Vitamin D and Osteoporosis

Vitamin D and Osteoporosis Iris Thiele Isip Tan MD, FPCP, FPSEM Clinical Associate Professor, UP College of Medicine Section of Endocrinology, Diabetes & Metabolism Department of Medicine, Philippine General Hospital

Disclosure Merck Sharp & Dohme (MSD) Honoraria as RTD speaker Travel grant for regional endocrine meeting

How much vitamin D is enough?

How much vitamin D is enough? Should vitamin D levels be measured?

How much vitamin D is enough? Should vitamin D Does supplemental levels be measured? vitamin D reduce fractures and falls?

How much vitamin D is enough?

Vitamin D and Bone Metabolism Balanced System Low Levels of Vitamin D Calcium absorption meets metabolic demands Calcium reservoir of bone is depleted to Normal bone mineralization is maintained correct for low calcium absorption in gut Dietary calcium 4 Mobilization of calcium Gut from bone 1 Vitamin D Circulation Vitamin D PTH 3 In vitamin D- 2 Calcium PTH deficient state, Parathyroid reabsorption calcium absorption Renal distal decreases Low calcium causes tubule increase in PTH secretion Adapted from Holick M. Curr Opin Endocrinol Diabetes. 2002;9:87–98; DeLuca HF. Am J Clin Nutr. 2004;80(suppl 1):1689S–1696S; Lips P. Endocr Rev. 2001;22:477–501; Holick MF. J Nutr. 2005;135:2739S–2748S.

isolated groups of individuals with discrete diseases (11–15). much vitam Individuals who would otherwise be considered healthy typi- indeed, vita Calcium Absorption: Threshold Effect nutrients be because pe need at all Quantita these recom optimal lev vitamin D sources acc total, the re result in a s Vitamin D Much wo metabolic utilization synthesis o 4,000 IU/day D economy supplemen 32 ng/dL 25(OH)D co viously (18 each 100 IU an elevation nmol/L). T Figure 3. Relationship of calcium absorption fraction to vitamin serum Clin J Am Soc (9). nmol/L) w D nutritional status [as measured by Heaney R. 25(OH)D] Nephrol 2008;3:1535-41 or her serum

Chief Dietary Sources of Vitamin D Vitamin D-fortiﬁed milk (400 IU/quart) Cereals (40-50 IU/serving) Egg yolks Saltwater ﬁsh Liver Clinician’s Guide to the Prevention & Treatment of Osteoporosis National Osteoporosis Foundation, 2008

Vitamin D: Recommended daily intake Recommended Vitamin D Calcium daily intake Under age 50 400-800 IU at least 1,000 mg Over age 50 800-1,000 IU at least 1,200 mg The Hormone Foundation 2009

Response to Fortiﬁed Food • 10/11 RCTs: ↑ serum 25(OH)D • Response depends on baseline level ‣ Greater if baseline 25(OH)D <50 nmol/L • 0.7 nmol increase in serum 25(OH)D in healthy young men for each 1 ug (40 IU) of vitamin D Brannon et al, Am J Nutr 2008;88:483S-90S

Rule of Thumb Patient with a starting serum 25(OH)D of 15 + 100 IU oral ng/mL would require 1,500 IU/d to bring his vitamin D intake level to 30 ng/mL = + 1 ng/mL (2.5 nmol/L) serum 25(OH)D Heaney R. Clin J Am Soc Nephrol 2008;3:1535-41

Individualize requirements for vitamin D supplementation Base Sunlight line Intestinal vitam e xposure in D absorption Skin level rates pigmentation Age Gene (reduc ed photo- Type of vit D varia tic f tion i co nversion o supplement vitam n 7-dehydrocholest erol in D (D3 is 3x recep to vit D) tor more potent activ ity than D2) Brown S, Alternative Medicine Review 2008

