FRAX

and

the

assessment

of

fracture

probability

in

men

and

women

from

the

UK

Summary

A

fracture

risk

assessment

tool

-LRB-

FRAX

-RRB-

is

developed

based

on

the

use

of

clinical

risk

factors

with

or

without

bone

mineral

density

tests

applied

to

the

UK

Introduction

Several

multi-factorial

diseases

-LRB-

e.g.

diabetes

hypertension

-RRB-

are

defined

on

the

basis

of

important

risk

factors

for

the

clinical

outcome

Hypertension

for

example

is

defined

from

the

measurement

of

blood

pressure

that

provides

information

on

the

likelihood

of

stroke

Hypercholesterolaemia

and

osteoporosis

are

also

examples

In

the

case

of

osteoporosis

bone

mineral

density

-LRB-

BMD

-RRB-

is

measured

both

to

provide

a

diagnosis

and

to

yield

information

on

fracture

risk

-LSB-

-RSB-

Many

well-controlled

prospective

studies

with

dual

energy

X-ray

absorptiometry

-LRB-

DXA

-RRB-

particularly

in

elderly

women

indicate

that

the

risk

of

fracture

about

doubles

for

each

SD

reduction

in

BMD

-LSB-

-RSB-

The

measurement

of

a

risk

factor

for

diagnostic

use

however

can

only

capture

one

aspect

of

the

likelihood

of

the

outcome

when

the

disease

is

multifactorial

and

in

osteoporosis

assessment

with

BMD

captures

a

minority

of

the

fracture

risk

For

example

the

annual

incidence

of

hip

fracture

increases

approximately

between

the

ages

of

and

years

but

from

the

known

relationship

between

BMD

and

fracture

risk

and

the

loss

of

bone

with

age

it

is

expected

that

hip

fracture

risk

would

rise

only

fourfold

-LSB-

-RSB-

Thus

the

increase

in

risk

with

age

is

approximately

sevenfold

greater

than

can

be

explained

on

the

basis

of

BMD

alone

The

imperfect

capture

of

risk

with

BMD

alone

poses

several

problems

for

the

clinical

assessment

of

fracture

risk

In

the

context

of

population

screening

with

BMD

alone

the

performance

characteristics

of

the

test

are

less

than

optimal

in

terms

of

the

trade-off

between

sensitivity

and

specificity

-LSB-

-RSB-

Thus

osteoporotic

fractures

affect

a

substantial

minority

of

the

population

but

intervention

thresholds

based

on

BMD

alone

lack

sensitivity

over

most

reasonable

assumption

i.e.

the

detection

rate

is

low

For

example

at

the

age

of

years

the

proportion

of

women

with

osteoporosis

is

approximately

-LSB-

-RSB-

The

proportion

of

these

who

will

fracture

in

the

next

years

-LRB-

i.e.

