European Journal of Clinical Nutrition (2011) 65, 9941004

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REVIEW

Calcium and vitamin D for obesity: a review of randomized controlled trials

MJ Soares1, W Chan She Ping-Delfos2 and MH Ghanbari1
1

Program of Nutrition, School of Public Health, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia and 2Population Science, Telethon Institute for Child Health Research, West Perth, Western Australia, Australia

Obesity often coexists with low calcium intake and vitamin D insufficiency. There is emerging evidence of a role for these nutrients in the regulation of body weight. However, it is unclear whether increasing intakes of calcium and/or vitamin D during energy restriction, is a better strategy for weight and fat loss. We searched the literature from 2000 to date for randomized controlled trials (RCTs) on weight loss that had increased calcium or vitamin D per se, or in combination. Primary and secondary studies were included for this analysis. A total of 15 RCTs on calcium with or without vitamin D and seven on vitamin D alone met our criteria. Two studies reported that supplemental calcium significantly increased fat loss during caloric restriction by 1.8 and 2.2 kg, three found differences between 1 and 3.5 kg but were statistically nonsignificant, while nine trials were equivocal (0.7 kg). The data on vitamin D supplementation during weight loss were too few to make firm conclusions. Current evidence from RCTs did not consistently support the contention that calcium and vitamin D accelerated weight or fat loss in obesity. There were studies that favoured the hypothesis but lacked the statistical power. There is a need for RCTs to examine the influence of vitamin D on body fat.

European Journal of Clinical Nutrition (2011) 65, 9941004; doi:10.1038/ejcn.2011.106; published online 6 July 2011
Keywords: calcium; vitamin D; weight loss; body fat; obesity

Introduction
Calcium accounts for 24% of gross body weight in mammals. Of this, more than 95% is present in bones and teeth and the remainder is either found in plasma bound to plasma proteins, or in extra-cellular fluid as ionic calcium concentration (Ca2 ) (Weaver and Heaney, 2006). The latter is tightly regulated by parathyroid hormone (PTH), calcitonin and vitamin D. The physiological importance of calcium in human physiology is well established and is covered in this issue. There is growing evidence that poor calcium intake, inadequate vitamin D status, obesity and chronic non-communicable disease often cluster. This presents a paradigm that can be acted upon at the individual and population level, if causality of effect is secured.

Correspondence: Professor MJ Soares, School of Public Health, Curtin University, Bentley Campus Curtin University, Kent Street, Perth, Western Australia 6845, Australia. E-mail: m.soares@curtin.edu.au Contributors: WCSP-D and MHG independently conducted the literature searches, assembled the initial tables and contributed to the writing of the manuscript. MJS planned the review, screened the evidence for inclusion, and wrote the manuscript. Received 6 April 2011; accepted 5 May 2011; published online 6 July 2011

A potential role for calcium in body-weight regulation came from observations that a high-calcium diet attenuated adipocyte lipid accretion and weight gain, during periods of overconsumption of an energy-dense diet (Zemel et al., 2000; Shi et al., 2001; Teegarden and Zemel, 2003; Zemel, 2003). Based primarily on the agouti mouse model, Zemel et al. (2000) proposed that intracellular calcium (iCa2 ) held the key to fat deposition and obesity. According to their scheme, increases in dietary calcium would, via PTH, chronically lower iCa2 in the adipocyte. Directly, or possibly via insulin, iCa2 would then act to reciprocally regulate; a reduced expression of fatty acid synthase (FAS)a key enzyme regulating lipid depositionwhile stimulating adipose tissue lipolysis. An increased fat oxidation and thermogenesis through upregulation of uncoupling proteins could also account for the greater weight/fat loss following calcium (Zemel et al., 2000; Shi et al., 2001; Teegarden and Zemel, 2003; Zemel, 2002, 2003). Dietary calcium has also been known to act at the level of the gastrointestinal tract to increase energy loss, through increased fecal-fat excretion (Figure 1) (Soares and Chan She-Ping-Delfos, 2010). These observations predate the calcium-body-weight hypothesis. A recent meta-analysis confirms that dietary calcium has a small but significant

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SNS activity Calcium GI Tract PTH GI Hormones FOR & Thermogenesis De novo Lipogenesis

Calciumfatty acid soaps

Faecal Fat & energy loss

REDUCED BODY FAT

Vitamin D

Food Intake Insulin Sensitivity Hunger

Figure 1 A simplified scheme of the potential anti-obesity effects of calcium and vitamin D. PTH, parathyroid hormone; SNS, sympathetic nervous system; GI, gastrointestinal; FOR, fat oxidation rate.