TOXICITY Vitamin D supplementation Trial characteristics 22 vitamin D trials with AE outcomes Most frequently reported 19 trials: adults only Hypercalcemia Many too short to observe AEs Hypercalciuria 400-4,000 IU/d vit D3 (n=19) More events in vit D 5,000-10,000 IU/d vit D2 (n=2) group but difference with placebo group NS Asymptomatic Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S

TOXICITY Vitamin D supplementation Trial characteristics 7 trials reported kidney stone incidence Women’s Health Initiative 5 trials had no cases n = 36,282 1 trial reported NS difference 400 IU vitamin D3 + 1 reported increase in stones 1000 mg Ca vs Ca alone (WHI) 5.7 events/10,000 women-years exposure Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S

Institute of Medicine Tolerable Upper Intake Level (TUIL) No-observed-adverse- 2,000 IU/day effect-level (NOAEL) 10,000 IU/day Serum 25(OH)D 32 ng/mL = minimum daily intake of 2,600 IU vitamin D (US residents) Heaney R. J Musculoskelet Neuronal Interact 2006:6(4):334-

Limited by age higher latitudes working indoors use of sunscreen skin pigmentation 80-90% of vitamin D is cultural practices cutaneously produced precluding skin exposure from sunlight

Bathing suit exposure during summer until skin just begins to turn pink skin production of 10,000 - 50,000 IU of vitamin D3 Adams et al. NEJM 1982;306:772-775

Effect on serum 25(OH)D 4 RCTs using artiﬁcial Nursing home residents UVB light source with low baseline 25(OH)D 4 RCTs using solar Suberythemal UV light exposure exposure = 25(OH)D 28-42 nmol/L after 3 mos. Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S

“Fair evidence to suggest that artiﬁcial and solar exposure increases 25(OH)D levels in vitamin D- deﬁcient and replete persons, including the elderly.” Brannon et al, Am J Nutr 2008;88:483S-90S

TOXICITY Sun exposure “Is a speciﬁc level of sunlight exposure sufﬁcient to maintain adequate vitamin D levels without increasing the risk of non-melanoma skin cancer or melanoma?” No studies! Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S

Should vitamin D levels be measured?

National Osteoporosis Foundation Measure serum 25(OH)D in those at risk of deﬁciency elderly malabsorption (i.e. celiac disease) chronic renal insufﬁciency housebound chronically ill limited sun exposure

Low Vit D Status Despite Abundant Sun Exposure Convenience sample of adults Mean self-reported in Honolulu, Hawaii (lat 21 ̊ ) sun exposure without n = 93 (63 , 30 ) sunscreen use 22.4 h (range 2-96) 28.9 + 1.5 h/wk University of Hawaii A’ala Park Board Shop Serum 25(OH)D and PTH Skin color: reﬂectance colorimetry Sun exposure index: amount of skin exposed X reported average sun exposure per week without sunscreen Binkley et al, JCEM 2008; 92;2130-5

Low Vit D Status Despite Abundant Sun Exposure Evolutionary? Genetic differences: Optimal amount of vit D Cytochrome P450 Inadequate D3 Inadequate cutaneous production Enhanced cutaneous destruction of previt D3 or D3 Downregulation of cutaneous synthesis by sun-induced melanin production 51% of subjects had low vit D status Abnormalities of transport from with serum 25(OH)D cutpoint of 30 ng/mL skin to circulation Binkley et al, JCEM 2008; 92;2130-5

Low Vit D Status Despite Abundant Sun Exposure Sun exposure to the hands and face for 15 minutes may not be enough Measure serum 25(OH)D? Binkley et al, JCEM 2008; 92;2130-5

