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VITAMIN D, FALLS AND FRACTURE Julie A Pasco The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health.

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Presentation on theme: "VITAMIN D, FALLS AND FRACTURE Julie A Pasco The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health."— Presentation transcript:

1 VITAMIN D, FALLS AND FRACTURE Julie A Pasco The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health

2 The term “vitamin D” encompasses two molecules: Cholecalciferol (vitamin D 3 ) –formed in skin through action of UV light on 7- dehydrocholesterol to produce cholecalciferol Ergocalciferol (vitamin D 2 ) –produced by UV irradiation of the plant steroid ergosterol –major form of supplemental vitamin D currently available in Australia (eg Ostelin) Vitamin D

3 25OHD and 1,25(OH) 2 D Vitamin D 3 and D 2 (made in skin or ingested) are transported to liver and metabolised to 25OHD –25OHD is the major circulating form Further hydroxylation occurs in kidney to form highly biologically active 1,25(OH) 2 D that promotes –absorption of calcium and phosphate from small intestine –extracellular calcium homeostasis, directly and through interaction with PTH –mineralisation of skeleton (DeLuca and Zierold 1998)

4 Sources: diet Vitamin D 3 found in small quantities in a few foods: –fatty fish (salmon, herring, mackerel) –liver and eggs –fortified foods (margarine, some low-fat milks) Adequate vitamin D unlikely achieved through diet alone –average intake 2-3  g or 80-120 IU per day –extending fortification of food would result in a modest  dietary vitamin D, taking average intakes to ~200 IU (insufficient to maintain vitamin D status in high risk groups) (Nowson, 2002)

5 New AIs for Vitamin D in Australia Age (yr) ggIU 0-505200 51-7010400 71+15600 (Commonwealth Department of Health and Ageing, NHMRC, 2004) (New AIs based on joint US/Canada Dietary Reference Intakes, 1997; similar to recommendations by Food & Agriculture Organization of the United Nations)

6 Sources: sunlight Main source of vitamin D is exposure to sunlight whole body exposure 10-15 min midday sun in summer (~1 MED) Ξ 15 000 IU (375  g) orally exposure of hands, face and arms (~15% body surface) to ~1/3 MED should produce ~1000 IU less vitamin D synthesised in winter, in those with dark skin or older, and those who cover up for cultural reasons or sun protection amount of sun exposure to produce 1/3 MED varies with latitude, season, time of day, skin type short exposures to UV are more efficient: prolonged exposure to high UV doses may degrade pre-vitamin D

7 Sun exposure times  1/3MED Dec-JanJul-Aug (mod fair skin*) 10:00 or 14.00 12:00 Cairns6-79-127 Townsville5-79-137 Brisbane6-715-1911 Perth5-620-2815 Sydney6-826-2816 Adelaide5-725-3819 Melbourne6-832-5225 Hobart7-940-4729 Auckland6-830-4724 Christchurch6-949-9740 *Exposure times for highly pigmented skin are 3-6 times greater (Pathak 1999)

8 UV exposure and skin damage A balance is required between avoiding skin damage (skin cancer & wrinkling) and maintaining adequate vitamin D levels Australia has highest reported rates of NMSC sun exposure causes ~99% NMSC and 95% melanoma sun protection required when UV index > 3 deliberate sun exposure between 10am-2pm in summer (11am –3pm Daylight saving time) is not advised for regions south of 37 o sun protection probably not needed during June-July

9 Alternatives to UV exposure Exposure of hands, face and arms to ~1/3 MED of sunlight most days is considered adequate to produce sufficient endogenous vitamin D if adequate sunlight exposure is not possible, or practical, then vitamin D supplementation is recommended (at least 400 IU per day) because of high UV radiation, solaria are not recommended for boosting vitamin D levels (National Radiological Protection Board, 2002)

10 Causes of deficiency Reduced intake or synthesis of cholecalciferol –  sunlight: ageing, veiling, illness, immobility –  synthesis for a given UV exposure: ageing, dark skin –as above combined with low dietary intake Disorders associated with abnormal gut function and malabsorption –small bowel disorders: coeliac disease, sprue, IBD, infiltrative disorders, small bowel resection –pancreatic insufficiency: chronic pancreatitis, cystic fibrosis –biliary obstruction: 1° biliary cirrhosis, external biliary drainage Reduced synthesis or enhanced degradation of 25OHD –chronic hepatic disorders: hepatitis, cirrhosis –drugs: rifampicin, anticonvulsants

11 Who is at risk? People at risk for vitamin D deficiency: those with limited mobility –elderly (institutionalised or housebound) –disabled (motor or intellectual disability) dark skin skin conditions where sunlight avoidance is necessary malabsorption drug exposures that  synthesis or  degradation 25OHD osteoporosis or minimal trauma fracture

