Sarcopenia in Women

Sarcopenia and low vitamin D in the elderly woman: the undiagnosed epidemicIris Thiele Isip Tan MD, FPCP, FPSEMClinical Associate Professor, University of the Philippines College of MedicineSection of Endocrinology, Diabetes & MetabolismDepartment of Medicine, Philippine General Hospital

Sarcopenia

Greek, ‘lack of flesh’

Loss of muscle mass and strength with aging

Sarcopenia Disease or normal aging?

Sayer et al J Nutr Health Aging 2008;12(7):427-432

A Life Course Model of Sarcopenia

Sarcopenia

What It is NotSarcopenia: loss of skeletal muscle and strength with aging

Wasting: loss of weight driven by inadequate nutrition

Cachexia: loss of fat-free mass from hypermetabolism and hypercatabolism

Acute disuse atrophy: muscle mass is reduced but fiber number and specific force maintained with shift toward fast fiber types

Bross et al JCEM 1999;84(10):3420-30

SarcopeniaNo consensus on threshold of muscle loss to be used in definition

Absolute appendicular skeletal mass >2 SDs below mean of young adults

Skeletal muscle index (SMI) 1-2 SDs (Class 1) or >2 SDs (Class 2) of young adults

SMI = muscle mass/body mass X 100

Baumgartner at al Am J Epidemiol 1998;147:755-63

Melton at al J Am Geriatr Soc 2000;48:625-30

Janssen at al J Am Geriatr Soc 2002;50:889-96

Two-compartment Model of Body Composition

Body weight = fat mass + fat-free mass

Bross et al JCEM 1999;84(10):3420-30

Aging-associated Changes in Body Composition ↑ adiposity (more central distribution)

↓ fat-free mass (loss of muscle mass) 35-40% cumulative decline between 20-80 yr of age

No weight loss: muscle depletion with fat accumulation

SarcopeniaPotentially a greater public health concern for women Rates of decline in strength twice as high in men compared to women

Men on average have larger amounts of muscle mass

Men have shorter survival than women

Abellan Van Kan G. J Nutr Health & Aging 2009;13:708-12

Sarcopenia Changes in Muscle AnatomyPreferential atrophy of fast-twitch type II fibers (reduced reinnervation capacity vs type I fibers)

Reduced contractile tissue volume for locomotion and metabolism

Increase in intramuscular fat and connective tissue

Friction brake to slow contractile velocity

Bross et al JCEM 1999;84(10):3420-30

Scanning electron micrograph of skeletal muscle fibres

ST

EV

EG

SC

HE

ISS

NE

R/S

PL

Sarcopenia Changes in Muscle FunctionPreferential loss of type II fibers → less strength and power-generating capacity

Walking, stair climbing, rising from a chair and load carrying deteriorate

Increased risk of falls

Decreased oxidative capacity of skeletal muscle → decline in maximal aerobic capacity

Bross et al JCEM 1999;84(10):3420-30

Is there a link between vitamin D and sarcopenia?

How much vitamin D is enough?

Does supplemental vitamin D reduce falls?


Role of Vit D in Muscle FunctionVDR in skeletal muscles cells that specifically bind 1,25(OH)D3

Panel A ATP-dependent Ca uptake by SR vesicles isolated from rabbit skeletal muscle: vit. D-deficient (▢) vs vit. D-replete (▨)

Panel B Time course of ATP-dependent Ca uptake by SR vesicles isolated from chick skeletal muscle: vit. D-deficient (◦) vs vit. D-replete (△). ATP-independent Ca uptake in both preps (□).

Impairment of active calcium transport

Boland AR et al J Biochim Biophys Acta 1983;733:264

Role of Vit D in Muscle FunctionVDR in skeletal muscles cells that specifically bind 1,25(OH)D3

Role of vit D in phosphate transport Panel A Increased Na-dependent phosphate transport in skeletal muscle SR vesicles from vit. D-deficient chicks: (+) vit. D (△) vs (-) vit. D (◦)

Panel B Stimulatory action of 25OHD of the Na-linked component of phosphate uptake by chick embryo skeletal muscle myoblast cultures. Muscle cells treated 8h with 25OHD (250 ng/mL)

Boland AR et al J Biochim Biophys Acta 1983;733:264

Association between Vit D status and Physical Performance

The InCHIANTI Study

P: 976 persons age >65 y at baseline

I: Short physical performance battery (SPPB) and handgrip strength

O: Multiple linear regression to examine association between serum 25(OH)D, PTH and physical performance (adjusted for sociodemographic variables, behavioral characteristics, BMI, season, cognition, health conditions, creatinine, Hb and albumin)

M: Cross-sectional data from prospective population-based study

Houston et al J Gerontol A Biol Sci Med Sci 2007;62(4):440-46

Short Physical Performance Battery (SPPB)Used in the Established Populations for the Epidemiology Studies of the Elderly (EPESE)

Walking speed

Three measures added from 0 (worst) to 12 (best)


Ability to stand from a chair

Standing balance test

5 Highest performance level

0 Unable to do test

Selected Participant Characteristics

The InCHIANTI Study

0

25

50

75

100

<25 25 to <50 >=50

25

46

29

4938

14

Men Women

Serum 25(OH)D (mmol/L)

%

WomenSerum 25(OH)D

p<25 25 to <50 >50

Age 78.3 (0.6) 75.1 (0.4) 72.5 (0.6) <0.0001

Season (Nov-Feb, %) 55.9 38.3 22.4 <0.0001

PTH, ng/L 34.5 (1.3) 26.7 (1.0) 21.3 (1.4) <0.0001


Vit D Status and Adjusted Physical Performance Measures

The InCHIANTI Study


Physical Performance Measure

Serum 25(OH)D (nmol/L) p value for

<25 vs >25p value for <50 vs >50

p for trend

<2525 to <50

>50

Women

SPPB score*9.29 (0.19)

9.85 (0.14)

9.59 (0.20)

0.03 0.74 0.58

Handgrip strength*20.58 (0.60)

21.52 (0.41)

22.83 (0.57)

0.06 0.02 0.009

* Adjusted for sociodemographic variables, smoking status, physical activity, BMI, total energy intake, season, cognition, CHF, COPD, CVD and levels of creatinine, Hb and albumin

Women with lower 25OHD levels had lower SPPB scores and handgrip strength.

PTH Status and Adjusted Physical Performance Measures

The InCHIANTI Study


Physical Performance Measure

PTH Status(ng/L)

p value for 1st tertile vs 2nd & 3rd

tertiles

p value 1st and 2nd

tertiles vs 3rd tertile

p for trend1st

tertile2nd

tertile3rd

tertile

Women

SPPB score*9.58 (0.18)

9.73 (0.18)

9.60 (0.16)

0.69 0.82 0.44

Handgrip strength*22.29 (0.51)

21.69 (0.52)

21.00 (0.51)

0.14 0.12 0.08

* Adjusted for sociodemographic variables, smoking status, physical activity, BMI, total energy intake, season, cognition, CHF, COPD, CVD and levels of creatinine, Hb and albumin

Trend towards lower handgrip strength across PTH tertilesSPPB scores not significantly associated with PTH levels

Association between Vit D status and Physical Performance

The InCHIANTI Study

Low vitamin D status was associated with poor physical performance among elderly women (cross-sectional data)


Low Vit D/High PTH and Sarcopenia

The Longitudinal Aging Study Amsterdam

P: 1509 persons age >65 y in LASA cohort

I: Grip strength (n=1008) and appendicular skeletal muscle mass (n=331, DXA)

O: Multiple linear regression to examine association between serum 25(OH)D, PTH and grip strength and appendicular skeletal muscle mass

M: Baseline and 3-y data from prospective population-based study

Visser et al JCEM 2003;88:5766-72

copenia were tested by using sex/hormone product terms in additionalanalyses. Interaction between PTH and 25-OHD concentration wastested using the PTH/25-OHD product term in additional analyses. Fortesting interaction P ! 0.1 was considered statistically significant.

