JOURNAL OF BONE AND MINERAL RESEARCH Volume 6, Number 2, 1991 Mary Ann Liebert, Inc., Publishers
Interrelationship Among Vitamin D Metabolism, True Calcium Absorption, Parathyroid Function, and Age in Women: Evidence of an Age-Related Intestinal Resistance to 1,25-Dihydroxyvitarnin D Action RICHARD EASTELL,’ ALFRED L. YERGEY,’ NANCY E. VIEIRA,’ SANDRA L. CEDEL,3 RAJIV KUMAR,4 and B. LAWRENCE RIGGS’
ABSTRACT We studied the mechanism of impaired calcium absorption with aging in 51 healthy women whose ages ranged from 26 to 88 years. Serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH),D, mean of four measurements per subject] increased with age by 22% ( P < 0.05) but, by split-point analysis, plateaued or decreased slightly after age 65. In a subset of 20 subjects, [3H]1,25-(OH),D, kinetic analysis showed that this increase with age resulted from both increased production and decreased metabolic clearance of 1,25(OH),D. Despite the increase in serum 1,25-(OH),D concentration, true calcium absorption did not change with age. The expected inverse correlation between true fractional calcium absorption and dietary calcium intake, however, was easily demonstrated ( r = 0.66, P < 0.001). Serum intact parathyroid hormone (PTH) increased with age by 35% ( P < 0.02) and serum bone gla protein (BGP, osteocalcin) increased by 47% (P < 0.001); the increases in serum PTH and serum BGP were directly correlated ( r = 0.32, P < 0.05). The data are consistent with the following hypothetical model: (1)intestinal resistance to 1,25-(OH),D action accounts for the increase in serum 1,25-(OH)zD concentrations with aging with no change in true calcium absorption; (2) this results in a compensatory increase in PTH secretion and in 1,25-(OH),D production that prevents true calcium absorption from decreasing; (3) the previously described defect in 25-hydroxyvitamin D (25-OHD) la-hydroxylase activity in aging animals and humans acccounts for the leveling off in serum 1,25-(OH),D concentration after age 65 years; and (4) the secondary hyperparathyroidism leads to increased bone turnover and thus contributes to age-related bone loss.
INTRODUCTION
Ars
MEASURED BY THE ABSORPTION of radiocalcium in a ixed amount of calcium carrier, calcium absorption has been reported to decrease with age in normal The cause of this decrease is disputed. The main hormonal factor regulating calcium absorption is
1,25-dihydroxyvitamin D [ 1,25-(OH),D]. Some studies have found lower values for this physiologically important vitamin D metabolite in elderly subjects,(4.6-8)whereas others have found no change with age.(y-”) Epstein et aI.,(”) who studied the largest group of women, found that serum 1,25-(OH),D concentration increased up to age 65 years and then decreased. This suggests that there may
‘Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester MN 55905. ’Section of Metabolic Analysis and Mass Spectroscopy, National Institute of Child Health and Human Development, Bethesda, M D 20205. ’Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, MN 55905. 4Nephrology Research Unit, Mayo Clinic and Mayo Foundation, Rochester, MN 55905. Copyright 1990 Mayo Foundation.
125
126
EASTELL ET AL.
be more than one mechanism for the age-related decrease in calcium absorption. Inadequate calcium absorption could be an important cause of negative calcium balance and bone loss in elderly women. Thus we attempted t o identify the mechanisms of this abnormality and to define its effect on overall calcium metabolism in elderly women. We studied a group of 5 1 normal women ranging from young adulthood to old age who had the usual age-related decreases in bone density and creatinine clearance. True calcium absorption (TCA), the actual amount of calcium absorbed from the habitual diet, was determined by a newly developed method. We then related calcium absorption to concentrations of intact parathyroid hormone (PTH) and 1,25-(OH),D in the serum to concentrations of serum bone gla protein (BGP, osteocalcin), a specific marker for bone turnover, and, in a selected subgroup, to vitamin D metabolism assessed by (3H]1,25-(OH),D kinetics.
