Faculty Bibliography

Dual-energy X-ray absorptiometry (DXA) has recently been applied to the measurement of body composition using a three-compartment model consisting of fat, lean and bone mineral. The mass of skeletal muscle may be approximated by measurement of the lean tissue mass of the extremities. In addition, body fat distribution can be estimated by determining the ratio of fat in the trunk to the fat in the extremities. In the current study, DXA was used to compare body composition and fat distribution between black (n = 162) and white women (n = 203). Black women had a higher mineral mass and a higher skeletal muscle mass. The ratio of mineral to muscle mass was higher in black women, even when the data were adjusted for age, height and weight. Both total body bone mineral and muscle mass declined with age in both races, with evidence for an accelerated loss of bone mineral after menopause. Body size (height and weight) was generally a significant variable in developing regressions of each compartment against age. Their higher musculoskeletal mass may lead to misclassification of 12% of black women as obese if body mass index is used as an index of obesity. Body fat distribution (trunk/leg) did not differ between races in the raw data. However, for women of the same age, height and weight, white women have a significantly higher trunk/leg fat ratio. Body composition values for fat, lean and bone mineral obtained from DXA should be adjusted not only for gender but also for age, height, weight and ethnicity.

We measured the ultrasound parameters of the heels of 49 women with vertebral fractures and 87 age-matched controls using an Achilles ultrasound device. Average broadband ultrasound attenuation (BUA), speed of sound (SOS) and Stiffness were significantly lower in fracture patients (p < 0.0001). We also estimated the ultrasound parameters of patients compared with age-matched non-fracture controls and found the mean BUA to be -1.02 SD below control values. The mean SOS was -0.97 SD and the mean Stiffness was -1.12 SD below control values. Femoral bone mineral density (BMD) at the neck, Ward's triangle and the trochanter, the total-body BMD and L2-4 BMD were measured with dual-energy X-ray absorptiometry (DXA) and found to be significantly lower in fracture patients (p < 0.0001). All correlation coefficients between ultrasound parameters and DXA measurements were > 0.5 and statistically significant (p < 0.0001). A stepwise logistic regression with presence or absence of vertebral fracture as the response variable and all ultrasound--DXA parameters as the explanatory variables indicated that the best predictor of fracture was Stiffness, with additional predictive ability provided by spine BMD. Sensitivity and specificity of all measures were determined by the areas under the receiver operating characteristic (ROC) curve, which were 0.76 +/- 0.04 for BUA, 0.77 +/- 0.04 for SOS, 0.78 +/- 0.04 for Stiffness and 0.78 +/- 0.03 for spine BMD. The areas under the ROC curves of BUA, SOS, Stiffness and spine BMD were compared and it was found that Stiffness and spine BMD were significantly better predictors of fracture than BUA and SOS. These results support many recent studies showing that ultrasound measurements of the os-calcis have diagnostic sensitivity comparable to DXA, and also demonstrated that Stiffness was a better predictor of fracture than spine BMD.

Water compartments were studied in 72 black and 128 white women, aged 20 to 70 years. Total body water (TBW) was measured by tritiated water dilution, and extracellular water (ECW) was measured by using delayed gamma neutron activation for the determination of total body chloride. Intracellular water (ICW) was assessed as the difference between TBW and ECW. Fat-free mass (FFM) was estimated by the measurement of total body potassium (TBK) and total body fat (TBF) by measurement of total body carbon (TBC). Total body protein was calculated from total body nitrogen (TBN). TBW was found to decline with age and to also be significantly influenced by body size. The extracellular water space was 41.5% of TBW. The decline of TBW with age is due primarily to a decline in ICW. The hydration of the FFM increased with age for the overall population because of a decline in TBK and TBN and an increase in ECW. Body composition models that have assumed constancy of hydration should be adjusted not only for gender but for age and body size.

