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Prof. Johann D. Ringe, MDHead of West German Osteoporosis Center (WOZ)

Med. Klinik 4, Klinikum LeverkusenUniversity of Cologne, Germany

The Effects of Vitamin D on

Falls and Fractures

ECOO-Cairo

April 26, 2012

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What is the rationale behind thefracture reducing potency of Vitamin D(especially non-vertebral fractures)?

(= Hip-fractures and other Non-vert-fractures)

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BONE FALLS

Reduction in:- Bone mass- Bone quality- Bone strenght

- External factors- muscle weakness

- Imbalance- Frailty

Fracture

Pathogenesis of Non-vert. Fractures inOsteoporosis:

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Old knowledge: Severe osteomalacia is associatedwith muscle weakness (but longtime no link to Vit.D)

Trendelenburgs sign (1895):When standing on one leg, the pelvisdrops on the opposite side of thestance leg, due to weakness ofabductor muscles of the hip (namelygluteus medius and minimus).

Illustration from the first description by theGerman surgeon Friedrich Trendelenburg (1895)

Description of 1,25-dihydroxyvitaminD3-receptor in human skeletal

muscle tissue. Bischoff HA et al.,Histochem J 2001;33:19-2415

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BONE FALLS

Reduction in:- Bone mass

- Bone quality(microarchitecture)

- Bone strenght

- External factors- Frailty

-D-hormone deficiency- Muscle weakness- Imbalance

Fracture

Pathogenesis of Non-vert. FracturesDual effect of vitamin D

Vit. D

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Reduced MuscleMass + Function

No strain on bone

Fracture

Osteopenia

Pathogenesis of osteoporotic fractures:The important role of muscle strength and function

was long time neglected

Sarkopenia

Falls

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Reduced MuscleMass + Function

No strain on bone

Fracture

Osteopenia

Dual effect of Vitamin D on bone and muscle reduces risof osteopenia and falls and thereby fractures

1,25-Vit. D

+

+

Sarkopenia

Falls

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Vitamin D-Hormone-Receptor (VDR) expression inhuman muscle tissue decreases with age *

* Bischoff-Ferraet al. J Bone MinRes 2004;19:265

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Pleiotropic way of action of Vitamin D has aneffect on the risk of falls and fractures:

Muscle Strength

Muscle cells

Calcium absorption

Bone Formation

Bone Mineralization

Bone Resorption

Falls &

Fractures

Bone mass

Bone Quality

Bone Strengt

Sec. Hyperparathyr.Parathyr.

Improved balance

Cognitive abilities

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Evidence that Vitamin D (plus

Calcium) reduces the risk of falls *

Highly significant effect on falls would suggest a risk reduction atleast for non-vertebral fractures

Indirect evidence:

Earlier studies showing positive effect of plain vitamin D or

alfacalcidol on - Body sway

- Walking speed

- Muscle strength

- Timed Up-and-Go test (TUG)

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Risk of Falling with Calcium andVitamin D Supplementation

122 women, Age: 6399

Randomized, double-blind,controlled trial

Calcium 1200 mg/day

Calcium 1200 mg/day+ vitamin D 800IU/day

12-week duration

Mean serum 25(OH)D

12 ng/ml at baseline Women living in long-term

care unitsBischoff HA et al J Bone Miner Res 2003;18:343351.

Calcium(n=44)

Calcium +vitamin D

(n=45)

Fallrisk

0.0

0.2

0.4

0.6

0.8

1.0

1.2

49%P = 0.01

Reduction in falls

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Effect of Vitamin D on Falls inAssisted-Living Residents

Mean age: 83.4 years, n = 625Serum 25 (OH)D levels: 25 to 90 nmol/L

Treatment: - 10,000 IU Vitamin D2 per week

then 1,000 IU per day or placebo

- all received 600 mg of calcium/day

Outcome (n) All subjects Compliant (>50%)

n = 625 (ns) n = 540 (sign.)