positive

predictive

value

-RRB-

is

about

The

detection

rate

for

these

fractures

-LRB-

sensitivity

-RRB-

is

however

low

and

of

fragility

fractures

would

arise

in

women

without

osteoporosis

given

a

test

like

BMD

where

the

fracture

risk

doubled

for

each

SD

decrease

-LSB-

-RSB-

Low

sensitivity

is

one

of

the

reasons

why

wide-spread

population

screening

is

not

widely

recommended

in

women

at

the

menopause

-LSB-

-RSB-

Moreover

a

normal

BMD

measurement

is

no

guarantee

that

a

fracture

will

not

occur

The

use

of

risk

factors

that

add

information

on

fracture

risk

independently

of

BMD

improves

the

sensitivity

of

the

assessment

for

any

specificity

-LSB-

-RSB-

Over

the

past

several

years

we

have

undertaken

a

series

of

meta-analyses

to

identify

clinical

risk

factors

for

fracture

that

provide

independent

information

on

fracture

risk

-LSB-

-RSB-

The

analyses

were

based

on

the

primary

data

from

prospective

population

based

studies

This

permits

the

inter-dependence

of

each

of

the

candidate

risk

factors

to

be

examined

so

that

they

can

be

accurately

combined

for

clinical

use

In

the

case

of

the

clinical

risk

factors

BMI

is

used

as

a

continuous

variable

so

that

its

distribution

is

preserved

by

the

addition

of

dichotomous

variables

-LSB-

-RSB-

For

hip

fracture

prediction

the

gradient

of

risk

-LRB-

increase

in

fracture

risk

per

standard

deviation

increase

in

risk

score

-RRB-

for

the

CRFs

is

comparable

to

the

use

of

DXA

alone

and

the

gradient

of

risk

is

further

enhanced

by

the

addition

of

BMD

to

the

CRFs

-LSB-

-RSB-

These

inter-relationships

assessed

from

multiple

populations

and

validated

in

independent

cohorts

permit

the

more

accurate

identification

of

individuals

who

will

fracture

so

that

the

average

risk

in

any

given

proportion

of

the

population

identified

for

treatment

will

be

higher

-LSB-

-RSB-

These

considerations

indicate

that

assessment

can

be

improved

by

the

integration

of

clinical

risk

factors

with

or

without

BMD

In

other

words

treatment

should

be

directed

not

only

on

the

basis

of

T-score

for

BMD

but

also

on

the

independent

contribution

of

other

validated

risk

factors

However

the

use

of

different

metrics

-LRB-

the

T-score

gradients

of

risk

risk

ratios

etc

-RRB-

is

confusing

for

clinicians

and

patients

alike

For

this

reason

there

has

been

interest

in

the

development

of

algorithms

that

express

absolute

risk

or

the

probability

of

fracture

within

a

given

time

period

-LSB-

-RSB-

as

has

been

done

for

cardiovascular

and

other

diseases

-LSB-

-RSB-

The

aim

of

the

present

study

was

to

develop

a

model

for

the

clinical

assessment

of

fracture

probability

in

men

and

women

based

on

the

epidemiology

of

the

UK

Methods

Cohorts

In

order

to

identify

the

relevant

risk

factors

we

used

baseline

and

follow-up

data

from

nine

prospective

population-based

cohorts

comprising

the

Rotterdam

Study

The

European

Vertebral

Osteoporosis

Study

-LRB-

later

the

European

Prospective

Osteoporosis

Study

-LRB-

EVOS/EPOS

-RRB-

The

Canadian

Multicentre

Osteoporosis

Study

-LRB-

CaMos

-RRB-

Rochester

Sheffield

Dubbo

a

cohort

from

Hiroshima

and

two

cohorts

from

Gothenburg

Details

of

each

of

the

cohorts

have

been

recently

published

elsewhere

-LSB-

-RSB-

Baseline

and

outcome

variables

Height

and

weight

were

measured

using

standard

techniques

in

all

cohorts

Body

mass

index

-LRB-

BMI

-RRB-

was

calculated

as

weight

divided

by

height

squared

-LRB-

-RRB-

and

used

as

a

continuous

variable

BMD

was

assessed

at

the

femoral

neck

by

DXA

with

the

exception

of

the

two

Gothenburg

cohorts

in

which

BMD

was

measured

elsewhere

Femoral

neck

BMD

was

used

as

a

continuous

variable

-LRB-

cohort-specific

Z-scores

excluding

the

two

cohorts

from

Gothenburg

-RRB-

The

clinical

risk

factors

utilised

were

those

identified

from

the

previous

meta-analyses

-LSB-

-RSB-

These

comprised

a

parental

history

of

hip

fracture

exposure

to

systemic

glucocorticoids

a

prior

history

of

fragility

fracture

current

smoking

high

intake

of

alcohol

-LRB-

or

more

units

daily

on

average

-RRB-

and

the

