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Background: There is uncertainty about the calcium requirement with particular respect to age and sex differences and the calculation of skin calcium losses. Objective: We calculated the calcium requirement of adult men from a homogenous set of calcium balances and a robust estimate of calcium loss through the skin. Design: We reviewed available high-quality published calcium balances in men and retrieved 219 balances; we noted a fall in calcium absorption in individuals .60 y of age. Our analysis was confined to 157 men � 59 y of age with intakes of � 1100 mg Ca. Results: The mean age of the men was 38 y (range: 17‐59 y), and the mean duration of the balances was 107 d (9‐480 d). We assumed skin calcium losses of 40 mg Ca/d on the basis of the calcium content of insensible water loss. There was a highly significant correlation between calcium intake and the net absorbed calcium (R 2 = 0.59), but inspection and physiologic considerations led us to use the logarithmic transformation of intake, which yielded the equation Ca absorbed = 210 log Ca intake 2 1135 mg Ca. The calcium intake at which urine calcium plus skin calcium losses were equal to the net absorbed calcium was rounded to 750 mg Ca as the requirement, which implied a recommended allowance of 900 mg Ca. Conclusion: We conclude that the mean calcium requirement of adult men ,60 y of age is 750 mg Ca/d, and the Recommended Dietary Allowance should be 900 mg Ca. Am J Clin Nutr doi: 10.3945/ajcn.110.004382.

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.

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.

Contrary to frequent claims, vitamin D insufficiency does not generally cause malabsorption of calcium because serum 1,25(OH)(2)D, which is the major determinant of calcium absorption, is maintained by secondary hyperparathyroidism. Nevertheless, because malabsorption of calcium has been described in osteomalacia, there must be a 25(OH)D level below which the serum 1,25(OH)(2)D can no longer be sustained, although it has never been defined. This paper seeks to define it. We examined the records of 3661 patients and found 319 with a serum 25(OH)D < or = 40 nM, in whom calcium absorption, serum calcium, PTH, bone markers, and vitamin D metabolites had been measured. They were grouped according to their serum 25(OH)D into four categories, 0-10, 11-20, 21-30, and 31-40 nM, and differences between the groups were tested by ANOVA. Correlations between the variables were also examined. Serum calcium, 1,25(OH)(2)D, and calcium absorption were significantly decreased and serum PTH and alkaline phosphatase (ALP) and urine hydroxyproline were increased in those with 25(OH)D < or = 10 nM. Serum ALP and urine hydroxyproline were more strongly related, inversely, to calcium absorption than to the vitamin D metabolites. We conclude that vitamin D deficiency does not reduce serum 1,25(OH)(2)D, and therefore calcium absorption, until the serum 25(OH)D falls to approximately 10 nM. At this level, the substrate concentration seems to be insufficient to maintain the level of the dihydroxy metabolite despite secondary hyperparathyroidism. Further studies are needed to see how these changes correlate with the histological changes of osteomalacia.

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.

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.

Summary Objective To determine the effects of menopause on bone-related variables in Indonesian women and to compare them with corresponding data in Caucasian Australian women. Design A study of bone-related variables in women aged 45 ‐55 years in Jakarta compared with corresponding historical data from Caucasian Australian women. Measurements Dietary intakes, bone mineral density (BMD) and calcium-related variables in blood and urine. Results Dietary calcium, phosphorus and protein intakes were significantly lower in the women from Jakarta than in those from Adelaide (all P < 0·001), probably because of lower milk consumption, but energy intake was similar in the two cities. Indonesian women were shorter and lighter than Australian women ( P < 0·001) but had a comparable body mass index (BMI). The Indonesians also had a lower spinal BMD than the Australians but this was accounted for by the differences in height and weight between the two populations. The differences in serum and urinary calcium and phosphate and serum alkaline phosphatase across the menopause were comparable in Indonesian and Australian women but creatinine excretion was 25% lower in Jakarta than in Adelaide ( P < 0·001) and this was probably sufficient to account for higher ratios of some urinary solutes to urinary creatinine in the Indonesians. Serum 25-hydroxyvitamin D (25OHD) levels were significantly lower ( P < 0·001) and serum PTH levels significantly higher ( P = 0·0045) in Jakarta than in Adelaide. Conclusions The differences in bone-related biochemical variables across the menopause were similar in the two populations, but calcium and protein intake and urine creatinine were lower in Indonesian than in Australian women. Serum 25OHD was lower and PTH higher in the Indonesian women, probably because of their darker skin, their practice of avoiding direct sunlight and the heavy atmospheric pollution in Jakarta.

