Calcium and Vitamin D: Current Evidence for Benefit and Harm 2014 David A Hanley, MD, FRCPC Professor, Depts. of Medicine, Community Health Sciences, and Oncology University of Calgary
Disclosures (None are relevant to this presentation) Advisory Boards: Novartis Canada, Warner Chilcott, Eli Lilly Canada, Merck Canada, Amgen Canada Clinical Trials: Amgen, Eli Lilly, Merck, Novartis, NPS Pharmaceuticals I have received honoraria for speaking from most of the above companies Grant Support: CIHR, Pure North S Energy Foundation
Outline Calcium Supplements controversy Basics of vitamin D Recent media interest papers Evidence from Canadian Multicentre Osteoporosis Study (CaMOS) and Canadian Health Measures Survey Current recommendations for vitamin D and calcium intake and targets
Bone is Sacrificed to Correct Calcium Deficiency But How Much Calcium is Needed? Total intake requirements of around 1000 mg/d based on early calcium balance studies that will never be repeated. For many years the standard recommendation was 1000-1500 mg/d (as supplement) often prescribed while ignoring dietary intake IOM recommendation 1000-1200 mg/d European recommendations lower (700-800 mg/d) Simple dietary history: Diet without dairy ~ 400 mg/d; cup of milk = 300 mg Few patients need more than 5-600 mg supplement/d
Observational Studies Low calcium intake (<400-700mg/d) may contribute to an increased risk of fracture Most studies fail to demonstrate incremental benefit of calcium intake >700-800mg/d in fracture prevention Use of calcium supplements may be associated with increased risk of hip fracture Looker AC, et al. Osteoporosis Int 1993; 3:177-184. Warensjo E, et al. BMJ 2011; 342:d1473. Key TJ, et al. Public Health Nutrition 2007; 10:1314-1320. Cumming RG et al. Am J Epidemiol 1997; 145:928-934.
Calcium and Fractures: Controlled Studies Most studies compared Ca + vitamin D to placebo Conflicting results Chapuy (1992): Ca/D significantly reduced hip # by 43% in institutionalized patients WHI (2006): Ca/D did not significantly reduce # risk, but many patients taking personal supplements Reid (2006): Ca alone increased risk of hip # Chapuy MC, et al. NEJM 1992; 327:1637-1642. Jackson RD, et al. NEJM 2006; 354:669-683. Cauley JA, et al. J Womens Health 2013; 22:915-929. Reid et al. Am J Med 2006; 119:777-785.
Are Calcium Supplements Dangerous?
Calcium Supplements and Increased Risk of CVD: Auckland Calcium Study Bolland MJ, et al. BMJ 2008; 336:262.
Bolland (2011) Calcium and CVD Ca supps with or without vitamin D Bolland MJ, et al. BMJ 2011; 342:d2040.
Studies Reporting No CV Risk Iowa Women s Health Study Supplemental Ca (1300-1700mg/d) associated with a decreased risk of IHD death RR = 0.50 (0.28-0.88) Health Professionals Follow-up Study Prospective cohort study of men No significant associations between dietary or supplemental Ca and ischemic heart disease CaMOS: Calcium (any source) protective for women WHI (allowed subjects to take 1000 mg calcium/day, in addition to the trial s treatment package) Bostick RM, et al. Am J Epidemiol 1999;149:151-161. Al-Delaimy WK, et al. Am J Clin Nutr 2003; 77:814-818 Langsetmo L, et al. JCEM 2013; 98:3010-3018. LaCroix, et al. J Gerentology 2009; 64A:559-567.
Wang et al: Meta-analysis 4 prospective cohort studies of Ca supplements: no effect on CVD incidence 8 RCTs: CaD or Ca alone: no effect on CVD incidence Wang L et al. Ann Intern Med 2010; 152:315-323.
Calcium and Cardiovascular DIsease Remains an unanswered question Recommend D. Bauer s recent reviews: Clinical practice. Calcium supplements and fracture prevention. N Engl J Med. 2013;369(16): 1537-43. The calcium supplement controversy: Now what?. J Bone Miner Res 2014; 29:531-33.