Measure serum 25(OH)D in otherwise healthy women with osteoporosis? n = 173 postmenopausal women, no known contributors to osteoporosis on past medical history Objective: 24-h urine Ca & Identify most useful/ 24-h urine Ca for all serum Ca for all cost-efﬁcient screening If urine Ca abn, If urine Ca or serum tests in detecting serum Ca and PTH Ca abn, serum PTH secondary contributors Serum TSH for all to osteoporosis Serum TSH for all on T4 replacement 1 on T4 replacement 2 24-h urine Ca, serum 24-h urine Ca, serum Serum Ca, PTH and Ca, PTH and Ca & PTH for all 25(OH)D for all 25(OH)D for all Serum TSH for all on Serum TSH for all on Serum TSH for all on T4 replacement T4 replacement T4 replacement 3 4 5 Tannenbaum et al, JCEM 2002:87;4431-7

Measure serum 25(OH)D in otherwise healthy women with osteoporosis? n = 173 postmenopausal women, no known contributors to osteoporosis on past medical history Disorders identiﬁed: n=33 n=35 56/173 women 24-h urine Ca ➜ 24-h urine Ca & Hypercalciuria most serum Ca & PTH serum Ca ➜ PTH common (9.8%; n=17) Serum TSH for all Serum TSH for all vitamin D deﬁciency on T4 replacement on T4 replacement (4.1%; n=7) 1 2 n=48 n=55 n=37 24-h urine Ca, serum 24-h urine Ca, Ca & PTH serum Ca, PTH and Serum Ca, PTH and 25(OH)D for all 25(OH)D for all Serum TSH for all on T4 replacement Serum TSH for all on Serum TSH for all on 3 T4 replacement 4 T4 replacement 5 Tannenbaum et al, JCEM 2002:87;4431-7

Measure serum 25(OH)D in otherwise healthy women with osteoporosis? 24-h urine Serum Ca, 24-h urine 24-h urine 24-h urine Ca, serum PTH, Ca ➜ serum Ca & serum Ca, serum Ca, PTH, 25(OH)D Ca & PTH Ca ➜ PTH Ca & PTH 25(OH)D Serum TSH Serum TSH Serum TSH Serum TSH if Serum TSH indicated if indicated if indicated if indicated 1 2 3 if indicated 4 5 n=33 (59%) n=35 (63%) n=48 (86%) n=55 (98%) n=37 (66%) $22/patient $30/patient $75/patient $116/patient $108/patient $116 per $148 per $272 per $366 per $506 per diagnosis diagnosis diagnosis diagnosis diagnosis 1999: 24h urine Ca $8, serum Ca $7, PTH $57, serum 25(OH)D $41, TSH $23 Tannenbaum et al, JCEM 2002:87;4431-7

review analyzed 44 orthopedic trauma in-patients admitted ml (Fig. 1). from June 1, 2006 to February 1, 2007 for fracture care. The The women in this series were more likely to be vitamin 44 patients comprised a consecutive series of patients seen D insuf cient than the men, (p=0.03). Seventy ve percent Vitamin D Deﬁciency: A Common Occurrence in by one physician on the metabolic bone disease team. As standard protocol, all patients admitted to the trauma service (18/24) of women and 40% (8/20) of men were vitamin D insuf cient. Speci cally, this gender difference was seen Both High- and Low-energy Fractures at this hospital were seen by both the orthopedic trauma within the high-energy fracture group in which signi cantly service and the metabolic bone disease team. This standard more women (80%, 8/10) than men (25%, 4/16) were of care was established based on an increased awareness of vitamin D insuf cient (p=0.01; Table 1a). There was a vitamin D de ciency and osteoporosis seen in orthopedic arthroplasty patients [7]. Patients were included if they 44 orthopedic 70 sustained a documented fracture, had a 25-hydroxyvitamin D level drawn after surgery in the hospital, and were greater 26/44 (59%) trauma in-patients than or equal to 18 years of age. Patients were excluded if they had any known risk factors for vitamin D de ciency, 60 vit D deﬁcient (20 , 24 )such as renal insuf ciency (as indicated by a creatinine level of ≥2 mg/dl), malabsorption, gastrectomy, active liver disease, acute myocardial infarction, alcoholism, anorexia 50 nervosa, or steroid dependency. In this study, the 25(OH)D metabolite was used as a measurement of vitamin D status. Although calcitriol (1,25-dihydroxvitamin D) is the most 25(OH)D [ng/ml] potent vitamin D metabolite, the metabolite 25(OH)D 40 provides a more accurate account of vitamin D status [9, 20, 26, 29]. Serum 25(OH)D levels were measured through Median 33.5 the use of liquid chromatography/mass spectrometry. 32 30 Mean 30.3 Age, gender, and type of fracture were recorded for each Mean 29.8 Median 27.5 patient. This study included a total of 44 patients, 45.5% men (n=20) and 54.5% women (n=24). The mean age for all patients was 59±20 years, range 19–95 years. The mean 20 age for men was younger at 51±21 years than for women, which was 66±17 years (p=0.02). The fractures were Low-energy fracture classed as low-energy fracture vs. high-energy fracture. 10 8/20 (40%) Low-energy fractures were de ned as fractures sustained fracture from a fall of standing height from a fall of standing height or less, while high-energy fractures resulted from a fall greater than standing height or 18/24 (75%) High-energy fracture a motor vehicle impact. 0 Univariate analysis was run on all variables; means, Men Women fracture from a fall greater than standard deviations, medians, frequencies, etc., as appropri- Fig. 1. Vitamin D levels in this patient population sorted by patient ate. All demographic and clinical variables were assessed gender standing height or motor vehicle impact Steele et al, HSSJ 2008:4;143-8