presence

of

rheumatoid

arthritis

as

an

indicator

for

secondary

osteoporosis

Fracture

ascertainment

in

the

primary

cohorts

was

undertaken

by

self-report

-LRB-

Sheffield

EVOS/EPOS

Hiroshima

-RRB-

and/or

verified

from

hospital

or

central

data-bases

-LRB-

Gothenburg

CaMos

DOES

Sheffield

EVOS/EPOS

Rochester

Rotterdam

-RRB-

Models

used

Four

models

were

constructed

from

the

risk

factor

analysis

to

compute

fracture

probabilities

These

comprised

the

probability

of

hip

fracture

with

and

without

BMD

and

the

probability

of

other

major

osteoporotic

fractures

-LRB-

clinical

spine

forearm

and

proximal

humerus

-RRB-

with

and

without

BMD

For

each

model

fracture

and

death

as

continuous

hazard

functions

were

computed

using

a

Poisson

regression

-LSB-

-RSB-

and

detailed

in

the

Appendix

In

brief

for

each

risk

factor

all

significant

interactions

terms

that

were

identified

by

meta-analysis

were

entered

-LRB-

with

age

time

sex

and

the

risk

factor

-RRB-

with

and

without

BMD

-LSB-

-RSB-

Interactions

that

were

significant

for

hip

fracture

risk

were

also

entered

into

the

model

for

other

osteoporotic

fractures

and

also

included

in

the

model

for

death

Where

interactions

noted

in

the

mega-analyses

were

no

longer

significant

for

both

hip

fracture

and

other

osteoporotic

fractures

these

were

omitted

in

a

step-wise

manner

by

dropping

the

interaction

with

the

largest

p

value

For

the

death

hazard

all

significant

interactions

for

fracture

risk

were

included

and

thereafter

omitted

if

appropriate

in

a

step-wise

manner

as

described

for

the

fracture

hazard

Epidemiology

The

incidence

of

hip

forearm

and

proximal

humerus

fractures

in

the

UK

was

taken

from

Singer

et

al.

-LSB-

-RSB-

Vertebral

fractures

can

be

classified

as

clinically

overt

fracture

that

is

a

symptomatic

fracture

that

comes

to

clinical

attention

or

a

morphometric

fracture

which

includes

both

symptomatic

and

asymptomatic

fractures

For

the

purposes

of

this

study

the

clinical

definition

of

a

vertebral

fracture

was

used

Because

data

on

vertebral

fracture

risk

in

the

UK

are

scarce

with

a

great

deal

of

variation

in

reported

rates

-LSB-

-RSB-

the

clinical

vertebral

fracture

incidence

was

calculated

by

assuming

that

the

ratio

of

clinical

vertebral

fracture

to

hip

fracture

would

be

similar

in

the

UK

compared

to

Sweden

-LSB-

-RSB-

The

validity

of

the

assumption

can

not

be

directly

tested

but

in

the

case

of

long

bone

fractures

there

is

a

close

concordance

of

relative

incidence

at

different

fracture

sites

despite

marked

differences

in

absolute

risk

-LSB-

-RSB-

Swedish

fracture

risk

data

were

taken

from

Kanis

et

al.

-LSB-

-RSB-

The

models

were

then

calibrated

so

that

the

mean

hazard

functions

of

fracture

-LRB-

and

death

-RRB-

equalled

that

of

the

UK

as

detailed

in

the

Appendix

Input

and

output

variables

Individual

patient

details

comprise

age

-LRB-

to

years

-RRB-

sex

weight

-LRB-

in

kg

-RRB-

and

height

-LRB-

in

cm

-RRB-

BMI

is

automatically

computed

from

height

and

weight

Dichotomised

risk

variables

are

then

entered

A

prior

fragility

fracture

-LRB-

yes/no

-RRB-

Parental

history

of

hip

fracture

-LRB-

yes/no

-RRB-

Current

tobacco

smoking

-LRB-

yes/no

-RRB-

Ever

long-term

use

of

oral

glucocorticoids

-LRB-

yes/no

-RRB-

Rheumatoid

arthritis

-LRB-

yes/no

-RRB-

Other

causes

of

secondary

osteoporosis

-LRB-

yes/no

-RRB-

Daily

alcohol

consumption

of

three

or

more

units

daily

-LRB-

yes/no

-RRB-

A

distinction

is

made

between

rheumatoid

arthritis

and

other

secondary

causes

of

osteoporosis

Rheumatoid

arthritis

carries

a

fracture

risk

over

and

above

that

provided

by

BMD

-LSB-

-RSB-

Whereas

this

may

hold

true

for

other

secondary

causes

of

osteoporosis

the

evidence

base

is

weak

Of

the

many

secondary

causes

of

osteoporosis

the

following

have

been

consistently

documented

to

be

associated

with

a

significant

increase

in

fracture

risk

Untreated

hypogonadism

in

men

and

women

e.g.

bilateral

oophorectomy

or

orchidectomy

anorexia

nervosa

chemotherapy

for

breast

cancer

hypopituitarism

-LSB-

-RSB-

Inflammatory

bowel

disease

e.g.

