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To determine if estrogen replacement therapy (ERT) is associated with improved tooth retention and lower risk of edentulism (no natural teeth remaining) in a cohort of elderly women.Subjects were 488 women, aged 72 to 95, who participated in the 23rd examination cycle (1994 to 1995) of the Framingham Heart Study, a population-based study begun in 1948. The number of teeth remaining and their location were recorded by a trained observer. History and duration of ERT were obtained from records kept since cycle 10 (1960 to 1963). Third molars were excluded from all analyses.Women who ever used ERT were younger than nonusers by 1 year (80 +/- 4 years, n = 184, versus 81 +/- 4 years, n = 304, P = 0.019). Estrogen users had more teeth remaining than nonusers (12.5 +/- 0.8 versus 10.7 +/- 0.8 versus 10.7 +/- 0.6 teeth, P = 0.046, mean +/- SE) after controlling for age, smoking status, and education. Duration of estrogen use was an independent predictor of the number of teeth remaining (P = 0.015) such that each 4.2-year interval of use was associated with an increased mean retention of 1 tooth. Long-term estrogen users (more than 8 years, n = 48) had an average of 3.6 more teeth than women who never used estrogen (14.3 +/- 1.5 versus 10.7 +/- 0.6 teeth, P0.02). The association with duration of use was present among different types of teeth (incisors, canines, and premolars) but less strong for molars. The odds of being edentulous were reduced by 6% for each 1-year increase in duration of estrogen use (odds ratio = 0.94, P = 0.038, 95% confidence interval = 0.90 to 0.99).These data suggest that ERT protects against tooth loss and reduces the risk of edentulism. The associations of estrogen use and tooth retention are evident for all but the molars.

BACKGROUND Osteoporosis risk in middle-aged women is twofold greater than that in men, and the difference increases with age. Gender differences in bone mineral density, estimated rates of bone loss, and usefulness of markers of bone metabolism for predicting bone density have not been well described in healthy elders aged 65 and above. The purpose of this cross-sectional analysis was to describe associations of bone mineral density at the hip, spine, and whole body with age, serum osteocalcin, and urinary N-telopeptide crosslinks of Type I collagen in healthy elderly men and women. METHODS A total of 1,087 healthy adults (273 men and 814 women) aged 65 to 87 years were enrolled in a collaborative study at 3 sites: Tufts University (Boston, MA), University of Connecticut Health Center (Farmington, CT), and Creighton University (Omaha, NE). Bone mineral density (BMD) at three regions of the hip, the lumbar spine, and whole body was determined by dual-energy x-ray absorptiometry. Serum osteocalcin was measured by immunoassay, and measurement of N-telopeptide crosslinks (Ntx) in urine was made using an enzyme-linked radioimmunoassay (ELISA). RESULTS Among women, the age-related decline in BMD at all non-spine skeletal sites was significantly different from zero, with the largest decline seen at the femoral neck (-.0038 g/cm2/y, p < .001) and the smallest at the trochanter of the hip (-.0023 g/cm2/y, p = .03). Among men, the changes at all non-spine sites were not significant. In both sexes, spine BMD tended to increase with age (men, +.0045 g/cm2/y, women, +.0003 g/cm2/y). Serum osteocalcin and urinary Ntx were inversely related to BMD at all skeletal sites, but the weakest associations were observed at the spine. Individuals whose values of both osteocalcin and Ntx were in the lowest quartiles of the respective sex-specific distributions had mean femoral neck BMD that were 11% higher than individuals with marker values in the highest quartiles. CONCLUSIONS These findings suggest that age-related decreases in BMD may vary by gender and skeletal site. Determinations of osteocalcin and N-telopeptide crosslinks at a single point in time may potentially be used as indicators of current bone status, particularly at non-spine skeletal sites.

Wintertime declines in vitamin D lead to increased concentrations of parathyroid hormone (PTH) and accelerated bone loss in postmenopausal women. We conducted this study to compare calcidiol (25-hydroxyvitamin D) concentrations of men and women, to examine the influence of season, travel, vitamin D intake, and other variables on these concentrations, and to compare associations between calcidiol and PTH concentrations in elderly men and women. In this cross-sectional study of 182 men and 209 women aged > 65 y, mean calcidiol concentrations were higher in men than in women overall (mean +/- SD: 82.4 +/- 35.8 compared with 68.9 +/- 32.1 nmol/L, P < 0.001). In the subset measured in winter (February-May), plasma calcidiol concentrations were lower and not significantly different in men (59.4 +/- 21.8, n = 52) and women (57.7 +/- 23.4 nmol/L, n = 83). In a multiple-regression model, calcidiol concentrations were positively influenced by wintertime travel (P = 0.012), vitamin D intake (P = 0.002), and time spent outdoors (P = 0.096) and negatively influenced by weight (P < 0.001) and age (P = 0.039). Plasma calcidiol and serum PTH concentrations were inversely related, with PTH rising slowly as calcidiol concentrations declined below 110 nmol/L (95 CI: 60, 168 nmol/L). More than 90% of the men and women had calcidiol concentrations below this value in the wintertime. The high prevalence of lower wintertime calcidiol values may increase risk of bone loss in elderly men and women.

