Fall prevention in older people: an update of the evidence

Medications for fall prevention, vitamin D supplementation – friend

or foe, systematic review evidence for step training as a fall prevention strategy

Stephen Lord

Medications for Fall Prevention?

Pharmaceutical company initiated trial

Myostatin antibody – mechanism for action

Myostatin inhibits skeletal muscle growth and a humanized monoclonal antibody binds and neutralizes myostatin leading to muscle hypertrophy

Loss of myostatin function is associated with muscle hyperplasia and hypertrophy with no known effect on internal organs1-5

Myostatin inhibition stimulates protein synthesis in muscle fibers, resulting in muscle hypertrophy7,8

4

Copyright © 2004. Reproduced with permission from MASSACHUSETTS MEDICAL SOCIETY.

1. McPherron et al. Nature 1997;387(6628):83-90.

2. Schuelke et al. N Engl J Med 2004;350(26):2682-8.

3. Mosher et al. PLoS Genet 2007;3(5):e79.

4. Grobet et al. Nat Genet 1997;17(1):71-4.

5. Clop et al. Nat Genet 2006;38(7):813-8.

6. Amirouche et al. Endocrinology 2009;150(1):286-94.

7. Rodriguez et al. J Cell Biochem 2011;112(12)3531-42.

8. Welle et al. Am J Physiol Endocrinol Metab 2011;300(6):E993-E1001.

Study Design

5

Population

• Elderly: age ≥75 years

• Fallers: ≥1 fall in last year

• Low muscle strength: assessed by grip, chair stand

• Exclusions: severe mobility impairments, etc

Objectives

• Primary: appendicular lean body mass (aLBM) at 6 months

• Secondary and exploratory

− Physical performance based measures (PBMs)

− Body composition, falls and related injuries

− The study was powered to detect differences in aLBM and several PBMs, but not falls or injuries

99 randomized to placebo and 102 to treatment

Body composition and performance based measures

Performance based measures

Secondary and Exploratory Measures

♦ Falls

• Incidence rate (IR) per patient year = 1.6 (LY) versus 2.0 (placebo); IR ratio = 0.82 (NS)

♦ Fat mass

• Decreased progressively in LY patients

• -0.3 kg (-1%) at 3 mos; -1.0 kg (-4%) at 6 mos(p<.001)

Conclusions

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Safety

• No observed safety issues preventing further clinical development

Efficacy

• Primary objective reached

– Increased aLBM by 0.43 kg (p<.001) at 6 months versus placebo (2.50%)

• Consistent improvements in power intensive performance based measures observed

– No effect on non-power intensive measures and isometric strength

Phase 3 trial not proceeding

Investigator initiated trial

Rivastigmine – mechanism for action

The role of the brainstem pedunculopontine nucleus (PPN) in gait and falls has been shown by neuroimaging, lesioning, and deep-brain stimulation studies

Parkinson’s disease is associated with loss of cholinergic cell bodies in the PPN and cholinergic output loss in the thalamus (the main target for cholinergic projection from the PPN).

Cholinergic loss also occurs in the nucleus basalis of Meynert in the forebrain, which projects to the cortex and is thought to contribute to cognitive dysfunction in Parkinson’s disease.

Loss of cholinergic function contributes to freezing and other gait changes, postural instability and cognitive dysfunction.

It is thought to work by inhibiting cholinesterase enzymes, which would otherwise break down the brain neurotransmitter acetylcholine

Main findings

• 130 patients with PD enrolled and randomly assigned 65 to the rivastigmine group and 65 to the placebo group.

• At week 32, compared with patients assigned to placebo (59 assessed), those assigned to rivastigmine (55 assessed) had: – improved step time variability for

• normal walking (ratio of geometric means 0·72, 95% CI 0·58–0·88)

• simple dual task walking RGM=(0·79; 0·62–0·99; p=0·045).

– But not • Complex dual task walking (RGM= 0·81, 0·60–1·09; p=0·17)

Falls

Incidence Rate ratio = 0.55 (0.38 to 0.81)

Secondary outcome measures

Conclusions

• Rivastigmine can improve gait stability and might reduce the frequency of falls in people with PD

• A phase 3 study is needed to confirm these findings and show cost-effectiveness of Rivastigmine treatment

Vitamin D supplementation:

friend or foe?

