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.

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.

Vitamin D, glucose, insulin, and insulin sensitivity.

This review examines available evidence of links between abnormalities of glucose and insulin metabolism and vitamin D deficiency. Possible mechanisms of action of vitamin D include stimulation of insulin secretion and effects on insulin sensitivity. Sun exposure usually implies greater outdoor physical activity, which in itself may have beneficial effects on insulin sensitivity, unrelated to serum 25-hydroxyvitamin D concentrations. The observed associations in humans among vitamin D, insulin, and glucose metabolism have not yet been confirmed by intervention studies and, hence, a causal association has not been established. Clinical trials are needed to determine whether vitamin D treatment of vitamin D-deficient individuals is able to prevent or treat diabetes mellitus.

Glucose tolerance and vitamin D: effects of treating vitamin D deficiency.

OBJECTIVE: We investigated the effects of vitamin D treatment on plasma glucose, serum insulin, and insulin sensitivity in vitamin D-deficient individuals without diabetes mellitus. METHODS: Thirty-three adults with vitamin D insufficiency (serum 25-hydroxyvitamin D concentration < or = 50 nmol/L) and without diabetes (12 with impaired glucose tolerance) were given two oral doses of 100 000 IU of cholecalciferol, 2 wk apart. Before the first dose and 2 wk after the second dose, a 75-g oral glucose tolerance test was performed. Plasma glucose, serum insulin, 25-hydroxyvitamin D, and parathyroid hormone concentrations were measured and insulin sensitivity was calculated from the oral glucose tolerance test. RESULTS: Mean serum 25-hydroxyvitamin D increased from 39.9 +/- 1.5 (SEM) to 90.3 +/- 4.3 nmol/L (P < 0.0001) and mean serum parathyroid hormone decreased from 6.7 +/- 1.2 to 4.5 +/- 0.6 pmol/L (P = 0.055). There was no change in blood glucose mean of 0-120 min (6.1 +/- 0.3 before versus 6.2 +/- 0.3 mmol/L, P = 0.63) or insulin mean of 0-120 min (47.8 +/- 5.35 versus 48.9 +/- 5.22 mU/L, P = 0.67) concentrations, and no change in insulin sensitivity (Avignon's insulin sensitivity index [SiM], P = 0.97; insulin sensitivity index at 0 and 120 min [ISI(0,120)], P = 0.74; Quantitative Insulin Sensitivity Check Index [QUICKI], P = 0.88; homeostasis model assessment [HOMA], P = 0.99) after vitamin D treatment. Results did not differ between subjects, with and without, impaired glucose tolerance. CONCLUSION: In adults without diabetes, correction of vitamin D deficiency is not associated with any effect on blood glucose or insulin concentrations or insulin sensitivity as assessed during an oral glucose tolerance test. These observations do not support an association between glucose/insulin homeostasis and vitamin D, at least in the short term.

Seasonal change in osteoid thickness and mineralization lag time in ambulant patients.