In Reply: Dr Ding and colleagues highlight some challenges inherent in performing studies among individuals with knee osteoarthritis. As they indicate, in the interests of generalizability (and in the absence of compelling reasons for excluding any particular subset), our enrollment criteria were generally inclusive.

Background The reliability of estimating muscle fiber cross-sectional area (measure of muscle fiber size) and fiber number from only a subset of fibers in rat hindlimb muscle cross-sections has not been systematically evaluated. This study examined the variability in mean estimates of fiber cross-sectional area as a function of the number of fibers measured, and tested whether counting a subset of fibers in a cross-section could predict total fiber number in middle-aged rats. Results Soleus and extensor digitorum longus (EDL) muscle cross-sections from 23-month-old, male Fisher 344 x Brown Norway rats were stained for myofibrillar ATPase activity to identify muscle fiber type (either type I [slow-twitch] or II [fast-twitch]) and laminin to facilitate fiber cross-sectional measurements. We outlined the circumference of 1000 to 1600 single muscle fibers for measurement of fiber cross-sectional area within muscle sections. Mean type I fiber cross-sectional area was based on soleus muscle sections which were predominantly composed of type I muscle fibers. Mean type II fiber cross-sectional area was based on EDL muscle sections which were predominantly composed of type II muscle fibers. A bootstrapping resampling technique demonstrated that variability in sampling distribution of mean type I and II fiber cross-sectional areas decreased and gradually stabilized as the number of fibers measured increased with large declines in variability occurring at numbers below 150 fibers. Coefficients of variation for bootstrapped mean type I fiber cross-sectional areas were lower than for type II. In the same muscle sections, total fiber number was compared to fiber numbers within 1, 2, 3, and 4 fixed field areas (10x magnification; 1000 x 1500 pixels in size/field) on the cross-section. Fiber numbers from 3 to 4 fields (approximating 15 to 20% of the cross-section) provided a reasonably predictive value of total fiber number (r=0.57-0.59, P=0.003). Conclusions These data describe a pattern of improved precision in estimating mean fiber cross-sectional area as sample size of fibers measured increases to at least 150 in this rat model. Counting 15-20% of the fibers in cross-sections provides a reasonably reliable estimate of the total fiber number.

This study was conducted to compare associations between urinary sodium and calcium in elderly men and women, overall and by level of calcium intake, and to examine associations between urinary sodium excretion and bone mineral density in the same population. Healthy men (n = 249) and women (n = 665) over age 65 y had measurements of 24-h urinary sodium and calcium and spine, hip, and whole-body bone mineral density. Urinary sodium and calcium excretion were significantly correlated in men (r = 0.42, P = 0.0001) and women (r = 0.26, P = 0.0001), but the regression coefficient was greater in men than in women (beta = 0.017 vs. 0.010, P = 0.007). Within each gender, associations between 24-h urinary sodium and calcium were similar and significant at intermediate and high calcium intakes but were not significant at very low intake levels. Urinary sodium was not correlated with bone mineral density. In conclusion, in healthy elderly men and women, urinary sodium and calcium excretion are linked at moderate and high dietary calcium intakes but not at low calcium intakes. For a given sodium excretion, elderly men excrete more calcium than women.

Describe plasma amino acid concentrations and total urinary amino acid excretion in subjects from an elderly female population.Fasting plasma samples, complete 24-hour urine samples, and 3-day diet records were obtained from 96 healthy postmenopausal women in one study and fasting plasma samples were obtained from an additional 44 subjects in 3 separate studies. In one study, nonfasting plasma samples were also collected. The subjects ranged in age from 49 to 80 years of age. Samples were obtained to allow the evaluation of the effects of fasting vs. nonfasting, normal vs. Alzheimers subjects, and level of protein intake effects.Heparinized plasma samples were deproteinized with a 5-sulfosalicylic acid solution and centrifuged at 14,900 x g. Deproteinized plasma and urine samples were analyzed for free amino acids on a Beckman System 6300 analyzer using a postcolumn reaction with ninhydrin to quantitate the amino acids.It is concluded that: 1) From fasting plasma samples, 1 or 2 sampling days are sufficient to establish a characteristic concentration for most plasma amino acids. 2) Fasting amino acid concentrations do not reflect levels of dietary protein intake when dietary amino acid composition is similar. Shifts in fasting amino acid concentrations would be more indicative of changes in relative amounts of amino acids absorbed rather than level of dietary protein per se. 3) Totals of fasting plasma concentrations of arginine, citrulline and ornithine were relatively constant, but fluctuations occurred in the ratio of ornithine to arginine in the different populations; and 4) Patients with Alzheimers disease exhibited altered plasma ornithine and arginine concentrations relative to active or sedentary controls.