Vitamin D 3 Metabolism Acetate CH 3 COO - Skin Vitamin D 2 (ergocalciferol) follows the same pathway - Potency equivalent to D 3? HO Cholesterol HO CH 3 CH 3 CH 3 CH 3 H CH 3 UV irradiation 7-Dehydrocholesterol HO CH 3 CH 3 CH 2 CH 3 OH OH CH 3 24,25-(OH) 2 D 3 Ingested D3 Cholecalciferol CH 3 CH 3 CH 3 CH 2 H CH 3 Liver 25-Hydroxylase HO HO D 3 25-(OH)D 3 25-Hydroxylase = CYP2R1 24-Hydroxylase = CYP24A1 CH 3 CH 3 CH 3 CH 2 OH CH 3 Kidney 24-Hydroxylase 1-Hydroxylase PTH FGF-23 PO 4 Ca HO CH 3 CH CH 3 3 OH CH 3 1-alpha Hydroxylase = CYP27B1 CH 2 OH 1,25(OH) 2 D 3 1,25-(OH) 2 D 3 Adapted from DeLuca HF. Monographs on Endocrinology 13, Vitamin D: Metabolism and Function
Photobiology of Vitamin D Skin HO CH 3 H Lumisterol CH 3 CH 3 Heat CH 2 HO 7-Dehydrocholesterol HO Pre D 3 HO D 3 CH 3 CH 2 In presence of UV B 7-Dehydrocholesterol is converted to Pre-Vitamin D 3, which undergoes heat-dependent isomerization to Vitamin D 3 If UV exposure continues, Pre- D 3 is preferentially converted to lumisterol and tachysterol, which can revert back to Pre- D 3 when it is dark, but then there is not enough heat to convert Pre- D 3 to D 3 HO Adapted from Bikle D 2004: Endotext.com
WHAT S AN OPTIMAL VITAMIN D LEVEL?
25OHD Levels in Traditionally Living Adults in Equatorial Africa (Hunter-Gatherers) Two groups living in Tanzania, within 3-4 o of the equator: - Nilotic Maasai (semi-nomadic) - Hadzabe (hunter-gatherers) Avoid direct sun mid-day Clothing: upper body, upper legs Outside most of the day 25-OHD measured by LC/MS-MS: Mean = 115 nmol/l, range 58-171 Maasai: 119 nmol/l +/- 26 (SD) Hadzabe: 109 nmol/l +/- 28 Luxwolda MF et al. Brit J Nutr 2012; 108: 1557 1561
Seasonal Change in Vitamin D 30 Male Outdoor Workers Nebraska 225 200 175 Median 25(OH)D (inter-quartile range) 25(OH)D (nmol/l) 150 125 100 75 50 25 0 * Late summer Late winter Late summer 122 (95-154) Late winter 74 (60-94) Seasonal difference 49 (29-67) Unanswered Question: Is the seasonal fluctuation in vitamin D adequacy bad for bone or other health outcomes? * Sunscreen user Barger-Lux & Heaney JCEM 2002; 87:4952-56
If Equatorial Humans and Outdoor Workers Have Average 25OHD Levels of 115 nmol/l What does this mean for us, living in the Frozen North? Probably not much more than an indication that these are safe levels, in that our skin synthesis of vitamin D is regulated Many are of the opinion that this should be a target level for optimal vitamin D effects, but this remains controversial
Non-Skeletal Roles for Vitamin D?
Note the Crucial Role of 25-OH Vitamin D Substrate for Production of 1,25(OH) 2 Vitamin D Liver Paracrine/Autocrine System D 3 25(OH)D 3 Endocrine System Kidney Many Tissues: Immune System Breast, Colon, Prostate, Parathyroid, etc 1,25(OH) 2 D 3 plasma/circulation Gut Calcium absorption Muscle health Bone health 1,25(OH) 2 D 3 intracellular and local Holick MF. J Cell Biochem 2003; 88:296-307
Basic Role for 1,25(OH) 2 -Vitamin D Classical, physiological role of 1,25(OH) 2 D 3 is the regulation of calcium and phosphate homeostasis and bone mineralization Transcriptome-wide analysis indicates that between 200 and 600 genes are primary targets of vitamin D Since most of these genes respond to vitamin D in a cell-specific fashion, the total number of vitamin D targets in the human genome is far higher than 1,000. Carlberg C et al. Primary vitamin D target genes allow a categorization of possible benefits of vitamin D₃ supplementation. PLoS One. 2013 Jul 29;8(7):e71042.