Crohn

's

disease

and

ulcerative

colitis

-LSB-

-RSB-

It

should

be

noted

that

the

risk

is

in

part

dependent

on

the

use

of

glucocorticoids

but

an

independent

risk

remains

after

adjustment

for

glucocorticoid

exposure

-LSB-

-RSB-

Prolonged

immobility

e.g.

spinal

cord

injury

Parkinson

's

disease

stroke

muscular

dystrophy

ankylosing

spondylitis

-LSB-

-RSB-

Organ

transplantation

-LSB-

-RSB-

Type

I

diabetes

-LSB-

-RSB-

Thyroid

disorders

e.g.

untreated

hyperthyroidism

over-treated

hypothyroidism

-LSB-

-RSB-

Whereas

there

is

strong

evidence

for

the

association

of

these

disorders

and

fracture

risk

the

independence

of

these

risk

factors

from

BMD

is

uncertain

It

was

conservatively

assumed

therefore

that

the

fracture

risk

was

mediated

via

low

BMD

but

with

a

risk

ratio

similar

to

that

noted

in

rheumatoid

arthritis

From

an

operational

view

where

the

field

for

rheumatoid

arthritis

is

entered

as

yes

a

risk

is

computed

with

and

without

BMD

If

the

field

for

other

secondary

osteoporosis

is

also

filled

as

yes

this

does

not

contribute

to

the

calculation

of

fracture

probability

Conversely

where

the

field

for

rheumatoid

arthritis

entered

as

no

and

the

field

for

secondary

osteoporosis

is

yes

the

same

β

coefficients

as

used

for

rheumatoid

arthritis

contribute

to

the

computation

of

probability

where

BMD

is

not

entered

In

the

presence

of

BMD

however

no

additional

risk

is

assumed

in

the

presence

of

secondary

osteoporosis

since

its

independence

of

BMD

is

uncertain

If

any

of

the

fields

for

dichotomous

variables

is

not

completed

a

negative

response

is

assumed

Fractures

probability

can

then

be

calculated

The

output

-LRB-

without

BMD

-RRB-

comprises

the

probability

of

hip

clinical

spine

shoulder

or

wrist

fracture

and

the

probability

of

hip

fracture

-LRB-

Fig.

-RRB-

Fig.

and

output

for

the

FRAX

model

Femoral

neck

BMD

can

additionally

be

entered

either

as

a

Z-score

or

a

T-score

The

transformation

of

Z

to

T-score

and

vice

versa

is

derived

for

the

NHANES

III

database

for

female

Caucasians

aged

years

-LSB-

-RSB-

When

entered

calculations

give

the

probabilities

as

defined

above

with

or

without

the

inclusion

of

BMD

Results

Clinical

risk

factors

The

contribution

of

single

clinical

risk

factors

is

shown

in

Table

for

men

and

women

aged

years

In

the

example

the

BMI

is

set

at

In

the

absence

of

BMD

hip

fracture

probabilities

were

higher

in

women

than

in

men

Each

clinical

risk

factor

had

a

different

significance

for

hip

fracture

probability

with

a

family

history

having

the

least

and

a

prior

fracture

the

greatest

weight

in

the

absence

of

BMD

The

rank

order

of

weighting

differed

for

the

major

osteoporotic

fractures

For

example

a

parental

history

of

hip

fracture

was

a

strong

risk

factor

close

to

that

provided

by

a

prior

fragility

fracture

The

contribution

of

age

to

the

assessment

of

probability

is

shown

in

Table

In

both

men

and

women

there

was

greater

than

difference

in

hip

fracture

probability

between

the

age

of

years

-LRB-

no

risk

factors

-RRB-

and

years

-LRB-

parental

history

of

hip

fracture

-RRB-

Table

probability

-LRB-

-RRB-

of

a

major

osteoporotic

fracture

or

hip

fracture

in

men

and

women

aged

years

according

to

the

presence

of

a

single

clinical

risk

factor

Without

BMDT-score

SDMenWomenMenWomenOsteoporoticaHipOsteoporoticaHipOsteoporoticaHipOsteoporoticaHipNo

