Relationship between calcium absorption and plasma dehydroepiandrosterone sulphate (DHEAS) in healthy males.

CONTEXT: Impaired gut sensitivity to 1,25-dihydroxyvitamin D (1,25(OH)(2)D), leading to reduced intestinal calcium absorption, has been reported in older men and women. While this phenomenon in postmenopausal women has been attributed to oestrogen deficiency, it is unclear whether the same observation in older men correlates with the age-related decline in androgen concentrations. OBJECTIVE: To examine the relationship between androgens and intestinal calcium absorption in older men. DESIGN: Cross-sectional study on 55 healthy male volunteers, divided into younger (n = 27) and older (n = 28) groups separated according to the median age of 59 years. MAIN OUTCOME MEASURES: Calcium absorption, total and free (calculated) testosterone, dehydroepiandrosterone sulphate (DHEAS), SHBG, and 1,25(OH)(2)D, among others, were measured. RESULTS: Calcium absorption, free testosterone and DHEAS, but not 1,25(OH)(2)D, declined significantly with age. After adjusting for age and body mass index, stepwise regression showed that 1,25(OH)(2)D and serum albumin were the only significant determinants of calcium absorption in younger men, while the sole determinant in older men was DHEAS, not testosterone. Residual deviations from the regression of calcium absorption on 1,25(OH)(2)D, reflecting the efficiency of 1,25(OH)(2)D-induced calcium absorption, was positively correlated with DHEAS (r = 0.27, P = 0.027). CONCLUSIONS: DHEAS is an independent determinant of calcium absorption in older men, although its manner of influence is, as yet, undefined. The age-related decline of DHEAS may, partly, account for the observed 'intestinal resistance to 1,25(OH)(2)D' in older men.

Relation between calcium absorption and serum calcitriol in normal men: evidence for age-related intestinal resistance to calcitriol.

OBJECTIVE: To obtain information on the causes of age-related bone loss in men and the concomitant decline in calcium absorption. DESIGN: Cross-sectional study. SETTING: Adelaide, South Australia, Australia. SUBJECTS: A total of 95 healthy, Caucasian men (age range 27-87 y). RESULTS: Calcium absorption declined with age (r=-0.46, P<0.0001), as did 24-h urine calcium, phosphate and creatinine (r>-0.21, P<0.05 for all); serum calcitriol and 25 hydroxyvitamin D did not change with age. Calcium absorption was related to serum calcitriol (r=0.20, P=0.05). An inverse relation between the residual deviations in calcium absorption, after allowing for its dependence on calcitriol, and age (F=5.4, P<0.005) was observed. The 24-h urinary calcium, phosphate and creatinine were all related to calcium absorption (r>0.41, P<0.0001). Forearm bone density fell with age (r=-0.45, P<0.0001) but was not related to calcium absorption, or markers of bone turnover. CONCLUSIONS: In healthy Caucasian males (i) calcium absorption falls, but serum calcitriol does not change with age, (ii) the relation between calcium absorption and serum calcitriol changes with age, indicative of an intestinal resistance to calcitriol and (iii) calcium absorption is a significant determinant of 24-h urinary calcium excretion.

Relationship between serum 25-hydroxyvitamin D and bone resorption markers in vitamin D insufficiency.

It is known that nursing-home patients with vitamin D insufficiency have elevated serum parathyroid hormone (PTH) as well as raised serum alkaline phosphatase (ALP). Although it is well known that vitamin D insufficiency and secondary hyperparathyroidism are common among the elderly in western countries, there is continuing controversy over the level of serum 25-hydroxyvitamin D [25(OH)D] necessary for bone health. We approached this issue by examining the relationships between serum 25(OH)D, ionized calcium, PTH, and ALP and the urinary bone resorption markers hydroxyproline, pyridinoline, and deoxypyridinoline, corrected for creatinine (OHPr/Cr, Pyd/Cr, and Dpd/Cr, respectively), in 486 postmenopausal women of mean age 63 (SD 9.5) years, who were referred to our osteoporosis and menopause clinics for investigation. When the patients were divided into two groups with 25(OH)D above and below 20 nmol/L, 30 nmol/L, 40 nmol/L, 50 nmol/L, 60 nmol/L, or 70 nmol/L, the most significant differences between the two groups thus derived was found at a serum 25(OH)D level of 60 nmol/L (P < 0.001 for all markers). The most significant difference between groups for serum PTH was found when the patients were divided at a serum 25(OH)D of 50 nmol/L. PTH, OHPr/Cr, Pyd/Cr, and ALP were inversely related to serum 25(OH)D. PTH was inversely related to serum ionized calcium. There was a trend for ionized calcium to be positively related to 25(OH)D, but this did not reach statistical significance. We conclude that rises in three bone resorption markers and ALP can be detected in postmenopausal women when the serum 25(OH)D level falls below 60 nmol/L. Levels above this may be required for optimal bone health.

