Acute effect of a supplemented milk drink on bone metabolism in healthy postmenopausal women is influenced by the metabolic syndrome.

BACKGROUND: Dietary factors acutely influence the rate of bone resorption, as demonstrated by changes in serum bone resorption markers. Dietary calcium exerts its effect by reducing parathyroid hormone levels while other components induce gut incretin hormones both of which reduce bone resorption markers. The impact of dietary calcium on bone turnover when energy metabolism is modulated such as in metabolic syndrome has not been explored. This study was designed investigate whether metabolic syndrome or a greater amount of visceral fat influences the impact of dietary calcium on bone turnover. METHODS: The influence of the metabolic syndrome on effects of dietary calcium on bone turnover in community dwelling postmenopausal women was studied. Twenty five volunteers consumed 200 mL of low fat milk with additional 560 mg calcium (one serve of Milo®) in the evening on one occasion. Fasting morning serum biochemistry before and after the milk drink with lumber spine bone density, bone mineral content, fat and lean mass using dual energy X-ray absorptiometry (DXA) and waist circumference were measured. The women were divided into 2 groups using the waist measurement of 88 cm, as a criterion of metabolic syndrome. Student's t tests were used to determine significant differences between the 2 groups. RESULTS: The lumbar spine mineral content was higher in women with metabolic syndrome. After consuming the milk drink, serum bone resorption marker C terminal telopeptide (CTX) was suppressed to a significant extent in women with metabolic syndrome compared to those without. CONCLUSIONS: The results suggests that dietary calcium may exert a greater suppression of bone resorption in post-menopausal women with metabolic syndrome than healthy women. Despite substantial evidence for close links between energy metabolism and bone metabolism this is the first report suggesting visceral fat or metabolic syndrome may influence the effects of dietary calcium on bone metabolism.

The calcium scare--what would Austin Bradford Hill have thought?

UNLABELLED: Detailed consideration of the suggested association between calcium supplementation and heart attacks has revealed weakness in the evidence which make the hypothesis highly implausible. INTRODUCTION: The aim of this study was to evaluate the strength of the evidence that calcium supplementation increases the risk of myocardial infarction. METHODS: This study used critical examination of a meta-analysis of the effects of calcium supplements on heart attacks in five prospective trials on 8,016 men and women, and consideration of related publications by the same author. RESULTS: The meta-analysis was found to be subject to several limitations including non-adherence to the clinical protocol, multiple endpoint testing and failure to correctly adjust for endpoint ascertainment. The main risk factors for myocardial infarction were not available for 65% of the participants, and none of the trials had cardiovascular disease as its primary endpoint. There were more overweight participants, more subjects on thyroxine and more men on calcium than on placebo. In particular, over 65% of all the heart attacks were self-reported. When the evidence was considered in the light of Austin Bradford Hill's six main criteria for disease causation, it was found not to be biologically plausible or strong or to reflect a dose-response relationship or to be consistent or to reflect the relationship between the trends in calcium supplementation and heart attacks in the community or to have been confirmed by experiment. The addition of a more recent trial on 1,460 women over 5 years reduced the relative risk to 1.23 (P = 0.0695). CONCLUSION: Present evidence that calcium supplementation increases heart attacks is too weak to justify a change in prescribing habits.

Suppression of C-terminal telopeptide in hypovitaminosis D requires calcium as well as vitamin D.

We compared the effects of oral calcium and vitamin D separately and together on relevant variables in 22 postmenopausal volunteers with initial serum 25OHD levels below 60 nmol/L. Subjects were allocated randomly to two regimens: group 1 received 1 week of calcium 1,000 mg, followed by 7 weeks with additional vitamin D3 1,000 i.u. daily; group 2 received 7 weeks of D3 1,000 i.u. daily, followed by 1 week with additional calcium 1,000 mg. We measured serum calcium, phosphate, PTH, 25OHD, CTX, and ALP at baseline and after 1 and 8 weeks in group 1 and after 7 and 8 weeks in group 2. There were no significant changes in ALP from either vitamin D or calcium. Calcium caused significant elevation of serum 25OHD as well as major suppression of serum CTX, which could not easily be accounted for by suppression of PTH. Vitamin D caused no significant change in any variable except elevation of serum 25OHD. The suppressive effect of calcium (whether given first or second) on serum CTX was threefold greater than that of vitamin D (whether given first or second) (P < 0.001), although their suppressive effects on serum PTH were the same. Calcium and vitamin D yielded greater and more significant effects on all variables (except ALP) than either treatment alone. We suggest that calcium may elevate serum 25OHD by prolonging its half-life and that it may have an inhibitory effect on bone resorption independent of, or in addition to, its suppression of PTH.

The effect of calcium supplementation on bone loss in 32 controlled trials in postmenopausal women.

