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In summary, the optimal model for the prevention of osteoporotic fractures includes maximization and maintenance of bone strength and minimization of trauma. Numerous determinants of each have been identified, but further work to develop preventative strategies based on these determinants remains to be undertaken. Physical activity is a determinant of peak BMD. There also is evidence that activity during growth modulates the external geometry and trabecular architecture, potentially enhancing skeletal strength, while during the adult years activity may reduce age-related bone loss. The magnitude of the effect of a 7% to 8% increase in peak BMD, if maintained through the adult years, could translate to a 1.5-fold reduction in fracture risk. Moreover, in the older population, appropriate forms of exercise could reduce the risk of falling and, thus, further reduce fracture risk. These data must be considered as preliminary in view of the paucity of long-term fracture outcome data from randomized clinical trials. However, current information suggests that the optimal form of exercise to achieve these objectives may vary through life. Vigorous physical activity (including weight-bearing, resistance, and impact components) during childhood may maximize peak BMD. This type of activity seems optimal through the young adult years, but as inevitable age-related degeneration occurs, activity modification to limit the impact component of exercise may become necessary. In the elderly, progressive strength training has been demonstrated to be a safe and effective form of exercise that reduces risk factors for falling and may also enhance BMD. In the frail elderly, activity to improve balance and confidence also may be valuable. Group activities such as Tai Chi may be cost-effective. Precise prescriptions must await the outcome of well-designed, controlled longitudinal studies that include fracture as an outcome. However, increased physical activity seems to be a sensible component of strategies to reduce osteoporotic fracture.

Osteoporosis among older women is a major public health problem. We studied the effects of three approaches to the prevention of osteoporosis in women with low bone density.One hundred twenty postmenopausal women (mean [+/- SD] age, 56 +/- 4) who were selected because they had low forearm bone density were enrolled in a double-blind, placebo-controlled, randomized study comparing the effects of an exercise regimen (exercise group, n = 41), exercise plus dietary calcium supplementation (exercise-calcium group, n = 39), and exercise plus continuous replacement of estrogen and progesterone (exercise-estrogen group, n = 40). Periodically during the two-year study period, we measured the women's bone density at three forearm sites, measured indexes of calcium metabolism, and recorded symptom scores. A comparison group of 42 women (mean age, 55.5 +/- 3.1) with normal bone density was also followed for two years.Significant bone loss in the distal forearm occurred in the group with normal bone density (control group) and the exercise group (change, -2.7 percent and -2.6 percent of the base-line value per year, respectively). Bone loss at the distal forearm site was significantly lower in the exercise-calcium group (-0.5 percent of the base-line value per year), and bone density increased at this site in the exercise-estrogen group (+2.7 percent of the base-line value per year). Bone loss at the median forearm site was significantly lower in the exercise-calcium group (-1.3 percent of the base-line value per year) than in the exercise group (-2.4 percent), and bone density at this site increased significantly in the exercise-estrogen group (+0.8 percent of the base-line value per year). Breast tenderness occurred in 47 percent of the women in the exercise-estrogen group but in only 20 percent in the other two treatment groups. Vaginal bleeding occurred at some time in 52 percent of the women who had not had a hysterectomy in the exercise-estrogen group, as compared with 11 percent and 12.5 percent, respectively, in the exercise and exercise-calcium groups.In postmenopausal women with low bone density, bone loss can be slowed or prevented by exercise plus calcium supplementation or estrogen-progesterone replacement. Although the exercise-estrogen regimen was more effective than exercise and calcium supplementation in increasing bone mass, it also caused more side effects.

There are uncertainties concerning the optimal threshold value of bone mineral density (BMD) for the diagnosis of osteoporosis using dual-energy X-ray absorptiometry (DXA). The most widely accepted clinical criteria are based on T- and Z-scores, derived statistically from an age-dependent BMD reference range that includes healthy young adults. This study has compared different analyses of BMD data of healthy, nonfractured, adult white females aged 18–90 years, consisting of 953 studied with DXA in the L1–L4 spine and 1018 measured at the hip. Four regression curves were applied to each reference data set; mean peak BMD (PBMD R ) and the age-independent standard deviation (SD R ) were calculated. These data, plus derived T-score thresholds, were compared with equivalent values (PBMD YN , SD YN ) determined from BMDs of a subgroup of young normals. Choice of regression curve caused a variation of 0.044 g/cm 2 in spinal PBMD R and 0.015–0.022 g/cm 2 in the hip. The variation in calculated SD R between the regressions was minimal (maximum variation, 0.03 SD unit in the spine). A split-linear model was chosen as the best overall fit for both the spine and the hip on the basis of goodness-of-fit and biological plausibility. PBMD R and PBMD YN varied by less than 1% at the spine or hip. Although the difference between SD R and SD YN was ≤7% for the hip sites, SD R was 0.022 g/cm 2 > SD YN for the spine (17% difference). At each hip site, BMD T-score thresholds, derived from regression analysis of the entire reference range (T R ) or from young normals only (T YN ), were not significantly different; however, equivalent spinal values differed by 0.062 g/cm 2 for T=–2.5. The percentage of the Australian female population (AFP) aged 50 yr or older and classified as osteoporotic, using population census data and the split-line-based T-score threshold of T R = –2.5, was 23% for spinal BMD and 17% for the total hip. For T YN = –2.5, the values were 36% (spine) and 17% (total hip). The hip BMDs of this study were greater than those of NHANES III in the third, seventh and eighth decades by as much as 0.6 SD. This produced a difference of 0.049–0.077 g/cm 2 for T YN = –2.5 between the two reference ranges. However, this study is in broad agreement with an Eastern Australian and the U.S. DXA manufacturer's reference range. It is concluded that (i) derivation of peak BMD and its standard deviation are critical for calculation of T-scores in the spine but not in the hip; (ii) there are significant differences between the hip peak BMDs of young normals, as derived from studies of similar populations in different regions, significantly affecting the impact of the subsequent clinical application of the calculated T-score.