Bone density and bone-related biochemical variables in normal men: a longitudinal study.

BACKGROUND: The objective of this study was to determine the pattern of forearm bone loss and its relationship to markers of bone turnover and sex steroids in normal men. This was a longitudinal study over a median interval of 41 months. The study was conducted in Adelaide, Australia. Study participants were 123 healthy male subjects, between the ages of 20 and 83 years. METHODS: Fat-corrected forearm bone mineral content (fcBMC), markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type 1 C-terminal extension peptide) and bone resorption (collagen type I cross-linked telopeptide, hydroxyproline/creatinine, pyridinoline/creatinine, and deoxypyridinoline/creatinine), calculated serum bioavailable testosterone, and serum estradiol were measured. RESULTS: The mean time-weighted rate of change in forearm fcBMC was -0.33% +/- 0.72 (SD) per year. Bone loss commenced after 30 years of age and increased with age (p <.001), particularly after age 70 years. There was no relationship between the rate of change in fcBMC and either markers of bone turnover or serum sex steroids. CONCLUSIONS: In normal men, bone loss increases with age; there does not appear to be any relationship between this loss and either markers of bone turnover or levels of free androgen or estrogen.

Relationships between intestinal calcium absorption, serum vitamin D metabolites and smoking in postmenopausal women.

Smoking has been associated with low bone density, fractures and poor intestinal calcium absorption. Calcium absorption is a critical factor in calcium balance in postmenopausal women but the mechanisms causing decreased absorption efficiency in postmenopausal smokers are controversial and poorly defined. We performed a cross-sectional study of 405 postmenopausal women attending a clinic for the management of osteoporosis to compare intestinal calcium absorption efficiency, serum vitamin D metabolites and parathyroid hormone levels in postmenopausal women who had never smoked, who were smokers previously or who were current smokers, to examine the relationships between these variables in smokers. Two hundred and fifty-two of the women had never smoked, 79 had smoked previously and 74 were current smokers. The hourly fractional rate of calcium absorption was similar in non-smokers and those who had previously smoked. Radiocalcium absorption was less in the 74 smokers compared with the 331 non-smokers [0.60 (0.29 SD) vs 0.71 (0.27); p = 0.004], as were serum calcitriol (p<0.001) and parathyroid hormone (PTH) (p<0.01). There was no difference in the relationship between calcium absorption and serum calcitriol between smokers (r = 0.38) and non-smokers (r = 0.28); hence the impaired calcium absorption in the smokers was almost entirely attributable to suppression of the PTH-calcitriol endocrine axis. In postmenopausal women smoking is associated with a reduction in calcium absorption efficiency due to suppression of the PTH-calcitriol axis. This impairment of calcium absorption could lead to accelerated bone loss and limit the usefulness of dietary calcium supplementation.

Effects of dose and timing of calcium supplementation on bone resorption in early menopausal women.