Skeletal and Non-Skeletal Consequences of Vitamin D Deficiency Population studies reasonably consistent: Vitamin D deficiency (25-OHD levels < 50-75 nmol/l) associated with bad outcomes Any benefit (or harm) in aiming for higher levels? IOM report chose 125 nmol/l as upper level for safety - a level commonly achieved with summer sunlight exposure
Adjusted Hazard Ratio for MACS (Mortality and Acute Coronary Syndromes) by Serum Calcidiol Israeli Health Services plan 25OHD in 422,822 subjects (aged>45) 16,213 had MACS events within 54 months 12 280 died (905 with ACS); 3933 had ACS 125 nmol/l Vitamin D skeptics call this a U-shaped curve ; Enthusiasts call it an L- or J-shaped curve 2013 by Endocrine Society Dror Y et al. JCEM 2013;98:2160-2167
25-OHD and Mortality Risk For a 75 Year Old Man Median Johansseon H, et al. Low serum vitamin D is associated with increased mortality in elderly men: MrOS Sweden. Osteoporos Int 2012; 23: 991-99. epub 19 October 2011
Recent Controversies/Papers
Clinical Trial Calcium 1200 mg daily vs 4000 IU vit D vs Both vs Placebo: PTH and Bone Turnover Markers Aloia JF et al. Calcium and Vitamin D Supplementation in Postmenopausal Women. JCEM 2013; 98: E1702-09
Clinical Trial: 1200 mg Calcium vs 4000 IU Vit D vs Both vs Placebo Effect on PTH and Bone Turnover Markers Baseline 15 weeks 28 weeks Vitamin D alone: No effect on bone turnover markers Calcium loading suppressed PTH and bone turnover markers Aloia JF et al. Calcium and Vitamin D Supplementation in Postmenopausal Women. JCEM 2013; 98: E1702-09
Aloia Study: Conclusions in Lay Press Vitamin D has no effect on bone. Before taking vitamin D, you should consult with your doctor - more than 800 IU/day is dangerous (Mansbridge on The National ) Problems with Aloia study: Vitamin D suppresses PTH gene expression, effect on PTH levels occurs gradually If vitamin D has any direct effects on bone, they are complex, and mediated through the osteoblast, probably not via PTH suppression and reduced bone turnover
Reid Meta-analysis Vitamin D and BMD Large number of studies and subjects, wide range of ages, doses, calcium use and other variables No clear benefit of vitamin D on BMD Explanation: Vit D does not have a direct effect on bone bone density benefit (if present at all) is probably through effect on calcium absorption and provision of adequate mineral to bone matrix Authors Conclusion: Vitamin D supplement recommendations for general population to enhance BMD not warranted Vitamin D recommendations for bone health should be targeted to high risk populations Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2014; Published Online January 24.
Bolland: Trial Sequential Meta-analysis: Vit D Effect on Skeletal and Non-Skeletal Events Research Question: Can previous clinical trials predict whether future RCTs will be able to show an effect of vitamin D? Only Hip Fracture trials exceeded 15% futility boundary (only in trials with institutionalized individuals) Vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Uncertain whether vitamin D reduces risk of death Basic Conclusion: Future trials with similar designs unlikely to alter these conclusions advised funding agencies to consider the low likelihood of value in funding studies of vitamin D. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet. 2014; 383: 146-55.
Vitamin D and Cancer, CV Disease: The VITAL Trial 5-year randomized placebo-control trial Omega-3 FAs and Vit D in healthy men 60, women 65 yrs Has recruited >20,000 subjects Treatment Groups: Vitamin D 2000 IU + Fish Oil: 840 mg Omega-3 [465 EPA & 375 DHA] Vit D + Placebo Fish Oil Placebo Vit D + Fish Oil Placebo Vit D + Placebo Fish Oil Potential Problem: All subjects will be allowed to take up to 800 IU Vitamin D supplement/day
Recent Umbrella Systematic Review of Meta-analyses and Systematic Reviews Conclusion: Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable. Theodoratou E, et al. BMJ 2014;348:g2035
Time for a Moratorium on Vitamin D Meta-Analyses MJ Bolland, A Grey, IR Reid Letter to editor, BMJ 2009; 339: b4394 Response to a Meta-analysis by Bischoff-Ferrari et al, finding vitamin D prevents falls in the elderly The ratio of the number of RCTs to meta-analyses for vitamin D and falls is 17:9 The RCT to meta-analyses ratio for vitamin D and fractures is 22:14 We suggest that no further meta-analyses are conducted on vitamin D and falls or fractures until more adequately powered RCTs are performed. With due respect to the New Zealand group, I think they should have taken their own advice