Results

Among the 1008 LASA participants with complete fol-low-up data, the mean change in grip strength during 3 yrof follow-up was "7.7 kg (sd 12.8) or "13.2% (sd 23.9%).Using these prospective data, sarcopenia was defined as aloss of grip strength greater than 40% and was experiencedby 136 respondents (13.5%). The mean 3-yr change in ASMM(n # 331) was $0.3 kg (sd 0.9) or $1.9% (sd 5.4%). A declinein ASMM was experienced by 37.5% of the respondents, and52 respondents (15.7%) met our definition of sarcopenia(ASMM loss % 3%).

Vitamin D deficiency, using the proposed definition of aserum concentration less than 25 nmol/liter (5), was ob-served for 9.6% of the study sample, and severe vitamin Ddeficiency (!12.5 nmol/liter) was observed for 1.3% of thestudy sample. Hyperparathyroidism (%7 pmol/liter) wasdetected in 3.8% of the study sample.

The baseline characteristics (1995–1996) for participantswith and without sarcopenia are shown in Table 1. Partici-pants who lost grip strength were older, weighed less, hada poorer health status (higher prevalence of stroke and ar-thritis), had a lower initial grip strength, and were morelikely to be female and never smoker. No differences inbaseline characteristics were observed between those withand without ASMM loss.

An association was observed between the 25-OHD cate-gories and sarcopenia (Fig. 1). Those with lower 25-OHDlevels were more likely to experience loss of grip strength(P # 0.001) and tended to experience a loss of ASMM (P #

0.09). In addition, those with higher PTH concentrationswere more likely to experience loss of grip strength (P # 0.02)and tended to lose more ASMM (P # 0.1) (Fig. 2).

Higher PTH concentration was associated with an in-creased risk of sarcopenia. Per unit increase in ln(PTH), therisk of sarcopenia was 1.52 [95% confidence interval (CI)0.97–2.39] based on grip strength and 3.52 (95% CI 1.43–8.67)based on ASMM after adjustment for all potential confound-ers. Higher 25-OHD concentration was protective of sar-copenia. Per unit increase in ln(25-OHD), the risk of sar-copenia was 0.55 (95% CI 0.36–0.83) based on grip strengthand 0.59 (95% CI 0.29–1.20) based on ASMM after adjustment

FIG. 1. Prevalence of grip strength loss (defined as loss %40%, studysample n # 1,008) and appendicular muscle mass loss (defined as loss%3%, study sample n # 331) during 3-yr follow-up according to cat-egories of baseline serum 25-OHD concentration. P value of !2 test.

TABLE 1. Baseline characteristics according to 3-yr change in grip strength and appendicular skeletal muscle mass

Grip strength (n # 1008) Appendicular skeletal muscle mass (n # 331)

Stable/gain(n # 872)Mean (SD)

Loss % 40%(n # 136)Mean (SD)

P Stable/gain(n # 279)Mean (SD)

Loss % 3%(n # 52)

Mean (SD)

P

Age (yr) 74.2 (6.1) 76.9 (6.5) 0.0001 73.7 (5.9) 74.9 (6.4) 0.2Body weight (kg) 75.3 (12.4) 71.8 (12.1) 0.002 75.1 (11.9) 74.8 (13.4) 0.9BMI (kg/m2) 26.8 (4.0) 26.8 (4.3) 0.9 26.7 (4.0) 26.2 (3.7) 0.4Physical activity (kcal/wk) 175 (198) 144 (204) 0.09 193 (209) 208 (191) 0.6Serum creatinine ("mol/liter) 89 (79–102)a 85 (78–99)a 0.2 90 (80–100)a 92 (75–102)a 0.8Chronic diseases (no.) 1.1 (1.0) 1.5 (1.3) 0.002 1.1 (1.0) 1.0 (1.0) 0.4Grip strength (kg) 59.0 (20.0) 49.0 (21.7) 0.0001Muscle mass (kg) 17.9 (4.3) 18.9 (4.3) 0.12Follow-up weight change (%) $0.6 (5.6) "1.8 (6.7) 0.0001 "0.5 (5.1) "1.9 (4.6) 0.06Female (%) 50.2 68.4 0.001 53.8 42.3 0.13Data collection in summer/spring (%) 41.6 37.5 0.4 42.7 40.4 0.8Smoking (%)

Never 34.9 44.1 30.1 34.6Former 48.5 35.3 52.7 46.2Current 16.6 20.6 0.02 17.2 19.2 0.7

Pulmonary disease (%) 13.8 11.8 0.5 11.1 11.5 0.9Cardiac disease (%) 24.4 27.9 0.4 21.9 15.4 0.3Peripheral atherosclerosis (%) 11.5 16.9 0.07 12.5 13.5 0.9Diabetes mellitus (%) 5.9 8.8 0.2 6.1 5.8 0.9Stroke (%) 6.2 11.0 0.04 5.4 5.8 0.9Arthritis (%) 45.9 62.5 0.001 50.5 40.4 0.2Cancer (%) 10.9 13.2 0.4 9.7 15.4 0.2a Median (interquartile range).

5768 J Clin Endocrinol Metab, December 2003, 88(12):5766–5772 Visser et al. • Vitamin D, PTH, and Sarcopenia

by on February 22, 2010 jcem.endojournals.orgDownloaded from







for all potential confounders. An interaction was observedbetween PTH and 25-OHD concentration for loss of ASMM(P ! 0.06). No interaction was observed between PTH and25-OHD concentration for loss of grip strength (P ! 0.4).

After adjustment for age and sex, participants with 25-OHD levels less than 25 nmol/liter were more likely toexperience loss of grip strength, compared with those withlevels 50" nmol/liter (Table 2). The odds ratio did not mark-edly change (from 2.67 to 2.57) after adjustment for all po-tential confounders. To investigate whether the associationbetween 25-OHD and sarcopenia was still present at higherlevels of 25-OHD, we repeated the analyses using four in-stead of three 25-OHD categories: less than 25, 25–49.9, 50–74.9, and 75" nmol/liter. The odds ratios for sarcopeniabased on grip strength were 4.41 (1.93–10.08), 1.99 (0.97–4.07), 2.05 (1.01–4.16), and 1.0, respectively, indicating thatpersons with 25-OHD levels between 50 and 74.9 nmol/literstill had an increased risk of sarcopenia. High PTH status wasalso associated with loss of grip strength. After adjustmentfor all potential confounders, participants in the highest ter-tile of PTH (4.0" pmol/liter) were 1.71 times more likely to

experience a loss of grip strength (95% CI 1.07–2.73), com-pared with those in the lowest tertile (#3.0 pmol/liter).

