Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal women.

Estrogen deficiency is a risk factor for osteoporosis and coronary artery disease. Osteoporosis can be evaluated by measuring bone mineral density (BMD). Coronary atherosclerotic burden can be evaluated by measuring coronary calcium using electron beam computed tomography (EBT) of the heart. We compared coronary calcium scores in 45 asymptomatic postmenopausal women with normal and low BMD. BMD of the lumbar spine and proximal femur was measured by dual X-ray absorptiometry (DXA), and coronary calcium was measured quantitatively by EBT. Women were divided into control, osteopenia, and osteoporosis groups based on the T score of the lumbar spine. Women were similar in age, years since menopause, height, weight, and body mass index (BMI). BMD +/- SD (g/cm2) of L1-L4 was 0.96 +/- 0.11, 0.83 +/- 0.03, and 0.73 +/- 0.05, in control, osteopenia, and osteoporosis group, respectively. The total coronary calcium score +/- SD (relative units) was 41.9 +/- 83.1, 115.1 +/- 181.9, and 221.7 +/- 355.4 for control, osteopenia, and osteoporosis group, respectively; the score was significantly higher in the osteoporosis than in the control group. This study provides initial data suggesting that women with osteoporosis may have a higher risk of developing coronary atherosclerosis.

Effects of progesterone on serum levels of IGF-1 and on femur IGF-1 mRNA in ovariectomized rats.

Local and systemic insulin-like growth factors (IGFs) may be involved in the regulation of bone formation by sex hormones. The present studies describe the in vivo effects of estradiol, progesterone, or both on IGF-1 mRNA abundance in bone, serum IGF-1 levels, and bone formation. Rats were sham-operated (SHAM) or ovariectomized (OVX) at 12 weeks of age and used a week later in three experiments. First, OVX rats were treated with vehicle, estradiol, and/or medroxyprogesterone (MPA) for 3 weeks, and bone formation was assessed in the tibial metaphysis. Second, OVX rats were treated in the same manner and serum IGF-1 levels measured. Third, OVX rats were treated with an injection of vehicle, estradiol, and/or progesterone, and 24 h later, levels of IGF-1 mRNA in the femur were analyzed. The mineralized surface, mineral opposition rate, and bone formation rate (BFR) were higher in OVX than in SHAM rats. The BFR was decreased in estrogen-treated but increased in MPA-treated rats compared with vehicle-treated OVX rats. Circulating levels of IGF-1 were higher in OVX than in SHAM rats but were not affected by sex hormones in a 3-week experiment, whereas these levels were not different among groups in a 24-h experiment. Northern analysis detected 7.5 and 0.8 kb IGF-1 mRNA transcripts. The abundance of IGF-1 mRNA was higher in OVX than in SHAM rats. IGF-1 transcripts 7.5 and 0.8 kb were decreased by 72 and 29%, respectively, in estrogen-treated and increased by 44 and 43%, respectively, in progesterone-treated rats compared with vehicle-treated OVX rats. We conclude that in the short term, estrogen lowers and progesterone raises bone IGF-1 mRNA and these changes are followed by coordinated changes in bone formation rate.

Effect of heavy alcohol intake in the absence of liver disease on bone mass in black and white men.

Previous studies have shown that bone mass is significantly decreased in chronic alcoholic white patients, especially those with evidence of liver involvement. However, liver disease is an independent risk factor for bone loss. In vitro studies have shown that alcohol has a direct effect on osteoblasts. The effects of chronic alcohol consumption on bone mass in the absence of liver disease are not known. In addition, the effect of alcohol on bone in black alcoholic subjects has not been examined previously. In the present study, we evaluated the effects of prolonged heavy alcohol intake on bone mass in both black (n = 21) and white (n = 19) male subjects without significant liver disease. Bone mineral density (BMD) of the lumbar spine and hip and various markers of bone metabolism in alcoholic subjects were compared with those in respective age-matched controls (n = 16 blacks and 14 whites). Mean values for BMD of the lumbar spine, total hip, and femoral neck were not significantly different between alcoholic subjects and their respective controls among either blacks or whites. In white subjects, age and duration of alcohol were noted to have significant independent effects on BMD, whereas in blacks, age was the only factor that significantly affected bone mass independently. In the absence of liver disease, prolonged heavy alcohol intake results in bone loss in white subjects. The skeleton of black subjects may be less affected by alcohol.

