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Clinical Studies |
Department of Medicine, University of Western Australia (R.L.P., I.M.D., J.L.), and the Department of Endocrinology and Diabetes (R.L.P.) and PathCentre (D.R.), Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
Address all correspondence and requests for reprints to: Dr. R. L. Prince, Department of Medicine, University of Western Australia, Sir Charles Gardner Hospital, Western Australia, Australia.
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Abstract |
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At baseline, the osteoporotic patients were well matched to normal subjects in terms of calcium intake and absorption and renal function, but had higher bone turnover and relative secondary hyperparathyroidism. After the low calcium diet, the rise in calcitriol was deficient in the osteoporotic subjects.
These data are consistent with the suggested pathogenesis of type II or age-related osteoporosis and show that in these subjects with osteoporotic fracture there was a primary defect in calcitriol production that resulted in secondary hyperparathyroidism. This defect may be the cause of the high bone turnover and may play an important role in the development of bone loss in these subjects.
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Introduction |
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In this study we investigated bone metabolism in female osteoporotic fracture subjects with particular reference to the main calcitropic hormones, calcitriol and PTH, at baseline and after a low dietary calcium intervention. The controls had normal bone density and no fracture, and were well matched for years since menopause, basal dietary calcium intake, 25-hydroxyvitamin D (25OHD) status, and renal function.
A low dietary calcium intervention was undertaken to act as a stress test to determine its effect on the secretory reserve for calcitriol and PTH in osteoporotic fracture subjects compared with healthy controls. This also allowed study of potential differences in the stimulated levels of these hormones, which were apparent only when dietary calcium intake was equalized at a low level. This approach has previously been used to determine calcitriol reserve in healthy pre- and postmenopausal women and in patients with chronic renal failure (5, 6, 7).
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Subjects and Methods |
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Seventeen women with postmenopausal osteoporosis were recruited into the study. All osteoporotic subjects had at least one clinically significant vertebral fracture and a total lumbar spine bone mineral density (L1 to L4) of less than 0.84 mg/cm2, measured using dual energy x-ray technology on a QDR 1000 machine (Hologic, Waltham, MA). Seventeen normal postmenopausal subjects with a vertebral bone density above 0.84 g/cm2 and without atraumatic vertebral or long bone fracture were recruited; (a population study in Western Australia showed that 60% of 70-yr-old normal subjects had a bone density greater than 0.84 g/cm2). Subjects from both groups were excluded if they had significant chronic diseases or if they had received estrogen or other steroid hormones, anticonvulsant drugs, thiazide diuretic drugs, or other medication that would influence calcium metabolism in the previous 12 months.
Study design
The study protocol was similar to that of a previous calcium deprivation study (6). Baseline dietary calcium intake was measured using a 2-day, measured diet record. The diet was analyzed using the NUTTAB database, a nutritional database that uses chemical analysis of Australian foods. Baseline samples were taken in the morning of the beginning of the study while the subject was consuming the normal self-selected diet before commencement of a low calcium diet for the next 4 days. This low calcium diet was achieved by avoiding foods containing large amounts of calcium, such as dairy products, eggs, seafood, and calcium-containing vegetables, resulting in approximately 170 mg dietary calcium/day. Oral cellulose phosphate (5 g, four times per day) was also taken with meals to bind calcium and inhibit its absorption from the intestine. The diet was maintained for the next 4 days.
Calcium absorption test
Gut calcium absorption was measured in each subject by a stable strontium method (8) in which fasting subjects were given 2.5 mmol strontium chloride hex-hydrate with 110 mL (100%) orange juice. Four hours after the ingestion of this dose, subjects had a sample of blood taken for analysis of strontium, having only been allowed to consume water during that time. The samples were analyzed as previously described (9). The intra- and interassay coefficients of variation for the method at 24 µmol/L were 4.3% and 9.6%, respectively. Fractional absorption was expressed as the concentration of strontium in blood multiplied by 0.2 times body weight.
Biochemical studies
Morning blood and urine samples were collected after an overnight fast. Blood was collected on each day of the study, and a fasting urine sample was collected on days 0, 2, and 4. A 24-h urine sample was also collected at the beginning and end of the study. The urine samples were analyzed for creatinine, calcium, and phosphorus using routine methods with a Technicon SMAC analyzer (Technicon Corp., Tarrytown, NY); hydroxyproline was measured colorimetrically in an acid hydrolysate of the fasting urine. Plasma creatinine, alkaline phosphatase, calcium, phosphorus, and albumin concentrations were measured using routine methods with a Technicon SMAC analyzer. Serum calcitriol (1,25-dihydroxyvitamin D) was measured by a column extraction technique followed by an assay using calf thymus cytosol-binding protein (10); intra- and interassay coefficients of variation for the calcitriol assay were 14% and 20%, respectively. Serum intact PTH was measured using an immunochemiluminometric method (11); intra- and interassay coefficients of variation were 3.6% and 6.2%, respectively. Serum 25OHD was measured using an extraction technique followed by a competitive binding assay using diluted human serum (12); intra- and interassay coefficients of variation were 8% and 16%, respectively. Vitamin D-binding protein was measured by RIA, using an antibody kindly donated by Dr. R. Bouillon, with intra- and interassay coefficients of variation of 4% and 11%, respectively (13). Deoxypyridinoline was measured on hydrolyzed and extracted urine samples (14) with isodesmosine used as an internal standard. High performance liquid chromatographic analysis of the urine extracts was based on the methodology of Colwell et al. (15). All deoxypyridinoline results were corrected for internal standard recovery. Between-run coefficients of variation for urine specimens run as a quality control ranged from 7–9% for 15–400 nmol/L. The glomerular filtration rate was calculated from creatinine clearance and corrected for body surface area. The renal phosphorus threshold was calculated using the method of Bijvoet (16).
