Faculty Bibliography

Calcitriol was compared with placebo in the treatment of postmenopausal osteoporosis in a double-blind, randomized, parallel clinical trial of 24 months' duration. Adjustment was made in dietary calcium to maximize the dose of calcitriol. The study was completed by 15 patients who received placebo and 12 patients who received calcitriol. The calcitriol group had positive slopes (compared with negative slopes for the placebo 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. The difference between the two groups was statistically significant for each of these measurements. The fracture rate in the treatment group was 250 per 1,000 patient-years as compared with 333 for the placebo group. The mean dose of calcitriol was 0.8 micrograms per day. Hypercalcemia, hypercalciuria, and perhaps nephrolithiasis were observed as complications of treatment. Calcitriol increased bone mineral density by decreasing bone resorption, but not by increasing bone formation. Future studies should concentrate on treatment with oral calcitriol in lower doses. It would also be of interest to examine parenteral administration of calcitriol. It is possible that bone formation can be increased by achieving higher serum levels of the drug, whereas complications may be avoided by using a non-oral route of administration.

The relationship between physical activity and bone mass was investigated in 24 healthy, white, premenopausal women (mean age [+/- SE], 39.0 +/- 1.39 years). Physical activity was determined by a sensor that measures movement of the trunk, and bone mineral levels were determined by means of single- and dual-photon absorptiometry and neutron activation analysis. Total physical activity levels were related both to bone mineral density of the spine (r = .41) and to total body calcium levels (r = .51). There was no significant relationship between the bone density of the distal portion of the radius and activity (r = .20). Nonparametric analysis and stepwise multiple regression analysis revealed negative correlations between cigarette smoking and bone density of the spine and radius. These data suggest that the level of physical activity in sedentary white women may be a determinant of peak total skeletal mass and bone density of the spine.

Fourteen women with postmenopausal osteoporosis, all having at least one vertebral crush fracture, were randomly assigned to two treatment arms, each lasting 24 months. The coherence treatment group (7 patients) was treated in the following sequence: human growth hormone (hGH) 7 IU subcutaneously daily for 2 months, followed by 3 months of salmon calcitonin (CT), 100 MRC units every other day. After a 3 month rest period, this sequence was repeated twice. The contrast group (7 patients) was treated intermittently with salmon CT given in the same time periods and at the same dose as in the coherence treatment group. Bone mass was measured every 4 months by neutron activation analysis for total body calcium (TBCa) and by single photon absorptiometry for bone mineral content (BMC) of the distal radius. Although there were no significant differences between the two groups (two-way ANOVA), the rate of change in TBCa in the coherence treatment group was significantly different from zero (F = 3.8, P less than .05) and was +2.3%/year. The increase in bone mass appeared to be sustained throughout the 2 year study, in contrast with previous studies where a plateau effect was observed with calcitonin given alone or continuously with growth hormone. No significant change was found in bone histomorphometric values measured before and after treatment in 4 patients from each group.

Serum osteocalcin was measured in 51 normal pre- and 114 postmenopausal women and in 41 postmenopausal osteoporotic patients. Total body calcium (TBCa) was determined in the same individuals by neutron activation analysis. Many of the perimenopausal nonosteoporotic women had increased serum osteocalcin values, but 15 yr or more after the menopause most of the women had serum osteocalcin levels in the normal range. Comparing normal women before and after menopause, the mean serum osteocalcin levels [7.8 +/- 4.7 (+/- SE) and 10.1 +/- 9.4 ng/mL] were not significantly different; however, the TBCa values (898 +/- 99 and 806 +/- 111 g) were significantly different (P less than 0.001). When the normal postmenopausal women were regrouped according to high vs. low osteocalcin values, TBCa and phosphorus content as well as forearm linear bone density were significantly lower in the high osteocalcin group, even though most of the other variables, including urinary hydroxyproline excretion, serum alkaline phosphatase, age, height, and weight, were not different. Osteoporotic women had a mean serum osteocalcin concentration of 17.4 +/- 8.6 ng/ml and a TBCa of 657 +/- 83 g, both significantly different from the respective values in normal and pre- and postmenopausal women (P less than 0.001 for both variables in comparison to each group). These data suggest that high serum osteocalcin levels, at least on a group basis, are an index of low skeletal mass.

We investigated the influence of glucocorticoids on phosphate absorption in the duodenum, mid-jejunum, ileum and colon. Phosphate transport, fluid absorption and sodium absorption were determined by the in vivo ligated loop technique. The administration of cortisone stimulated intestinal fluid absorption in each segment of the small intestine, but not in the colon. Cortisone enhanced net sodium absorption in proportion to the increase in fluid absorption. Phosphate was most effectively absorbed in the duodenum and jejunum. Net phosphate absorption in the ileum and colon was negligible. Administration of cortisone stimulated the passive transport of phosphate in each segment of the small intestine studied. The 32Pi absorption was increased 56, 54 and 97% in the duodenum, jejunum and ileum, respectively. There was no apparent stimulation of passive transport of phosphate by cortisone in the colon. Although the exact mechanism is unknown, increased luminal phosphate concentration gradient or enhanced sodium and water absorption after cortisone administration could account for the increase in phosphate transport in the small intestine. However, the effects of these factors vary from segment to segment.

The aim of the study was to investigate the link, if any, between alkaline phosphatase activity and intestinal calcium and phosphate transport using the hypophysectomized (HX) rat model. Ionic transport was evaluated by the in situ ligated loop technique. Hypophysectomy (HX) resulted in a decrease in both duodenal and jejunal alkaline phosphatase activity but did not alter the active transport of calcium and phosphate. Vitamin D depletion (-D), suppressed intestinal transport in the HX rat without altering alkaline phosphatase activity. Repletion of 1,25(OH)2D3 in the -DHX rat resulted in an increase in active transport of calcium and phosphate without altering the alkaline phosphatase activity. Thus, using the HX animal model, we were able to differentiate intestinal alkaline phosphatase activity from the overall intestinal transport of calcium and phosphate.

Since coffee drinking may lead to a worsening of calcium balance in humans, we studied the serial changes of serum calcium, PTH, 1,25-dihydroxyvitamin D (1,25(OH)2D) and calcium balance in young and adult rats after daily administration of caffeine for 4 weeks. In the young rats, there was an increase in urinary calcium and endogenous fecal calcium excretion after four days of caffeine administration that persisted for the duration of the experiment. Serum calcium decreased on the fourth day of caffeine administration and then returned to control levels. In contrast, the serum PTH and 1,25(OH)2D remained unchanged initially, but increased after 2 weeks of caffeine administration. The intestinal absorption coefficient of calcium remained unchanged, instead of declining gradually as observed in the young control group. This finding suggests that the intestinal absorption of calcium was stimulated by the increase in 1,25(OH)2D production after chronic administration of caffeine. In the adult rat group, an increase in the urinary calcium and endogenous fecal calcium excretion and serum levels of PTH was found after caffeine administration. However, the serum 1,25(OH)2D levels and intestinal absorption coefficient of calcium remained the same as in the adult control group. A decrease in the net balance of calcium occurred as a result of increased calcium excretion. The current study, using an animal model, supports the suggestion that chronic administration of caffeine could lead to negative calcium balance when there is an impaired ability to increase the efficiency of calcium absorption. Such a situation exists in elderly human subjects, since they have a reduced capacity to synthesize 1,25(OH)2D.