Problems with Clinical Studies of Vitamin D Supplementation Opinion: Main Problem: RCTs poorly designed: optimal dose not identified, wide variability in vitamin D status at entry Evidence Based Medicine has failed vitamin D inadequate data meta-analyzed to death almost as many meta-analyses as RCTs garbage in garbage out readers of the meta-analyses often conclude that absence of evidence = evidence of absence, thereby discouraging proper studies It s easier to fund Cochrane reviews than proper RCTs
Vitamin D and Bone Clinical Trials and Meta-Analyses Problem: For bone studies, should we separate vitamin D and calcium effects? Beneficial effect of D must be related to mineral absorption early RCTs combine Ca and D: fracture prevention Modest BMD benefit Later trials suffer from poor design, poor adherence Meta-analyses even less convincing To paraphrase the great 20 th Century Philosopher, Tom Lehrer s comment on life: Meta-analysis is like a sewer. What you get out of it depends on what you put into it
Key Points in Assessing Clinical Studies of Vitamin D Supplementation Opinion: Vitamin D is a facilitator in many biological systems an essential component at a threshold level, but pushing levels higher may not have any effect we haven t defined optimal level adequately Vitamin D RCTs not the same as a clinical trial of a drug: e.g. we re not correcting a bisphosphonate deficiency in osteoporosis therapy clinical trials Demonstrating positive effect in a clinical trial requires a D-deficient subject population (e.g. 1992 Chapuy study) But RCTs have not specifically recruited a vitamin D-deficient population Remember: RCTs of OP drugs use Ca + D as a placebo comparator we shouldn t expect huge benefits, except in D-deficiency So maybe Bolland is right re. more clinical trials
Vitamin D and Osteoporosis Vitamin D Insufficiency Hypothesis: Vit D Insufficiency causes increased risk of osteoporotic fractures due to: malabsorption of calcium and phosphate and relative deficiency of mineral for bone maintenance secondary hyperparathyroidism increases bone turnover resulting in net bone loss Vitamin D insufficiency? Defined by serum 25-OH vitamin D and relationship to PTH Weak, mainly observational evidence supporting its role in predicting osteoporotic fracture risk
Vitamin D from Diet and Supplements 2011 Institute of Medicine Report Recommended Dietary Allowance (RDA) Vitamin D 2011 US and Canada: IOM Report 1 : 600 IU/d for adults up to age 70 800 IU/d for adults over age 70 No change in requirements for Pregnancy and Lactation Tolerable Upper Intake Level (TUL) = 4000 IU/d RDA = 2 standard deviations above Estimated Average Requirement (EAR) EAR = Average daily intake that meets the nutrient needs of half of the healthy individuals in the age or gender group in question TUL = maximum chronic daily intake judged likely to pose no risk of adverse health effects to the most sensitive members of the healthy population 1. Institute of Medicine 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington DC, National Academies Press.
Scientific Advisory Council 2010 Guidelines Osteoporosis Canada Adults under age 50 years: 400-1000 IU/day (10-25µg) Adults 50 years: 800-2000 IU/day (20-50 µg) Hanley DA, Cranney A, Jones G, Whiting S, Leslie WD, Cole DEC, Atkinson SA, Josse RG, Feldman S, Kline GA, Rosen C, for the Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada. Vitamin D in Adult Health and Disease: A Review and Guideline Statement from Osteoporosis Canada. CMAJ. 2010; 182: E610-8. (Epub 2010 July 12). s
Vitamin D Guidelines: Adequate Vitamin D as Reflected by Serum 25OHD Institute of Medicine: RDA (by definition) should be adequate for bone health for 97.5% of healthy Canadians, and this should be achieved at a serum 25OHD of 50 nmol/l. Endocrine Society, Osteoporosis Canada recommend a target of 75 nmol/l, based on some clinical trials showing fracture benefit at levels higher than 50, and the relationship of 25OHD to serum PTH suppression plateaus around 75-80 nmol/l (higher in CaMOS)
Canadian Health Measures Survey (CHMS) Cycle 1: 2007-09; Cycle 2: 2009-11 CHMS samples collected 2007-9. representative cross-country sample of Canadians aged 6 to 79 years analysis of 5604 samples mean serum 25OHD 64 nmol/l (combined CHMS) highest levels = children aged 3 to 5 (74.0 nmol/l) next highest = age 60 to 79 (70.0 nmol/l) 25.7% below 50 nmol/l (20% in CaMOS) 5.4% < 30 nmol/l (frank deficiency) Whiting SJ et al. The vitamin D status of Canadians relative to the 2011 Dietary Reference Intakes: an examination in children and adults with and without supplement use. Am J Clin Nutr 2011; 94:128-135 Statistics Canada Catalogue no. 82-624-X: Vitamin D Blood Levels of Canadians
If 20-25% of Canadians have 25OHD levels below 50 nmol/l, the use of supplements seems justifiable. Unanswered Question: Is the seasonal fluctuation in vitamin D adequacy bad for bone or other health outcomes?
