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Both late menarcheal age and low calcium intake (Ca intake) during growth are risk factors for osteoporosis, probably by impairing peak bone mass. We investigated whether lasting gain in areal bone mineral density (aBMD) in response to increased Ca intake varies according to menarcheal age and, conversely, whether Ca intake could influence menarcheal age. In an initial study, 144 prepubertal girls were randomized in a double-blind controlled trial to receive either a Ca supplement (Ca-suppl.) of 850 mg/d or placebo from age 7.9-8.9 yr. Mean aBMD gain determined by dual energy x-ray absorptiometry at six sites (radius metaphysis, radius diaphysis, femoral neck, trochanter, femoral diaphysis, and L2-L4) was significantly (P = 0.004) greater in the Ca-suppl. than in the placebo group (27 vs. 21 mg/cm(2)). In 122 girls followed up, menarcheal age was recorded, and aBMD was determined at 16.4 yr of age. Menarcheal age was lower in the Ca-suppl. than in the placebo group (P = 0.048). Menarcheal age and Ca intake were negatively correlated (r = -0.35; P < 0.001), as were aBMD gains from age 7.9-16.4 yr and menarcheal age at all skeletal sites (range: r = -0.41 to r = -0.22; P < 0.001 to P = 0.016). The positive effect of Ca-suppl. on the mean aBMD gain from baseline remained significantly greater in girls below, but not in those above, the median of menarcheal age (13.0 yr). Early menarcheal age (12.1 +/- 0.5 yr): placebo, 286 +/- 36 mg/cm(2); Ca-suppl., 317 +/- 46 (P = 0.009); late menarcheal age (13.9 +/- 0.5 yr): placebo, 284 +/- 58; Ca-suppl., 276 +/- 50 (P > 0.05). The level of Ca intake during prepuberty may influence the timing of menarche, which, in turn, could influence long-term bone mass gain in response to Ca supplementation. Thus, both determinants of early menarcheal age and high Ca intake may positively interact on bone mineral mass accrual.

Stature, bone size, and bone mass are interrelated traits with high heritability, but the major genes that govern these phenotypes remain unknown. Independent genomewide quantitative-trait locus studies have suggested a locus for bone-mineral density and stature at chromosome 11q12-13, a region harboring the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Mutations in the LRP5 gene were recently implicated in osteoporosis-pseudoglioma and "high-bone-mass" syndromes. To test whether polymorphisms in the LRP5 gene contribute to bone-mass determination in the general population, we studied a cross-sectional cohort of 889 healthy whites of both sexes. Significant associations were found for a missense substitution in exon 9 (c.2047G-->A) with lumbar spine (LS)-bone-mineral content (BMC) (P=.0032), with bone area (P=.0014), and with stature (P=.0062). The associations were observed mainly in adult men, in whom LRP5 polymorphisms accounted for

Osteoporosis is a major public health problem with an increase of its prevalence with age and growing consequences because of the increase of life expectancy. Peak bone mass which corresponds to the amount of bony tissue present at the end of skeletal maturation, is a major determinant of the risk of fractures, such as those observed at the radial, vertebral, or femoral sites in osteoporotic patients. Therefore, strategies of primary prevention of osteoporosis and associated fractures consist in increasing bone mass acquisition during skeletal growth. Physical activity and some nutrients such as calcium and proteins may influence positively the trajectory of bone mass acquisition and therefore increase peak bone mass.

Osteoporosis is a major public health problem with an increase of its prevalence with age and growing consequences because of the increase of life expectancy. Peak bone mass, which corresponds to the amount of bony tissue present at the end of skeletal maturation, is a major determinant of the risk of fractures, such as those observed at the radial, vertebral, or femoral sites in osteoporotic patients. Therefore, strategies of primary prevention of osteoporosis and associated fractures consist in increasing bone mass acquisition during skeletal growth. Some nutrients such as calcium and proteins may influence positively the trajectory of bone mass acquisition and therefore increase peak bone mass.

Malnutrition, most notably protein deficiency, contributes to the occurrence of osteoporotic fractures not only by decreasing bone mass but also by altering muscle function. Furthermore, malnutrition is associated with increased morbidity in patients with osteoporotic fractures. The somatomedin system (IGF-1) may be directly involved in the pathogenesis of osteoporotic hip fractures and their complications in elderly patients. A low IGF-1 level is a risk factor for hip fracture. In subjects with appropriate intakes of vitamin D and calcium, giving protein supplements to correct an inadequate spontaneous protein intake increases circulating IGF-1 levels, improves clinical outcomes after hip fracture, and prevents bone mineral density loss at the proximal femur. Supplemental protein also significantly reduces the length of inpatient rehabilitation care. These data emphasize the importance of adequate nutrient intake in the prevention and treatment of osteoporotic fractures.