The relation between fracture risk and bone density is frequently defined in terms of a relative hazard derived from the Cox proportional hazards model. The relative hazard is a multiplicative factor representing the rise in hazard for each standard deviation fall in bone mineral density, which has a typical value of about 1.5. It is not generally appreciated that this hazard may only be equated with absolute risk when risk is very low; at higher risk and over long periods, it is inappropriate to apply a multiplicative factor to absolute risk because risk has a range of 0-1 and cannot exceed unity. Here, we show how "hazard" can be converted to risk and how misleading the current practice of equating relative hazards with relative risks can be.

OBJECTIVE: Because it has been reported that vitamin D, given to mother or infant, can prevent type I diabetes in children, that diabetes is more common in adults with low serum vitamin D and that insulin secretion and action are related to vitamin D levels in healthy young adults we examined the relationship between serum vitamin D metabolites and fasting serum glucose in patients attending our outpatient clinics. DESIGN: Retrospective examination of convenience sample of postmenopausal women attending our osteoporosis clinics. PATIENTS: A total of 753 postmenopausal women attending a university hospital outpatient clinic and not on any treatment known to affect glucose metabolism. MEASUREMENTS: Body weight and height, serum 25-hydroxyvitamin D [25(OH)D], serum 1,25-dihydroxyvitamin D [1,25(OH)2D], serum PTH and fasting serum glucose. RESULTS: On simple correlation fasting serum glucose was a positive function of age (P < 0.05), weight (P < 0.001) and body mass index (BMI) (P < 0.001) and a negative function of serum 25(OH)D (P < 0.001), but it was not significantly related to either serum 1,25(OH)2D, PTH or creatinine. When fasting serum glucose was regressed simultaneously on age, BMI and 25(OH)D, glucose was still an inverse function of 25(OH)D (P = 0.006). CONCLUSIONS: Fasting serum glucose increased as 25(OH)D levels fell throughout the range of serum 25(OH)D measured but the greatest increase was observed in those with 25(OH)D below 40 nmol/l.

Background: It is assumed that calcium absorption decreases with age, but this is not well documented. We report a study that addresses this issue. Objective: The aim was to establish the extent and timing of any age-related change in calcium absorption in postmenopausal women. Design: We measured radiocalcium absorption (a) in 262 healthy postmenopausal women aged 40-87 y. We also measured the serum vitamin D metabolites, parathyroid hormone (PTH), and other biochemical variables. Results: Radiocalcium absorption decreased with age (P = 0.018); it was 28% lower in the 25 women aged >75 y than in the rest (P < 0.001). It was significantly related to serum 1,25-dihydroxyvitamin D [1,25(OH) 2 D] in the whole set and in both the younger and older subsets, but it was not related to either 25-dihydroxyvitamin D [25(OH)D] or PTH or to any other measured variable. No decrease in 1.25(OH) 2 D was seen with age to account for the decrease in calcium absorption, so radiocalcium absorption corrected for serum 1,25(OH) 2 D decreased significantly after age 75 y. On multivariate analysis, the serum 1,25(OH) 2 D concentration was a positive function of 25(OH)D (P < 0.001). albumin (P = 0.010), and PTH (P = 0.012) and a negative function of serum creatinine (P = 0.003). PTH was a negative function of calculated ionized calcium (P = 0.004) and 25(OH)D (P = 0.009) and a positive function of weight (P = 0.011) and age (P = 0.028). Conclusions: A late age-related decrease in calcium absorption is seen in postmenopausal women in addition to the decline that occurs at menopause. This decrease could be due to a decline in either the active calcium transport or diffusion component of the calcium absorption system.