A strong association was observed between the 25-OHDcategories and loss of ASMM (Table 2). The adjusted oddsratio for loss of ASMM was 2.14 (95%CI 0.73–6.33) for par-ticipants with 25-OHD levels less than 25 nmol/liter and 2.25(1.11–4.56) for participants with 25-OHD between 25 and 50nmol/liter. Furthermore, persons with PTH levels 4.0 pmol/liter or greater were 2.35 times (95% CI 1.05–5.28) more likelyto experience loss of ASMM. The associations of PTH and25-OHD with sarcopenia were similar in men and women(for interaction P $ 0.12).

We also investigated whether the observed association ofPTH and 25-OHD with sarcopenia could be explained bydifferences in body weight change. Indeed, participants wholost ASMM experienced a larger weight change [%1.9% (sd4.6%)] during follow-up, compared with those withoutASMM loss [%0.5% (sd 5.1%), P ! 0.06]. However, when weadditionally adjusted for relative weight change in the lo-gistic regression models, the odds ratios were only slightlyattenuated. For example, the odds ratio for 25-OHD levelsless than 25 nmol/liter changed from 2.14 (0.73–6.33) to 2.24(95%CI 0.76–6.66). Adjustment for relative weight changealso did not change the relationship of PTH and 25-OHDwith loss of grip strength.

We also investigated the risk of sarcopenia using com-bined categories of PTH and 25-OHD. Participants with ahigh PTH concentration (4.0" pmol/liter) as well as a 25-OHD concentration less than 25 nmol/liter were 2.51 (95% CI1.12–5.62) times more likely to experience loss of gripstrength and 2.38 (95% CI 0.56–10.18) times more likely toexperience loss of ASMM, compared with persons with a lowPTH and a high 25-OHD concentration.

Discussion

The results of our study suggest that a lower 25-OHDconcentration and a higher PTH concentration increase therisk of sarcopenia (loss of grip strength and loss of appen-dicular muscle mass) in old age. These relationships werepresent after careful adjustment for health factors and life-style factors, including physical activity. The results are evenmore striking when considering that we used a large, pop-ulation-based cohort of older men and women that included

FIG. 2. Prevalence of grip strength loss (defined as loss $40%, studysample n ! 1,008) and appendicular muscle mass loss (defined as loss$3%, study sample n ! 331) during 3-yr follow-up according to tertilesof baseline serum PTH concentration. P value of !2 test.

TABLE 2. Adjusted odds ratios (95% confidence interval) for loss of grip strength and loss of appendicular skeletal muscle massaccording to categories of baseline concentration of 25-OHD and PTH

Loss of grip strength (n ! 1008) Loss of appendicular skeletal muscle mass(n ! 331)

Model 1OR (95% CI)

Model 2OR (95% CI)

Model 1OR (95% CI)

Model 2OR (95% CI)

25-OHD (nmol/liter)#25.0 2.67 (1.52–4.71)a 2.57 (1.40–4.70)a 1.96 (0.70–5.45) 2.14 (0.73–6.33)25.0–49.9 1.12 (0.72–1.74) 1.17 (0.74–1.83) 2.05 (1.06–3.95)a 2.25 (1.11–4.56)a

50.0" 1.0 1.0 1.0 1.0PTH (pmol/liter)

#3.0 1.0 1.0 1.0 1.03.0–3.9 1.31 (0.83–2.07) 1.39 (0.87–2.23) 1.51 (0.71–3.20) 1.59 (0.74–3.44)4.0" 1.56 (1.00–2.42)a 1.71 (1.07–2.73)a 1.81 (0.85–3.87) 2.35 (1.05–5.28)a

Model 1, Adjusted for age and sex; Model 2, additionally adjusted for smoking, in serum creatinine concentration, chronic disease, body massindex, season of data collection, and physical activity level.

a P # 0.05 vs. reference category.

Visser et al. • Vitamin D, PTH, and Sarcopenia J Clin Endocrinol Metab, December 2003, 88(12):5766–5772 5769

by on February 22, 2010 jcem.endojournals.orgDownloaded from

Lower 25OHD and higher PTH levels increase the risk of sarcopenia in older women.





Vitamin D and Bone Metabolism

GUT

RENAL DISTAL TUBULE

In vitamin D-deficient state, calcium absorption decreases Low calcium causes

increase in PTH secretion

PTH

Low Levels of Vitamin DCalcium reservoir of bone is depleted to correct for low calcium absorption in gut

Mobilization of calcium from bone

PTH

Balanced SystemCalcium absorption meets metabolic demands

Normal bone mineralization is maintained

Dietary calcium

CIRCULATION

Calcium reabsorption

1

23

4

VITAMIN D

VITAMIN D

Adapted from Holick M. Curr Opin Endocrinol Diabetes. 2002;9:87–98; DeLuca HF. Am J Clin Nutr. 2004;80(suppl 1):1689S–1696S; Lips P. Endocr Rev. 2001;22:477–501; Holick MF. J Nutr. 2005;135:2739S–2748S.

PARATHYROID

Threshold Effect

Calcium Absorption

32 ng/dL

Heaney R. Clin J Am Soc Nephrol 2008;3:1535-41

Vitamin D metabolic utilization

4,000 IU/day

Chief Dietary Sources of Vit D

Clinician’s Guide to the Prevention & Treatment of Osteoporosis National Osteoporosis Foundation, 2008

Vitamin D-fortified milk (400 IU/quart)Cereals (40-50 IU/serving)Egg yolksSaltwater fishLiver

Vitamin D: Recommended daily intake

The Hormone Foundation 2009

Recommended daily intake

Vitamin D Calcium

Under age 50 400-800 IU at least 1,000 mg

Over age 50 800-1,000 IU at least 1,200 mg

+ 100 IU oral vitamin D intake

= + 1 ng/mL (2.5 nmol/L)

serum 25(OH)D

Rule of ThumbPatient with a starting serum 25(OH)D of 15 ng/mL would require 1,500 IU/d to bring his level to 30 ng/mL

Heaney R. Clin J Am Soc Nephrol 2008;3:1535-41

Individualize requirements for vit D supplementation

Sunlight

exposureSkin

pigmentation

Baseline vitamin D level

Intestinal

absorption

rates

Type of vit D supplement

(D3 is 3x more potent

than D2)

Age (reduced photo-

conversion of

7-dehydrocholesterol

to vit D)

Genetic variation in vitamin D receptor activity

Brown S, Alternative Medicine Review 2008

Trial characteristics

22 vitamin D trials with AE outcomes

19 trials: adults only

Many too short to observe AEs

400-4,000 IU/d vit D3 (n=19)

5,000-10,000 IU/d vit D2 (n=2)

Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S

Most frequently reported

Hypercalcemia HypercalciuriaMore events in vit D group but difference with placebo group NS

Asymptomatic

Vitamin D Supplementation

Toxicity

Trial characteristics

7 trials reported kidney stone incidence

5 trials had no cases

1 trial reported NS difference

1 reported increase in stones (WHI)


Women’s Health Initiative

n = 36,282

400 IU vitamin D3 + 1000 mg Ca vs Ca alone

5.7 events/10,000 women-years exposure

Vitamin D Supplementation

Toxicity

Institute of MedicineTolerable Upper

Intake Level (TUIL)2,000 IU/day

No-observed-adverse-effect-level (NOAEL)

10,000 IU/day

Heaney R. J Musculoskelet Neuronal Interact 2006:6(4):334-

Serum 25(OH)D 32 ng/mL = minimum

daily intake of 2,600 IU vitamin D

(US residents)

80-90% of vitamin D is cutaneously produced

from sunlight

Limited by

age

higher latitudes

working indoors

use of sunscreen

skin pigmentation

cultural practices precluding skin exposure

Bathing suit exposure during summer

until skin just begins to turn pink

⬇skin production of

10,000 - 50,000 IU of vitamin D3

Adams et al. NEJM 1982;306:772-775

Effect on serum 25(OH)D

4 RCTs using artificial UVB light source

4 RCTs using solar exposure

Nursing home residents with low baseline 25(OH)D

Suberythemal UV light exposure = 25(OH)D 28-42 nmol/L after 3 mos.


