Faculty Bibliography

OBJECTIVE: To determine whether augmentation of dietary calcium is effective in the prevention of early postmenopausal bone loss. DESIGN: Three-arm, placebo-controlled, randomized parallel trial. The study duration was 2.9 +/- 1.1 (SD) years. SETTING: General community. PARTICIPANTS: 118 healthy, white women 3 to 6 years after spontaneous menopause, recruited by community announcement. INTERVENTIONS: Random allocation to daily intake of 1700 mg of calcium (calcium carbonate given in divided doses with meals); placebo; or conjugated equine estrogens (0.625 mg; days 1 to 25), progesterone (10 mg; days 16 to 25), and 1700 mg of elemental calcium daily. Each participant received 400 IU of vitamin D daily. MAIN OUTCOME MEASURES: Total body calcium measured by delayed gamma neutron activation analysis and whole-body counting; bone mineral density of the spine, femur, and radius measured by photon absorptiometry. RESULTS: Bone mineral density declined in the placebo group for the lumbar spine (-2.1%/y; 95% Cl, -3.3 to -0.9), femoral neck (-2.0%/y; Cl, -2.6 to -1.2), trochanter (-1.6%/y; Cl, -2.4 to -0.8), Ward triangle (-2.7%/y; Cl, -3.7 to -1.7), and total body calcium (-2.0%/y; Cl, -2.2 to -1.8). Rates of change were intermediate for calcium augmentation compared with placebo and estrogen-progesterone-calcium but statistically significant compared with placebo for total body calcium (-0.5%/y; Cl, -0.9 to -0.1; P = 0.006) and the femoral neck (-0.8%/y; Cl, -1.4 to -0.2; P = 0.03). CONCLUSIONS: Although less effective than estrogen-progesterone-calcium, calcium augmentation alone significantly retards bone loss from the femoral neck and improves calcium balance in recently postmenopausal women. Dietary calcium augmentation should be recommended as a strategic option in helping to prevent early postmenopausal bone loss.

Growth factors may be mediators of local and systemic factors that enhance bone formation. This study examined the effect of treadmill exercise and ovine growth hormone administration on levels of insulin-like growth factor I (IGF-I) in serum (ng/ml), long bone, and vertebrae and on bone formation rate. Forty female rats were divided into four groups: control; exercise (17 m/min, 1 h/day); growth hormone (0.05 mg.100 g-1.day-1); growth hormone plus exercise. After 9 wk of study, the serum levels of IGF-I were higher in the intervention groups than in the control group; however, the IGF-I concentration and the periosteal bone formation rate in the long bone were significantly higher only in the exercised rats. The IGF-I concentration and the cancellous bone formation rate in the vertebrae did not differ among the experimental groups. The vertebral and long bone formation rate were correlated with bone concentrations of IGF-I. Serum levels of IGF-I were also correlated with serum osteocalcin and the long bone formation but not with the vertebral bone formation. The association of bone formation with serum and bone IGF-I supports the suggestion that IGF-I is one of the growth factors that regulate bone formation, in particular as a mediator of the response of bone to exercise.

To determine whether growth hormone administration would potentiate bone response to the stimulation of exercise, 80 female rats aged 14 months were divided into control (CON), ovine growth hormone administration (0.5 mg/kg daily) (GH), treadmill exercise (17 m/minute, 60 minutes daily) (EX), and GH+EX groups for 9 and 16 weeks. Static and dynamic histomorphometry were measured on the tibial shaft and (L-5) vertebral cortical bone. The periosteal and endocortical bone formation rate of the tibial shaft were higher in both EX and GH+EX than in the CON group in the 9-week study. There is a synergistic interaction between the two interventions in both cortical surfaces. After 16 weeks of study, the cortical bone area and periosteal bone formation rate were higher only in the EX than in the CON group. In the L-5 vertebra, the labeled surface on the periosteum was higher in the EX and the bone formation rate on the endocortical surface was higher in the GH than in the CON group. However, there was a negative interaction when the two interventions were combined. We conclude that a low-dose of growth hormone administration could initially potentiate long bone response to exercise. However, from the present study, long-term treatment with low-dose growth hormone administration does not enhance the increase in bone mass from exercise.