effect on fat excretion. However, the data on dairy calcium were more robust than non-dairy calcium, with intakes of 1200 mg/d resulting in an increased fecal-fat excretion of B5.2 g/d. Although not substantial, the latter could theoretically account for a weight loss of B 2.2 kg over a year (Christensen et al., 2009). Tordoff (2001) has hypothesized a calcium appetite as the innate drive for calcium-rich food sources when faced with calcium depletion. Although confirmation comes from animal studies, this has proved difficult to demonstrate in humans, given the complex behavioural control of food intake in man. Nevertheless, the expectation would be that those with low calcium status somehow make inappropriate choices leading to increased energy intake, in their drive to meet their calcium requirements. Some indication for such effects comes from the observations that during weight loss, additional calcium (1200 mg/d) as a milk supplement attenuated subjective feelings of hunger and desire to eat, and resulted in a trend for a lower fat and energy intake (Gilbert et al., 2011). Suppression of hunger sensations by calcium has also been described during short-term weight -Hlavata et al., 2008). Our own observations loss (Kabrnova through a sequential meal design indicate that calcium plus vitamin D acutely attenuated buffet meal intake, prolonged the inter-meal interval between buffet and dinner, and significantly reduced spontaneous 24-h food intake the following day (Chan She Ping-Delfos and Soares, 2011). Whether such potential roles for calcium on food and fat -Hlavata intake are mediated through resistin (Kabrnova et al., 2008), ghrelin (Gilbert et al., 2011), leptin (Astrup et al., 2010) or by other gastrointestinal tract hormones controlling food intake, remain a fertile area of future research (Figure 1). There are some issues with studies investigating the antiobesity mechanism of calcium. These include the source used that is, dairy versus non-dairy, the formulation of the pharmaceutical preparation and the dosage administered. These facets of study design impinge on the effective dose

absorbed and hence the ability to document metabolic versus gastrointestinal effects of calcium (Soares and Chan She-Ping-Delfos, 2010). Using milk or dairy product as a vehicle for increasing calcium, introduces milk bioactives, milk protein, probiotics, and in countries with mandatory fortification, vitamin D as well into the picture. It was therefore encouraging that despite these limitations, there was consistent evidence to support the stimulation of fat oxidation, following calcium alone or in combination with vitamin D (Soares and Chan She-Ping-Delfos, 2010). However, an increased thermogenesis and greater lipolysis were not always observed. Overall, there is good evidence to support many of the mechanistic pathways for an antiobesity effect of calcium (Figure 1). There is now a flurry of activity on the role of vitamin D in chronic disease and a meta-analysis on its role in type II diabetes is presented in this series. The active metabolite, 1, 25 (OH)2D3, independent of PTH, seems to modulate adipogenesis. This is achieved by inhibiting critical molecular components of adipogenesis, such as peroxisome proliferation (Duque et al., 2004). Hence, reduced vitamin D stores have the potential to cause excess differentiation of pre-adipocytes to adipocytes. Animal studies on VDR null mice strongly indicate a role for the vitamin in energy regulation (Wong et al., 2009). However, there is mixed evidence in humans to support a role in energy expenditure and fat oxidation (Boon et al., 2006; Teegarden et al., 2008). Could vitamin D hence modify insulin sensitivity and influence food intake (Figure 1) or is its action through improved calcium absorption and a reduction in PTH levels? One opinion is that the long-term suppression of PTH may hold the key to obesity prevention (McCarty and Thomas, 2003). A reduced activation of the sympathetic nervous system has long been implicated in the weight gain of both animals and man. Chronic lowering of PTH would then allow the sympathetic nervous system to normally stimulate thermogenesis and lipolysis. Validation of such a mechanism would be important to the management and prevention of European Journal of Clinical Nutrition

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obesity, as increases in vitamin D should complement increases in calcium, in suppressing PTH (Figure 1). The last 10 years has seen an abundance of data from cellular, animal and epidemiological studies that have addressed the potential role of calcium and vitamin D in body-weight regulation. Consequently some reviews and meta-analyses have appeared in the literature, as evidence has become available (Barr, 2003; Shapses et al., 2004; Trowman et al., 2006; Dougkas et al., 2011). One area not specifically covered so far is whether calcium and vitamin D, per se or in combination, accelerate weight and fat loss during caloric restriction. The outcome is important to both clinical practice and strategies for public health, and forms the mainstay of this review. studies and were not designed with body weight and composition as their primary endpoint (Davies et al., 2000; Zemel et al., 2000; Heaney, 2003; Teegarden, 2003; Drapeau et al., 2004; Loos et al., 2004). More recent analyses on a range of study designs by Shapses et al. (2004) and Trowman et al. (2006) conclude that there was no reason to expect a benefit of the nutrient on body weight. This is in contrast to the most recent meta-analysis by Dougkas et al. (2011) where a significant inverse relationship between calcium intake and BMI was obtained. The latter indicated that an 800-mg/d increase in calcium could reduce BMI by1.1 kg/m2. At a population level, such effects are not trivial (Heaney, 2003).