Because osteoporosis is irreversible, the most effective approach to reduce morbidity and mortality from this disease is to maximize peak bone mass and minimize bone loss. This presentation reviews the evidence that calcium and vitamin D influence rates of bone loss in postmenopausal women. In the first five or more years after menopause, women lose bone very rapidly. During this period, high dose calcium supplementation modestly reduces cortical loss from long bones but has minimal effect on more trabecular sites such as the spine. In addition, vitamin D appears to enhance the effectiveness of supplemental calcium. Late postmenopausal women are generally more responsive to added calcium, and those with the lowest dietary calcium intakes benefit the most. In calcium-replete women, supplementation with vitamin D reduces bone loss and fracture incidence. Available evidence indicates that postmenopausal women should consume 1000-1500 mg of calcium and 400 to 800 IU of vitamin D per day to minimize bone loss.

Familial resemblance in fat and lean soft tissue and the influence of these body composition measures on bone mineral density (BMD) were determined in 162 adult members of 42 families. Whole body fat and lean mass and BMD of the spine and femoral neck were measured by dual-energy X-ray absorptiometry and BMD of the heel and radius by single-photon absorptiometry. Significant correlations of lean tissue were observed between mothers and daughters (r = 0.35, p < 0.05), fathers and sons (r = 0.36, p < 0.05), and daughters and sons (r = 0.42, p < 0.01) after adjustment for age, height, fat mass, physical activity, and parity (among women). Fat tissue was not significantly correlated among any family member pairs. Lean tissue, but not fat, was positively associated with BMD in one or more family member subgroups at all skeletal sites. These findings suggest a hereditary component to muscle mass. Previously documented familial similarities in bone density may be related in part to the influence of lean mass on bone density.

As part of a longitudinal comparison of bone mineral density (BMD) results originally obtained using a Lunar dual photon absorptiometry (DPA) scanner and later, using a Lunar dual X-ray absorptiometry (DXA) scanner, we compared femur results between DPA and DXA according to DXA analytic software (versions 1.3y and 1.4), and according to the method of placement of the femoral neck box (software algorithm or operator placement according to the appearance of the pair of images) in 58 elderly men and women. The mean BMD at each of three femoral sites was higher using DXA version 1.3y than DPA, but the use of software version 1.4 brought the BMD value closer to that of DPA at all sites. Of 58 scans, 12 (21%) were changed by the operator, resulting in an overall reduction in mean percent BMD difference between scan pairs of 79% (from 1.24% to 0.29%). Although the differences between the DPA/DXA software-driven analysis and the DPA/DXA operator-driven analysis appeared small (high r2 values and intra-class correlation coefficients), the increase in sample size that would be required for the same power to detect 2-year changes in BMD if the software-driven analysis was used instead of taking the time to perform the operator-driven analysis was 18%. The findings of this study highlight the need to account for upgrades in analytic software. Furthermore, we present a rational approach for the analysis of serial scans that has face validity and that results in smaller differences between pairs of scans performed on the same individual. The decision to adapt these methods must be based on the relative costs of reducing unwanted scan variability.

A genetic marker for the 1,25-dihydroxyvitamin D receptor (VDR) is reported to account for much of the heritable component of bone density. It is not known whether VDR genotype influences bone accretion or loss, or how it is related to calcium metabolism. The VDR genotype was determined in 229 healthy postmenopausal women who previously participated in a calcium trial. VDR alleles were designated according to presence (b) or absence (B) of the BsmI restriction enzyme cutting site. There were 83 bb, 102 Bb, and 44 BB individuals. Two-thirds of the women took 500 mg of calcium supplement (mean calcium intake = 892 mg/day) and one-third a placebo (mean = 376 mg/day). Bone mineral density (BMD) at the femoral neck, spine, and radius were measured by dual- and single-photon absorptiometry at baseline and after 1 and 2 years. Among women more than 10 years postmenopausal, those with the BB genotype had the lowest femoral neck BMD. Rates of bone loss over 2 years were greater in the BB group at all sites (e.g., at the femoral neck, bb, 0.45 ± 0.43; Bb, -0.01 ± 0.40; BB, -0.99 ± 0.50%/year; BB vs. bb, p = 0.01), and this trend was found both in women

