VITAMIN D,VITAMIN D,

FALLS AND FRACTUREFALLS AND FRACTURE

Julie A Pasco

The University of Melbourne,Department of Clinical and Biomedical Sciences:

Barwon Health

The term “vitamin D” encompasses two molecules:

• Cholecalciferol (vitamin D3)– formed in skin through action of UV light on 7-

dehydrocholesterol to produce cholecalciferol

• Ergocalciferol (vitamin D2)– produced by UV irradiation of the plant steroid

ergosterol– major form of supplemental vitamin D

currently available in Australia (eg Ostelin)

Vitamin D

25OHD and 1,25(OH)2D

• Vitamin D3 and D2 (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)2D 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)

Sources: diet

• Vitamin D3 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)

New AIs for Vitamin D in Australia

Age (yr) g IU

0-50 5 200

51-70 10 400

71+ 15 600

(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)

Sources: sunlightMain 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

Sun exposure times1/3MED

Dec-Jan Jul-Aug Jul-Aug

(mod fair skin*) 10:00 or 14.00 10:00 or 14.00 12:00

Cairns 6-7 9-12 7

Townsville 5-7 9-13 7

Brisbane 6-7 15-19 11

Perth 5-6 20-28 15

Sydney 6-8 26-28 16

Adelaide 5-7 25-38 19

Melbourne 6-8 32-52 25

Hobart 7-9 40-47 29

Auckland 6-8 30-47 24

Christchurch 6-9 49-97 40

*Exposure times for highly pigmented skin are 3-6 times greater (Pathak 1999)

UV exposure and skin damageA 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 37o sun protection probably not needed during June-July

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)

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

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

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)

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

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)

RCT VitD supplements & falls• Aim: to determine whether vitD supplementation

(D2) 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

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

Vitamin D and Fracture Prevention

• Pivotal 1 prev trial relating fracture reduction in high risk group: 800 IU D3 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)

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

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 D3 + 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)

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 1o and 2o 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

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

GEELONG OSTEOPOROSIS STUDY

• 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

AGE-RELATED INCIDENCEOF HIP AND COLLES’ FRACTURES

90+80-8970-7960-6950-5940-4935-39

400

300

200

100

0

Age (years)

(n/1

0,00

0 p-

yr)

Fra

ctur

e in

cide

nce Hips

Colles'

GEELONG OSTEOPOROSIS STUDY

95755535

1.9

1.4

0.9

0.4

SPINE BMD

AGE

SPINE FRACTURE CASES

Henry et al, Geelong Osteoporosis Study

VERTEBRAL FRACTURES PREDICTED BY AGE & BMD

35 55 75

0.5

1.0

1.5

95

AGE

HIP

BMD

HIP FRACTURES PREDICTED BY AGE & BMD

HIP FRACTURE CASES

Henry et al, Geelong Osteoporosis Study

“Osteoporosis is characterised by low bone mass andmicro-architectural deterioration of bone tissue. Thereis a consequent increase in bone fragility andsusceptibility to fracture” (WHO 1994)

Normal Osteoporosis

OSTEOPOROSISmicro-architectural changes

SURIVIAL PLOTS

543210

1.0

0.9

0.8

0.7

Time to fracture (yr)

Pro

babi

li ty

of r

emai

ning

fr a

c tur

e-fr

ee

Normal

Osteopenic

Osteoporotic

u vv l l t s o i t .

LOW BONE MASS - A RISK FACTOR FOR FRACTURE

BMD (g/cm2)0.5 1.0 1.5

Osteoporosis Osteopenia Normal

T-score = -2.5 T-score = -1.0

10

20

30

40

50

60

70

0

10

20

30

40

Proportion of fractures

Absolute risk

0

Pro

port

ion

of f

ract

ures

(%

)

Abs

olut

e fr

actu

re r

isk

(%) 30.8

26.9

17.5

56.5

7.216.6

RR FRACTURE FOR FALLERS/NON-FALLERS

porotic penic normal

non-fallersfallers0

1234567

RR

BMD total hip

non-fallers

fallers

n = 616, age 60+Age-adj, Cox proportional hazards

model

PREVALENCE OF LOW 25OHD IN WINTER

Prevalence (%)

DNOSAJJMAMFJ

50

40

30

20

10

0

Month

<50 nmol/L

<38 nmol/L

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

SEASONAL CHANGES IN PTH AND CTx

-1

0

1

Month

Am

plitu

de

UV

25OHD

PTH

CTx

J F M A M J J A S O N D

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

Fractures from falls

Hip fractures

Wrist fractures

SEASONAL CHANGES

p=0.001

p=0.078

p=0.002

PHASE SHIFTS

1

0

-1

Month

Ampl

itud e

UV

25OHD

PTH

CTx

Wrist fracturesHip fractures

J F M A M J J A S O N D

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

CONCLUSION

Low 25OHD during winter

Muscle strength Mineralisation PTH

Falls Bone fragility

Fractures

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

VITAL D TRIAL

• 1500 non-institutionalised women (aged 70+ yr) recruited

• Randomised to receive a high annual

dose of vitamin D (500,000 IU D2/yr) or

placebo

• Groups monitored over 5 years to see whether intervention with vitamin D protects against falls and fracture

Recommendations - SummaryVitamin 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

Recommendations - SummaryVitamin D and Calcium Forum,

2005

• In people with severe deficiency replacement doses 5,000-10,000 IU (125-250g) 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

ACKNOWLEDGEMENTS

Gosia Bucki-Smith

Eloise Clark

Rosalynn Garcia

Amanda Hayles

Margaret Henry

Felice Jacka

GEELONG OSTEOPOROSIS STUDYGEELONG OSTEOPOROSIS STUDY

Therese Jeavons

Sam Korn

Mark Kotowicz

Elizabeth Merriman

Geoff Nicholson

Anna Petrovski

Lana Williams