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Osteoporosis causes considerable morbidity and mortality in later life, and the risk of the disease is strongly determined by peak bone mass, which is achieved in early adulthood. Poor intrauterine and early childhood growth are associated with reduced peak bone mass, and increased risk of osteoporotic fracture in older age. In this review we describe the regulatory aspects of intrauterine bone development, and then summarize the evidence relating early growth to later fracture risk. Physiological systems include vitamin D, parathyroid hormone, leptin, GH/IGF-1; finally the potential role of epigenetic processes in the underlying mechanisms will be explored. Thus factors such as maternal lifestyle, diet, body build, physical activity, and vitamin D status in pregnancy all appear to influence offspring bone mineral accrual. These data demonstrate a likely interaction between environmental factors and gene expression, a phenomenon ubiquitous in the natural world (developmental plasticity), as the potential key process. Intervention studies are now required to test the hypotheses generated by these epidemiological and physiological findings, to inform potential novel public health interventions aimed at improving childhood bone health and reducing the burden of osteoporotic fracture in future generations.

Osteoporotic fracture has a major impact upon health, both in terms of acute and long term disability and economic cost. Peak bone mass, achieved in early adulthood, is a major determinant of osteoporosis risk in later life. Poor early growth predicts reduced bone mass, and so risk of fracture in later life. Maternal lifestyle, body build and 25(OH) vitamin D status predict offspring bone mass. Recent work has suggested epigenetic mechanisms as key to these observations. This review will explore the role of the early environment in determining later osteoporotic fracture risk.

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.1 Osteoporosis remains a major health problem worldwide, costing an estimated $13.8 billion in health care each year in the United States. Despite advances in treating osteoporosis in the elderly, no cure exists. Osteoporosis has its roots in childhood. Accrual of bone mass occurs throughout childhood and early adulthood, and peak bone mass is a key determinant of the lifetime risk of osteoporosis. Because the foundation for skeletal health is established so early in life, osteoporosis prevention begins by optimizing gains in bone mineral throughout childhood and adolescence.2,3

Osteoporosis evaluation and prevention is relevant to children with cerebral palsy (CP). CP is the most prevalent childhood condition associated with osteoporosis. Bone density is significantly decreased, and children with CP often sustain painful fractures with minimal trauma that impair their function and quality of life. Preventing or improving osteoporosis and maximizing bone accrual during critical stages of growth will minimize the future lifelong risks of fractures in children with CP. This article addresses the anatomy and structure of bone and bone metabolism, the clinical assessment of bone mass, the causes of osteoporosis and its evaluation and treatment in children with CP.

OBJECTIVE: To recommend appropriate levels of calcium intake in light of the most recent studies. OPTIONS: Dietary calcium intake, calcium supplementation, calcium and vitamin D supplementation; ovarian hormone therapy in postmenopausal women. OUTCOMES: Fracture and loss of bone mineral density in osteoporosis; increased bone mass, prevention of fractures and improved quality of life associated with osteoporosis prevention. EVIDENCE: Relevant clinical studies and reports were examined, in particular those published since the 1988 Osteoporosis Society of Canada position paper on calcium nutrition. Only studies in humans were considered, including controlled, randomized trials and prospective studies, using bone mass and fractures as end-points. Studies in early and later phases of skeletal growth were noted. The analysis was designed to eliminate menopause as a confounding variable. VALUES: Preventing osteoporosis and maximizing quality of life were given a high value. BENEFITS, HARMS AND COSTS: Adequate calcium nutrition increases bone mineral density during skeletal growth and prevents bone loss and osteoporotic fractures in the elderly. Risks associated with high dietary calcium intake are low, and a recent study extends this conclusion to the risk of kidney stones. Lactase-deficient patients may substitute yogurt and lactase-treated milk for cow's milk. True milk allergy is probably rare; its promotion of diabetes mellitus in susceptible people is being studied. RECOMMENDATIONS: Current recommended intakes of calcium are too low. Revised intake guidelines designed to reduce bone loss and protect against osteoporotic fractures are suggested. Canadians should attempt to meet their calcium requirements principally through food sources. Pharmaceutical calcium supplements and a dietician's advice should be considered where dietary preferences or lactase deficiency restrict consumption of dairy foods. Further research is necessary before recommending the general use of calcium supplements by adolescents. Calcium supplementation cannot substitute for hormone therapy in the prevention of postmenopausal bone loss and fractures. Adequate amounts of vitamin D are necessary for optimal calcium absorption and bone health. Elderly people and those who use heavy sun screens should have a dietary intake of 400 to 800 IU of vitamin D per day.