We investigated the contributions (1.00-8.03 micrograms/d, or 40-321 IU/d) of vitamin D intake and seasonal sunlight exposure to plasma 25(OH)D in 59 healthy women aged 70-97 y with a mean total vitamin D intake of 8.58 micrograms/d (343 IU/d). In the summer and winter, each subject had a fasting blood measurement and assessments of vitamin D intake and sunlight exposure. Vitamin D intake was significantly correlated with plasma 25(OH)D in the summer (r = 0.52, P < 0.01) and winter (r = 0.63, P < 0.01). The influence of sunlight exposure measured in the summer on the 25(OH)D concentration was dependent on the vitamin D intake. In subjects with lower vitamin D intakes (1.00-8.03 micrograms/d, or 40-321 IU/d), the wintertime 25(OH)D concentrations of those with low and high sunlight exposure were comparable. In subjects with higher vitamin D intakes (11.15-28.68 micrograms/d, or 446-1147 IU/d), however, the wintertime 25(OH)D concentrations of those with high sunlight exposure were lower than those with lower exposure [63.8 +/- 3.9 and 80.6 +/- 6.7 nmol/L, respectively, P = 0.066; P (intake by exposure interaction) < 0.05]. This suggests that the contribution of vitamin D intake to plasma 25(OH)D concentration may be influenced by sunlight exposure.

A 1-year prospective study of seasonal mood changes was conducted in 250 female Boston area residents, aged 43 to 72, who were participants in a study of vitamin D supplementation. Each woman completed the Profile of Mood States questionnaire at four study visits. There were significant changes over the year in scores for Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue-Inertia, and Confusion-Bewilderment. These scores were all highest or "worst" in the fall and lowest in the spring or summer. Worse mood scores were associated with fewer hours of sleep. Serum thyroxine was positively associated with higher Depression-Dejection scores in August through November and with higher (better) Vigor-Activity scores in February through May. Supplementation with 400 IU of vitamin D did not appear to affect levels or changes in mood scores.

Black-white differences in calcium metabolism are sought because they may reveal why blacks have higher bone mass than whites. Comparative studies of calcium absorption in blacks and whites are not available. In this study, we compare fractional calcium retention, an index of calcium absorption, and calcium regulating hormone levels in black and white women on a high-calcium diet and after adaptation to a low-calcium diet. A total of 30 healthy women (15 black and 15 white) had measurements of fractional 47Ca retention and calcium regulating hormone levels after 8 weeks on a 2000 mg calcium diet and, subsequently, after 1, 2, 4, and 8 weeks on a 300 mg calcium diet. By 2 weeks after the diet change, fractional 47Ca retention, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D [1,25-(OH)2D] had reached a plateau at higher levels, urine calcium at a low level, and serum calcium at the same level (repeated-measures ANOVA). Fractional 47Ca retention, serum calcium, and PTH were similar on both diets in blacks and whites. Blacks had higher levels of 1,25-(OH)2D on both diets (e.g., 125.1 +/- 53.5 SD versus 73.4 +/- 19.0 pmol/liter, P = 0.003 on low-calcium diet) and a greater increase in 1,25-(OH)2D after the diet change (33.9 +/- 30.1 SD versus 11.8 +/- 17.9 pmol/liter, P = 0.021). Serum phosphorus was lower in blacks throughout. For hormone levels and fractional calcium retention to stabilize after a diet change, 2 weeks was needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial resemblance in bone mineral density at five skeletal sites was measured among 160 adult members of 40 families. Each family included a postmenopausal mother, one premenopausal daughter, one son, and the children's father. Similarities in selected life-style factors thought to influence bone density, such as physical activity, smoking, alcohol use, and diet, were also evaluated. Bone density was measured by dual-energy (total body, femoral neck, and lumbar spine) or single-photon (radius and os calcis) absorptiometry. Correlation coefficients between the midparent Z score and offspring Z scores of bone mineral density ranged from 0.22 to 0.52 among daughters and from 0.27 to 0.58 among sons. Adjustment of bone density for age, height, weight, and significant life-style or environmental factors yielded heritability estimates for the five skeletal sites between 0.46 and 0.62. That is, 46-62% of variance in bone density was attributable to heredity. Most estimates derived from the group of daughters were similar to those from the sons. These observations provide support for a significant contribution of heredity to bone density. However, an individual's life-style may account for a potentially large proportion of the nonheritable variance in bone density.