Problems with Reliance on 25OHD Levels Access to the assay Issues with available assay systems: role of Vitamin D-Binding Protein do we need to calculate a free 25OHD?? detection of vitamin D2 How good is the assay in your neighbourhood?
Variability in Reported 25-OHD Results Binkley N, Wiebe D. Clinical Controversies in Vitamin D: 25(OH)D Measurement J Clin Densitom 2013; 16: 402-408
Variability in Reported 25-OHD Results Binkley s main point: Because of the variability in 25OHD assays, if you re treating a person and want to assure the patient is above the desired threshold level, you need to aim higher. - No evidence of harm of supplement use to achieve these levels comparable to normal UV light exposure response Binkley N, Wiebe D. Clinical Controversies in Vitamin D: 25(OH)D Measurement J Clin Densitom 2013; 16: 402-408
Recommendations re. Vitamin D Dosing and Monitoring in Osteoporosis Most Canadian clinical laboratories have set the lower optimal serum 25-OH-vitamin D level at 75-80 nmol/l IOM 2011 Report supports 50 nmol/l (Healthy Population) To achieve either optimal level, Canadians need to take vitamin D supplements (CaMOS, CHMS) patients over the age of 50 probably need doses closer to 2000 IU/day) for adults under 50: 400-1000 IU/day Only moderate evidence for 800-2000 IU/day for prevention of fractures and falls BUT: No evidence of harm
My Opinion: What Is Optimal Vitamin D Intake? Maintain serum 25-OH vitamin D levels at 75 nmol/l (Osteoporosis Canada 2010 Guidelines) Evidence for Benefit*: fair; Evidence for Risk: none; Cost: minimal * Bones and Falls: systematic reviews show clear benefit for institutionalized elderly CaMOS and CHMS indicate 25% of Canadians below 50 nmol/l in winter supplements are necessary to attain optimum levels Dose of vitamin D to consistently achieve this is probably more than 800 IU vitamin D per day 800-2000 IU/d (Osteoporosis Canada) seems reasonable and safe Elderly may need total intake of 3200 IU/day (food, sunlight and supplements) to consistently achieve this (J Am Geriatr Soc 62:147 152, 2014)
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Calcium and Vitamin D: Differences in Regulation of PTH Secretion Calcium High ECF Ca suppresses secretion of intact PTH and increases secretion of inactive PTH fragments Low Ca increases release of intact active PTH and reduces PTH catabolism Long term hypocalcemia: PT hyperplasia, slow increase in PTH Gene expression Long term hypercalcemia: suppression of PTH gene expression,? involution of PT glad tissue Vitamin D (calcitriol) no direct (acute) effect on PTH secretion suppresses PTH gene expression and may increase apoptosis/ autophagy (?involution of PT hyperplasia) Vitamin D deficiency causes hyperplasia (larger adenomata) PT cells express 1-α hydroxylase, 24-hydroxylase and VDR: Can synthesize and degrade calcitriol. Therefore, high doses of vitamin D can gradually suppress PTH synthesis
Calcium and Vitamin D: Differences in Skeletal Effect of Deficiency Calcium Deficiency increases PTH secretion, resulting in increased bone turnover increased turnover means increased bone loss in adult humans severe Ca deficiency has been associated with mineralization defect in children high dose calcium can partially heal Type II Vitamin D-Dependent Rickets/ osteomalacia (VDR mutations) Vitamin D Deficiency causes reduced intestinal Ca and PO 4 absorption secondary HPT may be mediated through effects on Ca absorption Decreased Ca and PO 4 means poor bone matrix mineralization (osteomalacia) and inadequate mineralization around growth plate in children means rickets: deformities and short stature role of vitamin D in human bone physiology less clear, but effects not just via Ca and PO 4 absorption. Bone cell regulation D-dependent protein synthesis (e.g. osteocalcin)