Bone resorption follows a circadian rhythm that peaks at night, reflecting the circadian rhythm of serum parathyroid hormone. Our previous studies in early postmenopausal women have established that 1000 mg of calcium given at 9 p. m. reduced bone resorption markers overnight, but not during the day. In contrast, 1000 mg given as a divided dose (500 mg doses at 9 a. m. and 9 p. m. each) reduced bone resorption markers during the day, but not during the night. We have now evaluated the effect of 1500 mg of calcium given as a divided dose of 500 mg in the morning and 1000 mg in the evening on bone resorption. We studied 26 healthy women (median age 56 years) whose menopause was less than five years before. On two days, urine was collected from 9 a. m. to 9 p. m. (day collection), and from 9 p. m. to 9 a. m. (night collection); a further fasting (spot) urine sample was obtained at 9 a. m. at the end of the night collection. On the second day, 500 mg of calcium in the carbonate form was taken at 9 a. m. (at the start of the collection) and a further 1000 mg at 9 p. m. (at the start of the second night collection). Calcium supplementation decreased urinary deoxypyridinoline (DPyr/Cr) during the day (p = 0.08) and night (p < 0.05), as well as urinary pyridinoline (Pyr/Cr) both by day (p < 0.05) and night (p < 0.001). There were also decreases in urine hydroxyproline. We conclude that the acute administration of 500 mg of calcium in the morning and 1000 mg in the evening to early postmenopausal women suppresses bone resorption markers during both the day and night.

Vitamin D status: effects on parathyroid hormone and 1, 25-dihydroxyvitamin D in postmenopausal women.

BACKGROUND: Low serum 25-hydroxyvitamin D ¿25(OH)D concentrations are commonly found in the elderly and are associated with hip fracture. Treatment with vitamin D and calcium can reduce the risk of fracture. The relation between the rise in parathyroid hormone (PTH) with age and the decrease in 25(OH)D is not clear. Neither is there any consensus on the serum concentration of 25(OH)D required for bone health. OBJECTIVE: Our objective was to study the relations between serum PTH, serum vitamin D metabolites, and other calcium-related variables in postmenopausal women. DESIGN: This was a cross-sectional study of 496 postmenopausal women without vertebral fractures attending our menopausal osteoporosis clinics. RESULTS: PTH was significantly positively related to age and serum 1, 25-dihydroxyvitamin D ¿1,25(OH)(2)D and inversely related to 25(OH)D and plasma ionized calcium. There was a step-like increase in PTH as serum 25(OH)D fell below 40 nmol/L. In women with 25(OH)D concentrations >40 nmol/L, 1,25(OH)(2)D was positively related to 25(OH)D; in women with 25(OH)D concentrations 40 nmol/L, 1,25(OH)(2)D was most closely (inversely) related to plasma creatinine. Therefore, with serum 25(OH)D concentrations increasingly <40 nmol/L, serum 1,25(OH)(2)D becomes critically dependent on rising concentrations of PTH. CONCLUSION: The data suggest that aging women should maintain 25(OH)D concentrations >40 nmol/L (which is the lower limit of our normal range for healthy young subjects) for optimal bone health.

The relation between bone density, free androgen index, and estradiol in men 60 to 70 years old.

The cause of age-related bone loss in men is poorly understood. Previous studies of the relationship between bone density and serum androgens have yielded inconsistent results, perhaps partly because age is a determinant of both. Recent studies suggest that serum estrogen levels influence bone density in adult men. In order to determine whether bone mineral density (BMD) and bone turnover are associated with serum sex steroids, we investigated 37 normal men within a narrow age range (60-70 years). Bone mineral density at the forearm, hip, and spine, testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI:T/SHBG), estradiol (E), free estradiol index (FEI:E/SHBG), and markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type I C-terminal extension peptide) and bone resorption (hydroxyproline/creatinine [OHPr/Cr], deoxypyridinoline/creatinine [Dpd/Cr], pyridinoline/creatinine, collagen type I cross-linked telopeptide) were measured. Bone mineral density was positively related (r > 0.35, p < 0.05 at all sites) to log FAI, whereas there was no significant relationship between BMD and either serum total testosterone, serum E, or FEI. Bone density at the spine and hip were inversely related to both OHPr/Cr (r > -0.41, p < 0.05 for all sites) and Dpd/Cr (r > -0.36, p < 0.05 for all sites). OHPr/Cr (r = -0.41, p < 0.05) and Dpd/Cr (r = -0.41, p < 0.05) were both inversely related to log FAI. We conclude that BMD and bone turnover in adult men are related to plasma free androgens.

Inhibition of bone resorption by divided-dose calcium supplementation in early postmenopausal women.