In their meta-analysis Bolland and colleagues conclude: “Calcium supplements without vitamin D are associated with an increased risk of myocardial infarction.”1 This conclusion relies heavily on unpublished data from the RECORD trial, the source of over half of the cardiovascular disease events in the meta-analysis. In this trial, investigators posted calcium, vitamin D, their combination, …

Background Care of elderly patients after hip fracture is not well established. Methods We enrolled 173 patients with acute hip fracture who were 65 years or older (79.2% women; mean age, 84 years; 77.4% living at home). Using a factorial design, we randomly allocated patients to extended physiotherapy (PT) (supervised 60 min/d during acute care plus an unsupervised home program) vs standard PT (supervised 30 min/d during acute care plus no home program; single-blinded), and to cholecalciferol therapy, 2000 vs 800 IU/d (double-blinded). Primary outcome was rate of falls; secondary outcome was rate of hospital readmissions during the 12-month follow-up. All analyses included 173 individuals and used multivariate Poisson regression analyses. Results At baseline, 50.9% of participants had 25-hydroxyvitamin D levels of less than 12 ng/mL and 97.7% of less than 30 ng/mL. We documented 212 falls and 74 hospital readmissions. Because this was a factorial design trial, all analyses tested the main effect of each treatment while controlling for the other in 173 participants. Extended vs standard PT reduced the rate of falls by 25% (95% confidence interval [CI], −44% to −1%). Cholecalciferol treatment, 2000 vs 800 IU/d, did not reduce falls (28%; 95% CI, −4% to 68%), but reduced the rate of hospital readmissions by 39% (95% CI, −62% to −1%). Conclusions Extended PT was successful in reducing falls but not hospital readmissions, whereas cholecalciferol treatment, 2000 IU/d, was successful in reducing hospital readmission but not falls. Thus, the 2 strategies may be useful together because they address 2 different and important complications after hip fracture. Trial Registration clinicaltrials.gov identifier:NCT00133640

Two hundred eighty-four female adults (aged 40-70 years) were longitudinally studied to investigate the relationship between dietary supplemental vitamin A and serum biochemical markers of vitamin A toxicity. Serum retinol, retinyl esters, and retinol-binding protein (RBP), alkaline phosphatase and aspartate aminotransferase activities and bile acids were measured at baseline, 1 and 2 years. Fasting serum retinol and retinyl ester concentrations were determined by high-performance liquid chromatography, and dietary and supplemental intake of vitamin A were assessed by 3-day food records. There was no difference in dietary vitamin A intake between supplement users and nonusers. In supplemental users, the mean +/- SEM supplemental vitamin A intake was 952 +/- 81 IU/day (range 250-5000 retinol equivalents/day). Serum retinol, retinyl esters, and RBP concentrations were not different between the two groups during the 2-year period. For each group, serum retinyl esters significantly increased over time (p < 0.03), but the magnitude of the increase was not different between the groups. Serum levels of retinol, retinyl esters, and RBP were not correlated with vitamin A intake or age in either group. Biochemical measures of liver damage (serum alkaline phosphatase and aspartate aminotransferase activities and serum bile acids) were not related to serum retinol, retinyl esters or RBP concentrations, nor were they different between nonusers and users of supplemental vitamin A. This study provides evidence that long-term supplemental vitamin A in doses commonly found in multivitamin supplements does not present a risk for hypervitaminosis A.

Rates of change in bone mineral density (BMD) at four skeletal sites were measured in 288 healthy postmenopausal women (41-71 years) who were participants in a 2-year calcium supplement trial. Mean calcium intake from food and supplements was 719 +/- 299 (sd) mg/day during the study. Annualized change in spine (L2-4) BMD, adjusted for body size, dietary calcium intake, treatment group and smoking was -2.24% +/- 2.07% (sd) in women who were 1 to 2 years postmenopausal and declined in women through 5 years after menopause. The rate of change in women who were 6 or more years postmenopausal was -0.96% +/- 2.96%. Mean adjusted change in heel BMD in all women was -1.16% +/- 3.26%. At the femoral neck and radius there was no significant adjusted change in BMD in the group as a whole (femoral neck -0.24% +/- 2.55%; radius -0.14% +/- 2.24%), and the rate of bone loss was not detectably accelerated in women closest to menopause. Rates of bone loss in the subset of subjects who received no calcium supplementation tended to be greater at all skeletal sites.

Interrelationships between percent of ideal body weight (%IBW), serum estrogen levels, and change in bone mineral density (delta BMD) and bone mineral content (delta BMC) were studied in 288 postmenopausal women aged 41-71 years who participated in a 2-year calcium supplement trial. The spine (L2-L4) and femoral neck were measured by dualphoton absorptiometry, and the radius was measured by single-photon absorptiometry. Years since menopause, calcium intake, and initial BMD or BMC were included as independent variables in two-phase regressions of delta BMD and delta BMD on %IBW. Increased %IBW protected against loss of spine BMD [regression slope estimate = 0.05, 95% C.I.: (0.03, 0.26)] and BMC in women up through about 106 %IBW but not in heavier women. Increased %IBW was not significantly related to delta BMD or delta BMC at the femoral neck or radius. Women above 106 %IBW had significant gains in spine and femoral neck area (P less than 0.05). Serum estrone and estradiol were positively correlated with delta BMD and delta BMC at the femoral neck only.

