insertion combined with high-frequency loading enhances osteogenesis.

Mechanical loading can significantly affect skeletal adaptation. High-frequency loading can be a potent osteogenic stimulus. Additionally, insertion of rest periods between consecutive loading bouts can be a potent osteogenic stimulus. Thus we investigated whether the insertion of rest-periods between short-term high-frequency loading bouts would augment adaptation in the mature murine skeleton. Right tibiae of skeletally mature (16 wk) female C57BL/6 mice were loaded in cantilever bending at peak of 800 microepsilon, 30 Hz, 5 days/wk for 3 wk. Left tibiae were the contralateral control condition. Mice were randomly assigned into one of two groups: continuous high-frequency (CT) stimulation for 100 s (n = 9), or 1-s pulses of high-frequency stimuli followed by 10 s of rest (RI) for 100 s (n = 9). Calcein labels were administered on days 1 and 21; label incorporation was used to histomorphometrically assess periosteal and endosteal indexes of adaptation. Periosteal surface referent bone formation rate (pBFR/BS) was significantly enhanced in CT (>88%) and RI (>126%) loaded tibiae, relative to control tibiae. Furthermore, RI tibiae had significantly greater pBFR/BS, relative to CT tibiae (>72%). The endosteal surface was not as sensitive to mechanical loading as the periosteal surface. Thus short-term high-frequency loading significantly elevated pBFR/BS, relative to control tibiae. Furthermore, despite the 10-fold reduction in cycle number, the insertion of rest periods between bouts of high-frequency stimuli significantly augmented pBFR/BS, relative to tibiae loaded continually. Optimization of osteogenesis in response to mechanical loading may underpin the development of nonpharmacological regiments designed to increase bone strength in individuals with compromised bone structures.

Adaptation, Physiological↗

Unweighting accelerates tidemark advancement in articular cartilage at the knee joint of rats.

Morphologic development of articular cartilage is influenced by biologic adaptation to functional demands. It has been theorized that intermittent stresses generated by load bearing and motion determine cartilage thickness by controlling advancement of the subchondral mineralization front. The mineralization front is comprised of two interfaces, the tidemark and chondroosseus junction, each of which advances through a different biologic process. This study was designed to evaluate the influence of one month of hind limb unweighting, with and without concurrent restriction of joint motion, on mineral apposition at the tidemark and vascular invasion at the chondroosseus junction in the knee joints of young adult rats. In mobile joints, hind limb unweighting induced a 2-fold increase in the tidemark mineral apposition rate (p = 0.0001) at the primary weight bearing region, resulting in a thinning of the uncalcified cartilage layer and a concurrent thickening of the calcified layer. Cast immobilization negated the effect of unweighting at the tidemark while it activated subchondral vascular encroachment into the calcified cartilage (p = 0.001). These findings suggest that cartilage thinning associated with the elimination of weight bearing is mediated through a different biological mechanism than cartilage loss associated with restriction of joint motion.

Adaptation, Physiological↗

[Some problems of space medicine].

The paper discusses the problems to be resolved by space medicine and the main stages in the development of this branch of science, beginning with the vertical launches of rockets and ending with the flights of orbital stations. On the basis of ground-based simulation experiments and real space flights it presents a classification of the major symptomocomplexes that may occur inflight. The paper describes the main stages of adaptation to weightlessness and physiological changes in the weightless state. The paper also outlines further pathways in the development of space medicine.

Adaptation, Physiological↗

The effect of 6'-galactooligosaccharides on bone mineralization of rats adapted to different levels of dietary calcium.

6'-galactooligosaccharides (6'-GOS), a mixture of galactosyl oligosaccharides formed from lactose by the transgalactosyl reaction with beta-D-galactosidase derived from Aspergillus oryzae and Streptococcus thermophillus, are unhydrolyzed in the small intestine and are fermented by the intestinal bacteria. The effects of 6'-GOS on calcium (Ca) absorption and bone mineralization were examined in male Wistar rats adapted to different levels of dietary Ca for 30 days. Dietary 6'-GOS (5 g/100 g of diet) were more potent than control in stimulating Ca absorption in rats fed the Normal-Ca diet (0.5 g of Ca/100 g of diet) after 8-10 days and 18-20 days, and the bone (femur and tibia) Ca content of rats fed the Normal-Ca diet with 6'-GOS were significantly higher than those of the control animals. However, in rats fed the Low-Ca diet (0.05 g of Ca/100 g of diet), 6'-GOS feeding did not affect both the absorption of Ca and the bone mineralization. Ca content in the liquid phase of the cecal digesta was significantly elevated by 6'-GOS feeding in the rats fed the Normal-Ca diet, however, this was unchanged in the rats fed the Low-Ca diet. We conclude that the effect of 6'-GOS on the bone mineralization is affected by dietary Ca concentration used in the experiment, and the stimulatory effect of 6'-GOS on Ca absorption may be partly associated with increased solubility of Ca in the intestinal digesta.

Absorption↗