145 Vitamin D Deﬁciency: A Common Occurrence in Both High- and Low-energy Fractures y Table 2 Age and 25(OH)D level vs. fracture etiology %, e Low-energy High-energy p value fractures fractures - s, a. Men n Agea 72.5±16 45.9±19 0.02 c s 25(OH)D b 19.5 34 0.007d h b. Women % Agea 71.1±14 57.8±18 0.053c b d e 25(OH)D 28 27 0.7 s. a Mean age in years ± standard deviation e- b Median 25(OH)D ng/ml el c p values were calculated using the t test d ) p values were calculated using the Mann–Whitney test Steele et al, HSSJ 2008:4;143-8

What cut-off value defines low vitamin D status? Serum 25(OH)D <25 nmol/L 25-75 nmol/L >75 nmol/L Deficiency Insufficiency Sufficiency Optimal level of Variability of vit D concentration 25(OH)D 30 ng/mL by geographical location determined in a Differences in assay methodology Caucasian population Dawson-Hughes B, Am J Clin Nutr 2008:88(suppl);537S-40S

Goal of vit D supplementation? Serum 25(OH)D greater than an accepted cutpoint (e.g. 30 ng/ml) Upper limit of normal (a value that varies between laboratories) Binkley et al, JCEM 2008; 92;2130-5

Does supplemental vitamin D reduce fractures and falls?

Meta-analysis of the Efﬁcacy of Vitamin D Treatment in Preventing Osteoporosis in Postmenopausal Women Objective Data Source Study S election To review the MEDLINE and Standard o r effect of vitamin D EMBASE from hydroxylat ed vitamin a D with o r without C on bone density 1966 to 1999 l and fractures in sup pl vs contro 25 trials postmenopausal Meas ured bone women densit y or fracture inciden ce >1 year Guyatt et al, Endoc Rev 2002; 23(4);560-9

Meta-analysis of the Efﬁcacy of Vitamin D Treatment in Preventing Osteoporosis in Postmenopausal Women Vitamin D (n=4017) vs Follow-up: 1-5 y control (n=4107) Loss to follow-up Patients with ↓bone <10% (2 trials) density (17 trials) 10-20% (8 trials) >20% (13 trials) Standard vitamin D unknown (2 trials) (10 trials) Blinded (18 trials) Hydroxylated vitamin D (14 trials) Unblinded (5 trials) Both forms of Blinding unclear (2 trials) 25 trials vitamin D (1 trial) Guyatt et al, Endoc Rev 2002; 23(4);560-9

