The Effects of Vitamin D on Falls and Fractures

ECOO-Cairo April 26, 2012

Prof. Johann D. Ringe, MD Head of West German Osteoporosis Center (WOZ) Med. Klinik 4, Klinikum Leverkusen University of Cologne, Germany

What is the rationale behind the fracture reducing potency of Vitamin D (especially non-vertebral fractures)?
(= Hip-fractures and other Non-vert-fractures)

Pathogenesis of Non-vert. Fractures in Osteoporosis:

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

FALLS
- External factors - muscle weakness - Imbalance - Frailty

Fracture

Old knowledge: Severe osteomalacia is associated with muscle weakness (but longtime no link to Vit.D)
Trendelenburgs sign (1895):
When standing on one leg, the pelvis drops on the opposite side of the stance leg, due to weakness of abductor muscles of the hip (namely gluteus medius and minimus).

Description of 1,25-dihydroxyvitamin D3-receptor in human skeletal muscle tissue. Bischoff HA et al., Histochem J 2001;33:19-2415
Illustration from the first description by the German surgeon Friedrich Trendelenburg (1895)

Pathogenesis of Non-vert. Fractures

Dual effect of vitamin D

BONE
Reduction in: - Bone mass - Bone quality (microarchitecture) - Bone strenght

FALLS
- External factors - Frailty - D-hormone deficiency - Muscle weakness - Imbalance

Vit. D

Fracture

Pathogenesis of osteoporotic fractures: The important role of muscle strength and function was long time neglected

Reduced Muscle Mass + Function

No strain on bone

Sarkopenia

Osteopenia
Fracture

Falls

Dual effect of Vitamin D on bone and muscle reduces risk of osteopenia and falls and thereby fractures 1,25-Vit. D
+

Reduced Muscle Mass + Function Sarkopenia

No strain on bone
+

Osteopenia
Fracture

Falls

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

* Bischoff-Ferrari H. et al. J Bone Miner Res 2004;19:265-69

Pleiotropic way of action of Vitamin D has an effect on the risk of falls and fractures:
Calcium absorption
Parathyr.

Sec. Hyperparathyr.

Bone Resorption
Bone Formation Bone Mineralization

Bone mass Bone Quality Bone Strength

Muscle Strength
Muscle cells
Improved balance Cognitive abilities

Falls & Fractures

Evidence that Vitamin D (plus Calcium) reduces the risk of falls *

Highly significant effect on falls would suggest a risk reduction at least 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)

Risk of Falling with Calcium and Vitamin D Supplementation

Reduction in falls

122 women,

Age: 6399

1.2 1.0 0.8

Randomized, double-blind, controlled trial Calcium 1200 mg/day Calcium 1200 mg/day + vitamin D 800 IU/day 12-week duration Mean serum 25(OH)D 12 ng/ml at baseline Women living in long-term care units

Fall risk

49%
0.6
0.4 0.2 0.0

P = 0.01

Calcium (n=44)

Calcium + vitamin D (n=45)

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

Effect of Vitamin D on Falls in Assisted-Living Residents

Mean age: 83.4 years, n = 625 Serum 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) First fall (355) All falls (1555) All subjects Compliant (>50%) n = 625 (ns) n = 540 (sign.) 0.82 [0.59-1.12] 0.70 [0.50-0.99] 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 falls and parameters of muscle function: a prospective, randomized, double-blind multicenter study
Minne 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 25-OH-D3 (nmol/l) Falls per subjects (n) Body sway (mm) Quadr. str. (Newton) 38 0.69 12.9 175 Calcium +Vit.D 48 0.45 9.2 210 p< 0.01 0.01 0.01 0.01

TUG-test* (sec.)

8.1

7.3

0.01

* Timed up and go Test

Reducing the risk of falls by Vitamin D

Primary Analysis Odds ratio (95% CI) Vitamin D Referencesubstance

Pfeifer, et al, 2000 Bischoff, et al, 2003 Dukas, et al, 2004

(n=137) (n=122) (n=378)

0.47 (0.201.10) 0.68 (0.301.54) 0.53 (0.320.88) 0.69 (0.411.16)

Gallagher, et al, 2001 (n=246)

Graafmans, et al, 1996 (n=354) 0.91 (0.591.40) Pooled (uncorrected) (n=1237) 0.69 (0.530.88) Pooled (corrected) (n=1237) 0.78 (0.640.92) 624 of 1237 patients treatment with active analogs !!
CI = confidence interval According to Bischoff-Ferrari HA. JAMA. 2004;291:19992006; Pfeifer M, et al. J Bone Miner Res. 2000;15:11131118; Bischoff HA, et al. J Bone Miner Res. 2003;18:343351; Gallagher JC, et al. J Clin Endocrinol Metab. 2001;86:36183628; Dukas L, et al. J Am Geriatr Soc. 2004;52:230236; Graafmans WC, et al. Am J Epidemiol. 1996;143:11291136.

22%
0.1 0.5 1.0 5.0 10.0

Odds Ratio

Reducing the risk of falls by Vitamin D

(Importance of dosage per day)

Another meta-analysis from 2009 involving eight trials and 2426 individuals revealed that doses of Vitamin D up to 600 IU were ineffective, whereas higher doses that ranged from 700 to 1000 IU reduced risk of falling by about 20% *

* Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB et al. Fall prevention with supplemental and active forms of vitamin D: A meta-analysis of randomised controlled trials. BMJ 2009;339:339.b3692

Evidence that Vitamin D (plus Calcium) reduces the risk of fractures

Reduced Fracture Risk with Ca/D-Suppl.