METHODS Experimental subjects We studied 5 1 healthy women (ages 26-88 years; mean SD, 55 f 19 years); 19 were premenopausal and 32 were postmenopausal (range 1-43 years after menopause). None had any detectable disease or were taking any drugs known to affect calcium metabolism. As assessed by dualphoton absorptiometry of the lumbar spine,(13)all had values within the 95% confidence intervals for normal women as adjusted for age. The first 20 women entered into the study also had measurement of 1,25-(OH)D kinetics. None of the postmenopausal women had vertebral fractures on thoracic and lumbar roentgenograms. The studies were approved by the Mayo Institutional Review Board, and signed informed consent forms were obtained from all the women. All studies were carried out in the Mayo Clinical Research Center.
The doses of 44Ca (12-36 mg) and of W a (2-6 mg) were divided and given in proportion to the calcium content of each meal (for example, if breakfast provided 50% of the daily dietary calcium, 50% of the total doses of 44Caand 42Cawere given with this meal). The 44Ca was mixed with milk or orange juice and given toward the end of the meal. The 42Ca was given intravenously 15 minutes later by means of the indwelling catheter. An aliquot of the 24 h urine specimen was prepared for mass spectroscopy by an oxalate precipitation procedure.‘l5) Stable isotope ratios were measured by thermal ionization mass spectrometry with a Finnegan MAT Thermoquad (THQ) Quadrupole mass spectrometer (Bremen, FRG). All ratios were measured relative to 48Ca. The relative precision of all determinations was 0.3-0.5%. Each sample was assayed in duplicate or triplicate, as required. True fractional calcium absorption (TFCA) were calculated as described previously, and TCA was estimated from TFCA multiplied by dietary calcium.‘14)Dietary calcium was estimated by homogenizing a duplicate diet, ashing the diet in a muffle furnace, and then measuring the calcium content by atomic absorption spectroscopy.
I,ZS-(OH),D kinetics
f
Study protocol The study diet was matched to each subject’s habitual intake of calcium and phosphorus as assessed by a 7 day diet record and interview by a dietitian. The distribution of calcium among the meals was also matched to that in the habitual diet. Each subject was admitted to the clinical research center at 0715 h for a 24 h study. The meals were consumed at 0800, 1200, and 1800 h. No other food was allowed, but consumption of deionized water was encouraged. Blood was drawn after an overnight fast through an indwelling catheter at 0730 h, and the serum was separated and stored at -70°C until analysis. A 24 h urine collection was started at 0730 h.
The primed-infusion technique described by Eastell et aI.(l6) was used. 1,25-(OH),[26,27-JH]Dx (170 to 180 Ci/ mmol) was obtained from Amersham (Arlington Heights, IL). 1,25-(OH),D, was a gift from Dr. M. Uskokovic (Hoffman-LaRoche, Nutley, NJ). The tracer was dissolved in propylene glycol; the priming dose (mean SD 36,088 + 8,230 dpm/kg) was given in 1.2 ml, and the infusion dose (mean + SD 3109 + 798 dpm/kg per h) was given in 6 ml. The priming dose was administered via an indwelling intravenous cannula over 2 minutes; the cannula was then flushed with 5 ml sterile 0.9% saline. The infusion was administered by Harvard infusion pump (model 975, Harvard Apparatus, South Natick, MA) over 6 h. Blood was drawn for measurement of radioactivity at 0, 60, 120, 150, 180, 210, 240, 260, 280, 300, 320, 340, and 360 minutes after the start of the infusion. Steady state was usually reached by 180 minutes, and the mean radioactivity of samples taken between 210 and 360 minutes was used to calculate metabolic clearance rate (MCR) and production rate (PR) by