Vitamin D Treatment in Preventing Osteoporosis in Postmenopausal Women RR with 95%CI for vertebral fractures August 2002, 23(4):560 –5 . • Meta-Analyses of Osteoporosis Therapies Endocrine Reviews, FIG. 2. RR with 95% CI for vertebral fractures after treatment with vitamin D. Guyatt et al, Endoc Rev 2002; 23(4);560-9

sites RR (95% CI) hydroxylated trials patients value valu Vitamin D Treatment in Preventing Combined Standard 8 1 1130 160 0.63 (0.45, 0.33 (0.01, 0.88) 8.05) 0.01 0.49 0.16 – Hydroxylated 7 970 0.64 (0.44, 0.92) 0.02 0.11 rtebral Osteoporosis in Postmenopausal Women Combined Standard 6 3 6187 5399 0.77 (0.57, 0.78 (0.55, 1.04) 1.09) 0.09 0.15 0.09 0.05 eted P RR with 95%CI for nonvertebral fractures Hydroxylated 3 788 0.87 (0.29, 0.05 as indicating important between-study differences in results. 2.59) 0.80 0.19 FIG. 3. RR with 95% CI for nonvertebral fractures after treatment with vitamin D. Guyatt et al, Endoc Rev 2002; 23(4);560-9

Proposed Scientific and Ethical Guidelines for Clinical Trials on Vitamin D and Fracture Osteoporosis Education Project Achievement of Only those with Vitamin D levels vit D sufficiency 25(OH)D >32 ng/ achieved should should be verified mL should be be 32 ng/mL 1 by 25(OH)D 2 included 3 Vit D 4 Vit D3 5 supplementation (cholecalciferol) must be continued should be used for at least 12 mos Brown S, Alternative Medicine Review 2008

Vitamin D and Fracture Trials Serum Vit D Trial Overview Trial (Therapeutic % Fracture Trial (All RCTs) Compliance threshold is 32 Reduction ng/mL) 3270 ambulatory 1,762 (54%) 16 ng/mL average 32% ↓ in all elderly French completed the trial Vit D level at non-vertebral women Good supplement baseline fractures French Decalyos 18-month trial compliance 42 ng/mL average I Study 800 IU D3 w/ tri- vit D level at 43% ↓ in hip calcium phosphate completion of trial fractures (1,200 mg elemental Ca) 3270 ambulatory Supplement 16 ng/mL average 24% ↓ in all elderly French compliance unclear Vit D level at non-vertebral women but appears baseline French Decalyos adequate fractures 18-month extension 42 ng/mL average I Study of trial vit D level at 29% ↓ in hip Extension 800 IU D3 w/ tri- completion of trial fractures calcium phosphate (1,200 mg elemental Ca) Brown S, Alternative Medicine Review 2008

Vitamin D and Fracture Trials Serum Vit D Trial Overview Trial (Therapeutic % Fracture Trial (All RCTs) Compliance threshold is 32 Reduction ng/mL) 610 ambulatory 422 (69%) 9 ng/mL average Vit Non-signiﬁcant French women completed the trial D level at baseline ↓ in all non- 2-year trial 95% supplement 30 ng/mL average vertebral French Decalyos 800 IU of D3 with compliance vit D level at II Study completion of trial fractures tri-calcium phosphate (1,200 31-38% ↓ in hip mg elemental Ca) fractures 2,686 community 75% of participants At 4 years 33% overall ↓ of living men and took the vit D at 29 ng/mL average fractures (hip, British study of women aged 65-85 least 80% of the Vit D level in those vit D and time wriat, spine, 5-year trial on supplements osteoporotic 66% compliance for forearm) 100,000 IU tablets 21 ng/mL average fracture of vit D3 every 4 ﬁnal dose vit D in placebo months group Brown S, Alternative Medicine Review 2008