Intestinal calcium absorption accounts for 60% of the variance in calcium balance and is therefore a potentially very important determinant of bone status. Whether measured by the balance technique or with radiocalcium, it is known to be significantly reduced in postmenopausal women with vertebral and hip fractures. By contrast, there is very little information about calcium absorption in other types of postmenopausal fracture. We now report a series of 549 untreated, Caucasian postmenopausal women in whom we recorded prevalent fractures, measured radiocalcium absorption, and obtained radiographs of the lateral thoracic and lumbar spine. Of these women, 172 had no prevalent fractures, showed normal spine radiographs, and served as controls; 72 had one or more peripheral fractures but normal spine radiographs; 147 had one or more wedged or crushed vertebrae but no peripheral fractures; and 158 had a history of peripheral fracture and one or more fractured vertebrae. Age-adjusted radiocalcium absorption was significantly lower in the two groups with spinal fractures than in the controls ( P

Osteoporosis is best defined in terms of whole bone density (apparent density) and is present when this variable falls below the young normal range. Low bone density may be genetically determined or acquired. If acquired it may in principle be due to low bone formation or high resorption. It is most easily produced in experimental animals by calcium deprivation and/or ovariectomy, both of which induce high bone resorption; their effects are additive. The postmenopausal rise in bone resorption is associated with a fall in calcium absorption and a renal tubular leak of calcium which combine to increase requirement of this element but there is also an increase in the sensitivity of bone to resorbing agents. Calcium supplementation inhibits postmenopausal bone loss but not as effectively as oestrogen. Protein and sodium are nutrients which increase calcium requirement by increasing obligatory urine calcium loss. Vitamin D is a nutrient, the deficiency of which increases the risk of hip fracture and the administration of which (with calcium) has been shown to reduce the risk of this fracture in vulnerable nursing-home residents. The implications of these findings are that postmenopausal women should ingest more calcium than premenopausal women, be moderate in their consumption of protein and salt, and receive vitamin D supplementation if their 25-hydroxyvitamin D level falls below about 50 nmol/L.

Loss of bone is an almost universal accompaniment of aging that proceeds at an average rate of 0.5-1% per annum from midlife onwards. There are at least four nutrients involved in this process: calcium, salt, protein, and vitamin D, at least in women. The pathogenesis of osteoporosis in men is more obscure. Calcium is a positive risk factor because calcium requirement rises at the menopause due to an increase in obligatory calcium loss and a small reduction in calcium absorption that persist to the end of life. A metaanalysis of 20 calcium trials shows that this process can generally be arrested by calcium supplementation, although there is some doubt about its effectiveness in the first few years after menopause. Salt is a negative risk factor because it increases obligatory calcium loss; every 100 mmol of sodium takes 1 mmol of calcium out of the body. Restricting salt intake lowers the rate of bone resorption in postmenopausal women. Protein is another negative risk factor; increasing animal protein intake from 40 to 80 g daily increases urine calcium by about 1 mmol/day. Low protein intakes in third world countries may partially protect against osteoporosis. Vitamin D (sometimes called a nutrient and sometimes a hormone) is important because age-related vitamin D deficiency leads to malabsorption of calcium, accelerated bone loss, and increased risk of hip fracture. Vitamin D supplementation has been shown to retard bone loss and reduce hip fracture incidence in elderly women.