UNLABELLED: Low vitamin D levels are common. Bone biopsies taken from 121 ambulant patients were therefore reviewed. Seasonal changes in mineralization correlated inversely with serum 25-hydroxyvitamin D but not the more active metabolite, 1,25-dihydroxyvitamin D. This implies that the latter is produced in bone. INTRODUCTION: It has been 30 yr since a seasonal variation in osteoid surfaces and calcification fronts was noted in bone biopsies from hip fracture patients in Leeds and attributed to vitamin D status. It was suggested at that time that mild vitamin D deficiency might cause osteoporosis from malabsorption of calcium and more severe deficiency osteomalacia, but little has been published on this subject since. MATERIALS AND METHODS: We examined bone biopsies, calcium absorption data, and serum vitamin D metabolites in 121 patients attending our osteoporosis clinics in Adelaide. Biopsies were collected from the anterior iliac crest with a Jamshidi needle after two stat oral doses of 1 g of tetracycline 10 days apart, processed into plastic without demineralization, and all parameters were measured by point counting using a Weibel II graticule. Calcium absorption was measured after an oral dose of 5 microCi of (45)Ca in 250 ml of water with 20 mg of calcium carrier. Serum 25-hydroxyvitamin D [25(OH)D] was measured by radioimmunoassay and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] by radioimmunoassay after high-performance liquid chromatography (HPLC). RESULTS: 25(OH)D levels were lower from late autumn to early spring (April to September) than from late spring to early autumn (October to March) (51 +/- 23 versus 61 +/- 27 [SD] nM; p=0.040). None of the biopsies yielded a diagnosis of osteomalacia, but osteoid thickness (O.Th.) was greater in the winter than the summer months (8.5 +/- 3.6 versus 7.1 +/- 2.8 microm; p=0.015) as was mineralization lag time (MLT; 11.9 +/- 5.2 versus 9.5 +/- 3.6; p=0.005). O.Th and log MLT were both inversely related to serum 25(OH)D (p=0.014 and 0.036) but not serum 1,25(OH)(2)D. Calcium absorption was related to serum 1,25(OH)(2)D but not serum 25(OH)D. CONCLUSIONS: We conclude that circulating 25(OH)D affects the mineralization process, whereas circulating 1,25(OH)(2)D affects bone indirectly through its effect on calcium absorption.

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.

Bone resorption markers in vitamin D insufficiency.

Severe vitamin D deficiency (serum 25 hydroxyvitamin D (25(OH)D) below 12.5 nmol/L) causes rickets and osteomalacia, but there is good evidence that lesser degrees of hypovitaminosis D (vitamin D insufficiency) have deleterious effects on bone and other organs. Evidence of impaired mineralization, suggestive of vitamin D insufficiency, has been found in bone biopsies of hip fracture patients in the UK, and several studies around the world have shown a rise in serum parathyroid hormone (PTH) as 25(OH)D levels fall below 50 nmol/L. Fifty-seven percent of hospital inpatients in a Boston study had vitamin D insufficiency and their serum 25(OH)D showed an inverse relationship to their serum alkaline phosphatase (ALP) levels. Thirty-five percent of outpatients had vitamin D insufficiency in an Adelaide study, where ALP and urine hydroxyproline and pyridinium cross-links were all inversely related to serum 25(OH)D. The increased bone resorption of vitamin D insufficiency is important on two counts. Firstly, increased bone resorption may lead to increased bone loss and osteoporosis and, secondly, increased turnover appears to increase fracture risk in its own right. A consensus is developing that serum 25(OH)D levels should be maintained at 50 nmol/L or greater in the elderly to minimize the occurrence of fractures. In addition, it appears that optimal levels of bone resorption markers in this population are at or just below the mean level for premenopausal women.

Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis.

Both raloxifene (RLX) and alendronate (ALN) can treat and prevent new vertebral fractures, increase bone mineral density (BMD), and decrease biochemical markers of bone turnover in postmenopausal women with osteoporosis. This phase 3, randomized, double-blind 1-yr study assessed the effects of combined RLX and ALN in 331 postmenopausal women with osteoporosis (femoral neck BMD T-score, less than -2). Women (aged < or = 75 yr; > or = 2 yr since their last menstrual period) received placebo, RLX 60 mg/d, ALN 10 mg/d, or RLX 60 mg/d and ALN 10 mg/d combined. At baseline, 6 and 12 months, BMD was measured by dual x-ray absorptiometry. The bone turnover markers serum osteocalcin, bone-specific alkaline phosphatase, and urinary N- and C-telopeptide corrected for creatinine were measured. The effects of RLX and ALN were considered to be independent and additive if the interaction effect was not statistically significant (P > 0.10) in a two-way ANOVA model. All changes in BMD and bone markers at 12 months were different between placebo and each of the active treatment groups, and between the RLX and RLX+ALN groups (P < 0.05). On average, lumbar spine BMD increased by 2.1, 4.3, and 5.3% from baseline with RLX, ALN, and RLX+ALN, respectively. The increase in femoral neck BMD in the RLX+ALN group (3.7%) was greater than the 2.7 and 1.7% increases in the ALN (P = 0.02) and RLX (P < 0.001) groups, respectively. The changes from baseline to 12 months in bone markers ranged from 7.1 to -16.0% with placebo, -23.8 to -46.5% with RLX, -42.3 to -74.2% with ALN, and -54.1 to -81.0% in the RLX+ALN group. RLX and ALN increased lumbar spine and femoral neck BMD, and decreased osteocalcin and C-telopeptide corrected for creatinine in an additive and independent manner, because the interaction effects were not significant. Although the ALN group had changes in BMD and bone markers that were approximately twice the magnitude as in the RLX group, it is not known how well these changes correlate to the clinical outcome of fracture. RLX+ALN reduced bone turnover more than either drug alone, resulting in greater BMD increment, but whether this difference reflects better fracture risk reduction was not assessed in this study.