Vitamin D and Fracture Trials Serum Vit D Trial Overview Trial (Therapeutic % Fracture Trial (All RCTs) Compliance threshold is 32 Reduction ng/mL) 389 community 318 (82%) 30 ng/mL average 60% ↓ in all non- dwelling men & completed the trial Vit D level at vertebral fractures women (mean age Supplement baseline 74) compliance 44 ng/mL average 60% ↓ in hip Boston area fractures 3-year trial appears good vit D level at study completion of trial Intervention: 700 IU D3 and 500 mg elemental Ca (as citrate maleate) Japanese study 258 stroke patients Compliance with 6.8 ng/mL average Sixfold ↓ in hip of sunlight 12-month trial sunlight exposure Vit D level at fracture incidence appears good baseline exposure on 50% of patients in the sunlight- had 15 minutes/day 20.8 ng/mL average BMD & hip vit D level at exposed group of sunlight exposure fracture to face and hands completion of trial 3.1%↑ in BMD in incidence 50% were sunlight sunlight-exposed among vit D deprived 3.3% ↓ in BMD in deﬁcient stroke sunlight-deprived patients Brown S, Alternative Medicine Review 2008

Vitamin D and Fracture Trials Serum Vit D Trial Overview Trial (Therapeutic % Fracture Trial (All RCTs) Compliance threshold is 32 Reduction ng/mL) 284 Alzheimer’s Compliance with 9.6 ng/mL average 4x more frequent patients sunlight exposure Vit D level at non-vertebral 12-month trial appears good baseline fractures in Japanese study 1,200 mg elemental 20.8 ng/mL average vit D level at sunlight-deprived of hip fracture calcium 2x/day to both groups; 50% completion of trial group (11 vs 3) reduction of patients had 15 4x more frequent among min/day of sunlight hip fractures in Alzheimer’s exposure to face, sunlight deprived- patients through hands and forearms (total exposed skin group (9 vs 2) sunlight area 426 +32 cm3); 2.7% ↑ in BMD in exposure 50% of patients sunlight-exposed were sunlight deprived 5.6% ↓ in BMD in sunlight-deprived Brown S, Alternative Medicine Review 2008

Vitamin D and Fracture Trials Some observations Bischoff-Ferrari et al meta-analysis Pooling of 12 studies with 400 IU vitamin D daily failed to inﬂuence Supplementation fracture incidence with 400 IU vitamin 700-800 IU daily of vitamin D ↓ hip fracture by 26% D repeatedly found ↓ all fractures by 23% to have no impact on fracture incidence Brown S, Alternative Medicine Review 2008

Vitamin D and Fracture Trials Some observations British RECORD trial 800 IU vitamin D in older adults raised Vitamin D at an vit D to an average of 24.8 ng/mL 800 IU daily dose Swiss study Vit D levels increased from 12.3 ng/mL leads to 25(OH)D to 26.2 ng/mL in ambulatory elderly levels of 32 ng/mL given 800 IU D3 daily x 3 months in some but not all subjects Less than half of adults will achieve 25(OH)D of 32 ng/mL with 700-1,000 IU vitamin D supplementation x 8 weeks Brown S, Alternative Medicine Review 2008

Vitamin D Status and Treatment of Postmenopausal Osteoporosis with Bisphosphonates 112 women On bisphosphonate # Etidronate (n=30) Alendronate (n=64) Risedronate (n=38) Serum 25(OH)D <70 nmol/L (53%) 25 (OH) D : 93 [3.3] nmol/L 25 (OH) D : 50 [1.9] nmol/L Deane et al, Alternative BMC Musculoskeletal Disorders 2007

Meta-analysis: Vitamin D and the Risk of Falls Objective Data Source Selection Study To evaluate how MEDLINE, vs placebo Vitamin D supplementation EMBASE, BIOSIS Vit D + C a vs calcium with vit D alone and Cochrane alone affects risk of database from Jan tudies whic h S falling, primarily in 1985 to June 2005 enrolle d both men postmenopausal 5 studies and wome n included women Risk of falls Jackson et al, QJM 2007;100:185-192