Calcium is an essential nutrient that is involved in most metabolic processes and the phosphate salts of which provide mechanical rigidity to the bones and teeth, where 99% of the body's calcium resides. The calcium in the skeleton has the additional role of acting as a reserve supply of calcium to meet the body's metabolic needs in states of calcium deficiency. Calcium deficiency is easily induced because of the obligatory losses of calcium via the bowel, kidneys, and skin. In growing animals, it may impair growth, delay consolidation of the skeleton, and in certain circumstances give rise to rickets but the latter is more often due to deficiency of vitamin D. In adult animals, calcium deficiency causes mobilization of bone and leads sooner or later to osteoporosis, i.e., a reduction in the "amount of bone in the bone" or apparent bone density. The effects of calcium deficiency and oophorectomy (ovariectomy) are additive. In humans, osteoporosis is a common feature of aging. Loss of bone starts in women at the time of the menopause and in men at about age 55 and leads to an increase in fracture rates in both sexes. Individual fracture risk is inversely related to bone density, which in turn is determined by the density achieved at maturity (peak bone density) and the subsequent rate of bone loss. At issue is whether either or both of these variables is related to calcium intake. The calcium requirement of adults may be defined as the mean calcium intake needed to preserve calcium balance, i.e., to meet the significant obligatory losses of calcium through the gastrointestinal tract, kidneys, and skin. The calcium allowance is the higher intake recommended for a population to allow for individual variation in the requirement. The mean requirement defined in this way, calculated from balance studies, is about 20 mmol (800 mg) a day on Western diets, implying an allowance of 25 mmol (1000 mg) or more. Corresponding requirements and allowances have been calculated for pregnancy and lactation and for children and adolescents, taking into account the additional needs of the fetus, of milk production, and of growth. There is a rise in obligatory calcium excretion at menopause, which increases the theoretical calcium requirement in postmenopausal women to about 25 mmol (1000 mg) and implies an allowance of perhaps 30 mmol (1200 mg) or even more if calcium absorption declines at the same time. At issue here, however, is whether menopausal changes in calcium metabolism are the cause or the result of postmenopausal bone loss. The first interpretation relies on evidence of a positive action of estrogen on the gastrointestinal absorption and renal tubular reabsorption of calcium; the latter interpretation relies on evidence of a direct inhibitory effect of estrogen on bone resorption. The calcium model for postmenopausal bone loss tends to be supported by the effect of calcium therapy. An analysis of the 20 major calcium trials in postmenopausal women reported in the last 20 years yielded a mean rate of bone loss of 1.00% per annum (p.a.) in the controls and 0.014% p.a. (NS) in the treated subjects (P < 0.001). However, trials in which calcium and estrogen have been directly compared have shown that the latter is generally more effective than calcium in that it produces a small, but often significant bone gain. This superiority of estrogen over calcium could be due to the former's dual action on calcium absorption and excretion or to a direct action of estrogen on bone itself. In older women, the importance of calcium intake is overshadowed by the strong association between vitamin D insufficiency and hip fracture. Whether this insufficiency arises primarily from lack of exposure to sunlight or to a progressive failure to activate the vitamin D precursor in the skin or both is uncertain but it is compounded by a general decline in dietary vitamin D intake with age. The biological effect is probably an impairment of calcium absorption and c

Osteoporosis can be defined in terms of apparent bone density and can be determined by densitometry. But differences between reference standards and instruments make standardization difficult. Conventional classification schemes are not applicable but analysis by risk factors does permit a systematic approach.

Reports of adverse events related to calcium supplementation should be supported by rigorous evidence .