Weight and age may influence the levels of indexes of bone remodeling and the calciotropic hormones. In a study of interracial differences in these women, our black population was heavier than our white population. We therefore matched a subset of 96 black and 96 white women from our larger population for age and weight to determine whether a racial difference exists independent of the effects of weight and age. In addition, we were able to measure other indexes of bone remodeling (N-telopeptide of cross-linked collagen and pyridinoline cross-links), as well as hormones that may influence calcium metabolism (insulin-like growth factor-1 (IGF-1), insulin, calcitonin, and gastrin) in this subset. All indexes of bone remodeling were lower in black women. Black postmenopausal women had lower serum levels of calcidiol and higher parathyroid hormone (PTH) levels. The higher bone mass of black women is associated with lower bone remodeling in the presence of skeletal resistance to PTH. Serum IGF- 1, insulin, and calcitonin levels did not differ significantly between races. Serum gastrin levels were higher in black women. The higher levels of gastrin in black women should be investigated further for its possible effect on the absorption of calcium salts.

Prostaglandin E2 (PGE2) is an anabolic agent of bone in vivo but the mechanism of its action still remains unclear. The aim of this study was to determine whether the effect of PGE2 on skeleton is mediated by pituitary hormones. Forty female, Sprague-Dawley rats were divided into four groups: baseline control (basal), age-matched intact control (CON), hypophysectomy (HX), and HX + PGE2 (2 mg/kg/day) with 10 animals in each group. The basal group was sacrificed at 2 months of age, and the remaining groups after 6 weeks of treatment. Cancellous and cortical bone histomorphometry was performed on double fluorescent-labeled 40 micron-thick sections of the proximal tibia and tibial shaft. Our results show that HX resulted in a cessation of bone growth, a decrease in cancellous bone volume, and cortical bone gain compared with the age-matched, intact CON rats. Compared with the HX group, the HX + PGE2 group had a significantly greater tibial bone density (mean +/- SE, HX + PGE2:1.595 +/- 0.007 versus HX:1.545 +/- 0.013), percent cancellous bone volume (21.4 +/- 2.0 versus 8.41 +/- 1.70), percent cortical bone area (87.2 +/- 0.85 versus 81.7 +/- 0.7), and ratio of cortical area to marrow area (7.14 +/- 0.56 versus 4.52 +/- 0.21). Increased bone masses by PGE2 in the HX animals were accompanied by an increase in the trabecular and endosteal-labeled surface and bone formation rate. The trabecular number and width were increased whereas trabecular separation was decreased in the HX + PGE2 group compared with the HX group (P < 0.05). PGE2 treatment also caused a decrease in the tibial endosteal eroded surface and medullar cavity of the HX animals. In conclusion, this study clearly demonstrates that PGE2 (2 mg/kg/day) in the HX rats increases both cortical and cancellous bones and improves trabecular architecture in the tibia after 6 weeks of treatment. These skeletal alterations are due to a stimulation of bone formation and a suppression of bone resorption activity. These findings suggest that the anabolic effect of PGE2 in bone is independent of pituitary hormones.

Black women have 40% of the incidence rate for hip fracture and have a higher bone mineral density (BMD) than white women. The possibility was raised that bone quality may be disproportionately greater than the advantage in bone density in protection against osteoporotic fractures in black versus white women. Ultrasound (US) of the calcaneus is believed to measure properties of bone in addition to its density. We performed bone density measurements and US of the calcaneus in 108 black and 177 healthy white women, aged 20-70 years. The highest correlation was seen between total body bone density and speed of sound (r = 0.75). The interracial differences in BMD were all statistically significant and varied from 3.4 to 7.6%. The US measurements had lesser interracial differences than the bone density measurements, with velocity barely different between races. These findings suggest that US of the calcaneus measures properties of bone different from density. Fracture prediction data using US from prospective data in white women should not be extrapolated to black women because of the discordance between bone density and US measurements. Prospective studies are needed comparing US measurements in black women to the occurrence of osteoporotic fractures.