Women's nutrition has received little attention in nutrition programming, even though clinical trials and intervention trials have suggested that dietary improvement or supplementation with several nutrients may improve their health, especially in low-income settings, the main focus of this paper. Most attention so far has focused on how improvements in maternal nutrition can improve health outcomes for infants and young children. Adequate vitamin D and calcium nutrition throughout life may reduce the risk of osteoporosis, and calcium supplementation during pregnancy may reduce preeclampsia and low birth weight. To reduce neural tube defects, additional folic acid and possibly vitamin B12 need to be provided to non-deficient women before they know they are pregnant. This is best achieved by fortifying a staple food. It is unclear whether maternal vitamin A supplementation will lead to improved health outcomes for mother or child. Iron, iodine and zinc supplementation are widely needed for deficient women. Multimicronutrient supplementation (MMS) in place of the more common iron-folate supplements given in pregnancy in low-income countries may slightly increase birth weight, but its impact on neonatal mortality and other outcomes is unclear. More sustainable alternative approaches deserve greater research attention.

Background

Vitamin D is a strong immunomodulator and may protect against adverse pregnancy outcomes, mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV), and child mortality.

Methods

A total of 884 HIV-infected pregnant women who were participating in a vitamin supplementation trial in Tanzania were monitored to assess pregnancy outcomes and child mortality. The association of these outcomes with maternal vitamin D status at enrollment was examined in an observational analysis.

Results

No association was observed between maternal vitamin D status and adverse pregnancy outcomes, including low birth weight and preterm birth. In multivariate models, a low maternal vitamin D level (<32 ng/mL) was associated with a 50% higher risk (95% confidence interval [CI], 2%–120%) of MTCT of HIV at 6 weeks, a 2-fold higher risk of MTCT of HIV through breast-feeding among children who were HIV uninfected at 6 weeks (95% CI, 1.08–3.82), and a 46% higher overall risk of HIV infection (95% CI, 11%–91%). Children born to women with a low vitamin D level had a 61% higher risk of dying during follow-up (95% CI, 25%–107%).

Conclusions

If found to be efficacious in randomized trials, vitamin D supplementation could prove to be an inexpensive method of reducing the burden of HIV infection and death among children, particularly in resource-limited settings.

Background

The prevalence of both childhood and adult obesity is rising in the developed world and there is increasing interest in its underlying causes. A number of studies suggest a positive relationship between birth weight and childhood body mass index, but less is known about specific prenatal environmental influences on more direct measures of obesity. We utilised data from the Southampton Women's Survey to investigate parental influences on neonatal body composition ascertained by dual x-ray absorptiometry.

Methods

Participating mothers were characterised in detail (anthropometry, lifestyle, diet) before and during pregnancy; information was also obtained on their partners. The offspring underwent assessment of fat and lean body mass by dual x-ray absorptiometry (DXA) within 2 weeks of birth. Linear regression methods were used to explore the parental determinants of neonatal body composition.

Results

Complete data were available for 448 mother-offspring pairs. Taller women and those with higher parity had offspring with increased birth weight, fat and lean mass (p<0.05). Mothers who were taller, of greater parity, had greater fat stores or walked more slowly also had offspring with greater proportionate body fat at birth (all p<0.05). There was a weaker trend towards lower percentage fat and greater percentage lean in the offspring of mothers who smoked during pregnancy.

Conclusion

Maternal size, parity, smoking history, walking speed and fat stores are independent determinants of neonatal body composition. If these influences are shown to have persisting effects on body composition through to adulthood, they point to novel public health interventions early in life to prevent later obesity.

Sales of calcium supplements have increased dramatically since 1983, as middle-aged women seek to prevent or treat bone loss due to osteoporosis. However, epidemiologic studies have failed to support the hypothesis that larger amounts of calcium are associated with increased bone density or a decreased incidence of fractures. The authors examine the evidence from controlled trials on the effects of calcium supplementation and physical activity on bone loss and find that weight-bearing activity, if undertaken early in life and on a regular basis, can increase the peak bone mass of early adulthood, delay the onset of bone loss and reduce the rate of loss. All of these factors will delay the onset of fractures. Carefully planned and supervised physical activity programs can also provide a safe, effective therapy for people who have osteoporosis.

We examined whether there are sex differences in the effect of vitamin supplements on birth outcomes, mortality, and morbidity by two years of age among children born to HIV-infected women in Tanzania. A randomized placebo-controlled trial was conducted among 959 mother-infant pairs. HIV-infected pregnant women were randomly assigned to receive a daily oral dose of one of four regimens: multivitamins (vitamins B-complex, C, and E), vitamin A plus β-carotene, multivitamins including vitamin A plus β-carotene, or placebo. Supplements were administered during pregnancy and continued after delivery. The beneficial effect of multivitamins on decreasing the risk of low birth weight was stronger among girls (RR = 0.39, 95% CI 0.22 – 0.67) compared to boys (RR = 0.81, 95% CI 0.44 – 1.49; p for interaction = 0.08). Maternal multivitamin supplements resulted in 32% reduction in mortality among girls (RR = 0.68, 95% CI 0.47 – 0.97), whereas no effect was found among boys (RR = 1.20, 95% CI 0.80 –1.78; p for interaction = 0.04). Multivitamins had beneficial effects on the overall risks of diarrhea that did not differ by sex. Vitamin A plus β-carotene alone increased the risk of HIV transmission, but had no effect on mortality, and we found no sex differences in these effects. Sex differential effects of multivitamins on mortality may be due to sex related differences in the immunological or genetic factors. More research is warranted to examine the effect of vitamins by sex and better understand biological mechanisms mediating such effects.