Mechanisms

• Vitamin D receptors on muscle

• Vitamin D receptors on nerve tissue

• People with vitamin D deficiency have less muscle mass, and have reduced lower limb strength, slower simple and choice stepping reaction time, poorer leaning balance, slower gait speed, poorer executive function and visuospatial ability

High dose trials

The incidence of falls differed significantly among the treatment groups: higher incidences in the 60 000 IU group (66.9%; 95% CI, 54.4%to 77.5%) and the 24 000 IU plus calcifediol group (66.1%; 95%CI, 53.5%-76.8%) group compared with the 24 000 IU group (47.9%; 95%CI, 35.8%-60.3%) (P = .048).

JAMA Intern Med. doi:10.1001/jamainternmed.2015.7148

2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture Women in the cholecalciferol (vitamin D – 500,000 IU) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03).

Meta-analyses show different results

• Bolland MJ, Grey A, Reid IR. Differences in overlapping meta-analyses of vitamin D supplements and falls. J Clin Endocrinol Metab. 2014;99(11):4265-4272. doi:10.1210/jc.2014-2562.

• 9. Bolland MJ, Grey A, Gamble GD, Reid IR. Vitamin D supplementation and falls: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2 (7):573-580. doi:10.1016/s2213-8587(14)70068-3.

“The vitamin D story seems to be following the familiar pattern observed with antioxidant vitamins. Enthusiasm for the health benefits of vitamin supplements is coupled with the belief that “vitamins” are inherently safe and reinforced by observational studies showing, essentially, that healthy people have higher vitamin levels. Then RCTs and meta-analyses proved that the supplements in fact increase mortality (β-carotene, vitamin E), or have no health benefits (vitamin A, vitamin C).”

Conclusions: Increased sunlight exposure did not reduce vitamin D deficiency or falls risk in frail older people. This public health strategy was not effective most likely due to poor adherence to the intervention.

Prevention and treatment of vitamin D deficiency: Osteoporosis Australia Consensus statement

To prevent vitamin D deficiency in people who receive less than optimal sun exposure, vitamin D supplementation is recommended:

• at least 600 IU per day for people under 70

• at least 800 IU per day for people over 70

• sun avoiders or those at high risk of deficiency (housebound or in residential care ) may require 1000-2000 IU per day

http://www.osteoporosis.org.au/sites/default/files/files/Vit%20D%20Position%20Statement%2010%202013%20V2(1).pdf

Vitamin D in drops and jubes

Conclusions

• Vitamin D in recommended daily or weekly doses should be provided to at-risk groups – frail older community dwellers and residents of RACFs

• Vitamin D testing is not required for these groups as it a) expensive, and b) the very low risk of side effects

• Vitamin D in mega-doses (half-yearly or yearly) should not be prescribed as two RCTs have now shown such doses increase fall risk

Stepping interventions for fall prevention

Systematic review on step training and falls

Background Older adults frequently use a protective stepping strategy to maintain balance at the critical moment of slipping or tripping.

(Rogers et al., 1996; McIlroy et al., 1993)

Training interventions focusing on the execution of correct, rapid and well-directed steps may have a very valuable role in preventing falls. Purpose of the systematic review To summarise the effects of stepping training on fall risk factors (e.g., strength) and the incidence of falls among older people. Included studies Randomised (RCT) or clinical controlled trials (CCT) Reactive and volitional stepping interventions Older (minimum age 60) people Data on falls or fall risk factors

16 RCTs/CCTs were selected 7 RCTs (n=660) were included in a meta-analysis Okubo et al., Br J Sports Med, 2016

Reactive and volitional step training

Reactive step training Exposure to repeated postural perturbations to evoke rapid balance reactions.

Volitional step training Practice rapid and appropriate steps in various directions.

Short term interventions (average 34 days)

High impact Individual supervision Expensive equipment

(e.g., special treadmill)

Long term interventions (average 105 days)

Individual or group Centre or home Easier and cheaper + Cognitive training

Effect of step training on falls prevention

Step training reduced falls 50%. Both reactive (-48%) and volitional (-57%) step training reduced falls in similar magnitude. The falls reduction effect was not affected by

• Participant’s living status (community vs institution), • Characteristics (healthy vs high-risk), • Intervention periods, and follow-up periods.