*
MCR (ml/minute)
=
infusion rate (dpm/minute) steady-state plasma radioactivity (dpm/ml)
and PR pmol/day &g/day) = MCR x serum I,ZS-(OH),D [pmol/liter (pg/ml)] x (24 x 60)/10“
Biochemical measurements Calcium absorption Stable isotopes of calcium (42Cafor intravenous administration and “Ca for oral administration) were purchased from Oak Ridge National Laboratories (Oak Ridge, TN) and prepared as sterile solutions of calcium chloride.‘“)
The serum 1,25-(OH),D value used was the mean of two assays on duplicate samples (i.e., four measurements per subject) of blood taken at 0730 h by the microassay method of Reinhardt et al.(”’ This assay involves rapid extraction and preliminary purification on a silica Sep-Pak
EFFECT OF AGE ON TRUE CALCIUM ABSORPTION
127
with hexane and isopropanol followed by nonequilibrium assay with 1,25-(OH),D receptor from calf thymus. Serum 25-hydroxyvitamin D was measured by high-pressure liquid chromatography.'"' Serum intact parathyroid hormone (PTH) was measured in duplicate by an immunoradiometric assay (Allegro intact PTH immunoassay system, Nichols Institute Diagnostics, San Juan Capistrano, CA). The intraassay variation was < 8 % ; the interassay variation was < 11%. Serum bone gla protein (BGP, osteocalcin) was measured by radioimmunoa~say"~'with antiserum raised in rabbits to bovine BGP and homogeneous bovine BGP for tracer and standard. Antibody-bound and free "51-labeled BGP were separated by the double-antibody method. The intra-assay variation was < 7%; the interassay variation was < 10%. All measurements were made in duplicate. Serum and urinary calcium were measured by atomic absorption spectroscopy (model 2380, Perkin-Elmer Instruments, Norwalk, CT). Serum and urinary creatinine,""' serum and urinary phosphorus,('" and serum alkaline phosphatase activity"" were measured with a centrifugal analyzer (Multistat Plus System, lnstrumentation Laboratory, Inc., Spokane, WA). Urinary hydroxyproline was measured by a colorimetric method,"') and the results were expressed as ratio to creatinine clearance.
TFCA strongly suggested this relationship, and the transformation helped normalize the residuals. The effect of age on serum 1,25-(OH)'D was tested by fitting different slopes to patients younger and older than 65 years. This analysis permits a comparison with data from Epstein et al."zJ to be made. In a subset of 20 of the women 1,25(OH),D kinetics were studied. The strength and existence of relationships between the metabolic clearance rate and production rate of 1,2S-(OH),D and age, creatinine clearance, intact PTH, and 25-(0H)D were examined using correlations. All analyses were performed by using the Statistical Analysis Systems software
Statistical methods The correlations existing among age and variables relating to bone and calcium metabolism were examined to assess the existence and strength of any associations. To better understand the effects of age, dietary calcium, and 1,25-(OH),D on TFCA, a multiple regression was fit with TFCA as the dependent variable and age, 1,25-(OH),D, the inverse of dietary calcium, and all interactions as the dependent variables. The inverse transformation of dietary calcium was used because a plot of dietary calcium against
RESULTS The mean f standard deviation (SD) of variables relevant to bone and calcium metabolism is shown in Table 1. The relationship between age and calcium absorption (and its putative determinants) and bone turnover are shown in Table 2.
