Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment

Throughout the life cycle the skeleton requires optimum development and maintenance of its integrity to prevent fracture. Bones break because the loads placed on them exceed the ability of the bone to absorb the energy involved. It is now estimated that one in three women and one in twelve men aged >55 years will suffer from osteoporosis in their lifetime and at a cost in the UK of > 1.7 pounds x 10(9) per year. The pathogenesis of osteoporosis is multifactorial. Both the development of peak bone mass and the rate of bone loss are determined by key endogenous and exogenous factors. Ca supplements appear to be effective in reducing bone loss in women late post menopause (>5 years post menopause), particularly in those with low habitual Ca intake (<400 mg/d). In women early post menopause (<5 years post menopause) who are not vitamin D deficient, Ca supplementation has little effect on bone mineral density. However, supplementation with vitamin D and Ca has been shown to reduce fracture rates in the institutionalised elderly, but there remains controversy as to whether supplementation is effective in reducing fracture in free-living populations. Re-defining vitamin D requirements in the UK is needed since there is evidence of extensive hypovitaminosis D in the UK. Low vitamin D status is associated with an increased risk of falling and a variety of other health outcomes and is an area that requires urgent attention. The role of other micronutrients on bone remains to be fully defined, although there are promising data in the literature for a clear link between vitamin K nutrition and skeletal integrity, including fracture reduction.     

Prevention of fractures in older people with calcium and vitamin D

The greatest cause of fracture in older people is osteoporosis which contributes to increased morbidity and mortality in older people. A number of meta-analyses have been performed assessing the effectiveness of calcium supplementation alone, vitamin D supplementation alone and the combined therapy on bone loss and fracture reduction in older people. The results of these meta-analyses indicate that vitamin D supplementation alone is unlikely to reduce fracture risk, calcium supplementation alone has a modest effect in reducing total fracture risk, but compliance with calcium supplements is poor in the long term. The combination of calcium supplementation with vitamin D supplementation, particularly in those at risk of marginal and low vitamin D status reduces total fractures, including hip fractures. Therefore older people would be recommended to consume adequate dietary calcium (>1100 mg/day) together with maintaining adequate vitamin D status (>60 nmol/L 25(OH)D) to reduce risk of fracture. It is a challenge to consume sufficient dietary calcium from dietary sources, but the increasing range of calcium fortified foods could assist in increasing the dietary calcium intake of older people. In addition to the usual dairy based food sources, vitamin D supplements are likely to be required for older people with reduced mobility and access to sunlight.     

Denosumab for the prevention of osteoporotic fractures in postmenopausal women

This paper presents a summary of the evidence review group (ERG) report into denosumab for the prevention of osteoporotic fractures in postmenopausal women. Denosumab has been shown in a large randomised trial to reduce the frequency of osteoporotic fractures when given subcutaneously at 6-monthly intervals. Compared with placebo, the relative risks of clinical vertebral and hip fractures were 0.32 and 0.60, respectively. Clinical vertebral fractures occurred in 0.8% of women taking denosumab and 2.6% of control subjects. Hip fractures occurred in 1.2% of women on placebo and 0.7% on denosumab. The expected use is in women who cannot tolerate oral bisphosphonates. Other options in that situation include strontium ranelate and zoledronate, which, compared with placebo, also reduced the risk of clinical vertebral fractures [relative risk (RR) 0.65 and 0.23, respectively]. Zoledronate also significantly reduced the risk of hip fractures (RR 0.59). The ERG concluded that zoledronate was the main comparator. The relative cost-effectiveness of denosumab and zoledronate depends mainly on assumptions about costs of administration.     