“Fair evidence to suggest that artificial and solar exposure increases 25(OH)D levels in vitamin D-deficient and replete persons, including the elderly.”

Brannon et al, Am J Nutr 2008;88:483S-90S

“Is a specific level of sunlight exposure sufficient to maintain adequate vitamin D levels without increasing the risk of non-melanoma skin cancer or melanoma?”


No studies!

Sun Exposure

Toxicity


No fall, no fracture!

Schact et al, J Musculoskelet Neuronal Interact 2005;5(3):273-284

“Muscle ↔ Bone Unit”

Parallel to ↓ bone strength, a loss of muscle and performance (sarcopenia), neuromuscular deficiencies, deterioration in gait and postural stability occur.

Is Vitamin D insufficiency common?

Rationale for Vitamin D Prescribing in a Falls Clinic

P: 400 consecutive patients in a falls clinic

>65 y and have fallen at least once in preceding 8 weeks

I: Serum 25(OH)D

O: Multivariate analysis to determine independent variables for vitamin D status

M: Prospective observational descriptive study

Dhesi et al Age and Ageing 2002;31:257-71

Is Vitamin D insufficiency common?

Rationale for Vitamin D Prescribing in a Falls Clinic

Dhesi et al Age and Ageing 2002;31:257-71

0

12.5

25.0

37.5

50.0

<12.0 21.1-20.0 20.1-40.0 >40.1

Per

cent

age

25OHD ug/L

31.8

40.7

26.2

1.3

72.5% had hypovitaminosis D (25OHD <20 ug/L)

ObjectiveTo test the efficacy

of supplemental

vit D + Ca in preventing falls

among older individuals

Data SourceMEDLINE, EMBASE, BIOSIS and Cochrane database up to Aug 2008

8 RCTs (n=2426)

Study Selection

Vit D3 or D2 or oral

active vit D

Age >65

Minimum ff-up 3 mos

Falls as primary or

secondary endpoint

Meta-analysis

Vitamin D and the Risk of Falls

Bischoff-Ferrari et al, BMJ 2009;339:b3692

masking of treatment allocation; blinding; adherence;and withdrawals.16 17 Given that vitamin D is availableover the counter, trials had to be double blind to beincluded in the primary analysis. Open design trialsthat met the general eligibility criteria were includedin the sensitivity analysis.

Differences in vitamin D assays

Interlaboratory and interassay variation limit com-parison between trials for achieved 25(OH)Dconcentrations,18 19 with competitive protein bindingassays tending to yield higher concentrations thanradioimmunoassays.20 To account for these variations,

we adjusted the 25(OH)D values from the two studieswhere a competitive protein binding assay was used toradioimmunoassay equivalent values, according to themethod described by Lips and colleagues.20

Statistical methodsOutcomeswere analysedon an intention to treat basis byusing random effect models.21 In addition, we calculatedthe difference in relative risks to determine the numberneeded to treat to prevent a person from falling.Heterogeneity among studies was explored by prede-

fined covariates using the Q statistic as a test (significantfor P<0.10).22 The presence of heterogeneity suggeststhat the studies should not be pooled because of signifi-cant differences in results.23 In such cases, we exploredheterogeneity by dose of vitamin D and 25(OH)D con-centration achieved by using visual inspection and ran-dom effect meta-regression analysis. Additionalsubgroup analyses undertaken for supplemental vitaminD included type of vitamin D (D2v D3), gender, age (<80 years v !80 years), treatment duration (<12months v!12months), level of independence (independentv insti-tutionalised), and additional calcium supplementation.To evaluate publication bias, we used Begg’s test andEgger’s test with all eight trials from theprimary analysisor all 15 trials from the sensitivity analysis.24 Statisticalanalysis was performed with STATA version 8.0 (Stata-Corp, College Station, TX, USA).

Box 1 Fall ascertainment in trials with supplemental vitamin D included in the primaryanalysis

Broe et al, 2007w1

Falls were defined as “a sudden, unintentional change in position causing a resident to fallon the ground.” Nursing staff filled out an incident report at the time of the event, theprimary care physician verified it, and the information was entered into the incident reportdatabase.

Bischoff-Ferrari et al, 2006w2

Falls were defined as “unintentionally coming to rest on the ground, floor, or other lowerlevel.” Participants were asked to send a postcard after every fall, which was then followedby a telephone call from a staff member to assess the circumstances of the fall. Inaddition, falls were ascertained at every follow-up visit (every six months).

Prince et al, 2008w3

Falls were defined as “unintentionally coming to rest on the ground, floor, or other lowerlevel.” Patients were interviewed by study staff every six weeks via telephone or duringclinic visits. The number of falls that had occurred in the previous six weeks and theassociated features of the falls were recorded on a questionnaire.

Flicker et al, 2005w4

Falls were defined as “an event that results in a person coming to rest inadvertently on theground or other lower level.” Residential care staff recorded falls continuously in diaries,and these were mailed monthly to the central study centre.

Pfeifer et al, 2008w5

A fall was defined as “falling on to the floor or ground, or hitting an object like a chair orstair.” Not included as falls were controlled or intentional movements towards a chair orbed or a near fall in which the participant caught oneself before falling on to the floor orground. The number of falls was recorded in fall diaries—each day the participants had tomake a cross in the diary depending on whether a fall had occurred or not. Every twomonths, the study participants were also asked via telephone interviews whether a fallhad happened.

Bischoff et al, 2003w6

Falls were defined as “unintentionally coming to rest on the ground, floor, or other lowerlevel.” Coming to rest against furniture or a wall was not counted as a fall. Falls wererecorded by nurses on the inpatient units who had received training in the use of the fallprotocol (which included recording date, time, circumstances, and injuries).


A fall was defined as “falling on to the floor or ground or hitting an object like a chair orstair.”Not included as falls were controlled or intentionalmovements toward a chair or bedor a near fall in which the participant caught herself before falling on to the floor or ground.The number of falls was recorded by questionnaires throughout the trial period.

Graafmans et al, 1996w8

A fall was defined as “unintentionally coming to rest at a lower level or on the ground.”Participants were asked to record in a diary any falls they had during a 28-week period.Every week, participants registered whether or not they had fallen, as well as the location,time, and circumstances of each fall.

