Skeletal and hormonal responses to vitamin D supplementation during sunlight deprivation in Antarctic expeditioners.

UNLABELLED: Sunlight deprivation results in vitamin D deficiency but serum vitamin D levels can be maintained above 50 nmol/L when supplemented with 50,000 IU at least every alternate month. INTRODUCTION: Antarctic expeditioners are exposed to prolonged sunlight deprivation resulting in vitamin D deficiency. We hypothesised that monthly dosing of 50,000 IU vitamin D (~1,600 IU daily) will increase serum 25-hydroxyvitamin D (25(OH)D), suppress parathyroid hormone (PTH) and improve bone mineral density (BMD), 50,000 IU alternate months (~800 IU daily) will maintain these measures, while a single 50,000 IU dose pre-departure (~1,00 IU daily) will not be protective. METHODS: This was a randomised double-blind study involving 110 healthy adults: 91 males, mean age 41 years (range 24-65 years) working in Antarctica for up to 12 months, who we administered 50,000 IU vitamin D3 monthly, alternate months or a single dose pre-departure. Serum 25(OH)D, PTH, osteocalcin, CTx and calcium were assessed at baseline, mid- and end of expedition. Proximal femur and lumbar spine BMD were assessed pre- and post-expedition. RESULTS: Baseline 25(OH)D was 59 ± 14 nmol/L. By mid-expedition, 25(OH)D increased by 7 nmol/L in those supplemented monthly (p < 0.05) and remained unchanged in those supplemented in alternate months. In those given a single dose pre-departure, 25(OH)D decreased by 8 nmol/L (p < 0.05) and PTH increased by 27% (p < 0.09). Serum osteocalcin increased by ~22% in all groups but BMD remained unchanged. If serum 25(OH)D was >50 nmol/L at baseline, 25(OH)D was maintained above this level with all regimens. If 25(OH)D was <50 nmol/L at baseline, monthly or alternate month regimens were needed to achieve levels >50 nmol/L, the single pre-departure dose was ineffective. CONCLUSION: During sunlight deprivation of up to 12 months, serum 25(OH)D levels can be maintained above 50 nmol/L when expeditioners are provided with 50,000 I U at least every alternate month.

Skeletal and hormonal responses to sunlight deprivation in Antarctic expeditioners.

UNLABELLED: Serum 25(OH)D levels decline without sunlight exposure. We studied 120 expeditioners to Antarctica to determine the skeletal and hormonal responses to sunlight deprivation. With emerging vitamin D insufficiency, serum calcium decreased, PTH increased, and bone loss at the proximal femur was observed. Baseline serum 25(OH)D levels >100 nmol/L prevented vitamin D insufficiency. INTRODUCTION: Vitamin D stores deplete without adequate sunlight exposure unless supplementation is provided. We studied 120 healthy adults who spent a year in Antarctica as a model for sunlight deprivation to define the timing and magnitude of the skeletal and hormonal responses to emerging vitamin D insufficiency. METHODS: Fasting blood samples were assessed at baseline, 6 and 12 months for serum 25-hydroxyvitamin D (25(OH)D), osteocalcin (OC), bone formation (P1NP) and resorption (CTx), PTH and calcium. Lumbar spine and proximal femur BMD was measured using DXA. Differences over time were determined using repeated measures ANOVA. Percent changes were expressed as (Delta value/(value A + value B)/2) x 100. Relationships between outcome measures were determined using Spearman's correlations. RESULTS: Vitamin D insufficiency (<50 nmol/L) was observed in 85% of expeditioners by 6 months when serum calcium decreased and PTH increased (p < 0.01). By 12 months, OC increased by 7.4 +/- 3.0% (p < 0.05), and BMD decreased by 1.0 +/- 2.0% at the total proximal femur (p < 0.05). For those with vitamin D sufficiency at baseline (>50 nmol/L), sunlight deprivation produced vitamin D insufficiency within 4 months unless baseline values were >100 nmol/L. CONCLUSION: Supplementation may be necessary for expeditioners with limited access to UV light.