First fall (355) 0.82 [0.59-1.12] 0.70 [0.50-0.99]

All falls (1555) 0.73 [0.57-0.95] 0.63 [0.48-0.82]

Flicker et al. JAGS 2005. 53:1881-1888.

Effects of vitamin D and calcium supplementation on fal

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Effects of vitamin D and calcium supplementation on faland parameters of muscle function: a prospective,

randomized, double-blind multicenter studyMinne HW et al. Osteoporos Int 2006;17 Suppl 1:S212

Study: Germany Austria, 242 healthy subj. over age 70

Treatment: 1 y. 1000mg Ca vs. 1000mg Ca + 800IU Vit. D

Calcium Calcium +Vit.D p 80%)

Not taking own 71 0.70 (0.51 0.98)

Supplements

Age: 60yrs + 62 0.79 (0.64 0.98)

Jackson. et al, N Engl J Med 2006; 354:669-683

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RECORD STUDY

RCT in 21 centres in UK. Recruited 5,292community-dwelling women or men aged above70 with low trauma fractures.

Randomised to receive 800 IU vitamin D &

placebo, 1 g calcium & placebo, 800 IU vitamin D& 1 g calcium or double placebo daily.

Main outcome was further low trauma fractures,

but others included falls and mortality and QoL.

RECORD Trial Group, Lancet 2005; 365: 1621-1628.

RECORD STUDY

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RECORD STUDY

Noreduction

fractures,

falls or

mortality

RECORD Trial Group, Lancet 2005; 365: 1621-1628.

COCHRANE REVIEW OF

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COCHRANE REVIEW OFVITAMIN D AND FRACTURES

Vitamin D alone showed no significant effecton hip fracture (7 trials, 18,668 participants,RR 1.17, 95% CI 0.98-1.41).

Vitamin D with calcium marginally reducedhip fractures (7 trials, 10,376 participants, RR0.81, 95% CI 0.68 to 0.96), ...but the effect

appeared to be restricted to those living ininstitutional care.

Avenell et al, The Cochrane Database of Systematic Reviews 2005, Issue 3.

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The Effects of Vitamin D on Falls and Fractures:

What are the major factors contributingto the discrepant data?

Overview on factors that may influence the outcome

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1. Medical intervention related factors:

Dosage of Vitamin D (400 IU insufficient, better 800 to 1000?) Additional Calcium supplements (amount, type of calcium salt ?

Compliance with Vitamin D and/or Calcium intake

Vitamin D status (25-OH-D level at onset of intervention)

Amount of regular dietary calcium intake Other osteotropic medications (e.g. estrogen, thiazides?)

Overview on factors that may influence the outcomeof trials on reducing the risk of falls by Vitamin D

supplementation with or without calcium

Ringe JD: The Effect of Vitamin D on Falls and Fractures.Scand J Clin Chem 2012 (in press)

Overview on factors that may influence the outcome

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2. Patients related factors: Age, fitness, physical activity, number of previous falls Independent living in the community or institutionalized Prevalent diseases (e.g. Parkinson, Polyneuropathy)

Renal function (no or insuff. Vit.D activat. with CrCl

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Summary: Efficacy of Vitamin D and calciunon falls and factures (I)

A sufficient supply with Vitamin D and calcium isimportant for normal development and maintenance

of the skeleton

Vit. D together with Ca is recomended as a basic

therapy for all forms of osteoporosis (i.e. should be

given together with any specific medication)

Better effects in elderly, institutionalized, Vitamin D/

Ca-deficient people 800 IU Vitamin D seems to be superior to 400 IU

Summary: Efficacy Vitamin D and calcium

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Summary: Efficacy Vitamin D and calciumon falls and fractures (II)

Discrepant data between different trials due to criteriaof patient selection (age, general health, renalfunction), dosage of Vit. D, with or without Ca,compliance, comedication etc.