We have previously shown that a calcium (Ca) supplement of 1000 mg given in the evening reduces the overnight and early morning, but not the daytime, excretion of bone resorption markers in postmenopausal women within five years of the menopause. In the present study, we have looked at the effect of splitting the Ca into two doses of 500 mg each given in the morning and evening. We studied 19 healthy women (median age 53 years) who were all within 5 years of the menopause. On the 2 study days, urine was collected from 9 a.m. to 9 p.m. (day collection), and from 9 p.m. to 9 a.m. (night collection); a further fasting (spot) urine sample was obtained at 9 a.m. at the end of the night collection. The first day was a control day; on the second day the subjects ingested 500 mg Ca as the carbonate at 9 a.m. and 9 p.m. We measured pyridinoline cross-links excretion in all the samples, as well as hydroxyproline in the fasting urine. The Ca supplements lowered urinary excretion of the markers during the day (P < 0.01), had only a marginal effect during the night, but reduced excretion significantly in the fasting urine (P < 0.001). In the whole 24-hour period, the falls in resorption markers were small but comparable to those seen after the ingestion of 1 g of Ca in the evening. We conclude that the acute administration of 0.5 g Ca in the morning and evening reduced the markers of bone resorption in early postmenopausal women during the day but not during the following night, whereas the single 1 g supplement had the reverse effect. Over the 24-hour period, there was nothing to choose between the two regimes. Women at this stage in their life cycle probably require a larger Ca supplement if they are not taking estrogen.

Effect of perimenopause on calcium absorption: a longitudinal study.

OBJECTIVE: Cross-sectional studies suggest that the rise in calcium requirement at the menopause may be attributable, at least in part, to a fall in intestinal calcium absorption. The aim of the present study was to determine the effect of the menopause on intestinal calcium absorption and the relationship between any change in calcium absorption and serum calcitriol. METHODS: Radiocalcium absorption and serum calcitriol were measured in 72 women aged 47.3 (standard error, SE 0.19) years who were initially premenopausal (as judged by menstrual history and serum follicle stimulating hormone (FSH)) and again 18 months later. RESULTS: Calcium absorption fell at the second visit from 0.72 (0.029)/h to 0.64 (0.029)/h (p = 0.003). Serum calcitriol had also fallen at the second visit from 124 (4.2) pmol/l to 111 (4.0) pmol/l (p = 0.007). At that visit, serum FSH exceeded the premenopausal reference range in 11 subjects and the menstrual cycle had become irregular in 24 of them. In the 11 women with raised FSH at the second visit, radiocalcium absorption fell from 0.85/h (0.097) at baseline to 0.57/h (0.049) (p = 0.008), but only from 0.70/h (0.028) to 0.65/h (0.033) (not significant) in the remaining 61. Similarly, radiocalcium absorption fell significantly (p = 0.003) in the 24 women with irregular menses, but not in the remaining 48 who continued to menstruate regularly. These changes in calcium absorption were still significant after correction for changes in calcitriol levels. CONCLUSION: The perimenopause is associated with a fall in calcium absorption, which is only in part attributable to a fall in calcitriol levels.

Biochemical variables in pre- and postmenopausal women: reconciling the calcium and estrogen hypotheses.

There is controversy as to whether the rise in urinary calcium at the menopause is the cause or the result of the rise in bone resorption at that time. In an attempt to resolve this issue, we have compared the relevant biochemical variables in 102 premenopausal volunteers (mean age 37 years; range 21-52) and 86 apparently normal postmenopausal women (mean age 55 years; range 40-60). We measured the fasting serum calcium, creatinine, proteins, electrolytes and intact parathyroid hormone (PTH), and the urinary calcium and creatinine both after an overnight fast and in a 24-h collection. We calculated serum calcium fractions, creatinine clearance and the notional tubular maximum reabsorptive capacity for calcium. Creatinine excretion and clearance were lower in the post- than in the premenopausal women after correction for surface area and age. Total serum calcium was higher in the post- than in the premenopausal women but this was accounted for by the higher ligand concentrations in the former. Fasting and 24-h urinary calcium were also higher in the post- than in the premenopausal women due in part to the former's higher filtered load of calcium (due to their higher serum complexed calcium) but mainly to their reduced tubular reabsorption of calcium despite their slightly raised serum PTH. Our analysis resolves the rise in urinary calcium at the menopause into its two components: increased filtered load and reduced tubular reabsorption. The changes in these two variables, neither of which can be attributed to increased bone resorption, produce an increase in calcium requirement that is sufficient to account for postmenopausal bone loss. However, the translation of this menopausal increase in calcium requirement into an increase in bone resorption at near-normal serum PTH levels requires some menopause-dependent change in the responsiveness of the bone to calcium demand. We suggest that this change may occur at the level of the osteoclasts and that estrogen may modify the calcium feedback setpoint in these cells in a manner analogous to calcitonin. This model resolves the apparent conflict between the estrogen and calcium hypotheses and explains the synergism between these two treatment modalities.