Prince et alw3

Broe et alw1

Flicker et alw4

Bischoff-Ferrari et alw2

Pfeifer et alw5

Bischoff et alw6

Pfeifer et alw7

Combined

Broe et alw1

(200 IU D2/day)

Broe et alw1

(400 IU D2/day)

Broe et alw1

(600 IU D2/day)

Graafmans et alw8

Combined

Relative risk (95% CI)High dose vitamin D

0.5 0 50.1 10

Favourssupplementalvitamin D

Favourscontrol

Low dose vitamin D

Pooled relativerisk (95% CI)0.81 (0.71 to 0.92)


Fig 2 |Fall prevention with high dose (700-1000 IU a day) andlow dose (200-600 IU a day) of supplemental vitamin D. Boxesrepresent relative risks, and the size of the boxes isproportional to the size of the high dose supplementalvitamin D trials included in the primary analysis. Error barsrepresent 95% confidence intervals. Shaded boxes indicatetrials with vitamin D3, and white boxes indicate those withvitamin D2

RESEARCH

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Meta-analysis


700-1000 IU/day

Vit D2

Vit D3

masking of treatment allocation; blinding; adherence;and withdrawals.16 17 Given that vitamin D is availableover the counter, trials had to be double blind to beincluded in the primary analysis. Open design trialsthat met the general eligibility criteria were includedin the sensitivity analysis.

Differences in vitamin D assays

Interlaboratory and interassay variation limit com-parison between trials for achieved 25(OH)Dconcentrations,18 19 with competitive protein bindingassays tending to yield higher concentrations thanradioimmunoassays.20 To account for these variations,

we adjusted the 25(OH)D values from the two studieswhere a competitive protein binding assay was used toradioimmunoassay equivalent values, according to themethod described by Lips and colleagues.20

Statistical methodsOutcomeswere analysedon an intention to treat basis byusing random effect models.21 In addition, we calculatedthe difference in relative risks to determine the numberneeded to treat to prevent a person from falling.Heterogeneity among studies was explored by prede-

fined covariates using the Q statistic as a test (significantfor P<0.10).22 The presence of heterogeneity suggeststhat the studies should not be pooled because of signifi-cant differences in results.23 In such cases, we exploredheterogeneity by dose of vitamin D and 25(OH)D con-centration achieved by using visual inspection and ran-dom effect meta-regression analysis. Additionalsubgroup analyses undertaken for supplemental vitaminD included type of vitamin D (D2v D3), gender, age (<80 years v !80 years), treatment duration (<12months v!12months), level of independence (independentv insti-tutionalised), and additional calcium supplementation.To evaluate publication bias, we used Begg’s test andEgger’s test with all eight trials from theprimary analysisor all 15 trials from the sensitivity analysis.24 Statisticalanalysis was performed with STATA version 8.0 (Stata-Corp, College Station, TX, USA).

Box 1 Fall ascertainment in trials with supplemental vitamin D included in the primaryanalysis

Broe et al, 2007w1

Falls were defined as “a sudden, unintentional change in position causing a resident to fallon the ground.” Nursing staff filled out an incident report at the time of the event, theprimary care physician verified it, and the information was entered into the incident reportdatabase.

Bischoff-Ferrari et al, 2006w2

Falls were defined as “unintentionally coming to rest on the ground, floor, or other lowerlevel.” Participants were asked to send a postcard after every fall, which was then followedby a telephone call from a staff member to assess the circumstances of the fall. Inaddition, falls were ascertained at every follow-up visit (every six months).

Prince et al, 2008w3

Falls were defined as “unintentionally coming to rest on the ground, floor, or other lowerlevel.” Patients were interviewed by study staff every six weeks via telephone or duringclinic visits. The number of falls that had occurred in the previous six weeks and theassociated features of the falls were recorded on a questionnaire.

Flicker et al, 2005w4

Falls were defined as “an event that results in a person coming to rest inadvertently on theground or other lower level.” Residential care staff recorded falls continuously in diaries,and these were mailed monthly to the central study centre.


A fall was defined as “falling on to the floor or ground, or hitting an object like a chair orstair.” Not included as falls were controlled or intentional movements towards a chair orbed or a near fall in which the participant caught oneself before falling on to the floor orground. The number of falls was recorded in fall diaries—each day the participants had tomake a cross in the diary depending on whether a fall had occurred or not. Every twomonths, the study participants were also asked via telephone interviews whether a fallhad happened.

Bischoff et al, 2003w6

Falls were defined as “unintentionally coming to rest on the ground, floor, or other lowerlevel.” Coming to rest against furniture or a wall was not counted as a fall. Falls wererecorded by nurses on the inpatient units who had received training in the use of the fallprotocol (which included recording date, time, circumstances, and injuries).


A fall was defined as “falling on to the floor or ground or hitting an object like a chair orstair.”Not included as falls were controlled or intentionalmovements toward a chair or bedor a near fall in which the participant caught herself before falling on to the floor or ground.The number of falls was recorded by questionnaires throughout the trial period.

Graafmans et al, 1996w8

A fall was defined as “unintentionally coming to rest at a lower level or on the ground.”Participants were asked to record in a diary any falls they had during a 28-week period.Every week, participants registered whether or not they had fallen, as well as the location,time, and circumstances of each fall.

Prince et alw3

Broe et alw1

Flicker et alw4

Bischoff-Ferrari et alw2

Pfeifer et alw5

Bischoff et alw6

Pfeifer et alw7

Combined

Broe et alw1

(200 IU D2/day)

Broe et alw1

(400 IU D2/day)

Broe et alw1

(600 IU D2/day)

Graafmans et alw8

Combined

Relative risk (95% CI)High dose vitamin D

0.5 0 50.1 10

Favourssupplementalvitamin D

Favourscontrol

Low dose vitamin D



Fig 2 |Fall prevention with high dose (700-1000 IU a day) andlow dose (200-600 IU a day) of supplemental vitamin D. Boxesrepresent relative risks, and the size of the boxes isproportional to the size of the high dose supplementalvitamin D trials included in the primary analysis. Error barsrepresent 95% confidence intervals. Shaded boxes indicatetrials with vitamin D3, and white boxes indicate those withvitamin D2

RESEARCH

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200-600 IU/day

Meta-analysis


Vit D2

Vit D3

individuals, in which a significant inverse relationshipwas found between dose and the risk of sustaining atleast one fall (beta estimate for dose: !700 IU v <700IU="0.337; P=0.02). Figure 3 also suggests that a 25(OH)D concentration of 60 nmol/l is required for fallprevention. This possibility was likewise confirmed bya meta-regression of 1447 individuals (two trials didnot provide 25(OH)D dataw4 w8), which indicated a sig-nificant inverse relationship between 25(OH)D serumconcentration and the risk of sustaining at least one fall(beta estimate for 25(OH)D concentration: !60 nmol/lv <60 nmol/l="0.586; P=0.005).