SUMMARY: In 32 controlled trials of calcium supplementation (700-2000 mg) in 3,169 postmenopausal women, mean bone loss in the controls was -1.07% p.a. and in the treated subjects -0.27% p.a. (P for difference <0.001). The effect was similar at all measured sites and at all doses of 700 mg or more but became weaker after 4 years. INTRODUCTION: We have reviewed 32 trials of calcium supplementation in 3,169 postmenopausal women. METHODS: We found 24 publications reporting 32 controlled trials lasting at least 1 year, which provided annual percentage changes in bone mass or density at one or more sites in the calcium-treated and control subjects. RESULTS: The median calcium supplement was 1,000 mg, median duration of the trials 2 years and total number of sites measured 79. The average of the mean rates of change in bone mass or density was -1.07% p.a. (P < 0.001) in the controls and -0.27% p.a. (ns) in the treated subjects (P for difference < 0.001). The effect of calcium was much the same at all measured sites (forearm/hand, proximal femur, spine, and total body and others). Supplements of less than 700 mg were not effective, but there was no significant beneficial effect of higher doses. There was significantly faster bone loss at total calcium intakes below 1,150 mg than on intakes over 1,350 mg. The effect of calcium appeared to be lost after 4 years of treatment. CONCLUSION: Calcium supplementation of about 1,000 mg daily has a significant preventive effect on bone loss in postmenopausal women for at least 4 years.

Calcium malabsorption does not cause secondary hyperparathyroidism.

We challenge the widespread assumption that malabsorption of calcium per se causes secondary hyperparathyroidism. Serum parathyroid hormone (PTH) does not rise at the menopause despite the fall in calcium absorption, nor is it raised in osteoporotic women with vertebral fractures despite their low calcium absorption. The age-related rise in serum PTH can be accounted for by the age-related fall in serum 25(OH)D and/or decline in renal function with consequent loss of the calcemic action of vitamin D on bone. The reference interval for serum PTH is established in the fasting state when it is at the top of its diurnal cycle and is maintaining serum ionized calcium at the expense of bone to meet the calcium being lost through skin, bowel, and kidneys. There is no evidence that the fasting PTH is influenced by the previous day's intake or absorption of calcium, although it can be lowered by a large evening calcium supplement. Malabsorption of calcium-like dietary calcium deficiency-is a risk factor for osteoporosis because it reduces or prevents the normal food-related daytime fall in PTH and bone resorption, not because it causes secondary hyperparathyroidism.

Misconceptions - vitamin D insufficiency causes malabsorption of calcium.

The negative effect of vitamin D insufficiency on bone is commonly attributed to a decrease in calcium absorption although little evidence has been produced to support this assumption. Using two previously published series of elderly patients we refute this common assumption and present evidence that low circulating levels of 25 hydroxyvitamin D have a direct and deleterious effect on bone.

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.

The importance of calculating absolute rather than relative fracture risk.

The relation between fracture risk and bone mineral density (BMD) is commonly expressed as a multiplicative factor which is said to represent the increase in risk for each standard deviation fall in BMD. This practice assumes that risk increases multiplicatively with each unit fall in bone density, which is not correct. Although odds increase multiplicatively, absolute risk, which lies between 0 and 1, cannot do so though it can be derived from odds by the term Odds/(1+Odds). This concept is illustrated in a prospective study of 1098 women over age 69 followed for 6 years in a calcium trial in which hip BMD was measured in the second year. 304 Women (27.6%) had prevalent fractures and 198 (18.1%) incident fractures with a significant association between them (P 0.005). Age-adjusted hip BMD and T-score were significantly lower in those with prevalent fractures than in those without (P 0.003) and significantly lower in those with incident fractures than in those without (P 0.001). When the data were analysed by univariate logistic regression, the fracture odds at zero T-score were 0.130 and the rise in odds for each unit fall in hip T-score was 1.55. When these odds were converted to risks, there was a progressive divergence between odds and risk at T-scores below zero. Multiple logistic regression yielded significant odds ratios of 1.47 for each 5-year increase in age, 1.47 for prevalent fracture and 1.49 for each unit fall in hip T-score. Calcium therapy was not significant. Poisson regression, logistic regression and Cox's proportional hazards yielded very similar outcomes when converted into absolute risks. A nomogram was constructed to enable clinicians to estimate the approximate 6-year fracture risk from hip T-score, age and prevalent fracture which can probably be applied (with appropriate correction) to men as well as to women. We conclude that multiplicative factors can be applied to odds but not to risk and that multipliers of risk tend to overstate the effect of continuous variables, such as age and T-score, particularly towards the end of their ranges.

Lactose and calcium absorption in postmenopausal osteoporosis.