Methods
We reviewed the literature from year 2000 to date, which directly and/or indirectly assessed the relationship between calcium, vitamin D and different measures of body fatness. Two researchers (WCSP-D and MHG) independently searched the literature for English language articles from databases including PubMed, Google scholar, ProQuest, Science Direct, Highwire Press and Wiley interscience. Keywords used for searching the articles were calcium, vitamin D, vitamin D supplementation, PTH, body fat, body weight, fat-free mass, fat mass, adiposity, fat distribution, body fat regulation, body mass index (BMI), weight loss and body composition. One researcher (MJS) screened all the papers and explored additional publications from the reference lists of obtained articles. Our main analysis included randomized controlled trials (RCTs) for weight loss that had manipulated calcium or vitamin D intake either through the diet or through supplementation. Studies that increased these nutrients through increasing serves of dairy were excluded, as that area has been recently covered in detail (Dougkas et al., 2011). The resultant 15 RCTs on calcium with or without vitamin D and seven on vitamin D alone are briefly described in Tables 1 and 2.

Discussion
Human evidence linking calcium with body-weight regulation first appeared as retrospective analyses of studies on bone mineral and hypertension (Zemel et al., 2000; Barr, 2003; Teegarden, 2003; Weaver and Heaney, 2006). Although some studies listed in Barrs review showed no significant benefit of increased calcium intake, others observed that dietary calcium, regardless of the source, negatively predicted changes in weight and fat mass (Davies et al., 2000; Zemel et al., 2000; Teegarden, 2003). Further calcium accelerated weight reduction on a calorie-restricted diet and attenuated weight gain when added to a diet without calorie restriction (Teegarden and Zemel, 2003; Lappe et al., 2004). These were retrospective analyses of clinical and observational European Journal of Clinical Nutrition

Randomized controlled trials (RCTs) There is still some conjecture on whether calcium and vitamin D, alone or in combination, accelerate the effects of energy restriction on fat loss. In the studies in Table 1, the amount of caloric restriction varied between studies but was always a fixed kcal amount of each subjects baseline requirements. Except one (Cummings, 2006), all other trials had parallel designs comparing two to four arms (Table 1). Only three studies (Bowen et al., 2005; Cummings, 2006; Gilbert et al., 2011) used dairy-derived calcium while others used different formulations of a pharmaceutical preparation. The majority of studies were only on women. Further although all authors report the targeted kcals of energy restriction, it is not clear from the details provided by some, whether this was actually achieved on each arm of the trial. According to the hypothesis increasing calcium intake during weight loss should result in greater fat loss and an attenuation of the loss in fat-free mass. From the tabled 15 RCTs that met our criteria, only two showed an effect of the nutrient. The results of Zemel et al. (2004) were the only clear cut example of a benefit a greater fat loss of calcium over placebo. Major et al. (2009) in an re-analysis obtained a significant effect of calcium plus vitamin D on weight and fat loss, with a significant time treatment interaction (Major et al., 2007; Table 1). This indicated that the differences obtained increased over time in the treatment group. Riedt et al. (2007) investigated the effect of weight loss on bone metabolism and the protective effect of additional calcium. Their control group was on a weight maintenance diet and a 200-mg calcium supplement. Interestingly, they observed that during weight loss, higher calcium (B1800 mg/d) was better than moderate calcium (B1100 mg/d) in accelerating weight over time (time intervention interaction, Table 1). However, differences in fat mass though sizeable (B1.8 kg) did not achieve statistical significance. There could be many reasons for a lack of treatment effect with calcium. There was a large range in calcium intake on control (350701 mg/d) and treatment arms (8501908 mg/d). Amount of energy restriction varied between trials from 1500 to 4500 kJ/d (there were smaller within trials variations). Higher calcium intake and greater weight loss per se are independently associated with reduced fractional and total

Table 1 Randomized controlled trials (RCTs) for weight loss investigating the effects of calcium with and without vitamin D on body fatness
Results Significance and direction of loss in measures of body fatness BW WC or WHR FM or %FM FFM Comments

Authors

Study location

Study details

No treatment effect on weight and FM loss observed. Decrease in WC greater on HC (P 0.052).