Optimization of calcium intake for the prevention of osteoporosis and osteoporotic fractures: a review of the evidence

One of the main focuses of lifestyle modification for the prevention of osteoporosis and osteoporotic fractures in Japan is improvement in dietary calcium intake. However, virtually no randomized controlled trial to assess the preventive effects of administration of calcium on the risk of fractures has been conducted in Japan. In this study, we reviewed all the scientific papers currently available from medical literature databases to propose evidence-based recommendations on the preventive procedures for osteoporosis. The result of the present systematic review gives the evidence showing that calcium supplementation or optimal dietary calcium intake increases bone density in childhood and adolescence and reduces the risk of fracture due to osteoporosis in the elderly people regardless of the gender. The evidence also supports the current health policy guiding the elderly to increase their dietary calcium intake in daily life.     

Calcium and vitamin D3 supplements in calcium and vitamin D3 sufficient early postmenopausal healthy women

OBJECTIVE: To study the calcium homeostasis in healthy, calcium and vitamin D replete early postmenopausal women during oral supplementation with calcium and vitamin D3. DESIGN: A prospective, placebo-controlled, randomised, double-single-blind, 3-week study. SETTING: Outpatient clinic at Copenhagen University Hospital, Denmark. SUBJECTS: In all, 17 started, one was excluded. Totally, 16 healthy women, 45-61 y of age (mean 57.3 y) who were at least 4 y after menopause (mean 6.7 y) completed. INTERVENTIONS: All underwent three consecutive 7-day study periods. Each began with 4 days of normal diet followed by 3 days treatment of either C: one tablet of 1.250 mg calcium carbonate (ie 500 mg Ca2+ per tablet) twice daily (breakfast and dinner), or CD3: as in C but plus 400 IU vitamin D3 b.i.d., or P (only) placebo tablets b.i.d. RESULTS: At baseline plasma 25-hydroxycholecalciferol was normal (66+/-22 nmol/l) and the calcium intake without supplements 850 mg/day. In group C, the 24-h urinary calcium increased by 35% (6.9+/-2.0 mmol), vs the placebo group P (5.1+/-1.6 mmol) (P < 0.05). Addition of 800 IU vitamin D3 daily (CD3) did not increase calcium excretion further (6.6+/-2.1 mmol) but decreased plasma 1,25-(OH)2-vitamin D3 by 21% (P < 0.05). CONCLUSIONS: In this carefully controlled study calcium plus vitamin D3 supplements only had minor influences of uncertain significance on the calcium balance in healthy, calcium and vitamin D sufficient early postmenopausal women.     

Efficacy of optimization of vitamin D in preventing osteoporosis and osteoporotic fractures: A systematic review

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.Key words: bone density, fractures, osteoporosis, systematic review, vitamin D     

Vitamins and bone health: beyond calcium and vitamin D

Osteoporosis is a major health disorder associated with an increased risk of fracture. Nutrition is among the modifiable factors that influence the risk of osteoporosis and fracture. Calcium and vitamin D play important roles in improving bone mineral density and reducing the risk of fracture. Other vitamins appear to play a role in bone health as well. In this review, the findings of studies that related the intake and/or the status of vitamins other than vitamin D to bone health in animals and humans are summarized. Studies of vitamin A showed inconsistent results. Excessive, as well as insufficient, levels of retinol intake may be associated with compromised bone health. Deficiencies in vitamin B, along with the consequent elevated homocysteine level, are associated with bone loss, decreased bone strength, and increased risk of fracture. Deficiencies in vitamins C, E, and K are also associated with compromised bone health; this effect may be modified by smoking, estrogen use or hormonal therapy after menopause, calcium intake, and vitamin D. These findings highlight the importance of adequate nutrition in preserving bone mass and reducing the risk of osteoporosis and fractures.     

Vitamin D supplementation and depression in the women's health initiative calcium and vitamin D trial

While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D(3) combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995-2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D(3) along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.     