Progesterone antagonist RU 486 has bone-sparing effects in ovariectomized rats.

We demonstrated previously that progesterone prevents ovariectomy-induced bone loss. RU 486 is a synthetic steroid with antiprogesterone activities in reproductive tissue. We used 12-week-old rats to evaluate effects of RU 486 in sham-operated rats and to compare medroxyprogesterone (MPA), RU 486, and medroxyprogesterone plus RU 486 combined treatment in ovariectomized rats. Ovariectomized rats were treated with MPA (60 mg/kg intramuscularly), RU 486 (10 mg/kg/day subcutaneously every 4 days), both, or vehicle. Sham-operated rats were treated with similar doses of RU 486 or vehicle. After 4 weeks of treatment the rats were sacrificed and bone histomorphometry was performed on proximal tibial metaphysis. Trabecular bone volume was lower (33.9 +/- 1.5% vs. 46.3 +/- 1.4%) and bone turnover was higher in ovariectomized than in sham-operated rats. The fraction of trabecular bone in OVX rats treated with MPA, RU 486, or both were 41.6 +/- 2.5%, 44.8 +/- 2.8%, and 38.4 +/- 1.4%, respectively. Medroxyprogesterone treatment tended to preserve bone mass by inhibiting the increased resorption indices while maintaining higher formation rates seen in ovariectomized rats. The effects of RU 486 were similar to those of medroxyprogesterone, suggesting an agonist-like effect. Medroxyprogesterone effects were attenuated when it was combined with RU 486, suggesting that RU 486 acted as a partial antagonist in the presence of exogenous progesterone. Bone parameters were less affected in sham-operated RU 486-treated rats, and there was no significant change in bone volume (43.2 +/- 1.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of endurance exercise on bone histomorphometric parameters in intact and ovariectomized rats.

Physical activity is important for maintenance of bone mass. The effects of exercise on bone histomorphometry were studied in 9-month-old intact (INT) and ovariectomized (OVX) rats. The rats were either kept sedentary (SED) or were exercised (EX) on a treadmill at 21 m/min for 1 h/day 5 days/week for 3 months. Bone resorption as well as formation parameters were significantly higher in OVX-SED than in INT-SED rats, indicating increased bone turnover in OVX rats. In OVX rats, lower osteoclast perimeter and number, lower labeled perimeter but higher mineral apposition rate (MAR) and bone formation rate (BFR) were associated with higher trabecular bone in OVX-EX compared with OVX-SED rats. In intact rats, trabecular bone mass and osteoclast number and perimeter were not affected by exercise. Labeled perimeter was slightly lower while MAR was higher and BFR was insignificantly higher in INT-EX than in INT-SED rats. Thus, exercise resulted in fewer resorption-formation sites, as indicated by lower labeled perimeter, but higher activity of individual osteoblasts, as indicated by higher MAR, both in estrogen-depleted and estrogen-replete states.

Effects of endurance exercise on bone mass and mechanical properties in intact and ovariectomized rats.

Exercise may play a role in the prevention of bone fractures in postmenopausal osteoporosis. The effects of endurance exercise on bone properties were assessed in 9-month-old sham-operated (SH) and ovariectomized (OVX) rats. The rats were either kept sedentary (SED) or were exercised (EX) on a rodent treadmill at 21 m/minute, 7% grade, 40 minutes/day, 4 days/week for 3 months. Bone mineral (by ash weight), morphometry, and biomechanical properties (by three-point bending) were evaluated after excision of bones at sacrifice. Ovariectomy resulted in a loss of bone mineral in femur, tibia, and fourth lumbar vertebra (L4), but biomechanical (force, deformation, stress, strain, and modulus of elasticity) and morphometric (length, cortical and medullary area, and moment of inertia) properties of femur were maintained. The ash weight of femur and tibia, but not L4, as well as femur yield and maximum force and moment of inertia, were improved in OVX-EX rats compared to OVX-SED animals. In SH rats exercise had no influence on ash weight of any of the three bones or femur morphometric properties, yet femur maximum force and plastic deformation were significantly enhanced compared to SH-SED rats. The results of the present study suggest that endurance exercise has beneficial effects on the bone mineral as well as biomechanical properties (femur yield and maximum force) during early stages after ovariectomy and improves the bending strength of the intact femur without an effect on bone mineral in sham-operated rats.