To investigate whether growth hormone (GH) and 17beta-estradiol (E2) replacement can prevent osteopenia induced by pituitary and ovarian hormone deficiency [by hypophysectomy and ovariectomy (HX+OV)], we administered relatively low doses of GH (2.3 IU x kg(-1) x day(-1)) and E2 (100 microg x kg(-1) x wk(-1)) in experiment 1 and relatively high doses of GH (13.5 IU x kg(-1) x day(-1)) and E2 (3,500 microg x kg(-1) x wk(-1)) in experiment 2 to 2-mo-old HX+OV Sprague-Dawley rats for 6 wk. Our data show that the HX+OV of rats results in diminished periosteal bone formation, longitudinal bone growth, and decreased cancellous bone volume. Administration of either the low or high dose of GH to these rats increased their systemic growth, serum levels of osteocalcin, and cortical bone formation. Either low or high doses of GH or E2 alone only partially prevent cancellous bone loss. However, the combined treatment of GH plus E2 resulted in an additive increase in the cancellous bone mass. We conclude that the additive effect of GH plus E2 on cancellous bone is attributed to the suppressive effect of E2 on bone resorption and the anabolic effect of GH on bone formation.

BACKGROUND: In previous studies we found that the cause of bone loss in young hypophysectomized (HX) animals was due primarily to an inhibition in growth-dependent bone gain and a decrease in bone turnover. The aim of this study was to determine whether growth hormone, which has stimulatory effects on bone growth and turnover, can prevent HX-induced skeletal alterations in rats. METHODS: Female Sprague-Dawley rats were divided into baseline control (BASAL), age-matched control (CON), HX, HX plus low-dose GH (1.5 mg/kg/d, subcutaneously), and HX plus high-dose GH (4.5 mg/kg/d) groups. The BASAL group was sacrificed at 2 months of age and the remaining groups were sacrificed after 6 weeks of treatment. Cancellous and cortical bone histomorphometry was performed on double-fluorescent-labeled 40 microm-thick sections of the proximal tibia and tibial shaft. RESULTS: Both low- and high-dose GH prevented the HX-induced decrease of IGF-I serum levels. High-dose GH also significantly increased the body weight and the wet weight of the gastrocnemius muscle when compared to the CON groups. In the tibial shaft, the periosteal labeled surface, mineral apposition rate and bone formation rate were higher in both of the GH-treated groups than in the HX group (P < 0.05). The tissue area and cortical bone area of the high-dose GH-treated rats were greater than those of the HX rats, but did not differ from those of the CON rats. In the proximal tibia, both low- and high-dose GH prevented an HX-induced decrease in the longitudinal growth rate and growth plate width, and increased surface-based bone formation compared to the HX and CON. Cancellous bone volume, tissue-based bone formation rate, and eroded surface in both of the GH-treated groups were higher than those of the HX group, but lower than those of the BASAL and CON groups (P < 0.05). Bone architecture of the HX rats was also improved after GH treatment. CONCLUSIONS: This study clearly demonstrates that GH replacement at the dosage of 4.5 mg/kg/d can completely prevent the HX-induced reduction in cortical bone gain in the tibial shaft, but can only partially prevent cancellous osteopenia in the proximal tibia after six weeks.

We reviewed data from 157 postmenopausal women who were treated with oral alendronate for osteoporosis. Sixty women completed approximately 1 year of therapy and had two bone density measurements. Significant increases (P&lt;.0001) in bone density occurred at the lumbar spine (4.3%) and femoral neck (2.8%). Bone density also increased in patients who had taken other antiresorptive agents prior to initiation of alendronate therapy. The frequency of side effects in our patients (20.3%) was higher than that previously reported in clinical trials. Twelve percent of our total population (59.3% of those with side effects) discontinued treatment because of side effects. Although this report describes an uncontrolled clinical experience, our results suggest that oral alendronate is an effective treatment of postmenopausal osteoporosis, producing responses in bone mineral density similar to those in clinical trials.