Fractures during growth: potential role of a milk-free diet.

UNLABELLED: Dietary calcium deficiency may increase fracture risk. In girls, 29.4% of fracture cases and 11.8% of controls without fracture had a history of milk-free diet. The odds ratio (OR) for fracture with a milk-free diet in girls was 4.6, p < 0.01. In boys, 23% of cases and 19% of controls had a history of a milk-free diet; OR = 1.3, NS). A milk-free diet due to cow's milk allergy is associated with increased fracture risk in girls. INTRODUCTION: An intake of calcium below the reference daily intake (RDI) of 800-1200 mg/day during growth is thought to increase fracture risk even though convincing evidence for this view is scarce. The paucity of evidence may be partly due to many trial participants being calcium replete. Children and adolescents with cow's milk allergy (CMA) avoid milk and have a calcium intake below the RDI. The aim of this study was to examine the association between consumption of a milk-free diet and fracture risk. METHODS: In this case-control study conducted in Poland, 57 boys and 34 girls aged 2.5-20 years with fractures (cases) were randomly matched by age and sex with 171 boys and 102 girls without fractures (controls). Weight and height were examined using standard methods. Bone mineral density (BMD) and body composition were measured using dual-energy X-ray absorptiometry. Conditional logistic regression and Bayesian analyses were used to determine the proportion of the fracture risk attributable to a milk-free diet. RESULTS: In girls, 29.4% of cases and 11.8% of controls had a history of milk-free diet producing an odds ratio (OR) for fracture associated with a milk-free diet of 4.6 (95% confidence interval [CI]: 1.4-15.5, p < 0.01). In boys, 23% of cases and 19% of controls had a history of a milk-free diet; OR = 1.3 (95% CI: 0.6-2.7, NS). If the prevalence of CMA in the population is 5%, only 6.7% of the fractures occurring are attributable to CMA and the associated nutritional deficit. CONCLUSIONS: Cow's milk allergy is associated with increased fracture risk in girls. Whether this association is due to the illness, calcium deficit or a deficit in other milk nutrients is uncertain. These data suggest that the contribution of milk-free diet to fracture liability among children and adolescents is modest.

Skeletal benefits from calcium supplementation are limited in children with calcium intakes near 800 mg daily.

INTRODUCTION AND HYPOTHESIS: Calcium supplementation enhances bone mass accrual during administration, with a sustained benefit observed using milk-based calcium but not calcium salts. We tested the hypothesis that calcium from milk minerals but not calcium carbonate will be sustained after supplementation was discontinued. METHODS: Ninety-nine pre-pubertal boys and girls aged 5-11 years were followed for 12 months after being randomized to receive 800 mg/day of calcium from milk minerals (MM) or calcium carbonate (CC), or a placebo (Pla) in a 10-month double blind study. Total body and regional BMC, and femoral shaft bone dimensions were measured using dual energy x-ray absorptiometry. Group differences were determined using ANCOVA. RESULTS: In the intention to treat analysis of the entire sample, no group differences were observed in increments in BMC or bone dimensions during or after supplementation. In those children who remained pre-pubertal, greater gains in pelvis BMC in the milk mineral group than controls were sustained (37.9 versus 29.3% respectively, p<0.02). CONCLUSION: In healthy children consuming about 800 mg calcium daily, calcium supplementation with milk minerals or calcium carbonate does not appear to be produce biologically meaningful benefits to skeletal health. A benefit of calcium supplementation in pre-pubertal was evident, but inconclusive, with the biological significance of the effect of calcium supplementation at the pelvis, and the longevity of this effect to be determined.

Modifiable determinants of bone status in young women.