1.2 P=0.02 1.0

Fracture RR (Hip, Wrist.,Spine

33%
0.8

0.6

0.4

0.2

Not significant in reducing falls !!!

0.0
Trivedi DP, et al. BMJ. 2003;326:469.

Untreated (n=1341)

Treated (n=1345)

5-year RCT, N=2686, age 65 to 85 y., Vitamin D = 100.000 IU every 4 months (equivalent to 833 IU/day)

Vitamin D and Calcium Supplementation Reduce Fracture Risk in Women with Osteoporosis
Population-based, three-year Danish intervention study Elderly, communitydwelling population Age 66 years Vitamin D=400 IU/day Calcium=1000 mg/day
1.2 p=0.025

Relative risk of fracture*

1.0 0.8 0.6 0.4 0.2 0.0

22%**

Controls (n=1273)

Vitamin D + calcium (n=2983)

*Humerus, distal forearm, vertebral column, pelvis, cervical femur, intertrochanteric femur **In the study population of women with osteoporosis

Adapted from Larsen ER et al J Bone Mineral Res 2004;19:370378.

Womens Health Initiative (WHI)

36,282 postmenopausal women age 50-79, mean 62.4 yrs BMI 29.0 + 5.9 52% taking estrogen 16.7% taking other bone medications 29% taking their own calcium supplements Usual mean calcium intake 1,150 mg/d Baseline 25(OH)D level 46 nmol/L (18.4 ng/ml) Intervention: 1000 mg calcium + 400 IU vitamin D Follow-up: mean of 7 years
Jackson. et al, N Engl J Med 2006; 354:669-683

WHI Fracture Results

Site Fractures (n) 374 378 1122 4260 HR 0.88 (0.72 1.08) 0.90 (0.74 1.10) 1.01 (0.90 1.14) 0.96 (0.91 1.02)

Hip Clinical vertebral Forearm All

Fracture rate: 14 rather than the expected 34/10,000 woman years

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

WHI Hip Fracture Risk Subset Analyses

Subset Adherent (> 80%) Not taking own Supplements Age: 60yrs + % of Population 59 HR 0.70 (0.52 0.96)

71

0.70 (0.51 0.98)

62

0.79 (0.64 0.98)

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

RECORD STUDY
RCT in 21 centres in UK. Recruited 5,292 community-dwelling women or men aged above 70 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
No reduction in fractures, falls or mortality

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

COCHRANE REVIEW OF VITAMIN D AND FRACTURES

Vitamin D alone showed no significant effect on hip fracture (7 trials, 18,668 participants, RR 1.17, 95% CI 0.98-1.41). Vitamin D with calcium marginally reduced hip fractures (7 trials, 10,376 participants, RR 0.81, 95% CI 0.68 to 0.96), ...but the effect appeared to be restricted to those living in institutional care.
Avenell et al, The Cochrane Database of Systematic Reviews 2005, Issue 3.

The Effects of Vitamin D on Falls and Fractures:

What are the major factors contributing to the discrepant data?

Overview on factors that may influence the outcome of 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)

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 outcome of trials on reducing the risk of falls by Vitamin D supplementation with or without calcium 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 <60 ml/min) Decrease in VDR-expression in muscle tissue with age ?

3. Study related factors:

Quality of fall and fracture assessment Measures to optimize patients adherence Follow-up of 25-OH-D, renal function

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

A sufficient supply with Vitamin D and calcium is important 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 on falls and fractures (II)

Discrepant data between different trials due to criteria of patient selection (age, general health, renal function), 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 daily 800-1000 IU Vitamin D and 500-1000 mg Ca (adapted to dietary Ca- intake) and adopting an high quality assessment of falls In elderly pat. with impaired renal function better use alfacalcidol 0.5 - 1g/d instead of plain vitamin D !!!

Back-up

NICE guidelines: Secondary Prevention of Osteoporosis

Bisphosphonates are recommended as first-line treatment options for the secondary prevention of fragility fractures 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 who receive treatment have an adequate calcium intake and are vitamin D replete
Adapted 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.

WHI: Calcium and Vitamin D for Osteoporosis

Not an osteoporotic population High baseline calcium and Vitamin D intake Vitamin D therapy only 400 IU/day Additional HRT in 52% Selected characteristic (%) Mean Age (yrs) White Caucasian Fx at age >55 yrs No falls in last yr BMI > 30 Total Ca intake > 1.2G/d Total Vit D intake > 400 IU/d Current HRT Hip T Score , -2.5 (6.7% popn) Ca + Vit D (18,176) 62.4 82.8 10.7 61.6 37.8 38.5 41.9 51.5 3.0 PBO (18,106) 62.4 83.4 10.9 61.9 37.0 39.2 42.3 52.4 4.0

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

Prevalence of Vitamin D-Insufficiency in Germany

Study on Vitamin D supply in a representative cohort 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% <12ng/ml, 94% < 32ng/ml = 80mmol/l) PTH: 29% upper normal tertile, 16% > 65 pg/ml
*Ringe

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

FURTHER NEGATIVE STUDIES WITH VITAMIN D

Cluster randomised trial of oral vitamin D 100,000 IU every 3 months in 3,717 care home residents (1). No decrease 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 in 3,440 care home residents (2). No reduction in fractures (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

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

NORTHERN & YORKSHIRE STUDY (n=3315, age >70y, 800 IU Vit. D, 1000mg Ca)
OR All Fractures Hip Fractures Falls 6 Months Mortality 1.01 0.75 0.99 1.26 95% CI 0.71-1.43 0.31-1.78 0.81-1.20 0.79-1.20 0.87-1.83

Falls 12 Months 0.98

No reduction in fractures, falls or mortality

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