Statistical analysis
The percent change in each variable between days 0 and 4 of the study was calculated for each individual in the study. This summary statistic was compared within groups vs. no change using the one-sample t test and between groups using the Mann-Whitney U test. Baseline values were compared using the Mann-Whitney U test. Results are reported as the mean and SD unless otherwise indicated; all P values are two-tailed. The statistical package used was SPSS for Windows (SSPS, Chicago, Ill).
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Results |
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The subjects in the normal and osteoporotic groups were matched
for age, number of years since menopause, and dietary calcium intake.
There were no differences in renal or bowel function. Bone resorption
was greater in the osteoporotic subjects, as shown by elevated
hydroxyproline creatinine and deoxypyridinoline creatinine ratios.
Although the plasma total calcium levels were high compared to normal
values, there was no difference in ionized calcium (Table 2). PTH, but not calcitriol, was elevated in the
osteoporotic subjects.
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The low calcium diet resulted in an approximately 70% decrease in
urinary calcium and a 30% increase in urinary phosphorus 24-h urinary
excretions, which were the same for both groups. The calcium/creatinine
ratio, renal phosphorus threshold, and plasma total calcium also fell
in an equivalent manner in both groups. Plasma phosphorus levels and
alkaline phosphatase activity fell significantly in the normal group,
but no change was seen in the osteoporotic group (Tables 2
and 3).
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and 3 and Fig. 1).
Calcitriol (Tables 2 and 3) and the free calcitriol index (Tables 2 and 3 and Fig. 2) both increased, with a statistically
greater increase observed in the normal group. Strontium absorption
increased significantly in the normal group, with no increase observed
in the osteoporotic group (Tables 2 and 3).
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), but neither age nor years since
menopause were correlated with other baseline variables.
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Discussion |
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The data assembled in this paper point to specific differences in calcium homeostasis in normal and osteoporotic subjects. At baseline, these consisted of high bone turnover and secondary hyperparathyroidism not due to differences in renal function, 25OHD status, or calcium intake. These data are consistent with a defect in calcium homeostasis outside the bone, because if the primary abnormality causing bone loss and negative calcium balance was within the bone, the resultant loss of calcium from the skeleton would have suppressed PTH.
After the stimulus of a reduction in calcium intake and, therefore, gut calcium absorption, which was of a similar magnitude in the two groups of subjects, the PTH level equalized, but the calcitriol concentration was clearly low in the osteoporotic subjects. Consistent with this is the fact that strontium absorption, which at baseline was indistinguishable in the two groups, rose in normal subjects, but not in osteoporotic patients. These data suggest that the primary abnormality causing the secondary hyperparathyroidism in these patients resided within the production (or destruction) of calcitriol, such that during normal dietary calcium intake, calcitriol and gut calcium absorption was normalized at the expense of a high PTH level and increased bone resorption. Under conditions of calcium deprivation, the normal homeostatic response of a rise in calcitriol did not occur in the osteoporotic patients, and gut calcium absorption of calcium did not increase. This relative deficiency of calcitriol and gut calcium absorption in osteoporotic patients is consistent with other studies that have shown similar defects in subjects labeled as having age-related osteoporosis (3, 4). Unfortunately, in these studies the osteoporotic patients either had early renal failure (3) or were compared to young normal subjects (4).
Our data do not support the contention that there is a defect in calcitriol action on the gut in these patients with age-related osteoporosis because in this study there was no difference in strontium absorption between the osteoporotic and normal subjects when calcitriol levels were similar at baseline. These finding also do not give strong support to the contention that there is altered skeletal responsiveness to PTH, as the change in bone turnover markers during the rise in PTH induced by the low calcium diet was not different between groups. Interpretation of these data is complicated by the fact that the increase in PTH was not identical in the two groups.
In relation to the factors determining the circulating calcitriol levels, it would appear that in both normal and osteoporotic subjects, the degree of rise in the calcitriol during the low calcium diet was determined by the baseline 25OHD level, such that the higher the 25OHD concentration, the greater the rise in calcitriol. 25OHD is, of course, the substrate for formation of calcitriol; thus, vitamin D status may be important across a broad range of 25OHD levels in optimizing the calcitriol response to reduced dietary calcium intake.
The data presented here are different from some previous studies of female vertebral fracture cases in which there was evidence of suppression of PTH consistent with the primary pathophysiological disorder residing within bone (1, 2). Thus, the findings in these subjects are most consistent with previous descriptions of age-related osteoporosis.
Received June 7, 1996.
Revised September 4, 1996.
Accepted September 13, 1996.
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References |
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This article has been cited by other articles:
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  K. Åkesson, K.-H. W. Lau, P. Johnston, E. Imperio, and D. J. Baylink Effects of Short-Term Calcium Depletion and Repletion on Biochemical Markers of Bone Turnover in Young Adult Women J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 1921 - 1927. [Abstract] [Full Text]
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