12 Documented vitamin D deficiency older people in high & low care (Flicker 2003, Sambrook 2002, Stein 1996) older people admitted to hospital (McGrath 1993, Inderjeeth 2000) hip fracture patients (Morris 1984, Diamond 1998, Crone 2002) dark-skinned women (particularly if veiled) (Grover 2001, Diamond 2002, Skull 2003) mothers of infants with rickets (Nozza 2001) children of mothers with low vitamin D levels (Nozza 2001) community-dwelling women in Geelong, especially during winter (Pasco 2001) “healthy” elderly men in southern Sydney (Sambrook 2002) men & women in SE Queensland (some with psychiatric disorders) (McGrath 2001) elderly non-institutionalised Tasmanians (Inderjeeth 2000)

13 Vitamin D deficiency & bone Mild –25OHD in range 25-50 nmol/L –increased PTH and high bone turnover Moderate –25OHD in range 12.5-25 nmol/L –  BMD,  bone turnover,  hip fracture risk Severe –25OHD < 12.5 nmol/L –osteomalacia (rare in Australia) –bone and muscle pain, weakness and pseudofractures –thickened unmineralised seams –cortical thinning because 2  hyperparathyroidism

14 Muscle function and falls Abnormal motor performance,  body sway and quadriceps weakness reported for 25OHD < 20-30 nmol/L (Glerup 2000, Dhesi 2002) Vitamin D deficiency –an independent predictor of falls in older women in residential care (Flicker 2003) –linked with falls and fractures in elderly men and women (Pfeifer 2000, Bischoff 2003, Flicker 2005)

15 RCT VitD supplements & falls Aim: to determine whether vitD supplementation (D 2 ) reduced falls in older people in residential care, not classically vitD deficient RCT, two years duration –60 hostels, 89 nursing homes across Australia –625 residents (mean age 83.4yr), 25OHD 25-90nmol/L ITT:  falls by 27%, RR 0.73 (0.57-0.95) Sub-grp (>half prescribed supps, n=540) –  falls by 37%, RR 0.63 (0.48-0.82) Estimated that 8 people need to be treated to prevent 1 fall/yr Flicker 2005

16 Vitamin D supplementation Some Ca and MV preparations contain vitamin D (32-200 IU) – too low Halibut or cod liver oil capsules (400 IU cholecalciferol) – cheap but also contain vitamin A (4000 IU) Single pure vitamin D preparation in Australia is Ostelin 1000 (1000 IU ergocalciferol) @~24cents Larger dose (50 000 IU) cholecalciferol available in NZ

17 Vitamin D and Fracture Prevention Pivotal 1  prev trial relating fracture reduction in high risk group: 800 IU D 3 for 18 mo –41%  hip fracs elderly women in residential care (Chapuy NEJM 1992) –NS when repeated by same investigators (Chapuy OI 2002) 389 people from community: benefit from daily Ca (500mg) + vitD (700 IU) on bone loss & frac (Dawson-Hughes NEJM 1997) 2578 people from community: no frac reduction with lower dose vitD (400 IU/d) (Lips Ann Intern Med 1996)

18 Vitamin D and Fracture Prevention Double-blind RCT oral 100,000 IU every 4mo for 5yr  risk of first hip, wrist, forearm, vert frac in 2686 people from community by 33% (Trivedi BMJ 2003) RCT 9440 community-dwelling people 75-100yr annual injection 300,000 IU D3: no protective effect on fracs (Anderson JBMR 2004) RECORD study of 5292 ambulatory patients with recent LT frac: Ca alone (1000mg/d), vitD (800 IU/d), both or placebo: (Lancet 2005) –after 24mo no sig diff in frac rates between 4 grps –interpretation limited by high non-compliance rate and no data about baseline vitD status

19 Vitamin D and Fracture Prevention One meta-analysis concluded vitD (Papadimitopoulos Endocr Rev 2002) –  vertebral frac risk 37% (RR 0.63; 95%CI 0.45-0.88) –but no sig  in non-vert fracs (RR 0.77; 0.57-1.04) More recent meta-analysis showed vitD (Bischoff-Ferrari JAMA 2005) –  hip frac (RR=0.74, 0.61-0.88) and –  non-vert frac (RR=0.77, 0.68-0.87) RCT WHI 36,282 women 50-79yr 400 IU D 3 + 1000mg Ca daily (Jackson NEJM 2006 ) –ITT: hip RR 0.88 (0.72-1.08), vert RR 0.90 (0.74- 1.10), total frac RR 0.96 (0.91-1.02) –Censoring data (non-compliance) hip RR 0.71 (0.52- 0.97)

20 Supplementation and fractures Greatest benefits: high-risk vitamin D- deficient patients, with low BMD Unlikely that supplementation effective in vitamin D replete individuals but optimal 25OHD levels unknown: thresholds 50-110 nmol/L reported (Parfitt 1990, Mithal 2000) Vitamin D examined in both 1 o and 2 o fracture prevention trials but differences in baseline PTH and 25OHD make comparisons difficult Adequate calcium AND vitamin D likely to be required to reduce fracture risk