No

Trend m No No

Yogurt given to both groups, experimental had additional calcium

Significant treatment effects for waist and WHR and trends for weight and BMI, favouring soy plus calcium and dairy over control diet. No significance for high calcium. Weight reductions in high milk, soy milk, calcium supplement and control groups were 4.431.93 kg, 3.461.28 kg, 3.892.40 and 2.871.55 kg, respectively. No No No

No

Baseline consumption of calcium o600 mg/day

Milk group had a small increase in appetite sensations than placebo group. Time treatment interactions for: (1) desire to eat P 0.03, and (2) hunger P 0.047. No treatment or treatment time interaction observed for weight loss, FM and FFM. Percentage of FM lost was lower in milk group (P 0.06). No differences in glucose, insulin, leptin, ghrelin and cortisol.

No

No

No

No

Trend for lower fat intake on treatment arm (P 0.06)

Calcium, vitamin D and fat loss MJ Soares et al

No significant differences of body weight, fat content, serum parathormone,25-(OH)-D3 concentration plasma total Ca and P concentration were observed between groups.

No

No

No

Ca with vitamin D supplementation showed no additional effect on weight loss

No between-group difference in weight loss and body composition. Addition of Ca resulted in lower hunger score and plasma resistin levels. Ca lead to preservation of FFM compared with placebo.

No

No

Yesk

Lactoval was prepared from milk and contained calcium as phosphate (70%), lactate (10%) and citrate (20%)

I Studies designed primarily for weight and body composition changes Cummings Perth, Study: single-blind crossover, comparing two (2006) Australia energy-restricted dairy diets: (1) high in dairy Ca (HC1200 mg/d) or low in Ca (LC600 mg/d). Subjects: 40 men and women, mean BMI 32.8 kg/m2, n 29 completers. Duration: 12 weeks on each arm with 12 week washout. Primary outcome: weight and fat loss, intention-to-treat analysis. Faghih et al. Iran Study: single-blind parallel, comparing four (2010) reduced calorie regimens (500 kcal/day): (1) control diet (500600 mg/day Ca), (2) Ca supplemented dietcontrol 800 mg/day Ca carbonate (3) milk diet (three serves of low-fat milk) and (4) soy milk diet (three serves of Ca-fortified soy milk). Subjects: 100 pre-menopausal women, mean BMI 30.86 kg/m2. Duration: 8 weeks. Primary outcome: Weight and fat loss Gilbert et al. Canada Study: parallel energy-restricted program (2011) (600 kcal/d) with either milk-based calcium supplement (1000 mg Ca/d) or isoenergetic placebo (rice based). Subjects: 41 women, low Ca consumers (p800 mg Ca/d), mean BMI at baseline 33.05 kg/m2. 25 completers at 6 months (Placebo n 12 and Milk n 13). Duration: 6 months. Primary outcome: subjective hunger/satiety, food intake, weight and fat loss. Holecki et al. Poland Study: subjects divided in two groups based (2008) on age and BMI. Group 1 was given Ca Carbonate and 1-(OH)-vitD supplement; and group 2 was provided with only a diet. Subject: 40 women, mean BMI 36.2 kg/m2. Duration: 3-month weight reduction. Primary outcome: evaluate influence of Ca and vitamin D supplementation on weight and fat loss. Kabrnova Czech Study: three arm parallel RCT emphasizing 2.5 Hlavata Republic MJ/d energy deficit and daily Ca intake of et al. (2008) 350 mg plus placebo, or Ca carbonate (500 mg/d) or dairy Ca (lactoval, 500 mg/d). One week run in for weight stability. Subject: 37 women, BMI 32.2 kg/m2. Duration: 3 weeks. Primary outcome: weight maintenance. Major et al. Canada Study: double-blind, placebo-controlled (2009) weight reducing programme; B2900 kJ/ d Ca and VitD supplementation (1200 mg/d elemental Ca and 10 mg/d VitD). Subject: sub analysis of very low consumers Group comparison showed no significant k in food intake with supplementation. Supplementation in very low-Ca consumers (p600 mg/d) resulted in: significant k in body weight and fat mass (P o0.01) Yesm Yesm Yesm No

Secondary analysis. No significant fat loss in either group despite caloric restriction

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Table 1 Continued
Results Significance and direction of loss in measures of body fatness BW WC or WHR FM or %FM FFM Comments