Study or Subgroup

2.3.1 Volitional step trainings

Shigematsu, 2008a

Shigematsu, 2008b

Yamada, 2013

Subtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 1.09, df = 2 (P = 0.58); I² = 0%

Test for overall effect: Z = 3.56 (P = 0.0004)

2.3.2 Reactive step trainings

Lurie, 2013

Mansfield, 2010

Pai, 2014

Shimada, 2004

Subtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 2.90, df = 3 (P = 0.41); I² = 0%

Test for overall effect: Z = 3.33 (P = 0.0009)

Total (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 4.37, df = 6 (P = 0.63); I² = 0%

Test for overall effect: Z = 4.83 (P < 0.00001)

Test for subgroup differences: Chi² = 0.38, df = 1 (P = 0.54), I² = 0%

log[Rate Ratio]

-0.5

-0.59

-1.05

-0.92

0.34

-0.69

-0.63

SE

0.57

0.48

0.31

0.36

0.65

0.3

0.46

Weight

7.0%

9.9%

23.8%

40.7%

17.6%

5.4%

25.4%

10.8%

59.3%

100.0%

IV, Random, 95% CI

0.61 [0.20, 1.85]

0.55 [0.22, 1.42]

0.35 [0.19, 0.64]

0.43 [0.27, 0.68]

0.40 [0.20, 0.81]

1.40 [0.39, 5.02]

0.50 [0.28, 0.90]

0.53 [0.22, 1.31]

0.52 [0.35, 0.76]

0.48 [0.36, 0.65]

Rate Ratio Rate Ratio

IV, Random, 95% CI

0.1 0.2 0.5 1 2 5 10

Favours [intervention] Favours [control]

Reactive step trainings

Volitional step trainings

Okubo et al., Br J Sports Med, 2016

Step training and fall risk factors

Step training improved Reaction time (simple reaction, choice stepping reaction)

Gait (timed up & go, gait speed)

Balance (single leg stance)

Balance recovery (after slip)

Did not improve Strength (knee extension strength, chair sit-to-stand)

No adequate evidence on Fear of falling Cognitive function

• Volitional step training may improve global cognition, executive function, short-term memory and dual-task ability

(Pichierri et al., 2012; Schoene et al., 2013; Teixeira et al., 2013)

Okubo et al., Br J Sports Med, 2016

How step training can be applied in practice?

Step training can be included as part of exercise fall prevention interventions.

This training could be either volitional or reactive but should be performed in an upright position and undertaken in response to environmental challenges which mimic common fall situations such as stepping onto a target, avoiding an obstacle or responding to a perturbation.

Reactive step training which requires a perturbation module and full body harness is not readily available but volitional step training can be applied to various settings including community exercise classes or an individual's home.

Okubo et al., Br J Sports Med, 2016

Falls prevention – what works

Highest level of evidence given by meta-analyses of RCTs

Gillespie LD et al. Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2012 Sep 12;9

Cameron ID et al. Interventions for preventing falls in older people in care facilities and hospitals. Cochrane Database Syst Rev. 2012 Dec 12;12:

Gold bar evidence scale

One good quality RCT

At least two good quality RCTs – little inconsistency

Multiple RCTs and/or systematic reviews –little inconsistency

Falls prevention – what works

High level balance exercise in group or home settings (functional balance exercises, Otago, Tai Chi)

Voluntary and reactive step training

Occupational therapy interventions (home safety modifications in association with transfer training and education) in high risk populations

Expedited first eye cataract surgery

Restriction of multifocal glasses use in older people who take part in regular outdoor activity

Pharmacist-led education and GP medication review

Podiatry intervention in people with disabling foot pain

Falls prevention – what works

Withdrawal of psychoactive medications

Intensive multidisciplinary assessment of high risk populations

Intensive interventions in hospitals

Comprehensive geriatric assessment in residential aged care

Vitamin D supplementation in residential aged care – excluding mega doses

Medication review in residential aged care

Thank you