The prevalence of lactase deficiency and the relationship between lactose and calcium malabsorption in postmenopausal osteoporosis has been assessed in 46 subjects. Malabsorption of lactose occurred in 25 (54%) of the subjects and was associated with a significantly lower milk intake. Malabsorption of calcium occurred in 11 (44%) of the lactase-deficient subjects and in 11 (52%) of normal lactose absorbers. There was no relationship between lactose and calcium malabsorption. Vertebral and forearm mineral densities were not significantly different between normal lactose absorbers and lactase-deficient subjects.

Relationship between forearm and vertebral mineral density in postmenopausal women with primary hyperparathyroidism.

Vertebral and forearm mineral density of 28 postmenopausal women with mild primary hyperparathyroidism was measured and compared with expected values on the basis of age and years since menopause. In these patients we found that the bone deficit in the distal forearm was greater than in the spine, and 8 patients had already suffered one or more peripheral fractures. This suggests that postmenopausal women with mild, asymptomatic hypercalcemia of primary hyperparathyroidism are likely to be relatively more predisposed to peripheral than vertebral fractures, which is clear evidence of the need for treatment to prevent bone loss in these patients.

Treatment of postmenopausal hyperparathyroidism with norethindrone. Long-term effects on forearm mineral content.

In 15 postmenopausal women with mild primary hyperparathyroidism, the long-term effect of norethindrone therapy (5 mg/d) on forearm bone mineral content (FMC) was evaluated. The FMC rose from 810 +/- 39 (SEM) mg/cm at baseline to 841 +/- 41 mg/cm after 2 years of treatment, representing a mean bone mineral gain of 1.9% per year. The majority of this bone gain occurred during the first 6 months of treatment. The rate of increase in FMC in the first 6 months was +3.71 +/- 0.12 mg/cm per month compared with -0.35 +/- 0.51 mg/cm per month during the second year. Fat-corrected FMC was measured to determine whether the bone gain was real or reflected a decrease in fat mass. There was a similar rise in fat-corrected FMC (from 885 +/- 36 mg/cm at baseline to 909 +/- 39 mg/cm at 2 years). The difference between fat-corrected and uncorrected FMC, however, decreased slightly on norethindrone treatment (from 75.2 +/- 11.9 mg/cm at baseline to 67.8 +/- 11.8 mg/cm at 12 months), indicating a reduction in the subcutaneous fat layer. We conclude that norethindrone therapy in postmenopausal women with mild primary hyperparathyroidism produces a gain in bone mass that is sustained for at least 2 years.

Treatment of postmenopausal hyperparathyroidism with norethindrone. Effects on biochemistry and forearm mineral density.

The effects of norethindrone (5 mg daily) on biochemical variables and forearm mineral density were assessed in 20 postmenopausal women with mild primary hyperparathyroidism. Norethindrone produced a significant fall in plasma calcium levels and the fasting urinary calcium-creatinine and hydroxyproline-creatinine ratios after three months of treatment. There was no change in the plasma parathyroid hormone concentrations. The forearm mineral density before treatment was low in 16 of the 20 patients and there was a significant increase in forearm mineral density after norethindrone treatment. No side effects were reported. We conclude that norethindrone is an effective treatment for mild hyperparathyroidism in postmenopausal women.

Effects of nandrolone decanoate and antiresorptive therapy on vertebral density in osteoporotic postmenopausal women.

Conventional antiresorptive therapy for osteoporosis can delay bone loss, but secondary inhibition of bone formation appears to prevent an increase in bone density. Recently, anabolic steroid therapy has been shown to increase total body calcium and forearm density in osteoporotic patients, perhaps by causing an increase in bone formation. It is not known if these agents affect vertebral density. We have measured vertebral mineral density in 71 postmenopausal osteoporotic women before and after treatment with either the anabolic steroid nandrolone decanoate or antiresorptive therapy. After a mean treatment period of 14 months, there was a mean increase of 20% in vertebral mineral density in the former group, and no significant change in the latter group. The difference in the time-weighted mean rates of change between the two groups was significant. The results suggest that nandrolone decanoate therapy increases bone formation.

Effect of salt restriction on urine hydroxyproline excretion in postmenopausal women.

Fasting calcium and hydroxyproline excretion are related to fasting sodium excretion in postmenopausal women. We postulate that calcium excretion is sodium dependent and that hydroxyproline excretion is calcium dependent. Therefore, we sought to lower urinary hydroxyproline, which is a marker of bone resorption, by lowering urinary sodium. Fasting urine samples were obtained from 59 postmenopausal women before and after 2 to 7 days of dietary salt restriction. The urinary sodium-to-creatinine ratio fell from 16 to 7; calcium to creatinine, 0.30 to 0.26; and hydroxyproline to creatinine, 18.2 to 16.8. In the 28 subjects with starting sodium-to-creatinine ratios greater than 15, the hydroxyproline-to-creatinine ratio fell from 19.6 to 16.3. Salt restriction may be one way of reducing bone resorption in postmenopausal women, particularly in those whose sodium intake is high.