Background

Vitamin D is required for normal bone growth and mineralization. We sought to determine whether vitamin D deficiency at birth is associated with bone mineral content (BMC) of Canadian infants.

Methods

We measured plasma 25-hydroxyvitamin D [25(OH)D] as an indicator of vitamin D status in 50 healthy mothers and their newborn term infants. In the infants, anthropometry and lumbar, femur and whole-body BMC were measured within 15 days of delivery. Mothers completed a 24-hour recall and 3-day food and supplement record. We categorized the vitamin D status of mothers and infants as deficient or adequate and then compared infant bone mass in these groups using nonpaired t tests. Maternal and infant variables known to be related to bone mass were tested for their relation to BMC using backward stepwise regression analysis.

Results

Twenty-three (46%) of the mothers and 18 (36%) of the infants had a plasma 25(OH)D concentration consistent with deficiency. Infants who were vitamin D deficient were larger at birth and follow-up. Absolute lumbar spine, femur and whole-body BMC were not different between infants with adequate vitamin D and those who were deficient, despite larger body size in the latter group. In the regression analysis, higher whole-body BMC was associated with greater gestational age and weight at birth as well as higher infant plasma 25(OH)D.

Conclusion

A high rate of vitamin D deficiency was observed among women and their newborn infants. Among infants, vitamin D deficiency was associated with greater weight and length but lower bone mass relative to body weight. Whether a return to normal vitamin D status, achieved through supplements or fortified infant formula, can reset the trajectory for acquisition of BMC requires investigation.

OBJECTIVE: To review recent findings on the skeletal actions of vitamin D and to examine results of the latest clinical trials of vitamin D in the treatment of osteoporosis. OPTIONS: The vitamin D analog 1-alpha hydroxycholecalciferol (1 alpha-OH-D3); the vitamin D metabolite calcitriol. OUTCOMES: Fracture and loss of bone mineral density in osteoporosis; increased bone mass, prevention of fractures and improved quality of life associated with vitamin D therapies. EVIDENCE: Relevant laboratory and clinical studies and reports were examined. Greatest reliance was placed on recent large-scale, randomized, controlled trials; others were noted and their methods critiqued. Clinical practice in Japan was also considered. VALUES: Reducing fractures, increasing bone mineral density and minimizing side effects of treatment were given a high value. BENEFITS, HARMS AND COSTS: Vitamin D maintains the dynamic nature of bone and so presumably helps to keep it healthy. Calcitriol and 1 alpha-OH-D3 may be effective in increasing bone mass and preventing fractures in osteoporosis. Calcitriol may be an alternative treatment in the prevention and management of corticosteroid-induced osteoporosis. Possible side effects of vitamin D analogs and metabolites are hypercalcemia, hypercalciuria, renal calcification and renal stones. RECOMMENDATIONS: The use of 1 alpha-OH-D3 for the treatment of osteoporosis in Canada cannot be supported without larger and longer randomized, controlled clinical trials. Calcitriol appears to prevent vertebral fractures in patients with osteoporosis. More information is needed on its mechanism of action and efficacy in preventing hip fractures. Future studies should focus on comparisons with other effective therapies and on determining whether its effect on fractures is greater than that achieved through improved vitamin D nutrition. Patients taking calcitriol at dose levels required for antifracture effects should be monitored for serum and urine calcium response to the drug. Calcitriol should not be given to patients whose calcium intake is at current generally recommended levels. At present, prescription of calcitriol for the treatment of osteoporosis should be reserved for physicians with a special interest in the treatment of metabolic bone disease.

Context:

Evidence suggests that babies' fat mass at birth is greater if their mothers were themselves fatter during pregnancy, but it is unclear whether this association persists into childhood.

Objective:

To examine the relation between maternal size in pregnancy, early growth and body composition in children.

Design:

Prospective cohort study

Setting:

Southampton, UK.

Participants:

216 nine-year-old children whose mothers had participated in a study of nutrition during pregnancy.

Main outcome measures:

Fat mass and lean mass measured by dual-energy X-ray absorptiometry, adjusted for height (“fat mass index” and “lean mass index”).