European Journal of Clinical Nutrition

significant k in spontaneous dietary lipid intake (Po0.05) ve correlation between fat mass and lipid intake Supplementation induced no significant m in fat-mass loss with whole-group comparison No No No No treatment effect on body weight. Body fat decreased in each group, with milk group showing the least changebut no between-group effects. No No

Authors

Study location

Study details

Major et al. (2007)

Canada

Wagner et al. (2007)

USA

Calcium, vitamin D and fat loss MJ Soares et al

Zemel et al. (2005) Greater weight loss, fat loss and trunk-fat loss in rank order, high dairy4high calcium4low calcium. Circulating leptin followed a similar pattern to body fat (Po0.01)

USA

Yesm

Yesm

Yesm

Zemel et al. (2009)

USA

(o600 mg/d Ca), mean BMI 30.95 kg/m2, n 7 for Ca and Vit D and n 6 for placebo. Duration: 15-week. Primary outcome: Body fat and food intake Study: same as above. Subject: 63 women, reported Ca intakeo800 mg/day, mean BMI 32 kg/m2. Duration: 15 weeks. Primary outcome: Lipoprotein and plasma lipid during weight loss. Study: 500-Kcal restriction diet containing B750 mg Ca/d with exercises three times/ week either (1) Ca lactate (B800 mg Ca/d), (2) Ca phosphate (B800 mg Ca/d), (3) low-fat milk (B800 mg Ca/d), or (4) placebo capsules. Subject: 58 subjects (Ca lactate, n 12; Ca phosphate, n ; milk, n 17 and placebo, n 13), mean BMI 33.2 kg/m2. Duration: 12 weeks. Primary outcome: body weight and composition and markers of bone turnover. Study: three arm parallel study of 500 kcal/d deficit diets 1 standard diet (400500 mg Ca/d placebo) 2 high-Ca diet (Standard diet 800 mg elemental Ca/d 12001300 mg Ca/d) 3 high-dairy diet (12001300 mg Ca/ d placebo). Subject: 32 obese subjects, mean BMI 34.9 kg/m2. Duration: 24 weeks. Primary outcome: body weight and fat loss. Study: four-site, three-arm parallel study of 500 kcal/d deficit diets 1 standard diet (500 mg Ca/d placebo) 2 high-Ca diet (standard diet 900 mg elemental Ca/d 1400 mg Ca/d) 3 high three serves of dairy diet (1400 mg Ca/d ). Subject: 106 overweight/obese subjects, only 68 adherent to protocol. Duration: 12 weeks. Primary outcome: body weight and fat loss. Greater weight, fat and trunk loss on high dairy versus low calcium, but only seen in adherers to intervention. No effect of high calcium. No No No

Outcomes were study sitespecific as seen by site treatment interactions. Issues with compliance reduced sample size, particularly in Ohio site.

II Studies with body composition changes as a secondary outcome Bowen et al. Adelaide, Study: parallelhigh dairy protein/high-Ca (2005) Australia (DP, 2400 mg Ca/d) versus high-mixed protein/moderate Ca (MP, 500 mg Ca/d). Subjects: 50 (30females and 20males) subjects, mean BMI 33.4 kg/m2. Duration: 12-week energy restriction and 4-weeks energy balance. Primary outcome: bone resorption during weight loss.

Weight loss during energy restriction was 10% but independent of diet. Similarly, total fat k by 21.81.3% but not different between diets. Lean body mass did not change in females after weight loss but a small reduction was seen in males (Po0.004); again independent of diet

No

No

No

Table 1
Results Significance and direction of loss in measures of body fatness BW WC or WHR Ca group had no overall weight regain FM or %FM FFM Comments

Continued

Authors

Study location

Study details

Jensen et al. (2001) Diet-induced weight loss is accompanied by bone loss. This can be reduced by supplementing with Ca. Mean weight loss at 1 month 3.3 and 3.1 kg for untreated group and Ca group, respectively. At 3-month weight loss 2.9 and 2.3 kg, respectively. At 6-month, untreated group regained 1.4 kg and Ca group had no overall weight change. No

Denmark

Riedt et al. (2007) Significant difference in weight loss between groups (Po0.0001), with high Ca resulting in greater weight loss. Similar effects for FM (P 0.015) and FFM (Po0.0001) were observed.

USA

Yesm

Calcium time interaction with high calcium showing greater weight loss than normal calcium during weight loss

Riedt et al. (2005)

USA

Women in both weight loss groups lost 9.33.9% of initial body weight. No significant difference in weight loss between groups observed. Similar trends were observed for FM and FFM.