clinical

risk

Parental

history

of

hip

Current

cigarette

Alcohol

intake

units

Rheumatoid

Oral

Previous

fragility

BMI

is

set

at

The

right-hand

panels

show

probabilities

at

a

T-score

of

SD

at

the

femoral

neckaHip

clinical

spine

humeral

or

forearm

fractureTable

probability

of

fracture

-LRB-

-RRB-

at

the

sites

shown

for

men

and

women

with

a

BMI

of

according

to

age

and

the

presence

or

absence

of

a

single

risk

factor

in

the

absence

of

BMD

Osteoporotic

fractureaHip

-LRB-

a

-RRB-

MenNo

clinical

risk

Parental

history

of

hip

Current

cigarette

Alcohol

intake

units

Rheumatoid

Oral

Previous

fragility

-LRB-

b

-RRB-

WomenNo

clinical

risk

Parental

history

of

hip

Current

cigarette

Alcohol

intake

units

Rheumatoid

Oral

Previous

fragility

aClinical

spine

hip

humeral

or

forearm

fracture

The

presence

of

more

than

one

risk

factor

increased

fracture

probability

in

an

incremental

manner

For

example

in

women

aged

years

with

a

BMI

of

the

hip

fracture

probability

was

With

one

clinical

risk

factor

the

probability

ranged

from

to

depending

on

the

risk

factor

With

two

risk

factors

the

range

was

and

with

and

risk

factors

the

ranges

were

and

respectively

In

the

presence

of

all

six

clinical

risk

factors

the

probability

of

hip

fracture

was

The

effect

of

several

clinical

risk

factors

on

the

probability

of

a

major

osteoporotic

fracture

is

shown

in

Fig.

for

a

woman

aged

years

and

a

BMI

of

In

women

with

rheumatoid

arthritis

there

was

a

increase

in

fracture

probability

compared

with

those

without

rheumatoid

-LRB-

from

to

-RRB-

When

women

additionally

took

oral

glucocorticoids

and

had

a

prior

fracture

there

was

a

fourfold

increase

in

fracture

probability

Fig.

of

combinations

of

clinical

risk

factors

on

the

probability

of

a

major

osteoporotic

fracture

in

women

aged

years

and

a

BMI

of

-LSB-

-RSB-

A

higher

or

lower

BMI

had

a

marked

effect

on

fracture

probability

-LRB-

Fig.

-RRB-

For

example

in

women

at

the

age

of

years

the

hip

fracture

probability

in

the

absence

of

risk

factors

was

with

a

BMI

of

but

was

fourfold

lower

-LRB-

-RRB-

at

a

BMI

of

At

each

level

of

BMI

fracture

probability

increased

with

an

increasing

number

of

clinical

risk

factors

Fig.

probability

of

hip

fracture

-LRB-

-RRB-

in

women

aged

years

according

to

the

number

of

clinical

risk

factors

with

a

BMI

of

-LRB-

left-hand

panels

-RRB-

and

a

BMI

of

-LRB-

right-hand

panels

-RRB-

The

intervals

reflect

the

different

weights

afforded

by

different

risk

factors

and

provide

a

range

of

probabilities

-LSB-

-RSB-

Bone

mineral

density

The

relationship

between

fracture

probability

and

BMD

is

shown

in

Table

In

general

fracture

risk

increased

with

increasing

age

and

decreasing

T-score

At

low

T-scores

however

fracture

probabilities

decreased

with

age

a

phenomenon

more

marked

in

men

than

in

women

For

example

at

the

age

of

years

the

probability

of

hip

fracture

was

in

men

with

a

T-score

of

SD

and

this

fell

progressively

with

age

so

that

at

the

age

of

years

the

probability

was

and

at

the

age

of

years

was

Table

fracture

probability

-LRB-

-RRB-

in

men

and

women

from

the

UK

with

a

BMI

of

and

no

clinical

risk

factors

according

to

age

and

T-score

at

the

femoral

neckAgeT-score

-LRB-

SD

-RRB-

-LRB-

years

-RRB-

-LRB-

a

-RRB-

Hip

fracture

0.10.10.41.34.716.0600.10.20.61.95.615.6700.20.51.12.65.912.9800.61.11.93.46.110.7901.21.82.53.85.68.3

-LRB-

b

-RRB-

Hip

fracture

0.10.10.20.83.211.7600.10.20.41.44.413.5700.10.40.92.46.316.2800.51.02.14.49.519.7901.22.03.55.89.816.9

-LRB-

c

-RRB-

Osteoporotic

fracturea

.52.73.55.19.220.9603.03.54.56.811.522.2703.64.35.58.212.820.9803.24.05.27.611.316.9903.13.95.16.99.713.5