Results:

Fat mass index at age nine years was greater in children whose mothers had a larger mid-upper arm circumference in late pregnancy or a higher pre-pregnant body mass index. For one standard deviation (SD) increase in maternal mid-upper arm circumference in late pregnancy, fat mass index rose by 0.26 (95% CI 0.06-0.46) SD in boys and by 0.44 (95% CI 0.31-0.57) SD in girls. For one SD increase in maternal pre-pregnant BMI, fat mass index rose by 0.26 (95% CI 0.04-0.48) SD in boys and by 0.42 (95% CI 0.29-0.56) SD in girls.

Conclusions:

Mothers with a higher pre-pregnant body mass index or a larger mid-upper arm circumference during pregnancy tend to have children with greater adiposity at age nine. The extent to which this is attributable to genetic factors, the influence of maternal lifestyle on that of her child, or maternal adiposity acting specifically during pregnancy on the child's fat mass cannot be determined in this study.

STUDY OBJECTIVE: To examine the relationship between dietary vitamin C and hip bone mineral density (BMD) in postmenopausal women. DESIGN: This was a cross sectional study using retrospective diet and vitamin supplement data. SETTING: The Seattle area of Washington State. PARTICIPANTS: Screenees for a clinical trial of a drug to prevent osteoporotic fractures; 1892 women aged 55-80 years who had hip bone densitometry and osteoporosis risk factor information. MAIN RESULTS: Mean energy adjusted dietary intake of vitamin C was 113 mg/day; including supplement use, mean intake was 407 mg/day. There were no differences in BMD according to diet-only vitamin C intake or combined dietary and supplemental vitamin C intake. Longer duration of vitamin C supplement use was associated with higher BMD in women who had not used oestrogen replacement therapy (trend p = 0.02) and among women aged 55-64 years (trend p = 0.01). Women aged 55-64 years who used vitamin C supplements for > or = 10 years had a higher BMD than non-users aged 55-64 years (multivariate adjusted mean BMD 0.699 (0.017) g/cm2 versus 0.655 (0.007) g/cm2, p = 0.02). Benefits were not evident in older age groups or in women who had used oestrogen in the past. Frequent intake of foods rich in vitamin C was not associated with BMD. CONCLUSION: There was no evidence that vitamin C from the diet was associated with BMD, although long term use of vitamin C supplements was associated with a higher BMD in the early postmenopausal years and among never users of oestrogen.

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Background

Intrauterine life may be a critical period for the programming of later obesity, but there is conflicting evidence about whether pregnancy weight gain is an important determinant of offspring adiposity.

Objective

The purpose of this study was to examine the relationship of pregnancy weight gain with neonatal and childhood body composition.

Design

The participants (n=948) were children born to women in the Southampton Women’s Survey who had dual-energy x-ray absorptiometry measurements of body composition at birth, 4 or 6 years. Pregnancy weight gain was derived from the mothers’ measured weights before pregnancy and at 34 weeks gestation, analyzed using 2009 Institute of Medicine (IOM) categories (inadequate, adequate or excessive), and as a continuous measure.

Results

Almost half (49%) the children were born to women who gained excessive weight in pregnancy. In comparison with children born to women with adequate weight gain, they had a greater fat mass in the neonatal period (0.17 SD (95% CI 0.02, 0.32), P=0.03), at 4 years (0.17 SD (0.00, 0.34), P=0.05) and at 6 years (0.30 SD (0.11, 0.49), P=0.002). Greater pregnancy weight gain, as a continuous measure, was associated with greater neonatal fat mass (0.10 SD per 5kg weight gain (0.04, 0.15), P=0.0004) and, weakly, with fat mass at 6 years (0.07 SD per 5kg (0.00, 0.14), P=0.05), but not at 4 years (0.02 SD per 5kg (−0.04, 0.08), P=0.55).

Conclusions

Appropriate pregnancy weight gain, as defined by 2009 IOM recommendations, is linked to lower levels of adiposity in the offspring.

Background

Decreased bone mineral density and osteoporosis in postmenopausal women represents a growing source of physical limitations and financial concerns in our aging population. While appropriate medical treatments such as bisphosphonate drugs and hormone replacement therapy exist, they are associated with serious side effects such as osteonecrosis of the jaw or increased cardiovascular risk. In addition to calcium and vitamin D supplementation, previous studies have demonstrated a beneficial effect of dietary silicon on bone health. This study evaluated the absorption of silicon from bottled artesian aquifer water and its effect on markers of bone metabolism.

Methods

Seventeen postmenopausal women with low bone mass, but without osteopenia or osteoporosis as determined by dual x-ray absorptiometry (DEXA) were randomized to drink one liter daily of either purified water of low-silicon content (PW) or silicon-rich artesian aquifer water (SW) (86 mg/L silica) for 12 weeks. Urinary silicon and serum markers of bone metabolism were measured at baseline and after 12 weeks and analyzed with two-sided t-tests with p < 0.05 defined as significant.