21 Urban and rural population = 221,000 Fracture cases Radiologically confirmed fractures documented during 2 yr Controls Age stratified sample, women 20-94 yr randomly selected from the compulsory electoral roll 77% participation rate Observational study Barwon region GEELONG OSTEOPOROSIS STUDY

22 Fracture cases –n = 728 –ages 35+ yr Controls (population sample) –n = 1,494 from electoral rolls –ages 20-94 years at baseline Data: demographics, diet, lifestyle, medical history, BMD, falls and fracture history, blood and urine samples

23 AGE-RELATED INCIDENCE OF HIP AND COLLES’ FRACTURES 90+80-8970-7960-6950-5940-4935-39 400 300 200 100 0 Age (years) (n/10,000 p-yr) Fracture incidence Hips Colles' GEELONG OSTEOPOROSIS STUDY

24 SPINE BMD AGE SPINE FRACTURE CASES Henry et al, Geelong Osteoporosis Study VERTEBRAL FRACTURES PREDICTED BY AGE & BMD

25 AGE HIP BMD HIP FRACTURES PREDICTED BY AGE & BMD HIP FRACTURE CASES Henry et al, Geelong Osteoporosis Study

26 “Osteoporosis is characterised by low bone mass and micro-architectural deterioration of bone tissue. There is a consequent increase in bone fragility and susceptibility to fracture” (WHO 1994) Normal Osteoporosis OSTEOPOROSIS micro-architectural changes

27 SURIVIAL PLOTS.

28 LOW BONE MASS - A RISK FACTOR FOR FRACTURE

29 RR FRACTURE FOR FALLERS/NON-FALLERS n = 616, age 60+ Age-adj, Cox proportional hazards model

30 PREVALENCE OF LOW 25OHD IN WINTER Prevalence (%) DNOSAJJMAMFJ 50 40 30 20 10 0 Month <50 nmol/L <38 nmol/L

31 Serum vitamin D Serum parathyroid hormone Serum bone resorption marker SEASONAL CHANGES Age-adjusted p=0.001 Age-adjusted p=0.058 Age-adjusted p=0.037

32 SEASONAL CHANGES IN PTH AND CTx -1 0 1 Month A m p l i t u d e UV 25OHD PTH CTx JFMAMJJASOND

33 FALLS AND FRACTURES Falls –1501 falls cases presented to the Emergency Department at The Geelong Hospital 1995-7 –946 fractures –proportion of falls resulting in fracture calculated for each month Fractures –all fractures of the hip (n=439) and wrist (n=307) occurring in BSD identified, 1994-7 –monthly tallies were calculated

34 Fractures from falls Hip fractures Wrist fractures SEASONAL CHANGES p=0.001 p=0.078 p=0.002

35 PHASE SHIFTS 1 0 -1 Month A m p l i t u d e UV 25OHD PTH CTx Wrist fractures Hip fractures JFMAMJJASOND

36 SUMMARY A trough of 25OHD in winter is accompanied by increases in PTH levels bone resorption proportion of falls resulting in fracture frequency of hip and wrist fracture

37 CONCLUSION Low 25OHD during winter  Muscle strength  Mineralisation  PTH  Falls  Bone fragility  Fractures

38 CONCLUSION Low vitamin D levels are common Dietary intakes are poor Few women take vitamin D supplements Systematic vitamin D supplementation may be indicated Data suggest that if lower fracture rates in summer were maintained through winter, hip and wrist fractures could be reduced by 16% and 30% Substantial implications for public health programs

39 VITAL D TRIAL 1500 non-institutionalised women (aged 70+ yr) recruited Randomised to receive a high annual dose of vitamin D (500,000 IU D 2 /yr) or placebo Groups monitored over 5 years to see whether intervention with vitamin D protects against falls and fracture

40 Recommendations - Summary Vitamin D and Calcium Forum, 2005 High dose vitD preparations (50,000 IU, 1.25mg) in Australia would be effective and cheap; monthly doses could be recommended for people with vitD deficiency Most older people in residential care would benefit from vitD supps to reduce falls & fracs VitD replacement is safe, even in high doses (up to 600,000 IU, 15 mg) per yr by intramuscular injections

41 Recommendations - Summary Vitamin D and Calcium Forum, 2005 In people with severe deficiency replacement doses 5,000-10,000 IU (125-250  g) often required for up to 3 mo to achieve normal vitD levels. Single oral dose 500,000 IU (12.5mg) can be given without significant risk of hypercalcaemia or hypercalciuria Reassessment of vitD status after 3 mo of therapy may be required by measuring serum 25OHD. Citation: Medicine Today, Dec 2005, 6 (12): 43-50

42 ACKNOWLEDGEMENTS Gosia Bucki-Smith Eloise Clark Rosalynn Garcia Amanda Hayles Margaret Henry Felice Jacka GEELONG OSTEOPOROSIS STUDY Therese Jeavons Sam Korn Mark Kotowicz Elizabeth Merriman Geoff Nicholson Anna Petrovski Lana Williams


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