-LRB-

d

-RRB-

Osteoporotic

fracturea

.03.33.85.28.517.7604.24.85.67.912.623.0705.66.88.411.518.230.4805.87.510.113.821.734.3905.17.19.913.820.030.3

aHip

clinical

spine

humerus

or

forearm

fracture

The

differences

in

probabilities

between

men

and

women

were

much

less

marked

for

any

given

age

and

T-score

than

the

differences

seen

with

the

use

of

clinical

risk

factors

alone

At

a

fixed

BMD

-LRB-

SD

in

Table

-RRB-

the

difference

in

probability

between

men

and

women

was

less

evident

For

example

the

hip

fracture

probability

ratio

-LRB-

women/men

-RRB-

with

glucocorticoid

use

was

in

the

absence

of

BMD

but

at

a

T-score

of

SD

In

the

case

of

all

major

osteoporotic

fractures

probabilities

remained

higher

in

women

than

in

men

at

a

T-score

of

SD

but

the

difference

in

probabilities

between

men

and

women

was

less

marked

Figure

compares

the

probability

of

hip

fracture

in

men

and

women

with

a

prior

fracture

according

to

age

In

the

absence

of

BMD

there

was

approximately

a

twofold

difference

in

probability

between

men

and

women

When

the

BMD

was

set

at

an

average

for

women

-LRB-

Z-score

-RRB-

there

was

little

difference

in

probabilities

up

to

the

age

of

years

Thereafter

men

had

a

lower

probability

than

women

due

to

the

higher

death

hazard

Fig.

hip

fracture

probability

-LRB-

-RRB-

in

men

and

women

with

a

prior

fracture

according

to

age

The

left-hand

panel

gives

probabilities

in

the

absence

of

BMD

In

the

right-hand

panel

probabilities

are

shown

at

an

average

BMD

for

women

at

each

specific

age

-LRB-

i.e.

a

Z-score

-RRB-

A

BMI

is

set

at

-LSB-

-RSB-

The

clinical

risk

factors

added

to

the

information

provided

by

BMD

Isopleths

for

fracture

probability

are

shown

in

Fig.

for

the

combination

of

several

of

the

clinical

risk

factors

The

clinical

risk

factors

were

somewhat

less

predictive

in

the

presence

of

BMD

in

the

models

For

example

in

women

aged

years

and

a

BMI

of

the

hip

fracture

probability

in

the

absence

of

BMD

ranged

from

in

the

absence

of

clinical

risk

factors

to

with

four

risk

factors

When

BMD

was

set

constant

at

a

T-score

of

SD

the

range

was

from

with

no

clinical

risk

factor

to

with

four

risk

factors

-LRB-

Fig.

-RRB-

The

effect

of

variations

in

BMI

was

even

more

markedly

affected

by

BMD

For

example

in

women

aged

years

the

hip

fracture

probability

was

at

a

BMI

of

and

decreased

progressively

at

higher

levels

of

BMI

to

with

a

BMI

of

When

BMD

was

fixed

hip

fracture

probability

remained

constant

irrespective

of

BMI

-LRB-

Fig.

-RRB-

Fig.

probability

of

a

major

osteoporotic

fracture

in

men

and

women

aged

years

according

to

T-score

and

clinical

risk

factors

Body

mass

index

is

set

at

-LSB-

-RSB-

Fig.

probability

of

hip

fracture

-LRB-

-RRB-

in

women

aged

years

according

to

the

number

of

clinical

risk

factors

The

left-hand

panel

shows

the

probabilities

without

BMD

at

a

BMI

fixed

at

The

right-hand

panel

illustrates

the

effects

with

BMD

fixed

at

the

threshold

for

osteoporosis

-LSB-

-RSB-

Fig.