True calcium absorption The normal range (95% confidence interval) for TCA SD was 2.0-8.5 mmol/day (79-341 mg per 24 h; mean 5.2 f 1.6 mmol/day, 210 + 65 mg per 24 h). TCA was not related to age (Fig. 1; r = 0.14, NS). In the postmenopause women TCA was not related to years postmenopause ( r = 0.09, NS). There was no decrease in TCA after age 60 years as tested by split-point analysis. For TFCA the normal range was 8-48'70 (mean f SD 28 f 10%). TFCA was related to the reciprocal of dietary Ca ( r = 0.66, P < 0.001; Fig. 2). TFCA did not correlate with serum 1,25-(OH),D concentration ( r = 0.07, NS; Table 3). In a multiple linear regression equation neither serum 1,25-(OH),D nor age (nor
*
TABLE 1. MEANVALUES OF VARIABLESRELEVANT TO BONEA N D CALCIUM I N 51 WOMEN METABOLISM Variable Serum Serum Serum Serum Serum Serum Serum
calcium, mmol/liter (mg/dl) phosphorus, mmol/liter (mg/dl) alkaline phosphatase, pkat/liter (U/liter) BGP, ng/ml 25-OHD, mmol/liter (ng/ml) I ,25-(OH),D,, pmol/liter (pg/ml) PTH, pg/ml
Creatinine clearance, ml/s (ml/minute) Urine calcium, mmol/day (mg per 24 h) Urine phosphorus, mmol/day (mg per 24 h) Urine hydroxyproline, ng/dl glomerular filtrate Lumbar spine bone mineral density, g/cmz Dietary calcium, mmol/day (mg per 24 h) True calcium absorption, mmol/day (rng per 24 h)
Mean f SD 2.30 f 0.07 (9.2 f 0.3) 1.16 f 0.13 (3.6 f 0.4) 0.53 f 0.19 (31.9 f 11.1) 8.1 f 1.9 62.2 f 21.5 (24.9 f 8.6) 77.3 f 19.4 (32.2 f 8.1) 34.5 f 10.0 1.33 f 0.32 (80 f 19) 3.62 f 1.47 (145 f 59) 25.8 f 5.8 (798 f 179) 20.5 f 8.6 1.13 f 0.20 20.7 f 9.0 (831 f 360) 5.2 f 1.6 (210 f 65)
128
EASTELL ET AL. TABLE 2. AGE-RELATED CHANGES IN VARIABLES RELATING TO BONEAND CALCIUM METABOLISM BETWEEN AGES26 AND 88 Years Variable
Yo Change
True calcium absorption (TCA) Serum 1,25-(OH),D Serum 25-OHD Serum PTH Creatinine clearance Urine calcium Serum BGP Urine hydroxyproline Lumbar spine, bone mineral density
r
P
-
0.14
NS
38 - 33 35 -40
0.40
< 0.01 < 0.02 < 0.02
-
47 -
-33
-0.33 0.32 -0.61 -0.23 0.53 0.24 -0.67
Interrelationship Among Vitamin D Metabolism, True Calcium Absorption, Parathyroid Function, and Age in Women: Evidence of an Age-Related Intestinal Resistance to 1,25-Dihydroxyvitarnin D Action RICHARD EASTELL,’ ALFRED L. YERGEY,’ NANCY E. VIEIRA,’ SANDRA L. CEDEL,3 RAJIV KUMAR,4 and B. LAWRENCE RIGGS’
ABSTRACT We studied the mechanism of impaired calcium absorption with aging in 51 healthy women whose ages ranged from 26 to 88 years. Serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH),D, mean of four measurements per subject] increased with age by 22% ( P < 0.05) but, by split-point analysis, plateaued or decreased slightly after age 65. In a subset of 20 subjects, [3H]1,25-(OH),D, kinetic analysis showed that this increase with age resulted from both increased production and decreased metabolic clearance of 1,25(OH),D. Despite the increase in serum 1,25-(OH),D concentration, true calcium absorption did not change with age. The expected inverse correlation between true fractional calcium absorption and dietary calcium intake, however, was easily demonstrated ( r = 0.66, P < 0.001). Serum intact parathyroid hormone (PTH) increased with age by 35% ( P < 0.02) and serum bone gla protein (BGP, osteocalcin) increased by 47% (P < 0.001); the increases in serum PTH and serum BGP were directly correlated ( r = 0.32, P < 0.05). The data are consistent with the following hypothetical model: (1)intestinal resistance to 1,25-(OH),D action accounts for the increase in serum 1,25-(OH)zD concentrations with aging with no change in true calcium absorption; (2) this results in a compensatory increase in PTH secretion and in 1,25-(OH),D production that prevents true calcium absorption from decreasing; (3) the previously described defect in 25-hydroxyvitamin D (25-OHD) la-hydroxylase activity in aging animals and humans acccounts for the leveling off in serum 1,25-(OH),D concentration after age 65 years; and (4) the secondary hyperparathyroidism leads to increased bone turnover and thus contributes to age-related bone loss.