No

No

No

Calcium, vitamin D and fat loss MJ Soares et al

Shapses et al. (2004)

USA

Study: low-caloric dietmeasurement performed after 1 and 3 months. 30 women received 1 g of elemental Ca daily. At 6 months, 24 women from each group were scanned using DXA. Subjects: 52 women, mean BMI 34.4 kg/m2. Duration: measurements at 1, 3 and 6 month. Primary outcome: bone resorption during weight loss. Study: assigned either normal (1 g/d, n 17) or high- (1.8 g/d, n 14) Ca intake during 6 months of energy restriction (12001500 kcal/d) or were recruited for weight maintenance at 1 g Ca/d intake (n 13). Ca was administered as Ca citrate. Subjects: 44 pre-menopausal women, mean BMI 27.7 kg/m2. Duration: 6 months. Primary Outcome: assess bone loss during weight loss at recommended or higher than recommended calcium intakes in premenopausal women. Study: assigned either normal (1g/d calcium citrate, n 24) or high- (1.8g/d calcium citrate, n 23) Ca intake during 6 months of energy restriction or were recruited for weight maintenance at 1 g Ca/d intake (n 19). Subjects: 66 postmenopausal women, BMI 27.0 kg/m2. Duration: 6 months. Primary Outcome: bone metabolism in obesity. Study: compilation of three parallel, double blind, RCTs of 1000 mg elemental Ca versus placebo. Subjects: 165 obese post- and premenopausal women, mean BMI 33.55 kg/m2. Duration: 25-week. Primary outcome: bone metabolism. No significant differences in body weight or fat change. Magnitude and direction of differences for group means are consistent with hypothesized small effect. No No

Abbreviations: BW, body weight; Ca, calcium; FFQ, food frequency questionnaire; FM, fat mass as % or kg; FFM, fat-free mass; HC, High dairy calcium; Vit D, vitamin D; WC, waist circumference; WHR, waist-hip ratio.

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Table 2 Randomized controlled trials on the influence of vitamin D on measures of body fatness
Outcomes Significance and direction of loss in measures of body fatness BW BMI WC or WHR FM or %FM FFM Comments

European Journal of Clinical Nutrition

kPTH and m 25(OH) D in both groups receiving D3; serum calcium unchanged. No No No No Large sample, long duration, good retention. Could calcium mask vitamin D effects? Lack of 4th arm with placebo for both. Vitamin D increased significantly more in supplemented group. No No No No

Authors and year Study location

Study details

I Studies designed primarily for weight and body composition changes Sneve et al. Troms, Study: three arms, parallel, double blind. (2008) Norway 20 000 IU D3 twice a week, or 20 000 IU once a week plus placebo or placebo twice a week. 500 mg calcium to all. Subjects: 445overweight, and obese men and women. Duration: 12 months. Primary outcome: anthropometry and body composition. Zittermann Leipzig, Study: double blind, parallel, either vitamin D3 et al. (2009) Germany (83 mg/d) or placebo during caloric restriction. Subjects: 200 subjects, BMI427 kg/m2 and 25OHDo30 nmol/l. Duration: 12 months. Primary outcome: weight and fat loss.

Calcium, vitamin D and fat loss MJ Soares et al

II Studies with body composition Jorde & Troms Figenschau Norway (2009) Significant reciprocal changes in 25(OH)D and PTH in the D3 group compared with placebo. No No

? Inadequate power, despite high dose of vitamin D. Body fatness was not primary outcome.

Nagpal et al. (2009)

No significant change in BW, BMI, WC, WHR between and within groups.

No

No

No

Anthropometric measures. 25(OH)D increased but below 75 nmol/l. Short duration.

Ortega et al. (2008)

Those with 25 (OH)D450 nmol/l showed greater body-fat loss and increase in FFM irrespective of diet allocation. Tertiles of change in serum 25(OH)D significantly associated with greater 24-months weight loss.

No

No

Yesm

Yesk

Short duration, secondary analysis.