Effects of two non-endurance exercise protocols on established bone loss in ovariectomized adult rats.

The effects of non-endurance exercise on bone properties were evaluated in 9-month-old sham-operated (SH) and ovariectomized (OVX) rats. The studies were started 3 months postsurgery, after bone mass was decreased in OVX rats. The sham and OVX rats were either kept sedentary (SED) or were trained to run with one of two protocols: 12 m/minute, 50 minutes/day, 4 days/week (low intensity, frequent, EX-1); or 21 m/minute, 40 minutes/day, 1 day/week (moderate intensity, infrequent, EX-2). A group of seven rats evaluated at the beginning of the study served as baseline control. The bone mineral was assessed by the ash weight of the left femur, tibia, and 4th lumbar vertebra. Biomechanical (strength, deformation, stress, strain, and stiffness) and morphometric (length, cortical and medullary area, moment of inertia) properties were evaluated for the right femur. There was a significantly lower bone mineral and mechanical properties in OVX-SED (n = 7) than in SH-SED (n = 10) rats. The OVX-EX-1 (n = 6) rats had higher ash content of femur and tibia than OVX-SED rats, but the change was significant only for tibia. The EX-2 had no effect on the ash content, but femur stress was higher in OVX-EX-2 (n = 8) than in OVX-SED rats. The femur yield force and deformation were improved in OVX rats with both exercise protocols, whereas the vertebra ash weight, femur strain, modulus of elasticity, length, cortical area, and moment of inertia were not changed.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of progesterone on postovariectomy bone loss in aged rats.

The effects of progesterone on oophorectomy-induced bone loss in aged rats were evaluated. Female rats aged 12 months were divided into three groups: (1) sham-operated controls (SHAM); (2) oophorectomized (OVX); (3) OVX rats treated with progesterone (OVX + PROG). After 20 weeks the dry weight, bone ash, and calcium content of femur, tibia, and fourth lumbar vertebra were significantly lower in OVX than in sham rats. These reductions did not occur in OVX rats treated with PROG. There was no difference in the bone composition between the control and progesterone-treated rats. Vertebral bone histomorphometry showed increased bone resorption as well as increased bone formation parameters in OVX rats. Progesterone treatment inhibited the increased resorption indices, but the bone formation remained elevated. The results indicate that progesterone therapy prevents the postovariectomy bone loss in aged rats. The protective effect of progesterone is mediated by inhibition of bone resorption while maintaining the increased bone formation. These findings suggest that progesterone alone may be a valuable agent for management of postmenopausal osteoporosis.

Tumor resection and antibodies to parathyroid hormone-related protein cause similar changes on bone histomorphometry in hypercalcemia of cancer.

Bone resorption is increased in both humoral hypercalcemia of malignancy (HHM) and primary hyperparathyroidism. On the other hand, bone formation parameters are increased in primary hyperparathyroidism and decreased in HHM. Recently, a PTH-related protein (PTHrP) has been shown to be responsible for the hypercalcemia in the syndrome of HHM. In the present study we evaluated the effects of a neutralizing antiserum to PTHrP on bone histomorphometric parameters in hypercalcemic athymic mice bearing a human squamous cell lung cancer. These effects were compared to those of tumor resection. Similar to the effects of tumor resection, the antiserum to PTHrP resulted in a decrease in serum Ca levels, a decrease in bone resorption, and an increase in bone formation parameters. The studies, therefore, indicate that PTHrP is the major factor responsible for all of the features, including the decreased bone formation seen in HHM.