Discordance between bone turnover and bone loss: effects of aging and ovariectomy in the rat.

Mechanical strain maintains bone architecture even under conditions of increased bone turnover such as occurs with ovarian hormone deficiency. The rat distal femur contains two sites that apparently experience different levels of mechanical strain and therefore the rat is a suitable model for investigating such effects. The femoral epiphysis experiences higher strain energy compared with the metaphysis and we report the effects of aging between 7 and 12 months and the postovariectomy effects over the same time period on cancellous bone variables measured at these two sites. Age-related bone loss in sham-operated (Sham) animals occurred in both regions, with a greater fall in the metaphysis than in the epiphysis (trabecular bone volume [BV/TV, %] Mean [SEM] Metaphysis: day 0, 25. 9 [2.4]; day 150, 8.8 [1.3]: Epiphysis: day 0, 44.8 [1.7]; day 150, 36.7 [1.4] [p < 0.0001]). With ovariectomy (OVX) there was a 73% reduction in cancellous bone at the metaphysis compared with no specific loss at the epiphysis (BV/TV [%] OVX: Metaphysis: day 150, 2.4 [0.4] [p < 0.01 compared with Sham]: Epiphysis: day 150 29.3 [2. 7] [NS]). Osteoblast cell activity and osteoclast surface were increased after ovariectomy in both regions. The mineral apposition rate decreased at 9.5 months of age in both regions (p < 0.0001), independent of ovariectomy, and was coincident with a reduction in trabecular number in the epiphyses of both operative groups and in the metaphysis of the ovary-intact group. These data suggest that local mechanical strain governs bone balance with aging and that architectural changes resulting from age-related bone loss may mirror those following estrogen deficiency but occur via a different cellular mechanism.

Relationships between age, dehydro-epiandrosterone sulphate and plasma glucose in healthy men.

BACKGROUND: dehydro-epiandrosterone sulphate (DHEAS) has been reported to ameliorate diabetes mellitus in rats. AIM: we investigated the relationships between plasma glucose, age, serum DHEAS and weight in healthy men. METHODS: we measured the serum DHEAS, fasting plasma glucose, plasma cortisol and body mass index in 169 subjects (mean age 46.5 years). RESULTS: there was a significant decline in serum DHEAS with age (P < 0.0001). Multiple linear regression showed significant relationships with plasma glucose for all measured variables. Age was not a significant determinant of plasma glucose after adjusting for log serum DHEAS, body mass index and log serum cortisol. CONCLUSIONS: a lowered serum DHEAS is paralleled by an elevated plasma glucose within the normal reference interval, and this may contribute to the rise in fasting plasma glucose which occurs with ageing.

The effects of low dose norethisterone on biochemical variables in postmenopausal women.

Norethisterone 2.5 mg/day was administered to 26 postmenopausal women (aged 54-79 years) with varying degrees of osteoporosis and with a forearm bone mineral density value more than 2 SD below the young normal mean. Fasting blood and urine samples were collected and radiocalcium absorption measured at baseline and after treatment for a median period of 4 months. There were significant falls in serum calcium and its fractions, phosphate, alkaline phosphatase and cholesterol (HDL and LDL), and significant rises in serum chloride and parathyroid hormone. In the urine, there were significant falls in calcium, sodium and hydroxyproline. These changes were in close agreement with our previously reported responses to norethisterone 5 mg/day. We conclude that norethisterone in a dose of 2.5 mg/day is probably as effective as 5 mg/day in reducing bone resorption in postmenopausal women with low bone density.