Primary subgroup analyses with trials assessing high dosesof supplemental vitamin DIn subgroup analyses of the trials that assessed a highdose of supplemental vitamin D (700-1000 IU), thepooled relative risk reduction was 12% in trials thatused vitamin D2 compared with 26% for trials thatused vitamin D3 (P=0.28; table 2). The combinedeffect of calcium plus vitamin D compared with pla-cebo in one study showed a relative risk reduction of19%.w2 The main effect of vitamin D, either vitamin Dcompared with placebo or vitamin D plus calciumcompared with calcium only, was tested in six studies.The pooled relative risk reduction for these six studieswas 23% (relative risk 0.77, 95% CI 0.65 to 0.92); thus,the main effect of vitamin D may not depend on addi-tional calcium supplementation. The effect of vitaminD in women was tested in six studies (n=1468), whichhad a pooled relative risk reduction of 15% comparedwith 19% in men and women combined. Data on menfrom two trials (n=211) were limited.w1 w2 Treatmentduration did not modulate the effect of vitamin D sig-nificantly: fall reduction was 38% with a treatmentduration of less than 12 months in three small trials(relative risk 0.62, 95% CI 0.42 to 0.91) comparedwith 17% with a treatment duration of 12 months ormore in four larger trials (relative risk 0.83, 95% CI0.72 to 0.96; P=0.07). The benefits of 700-1000 IUvita-min D a day on risk of falls were present in both ambu-latory and institutionalised older individuals, as well asin trials with a mean age 65-79 years or higher.

Sensitivity analysis of supplemental vitamin DIn a sensitivity analysis, we examined the effect size forsupplemental vitamin D when including studies

meeting less stringent quality criteria. Seven studieswere identified for the sensitivity analysis,w9-w15 sixthrough our MeSH term search and one in theabstracts of the American Society for Bone andMineral Research (table 4).w12 Three of these trials

Table 3 | Primary pooled analysis for low doses of supplemental vitamin D (<700 IU) and the prevention of falls

Study (daily dose of vitamin D)Number ofparticipants

Number offallers/total

treated


controlEffect

relative riskLower95% CI

Upper95% CI

Q testP value I2 Fall reduction

Broe et al, 2007w1(200) (200 IU D2) 51 15/26 11/25 1.31 0.76 2.27 — — —

Broe et al, 2007w1(400) (400 IU D2) 50 15/25 11/25 1.36 0.79 2.35 — — —

Broe et al, 2007w1(600) (600 IU D2) 50 15/25 11/25 1.36 0.79 2.35 — — —

Graafmans et al, 1996w8 (400 IU D3) 354 62/177 66/177 0.94 0.71 1.24 — — —

Primary pooled analysis(w1(200,400,600),w8)

505 107/253 99/252 1.10 0.89 1.35 0.42 0% +10% (ns)

Q test: P<0.100 indicates heterogeneity.I2 estimates above 25% are considered to represent modest heterogeneity, and values above 50% represent large heterogeneity beyond chance.ns=not significant.

Dose of vitamin D2 or vitamin D3 (IU)

Fall prevention by dose of vitamin D

Rela

tive

risk

(95%

CI)

200 D 2

400 D 2

400 D3 2

600 D 2

700 D 3

800 D 2

800 D 3

1000 D 20

w1 w1 w8 w1 w2 w1 w5,w6,w7 w3,w4

0.5

1.0

1.5

2.0

2.5

25-hydroxyvitamin D3 serum concentration (nmol/l)

Fall prevention by 25-hydroxyvitamin D3 level

Rela

tive

risk

(95%

CI)

044 48 60 66 85 95

w1(400) w1(200,600) w1(800),w3 w6,w7 w5 w2

0.5

1.0

1.5

2.0

2.5

Fig 3 |Fall prevention by dose and achieved 25(OH)Dconcentrations. Circles represent relative risks and error barsrepresent 95% confidence intervals. Trendline is based onseries of effect sizes (circles). There were three trials with 800IU D3,

w5 w6 w7 so the effect size for 800 IU D3 is the pooledresult from these three trials. Likewise, the effect size for1000 IU D2 is the pooled result from the two trials with 1000IU D2.

w3 w4 We have listed the same dose D2 and D3 separatelyin the graph to account for their potential different impact onfall reduction. As there were two data points from the Broe etal trial that reached 48 nmol/l,w1 two trials that reached 60nmol/l,w1 w3 and two trials that reached 66 nmol/l,w6 w7 wepooled each of the sets. On the basis of visual inspection offigure 3, the benefits of vitamin D for fall risk started at a doseof 700 IU a day

RESEARCH

page 6 of 11 BMJ | ONLINE FIRST | bmj.com

Meta-regression

Vit D dose and risk of >1 fall


Meta-regression

Serum 25OHD and risk of >1 fall


individuals, in which a significant inverse relationshipwas found between dose and the risk of sustaining atleast one fall (beta estimate for dose: !700 IU v <700IU="0.337; P=0.02). Figure 3 also suggests that a 25(OH)D concentration of 60 nmol/l is required for fallprevention. This possibility was likewise confirmed bya meta-regression of 1447 individuals (two trials didnot provide 25(OH)D dataw4 w8), which indicated a sig-nificant inverse relationship between 25(OH)D serumconcentration and the risk of sustaining at least one fall(beta estimate for 25(OH)D concentration: !60 nmol/lv <60 nmol/l="0.586; P=0.005).

Primary subgroup analyses with trials assessing high dosesof supplemental vitamin DIn subgroup analyses of the trials that assessed a highdose of supplemental vitamin D (700-1000 IU), thepooled relative risk reduction was 12% in trials thatused vitamin D2 compared with 26% for trials thatused vitamin D3 (P=0.28; table 2). The combinedeffect of calcium plus vitamin D compared with pla-cebo in one study showed a relative risk reduction of19%.w2 The main effect of vitamin D, either vitamin Dcompared with placebo or vitamin D plus calciumcompared with calcium only, was tested in six studies.The pooled relative risk reduction for these six studieswas 23% (relative risk 0.77, 95% CI 0.65 to 0.92); thus,the main effect of vitamin D may not depend on addi-tional calcium supplementation. The effect of vitaminD in women was tested in six studies (n=1468), whichhad a pooled relative risk reduction of 15% comparedwith 19% in men and women combined. Data on menfrom two trials (n=211) were limited.w1 w2 Treatmentduration did not modulate the effect of vitamin D sig-nificantly: fall reduction was 38% with a treatmentduration of less than 12 months in three small trials(relative risk 0.62, 95% CI 0.42 to 0.91) comparedwith 17% with a treatment duration of 12 months ormore in four larger trials (relative risk 0.83, 95% CI0.72 to 0.96; P=0.07). The benefits of 700-1000 IUvita-min D a day on risk of falls were present in both ambu-latory and institutionalised older individuals, as well asin trials with a mean age 65-79 years or higher.