Meta-analysis: Vitamin D and the Risk of Falls All RCTs except 1 Duration 18 weeks D3 used in all to over 5 years D3 + Ca (4 trials) D3 dose from 300 Postmenopausal to 800 IU except 1 women only (3 trials) trial (oral capsule of Mean baseline 100,000 IU vit D3 q4 25(OH)D were months) inadequate (deﬁned as <76.2 nmol/L) 5 trials Jackson et al, QJM 2007;100:185-192

, measured; N, not measured; aRR reported in forest plots. bMedian value (mean reported unless otherwise stated) Meta-analysis: Vitamin D and the Risk of Falls umber of subjects in both groups. Review: Vitamin D3 review Comparison: 01 Falls Outcome: 01 Falls including calcium Study Vitamin D3 (+/− Ca) Control RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Graafmans 62/177 66/177 16.82 0.94 [0.71, 1.24] Pfeifer 11/70 19/67 4.95 0.55 [0.29, 1.08] Bischoff 14/62 18/60 4.66 0.75 [0.41, 1.37] Trivedi 100/270 92/255 24.11 1.03 [0.82, 1.29] Grant 161/1306 196/1332 49.46 0.84 [0.69, 1.02] Total (95% CI) 1885 1891 100.00 0.88 [0.78, 1.00] Total events: 348 (Vitamin D3 (+/− Ca)), 391 (Control) Test for heterogeneity: Chi² = 4.36, df = 4 (P = 0.36), I² = 8.3% Test for overall effect: Z = 1.95 (P = 0.05) 0.1 0.2 0.5 1 2 5 10 Favours treatment Favours control igure 1. Results of the meta-analysis for falls. Pooled RR for D3 preventing falls 0.88 (95%CI 0.78-1.00) Review: Vitamin D3 review Postmenopausal women only Comparison: Outcome: 01 Falls 02 Falls including calcium in post-menopausal women Pooled RR 0.81 (95%CI 0.48-1.34) Study or sub-category Vitamin D3 (+/− Ca) n/N Control n/N RR (fixed) 95% CI Weight % RR (fixed) 95% CI Pfeifer 11/70 19/67 14.67 0.55 [0.29, 1.08] Bischoff 14/62 18/60 13.82 0.75 [0.41, 1.37] Trivedi 100/270 92/255 71.50 1.03 [0.82, 1.29] Total (95% CI) 402 382 100.00 0.92 [0.75, 1.12] Total events: 125 (Vitamin D3 (+/− Ca)), 129 (Control) Jackson et al, QJM 2007;100:185-192

Vitamin D and the Risk of Falls Randomized controlled trials Vit D dose/ 25(OH)D level Duration Trial preparation achieved Outcome of trial ug (IU)/d nmol/L Muscle performance Sato 25(1000) D2 3y 84 + Pfeiffer 20 (800) D3 2 mo 66 + Bischoff 20 (800) D3 3 mo 66 + Falls Bischoff 17.5 (700) D3 3y 99 + Broe 20 (800) D2 5 mo 75 + Flicker 20 (800) D2 2y NA + Grant 20 (800) D3 5y 62 Null Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

Vitamin D and Risk of Falls Some observations Presence of nursing staff More accurate Trials assessing ascertainment of falls impact of vit D on Higher supplement falling more likely compliance to have positive results when conducted in institutions Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

Vitamin D and Risk of Falls Some observations Trials indicate mean values Research has not of 75 nmol/L and 99 nmol/L identified the ? higher values might confer minimum 25(OH)D benefit level for maximal benefit in fall prevention Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

How much vitamin D is enough? Should vitamin D Does supplemental levels be measured? vitamin D reduce fractures and falls?

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Vitamin D and Osteoporosis

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