INTRODUCTION
Ars
MEASURED BY THE ABSORPTION of radiocalcium in a ixed amount of calcium carrier, calcium absorption has been reported to decrease with age in normal The cause of this decrease is disputed. The main hormonal factor regulating calcium absorption is
1,25-dihydroxyvitamin D [ 1,25-(OH),D]. Some studies have found lower values for this physiologically important vitamin D metabolite in elderly subjects,(4.6-8)whereas others have found no change with age.(y-”) Epstein et aI.,(”) who studied the largest group of women, found that serum 1,25-(OH),D concentration increased up to age 65 years and then decreased. This suggests that there may
‘Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester MN 55905. ’Section of Metabolic Analysis and Mass Spectroscopy, National Institute of Child Health and Human Development, Bethesda, M D 20205. ’Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, MN 55905. 4Nephrology Research Unit, Mayo Clinic and Mayo Foundation, Rochester, MN 55905. Copyright 1990 Mayo Foundation.
125
126
EASTELL ET AL.
be more than one mechanism for the age-related decrease in calcium absorption. Inadequate calcium absorption could be an important cause of negative calcium balance and bone loss in elderly women. Thus we attempted t o identify the mechanisms of this abnormality and to define its effect on overall calcium metabolism in elderly women. We studied a group of 5 1 normal women ranging from young adulthood to old age who had the usual age-related decreases in bone density and creatinine clearance. True calcium absorption (TCA), the actual amount of calcium absorbed from the habitual diet, was determined by a newly developed method. We then related calcium absorption to concentrations of intact parathyroid hormone (PTH) and 1,25-(OH),D in the serum to concentrations of serum bone gla protein (BGP, osteocalcin), a specific marker for bone turnover, and, in a selected subgroup, to vitamin D metabolism assessed by (3H]1,25-(OH),D kinetics.
METHODS Experimental subjects We studied 5 1 healthy women (ages 26-88 years; mean SD, 55 f 19 years); 19 were premenopausal and 32 were postmenopausal (range 1-43 years after menopause). None had any detectable disease or were taking any drugs known to affect calcium metabolism. As assessed by dualphoton absorptiometry of the lumbar spine,(13)all had values within the 95% confidence intervals for normal women as adjusted for age. The first 20 women entered into the study also had measurement of 1,25-(OH)D kinetics. None of the postmenopausal women had vertebral fractures on thoracic and lumbar roentgenograms. The studies were approved by the Mayo Institutional Review Board, and signed informed consent forms were obtained from all the women. All studies were carried out in the Mayo Clinical Research Center.
The doses of 44Ca (12-36 mg) and of W a (2-6 mg) were divided and given in proportion to the calcium content of each meal (for example, if breakfast provided 50% of the daily dietary calcium, 50% of the total doses of 44Caand 42Cawere given with this meal). The 44Ca was mixed with milk or orange juice and given toward the end of the meal. The 42Ca was given intravenously 15 minutes later by means of the indwelling catheter. An aliquot of the 24 h urine specimen was prepared for mass spectroscopy by an oxalate precipitation procedure.‘l5) Stable isotope ratios were measured by thermal ionization mass spectrometry with a Finnegan MAT Thermoquad (THQ) Quadrupole mass spectrometer (Bremen, FRG). All ratios were measured relative to 48Ca. The relative precision of all determinations was 0.3-0.5%. Each sample was assayed in duplicate or triplicate, as required. True fractional calcium absorption (TFCA) were calculated as described previously, and TCA was estimated from TFCA multiplied by dietary calcium.‘14)Dietary calcium was estimated by homogenizing a duplicate diet, ashing the diet in a muffle furnace, and then measuring the calcium content by atomic absorption spectroscopy.