Results

The urinary silicon level increased significantly from 0.016 ± 0.010 mg/mg creatinine at baseline to 0.037 ± 0.014 mg/mg creatinine at week 12 in the SW group (p = 0.003), but there was no change for the PW group (0.010 ± 0.004 mg/mg creatinine at baseline vs. 0.009 ± 0.006 mg/mg creatinine at week 12, p = 0.679). The urinary silicon for the SW group was significantly higher in the silicon-rich water group compared to the purified water group (p < 0.01). NTx, a urinary marker of bone resorption did not change during the study and was not affected by the silicon water supplementation. No significant change was observed in the serum markers of bone formation compared to baseline measurements for either group.

Conclusions

These findings indicate that bottled water from artesian aquifers is a safe and effective way of providing easily absorbed dietary silicon to the body. Although the silicon did not affect bone turnover markers in the short-term, the mineral's potential as an alternative prevention or treatment to drug therapy for osteoporosis warrants further longer-term investigation in the future.

Trial Registration

ClinicalTrials.gov Identifier: NCT01067508

Background

Bisphosphonates are indicated in the prevention and treatment of osteoporosis. However, bone mineral density (BMD) continues to decline in up to 15% of bisphosphonate users. While randomized trials have evaluated the efficacy of concurrent bisphosphonates and vitamin D, the incremental benefit of vitamin D remains uncertain.

Methods

Using data from the Canadian Database of Osteoporosis and Osteopenia (CANDOO), we performed a 2-year observational cohort study. At baseline, all patients were prescribed a bisphosphonate and counseled on vitamin D supplementation. After one year, patients were divided into two groups based on their response to bisphosphonate treatment. Non-responders were prescribed vitamin D 1000 IU daily. Responders continued to receive counseling on vitamin D.

Results

Of 449 patients identified, 159 were non-responders to bisphosphonates. 94% of patients were women. The mean age of the entire cohort was 74.6 years (standard deviation = 5.6 years). In the cohort of non-responders, BMD at the lumbar spine increased 2.19% (p < 0.001) the year after vitamin D was prescribed compared to a decrease of 0.55% (p = 0.36) the year before. In the cohort of responders, lumbar spine BMD improved 1.45% (p = 0.014) the first year and 1.11% (p = 0.60) the second year. The difference between the two groups was statistically significant the first year (p < 0.001) but not the second (p = 0.60). Similar results were observed at the femoral neck but were not statistically significant.

Conclusion

In elderly patients with osteoporosis not responding to bisphosphonates, vitamin D 1000 IU daily may improve BMD at the lumbar spine.

Background

Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.

Methods and Findings

This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.

Conclusions

Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.

Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)

Angela Cheung and colleagues investigate whether vitamin K1 can prevent bone loss among postmenopausal women with osteopenia.

Editors' Summary

Background.

Osteoporosis is a bone disease in which the bones gradually become less dense and more likely to break. In the US, 10 million people have osteoporosis and 18 million have osteopenia, a milder condition that precedes osteoporosis. In both conditions, insufficient new bone is made and/or too much old bone is absorbed. Although bone appears solid and unchanging, very little bone in the human body is more than 10 y old. Old bone is continually absorbed and new bone built using calcium, phosphorous, and proteins. Because the sex hormones control calcium and phosphorous deposition in the bones and thus bone strength, the leading cause of osteoporosis in women is reduced estrogen levels after menopause. In men, an age-related decline in testosterone levels can cause osteoporosis. Most people discover they have osteoporosis only when they break a bone, but the condition can be diagnosed and monitored using bone mineral density (BMD) scans. Treatments can slow down or reverse bone loss (antiresorptive therapies) and some (bone formation therapies) can even make bone and build bone tissue.

Why Was This Study Done?

Although regular exercise and a healthy diet can help to keep bones strong, other ways of preventing osteoporosis are badly needed. Recently, the lay media has promoted vitamin K supplements as a way to reduce bone loss in postmenopausal women. Vitamin K (which is found mainly in leafy green vegetables) is required for a chemical modification of proteins called carboxylation. This modification is essential for the activity of three bone-building proteins. In addition, there is some evidence that low bone density and fractures are associated with a low vitamin K intake. However, little is known about the long-term benefits or harms of vitamin K supplements. In this study, the researchers investigate whether a high-dose daily vitamin K supplement can safely reduce bone loss, bone turnover, and fractures in postmenopausal women with osteopenia in a randomized controlled trial called the “Evaluation of the Clinical Use of Vitamin K Supplementation in Post-Menopausal Women With Osteopenia” (ECKO) trial.

What Did the Researchers Do and Find?