The prevention of vitamin D deficiency in the elderly

Vitamin D deficiency is common in the house-bound and institutionalised elderly population of Britain. A study of patients over 65 years discharged with a diagnosis of osteomalacia from Greater Glasgow Health Board hospitals between 1970 and 1981 inclusive showed a low incidence in the 65 to 74 years age group but a steeply rising incidence in older age groups. The majority (83%) of patients were female. The fortification of margarine, butter and milk with concentrations of vitamin D acceptable to the general population does not produce significant elevations in serum 25-hydroxyvitamin D (25-OHD) levels in vitamin D-deficient elderly patients. Low intensity background ultraviolet radiation (UVR) and intermittent high intensity UVR produce significant elevations in serum 25-OHD levels in elderly patients but both methods have disadvantages which limit their widespread use. Vitamin D supplements equivalent to 10 micrograms daily produce significant elevations in serum 25-OHD levels in vitamin D-deficient elderly patients. A vitamin D supplement policy for the housebound and institutionalised elderly population of Britain is required.     

Association of hip fracture incidence and intake of calcium,magnesium, vitamin D,and vitamin K

Objective To analyze the association between hip fracture incidence in 12 regional blocks within Japan and dietary intake of four key nutrients: calcium, magnesium, vitamin D, and vitamin K. Design An ecological study. Methods Using data from the 2002 national survey on the incidence of hip fracture and the National Nutritional Survey of Japan, a standardized incidence ratio of hip fracture was calculated, and the association between the standardized incidence ratio and each nutritional intake was assessed for each region using Pearson’s correlation coefficient and partial correlation analysis. Results There were significant correlations between the standardized incidence ratio by region and magnesium, vitamin D, and vitamin K in both men and women, and calcium in women. The strongest inverse correlations were found in vitamin K in both men and women (r = −0.844, P = 0.001, and r = −0.834, P = 0.001, respectively). After adjusting for calcium, magnesium, and vitamin D, the partial correlation between the standardized incidence ratio by regional block and vitamin K was strongest in both men and women (partial correlation coefficient, pcc = −0.673, P = 0.04; pcc = −0.575, P = 0.106, respectively). Conclusions The significant correlation between hip fracture incidence and vitamin K intake, and also regional variations in food patterns, suggest that increasing intake of vegetables and legumes might lead to a decrease in hip fracture incidence in the future. Further, this study suggests that a review of the dietary reference value of vitamin K from the perspective of osteoporosis would be useful.     

The role of vitamin D in cancer prevention

Vitamin D status differs by latitude and race, with residents of the northeastern United States and individuals with more skin pigmentation being at increased risk of deficiency. A PubMed database search yielded 63 observational studies of vitamin D status in relation to cancer risk, including 30 of colon, 13 of breast, 26 of prostate, and 7 of ovarian cancer, and several that assessed the association of vitamin D receptor genotype with cancer risk.The majority of studies found a protective relationship between sufficient vitamin D status and lower risk of cancer. The evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects.     

The role of vitamin D deficiency in osteoporosis and fractures

Vitamin D deficiency is a major risk factor for accelerated bone loss, which contributes to morbidity in older adults. It is easy to diagnose, and treatment is safe and cost-effective. This article reviews the amount of vitamin D needed by certain populations in order to help prevent osteoporosis and fractures associated with the disease. It also summarizes the results of a study involving 81 hip-fracture patients that found 80% had abnormally low levels of 25-hydroxyvitamin D.     

Celiac disease is not increased in women with hip fractures and low vitamin D levels

Objective

Celiac disease is associated with decreased bone density; however, the risk of fractures in celiac disease patients is unclear. We compared the prevalence of celiac disease between a group of women with hip fractures and a group of women undergoing elective joint replacement surgery and the association between celiac disease and vitamin D levels.

Methods

Two hundred eight community dwelling and postmenopausal women were recruited from Boston, MA (n=81) and Baltimore, MD (n=127). We measured tissue transglutaminase IgA by ELISA to diagnose celiac disease and 25-hydroxyvitamin D (25(OH)D) levels by radioimmunoassay in both women with hip fractures (n=157) and a control group (n=51) of total hip replacement subjects from Boston. Subjects were excluded if they took any medications or had medical conditions that might affect bone.