A 5-year longitudinal study of forearm bone mass in 307 postmenopausal women.

We measured forearm bone mineral content at the beginning and end of a 5 year period in 307 untreated postmenopausal volunteers. We also measured height, weight, and a number of biochemical variables in plasma and urine after an overnight fast. The initial mean age of the subjects was 59.0 years (range 39-72), and the mean years since menopause was 10.0 (range 1-37). The mean forearm BMC fell from 1034 +/- 9.6 (SEM) to 982 +/- 9.3 mg/cm (P < 0.001). The coefficient of correlation between the first and second measurements was 0.96. The mean rate of change was -1.0% per annum (with a 99% range of -4 to 1% per annum), which agreed well with previous estimates from cross-sectional data. There was a significant negative correlation between rate of change in bone mass and initial value (r = -0.23; P < 0.001), which was eliminated by expressing change as a percentage of initial bone mass. Of the other variables measured, the one that was most significantly related to the percentage change in bone mass was the urinary hydroxyproline/creatinine ratio (r = -0.35; P < 0.001), which we regard as a marker only. By stepwise regression, the only significant determinants of the rate of change in bone mass were body weight (positive, P < 0.001), years since menopause (positive, P < 0.005), urine calcium (negative, P < 0.01), and serum estrone (positive, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Regional bone mineral density interrelationships in normal and osteoporotic postmenopausal women.

We describe a prospective study in which bone mineral density (BMD) was measured in total body and regions, proximal femur, lumbar spine, and forearm in 84 apparently normal postmenopausal women with normal spinal radiographs and in 47 women with 1-10 wedged or compressed vertebrae. There was a history of peripheral fracture in 35 of the 84 controls and 30 of the 47 osteoporotics (p < 0.02) but there was no association between vertebral fracture and wrist fracture. At all sites and regions, the differences in BMD between the "normal"and "osteoporotic" women was highly significant and all but "ribs" and "arms" remained significant after correction for menopausal age. In the whole set, and in both subgroups, the coefficients of correlation between sites and regions were all highly significant (p < 0.001). Nonetheless, some sites discriminated better between the two groups than others. Standardized odds ratios (OR) for vertebral fracture versus no-fracture were calculated by logistic regression and expressed as the rise in OR for each standard deviation (SD) fall in bone density. This ratio was greatest (3.4) in "pelvis" and weakest (1.7) in "ribs" but all were statistically significant. Geometric mean regression equations were calculated for all the 78 possible pairs of sites and regions in the 84 normal subjects and the deviations of the osteoporotic women from these normal slopes calculated. In most pairs of sites and regions, the vertebral fracture cases were scattered around the normal group's slope but fell lower down on both axes. The bone deficits in the osteoporotics compared with young normal women ranged from -14% in "head" to -40% in Ward's triangle and the T-scores ranged from -1.9 in "ribs" to -3.9 in the forearm. Sensitivity ranged from 17% in "ribs" to 36.2% in Ward's triangle. Specificity varied between 88 and 94% and the percent correctly classified ranged from 62.6% in "ribs" to 72.5% in Ward's triangle. We conclude that primary postmenopausal osteoporosis affects the entire skeleton but that some sites discriminate better between vertebral fracture and nonfracture cases regardless of whether they represent cortical or trabecular bone.

Relative contributions of years since menopause, age, and weight to vertebral density in postmenopausal women.

Vertebral mineral density (VMD) was measured by quantitative computerized tomography (QCT) in 16 premenopausal and 243 untreated postmenopausal women without vertebral compression. The mean VMD in the premenopausal group was 157 +/- 10.1 mg/mL, which is close to previously reported values. In the postmenopausal women, VMD fell significantly with age and years since menopause (YSM) separately and together, but the relation to YSM was more significant than that to age. After logarithmic transformation of YSM, the fall in bone density with logYSM was highly significant (P less than 0.001), and that with age was not quite significant. In 36 pairs of women matched for YSM, there was no significant difference in VMD between the subjects up to and over 55 yr of age. In 32 pairs matched for age, VMD was significantly lower in those over 55 yr than in those up to 55 yr (P = 0.005). There was also a significant correlation between VMD and body weight. After this was allowed for, the correlation between VMD and logYSM remained highly significant, but the correlation with age was not significant. We conclude that the fall in vertebral body trabecular bone in postmenopausal women is self-limiting, amounts to about 35% bone loss in 25 yr (most of it in the first 5 yr), and corresponds to but is proportionately greater than the trabecular component in postmenopausal forearm bone loss.