In the study, 440 postmenopausal women with osteopenia were randomized to receive 5mg of vitamin K1 (the type of vitamin K in North American food; the recommended daily adult intake of vitamin K1 is about 0.1 mg) or an inactive tablet (placebo) daily for 2 y; 261 of the women continued their treatment for 2 y to gather information about the long-term effects of vitamin K1 supplementation. All the women had regular bone density scans of their lower back and hips and were examined for fractures and for changes in bone turnover. After 2 y and after 4 y, lower back and hip bone density measurements had decreased by similar amounts in both treatment groups. The women who took vitamin K1 had 10-fold higher amounts of vitamin K1 in their blood than the women who took placebo and lower amounts of a bone formation marker; the levels of a bone resorption marker were similar in both groups. Over the 4-y period, fewer women in the vitamin K group had fractures (nine versus 20 women in the placebo group), and fewer had cancer (three versus 12). Finally, vitamin K supplementation was well tolerated over the 4-y period and adverse health effects were similar in the two treatment groups.

What Do These Findings Mean?

These findings indicate that a high daily dose of vitamin K1 provides no protection against the age-related decline in bone density in postmenopausal women with osteopenia, but that vitamin K1 supplementation may protect against fractures and cancers in these women. The apparent contradiction between the effects of vitamin K1 on bone density and on fractures could mean that vitamin K1 supplements strengthen bone by changing factors other than bone density, e.g., by changing its fine structure rather than making it denser. However, because so few study participants had fractures, the difference in the fracture rate between the two treatment groups might have occurred by chance. Larger studies are therefore needed to examine the effect of vitamin K1 on fractures (and on cancer) and, until these are done, high-dose vitamin K1 supplementation should not be recommended for the prevention of osteoporosis.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050196.

The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides detailed information about osteoporosis (in English and Spanish) and links to other resources, including an interactive web tool called Check Up On Your Bones

MedlinePlus provides links to additional information about osteoporosis (in English and Spanish)

The MedlinePlus Encyclopedia has a page about vitamin K

The UK Food Standards Agency provides information about vitamin K

Full details about the ECKO trial are available on the ClinicalTrials.gov Web site

The Canadian Task Force for Preventive Health Care provides recommendations on the prevention of osteoporosis and osteoporotic fractures in postmenopausal women

Osteoporosis Canada provides information on current topics related to osteoporosis

Evidence exists for an association between maternal use of a vitamin supplement with folic acid in early pregnancy and a reduced risk for offspring with conotruncal heart defects. Few inquiries about periconceptional nutrition, other than folate, and risk of heart defects have been made. Data derived from a population-based case-control study of fetuses and liveborn infants among a cohort of California births between July 1999 and June 2004. In total, 76% of eligible case mothers and 77% of eligible control mothers were interviewed. Cases included 140 with d-transposition of great arteries (dTGA), and 163 with tetralogy of Fallot (TOF). Total number of controls was 698. Self-reported use of vitamins was elicited by questionnaire for the periconceptional period, Dietary nutrient intake was elicited by a well-known food frequency questionnaire. The odds ratio for dTGA associated with supplemental vitamin use was 1.0 (95% confidence interval, 0.7-1.5) and for TOF was 0.9 (0.6-1.3). We observed increased risks associated with lower dietary intakes of linoleic acid, total carbohydrate, and fructose for dTGA, whereas decreased risks were observed for lower intakes of total protein and methionine for TOF. Lower dietary intake of several micronutrients, namely folate, niacin, riboflavin, and vitamins B12, A, and E, even after simultaneous adjustment for other studied nutrients, were associated with increased risks of dTGA, but not for TOF. These associations were observed among women who did not use vitamin supplements periconceptionally. Analytic consideration of several potential confounders did not reveal alternative interpretations of the results. Our population-based case-control study attempted to extend the knowledge base on nutrition and heart defect risk and prevention.

Increased intake or supplementation of vitamin D is often recommended for normal bone health; however, its preventive effect on osteoporosis has not been fully evaluated. The aim of this review is to gather evidence of the efficacy of the optimization of vitamin D nutrition in preventing osteoporosis and osteoporotic fractures. PubMed was used for searching the relevant literature using the MeSH terms “Bone Density (limited to “human”, “female”, and “English” literature)” or “Fractures (limited to “human”, “age ≥45 years”, and “English” literature)”, and “Vitamin D”. The searches yielded 19 randomized controlled trials (RCTs), nine cohort studies, 19 case-control studies, 19 cross-sectional studies, and one meta-analysis. We attempted to answer three questions: 1) does increased vitamin D intake prevent bone loss in peri- and postmenopausal women?, 2) does increased vitamin D intake prevent osteoporotic fractures in the elderly?, and 3) does increased vitamin D in take positively affect peak bone mass attainment in young women? The answer to questions 1 and 2 is that a vitamin D intake of 10–17.5 μg/day (400–700 IU/day) or more is effective in preventing bone loss in late postmenopausal women and an intake of 17.5–20 μg/day (700–800 IU/day) or more together with a calcium supplement reduces the risk of osteoporotic fractures. For question 3, some lines of evidence support the negative effect of low vitamin D nutrition on the attainment of peak bone mass in young women. Further studies are needed to clarify the effect of vitamin D in this age group.