Sensitivity analysis of supplemental vitamin DIn a sensitivity analysis, we examined the effect size forsupplemental vitamin D when including studies

meeting less stringent quality criteria. Seven studieswere identified for the sensitivity analysis,w9-w15 sixthrough our MeSH term search and one in theabstracts of the American Society for Bone andMineral Research (table 4).w12 Three of these trials

Table 3 | Primary pooled analysis for low doses of supplemental vitamin D (<700 IU) and the prevention of falls

Study (daily dose of vitamin D)Number ofparticipants


treated


controlEffect

relative riskLower95% CI

Upper95% CI

Q testP value I2 Fall reduction

Broe et al, 2007w1(200) (200 IU D2) 51 15/26 11/25 1.31 0.76 2.27 — — —

Broe et al, 2007w1(400) (400 IU D2) 50 15/25 11/25 1.36 0.79 2.35 — — —

Broe et al, 2007w1(600) (600 IU D2) 50 15/25 11/25 1.36 0.79 2.35 — — —

Graafmans et al, 1996w8 (400 IU D3) 354 62/177 66/177 0.94 0.71 1.24 — — —

Primary pooled analysis(w1(200,400,600),w8)

505 107/253 99/252 1.10 0.89 1.35 0.42 0% +10% (ns)

Q test: P<0.100 indicates heterogeneity.I2 estimates above 25% are considered to represent modest heterogeneity, and values above 50% represent large heterogeneity beyond chance.ns=not significant.

Dose of vitamin D2 or vitamin D3 (IU)

Fall prevention by dose of vitamin D

Rela

tive

risk

(95%

CI)

200 D 2

400 D 2

400 D3 2

600 D 2

700 D 3

800 D 2

800 D 3

1000 D 20

w1 w1 w8 w1 w2 w1 w5,w6,w7 w3,w4

0.5

1.0

1.5

2.0

2.5

25-hydroxyvitamin D3 serum concentration (nmol/l)

Fall prevention by 25-hydroxyvitamin D3 level

Rela

tive

risk

(95%

CI)

044 48 60 66 85 95

w1(400) w1(200,600) w1(800),w3 w6,w7 w5 w2

0.5

1.0

1.5

2.0

2.5

Fig 3 |Fall prevention by dose and achieved 25(OH)Dconcentrations. Circles represent relative risks and error barsrepresent 95% confidence intervals. Trendline is based onseries of effect sizes (circles). There were three trials with 800IU D3,

w5 w6 w7 so the effect size for 800 IU D3 is the pooledresult from these three trials. Likewise, the effect size for1000 IU D2 is the pooled result from the two trials with 1000IU D2.

w3 w4 We have listed the same dose D2 and D3 separatelyin the graph to account for their potential different impact onfall reduction. As there were two data points from the Broe etal trial that reached 48 nmol/l,w1 two trials that reached 60nmol/l,w1 w3 and two trials that reached 66 nmol/l,w6 w7 wepooled each of the sets. On the basis of visual inspection offigure 3, the benefits of vitamin D for fall risk started at a doseof 700 IU a day

RESEARCH

page 6 of 11 BMJ | ONLINE FIRST | bmj.com

25OHD >60 nmol/L pooled RR 0.77, 95% CI 0.65-0.90)

Some observations

Vitamin D and Risk of Falls

Trials assessing impact of vit D on falling more likely to have positive

results when conducted in institutions

Presence of nursing staffMore accurate ascertainment of fallsHigher supplement compliance

Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

Risk of Falls in Elderly High-risk Women Effect of Ergocalciferol added to Calcium

P: 302 community-dwelling ambulatory older women aged 70-90 y living in Perth, Australia

Serum 25(OH)D <24.0 ng/mL

History of falling in the previous year

I: Ergocalciferol (Vit D2) 1000 IU/d + Calcium Citrate 1000 mg/d vs Calcium Citrate 1000 mg/d + placebo

O: Risk of having at least one fall over 1 year

M: Population-based, double-blind RCT

Prince et al Arch Intern Med 2008;168(1):103-108

ment significantly reduced the percentage of subjects whosustained 1 fall (OR, 0.50; 95% CI, 0.28-0.88) but notthe percentage with multiple falls (Figure 2).

EXPLANATORY ANALYSIS

In the ergocalciferol group, supplementation consider-ably improved the 25OHD status in summer/autumn andwinter/spring, whereas the 25OHD status of the controlgroup improved only in summer/autumn (Figure 4). Inwinter/spring, the mean circulating 25OHD level was 28.1%higher in the ergocalciferol group compared with the con-trol group and in summer/autumn was 12.5% higher.

ADVERSE EVENTS

During the study period, there were no differences be-tween the ergocalciferol and the control groups in therate of incident cancer (ergocalciferol group, 0.7%; con-trol group, 3.3%), ischemic heart disease (ergocalciferolgroup, 1.3%; control group, 2.0%), stroke (ergocalcif-erol group, 2.0%; control group, 2.0%), constipation (er-gocalciferol group, 10.6%; control group, 11.9%), or frac-ture (ergocalciferol group, 2.6%; control group, 2.0%).One participant in the ergocalciferol group had mildasymptomatic hypercalcemia on 1 occasion.

COMMENT

The risk of falling increases with age and is the most fre-quent cause of fractures in elderly patients. This studyshowed that supplementation with ergocalciferol and cal-cium is associated with a 19% reduction in the RR of fall-ing in noninstitutionalized women with vitamin D in-sufficiency and high risk of falling compared with patientsgiven calcium alone. The size of the treatment effect isconsistent with the CI for RR reported in a recent meta-analysis of the effect of cholecalciferol.3 However, thereare important new findings related to the study designand outcomes that are of interest.

First, the seasonal variation in falling has been shownto be due in large part to the critical role of seasonal varia-tion in 25OHD levels. In this study, the effect of increas-ing 25OHD levels by mouth was principally confined toan effect on reducing the risk of falling in winter/springwhen the 25OHD levels were substantially lower in thecontrol group than in the ergocalciferol group. In summer/autumn, the risk of falling and 25OHD levels in the con-trol group approximated those of the ergocalciferol group.Thus, the effectiveness of the intervention could be con-sidered to be the result of the maintenance of higher sum-mer/autumn 25OHD levels, attained through increasedexposure to UV-B, through winter/spring. These data arealso consistent with the hypothesis that a 25OHD levellower than 24.0 ng/mL is a reasonable predictor of indi-viduals who may benefit from supplementation in winter/spring.

A seasonal effect of increased falling risk in winter hasbeen shown in a New Zealand study.15 In addition, a sea-sonal variation in hip fracture, usually caused by falling,has been shown in several epidemiological studies. In bothSydney and New York City, more hip fractures occur incolder months than warmer months,16,17 whereas stud-ies in Perth have shown that 25OHD levels in patientswith hip fractures were related to ambient sunshine andto ambient sunshine exposure in the 2 months before frac-ture.18 Taken together, these studies suggest that low

0.00 0.75 1.000.25 0.50 1.501.25Odds Ratio

2 or more falls:OR, 0.86 (95% CI, 0.50-1.49)†

1 Fall:OR, 0.50 (95% CI, 0.28-0.88)†

Summer/autumn:OR, 0.81 (95% CI, 0.46-1.42)†

Winter/spring:OR, 0.55 (95% CI, 0.32-0.96)†

Faller baseline height adjusted:OR, 0.61 (95% CI, 0.37-0.99)!

Faller :OR, 0.66 (95% CI, 0.41-1.06)!

Figure 2. Effects of treatment on falls. “Faller” refers to participant who hadat least 1 fall during the study period; CI indicates confidence interval; OR,odds ratio; asterisk, logistic regression analysis; dagger, multinomial logisticregression analysis; error bars, 95% CIs.