Among osteotrophic nutrients, proteins play an important role in bone development, thereby influencing peak bone mass. Consequently, protein malnutrition during development can increase the risk of osteoporosis and of fragility fracture later in life. Both animal and human studies indicate that low protein intake can be detrimental for both the acquisition of bone mass during growth and its conservation during adulthood. Low protein intake impairs both the production and action of IGF-I (Insulin-like growth factor-I). IGF-I is an essential factor for bone longitudinal growth, as it stimulates proliferation and differentiation of chondrocytes in the epiphyseal plate, and also for bone formation. It can be considered as a key factor in the adjustments of calcium-phosphate metabolism required for normal skeletal development and bone mineralization during growth. In healthy children and adolescents, a positive association between the amount of ingested proteins and bone mass gain was observed in both sexes at the level of the lumbar spine, the proximal femur and the midfemoral shaft. This association appears to be particularly significant in prepubertal children. This suggests that, like for the bone response to either the intake of calcium or weight-bearing exercise, the skeleton would be particularly responsive to the protein intake during the years preceding the onset of pubertal maturation.

ACTION OF PTH: Parathyroid hormone (PTH) stimulates both bone formation and bone resorption. It also stimulates synthesis of 1,25-dihydroxyvitamin D3 which increases intestinal absorption of calcium and phosphorus and stimulates bone resorption. In bone tissue, PTH acts mainly on osteoblasts which, unlike osteoclasts, carry PTH receptors. PTH also exerts an indirect action on osteoclasts, increasing their number and activity. IMPACT OF INSUFFICIENT PTH: In the absence of PTH, bone remodeling is greatly reduced. Increased bone density has been observed in patients with hypoparathyroidism studied 10 years after total thyroidectomy. IMPACT OF EXCESS PTH: Chronic excess of PTH accelerates bone loss. In primary hyperparathyroidism, reduction of bone density to the order of 10% has been observed, which corresponds to one standard deviation compared with normal subjects of the same age and sex. The hypothesis of an increased risk of fractures remains unresolved. ADMINISTRATION OF PTH: Intermittent rather than continuous subcutaneous administration appears to be necessary to observe the anabolic effects of PTH on bone. The conjunction of favorable anabolic effects demonstrated in animal models, concerning both bone density and mechanical properties, and early studies in humans, provide converging arguments similar to those observed in preclinical investigations, suggest that PTH could be a promising treatment for osteoporosis.

Glucocorticoids (GCs) inhibit bone formation in vivo and inhibit osteoblast proliferation and collagen synthesis in vitro. These effects may be mediated by alterations in the insulin-like growth factor (IGF) system. In the present study of normal human osteoblast-like (HOB) cells, we tested the hypothesis that dexamethasone (Dex) inhibits IGF anabolic activity in bone by altering expression of IGF binding proteins (IGFBPs), particularly by decreasing expression of IGFBP-5 and IGFBP-3 (which enhance IGF activity) and increasing expression of IGFBP-4 (which inhibits IGF actions). Dexamethasone treatment caused a dose-dependent inhibition of HOB cell proliferation (69 +/- 4% of control at 10(-8) mol/l Dex) in seven separate experiments. Dexamethasone decreased IGFBP-5 mRNA levels to 20-30% of control (10(-8) and 10(-7) mol/l for 24 h). In six of six HOB preparations, 10(-8) mol/l Dex decreased IGFBP-5 mRNA levels (35 +/- 7% of control) and this effect was time dependent. Dexamethasone also decreased IGFBP-3 mRNA levels (74 +/- 9% of control in three HOB preparations). Dexamethasone decreased secretion of 29-31-kD IGFBP-5 and 38-42-kD IGFBP-3 proteins, determined by Western ligand blot and IGFBP-5 immunoblot, and induced a dose-dependent decrease in IGFBP-3 and IGFBP-5 secretion determined by specific radioimmunoassays. The effects of Dex on IGFBP-4 mRNA and on secretion of 25-kD IGFBP-4 levels were inconsistent between different cell preparations. Results suggest that GC inhibition of IGFBP-5 and IGFBP-3 production could decrease IGF activities and contribute to GC inhibition of bone formation.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced by immune cells, which has multiple effects on bone cells and is therefore thought to mediate changes in bone metabolism occurring during inflammation. In the present study we have investigated the effect of TNF-alpha on the secretion of insulin-like growth factor I (IGF-I) and IGF binding protein 4 (IGFBP-4) by clonal mouse osteoblasts (MC3T3-E1 cells) using subconfluent in vitro cultures and serum-free conditions. The IGF-I was determined by radioimmunoassay under conditions eliminating the interference of IGFBPs. Treatment of MC3T3-E1 cultures with TNF-alpha for 24 h resulted in a dose-dependent decrease in IGF-I secretion (maximally to 34 +/- 9.7% of control with 60 pmol/l TNF-alpha; mean +/- SD). The TNF-alpha treatment also resulted in decreased messenger ribonucleic acid (mRNA) levels of IGF-I at 4 and 24 h, as detected by Northern analysis. Because basal secretion of IGFBPs is very low in MC3T3-E1 cells, effects of TNF-alpha on IGFBP secretion were studied in cultures in which IGFBP-4 expression was increased by calcitriol (1,25(OH)2D3) treatment. The presence of TNF-alpha (600 pmol/l) inhibited this calcitriol-induced stimulation of IGFBP-4 mRNA levels from 4 h onwards, with complete inhibition of the calcitriol effect occurring at 24 h. We also observed a dose-dependent inhibition of calcitriol-stimulated IGFBP-4 secretion into the culture medium (as detected by Western ligand blot), with the maximal inhibition occurring with 600 pmol/l TFN-alpha to 25 +/- 7% of control levels.(ABSTRACT TRUNCATED AT 250 WORDS)