Background

Calcium supplementation during pregnancy has been shown to reduce the incidence of hypertension in the mother, but the effects on the offspring are uncertain. Assessing the impact on the offspring is very important given the now large body of evidence indicating that blood pressure levels in childhood and young adulthood can be influenced by factors operating during fetal life. We conducted a systematic review of the literature to summarize the evidence supporting an association between maternal dietary calcium intake during pregnancy and blood pressure in the offspring.

Methods

A systematic review was performed to identify randomized, quasi-randomized and cohort studies reporting the relationship between offspring blood pressure or incidence of hypertension and levels of maternal dietary calcium intake during pregnancy, either from supplements (i.e. pills) or food. MEDLINE, EMBASE and the Cochrane Library Registry were searched for relevant trials.

Results

Two randomized trial and three observational studies were identified and included in this review. In 4 of the 5 studies, loss to follow-up was a serious concern. There was heterogeneity between the studies, particularly those conducted on children below 12 month of age. Results were more consistent among the studies including older children (1 to 9 years) where a higher maternal calcium intake was associated with a reduction of -1.92 mm Hg (95% CI -3.14 to -0.71) in offspring systolic blood pressure. One large randomized trial found a clinically and statistically significant reduction in the incidence of hypertension in 7-year-old children (RR = 0.59, 95% CI 0.39 to 0.90).

Conclusion

There is evidence in the literature to support an association between maternal calcium intake during pregnancy and offspring blood pressure. However, more research is needed to confirm these finding given the small sample sizes and the methodological problems in many of the studies conducted so far. More studies on populations with calcium deficit are also needed. If confirmed, these findings could have important public health implications. Calcium supplementation during pregnancy is simple and inexpensive and may be a way to reduce the risk of hypertension and its sequels in the next generation.

An earlier preliminary paper is expanded. Women who had given birth to one or more infants with a neural tube defect were recruited into a trial of per conceptional vitamin supplementation. Two hundred mothers attending five centres were fully supplemented (FS), 50 were partially supplemented (PS), and 300 were unsupplemented (US). Neural tube defect recurrences in the study pregnancies were 1 (0.5%), in FS, none in PS, and 13 (4%) in US mothers. The difference in outcome between FS and US mothers is significant. The most likely explanation is that supplementation has prevented some neural tube defects, but further studies are needed.

Background

Osteoporosis is a debilitating condition characterized by fractures, pain and premature death. Risk factors for osteoporosis predict the risk of fragility fractures.

Aim

To describe the occurrence of risk factors for osteoporosis among populations in Nuuk, the capital of Greenland.

Methods

A random sample of women born in 1934–42, 1945–47, 1956, and men born in 1956 were selected from the national civil registry. A questionnaire was sent out in Greenlandic and Danish on risk factors for osteoporosis: family history, smoking habits, alcohol intake, presence of disease, sun exposure, intake of dairy products, age at menopause (women) and number of falls. Additional questions included the frequency of back pain, previous fractures, intake of vitamin D and calcium supplements, use of anti-osteoporotic drugs, steroids and other drugs.

Results

The questionnaire was sent to 317 subjects confirmed to be living at an address in Nuuk and 181 (57.1%) responded. More young women than older women were smokers (60.6% vs. 35.0%; p=0.022) while limited sun exposure was reported by more of the old women (37.2% vs. 5.6%; p=0.003). Family history of osteoporosis was reported by 15.0%, without difference between groups. Alcohol and milk intake did not differ between groups. Premature menopause was reported by 17.9% of the women. Falls within the last year were reported by 42.4% with fewer falls in the oldest age group (21.9% vs. 50.0%; p=0.005). Frequency of fragility fractures increased with age (5.7% vs. 24.3% vs. 30.4%; p=0.02) and the risk of a fragility fracture increased with age (p=0.004; OR, 95% CI: 4.5, 1.6–12.2, reference: below 70 years), when adjusted for smoking, gender and falls. The use of anti-osteoporotic drugs was low (3.4%) while 28.8% took calcium and vitamin D supplements.

Conclusions

Age is a dominating risk factor for fragility fractures in Greenland. The use of anti-osteoporotic drugs is low in Greenland, even if osteoporotic fractures are common in old age.

Background

Periconceptional use of folic acid prevents most neural tube defects (NTDs). Whether folic acid and/or multivitamins can prevent other congenital anomalies is not clear. This study tested whether maternal blood levels of folate and vitamin B12 in pregnancies affected by congenital malformations excluding NTDs are lower when compared to non-affected pregnancies.