of

variations

in

BMI

on

hip

fracture

probability

-LRB-

-RRB-

in

women

aged

years

Probabilities

with

BMD

are

computed

at

a

T-score

of

SD

-LSB-

-RSB-

Discussion

The

present

study

provides

a

model

for

the

assessment

of

fracture

probability

in

men

and

women

The

model

-LRB-

FRAX

-RRB-

uses

data

derived

from

nine

cohorts

from

around

the

world

including

centres

from

North

America

Europe

Asia

and

Australia

and

has

been

validated

in

independent

cohorts

with

a

similar

geographic

distribution

-LSB-

-RSB-

The

use

of

primary

-LRB-

but

anonymized

-RRB-

data

for

the

model

construct

permits

the

interaction

of

each

of

the

risk

factors

to

be

determined

to

improve

the

accuracy

whereby

fracture

probability

can

be

computed

The

large

sample

permitted

the

examination

of

the

general

relationship

of

each

risk

factor

by

age

sex

duration

of

follow

up

and

for

continuous

variables

-LRB-

BMD

and

BMI

-RRB-

the

relationship

of

risk

with

the

variable

itself

in

a

manner

hitherto

not

possible

The

use

of

primary

data

also

eliminates

the

risk

of

publication

bias

The

validity

of

the

clinical

risk

factors

identified

are

supported

by

the

expected

relationships

between

BMD

and

fracture

risk

-LSB-

-RSB-

In

the

present

study

the

FRAX

model

has

been

calibrated

to

the

epidemiology

of

the

UK

but

could

be

calibrated

to

any

country

where

the

epidemiology

of

fracture

and

death

is

known

-LRB-

see

Appendix

-RRB-

FRAX

models

for

the

UK

and

some

other

countries

are

available

through

the

web

-LRB-

-RRB-

The

approach

uses

easily

obtained

clinical

risk

factors

to

estimate

risk

The

estimate

can

be

used

alone

or

with

BMD

to

enhance

fracture

risk

prediction

Several

previous

studies

have

developed

models

to

predict

fracture

risk

from

the

combination

of

clinical

risk

factors

and

BMD

-LSB-

-RSB-

The

risk

factors

used

include

activities

of

daily

living

impaired

cognition

liability

to

falls

poor

overall

health

history

of

stroke

seizure

disorder

and

several

different

medications

A

limitation

of

many

of

these

studies

is

that

with

the

exception

of

the

SOF

study

-LSB-

-RSB-

and

one

of

the

GPRD

studies

-LSB-

-RSB-

they

have

not

been

tested

in

other

cohorts

The

model

described

in

this

paper

has

been

validated

in

independent

prospectively

studied

cohorts

with

in

excess

of

one

million

patient

years

-LSB-

-RSB-

The

use

of

risk

factors

for

case

finding

presupposes

that

the

risk

so

identified

is

responsive

to

a

therapeutic

intervention

To

test

this

hypothesis

it

would

be

necessary

to

recruit

patients

selected

on

the

basis

of

the

risk

factor

-LRB-

s

-RRB-

to

a

randomised

controlled

trial

-LRB-

RCT

-RRB-

The

risk

factor

that

is

best

evaluated

in

this

way

is

BMD

and

indeed

the

vast

majority

of

therapeutic

studies

have

recruited

patients

on

the

basis

of

low

BMD

as

recommended

by

regulatory

agencies

in

the

US

and

Europe

-LSB-

-RSB-

In

recent

years

other

trials

have

recruited

patients

on

the

basis

of

age

gender

a

prior

vertebral

fracture

and

current

exposure

to

glucocorticoids

irrespective

of

BMD

and

have

shown

therapeutic

effects

similar

to

those

noted

in

RCT

's

based

on

BMD

selection

-LSB-

-RSB-

For

other

risk

factors

comparable

data

are

lacking

In

the

absence

of

empirical

data

an

alternative

approach

is

to

demonstrate

that

the

presence

-LRB-

or

absence

-RRB-

of

a

risk

factor

does

not

adversely

influence

therapeutic

efficacy

against

fractures

Several

studies

have

shown

no

significant

interaction

between

response

to

treatment

and

the

presence

or

absence

of

the

risk

factors

used

in

the

present

study

including

age

height

family

history

of

fracture

low

body

weight

or

BMI

smoking

alcohol

intake

or

prior

non-vertebral

fracture

-LSB-

-RSB-

In

contrast

some

risk

factors

may

be

associated

with

less

therapeutic

efficacy

For

example

patients

selected

on

the

basis

of

risk

factors

for

falling

may

respond

less

completely

to

agents

that

preserve

bone

mass

than

patients

selected

on

the

basis

of

low

BMD

-LSB-

-RSB-

This

concern

is

greatest

in

models

that

omit

BMD

because

pharmacological

agents

may

not

be

equally

effective

across

the

entire

range

of

BMD

-LSB-

-RSB-

The

present

model

has

several

unique

features

FRAX

uses

Poisson

regression

to

derive

hazard

functions

of

death

and

fracture

Such

hazard

functions

are

continuous

as

a

function