The purpose of this study was to evaluate the contributions of exercise, fitness, body composition, and calcium intake during adolescence to peak bone mineral density and bone structural measurements in young women. University Hospital and 75 healthy, white females in the longitudinal Penn State Young Women's Health Study were included. Body composition, total body, and hip bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry (DXA), exercise scores by sports-exercise questionnaire during ages 12-18 years, and estimated aerobic capacity by bike ergometry. Section modulus values (a measurement of bending strength) cross-sectional area (CSA), subperiosteal width, and cortical thickness were calculated from DXA scan data for the femoral neck and femoral shaft. Calcium intakes were calculated from 39 days of prospective food records collected at 13 timepoints between ages 12 and 20 years; supplemental calcium intakes were included. Section moduli at the femoral neck and shaft were correlated significantly with lean body mass, sports-exercise scores (R(2) = 0.07-0.19, p < 0.05), and aerobic capacity (R(2) = 0.06-0.57, p < 0.05). Sports-exercise scores correlated with BMD at the femoral neck and shaft. Average total daily calcium intake at age 12-20 years ranged from 486 to 1958 mg/day and was not significantly associated with total or regional peak BMD or bone structure measures at 20 years of age. It was shown that achievable levels of exercise and fitness have a favorable effect on BMD and section modulus of the femoral neck and femoral shaft in young adult women, whereas daily calcium intake of >500 mg in female adolescents appears to have little, if any effect.

Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial.

OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

Calcium intakes among Australian women: Geelong Osteoporosis Study.

BACKGROUND: Dietary calcium deficiency may be a risk factor for osteoporosis. AIMS: To estimate habitual calcium intakes and prevalence of calcium supplementation among free-living Australian women and validate a calcium-specific food-frequency questionnaire. METHODS: Calcium intakes for 1045 randomly selected women (20-92 years) were estimated by questionnaire which was tested against estimates from four day weighed records kept by 32 randomly selected women. RESULTS: The mean difference between calcium estimates was not statistically significantly different from zero (mean difference=121 mg; standard deviation of differences=357 mg; p>0.05). There was moderate agreement (weighted kappa=0.4) between methods in ranking subjects into tertiles of calcium intake. Mean dietary calcium intakes were 615 mg/day for 20-54 years, 646 mg/day for 55-92 years and 782 mg/day for lactating women. Seventy-six per cent of women aged 20-54 years, 87% of older and 82% of lactating women had intakes below the recommended dietary intake (RDI). There was no association detected between calcium intake and age. Dairy foods provided 79.0% of dietary calcium intake. Calcium supplements were used by 6.6% and multivitamins by a further 4.3% of women. Supplementation was independent of dietary calcium intake and more likely used by postmenopausal women. CONCLUSIONS: Our results suggest that 76% of women consume less than the RDI even when supplemental calcium is included. Furthermore, 14% have less than the minimal requirement of 300 mg/day and would, therefore, be in negative calcium balance and at risk of bone loss. Despite advertising campaigns promoting better nutrition and increased awareness of osteoporosis, many women are failing to achieve an adequate calcium intake.

Diagnosis and management of osteoporosis in postmenopausal women: clinical guidelines. International Committee for Osteoporosis Clinical Guidelines.

The authors, all physicians involved in clinical research on bone and practicing clinicians, propose practical guidelines for identifying persons with osteoporosis or those at high risk of developing the disease and for managing patients who may benefit from therapy. These guidelines are based on an analysis of peer-reviewed articles published before November 1998. A flowchart of women who might benefit from treatment is provided, including clinical presentation (recent fracture of the spine, hip, or other bone or no fracture; risk factors for osteoporosis); relevant investigations (bone mineral density measurement and laboratory tests required for the differential diagnosis); and therapeutic management (general measures such as calcium and vitamin D supplementation and specific pharmacologic interventions such as estrogen, bisphosphonates, intranasal calcitonin, raloxifene, fluoride salts, and other compounds that have been assessed in randomized clinical trials). The strongest evidence for antifracture efficacy (reduction of vertebral and nonvertebral fracture risk) was observed with alendronate.