Objective To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. Data sources We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D 3 (cholecalciferol) or vitamin D 2 (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D 3 (1α-hydroxycalciferol) or 1,25-dihydroxyvitamin D 3 (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. Results Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D 3 concentration (25(OH)D concentration: v ≥60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). Conclusions Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.

To determine whether relative vitamin D deficiency during the winter months contributes to age-related bone loss and whether rates of change in hard- and soft-tissue mass vary during the year.Double-blind, placebo-controlled, 1-year trial in 249 women in which equal numbers of women were randomized to either placebo or 400 IU of vitamin D daily. All women received 377 mg/d of supplemental calcium largely as calcium citrate malate.Healthy, ambulatory postmenopausal women with usual intakes of vitamin D of 100 IU/d.Duplicate spine and whole-body scans were done by dual energy x-ray absorptiometry at 6-month intervals that were timed to periods when 25-hydroxyvitamin D levels were highest and lowest. Period 1 was June-July to December-January and period 2 was December-January to the next June-July. Serum parathyroid hormone and plasma 25-hydroxyvitamin D levels were measured during periods 1 and 2.In the placebo group, spinal bone mineral density increased in period 1, decreased in period 2, and sustained no net change. Women treated with vitamin D had a similar spinal increase in period 1 (1.46% compared with 1.40% in placebo), less loss in period 2 (-0.54% compared with -1.22%, CI for the difference, 0.05% to 1.31%, P = 0.032) and a significant overall benefit (0.85% compared with 0.15%, CI for the difference, 0.03% to 1.37%, P = 0.04). In period 2, 25-hydroxyvitamin D levels were lower and parathyroid hormone levels were higher in the placebo than in the vitamin D group. Whole-body lean and fat tissue and bone mineral density varied during the year but did not change overall.At latitude 42 degrees, healthy postmenopausal women with vitamin D intakes of 100 IU daily can significantly reduce late wintertime bone loss and improve net bone density of the spine over one year by increasing their intake of vitamin D to 500 IU daily. A long-term benefit of preventing vitamin D insufficiency in the winter seems likely although it remains to be shown. Observed changes in bone as well as in fat and lean tissue appear to be related to season.

We examined the effect of smoking on bone mineral density (BMD), rates of bone loss, and fractional whole-body retention of 47Ca in healthy postmenopausal women enrolled in a 2-year calcium supplementation trial. Bone density was measured by single- and dual-photon absorptiometry. BMD of the radius at the study baseline was inversely related to pack-years of exposure when controlled for body mass index and years since menopause (partial r = -0.18, p = 0.05, n = 125). The adjusted mean (+/- SD) annualized rate of bone change from the radius was greater among smokers than nonsmokers (-0.914 +/- 2.624%/year, n = 34, versus 0.004 +/- 2.568%/year, n = 278, respectively; p = 0.05). Similar trends were observed at the femoral neck, os calcis, and spine. Rates were were adjusted for caffeine intake, alcohol use, supplement type, and, at the spine only, menopausal status. At entry into the trial higher serum levels of alkaline phosphatase and lower levels of total and ionized calcium were found in smokers compared to nonsmokers. These differences did not persist with supplementation. In 44 women studied fractional 47Ca retention was lower in the 8 smokers than the 36 nonsmokers (16.6 versus 19.1%, respectively; p = 0.03). These results demonstrate an increased rate of bone loss at the radius after menopause and suggest that smoking is associated with decreased calcium absorption.

When measured by dual-photon absorptiometry (DPA), the adjusted annual rate of change in bone mineral density (BMD) of the lumbar spine was 0.11 +/- 0.51 (SE)% in 44 healthy postmenopausal women with radiographic abnormalities in the scan field and -0.97 +/- 0.26% in 249 women with normal lateral lumbar radiographs (p = 0.046). Rates of loss of BMD from the radius were similar in the 2 groups. Spurious rates of loss of spine BMD are likely to be found in subjects with calcification of the aorta, osteophytes or other abnormalities in the spine scan field. This should be kept in mind when serial spine scans are being considered in these subjects.

We measured the effect of calcium from food and supplement sources on whole-body retention of 59Fe in 19 normal postmenopausal women. Each woman received a placebo and 500 mg calcium from a mixed calcium citrate-malate salt (CCM), from orange juice plus CCM, and from milk after a test breakfast meal to which 59Fe had been added. The test meal contained 238 mg calcium. Whole-body countings of 59Fe were performed before and 30 min and 2 wk after each test meal. Retention of 59Fe was 8.3 +/- 1.1% (means +/- SEM) with placebo, 3.4 +/- 0.78% with milk, 6.0 +/- 0.97% with CCM, and 7.4 +/- 1.7% with CCM plus orange juice. When compared with placebo, milk and CCM significantly lowered iron retention (p less than 0.05) whereas CCM plus orange juice did not. The reduction with milk was greater than that with CCM (p less than 0.05) or CCM plus orange juice (p less than 0.05). The differences in the effects of these calcium sources on 59Fe retention may result from their varied contents of citric and ascorbic acids, known enhancers of iron absorption.