I,ZS-(OH),D kinetics
f
Study protocol The study diet was matched to each subject’s habitual intake of calcium and phosphorus as assessed by a 7 day diet record and interview by a dietitian. The distribution of calcium among the meals was also matched to that in the habitual diet. Each subject was admitted to the clinical research center at 0715 h for a 24 h study. The meals were consumed at 0800, 1200, and 1800 h. No other food was allowed, but consumption of deionized water was encouraged. Blood was drawn after an overnight fast through an indwelling catheter at 0730 h, and the serum was separated and stored at -70°C until analysis. A 24 h urine collection was started at 0730 h.
The primed-infusion technique described by Eastell et aI.(l6) was used. 1,25-(OH),[26,27-JH]Dx (170 to 180 Ci/ mmol) was obtained from Amersham (Arlington Heights, IL). 1,25-(OH),D, was a gift from Dr. M. Uskokovic (Hoffman-LaRoche, Nutley, NJ). The tracer was dissolved in propylene glycol; the priming dose (mean SD 36,088 + 8,230 dpm/kg) was given in 1.2 ml, and the infusion dose (mean + SD 3109 + 798 dpm/kg per h) was given in 6 ml. The priming dose was administered via an indwelling intravenous cannula over 2 minutes; the cannula was then flushed with 5 ml sterile 0.9% saline. The infusion was administered by Harvard infusion pump (model 975, Harvard Apparatus, South Natick, MA) over 6 h. Blood was drawn for measurement of radioactivity at 0, 60, 120, 150, 180, 210, 240, 260, 280, 300, 320, 340, and 360 minutes after the start of the infusion. Steady state was usually reached by 180 minutes, and the mean radioactivity of samples taken between 210 and 360 minutes was used to calculate metabolic clearance rate (MCR) and production rate (PR) by
*
MCR (ml/minute)
=
infusion rate (dpm/minute) steady-state plasma radioactivity (dpm/ml)
and PR pmol/day &g/day) = MCR x serum I,ZS-(OH),D [pmol/liter (pg/ml)] x (24 x 60)/10“
Biochemical measurements Calcium absorption Stable isotopes of calcium (42Cafor intravenous administration and “Ca for oral administration) were purchased from Oak Ridge National Laboratories (Oak Ridge, TN) and prepared as sterile solutions of calcium chloride.‘“)
The serum 1,25-(OH),D value used was the mean of two assays on duplicate samples (i.e., four measurements per subject) of blood taken at 0730 h by the microassay method of Reinhardt et al.(”’ This assay involves rapid extraction and preliminary purification on a silica Sep-Pak
EFFECT OF AGE ON TRUE CALCIUM ABSORPTION
127
with hexane and isopropanol followed by nonequilibrium assay with 1,25-(OH),D receptor from calf thymus. Serum 25-hydroxyvitamin D was measured by high-pressure liquid chromatography.'"' Serum intact parathyroid hormone (PTH) was measured in duplicate by an immunoradiometric assay (Allegro intact PTH immunoassay system, Nichols Institute Diagnostics, San Juan Capistrano, CA). The intraassay variation was < 8 % ; the interassay variation was < 11%. Serum bone gla protein (BGP, osteocalcin) was measured by radioimmunoa~say"~'with antiserum raised in rabbits to bovine BGP and homogeneous bovine BGP for tracer and standard. Antibody-bound and free "51-labeled BGP were separated by the double-antibody method. The intra-assay variation was < 7%; the interassay variation was < 10%. All measurements were made in duplicate. Serum and urinary calcium were measured by atomic absorption spectroscopy (model 2380, Perkin-Elmer Instruments, Norwalk, CT). Serum and urinary creatinine,""' serum and urinary phosphorus,('" and serum alkaline phosphatase activity"" were measured with a centrifugal analyzer (Multistat Plus System, lnstrumentation Laboratory, Inc., Spokane, WA). Urinary hydroxyproline was measured by a colorimetric method,"') and the results were expressed as ratio to creatinine clearance.