The structural basis of bone fragility in men.

Understanding of the pathogenesis of bone fragility in men requires knowledge of its structural basis. There is no evidence that gender differences in fracture rates are explained by gender differences in bone mineral content (BMC) or areal bone mineral density (BMD). This is an untested assumption. The BMD measurement integrates the modeling and remodeling that occurs on the periosteal and endosteal surfaces of bone during growth and aging. The size, shape, and architecture of the bone so formed determine its breaking strength. None of these three-dimensional structural components is "seen" by the dual photons of the densitometer. Men and women attain a similar peak vertebral height during growth. Vertebral width is greater in men, conferring higher BMC and areal BMD, but trabecular number and thickness (trabecular volumetric BMD) is no greater in men than women. Blacks have shorter vertebra than whites, and vertebral width is similar. Trabecular thickness is greater in blacks than whites. Thus, at peak, gender differences in vertebral strength are likely to be size, not BMD, dependent. Racial differences in vertebral strength are likely to be BMD, not size, dependent. Greater periosteal expansion during growth in males than females, and blacks than whites, establishes the gender and racial differences in peak bone size. Men have wider long bones than women. Blacks have wider long bones than whites. The proximity of the endocortical surface to the periosteal surface determines peak cortical width, which is similar in men, women, blacks, and whites. It is the greater distance of the cortical mineral mass from the neutral axis of a long bone in males than in females, in blacks than in whites, and in men with, than men without, fractures, that partly accounts for the greater bone strength in the first mentioned in each group. Thus, at peak, racial and gender differences in long bone strength are likely to be size, not BMD dependent. Trabecular bone loss is similar in men and women. Loss of connectivity is greater in women. Endocortical resorption is greater in women than men, but men lose less cortical width because subperiosteal apposition during aging is greater in men than in women offsetting endocortical resorption. Men with spine fractures have smaller vertebrae because vertebral width is less. Men with hip fractures have smaller femoral neck width. In both types of fractures, there is less bone in the smaller bone-reduced volumetric BMD. The relative contributions of reduced accrual during growth, excessive bone loss during aging, or both to the deficit in volumetric BMD are undefined. No antifracture efficacy trials have been done in men. Reasonable approaches to treatment include the use of testosterone in hypogonadal men, and vitamin D if vitamin D deficiency is present. Calcium supplements may slow endocortical bone loss. Bisphosphonates may increase BMD.

Osteoporosis in men.

Hip fractures in men account for one third of all hip fractures and have a higher mortality than in women. The public health burden will increase as the increase in the numbers of elderly men in the community increases. In addition, the age-specific incidence of hip fractures may be increasing in some, but not all, countries. Vertebral fractures may be a public health problem as recent studies suggest that the prevalence in the community is 20-30%, similar to that reported in women. Forearm fractures should probably not be regarded as a public health problem. Peak bone mass is higher in men than women because men have bigger bones. Peak bone mineral density is the same. The amount of trabecular bone lost at the spine and iliac crest during ageing is similar in men and women. Cortical bone loss is less in men because endocortical resorption is less and periosteal formation is greater. Bone loss accelerates in elderly men because endocortical resorption and increasing cortical porosity increase the surface available for resorption. Bone fragility is less in men than women because: (a) the cross-sectional surface of the bone is larger; (b) trabecular bone loss is less as a percentage of the higher peak bone mass; (c) trabecular bone loss occurs by thinning rather than perforation; and (d) periosteal appositional growth compensates for endocortical resorption by maintaining the bending strength of bone. Reduced BMD in men with fractures may be due to reduced peak bone size and mass, and bone loss. Bone loss occurs by reduced bone formation. Whether men with fractures have increased bone fragility due to reduced periosteal appositional growth during ageing is unknown. The age-related decline in testosterone, adrenal androgens, growth hormone, and insulin-like growth factor 1 may contribute to reduced bone formation and bone loss. Men with vertebral fractures often have hypogonadism or illnesses with few clinical features that should be considered with a high index of suspicion (alcoholism, myeloma, malabsorption, primary hyperparathyroidism, haemochromatosis, Cushing's disease). Secondary hyperparathyroidism may contribute to bone loss by activating bone turnover and so increasing the number of bone remodelling units with impaired bone formation in each. There is no proven treatment for osteoporosis in men because there have been no trials using anti-fracture efficacy as an end point. Testosterone replacement should be considered in men with proven hypogonadism and vitamin D deficiency should be corrected if present. Calcium supplements and bisphosphonates are reasonable options given the lack of information.

