A Research Roundtable, organized by the American College of Sports Medicine with sponsorship from the National Aeronautics and Space Administration, met in November 1995 to define research strategies for effective exercise countermeasures to weightlessness. Exercise was considered both independently of, and in conjunction with, other therapeutic modalities (e.g., pharmacological nutritional, hormonal, and growth-related factors) that could prevent or minimize the structural and functional deficits involving skeletal muscle and bone in response to chronic exposure to weightlessness, as well as return to Earth baseline function if a degree of loss is inevitable. Musculoskeletal deficits and countermeasures are described with respect to: 1) muscle and connective tissue atrophy and localized bone loss, 2) reductions in motor performance, 3) potential proneness to injury of hard and soft tissues, and 4) probable interaction between muscle atrophy and cardiovascular alterations that contribute to the postural hypotension observed immediately upon return from space flight. In spite of a variety of countermeasure protocols utilized previously involving largely endurance types of exercise, there is presently no activity-specific countermeasure(s) that adequately prevent or reduce musculoskeletal deficiencies. It seems apparent that countermeasure exercises that have a greater resistance element, as compared to endurance activities, may prove beneficial to the musculoskeletal system. Many questions remain for scientific investigation to identify efficacious countermeasure protocols, which will be imperative with the emerging era of long-term space flight.

The temporal relationships between the circadian rhythms of serum PTH, total calcium (Cat), and phosphate (Pi) and plasma ionized calcium (Cai) concentrations were determined in 9 normal men. Blood samples were collected every half hour for 24 h. Serum PTH was measured by an RIA specific for the midregion of the molecule. The mean circadian pattern for each variable was derived by calculating the average value across all men at concurrent time points. After the data were smoothed by the method of running means, the correlations between PTH and mineral values from concurrent time points were calculated, as were cross-correlations to 12 lag periods (6 h). Spectral and cross-spectral analyses were performed on the same data set. Both statistical methods yielded consistent results: 1) at concurrent time points (0 lag), high correlations were found between serum PTH and Cat (r = -0.74), PTH and Pi (r = 0.79), and PTH and Cai (r = -0.53); and 2) when the PTH series was lagged by 2 h, the PTH/Cai correlation improved to -0.70. A direct PTH/Cai correlation of 0.50 was found when the Cai series was lagged about 4.5 h. No improvement in the correlations were found when the other series were lagged. Spectral analyses also detected significant interrelations between PTH and Cai at 2 and 3.5 h. These data describe the timing of the bidirectional interaction between serum PTH and plasma Cai under steady state conditions in normal adult men; changes in Cai concentrations precede inverse changes in PTH levels by 2 h, whereas changes in PTH precede similar directional alterations in Cai by about 4 h.

To evaluate the effects of a 12-month exercise intervention using either high-impact step aerobic exercise or moderate-intensity strength training on areal bone mineral density (aBMD) we studied 51 untrained women, aged 20-35 years, for this study. Whole body and heel and wrist aBMD were measured by dual-energy X-ray absorptiometry (DXA, Hologic or PIXI Lunar). Subjects were randomly assigned to: impact-loaded step aerobic exercise (SA, n=15), moderate-intensity lower body strength training (ST, n=16) or non-exercise control (CON, n=20). Data analysis only included those who completed 95% of each training routine and attended at least 80% of all sessions. Group differences in aBMD, leg press strength and urinary cross-link deoxypridinoline (μDPD) were analysed using analysis of variance. After a 12-month intervention, the SA elicited an increase in aBMD of the heel (4.4%, p<0.05) and leg press strength (15%, p<0.05), relative to baseline. Meanwhile, the ST showed an increase in leg press strength (48%, p<0.05) with no significant increase in aBMD at any measured site. Similar and unchanged μDPD was observed in all 3 groups at baseline, 6 and 12 months. In conclusion, a 12-month high-impact step aerobic exercise resulted in a significant increase in the heel aBMD in untrained young women, who complied with the exercise regimen. A moderate intensity strength training intervention of similar duration had no effect on aBMD although leg strength increased significantly.