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. Refereed/Peer-reviewed

This study was conducted to compare the suppressive effects of calcium carbonate and calcium citrate on bone resorption in early postmenopause. Calcium citrate is thought to be better absorbed. We therefore tested the hypothesis that calcium as citrate is more effective than calcium as carbonate in suppressing parathyroid hormone (PTH) and C-terminal telopeptide. Twenty-five healthy postmenopausal women were recruited in this double blind crossover study. The subjects were randomly allocated to receive either 1,000 mg of elemental calcium as carbonate or 500 mg of calcium as citrate. They were given the alternate calcium dose 1 week later. Serum measurements of total and ionized calcium, phosphate, PTH, and CrossLaps were repeated 12 hours after each dose. Analysis of variance found no significant difference between measures for the two salts. Tests for equivalence indicated that 500 mg of calcium citrate may be superior to 1,000 mg of calcium carbonate in raising serum total and ionized calcium (P = 0.04 and 0.05, respectively). For all parameters measured, 500 mg of calcium citrate was at least as beneficial as 1,000 mg of calcium carbonate. Calcium citrate is at least as effective as calcium carbonate in suppressing PTH and C-terminal telopeptide cross-links, at half the dose. This may be because calcium as citrate is better absorbed than calcium as carbonate. If calcium citrate can be used in lower doses, it may be better tolerated than calcium carbonate.

The main bone disease of the 19th century in Europe and the USA was rickets, largely due to the migration of rural populations into smoke-ridden cities as a consequence of the Industrial Revolution. Osteoporosis was unknown or unidentified, although hip fractures were recognized as a complication of aging by 1849, when Astley Cooper published his Treatise on Dislocations and Fractures.

The study comprises 186 untreated normal premenopausal, perimenopausal, and postmenopausal women in whom we measured serum follicle-stimulating hormone and a number of bone-related plasma and urinary variables. The calcium fractions in the plasma were calculated from the total calcium, albumin, globulin, anion gap, and bicarbonate concentrations. With a level of follicle-stimulating hormone within the reference range (up to 20 U/L) to define the premenopausal state, we confirmed previously reported menopausal rises in plasma calcium, phosphate, alkaline phosphatase, and bicarbonate, and in urinary calcium and hydroxyproline. However, inspection of the data, and t testing at different follicle-stimulating hormone criteria showed that these changes in bone-related variables did not generally occur until the level of follicle-stimulating hormone exceeded approximately 50 U/L. The plasma alkaline phosphatase level rose earlier than the other variables and was significantly elevated in subjects with follicle-stimulating hormone values above 30 U/L. The rise in plasma calcium was mainly a result of a rise in the ultrafiltrable fraction, which in turn was accounted for by rises in the ionized and complexed fractions, of which the complexed fraction was the most significant and proportionately the largest. The rise in the complexed fraction was accounted for by the increase in plasma bicarbonate.

It has been known for many years that serum PTH rises with age, and it has been suggested that this rise may contribute to bone loss in postmenopausal women. It has been variously attributed to declining renal function, declining calcium absorption efficiency, and declining serum 25-hydroxyvitamin D [25(OH)D] levels. We studied the effects of age, weight, renal function, radiocalcium absorption, serum ionized calcium, and serum 25(OH)D on serum PTH levels in 918 postmenopausal women attending an osteoporosis center. On simple linear regression, serum PTH was a positive function of age (P = 0.003) and weight (P < 0.001) and an inverse function of serum 25(OH)D (P < 0.001) and serum ionized calcium (P = 0.002). On stepwise regression, serum 25(OH)D was the most significant (negative) determinant of serum PTH, followed in decreasing order of significance by serum ionized calcium (negative) and body weight and age (positive). Serum PTH was not related to radiocalcium absorption. The reciprocal relation between serum PTH and serum 25(OH)D could not be explained by the serum concentration of 1,25-dihydroxyvitamin D, which did not change with age. After adjustment for serum ionized calcium, body weight, and age, the rise in serum PTH appeared to start when serum 25(OH)D fell less than 80 nmol/liter.