We suggest: Optimal results could be expected in:

Elderly institutionalized persons with Vit. D-insuffic.and normal renal function being compliant with daily800-1000 IU Vitamin D and 500-1000 mg Ca (adapted todietary Ca- intake) and adopting an high qualityassessment of falls

In elderly pat. with impaired renal function better usealfacalcidol 0.5 - 1g/d instead of plain vitamin D !!!

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Back-up

NICE guidelines:

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NICE guidelines:Secondary Prevention of Osteoporosis Bisphosphonates are recommended as first-line

treatment options for the secondary prevention of fragilityfractures

Adequate levels of calcium and vitamin D required to

ensure optimum effects of treatments for osteoporosis Calcium and/or vitamin D supplementation should be

provided unless clinicians are confident that women whoreceive treatment have an adequate calcium intake and

are vitamin D repleteAdapted from National Institute for Clinical Excellence. January 2005.

Bisphosphonates, selective oestrogen receptor modulators and parathyroid hormone for

the secondary prevention of osteoporotic fragility fractures in postmenopausal women.

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WHI: Calcium and Vitamin D for Osteoporosis

Jackson et al N Engl J Med 2006;354: 669-683

Not an osteoporotic population

High baseline calcium and Vitamin D intake

Vitamin D therapy only 400 IU/dayAdditional HRT in 52%

Selected characteristic (%) Ca + Vit D (18,176) PBO (18,106)

Mean Age (yrs) 62.4 62.4

White Caucasian 82.8 83.4Fx at age >55 yrs 10.7 10.9

No falls in last yr 61.6 61.9

BMI > 30 37.8 37.0

Total Ca intake > 1.2G/d 38.5 39.2

Total Vit D intake > 400 IU/d 41.9 42.3

Current HRT 51.5 52.4Hip T Score , -2.5 (6.7% popn) 3.0 4.0

Prevalence of Vitamin D-Insufficiency in German

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Study on Vitamin D supply in a representative cohor

without osteoporosis*:

Study population: n= 1343 (728 women, 615 men),

age range 20-99 y., homog. distribution

Blood sample Feb.Mai 2007 for 25-OH-D3, PTH, Ca etc.

MV 25-OH-D3 for all 1343 persons: 16,2 ng/ml

(16% < 8ng/ml, 37% 65 pg/ml

Prevalence of Vitamin D Insufficiency in German

*Ringe JD, Farahamd P, Kipshoven C, Rovati L. The DeVID Trial. Osteoporos Int 2008;19(Suppl):S46

FURTHER NEGATIVE STUDIES WITH VITAMIN D

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FURTHER NEGATIVE STUDIES WITH VITAMIN D

Cluster randomised trial of oral vitamin D 100,000 IUevery 3 months in 3,717 care home residents (1). Nodecrease in falls (RR 1.09, CI 0.95-1.25) or fractures(RR 1.48, CI 0.99-2.20)

(corr. to 1110 IU Vit. D/d, Calcium ?)

RCT of oral vitamin D 100,000 IU every 4 months in3,440 care home residents (2). No reduction infractures (HR 0.95, CI 0.8-1.20)

(corr. to 800 IU Vit. D/d, Calcium ?)

1. Law et al, Age Ageing, 2005. 2. Johansen et al, BGS, 2006.

VITAMIN D AND FX PREVENTION

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VITAMIN D AND FX PREVENTION

Bischoff-Ferrari et al, JAMA, 2005; 293: 2257-2264.

NORTHERN & YORKSHIRE STUDY

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NORTHERN & YORKSHIRE STUDY(n=3315, age >70y, 800 IU Vit. D, 1000mg Ca)

No reduction in fractures, falls or mortality

Porthouse et al, Br Med J 2005; 330: 1003-1008.

OR 95% CI

All Fractures 1.01 0.71-1.4

Hip Fractures 0.75 0.31-1.7

Falls 6 Months 0.99 0.81-1.2Falls 12 Months 0.98 0.79-1.2

Mortality 1.26 0.87-1.8