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1 alpha1 (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and Longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0,0006), In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003), Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03), This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the P nu uII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Publisher Summary With the widespread use of glucocorticoids for systemic diseases affecting nearly every bodily system, exogenous glucocorticoid is an important cause of osteoporosis. This chapter highlights major aspects of advances as well as current perspectives on treatment options of glucocorticoid bone disease. The adverse effect of glucocorticoid therapy on bone mineral density (BMD) is not linear with time. Bone loss and fracture risk seems to be related, at least to some extent, to the dose and duration of glucocorticoid exposure. The risk of fracture increases rapidly after the commencement of glucocorticoid therapy, but decreases again after cessation of therapy. Glucocorticoids contribute to increased fracture risk through a number of direct and indirect mechanisms that result in accelerated bone loss. The bone loss is biphasic, precipitous during the first 12 months, and more gradual but continuous in subsequent years as measured by DXA or histomorphometry. There are several issues to consider in reviewing studies on the efficacy of therapies available for glucocorticoidinduced osteoporosis. These include primary versus secondary prevention, underlying disease states, and fracture prevention. A distinction needs to be made between primary and secondary prevention trials. The former commence at or soon after glucocorticoid therapy is begun, because the greatest rate of bone loss due to glucocorticoids occurs within the first 6–12 months of use. Secondary prevention, or treatment trials are those that commence after the subject has already taken glucocorticoids for a significant period of time and in whom bone loss has already occurred. Very few prospective studies have been undertaken in children to determine the long-term effects on bone mass of chronic glucocorticoid administration. However, as the large majority of peak bone mass is acquired during the first two decades of life, glucocorticoid exposure during this critical time of bone mass accrual may impact negatively on peak bone mass.

The microarchitecture of bone is regulated by complex interactions between the bone-forming and resorbing cells, and several compounds regulate both actions. For example, vitamin D, which is required for bone mineralization, also stimulates bone resorption. Transgenic mice overexpressing the vitamin D receptor solely in mature cells of the osteoblastic bone-forming lineage were generated to test the potential therapeutic value of shifting the balance of vitamin D activity in favor of bone formation. Cortical bone was 5% wider and 15% stronger in these mice due to a doubling of periosteal mineral apposition rate without altered body weight or calcium homeostatic hormone levels. A 20% increase in trabecular bone volume in transgenic vertebrae was also observed, unexpectedly associated with a 30% reduction in resorption surface rather than greater bone formation. These findings indicate anabolic vitamin D activity in bone and identify a previously unknown pathway from mature osteoblastic cells to inhibit osteoclastic bone resorption, counterbalancing the known stimulatory action through immature osteoblastic cells. A therapeutic approach that both stimulates cortical anabolic and inhibits trabecular resorptive pathways would be ideal for treatment of osteoporosis and other osteopenic disorders.

Potential determinants of bone mineral density (BMD) were studied cross-sectionally in 115 healthy, sexually mature Caucasian women aged 18 years. Bone mineral density (Hologic QDR1000W) of the lumbar spine, proximal femur (five sites), and distal tibia and fibula; fasting blood and urine calcium biochemistry; serum sex hormone levels (follicular phase); nutrient intakes; aerobic fitness; trunk muscle strength; and habitual activity levels were measured. The effects of heredity were considered by measuring the BMD of 107 of the subjects' mothers. Simple and stepwise regression analysis were used to identify significant determinants of BMD at each of the regions studied. The analysis indicated that significant bivariate correlations exist between BMD at all sites and body weight (r = 0.23-0.47, por = 0.01), lean body weight (r = 0.34-0.46), trunk strength (r = 0.27-0.47), physical activity score (r = 0.20-0.25), and aerobic fitness (r = 0.29-0.45). Dietary calcium intake correlated significantly with BMD at the trochanter site only (r = 0.19), and none of the biochemical or hormonal indices measured correlated consistently with BMD at any site. Significant correlations between the BMD of mothers and daughters ranged from r = 0.43 at lumbar spine to r = 0.34 at the intertrochanteric site. Paired t-tests showed the daughters had significantly (p0.03) lower BMD than their mothers at the lumbar spine (98 +/- 12% [mean +/- SD]) and significantly higher (p0.002) BMD at the femoral neck, trochanter, and total hip sites (110 +/- 16%, 108 +/- 17%, 103 +/- 14%, respectively). When stepwise regression analysis included weight-corrected strength of the trunk flexor muscles (Corr Flex), weight-corrected aerobic fitness (Corr VO2max), physical activity score, and body weight, body weight was the only significant determinant of BMD at all sites. Corr Flex made significant contributions at all sites except the femoral neck, while Corr VO2max made additional contribution at the femoral neck, trochanter, total hip, and shaft of femur sites. These variables accounted for 13-27% of the variance in BMD. The addition of mother's BMD to these independent variables, in stepwise regression analysis, improved the prediction to 18-31% of the variance.