TFCA strongly suggested this relationship, and the transformation helped normalize the residuals. The effect of age on serum 1,25-(OH)'D was tested by fitting different slopes to patients younger and older than 65 years. This analysis permits a comparison with data from Epstein et al."zJ to be made. In a subset of 20 of the women 1,25(OH),D kinetics were studied. The strength and existence of relationships between the metabolic clearance rate and production rate of 1,2S-(OH),D and age, creatinine clearance, intact PTH, and 25-(0H)D were examined using correlations. All analyses were performed by using the Statistical Analysis Systems software
Statistical methods The correlations existing among age and variables relating to bone and calcium metabolism were examined to assess the existence and strength of any associations. To better understand the effects of age, dietary calcium, and 1,25-(OH),D on TFCA, a multiple regression was fit with TFCA as the dependent variable and age, 1,25-(OH),D, the inverse of dietary calcium, and all interactions as the dependent variables. The inverse transformation of dietary calcium was used because a plot of dietary calcium against
RESULTS The mean f standard deviation (SD) of variables relevant to bone and calcium metabolism is shown in Table 1. The relationship between age and calcium absorption (and its putative determinants) and bone turnover are shown in Table 2.
True calcium absorption The normal range (95% confidence interval) for TCA SD was 2.0-8.5 mmol/day (79-341 mg per 24 h; mean 5.2 f 1.6 mmol/day, 210 + 65 mg per 24 h). TCA was not related to age (Fig. 1; r = 0.14, NS). In the postmenopause women TCA was not related to years postmenopause ( r = 0.09, NS). There was no decrease in TCA after age 60 years as tested by split-point analysis. For TFCA the normal range was 8-48'70 (mean f SD 28 f 10%). TFCA was related to the reciprocal of dietary Ca ( r = 0.66, P < 0.001; Fig. 2). TFCA did not correlate with serum 1,25-(OH),D concentration ( r = 0.07, NS; Table 3). In a multiple linear regression equation neither serum 1,25-(OH),D nor age (nor
*
TABLE 1. MEANVALUES OF VARIABLESRELEVANT TO BONEA N D CALCIUM I N 51 WOMEN METABOLISM Variable Serum Serum Serum Serum Serum Serum Serum
calcium, mmol/liter (mg/dl) phosphorus, mmol/liter (mg/dl) alkaline phosphatase, pkat/liter (U/liter) BGP, ng/ml 25-OHD, mmol/liter (ng/ml) I ,25-(OH),D,, pmol/liter (pg/ml) PTH, pg/ml
Creatinine clearance, ml/s (ml/minute) Urine calcium, mmol/day (mg per 24 h) Urine phosphorus, mmol/day (mg per 24 h) Urine hydroxyproline, ng/dl glomerular filtrate Lumbar spine bone mineral density, g/cmz Dietary calcium, mmol/day (mg per 24 h) True calcium absorption, mmol/day (rng per 24 h)
Mean f SD 2.30 f 0.07 (9.2 f 0.3) 1.16 f 0.13 (3.6 f 0.4) 0.53 f 0.19 (31.9 f 11.1) 8.1 f 1.9 62.2 f 21.5 (24.9 f 8.6) 77.3 f 19.4 (32.2 f 8.1) 34.5 f 10.0 1.33 f 0.32 (80 f 19) 3.62 f 1.47 (145 f 59) 25.8 f 5.8 (798 f 179) 20.5 f 8.6 1.13 f 0.20 20.7 f 9.0 (831 f 360) 5.2 f 1.6 (210 f 65)
128
EASTELL ET AL. TABLE 2. AGE-RELATED CHANGES IN VARIABLES RELATING TO BONEAND CALCIUM METABOLISM BETWEEN AGES26 AND 88 Years Variable
Yo Change
True calcium absorption (TCA) Serum 1,25-(OH),D Serum 25-OHD Serum PTH Creatinine clearance Urine calcium Serum BGP Urine hydroxyproline Lumbar spine, bone mineral density
r
P
-
0.14
NS
38 - 33 35 -40
0.40
< 0.01 < 0.02 < 0.02
-
47 -
-33
-0.33 0.32 -0.61 -0.23 0.53 0.24 -0.67