OBJECTIVE To evaluate the effects of the menopause on bone-related biochemical variables in a longitudinal study. DESIGN Recruitment by advertisement of premenopausal women over the age of 44 for measurement of selected variables and collection of blood and urine samples for deep freezing, followed by annual check of menopausal status and repeat collection of blood and urine samples for deep freezing after the menopausal transition. PATIENTS A total of 104 women with confirmed premenopausal status and on no treatment likely to affect calcium or bone metabolism were admitted to the study over a period of 2 years. After 8 years, 43 of the volunteers had passed through the menopause and the study was closed. MEASUREMENTS Radiocalcium absorption was measured at the first attendance and again after the menopausal transition. Calcium and other relevant variables were measured consecutively on paired thawed-out samples of blood and urine. RESULTS The data were complete in 34 subjects. In these women, there were highly significant correlations between the first and second measurements of most variables - serum calcium and fractions, radiocalcium absorption, vitamin D metabolites, PTH and others - indicating significant 'tracking' of these variables across the menopause. Within that framework there were significant rises in serum total and calculated ionized calcium (both P < 0.001) without change in mean serum parathyroid hormone (PTH). Radiocalcium absorption fell (P < 0.001) without change in serum 1,25D. There was a rise in fasting urinary calcium (P < 0.001) which could not be explained by the rise in filtered load and therefore represented a fall in TmCa (P < 0.001). There were significant rises in urinary bone resorption markers, pyridinoline and deoxypyridinoline (P < 0.001). CONCLUSIONS We conclude that the menopausal rise in calculated serum ionized calcium without fall in PTH, indicates a change in PTH set-point, and that the falls in gastrointestinal absorption and renal tubular reabsorption of calcium reflect the loss of an oestrogen action at these two sites. Although these changes are sufficient to explain the rise in calcium requirement at the menopause, the association of high bone resorption with normal serum PTH suggests also an increased sensitivity of bone to the action of parathyroid hormone. There is significant 'tracking' of many variables across the menopause despite very significant changes in their absolute values.

There must be few fields of clinical medicine that are subject to as much confusion as osteoporosis. The diagnosis in any particular case is frequently uncertain, and may vary from specialist to specialist. There are no agreed investigation protocols, for diagnosing osteoporosis and the treatment tends to be arbitrary and stereotyped. There have been many excellent trials, but their clinical application is slow, and clinical results are seldom published.

steoporosis, most simply and elegantly defined as “too little bone in the bone”, is generally the result of progressive bone loss which, for all practical purposes, starts at menopause in women and at about the age of 50 years in men. Because women have a lower bone organ density than men and then lose bone more rapidly, and also because women live longer, osteoporotic fractures, particularly at the hip, affect more women than men in Western countries — there are 20 000 hip fractures per year in Australia, with women outnumbering men by a ratio of two to one. The immediate cost of osteoporosis in Australia has been estimated at nearly $2 billion per year, with a further $5–6 billion in indirect costs. Doctors are in a difficult position when it comes to managing osteoporosis and preventing fractures. As with most disorders, they need to know the risk of an event such as fracture before reaching a treatment decision. They know that bone mineral density (BMD), measured by dual energy x-ray absorptiometry (DXA), is a major determinant of fracture risk, and they may have read that the risk goes up by a factor of 1.5–2 for every standard deviation fall in BMD (which is actually incorrect, as shown below), but they have no means of converting this information into absolute numbers. This is partly because of long-standing confusion between odds and risk, exemplified by the fact that the relative risks quoted in the literature are generally odds ratios or hazard ratios. The difference between odds and risk, well understood by professional statisticians, is not well understood by most clinicians. If 30 women out of 100 develop a fracture over a given period, the fracture risk is 30/100 or 0.30, but the fracture odds are 30/70 or 0.43 — a very different figure. At low levels of risk, say below 0.10, the difference between odds and risk is very small (one in 10 is close to one to nine) and can legitimately be ignored. However, as the risk increases, or the period over which it is calculated is extended, odds rise in a multiplicative fashion with fall in BMD, but risk does not. Odds have no upper limit, whereas risk can never rise above unity or rise by a multiplicative factor. A recent article sought to dispel this confusion by explaining the difference between fracture odds and fracture risk by reference to published data. A follow-up article, based on a prospective study carried out in Perth, contained a graph representing true fracture risk as a function of age and BMD in women without prevalent fracture. For those who would like to calculate the 6-year risk, the formula is