Results

Median serum 25(OH)D levels were significantly lower (p< 0.0001) in the hip fracture cohorts compared to the elective joint replacement cohort (14.1 ng/ml vs. 21.3 ng/ml, respectively). There were no differences in the percentage of subjects with a positive tissue transglutaminase in the women with hip fractures versus the control group (1.91% vs. 1.96%, respectively).

Conclusion

Vitamin D levels are markedly reduced in women with hip fractures, however hip fracture patients did not show a higher percentage of positive tissue transglutaminase levels compared with controls. These data suggest that routine testing for celiac disease among hip fracture patients may not be necessary in the absence of clinical signs and symptoms, although data from larger studies among hip fracture subjects are needed.     

Using economics to prioritize research: a case study of randomized trials for the prevention of hip fractures due to osteoporosis

OBJECTIVES: To assess the role of economics, in combination with clinical judgement, for setting research priorities, using osteoporosis prevention (and, as a result, hip fracture prevention) as an example. METHODS: Modelling the cost and effectiveness of each of six potential interventions to prevent hip fractures over the 5-year length of a randomized trial (vitamin D injection; thiazide diuretics; hormone replacement therapy; oral calcium and vitamin D; calcium alone; calcitonin). Drug costs were derived from the Monthly Index of Medical Specialties (MIMS); averted fracture costs and estimates of effectiveness were derived from published sources. RESULTS: Vitamin D injection proved to be the most potentially cost-effective treatment with a cost-effectiveness ratio of 584 Pounds. If averted costs are included, this leads to a saving of 9,176,496 Pounds per 100,000 women treated. By contrast, the most expensive therapy was calcitonin (marginal cost-effectiveness ratio of 433,548 Pounds). This suggests that priority should be given to trials assessing the effectiveness of vitamin D injections. CONCLUSIONS: Relatively simple economic modelling exercises can inform research priorities and could help optimize the use of scarce research resources.     

Towards prevention of vitamin D deficiency and beyond: knowledge gaps and research needs in vitamin D nutrition and public health

The North American Institute of Medicine (IOM) recently published their report on dietary reference intakes (DRI) for Ca and vitamin D. The DRI committee's deliberations underpinning this most comprehensive report on vitamin D nutrition to date benefited hugely from a much expanded knowledge base in vitamin D over the last decade or more. However, since their release, the vitamin D DRI have been the subject of intense controversy, which is largely due to the persistence of fundamental knowledge gaps in vitamin D. These can be identified at the levels of exposure, metabolism, storage, status, dose-response, function and beneficial or adverse health effects, as well as safe and effective application of intake recommendations at the population level through sustainable food-based approaches. The present review provides a brief overview of the approach used by the IOM committee to revise the DRI for vitamin D and to collate from a number of authoritative sources key knowledge gaps in vitamin D nutrition from the public health perspective. A number of research topics are outlined and data requirements within these are identified and mapped to the risk assessment framework used by the DRI committee. While not intended as an exhaustive list, it provides a basis for organising and prioritising research efforts in the area of vitamin D, which may offer a perspective on the major areas in need of attention. It is intended to be of use to researchers, national policy makers, the public health community, industry groups and other relevant stakeholders including funding institutions.     

The second international standard for vitamin D: crystalline vitamin D3

This report was presented to the Subcommittee on Fat-Soluble Vitamins of the WHO Expert Committee on Biological Standardization in 1949 by the Vitamin D Sub-Committee of the Accessory Food Factors Committee of the Medical Research Council of Great Britain and formed the evidence on which the first-mentioned subcommittee based its recommendation of the adoption of crystalline vitamin D₃ as the International Standard for Vitamin D, replacing the solution of irradiated ergosterol which had been adopted as Standard in 1931.