Faculty Bibliography

In order to establish a comprehensive model for involutional bone loss, the following measurements were made of healthy white women: total body calcium by neutron activation analysis, bone density of the distal radius by single-photon absorptiometry, and dual-photon absorptiometry of the lumbar spine and femur (neck, Ward's triangle, and intertrochanteric areas). Longitudinal measurements were made for each of these skeletal sites except the femur. Evidence for a curvilinear component to the pattern of bone loss with aging was found for total body calcium and bone density of the radius, but not for the other measurements on analysis of cross-sectional data. Longitudinal studies confirmed that substantial bone loss begins only after menopause for the radius, whereas there is substantial premenopausal loss of bone from the lumbar spine. Prevention of vertebral osteoporosis requires maximizing bone mass before menopause. If longitudinal data confirm the model of linear rates of bone loss for the femur, there will be important implications for prevention of hip fractures.

Transilial bone biopsies following in vivo fluorochrome labeling were obtained from 90 women with postmenopausal osteoporosis and 34 healthy post-menopausal women. Standard histomorphometric data were collected from undecalcified sections. The distribution of values for both structural and remodelling indices was the same for each group. Bone volume was 35% lower (P less than 0.001), wall thickness was 12% lower (P less than 0.001), and trabecular thickness was 11% lower (P less than 0.02) in osteoporotics. Trabecular separation was 34% greater (P less than 0.001) and trabecular number was 36% lower (P less than 0.001) in osteoporotics. Biopsy core width was 11% less (P less than 0.02) and cortical width was 35-50% less (P less than 0.001) in osteoporotics. Static indices of remodelling, mineralizing surfaces, and mineral apposition rate were similar in the two groups. The absolute values for bone histomorphometric variables for both groups are similar to most published data. Osteoporotics had poorer bone structure, marked by decreased trabecular connectivity and thin cortices. There were no major differences in dynamic indices of remodelling. Since the histomorphometric data were distributed the same in both groups, special subsets of osteoporotic subjects not in the normal population did not exist.

The response of calcium metabolism and bone turnover to deconditioning after exercise training was studied in three groups of Sprague-Dawley female rats: age-matched controls, 12-week treadmill training, and 8-week treadmill training followed by 4-week discontinuation of training. The exercised rats had a higher absorption efficiency of calcium that decreased to control levels as early as 2 weeks following discontinuation of training. Urinary calcium excretion increased by 2 weeks of deconditioning and then reverted to control levels; bone mineral content measurements declined following deconditioning. Tracer uptake of 45Ca in the femur demonstrated an increase in bone formation that was present during exercise, but was not evident following 4 weeks of deconditioning. The urinary excretion of prelabeled 3H-tetracycline was used to investigate bone resorption in two groups of exercised rats; one group continued to exercise and in the other group the exercise was discontinued. Bone resorption increased within 4 to 11 days after deconditioning and returned to basal levels by the 10th day, at which time the net bone retention of 3H-tetracycline was 86% of that of the group that continued exercising. We conclude that exercise must be continued to sustain any gain it produces in bone mineral. Bone mass gained through exercise will be lost during deconditioning as a result of a decline in bone formation and an increase in bone resorption.

Treatment with 1,25-(OH)2D3 (calcitriol) was compared with placebo in a double-blind, randomized, parallel clinical trial of 24 months' duration. Subjects were white women with postmenopausal osteoporosis. The study was completed by 15 patients who received placebo and 12 patients who received calcitriol. Positive slopes were observed in the active treatment group for total body calcium, bone mineral content of the radius, bone mineral density of the lumbar spine, and radiographic absorptiometry of the middle phalanges. In contrast, negative slopes were observed for the bone mineral measurements in the placebo group. Measurement of urinary hydroxyproline and of serum alkaline phosphatase and osteocalcin suggested that the mechanism of action of 1,25-(OH)2D3 involved reduction of bone resorption. Hypercalciuria occurred regularly and preceded hypercalcemia by about 2 weeks. A decline in creatinine clearance was observed in two patients, one of whom had nephrolithiasis on sonography. Calcitriol is effective in preventing bone loss, but must be used with caution.

The response of calciotropic hormones and bone turnover to exercise and immobilization was examined by the measurement of calcium balance, bone turnover indexes, levels of parathyroid hormone, nephrogenous adenosine 3',5'-cyclic monophosphate (cAMP), and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] weekly for 6 wk in three groups of rats: control, exercise trained, and immobilized. Early in the experiment, increases were observed in excretion of urinary calcium, hydroxyproline, and in serum alkaline phosphatase after both exercise and immobilization. It was not until the latter part of the experimental period that changes were observed in nephrogenous cAMP and intestinal absorption efficiency of calcium. In the fasting state, the exercise group had a drop in serum calcium and phosphate and a rise in nephrogenous cAMP and serum 1,25(OH)2D3 compared with the control group. The exercised animals experienced an increase in bone mass, whereas the immobilized animals had a decline in bone mass. Thus exercise stimulates bone growth, resulting in an increased demand for minerals that is satisfied by an increase in serum 1,25(OH)2D3 levels and increased intestinal absorption of calcium. The increase in calcium absorption suppresses parathyroid hormone production (nephrogenous cAMP) in the exercised animal. Immobilization resulted in increased bone resorption that suppressed parathyroid hormone, nephrogenous cAMP, and the intestinal absorption of calcium.

Changes in skeletal mass, nutritional calcium and phosphorus balance, and intestinal calcium absorption were studied in four groups of rats: control, exercise allowing free access to food, exercise with pair-feeding to control levels, and immobilization. The exercise regimen consisted of treadmill running 25 m/min, 60 min/day, 5 days/wk for 13 wk; rats were immobilized by bilateral sciatic denervation. The total body Ca (TBCa) was measured by neutron activation analysis as an index of skeletal mass. Standard metabolic balance techniques were used to determine calcium and phosphorus balance, and an in situ duodenal loop ligation preparation was used to study the active and passive intestinal Ca transport processes. Exercise promoted a positive Ca and P balance and increased the skeletal mass, largely as a result of an increase in 1,25-dihydroxyvitamin D and an enhancement of the intestinal Ca absorption efficiency. Urinary excretion of Ca and P did not differ from control levels and food intake was not a factor because pair-fed rats responded to exercise almost identically to those fed ad libitum. Conversely, immobilization caused a decrease in TBCa and a lower Ca and P balance. These effects are the result of an increased urinary mineral excretion, greater endogenous fecal excretion, and decreased mineral absorption efficiency in the intestine.