Shahar et al. (2010)

Yesm

Lack of other measures of body fatness. Long-term, one-phase trial, high retention rate.

von Hurst et al. (2010)

as a secondary outcome Study: parallel, single blind, 40 000 IU D3 per week versus placebo. Subjects: 36 subjects with T2DM. Duration: 6 months. Primary outcome: glucose metabolism and changes in HbA1c. New Delhi, Study: parallel, double blind. India Subjects: 100 apparently healthy men, with central obesity, received three doses of vitamin D3 (120 000 IU per fortnight) or placebo. Duration: 6 weeks. Primary outcome: insulin sensitivity from a variety of measures. Madrid, Study: parallel, assigned to either of two Spain hypocaloric diets. Subjects: 60 women, 2035 years. Duration: 2 weeks. Primary outcome: body weight and composition. Leipzig, Study: parallel, Germany Subjects: 126 men and women, BMI427 kg/m2 or presence of T2DM or CHD formed a subset of a larger study. Duration: 2 years. Primary outcome: secondary analysis of body weight. Study: parallel, double blind, 100 mg/d Auckland, (4000 IU) D3 or placebo. New Subjects: 106 South Asian women, with D3 Zealand deficiency and insulin resistance. Duration: 6 months. Primary outcome: insulin resistance. 26% of intervention group achieved vitamin D480 nmol/l no relationship between change in vitamin D concentration and BMI. No

Body fatness was secondary outcome.

Abbreviations: BMI, body mass index; BW, body weight; D3, cholecalciferol; FM, fat mass in kg or % of weight; FFM, fat-free mass; T2DM, type 2 diabetes; WC, waist circumference; WHR, waist-hip ratio; Yes, significant effect; m or k, increase or decrease.

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calcium absorption (Cifuentes et al., 2004). This would reduce the metabolic effects of calcium on the treatment arm and contribute to between-trial differences. However, they would be offset by gastrointestinal tract mechanisms of calcium that promote energy loss through increased fat excretion (Figure 1). Threshold effects for both the processes can be expected but such data are not available as yet, so it is difficult to predict the net effect. Zemel et al. (2009) have argued that selection of subjects with habitually low calcium intakes (usually o600 mg/d) is important, as they are most likely to benefit from the extra calcium. Other authors suggest a range of 600800 mg/d above which effects of calcium may be anticipated (Major et al., 2009; Dougkas et al., 2011). All studies in Table 1 met the latter requirement, yet the majority did not detect differences in weight and fat loss. Monitoring compliance and determining adherers to the weight-loss program, is also crucial to the outcome measured. On the basis of these prerequisites, a re-analysis by Major et al. (2009) confirmed the beneficial effect of calcium plus vitamin D. Zemel et al. (2009), however, could only document the significant effects of increasing dairy intake over a control arm, but not the additional benefit of supplemental calcium; a facet they had observed earlier (Zemel et al., 2004). Potential effects of vitamin D through differences in intake between trial diets (supplemental or dietary) and through seasonal effects may also need to be considered, especially in those interventions of a long duration. Such information was lacking in many of the reported data. During sustained negative energy balance, the bodys switches its metabolism to counter the ensuing change in body weight. Calcium and vitamin D have many biological effects and in a situation such as weight loss, nutrient requirements will be directed towards vital functions at the expense of others. It is conceivable that the putative effects of calcium/vitamin D in a period of metabolic adaptation may then be masked, or too small to be detected. A quick tally of the direction and magnitude of differences suggests this to be true. In three trials, fat loss was marginally greater on the treatment arm by 0.21 to 0.6 kg (Major et al., 2007; -Hlavata et al., 2008; Faghih et al., 2010), and in Kabrnova four studies treatment was marginally lower than control by 0.13 to 0.7 kg (Riedt et al., 2005; Cummings, 2006; -Hlavata et al., 2008; Zemel et al., 2009), with two Kabrnova trials reported in Shapses et al. (2004) and those of Bowen et al. (2005) showing no net change. Another issue is the power to detect differences when they do exist. Zemel et al. (2004) detected a difference of B1.8 kg in fat mass, whereas Major et al. (2009) found a difference of B3.5 kg to be significant. This was in contrast to trials in pre-menopausal women where a B2.2 kg difference in fat loss (Shapses et al., 2004) and B1.8 kg in fat loss (Riedt et al., 2007) could not be detected; both in the direction of the hypothesis. Clearly, there is a need for consensus on subject characteristics and study execution/compliance, and the necessary statistical power if future trials are to advance this area.