Variation in the short-term changes in bone cell activity in three regions of the distal femur immediately following ovariectomy.

The effect of ovariectomy (OVX) on cancellous bone in the rat is not uniform at all sites of the skeleton. We report variation in the short-term effects of adult OVX in three regions of the distal femur: the diaphysis (DIA), the metaphysis (META), and the epiphysis (EPI). Cancellous bone parameters were estimated in the three separate zones of the femora and compared with changes in bone cell activity, as estimated by osteoclast surface (Oc.S) and bone formation rate (BFR). Changes were studied for 30 days in a series of rats either sham-operated (Sham) or ovariectomized (OVX) at 7 months of age. Oc.S and BFR were elevated following OVX in all regions. The time course for the OVX-induced changes differed between regions: DIA, both Oc.S and BFR were elevated at day 9; META, Oc.S was also elevated at day 9, while the rise in BFR was delayed until day 21; EPI, Oc.S remained stable but increased relative to ovary-intact rats by day 18 due to reduced levels in the latter, but BFR did not rise until day 28. These changes in bone cell activity following OVX produced a 71% reduction of cancellous bone in the DIA and a 35% reduction in the META. In contrast, no OVX-induced bone loss was observed in the EPI. This study shows that bone cell activity increases in each region of the distal femur within the first 30 days following OVX, independent of bone loss. However, the time course of increased bone cell activity is not uniform. These data highlight the role of local factors in the response to ovarian hormone deficiency.

Intestinal calcium absorption in men with spinal osteoporosis.

OBJECTIVE: To investigate the role of serum 1,25-dihydroxyvitamin D (1,25D) in the decreased calcium absorption found in men with osteoporosis. DESIGN: Prospective study of patients referred to a university teaching hospital clinic for investigation of possible osteoporosis. PATIENTS: Male patients referred for investigation for osteoporosis, from 1981 to 1995, because of specific risk factors or radiological suspicion of osteoporosis. Men with vertebral compression fractures were compared with those without. MEASUREMENTS: Height and weight, radiocalcium absorption, serum 1,25D and fasting urinary calcium and hydroxyproline excretion. RESULTS: The men with vertebral fractures had higher fasting urinary hydroxyproline excretion (P = 0.003) and lower calcium absorption (P = 0.002) than the men without. Calcium absorption was positively related to 1,25D in both groups but the estimated calcium absorption at zero 1,25D was lower in the osteoporotic than the normal group. 1,25D was lower in the osteoporotic group than in the normal group. However this difference could only explain about half of the difference in calcium absorption between the groups. CONCLUSIONS: Calcium absorption is low in men with osteoporosis. About half of the deficit is due to low serum 1,25-dihydroxy vitamin D levels but there appears, in addition, to be some intestinal resistance to its effect on calcium absorption.

Prepubertal oophorectomy limits the accumulation of cancellous bone in the femur of growing rats with long-term effects on metaphyseal bone architecture.

Bone loss after oophorectomy of adult rats is more rapid and complete in the metaphysis than in the epiphysis of the femur, particularly in the proximal region of the metaphysis distant from the growth plate. This study was undertaken to determine the effects of prepubertal oophorectomy, on femoral cancellous bone acquisition during growth. Rats were oophorectomized (OVX) or sham operated at 3 weeks of age and killed at intervals up to 78 weeks for scanning electron microscopy and histomorphometry of the distal femur. Differences in cancellous bone architecture between the two groups was evident after 6 weeks of age. Relatively minor differences were found in the part of the metaphysis near the growth plate and in the epiphysis, with less trabeculae in the primary spongiosa and 1 to 2 less trabeculae/mm in the secondary spongiosa. However, as metaphyseal growth proceeded, trabeculae were present for a greater distance up the femoral shaft in controls than in OVX rats, with mean BV/TV in the proximal part of the metaphysis increasing from 1.4% at 6 weeks to 13.4% at 20 weeks in controls, with no increase in the OVX rats. We find that the lack of ovarian hormones increases the rate of destruction of trabeculae near the metaphyseal-diaphyseal junction.