Experimentally diabetic rats have low serum 1,25-dihydroxyvitamin D, intestinal malabsorption of calcium, secondary hyperparathyroidism, and bone loss. To examine the hypothesis that abnormalities similar to those in the diabetic rat might explain human diabetic osteopenia, we studied calcium metabolism in 40 healthy control and 82 diabetic patients aged 18--75 yr [47 untreated: fasting plasma glucose (mean +/- SE), 267 +/- 8 mg/dl; 19 treated but hyperglycemic: glucose 305 +/- 24 mg/dl; 16 treated and in better control: glucose, 146 +/- 8 mg/dl]. Serum total calcium, ionic calcium, immunoreactive parathyroid hormone (Arnaud method, GP-1M and CH-12M antisera), 25-hydroxyvitamin D (Haddad method), and 1,25-dihydroxyvitamin D (Lambert method) concentrations were normal in all 3 groups of diabetics and were not significantly different from values in the control group. We determined absorption of calcium from the intestine by a double isotope method (100 mg Ca carrier; normal range, 40--80%) in 11 control and 13 untreated, uncontrolled diabetics (mean plasma glucose, 285 +/- 17 mg/dl). Absorption of calcium in controls was 60 +/- 3% and in diabetics was 56 +/- 3% (not significantly different). We have found no derangement of calcium metabolism in adults with insulin-requiring juvenile- and adult-onset diabetes regardless of treatment status. The experimental diabetic rat model does not appear to be useful for determining the pathogenesis of adult human diabetic osteopenia.

AND VAY L. W. G O Mayo Clinic and Mayo Foundation, Rochester, Minnesota 5590125-Hydroxyvitamin D3 (25-OH-D3) is a metabolite of vitamin D3 that has greater biologic potency than D3 (1) and is the predominant form of vitamin D in plasma (2), where it circulates bound to specific carrier proteins (3). The physiologic role of 25-OH-D3 is not entirely understood, but it is a precursor of more polar and biologically active forms of vitamin D in deficient animals (4, 5). Physiologic quantities may not be directly involved in biologic effects of vitamin D but pharmacologic doses of 25-OH-D3 have direct effects on calcium transport in tissue culture (6), induce calciumbinding proteins in vitro (7), and mobilize calcium from bone in the anephric animalIn the course of studies on the distribution and excretion of small doses (5 p g ) of intravenously administered [26, 27-3H]-25-hydroxyvitamin D3 (25-OH-D3), we discovered that, in addition to a role in the 25-hydroxylation of vitamin D3 (9), the liver participates in the secretion of this metabolite into the intestine. Subsequent reabsorption of intestinal radioactivity suggests that 25-OH-D3 undergoes an enterohepatic circulation similar to that of other constituents of bile, such as bile acids (10).Methods and Materials. In order to quantify the intestinal and plasma distribution of intravenously administered 25-OH-D3 simultaneously, normal adults (two men and one woman) were prepared for study by an overnight fast and by intubation a few hours before the study. A triple-lumen nasoduodenal tube was positioned so that the first aperture was located proximal to the ampulla of Vater, the second was distal to it at the ligament of Treitz, and the third was located 30 cm distal to the second (11). The lumen ending most proximally was perfused (8).570 at a rate of 2 ml/min with polyethylene glycol (PEG), 5 g/liter, a nonabsorbable marker used for quantification of duodenal contents. From the second lumen, duodenal aspirates were collected every hour, for 30-36 hr, into a chilled beaker, and the volume was measured; 10-ml samples were taken and the remainder was reinfused through the third lumen.Meals were given in liquid form while the tube was in place (11). Oral administration of a fecal marker (chromium sesquioxide, 0.5 g three times daily) was started just prior to the intravenous bolus injection of 8-10 pCi of [26, 27-3H]-25-OH-D31 (New England Nuclear, 1.2 Ci/mmole) dissolved in 1 ml of propylene glycol. Serial blood specimens and all the urine and feces excreted for 12 days after injection were collected for analysis.Total ?H in homogenized stool samples (1-2 g) and duodenal aspirates (0.3-0.5 ml) was determined by liquid scintillation counting after combustion in an oxidizer; values were corrected for volume and for recovery of isotope added to the samples. The volume and bile acid content of duodenal contents were determined by previously validated methods (12). Because of variable delays in passage of intestinal contents from duodenum to colon, fecal data were correct...