Dual-energy x-ray absorptiometry and dynamic histomorphometry were used to examine the effect of treadmill exercise on the bone density and cancellous bone formation and resorption in the proximal tibia and fifth lumbar vertebra (L5) of the aged female rat. Female rats aged 14 months were divided into four groups: 8 controls and 10 exercised for a 9 week study and 8 controls and 9 exercised for a 16 week study. Exercise consisted of running on a flat-bed treadmill, 17 m/minute, 1 h/day, 5 days/week. Tibial metaphysis and L5 vertebral density of each rat were measured in the 16 week study by DXA at weeks 0, 9, and 16. Compared to the control group, a significant increase in bone density in both metaphyseal tibia and L5 vertebra was apparent at 16 weeks after exercise training (P = 0.046 and 0.025, respectively, by two-way ANOVA). Histomorphometric analysis showed that the trabecular bone eroded surface and the ratio of eroded to mineralizing surface in tibial metaphysis were significantly lower in the exercised than in the respective control group in both the 9 and 16 week studies. In L5 vertebra, these decreases by exercise were apparent only in the 16 week study. A significant increase in the bone formation rate was apparent in the cancellous bone of the tibia but not of the vertebra after 16 weeks of exercise (P < 0.05). The trabecular architecture (bone number and separation) of the L5 vertebra in the exercised rats did not differ from that of the controls in either study.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of 17 beta-estradiol (E2) and treadmill exercise on tibial bone mass, tibial uptake of 45Ca, and proximal tibia osteoblast and osteoclast cell number were determined in adult ovariectomized rats. Female rats aged 10 months were ovariectomized and divided into five groups: (1) sham-operated; (2) ovariectomized; (3) ovariectomized, given 10 micrograms E2 biweekly; (4) ovariectomized, trained to exercise on a treadmill daily; and (5) ovariectomized, given E2 and exercised. E2 and/or exercise interventions were started 2 months following surgery and continued for 4 months. The calcium content of the tibial metaphysis and diaphysis and the proximal cancellous bone (BV/TV) were lower in the ovariectomized than in the sham-operated controls 6 months after ovariectomy. This lower bone content was associated with a greater bone uptake of 45Ca and a greater number of osteoblasts and osteoclasts in the proximal tibia compared to the control rats. The metaphyseal calcium content was higher and the 45Ca uptake and osteoblast and osteoclast number were lower in the E2-treated rats than in the nontreated rats. In the exercised group, higher diaphyseal calcium content and proximal cancellous bone were associated with lower bone resorption parameters without a significant effect on bone formation. This study demonstrates that E2 primarily influences tibial cancellous bone of the ovariectomized rat and a positive adaptation to exercise occurs in both cancellous and cortical bone. Under estrogen deficiency, E2 replacement suppresses increased bone formation and resorption; exercise suppresses mainly bone resorption. The effects of E2 replacement and exercise training are independent and additive.

Dual energy X-ray absorptiometry (DXA; Hologic QDR-1000W) in an ultrahigh-resolution mode, was used to examine the changes in tibial/fibula and vertebral L4 + L5 bone mineral content (BMC) and bone mineral density (BMD) in each 14-month-old female rat at 0, 9, and 16 weeks of study. Twenty rats were randomized by a stratified weight method into two groups, control and exercised. Exercise consisted of running on a flat-bed treadmill, 17 m/minute, 1 hour/day and 5 days/week. As compared with the control group, a significant increase in tibia/fibula BMC and vertebral BMD was apparent at 9 weeks after exercise training (P = 0.014 by 2-way analysis of variance). The slope of the gain of the tibia/fibula BMC and BMD by 16 weeks of training was ninefold and fivefold higher than that of the control group (P < 0.01 and P < 0.05, respectively, by Mann-Whitney test). The correlation coefficient (r) between the final dry weight of excised bone and the final BMC of the intact rat was 0.843 and 0.71 for tibia/fibula and vertebrae, respectively. In summary, we found that in the aged rat, by 9 weeks, exercise increases BMC and BMD in the tibia, whereas in the vertebrae, only increases in the BMD were found. This study demonstrates that this precise and accurate DXA technique is useful in a longitudinal study of in vivo bone mineral changes in the rat over time by taking into account the individual variation between animals as well as changes between groups.