We would like to thank Tournis and Mitrakou (1) for their comments on our recent publication (2), and we appreciate the opportunity to respond. We agree that the favorable effects of vitamin D on glycemia may, at least in part, be due to the favorable …

ContextFalls among elderly individuals occur frequently, increase with age, and lead to substantial morbidity and mortality. The role of vitamin D in preventing falls among elderly people has not been well established.ObjectiveTo assess the effectiveness of vitamin D in preventing an older person from falling.Data SourcesMEDLINE and the Cochrane Controlled Trials Register from January 1960 to February 2004, EMBASE from January 1991 to February 2004, clinical experts, bibliographies, and abstracts. Search terms included trial terms: randomized-controlled trial or controlled-clinical trial or random-allocation or double-blind method, or single-blind method or uncontrolled-trials with vitamin D terms: cholecalciferol or hydroxycholecalciferols or calcifediol or dihydroxycholecalciferols or calcitriol or vitamin D/aa[analogs & derivates] or ergocalciferol or vitamin D/bl[blood]; and with accidental falls or falls, and humans.Study SelectionWe included only double-blind randomized, controlled trials (RCTs) of vitamin D in elderly populations (mean age, 60 years) that examined falls resulting from low trauma for which the method of fall ascertainment and definition of falls were defined explicitly. Studies including patients in unstable health states were excluded. Five of 38 identified studies were included in the primary analysis and 5 other studies were included in a sensitivity analysis.Data ExtractionIndependent extraction by 3 authors using predefined data fields including study quality indicators.Data SynthesisBased on 5 RCTs involving 1237 participants, vitamin D reduced the corrected odds ratio (OR) of falling by 22% (corrected OR, 0.78; 95% confidence interval [CI], 0.64-0.92) compared with patients receiving calcium or placebo. From the pooled risk difference, the number needed to treat (NNT) was 15 (95% CI, 8-53), or equivalently 15 patients would need to be treated with vitamin D to prevent 1 person from falling. The inclusion of 5 additional studies, involving 10 001 participants, in a sensitivity analysis resulted in a smaller but still significant effect size (corrected RR, 0.87; 95% CI, 0.80-0.96). Subgroup analyses suggested that the effect size was independent of calcium supplementation, type of vitamin D, duration of therapy, and sex, but reduced sample sizes made the results statistically nonsignificant for calcium supplementation, cholecalciferol, and among men.ConclusionsVitamin D supplementation appears to reduce the risk of falls among ambulatory or institutionalized older individuals with stable health by more than 20%. Further studies examining the effect of alternative types of vitamin D and their doses, the role of calcium supplementation, and effects in men should be considered.

Cigarette use is a risk factor for increased bone mineral density (BMD) loss but the mechanisms are not well understood. The relationship of smoking to rates of BMD change at the femoral neck, spine, and total body, and to intestinal calcium absorption were examined in 402 elderly men and women (32 smokers, 370 nonsmokers) who participated in a 3-year placebo-controlled study of calcium and vitamin D supplementation. Subjects in the supplemented group took 500 mg/day of elemental calcium and 700 IU/day of cholecalciferol. Two-hour calcium absorption fraction was determined three times, at 18, 30, and 36 months, with a single isotope method utilizing45Ca in a subset of 333 subjects. Annualized rates of BMD loss (adjusted for baseline BMD, weight, age, gender, supplementation status, and dietary calcium intake) were higher in smokers than nonsmokers at the femoral neck (−0.714 ± 0.285 %/year vs. +0.038 ± 0.084 %/year, p < 0.02), and total body (−0.360 ± 0.101 %/year vs. −0.152 ± 0.030 %/year, p < 0.05). No significant difference was observed at the spine (+0.260 ± 0.252 %/year in smokers vs. +0.593 ± 0.074 %/year in nonsmokers, p = 0.21). The mean (± SEM) calcium absorption fraction was lower in smokers (12.9 ± 0.8%, n = 23) than nonsmokers (14.6 ± 0.2%, n = 310, p < 0.05) after adjustment for gender, age, supplementation status, and dietary calcium and vitamin D intakes. Smokers of at least 20 cigarettes per day (n = 15) had the lowest mean absorption fraction (12.1 ± 1.1%). With calcium and vitamin D supplementation, the proportionate increase in urinary calcium/creatinine excretion was lower in smokers (44 ± 12%) than nonsmokers (79 ± 9%, p < 0.05). These results suggest that smoking accelerates bone loss from the femoral neck and total body in the elderly and that less efficient calcium absorption may be one contributing factor.

