vit-d-falls-fxs-ecoo-cairo-412
TRANSCRIPT
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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