40

10

30

20

0

27.8% 27.2%

First Fall inSummer/Autumn

25.2%

35.8%

First Fall inWinter/Spring

P <.05

Perc

enta

ge o

f Sub

ject

s

Ergocalciferol + calcium citratePlacebo + calcium citrate

Figure 3. Percentages of subjects who had at least 1 fall, by season of firstfall. Percentages of fallers were compared using !2 testing.

80

10

30

40

50

70

60

20

0

Seru

m 2

5OHD

Con

cent

ratio

n, n

mol

/L

Summer/autumnBaseline

Winter/spring

P <.001

Ergocalciferol +Calcium Citrate

P <.001

Placebo +Calcium Citrate

Figure 4. Effect of season and treatment on the 25-hydroxyvitamin D(25OHD) status during the study. Error bars represent standard deviations.Means were compared using 1-factor repeated-measures analysis ofvariance. To convert serum 25OHD to nanograms per milliliter, divide by2.496.

(REPRINTED) ARCH INTERN MED/ VOL 168 (NO. 1), JAN 14, 2008 WWW.ARCHINTERNMED.COM106

©2008 American Medical Association. All rights reserved. on February 22, 2010 www.archinternmed.comDownloaded from


53% (n=80) of Vit D group vs 62.9% (n=95) of control group had falls

n = 83 (47%)

n = 92 (53%)




ADVERSE EVENTS


COMMENT




0.00 0.75 1.000.25 0.50 1.501.25Odds Ratio


1 Fall:OR, 0.50 (95% CI, 0.28-0.88)†




Faller :OR, 0.66 (95% CI, 0.41-1.06)!


40

10

30

20

0

27.8% 27.2%


25.2%

35.8%


P <.05Pe

rcen

tage

of S

ubje

cts



80

10

30

40

50

70

60

20

0

Seru

m 2

5OHD

Con

cent

ratio

n, n

mol

/L


Winter/spring

P <.001


P <.001





Prince at al Arch Intern Med 2008;168(1):103-108




ADVERSE EVENTS


COMMENT




0.00 0.75 1.000.25 0.50 1.501.25Odds Ratio


1 Fall:OR, 0.50 (95% CI, 0.28-0.88)†




Faller :OR, 0.66 (95% CI, 0.41-1.06)!


40

10

30

20

0

27.8% 27.2%


25.2%

35.8%


P <.05

Perc

enta

ge o

f Sub

ject

s



80

10

30

40

50

70

60

20

0

Seru

m 2

5OHD

Con

cent

ratio

n, n

mol

/L


Winter/spring

P <.001


P <.001






Risk of Falls in Ambulatory Older Men and Women Effect of Cholecalciferol and Calcium

P: 199 men and 246 women >65 y and living at home

I: 700 IU of cholecalciferol + 500 mg calcium citrate malate or placebo

O: Risk of falling at least once during follow-up (3 y)

M: Double-blind placebo-controlled randomized trial

Bischoff-Ferrari et al Arch Intern Med 2006;166:424-30

ily women were studied.1,9,29 One explanation may be thatambulatory women have lower muscle strength and anincreased susceptibility to falls than ambulatory men.5-7

Only among less active men who stayed on treatmentcould a possible benefit not be excluded. However, thisresult was not significant.

Cholecalciferol-calcium supplementation was more suc-cessful in reducing falls among less active individuals, andprimarily among less active women with a 65% fall reduc-tion. This benefit was enhanced among less active womenwho continued to receive treatment throughout the 3-yearfollow-up, leading to a 74% fall reduction. This may pos-

80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 36Time, mo

Cum

ulat

ive

% o

f Sub

ject

s W

ho F

ell

Cum

ulat

ive

% o

f Sub

ject

s W

ho F

ell

A

Cholecalciferol-Calcium (n = 77)Placebo (n = 93)

80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 36Time, mo

B


Figure 1. Cumulative percentage of falls by treatment group and sex. A, The women who received cholecalciferol (vitamin D) plus calcium citrate malate had lowerrates of falls starting after 12 months and then throughout the follow-up compared with women in the placebo group. B, In men, both groups had similar rates offalls throughout the study.

80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 36

Time, mo

Cum

ulat

ive

% o

f Sub

ject

s W

ho F

ell

Cum

ulat

ive

% o

f Sub

ject

s W

ho F

ell

A


80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 36

Cum

ulat

ive

% o

f Sub

ject

s W

ho F

ell

C


Time, mo

80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 36

Cum

ulat

ive

% o

f Sub

ject

s W

ho F

ell

D


80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 36


B

Figure 2. Cumulative percentage of falls by treatment group and activity level. A, Less active women who received cholecalciferol (vitamin D) plus calcium citratemalate had lower rates of falls starting after 12 months and then throughout the follow-up compared with women in the placebo group. B, In more active women,both groups had similar rates of falls throughout the study. C and D, In less active (C) and more active (D) men, the rate of falls was not consistently lower in thecholecalciferol-calcium group or the placebo group.

(REPRINTED) ARCH INTERN MED/ VOL 166, FEB 27, 2006 WWW.ARCHINTERNMED.COM428


Sex difference in response to Vit D3-calcium? ↓Risk of falling in women but not in men

Women Men

OR 0.54 (95% CI 0.30,0.97) OR 0.93 (95% CI 0.50,1.72)

Bischoff-Ferrari et al Arch Intern Med 2006;166:424-30

Baseline 25OHD level did not modulate the treatment effect.

Research has not identified the

minimum 25(OH)D level for maximal

benefit in fall prevention

Trials indicate mean values of 75 nmol/L and 99 nmol/L? higher values might confer benefit

Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

Some observations

Vitamin D and Risk of Falls

Randomized controlled trials Vitamin D and the Risk of Falls

TrialVit D dose/ preparation

ug (IU)/d

Duration of trial

25(OH)D level achieved

nmol/LOutcome

Muscle performance

SatoPfeiffer

Bischoff

25(1000) D220 (800) D320 (800) D3

3 y2 mo3 mo

846666

+++

Falls

BischoffBroe

FlickerGrant

17.5 (700) D320 (800) D220 (800) D220 (800) D3

3 y5 mo2 y5 y

9975NA62

+++

NullDawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

Potential candidates as functional indicators

Setting the EAR* for Vitamin D

* Estimated Average Requirement

Indicator Indicator of Suboptimal Status

Calciotropic function

Parathyroid hormone Stimulated level of PTH

Calcium absorptionPercentage absorption of Ca improves when Vit D provided

Fracture riskIncrease in fracture risk relative to adequate Vit D status

Muscle strength Muscle strength tests

Serum calcium and phosphorus

Relative hypocalcemia and hypophosphatemia

Bone turnover markersIncreased bone resorption and decreased bone formation

Whiting & Calvo, J Nutr 2005;135:304-9

Serum 25(OH)D

<25 nmol/L 25-75 nmol/L >75 nmol/L

Deficiency Insufficiency Sufficiency

Dawson-Hughes B, Am J Clin Nutr 2008:88(suppl);537S-40S

Variability of vit D concentration by geographical location

Differences in assay methodology

Optimal level of 25(OH)D 30 ng/mL determined in a Caucasian population

What cut-off value defines low vit D status?

Goal of vit D supplementation?

Serum 25(OH)D greater than an accepted cutpoint (e.g. 30 ng/ml)

Upper limit of normal (a value that varies between laboratories)

Binkley et al, JCEM 2008; 92;2130-5




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