Evidence for vitamin D in obesity

Cross-sectional studies It is currently unclear to what extent poor vitamin D status is a consequence of obesity or is somehow, involved in its aetiology (Florez et al., 2007). Between 2000 and 2011 there have been over 15 cross-sectional studies that have assessed the relationship between vitamin D status and different measures of body fatness. Most of these studies have confirmed an inverse association between vitamin D and total body fat and regional (subcutaneous and visceral) adipose tissue, whether measured directly or from anthropometry (Arunabh et al., 2003; Kamycheva et al., 2003; Parikh et al., 2004; Snijder et al., 2005; Aasheim et al., 2008; Cheng et al., 2009; Kremer et al., 2009; Lenders et al., 2009; Moan et al., 2009; Moschonis et al., 2009; Freedman et al., 2010; Frost et al., 2010; Soares et al., Unpublished). Other cross-sectional studies suggest that individuals with higher PTH have higher body weight and/or BMI (Parikh et al., 2004; Bolland et al., 2005; Snijder et al., 2005; Alemzadeh et al., 2008; Lenders et al., 2009; Frost et al., 2010). One explanation is that the fat-soluble vitamin is sequestered in the expanded mass of adipose tissue, resulting in an apparently lower level (Wortsman et al., 2000). It is also possible that the overweight or obese are less likely to venture outdoors to engage in activity, and so their exposure to sunlight is low (Harris and Dawson-Hughes, 2007). If vitamin D is to have a causal role, then changes in vitamin status should be related to changes in weight status. This is not always seen after planned weight-loss interventions (Zittermann et al., 2009).

RCTs It was therefore important to examine whether vitamin D supplementation during weight loss improved weight and fat change. We found only two studies that directly assessed the effects of supplementation with vitamin D3 on some measure of adiposity (Table 2). Sneve et al. (2008) and Zittermann et al. (2009) could not find any effect of supplementation with vitamin D3 on changes in body weight, waist-hip ratio or percent fat mass. Both studies were of a long duration (1 year) and achieved a 25(OH)D3 status 485 nmol/l.

Secondary studies There were more than 15 studies carried out to explore the effects of vitamin D supplementation on endpoints like insulin resistance, glucose metabolism and endothelial function. The majority of these studies assessed body fatness, but neither report differences in the outcome nor provide raw data of adiposity measures. We briefly describe those four papers having adequate data in Table 2. In a recent study, supplementation with vitamin D led to significant improvement in insulin resistance over 6 months, but there European Journal of Clinical Nutrition

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was no effect on body weight (von Hurst et al., 2010). Nagpal et al. (2009) explored the short-term effects of mega doses of vitamin D on insulin sensitivity but did not observe changes in body fatness. Consistent with these studies, Jorde and Figenschau (2009) did not report any impact of supplementation on BMI or waist-hip ratio. Finally, Kim et al. (2006) administered vitamin D (2 mg intravenously) twice a week over 15 weeks and examined cardiac endpoints. No change in body weight or BMI was reported. interpretation are far from easy. We have highlighted some issues in this area that need to be considered in future research.

Conflict of interest
The authors declare no conflict of interest.

Indirect evidence We found three studies that reported the impact of prevailing serum 25(OH)D on subsequent weight change. In the RCTs by Ortega et al. (2008) higher vitamin D at baseline (450 nmol/l; mean value: 85.944.4) resulted in greater fat loss and preservation of lean tissue over 2 weeks. This was partially supported by a long-term RCT where higher vitamin D at 6 months (median for tertiles 14.5, 21.2 and 30.2 ng/ml) predicted greater weight loss at 2 years (Shahar et al., 2010). However, no other measure of fatness was reported in that study (Table 2). In contrast, the observational study of Forouhi et al. (2008) did not find any association between prevailing vitamin D status and waist circumference over a 4.5- or 10-year period. Overall there is good evidence for an inverse relationship between vitamin D and obesity; however, evidence for causality from RCTs is meagre.

Acknowledgements
MJS acknowledges Dairy Australia and Diabetes Australia for grants in the area of calcium, dairy and energy balance. No prior permission was necessary from these organizations before submission of this manuscript.

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Limitations There are relatively few RCTs that have been primarily designed to uncover the potential of calcium or vitamin D alone, or in combination, to influence body fatness and its distribution during weight loss. There are many studies on bone density/dynamics during weight loss, where body composition was monitored. It remains to be determined whether primary versus secondary data contribute to systematic differences in trial outcomes. The evidence base currently available for the effect of vitamin D per se, is meagre. Future studies also need to address dose-response trials of sufficient duration, to examine whether threshold effects exist.

Conclusions
Currently available RCTs do not consistently provide evidence for an augmentation of weight or body-fat loss following calcium plus vitamin D. In part this may relate to the model of weight loss per se, as well as the statistical power to detect differences when they do exist. There are very limited RCTs data on vitamin D alone to enable any conclusion, however, crosssectional studies consistently link low vitamin D to greater obesity. RCTs are accepted as the highest level of evidence for cause and effect relationships, but their execution and European Journal of Clinical Nutrition

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