Methods

We measured pregnancy red cell folate (RCF), vitamin B12, and homocysteine (tHcy) concentrations in blood samples taken at the first antenatal clinic in Dublin maternity hospitals in 1986–1990 when vitamin supplementation was rare. The cases were mothers who delivered a baby with a congenital malformation other than NTD identified by the Dublin EUROCAT Registry; controls were a systematic sample of mothers of offspring without congenital malformations from the same hospitals in the same time period.

Results

The median maternal levels of RCF and tHcy did not differ significantly between cases and controls for any of the congenital malformation groups examined (RCF: all malformations 275.9 ug/L v controls 271.2; p=0.77; tHcy: all malformations 7.5 umol/L v controls 7.6; p=0.57). In an unadjusted analysis vitamin B12 was significantly higher in case-mothers whose babies had cleft palate only (p=0.006), musculoskeletal malformations (p=0.034) and midline defects (p=0.039) but not after adjustment for multiple testing.

Conclusions

Our data suggest that low maternal folate and B12 levels or high tHcy levels in early pregnancy are not associated with all congenital malformations excluding NTDs. Fortification with folic acid or B12 may not have a beneficial effect in the prevention of these anomalies.

Background

The prevalence of obesity amongst women bearing children in Australia is rising and has important implications for obstetric care. The aim of this study was to assess the prevalence and impact of mothers being overweight and obese in early to mid-pregnancy on maternal, peripartum and neonatal outcomes.

Methods

A secondary analysis was performed on data collected from nulliparous women with a singleton pregnancy enrolled in the Australian Collaborative Trial of Supplements with antioxidants Vitamin C and Vitamin E to pregnant women for the prevention of pre-eclampsia (ACTS). Women were categorized into three groups according to their body mass index (BMI): normal (BMI 18.5-24.9 kg/m2); overweight (BMI 25-29.9 kg/m2) and; obese (BMI 30-34.9 kg/m2). Obstetric and perinatal outcomes were compared by univariate and multivariate analyses.

Results

Of the 1661 women included, 43% were overweight or obese. Obese women were at increased risk of pre-eclampsia (relative risk (RR) 2.99 [95% confidence intervals (CI) 1.88, 4.73], p < 0.0001) and gestational diabetes (RR 2.10 [95%CI 1.17, 3.79], p = 0.01) compared with women with a normal BMI. Obese and overweight women were more likely to be induced and require a caesarean section compared with women of normal BMI (induction - RR 1.33 [95%CI 1.13, 1.57], p = 0.001 and 1.78 [95%CI 1.51, 2.09], p < 0.0001, caesarean section - RR 1.42 [95%CI 1.18, 1.70], p = 0.0002 and 1.63 [95%CI 1.34, 1.99], p < 0.0001). Babies of women who were obese were more likely to be large for gestational age (LFGA) (RR 2.08 [95%CI 1.47, 2.93], p < 0.0001) and macrosomic (RR 4.54 [95%CI 2.01, 10.24], p = 0.0003) compared with those of women with a normal BMI.

Conclusion

The rate of overweight and obesity is increasing amongst the Australian obstetric population. Women who are overweight and obese have an increased risk of adverse pregnancy outcomes. In particular, obese women are at increased risk of gestational diabetes, pregnancy induced hypertension and pre-eclampsia. Effective preventative strategies are urgently needed.

Trial Registration

Current Controlled Trials ISRCTN00416244

Abstract

Vitamin D has a potential role in preventing HIV-related complications, based on its extensive involvement in immune and metabolic function, including preventing osteoporosis and premature cardiovascular disease. However, this association has not been examined in large studies or in resource-limited settings. Vitamin D levels were assessed in 884 HIV-infected pregnant women at enrollment in a trial of multivitamin supplementation (excluding vitamin D) in Tanzania. Information on HIV related complications was recorded during follow-up (median, 70 months). Proportional hazards models and generalized estimating equations were used to assess the relationship of vitamin D status with these outcomes. Women with low vitamin D status (serum 25-hydroxyvitamin D<32 ng/mL) had 43% higher risk of reaching a body mass index (BMI) less than 18 kg/m2 during the first 2 years of follow-up, compared to women with adequate vitamin D levels (hazard ratio [HR]: 1.43; 95% confidence intervals: [1.03–1.99]). The relationship between continuous vitamin D levels and risk of BMI less than 18 kg/m2 during follow-up was inverse and linear (p=0.03). Women with low vitamin D levels had significantly higher incidence of acute upper respiratory infections (HR: 1.27 [1.04–1.54]) and thrush (HR: 2.74 [1.29-5.83]) diagnosed during the first 2 years of follow-up. Low vitamin D status was a significant risk factor for wasting and HIV-related complications such as thrush during follow-up in this prospective cohort in Tanzania. If these protective associations are confirmed in randomized trials, vitamin D supplementation could represent a simple and inexpensive method to improve health and quality of life of HIV-infected patients, particularly in resource-limited settings.