A B S T R A C T Pharmacologic doses of corticosteroids impair intestinal calcium absorption and contribute to negative calcium balance. However, the relationship between the impaired calcium absorption and a possible defect in the conversion of vitamin D to its physiologically active form, 1,25-dihydroxyvitamin D, is unknown. We compared fractional calcium absorption (double-isotope method, 100-mg carrier) and serum 25-hydroxyvitamin D (25-OH-D) (Haddad method) in 27 patients receiving pharmacologic doses of prednisone with 27 age-, sex-, and season-matched normal subjects. In patients receiving high daily doses of prednisone (15-100 mg/day), calcium absorption (P < 0.02) and serum 25-OH-D (P < 0.001) were decreased. However, in patients receiving low doses (8-10 mg/ day) or high doses (30-100 mg) of prednisone on an alternate-day schedule, both of these parameters were normal. Calcium absorption in the patients treated with daily prednisone correlated inversely with the dose ofcorticosteroids (r = -0.52, P < 0.025) and, in all steroid-treated patients, correlated directly with serum 25-OH-D (r = 0.58, P < 0.01). In four patients who received high-dose corticosteroid therapy for an average of 4 wk, serum 25-OH-D decreased by 35.5% from pretreatment values. Administration of a physiologic or near-physiologic dose of synthetic 1,25-dihydroxyvitamin D3 (0.4 ,ug

Biochemical and radiologic indices of bone disease were assessed in 26 insulin-dependent diabetic patients and 28 nondiabetic patients with endstage kidney disease. The two groups were comparable in age, sex, duration of renal failure, and length of time on dialysis. Diabetic patients showed significantly lower serum calcium and immunoreactive parathyroid hormone (iPTH) levels than nondiabetic patients. iPTH was not related to total serum calcium, but was positively correlated with serum phosphorous (r = 0.37, P less than 0.05 and r = 0.54, P less than 0.005, in nondiabetic and diabetic patients, respectively). iPTH correlated with alkaline phosphatase (r = 0.59, P less than 0.0009) and calcitonin (r = 0.51, P less than 0.05) only in nondiabetic patients. Osteitis fibrosa was noted radiologically in 30% of nondiabetic patients and in none of the diabetic patients (P less than 0.03). Bone morphology in eight diabetic patients who underwent iliac bone biopsy was characterized by reduced trabecular and osteoid bone volume, no woven bone, and marked reduction in indices of bone formation and resorption. The small amount of bone and lack of osteomalacia are a unique feature of the diabetic patient with chronic renal disease. The long-term sequelae of low bone turnover and reduced circulating iPTH may present a special problem to the long term diabetic survivor on the current therapies of uremia.

To study the mechanism of bone loss in physical unloading, we examined indices of bone formation and bone resorption in the serum and urine of eight healthy men during a 7 day -6 degrees head-down tilt bed rest. Prompt increases in markers of resorption--pyridinoline (PD), deoxypyridinoline (DPD), and hydroxyproline (Hyp)/g creatinine--during the first few days of inactivity were paralleled by tartrate-resistant acid phosphatase (TRAP) with significant increases in all these markers by day 4 of bed rest. An index of formation, skeletal alkaline phosphatase (SALP), did not change during bed rest and showed a moderate 15% increase 1 week after reambulation. In contrast to SALP, serum osteocalcin (OC) began increasing the day preceding the increase in Hyp, remained elevated for the duration of the bed rest, and returned to pre-bed rest values within 5 days of reambulation. Similarly, DPD increased significantly at the onset of bed rest, remained elevated for the duration of bed rest, and returned to pre-bed rest levels upon reambulation. On the other hand, the other three indices of resorption, Hyp, PD, and TRAP, remained elevated for 2 weeks after reambulation. The most sensitive indices of the levels of physical activity proved to be the noncollagenous protein, OC, and the collagen crosslinker, DPD. The bed rest values of both these markers were significantly elevated compared to both the pre-bed rest values and the post-bed rest values. The sequence of changes in the circulating markers of bone metabolism indicated that increases in serum OC are the earliest responses of bone to head-down tilt bed rest.