The effects of age and other variables on serum parathyroid hormone in postmenopausal women attending an osteoporosis center.

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.

Efficacy and safety of raloxifene 60 milligrams/day in postmenopausal Asian women.

In healthy Caucasian postmenopausal women, raloxifene increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and lowers low-density lipoprotein (LDL) cholesterol, without effects on high-density lipoprotein (HDL) cholesterol and triglycerides. This randomized, double-blind study examines the effects of raloxifene 60 mg/d (n = 483) or placebo (n = 485) in healthy postmenopausal Asian women (mean age 57 yr) from Australia, Hong Kong, India, Indonesia, Malaysia, Pakistan, Philippines, Singapore, Taiwan, and Thailand. Serum osteocalcin, serum N-telopeptide, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were assessed at baseline and 6 months. Lumbar spine BMD was measured at baseline and 1 yr in 309 women from 4 countries. Clinical adverse events were recorded at each interim visit. At 6 months, raloxifene 60 mg/d significantly decreased osteocalcin, N-telopeptide, total cholesterol, and LDL cholesterol by medians of 15.9%, 14.6%, 5.3%, and 7.7%, respectively, from placebo. Changes in HDL cholesterol and triglycerides were similar between raloxifene and placebo. Raloxifene 60 mg/d increased mean lumbar spine BMD (1.9%) from placebo at 1 yr (P = 0.0003). The incidences of hot flashes (placebo 3.5%, raloxifene 5.6%, P = 0.12), and leg cramps (placebo 2.7%, raloxifene 4.3%, P = 0.16) were not different between groups. No case of venous thromboembolism was reported. The effects of raloxifene 60 mg/d on bone turnover, BMD, and serum lipids in healthy postmenopausal Asian women were similar to that previously reported in Caucasian women.

Effect of age on calcium absorption in postmenopausal women.

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 (alpha) 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.

Does the response of bone mass to calcium supplements depend on calcium absorption efficiency?

OBJECTIVE: Calcium supplements can reduce bone resorption and slow bone loss after the menopause, but these effects may be limited by poor intestinal absorption. Since the increase in blood ionised calcium and decrease in serum parathyroid hormone after a calcium load are diminished in patients with poor calcium absorption, we aimed to see whether the response of bone mineral content (BMC) to calcium is related to initial calcium absorption. DESIGN: We retrospectively examined the changes in forearm BMC in 164 patients (139 women and 25 men) receiving calcium therapy alone for low bone density in a university hospital. METHODS: BMC was measured in a Molsgaard single energy absorptiometer and calcium absorption in a single blood sample 1 h after a dose of 5 microCi (45)Ca in 20 mg calcium carrier. Results were analysed by simple and multiple regression analysis. RESULTS: Mean forearm BMC did not change significantly over the mean 43 (S.D., 33) months of treatment (1.023 (0.247) to 1.017 (0.246) g/cm). The annual percentage of change was positively related to both body weight (r=0.180; P=0.020) and radiocalcium absorption (r=0.185; P=0.017). Multiple linear regression confirmed that both variables contributed to the change in BMC (P=0.023 and 0.019 respectively). The mean annual percentage of change in BMC on calcium therapy was not related to age, initial BMC, serum 1,25-dihydroxyvitamin D or fasting urinary calcium/creatinine ratio. CONCLUSIONS: These results support our earlier studies which suggest that poor calcium absorption limits the response of bone to calcium supplements.