To compare the rate of bone mineral loss in thyroxine-treated women with low thyrotropin (thyroid stimulating hormone, TSH) levels with that in women without known thyroid disease.Cases selected from a prospective calcium trial.Subjects were recruited from the Boston area.Of 361 women enrolled in a 2-year calcium supplement trial, 18 received thyroxine for hypothyroidism. Of these, 10 were considered overtreated, because they had low TSH levels. Rates of loss of bone mineral density from the radius, spine, and hip during 1.9 +/- 0.6 years were measured by single- and dual-photon absorptiometry. When compared with women with no known thyroid disease (236 controls for the spine, 246 for the radius, and 237 for the femoral neck), women with low TSH levels had greater annualized, adjusted mean rates of bone loss from the spine (-2.89% +/- 0.65% compared with -1.13% +/- 0.13%, P = 0.009) and similar but not significant trends at the radius (-1.18% +/- 0.75% compared with -0.13% +/- 0.17%) and femoral neck (-1.39% +/- 0.80% compared with -0.28% +/- 0.19%). These means were adjusted for variables that affected the rate of loss in the control group (baseline bone mineral density and body mass index, calcium intake, and years since menopause). There were no statistical differences between the low TSH and control groups for any laboratory variables measured, including serum calcium, phosphorus, parathyroid hormone or alkaline phosphatase, plasma 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D, or 24-hour urine calcium-to-creatinine ratio.Thyroxine-treated women with low TSH levels lose bone mineral from the spine more rapidly than do women without known thyroid disease. These patients are therefore at increased risk for osteoporosis. The absence of detectable biochemical changes in women with low TSH levels may result from their relatively modest degree of overtreatment.

To determine the effects of estrogen deficiency and replacement on GH secretion, we measured the 22-h GH secretory pattern and response to 1 h of light exercise in 16 normal postmenopausal women before and after treatment replacement with ethinyl estradiol (20 micrograms/day for 15 days). To determine whether the changes found were due to pituitary sensitization by estrogen, the response to synthetic GH-releasing hormone (GHRH; 1.0 microgram/kg, iv) was measured. To assess the biological effectiveness of GH in estrogen-treated women, somatomedin-C (Sm-C) responses to GHRH were measured. Pre- and postestrogen GH secretion rates, expressed as mean areas circumscribed by plasma GH values, were as follows: 22-h study, 1.4 +/- 0.1 (+/- SEM) vs. 2.0 +/- 0.3 ng/ml X h (P = 0.04; n = 5); during 1 h of exercise, 2.3 +/- 0.4 vs. 3.2 +/- 0.4 ng/ml X h (P = 0.03; n = 16); after GHRH-(1-40), 6.7 +/- 1.7 vs. 8.5 +/- 1.5 ng/ml X h (P = 0.12; n = 16). There also was a modest but significant increase in resting plasma GH (1.5 +/- 0.2 vs. 2.3 +/- 0.5 ng/ml (P = 0.039). Pre- and postestrogen plasma Sm-C concentrations were 0.56 +/- 0.08 and 0.32 +/- 0.03 U/ml, respectively (P = 0.006; n = 16). Thus, estrogen therapy increased spontaneous and exercise-induced GH secretion in postmenopausal women and reduced Sm-C levels. The mechanisms of GH elevation by estrogen may include both central effects and a negative feedback linkage to reduced plasma Sm activity.

1. Sodium restriction increases adrenal and decreases vascular sensitivity to angiotensin II (ANG II). These responses may be mediated either by the circulating level of ANG II or other mechanisms also modified by a change in sodium balance. To assess the importance of the ANG II level, captopril, an oral converting enzyme inhibitor, was used to lower the plasma ANG II level to the sodium-loaded range while maintaining subjects in low sodium balance. 2. Normal volunteer subjects received an infusion of ANG II in increasing doses in three states: high sodium intake, low sodium intake and low sodium intake after pretreatment with captopril. 3. Basal levels of ANG II on high-sodium diet and low-sodium diet plus captopril were similar. In the ANG II infusion studies the slope of the aldosterone—ANG II regression line on low sodium intake was significantly steeper than that on high sodium intake. After the addition of captopril the slope was not decreased, indicating that the endogenous ANG II concentration is not necessary to maintain adrenal sensitivity during sodium restriction. 4. In the ANG II infusion studies the slope of the mean blood pressure—ANG II regression line on high sodium intake was significantly steeper than that on low sodium intake. The addition of captopril to sodium-restricted subjects caused the slope of the regression relationship to increase significantly, consistent with an enhanced vascular responsiveness when endogenous ANG II levels were lowered. However, the slope on low sodium plus captopril did not increase to the level of subjects on a high-sodium diet, suggesting that factors in addition to the circulating ANG II level are also important in regulating the vascular responsiveness to ANG II.