Osteoporosis: trials and tribulations.

A 30-50% reduction in fracture risk produced by a drug is biologically "worthwhile." The detection of this benefit, when truly present, is a challenge requiring large studies of 3-5 years' duration, because only a small number of women at risk actually sustain a fracture during this time. For example, in any year, fractures occur in 1-2 per 100 women approximately 65 years of age, 6-10 per 100 women approximately 75 years of age, and only 1-2 per 2,000 of the 15% of women < 60 years of age with osteoporosis. An appreciation of this low annual event rate is important because (1) it helps patients to understand their illness, (2) it determines the power of clinical trials, (3) it underscores the large numbers of patients that must be treated to prevent one fracture, and (4) it underscores the need for safety, particularly in groups at low absolute risk of fracture; all are exposed to drug side effects, and the vast majority derive no benefit from treatment because they would not have had a fracture without it, despite being at risk. Few studies have met the design requirements needed to identify the antifracture efficacy of a drug when it really exists, namely, (1) large patient samples randomized to treatment or placebo for 3-4 years, (2) blinding throughout follow-up, (3) statistical analyses of preplanned comparisons using intention to treat, and (4) avoidance of statistical analyses of associations discovered by post hoc analyses. Moreover, (5) few studies have assessed long-term safety and quality of life. Consequently, the uncertainty regarding efficacy and safety of available treatments may be more of a problem of the design, execution, and interpretation of the clinical studies than of the drugs themselves. In the reduction of vertebral fracture risk, the greatest optimism exists for hormone replacement therapy (HRT) and the bisphosphonates. HRT reduces bone turnover, increases bone mineral density (BMD), and decreases vertebral fracture rates by approximately 40%, even in women > 70 years of age. Reduction in hip fracture risk with HRT has been reported in observational studies. Two rigorously conducted studies provide credible evidence that the bisphosphonate alendronate reduces the risk of vertebral and hip fractures by approximately 40-50%. Etidronate, calcitonin, and 1,25-dihydroxyvitamin D3 may reduce risk of vertebral fracture; however, problems in study design leave uncertainty. Although 2 trials using fluoride suggest a reduction in fracture rates, the more rigorously conducted trials do not, despite having adequate power to do so. Calcium supplements are likely to slow bone loss, but reduction in fracture risk is uncertain. Vitamin D and calcium supplementation reduce risk of hip fracture in nursing home residents but not in community residents. There have been no studies of the efficacy of any treatment to prevent hip or vertebral fractures in men or in corticosteroid-related osteoporosis. The treatment of osteoporosis is becoming a reality. HRT and the bisphosphonates, particularly alendronate, appear to be the best options at present.

Do men suffer with osteoporosis?

Osteoporotic fractures in men are a neglected public health problem. The pathogenesis of bone loss is incompletely understood but is probably due to reduced bone formation rather than increased bone resorption. Primary or secondary hypogonadism is a common and treatable cause of osteoporosis and should be excluded in all men presenting with spine or hip fractures. Alcohol excess, with or without hypogonadism, is a most important attributable risk factor for osteoporosis in men. There is no known treatment for osteoporosis in men (as there have been no clinical trials using anti fracture efficacy as an endpoint in men) and few well designed trials examining the effects of drugs on bone mineral density (BMD). Bisphosphonates, while reducing fracture rates in women, have only been shown to increase BMD in men Calcium supplementation may slow bone loss. Anabolic agents, such as nandrolone have not been adequately studied. Fluoride therapy cannot be recommended as bone strength does not appear to increase despite the well documented increase in BMD. Risk factors such as alcohol excess and tobacco use should be corrected.

Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis.

To determine the effects of long-term daily oral alendronate sodium (ALN) on bone mass in postmenopausal women with osteoporosis, 19 centers enrolled 516 postmenopausal women aged 45-80 years with spine bone mineral density (BMD) at least 2.5 SD below the mean for young premenopausal women in a 3-year, double-blind, placebo-controlled study. Subjects were randomly allocated to one of four treatment groups: placebo; alendronate, 5 or 10 mg/day for 3 years; or alendronate, 20 mg/day for 2 years followed by 5 mg/day for the 3rd year. All patients received 500 mg/day of supplemental calcium to ensure adequate calcium intake. BMD was measured by dual-energy X-ray absorptiometry at several skeletal sites. Nonsignificant mean decreases in BMD of the spine, femoral neck, and trochanter of 0.6, 0.7, and 0.4%, respectively, occurred in the placebo group at 3 years. Relative to placebo-treated patients, spine BMD increased by 5.4%, 7.4%, and 8.4% in the 5, 10, and 20/5 mg ALN groups, respectively. Increases at the femoral neck were 3.5%, 5.5%, and 4.3%, and those at the trochanter were 5.1%, 7.2%, and 7.2%, respectively. Thus, efficacy of 10 and 20/5 mg ALN was similar, whereas the 5 mg dose was less effective. BMD continued to increase over the entire 3-year study duration in the ALN-treated groups and, compared with the other dosage groups, 10 mg ALN produced the largest gains in BMD during the 3rd year. Changes in biochemical markers of bone turnover and mineral homeostasis confirmed the effect of ALN to decrease bone turnover to a new steady-state level. The safety and tolerability of ALN were comparable with those of placebo. In summary, 10 mg daily oral ALN given for 3 years significantly and progressively increases bone mass and is a generally well-tolerated treatment for osteoporosis in postmenopausal women.

Present and future of osteoporosis therapy.

In the 50-year "modern" history of osteoporosis, there have been about 17 antifracture studies with sufficient attention to design to allow inference regarding efficacy. Antivertebral fracture efficacy has been reported with etidronate, estrogen patch, calcitonin, and 1,25-dihydroxyvitamin D. Two studies using fluoride were positive, and two were negative. Hip fractures have been neglected. One study showed efficacy of hip protectors, one showed efficacy of vitamin D and calcium in nursing home dwellers. The source of most hip fractures is the community. One community based antihip fracture efficacy study using annual injections of vitamin D was positive. There have been no antivertebral or antihip fracture studies in men, or in corticosteroid-related osteoporosis in men or women. Lack of independently repeated demonstration of efficacy, small fracture numbers, and data pooling in some of these (the best) studies leave great uncertainty. Estrogen and bisphosphonates appear to be the best options at this time. New data suggest that calcium supplementation is likely to reduce the rate of bone loss and perhaps reduce fracture rates. The challenge is to maintain and restore the constituents of bone mineral density (BMD), that is: to promote periosteal and endosteal bone formation; reduce endosteal bone resorption and cortical porosity; and increase trabecular thickness, number, and connectivity. There are many opportunities, for instance, intermittent parathyroid hormone (PTH) increases bone strength and, with estrogen, may increase connectivity. The anabolic effects of PTH may be partly mediated by IGF-1. IGF-1 increases periosteal, endosteal, and trabecular bone formation, cortical and trabecular width, and trabecular and endocortical connectivity.(ABSTRACT TRUNCATED AT 250 WORDS)