Considers factors relating to bone loss. Looks at the scientific background with regard to calcium and its effects with regard to bone loss. Reports on the aims of a study in this area which will involve factors such as the measurement of bone loss and a thorough nutritional analyses.
\n \n\n \n \nEstrogen withdrawal in women leads initially to rapid bone loss caused by increased numbers or activity of osteoclasts. We previously have noted apoptosis of lacunar osteocytes associated with conditions of high bone turnover. Therefore, in this study, we investigated whether the increased bone loss associated with GnRH analogue (GnRH-a)-induced estrogen withdrawal affects osteocyte viability in situ in a way that would be directly contrary to the effect of estrogens on osteoclast viability. Transiliac biopsies were obtained from six premenopausal women, between 30-45 yr old, diagnosed as having endometriosis. Biopsies were taken before and after 24 weeks of GnRH-a therapy. Biopsies were snap-frozen and cryostat sectioned. Osteocyte viability, determined by the presence of lactate dehydrogenase (LDH) activity, was reduced in all but one subject after treatment. Furthermore, in every subject, the proportion of osteocytes showing evidence of DNA fragmentation typical of apoptosis increased, as demonstrated using in situ DNA nick translation (P = 0.008). Gel electrophoresis of extracted DNA and morphological studies of chromatin condensation and nuclear fragmentation confirmed that changes typical of apoptosis were affecting the osteocytes. It was concluded that GnRH-a therapy caused a higher prevalence of dead osteocytes in iliac bone, probably caused by the increase in the observed proportion of osteocytes showing apoptotic changes. The capacity of bone to repair microdamage and to modulate the effects of mechanical strain is currently believed to be dependent on osteocyte viability. Our findings have therefore revealed a possible mechanism whereby estrogen deficiency could lead to increased bone fragility with or without an accompanying net bone loss.
\n \n\n \n \nThe effects of estrogen suppression on osteonal remodeling in young women was investigated using transiliac biopsies (eight paired biopsies + four single pre; three single post biopsies) taken before and after treatment for endometriosis (6 months) with analogs of gonadotrophin releasing hormone (GnRH). Estrogen withdrawal increased the proportion of Haversian canals with an eroded surface (106%, p = 0.047), a double label (238%, p = 0.004), osteoid (71%, p = 0.002), and alkaline phosphatase (ALP) 116%, p = 0.043) but not those showing tartrate-resistant acid phosphatase (TRAP) activity (p = 0.25) or a single label (p = 0.30). Estrogen withdrawal increased TRAP activity in individual osteoclasts in canals with diameters greater than 50 microns (p = 0.0089) and also the number of osteons with diameters over 250 microns (p = 0.049). ALP activity in individual osteoblasts was increased but not significantly following treatment (p = 0.051). Wall thickness was significantly correlated with osteon diameter (p < 0.001). In a separate group of patients (four pairs + one post biopsy) on concurrent treatment with tibolone, there was no significant increase in the osteon density, cortical porosity, median canal diameter, or the markers of bone formation and resorption. Enzyme activities and numbers of active canals were also not increased with the concurrent treatment, but there was still an increase in the osteon diameter. As previously shown for cancellous bone, estrogen withdrawal increased cortical bone turnover. We have now shown that resorption depth within Haversian systems was also increased with treatment. The enhanced TRAP activity in individual osteoclasts supports the concept that osteoclasts are more active following estrogen withdrawal in agreement with theoretical arguments advanced previously. Understanding the cellular and biochemical mechanisms responsible for increased depth of osteoclast resorption when estrogen is withdrawn may allow the development of new strategies for preventing postmenopausal bone loss.