Ever since Walser (1961) demonstrated the powerful effect of sodium infusion on calcium excretion in dogs, there has been a continuing interest in the relationship between sodium and calcium excretion in human subjects and in various animal species. It has become increasingly clear that sodium intake is an important determinant of obligatory calcium loss, and this in turn has aroused interest in the role of sodium in the pathogenesis of osteoporosis and the role of salt restriction in its management. At the same time, renal physiologists have sought to describe and explain (with only partial success) the nature of the mechanisms which link sodium and calcium transport in the kidneys. The present position is that more is known about the empirical effects of sodium intake on urine calcium than on the nature of the mechanism which governs this relationship. This review is therefore necessarily more concerned with outcomes than with mechanisms, but the latter will be reviewed in brief.

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). The rate of change in BMC was not significantly related to dietary calcium, plasma alkaline phosphatase, serum DHEAS, or any other variable measured at the outset or to serum PTH or serum osteocalcin measured at the conclusion.

The paper by Bolland and colleagues is seriously flawed in many respects, the first being its misleading title.1 It is not a meta-analysis in the usually accepted sense—that is, a review of published trials. Most of the data are unpublished, were obtained by direct request from the relevant authors, and are impossible to investigate independently. The review provides some …

Bone “density” (bone mass/bone volume) declines with age from the menopause in women and from about age 55 in men. This fall in bone density (osteoporosis) weakens the bones and leads to a progressive rise in fracture rates, particularly in women. Many risk factors contribute to the bone-losing process, but one which attracts increasing attention is calcium absorption. The main physiological regulator of calcium absorption is vitamin D. This is manufactured in the skin under the influence of UV-light and then converted to more potent metabolites in the liver and kidney. Although the serum levels of the most potent metabolite 1,25(OH)2D3 (calcitriol) are generally normal in osteoporotic women, treatment with small doses of calcitriol (about 0.25 μg daily) has a remarkable effect on absorptive performance and slows down the rate of bone loss. Improved synthetic metabolites are under development. There is likely also to be greatly increased scope for the use of vitamin D itself in osteoporosis. With advancing age, there is a tendency for men and women to be exposed to less and less sunlight, which is the main natural source of vitamin D. Vitamin D levels, therefore, decline with age, particulaly in those who are housebound, and are found to be low in most reported series of hip fractures. It is likely that this form of vitamin D “insufficiency” has an adverse effect on calcium absorption in the elderly which accelerates bone loss and increases the risk of hip fracture and can be treated with small doses of vitamin D or its 25-hydroxy derivative. This offers a second important role for vitamin D in the prevention and management of osteoporosis.

Fracture histories were obtained from 492 normal postmenopausal women in 1983 and again in 1988, and related to forearm mineral content and density determined in 1983. All peripheral fractures, except those attributable to road traffic accidents, were included. There was only one hip fracture in the series. The total number of postmenopausal fractures was 183 in 149 subjects. In both the retrospective and prospective studies, fracture rates were inversely related to bone status and more significantly to bone density than to bone mass. In the pooled data, the fracture rate was three times as high in women with bone densities more than 4 standard deviations below the young normal mean as in those with bone densities above the mean. On logistic regression, the adjusted relative risk of fracture (odds ratio) in subjects more than 4 standard deviations below the young mean compared with those above the mean was 5.5 (2.7–11.4).

a Health Statistics Unit, Department of Health, Government of South Australia, Adelaide, South Australia b School of Mathematical Sciences, University of Adelaide, South Australia c Institute of Medical and Veterinary Science, Adelaide, South Australia d Department of Medicine, University of Adelaide at the Royal Adelaide Hospital, South Australia e Hanson Institute, Adelaide, South Australia f School of Medicine and Pharmacology, SCGH Unit, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia

The effects of oral calcitriol (0.25 and 0.50 micrograms/d), together with calcium (1 g/d), on calcium absorption and bone resorption were measured in postmenopausal osteoporotic women with calcium malabsorption. Radiocalcium absorption was significantly improved and urinary hydroxyproline/creatinine excretion significantly reduced on both doses, but the higher dose caused an unacceptable incidence of hypercalcemia. In 49 patients treated for an average of 15 months with the lower dose, there was a nonsignificant gain in forearm bone mass of 0.4 +/- 0.3 mg/cm/mo (approximately 1/2% per annum) compared with a significant decrease in 17 untreated patients of 3.8 +/- 1.3 mg/cm/mo (approximately 5% per annum).

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. ( Arch Intern Med. 1991;151:757-759)

• 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 ± 0.12mg/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. (Arch Intern Med. 1990;150:1951-1953)

Calcium deficiency causes osteoporosis in experimental animals because the skeleton is sacrificed for the preservation of the plasma (ionic) calcium and to meet obligatory calcium losses in the feces and urine. (Vitamin D deficiency, on the other hand, causes rickets and osteomalacia largely because of the loss of the calcemic action of vitamin D, which leads to hypocalcemia, secondary hyperparathyroidism, and hypophosphatemia.) The concept that human osteoporosis, particularly in postmenopausal women, results from negative calcium balance represents a working hypothesis that fits many, but not all of the available data. In normal women, the crucial event is a rise in obligatory urinary calcium loss, which may result from an increase in the complexed fraction of the plasma calcium, due in turn to an increase in plasma bicarbonate. Prospective trials with calcium supplements have, however, yielded conflicting results. In osteoporotic women, a further increase in urinary calcium combined with calcium malabsorption produces a further increase in bone resorption, but some impairment of bone formation due to declining androgens may constitute an additional risk factor with advancing age. The suppressibility of urinary hydroxyproline by calcium supplementation in those patients who can absorb calcium, and by calcitriol in those who cannot, supports the calcium deficiency model, but more trials are needed to establish its validity.

Vertebral and forearm mineral density (VMD and FMD, respectively) were determined in 124 postmenopausal women with no crushed vertebrae or peripheral fractures, 51 who had sustained peripheral fractures only since the menopause, 62 with vertebral compression(s) only and 75 with both types of fracture. There was a very significant correlation between the two measurements in the whole set. The scatter could not be accounted for by methodological error but was partly accounted for by body weight, since VMD was related to body weight and FMD was not. Whatever criterion was used for the diagnosis of osteoporosis (whether fracture or density) the percentage of misclassified cases was very similar by the two methods. However, VMD was relatively more reduced than FMD in vertebral fracture cases and FMD was marginally more reduced than VMD in peripheral fracture cases. There is little to choose between vertebral and forearm density in the diagnosis of osteoporosis but vertebral densitometry is slightly superior to forearm densitometry in describing the severity of osteoporosis in vertebral fracture patients.

Increased tubular reabsorption of calcium is one of the three variables which can contribute to the pathogenesis of hypercalcaemia. It is therefore important to establish the normal range for this variable in a manner which allows for its variation with the plasma calcium concentration. Graphic methods depicting the relationship between urinary calcium excretion and plasma calcium concentration are valid but cumbersome and imprecise. The notional tubular maximum for calcium reabsorption (TmCa) has therefore been calculated in 130 healthy young subjects and a normal range of 1.75–2.61 mmol/l of glomerular filtrate established. Owing to the dependence of urinary calcium on urinary sodium, TmCa was negatively related to sodium excretion. Because the latter was higher in the males than the females, mean TmCa was slightly (but not significantly) lower in our male than our female subjects. The normal range of TmCa, corrected to zero sodium excretion, is 1.98–2.76 mmol/l of glomerular filtrate. The TmCa was also calculated using plasma calcium values corrected for albumin concentration. The range of TmCa using both corrections is 1.98–2.71 mmol/l of glomerular filtrate.