Suppression of parathyroid hormone and bone resorption by calcium carbonate and calcium citrate in postmenopausal women.

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.

Vitamin D metabolites and calcium absorption in severe vitamin D deficiency.

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 effect of menopause on bone mineral density and bone-related biochemical variables in Indonesian women.

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.

A system for improving vitamin D nutrition in residential care.

OBJECTIVE: To assess the feasibility of administering an inexpensive preparation of vitamin D(3) 100 000 IU orally 3 monthly to aged-care residents. DESIGN: Prospective, controlled open-label implementation trial. SETTING: Residential aged care, November 2003 to May 2004 (primary study). PARTICIPANTS: 137 ambulant residents: 107 treated (mean age, 85 years; 79 were women), 30 untreated controls (mean age, 87 years; 22 were women). INTERVENTIONS: Lactose microencapsulated vitamin D(3) 100 000 IU orally at baseline, then 3 monthly (three or more doses); untreated subjects were observed contemporaneously. MAIN OUTCOME MEASURES: Serum levels of 25-hydroxyvitamin D [25(OH)D] at 6 months compared with baseline; acceptability of the program to residents and staff. RESULTS: At baseline, 95% of residents assessed (n = 137) had serum 25(OH)D levels below the desirable range of 60-160 nmol/L. At 6 months, all treated residents (n = 98) achieved desired levels, with the mean (+/- SD) 25(OH)D level increasing from 36.4 +/- 12.6 nmol/L (range, 12-75 nmol/L) at baseline to 124.0 +/- 27.9 nmol/L (range, 68-244 nmol/L). In no resident did 25(OH)D approach toxic levels. The mean serum 25(OH)D level remained low in the control group (n = 27): 42.8 +/- 18.3 nmol/L (range, 18-98 nmol/L). The difference between the mean 25(OH)D levels of treatment and control groups at 6 months was 81.2 nmol/L (95% CI, 69.7-92.0 nmol/L). The cost of the supplement was $4 per resident per annum. Substudies showed mean trough serum 25(OH)D levels in the desired range at 3 months (n = 31), but below the desired range at 6 months (n = 50). Subjects given 3-monthly doses for up to 2 years maintained serum 25(OH)D levels within the desired range, with no trend toward undesirable accumulation (n = 11). CONCLUSIONS: Vitamin D(3) 100 000 IU given orally 3 monthly is a practical, safe, effective and inexpensive way to meet the vitamin D(3) requirements of aged-care residents.

Relationship between fasting serum glucose, age, body mass index and serum 25 hydroxyvitamin D in postmenopausal women.

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.

Radiocalcium absorption is reduced in postmenopausal women with vertebral and most types of peripheral fractures.

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<0.001) but not in the group with peripheral fractures only. It was also lower in the cases with more than two spinal fractures than in those with two or less (P<0.001). In respect of peripheral fractures, the greatest age-adjusted absorption deficit was found in fractures of the humerus (35%) followed by hip (32%), spine (21%), wrist (19%), and rib 17% (all significant but not significantly different from each other). Lesser deficits in tibia, ankle and foot fractures were not significant but type 2 errors could not be excluded. We conclude that impaired calcium absorption is particularly associated with those fractures for which osteoporosis is a significant risk factor.

A longitudinal study of bone-related biochemical changes at the menopause.

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.