\n \n\n \n \nPrevious work on bone growth and biomechanics suggests that osteocytes might sense the requirement for bone remodeling and signal to cells in the basic multicellular unit that undertake this function. The present study looked for evidence of apoptosis in human osteocytes in adult, pediatric, and pathological bone to compare these situations of differing levels of turnover and considered the possibility of a functional role for this death mechanism in bone modeling and remodeling. Apoptosis was identified in bone tissue by agarose gel electrophoresis of DNA (to demonstrate DNA ladders). In cryostat sections it was possible to visualize individual cells with fragmented DNA in situ using a modified nick translation technique (NT). In addition, visualization of apoptotic morphology was undertaken using light and electron microscopy. Adult femoral head and iliac crest bone showed no evidence of DNA ladders and very small numbers of osteocytes with DNA fragmentation using NT. In contrast, samples of pediatric calvaria, adult heterotopic bone, and osteophytes all displayed characteristic laddering of extracted DNA and showed evidence of potentially apoptotic osteocytes in situ using NT. In agreement with these findings, transmission electron microscopy showed numbers of osteocytes in infant calvaria with advanced chromatin condensation and cell shrinkage indicative of apoptosis. Since all three types of positive bone are involved in rapid matrix turnover, apoptotic changes in human osteocytes in vivo might be related in general terms to the modeling and remodeling activity level of the bone sampled. It was further found that the distribution of potentially apoptotic cells in the infant and pathological bone was anatomically nonuniform, raising the intriguing possibility of a functional relationship between bone turnover and the controlled cell death of osteocytes.
\n \n\n \n \nOBJECTIVE: To investigate possible mechanisms of growth impairment in children with juvenile rheumatoid arthritis (JRA). METHODS: Eighteen prepubertal children with JRA and growth retardation received recombinant human growth hormone (rHuGH) for 1 year. Growth hormone profiles over 24 hours were obtained before treatment in 12 patients; the levels did not differ from those in \"short normal\" children. Levels of insulin-like growth factor 1 (IGF-1), IGF binding proteins (IGFBPs) 1 and 3, insulin, osteocalcin, and C-reactive protein (CRP), as well as the erythrocyte sedimentation rate were measured serially. Pretreatment levels were compared with control levels. RESULTS: In JRA patients, IGF-1, IGFBP-3, and osteocalcin levels were significantly lower and insulin levels significantly higher than those in controls, but there was no significant difference in the level of IGFBP-1. With rHuGH treatment, height velocity and mean levels of IGF-1, osteocalcin, and insulin increased significantly, while mean levels of IGFBP-1 fell significantly. Levels of IGFBP-3 correlated with those of IGF-1. The height velocity correlated positively with IGF-1 and osteocalcin, and negatively with IGFBP-1. Levels of IGFBP-1 were inversely related to those of insulin and IGF-1. There was a significant negative correlation between the CRP and height velocity, IGF-1 level, and osteocalcin level. CONCLUSION: IGF-1 production is impaired in children with active JRA. Treatment with a therapeutic dose of rHuGH can rectify the IGF-1 deficiency within 4 days, but its effect is adversely influenced by the acute-phase response, as reflected by an elevated CRP level.
\n \n\n \n \nThe pyridinium cross-links of collagen pyridinoline (Pyd) and deoxypyridinoline (Dpd) are released during bone resorption and are neither metabolized nor absorbed from the diet. The aim of this study was to validate their use in osteoporosis. We studied 19 women with osteoporosis and estimated the bone resorption rate from a combined calcium balance/kinetics technique without (R) and with partial (R(H)) and \"complete\" (Res) correction for long-term exchange. The strongest correlation was observed between the bone-specific marker (Dpd) and with complete correction for long-term exchange (Res) (r = 0.71, p < 0.001). The intercept was not different from zero, suggesting that bone was the major source for Dpd. The crude ratio of Dpd to Res in the 19 women was 54.5; but the regression coefficient relating Dpd as the dependent variable to Res was 31.8 (95% CI 15.6-48.0), which was higher, but not significantly, than the ratio between Dpd and calcium (16.4) in 10 bone samples (cortical and trabecular bone). The weakest correlations between a biochemical marker and a kinetic index were those between hydroxyproline (a nonspecific marker of bone resorption) and R or R(H). Treatment with hormone replacement therapy (HRT) or HRT and parathyroid hormone peptide 1-38 in seven women over 1 year resulted in similar percent changes in the biochemical markers and estimates of bone resorption. We conclude that the measurement of Dpd provides a reasonably accurate assessment of bone resorption in osteoporosis, and in the context of several repeat 24-h collections of urine offers measurement precision that is similar to that obtainable with methods depending on the use of radioisotopic tracers and the assessment of metabolic calcium balance.
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