of

time

unlike

Cox

's

regression

for

which

the

corresponding

hazard

functions

are

zero

except

at

the

time

points

of

a

fracture

or

death

There

are

also

several

advantages

of

the

Poisson

model

over

logistic

regression

analysis

Logistic

regression

does

not

take

account

of

when

a

fracture

occurred

nor

whether

individuals

without

a

fracture

died

or

when

death

occurred

Secondly

for

the

assessment

of

probabilities

by

logistic

regression

the

observation

period

should

be

for

years

Moreover

information

longer

than

the

period

can

not

be

used

for

analysis

The

cost

of

ignoring

information

when

fractures

occur

and

whether

and

when

deaths

occur

is

on

the

precision

of

the

estimate

In

simulation

experiments

the

Poisson

model

gives

the

same

precision

as

logistic

regression

with

fewer

numbers

of

individuals

In

our

own

simulations

in

the

present

context

-LRB-

data

on

file

-RRB-

the

Poisson

model

gave

the

same

precision

as

logistic

regression

with

half

the

number

of

individuals

Finally

the

Poisson

model

allows

adjustments

to

be

made

for

time

trends

The

ability

to

use

several

Poisson

models

permits

the

use

of

data

from

different

sources

to

integrate

fracture

and

death

hazards

and

to

calibrate

to

different

countries

A

further

feature

of

the

FRAX

model

is

that

it

takes

account

of

deaths

from

all

causes

In

several

recent

models

of

disease

probability

this

has

not

been

accounted

for

-LSB-

-RSB-

For

example

the

probability

of

stroke

has

been

determined

as

a

function

of

age

race

smoking

body

mass

index

atrial

fibrillation

systolic

blood

pressure

ratio

of

total

to

HDL

cholesterol

and

duration

of

diabetes

-LSB-

-RSB-

but

the

risk

of

dying

from

other

reasons

was

not

taken

into

account

In

the

context

of

osteoporosis

fracture

probabilities

are

markedly

underestimated

when

no

account

is

taken

of

the

competing

death

hazard

-LSB-

-RSB-

For

example

in

a

study

of

men

followed

after

orchidectomy

the

cumulative

incidence

of

fractures

was

after

years

but

the

figure

was

when

deaths

were

considered

as

a

competing

event

-LSB-

-RSB-

FRAX

also

takes

account

of

the

impact

of

risk

factors

on

the

death

hazard

For

example

smoking

and

low

BMD

are

risk

factors

for

fracture

but

also

significant

risk

factors

for

death

Thus

at

very

low

T-scores

for

BMD

hip

fracture

probabilities

decrease

with

age

-LRB-

see

Table

-RRB-

in

part

related

to

the

higher

mortality

associated

with

the

lower

values

for

BMD

There

are

several

limitations

that

should

be

mentioned

As

with

nearly

all

randomly

drawn

populations

non-response

bias

may

have

occurred

The

effect

is

likely

to

exclude

sicker

members

of

society

and

may

underestimate

the

absolute

fracture

risk

for

example

by

age

The

analyses

also

have

significant

limitations

that

relate

to

the

outcome

variables

and

the

characterisation

of

risk

factors

The

definition

of

what

was

considered

to

be

an

osteoporotic

fracture

was

not

the

same

in

all

cohorts

but

the

effect

of

this

inconsistency

is

likely

to

weaken

rather

than

strengthen

the

associations

that

were

found

For

the

hip

fracture

outcome

the

definition

was

similar

in

all

cohorts

and

may

explain

in

part

the

higher

risk

ratios

associated

for

this

fracture

rather

than

for

osteoporotic

fracture

Also

the

analyses

were

confined

to

clinical

fractures

and

the

results

might

differ

from

vertebral

fractures

diagnosed

by

morphometry

or

as

an

incidental

radiographic

finding

There

are

also

limitations

with

the

risk

factors

themselves

In

the

case

of

BMI

this

was

chosen

rather

than

weight

as

the

measure

for

body

composition

This

has

the

advantage

that

there

is

less

variability

across

countries

and

between

sexes

A

potential

drawback

is

that

BMI

can

be

influenced

by

height

loss

associated

with

vertebral

deformities

Therefore

in

individuals

with

important

loss

of

height

the

risk

conferred

through

BMI

could

be

underestimated

-LSB-

-RSB-

The

use

of

maximal

attained

height

rather

than

current

height

might

be

a

solution

in

the

future

if

it

were

shown

that

fracture

risk

prediction

could

be

improved

Further

problems

relate

to

the

construct

of

the

questions

to

elicit

the

presence

or

absence

of

risk

factors

which

varied

between

cohorts

These

included

questions

on

family

history

prior

fracture

smoking

and

glucocorticoid

use

The

effect

of

this

heterogeneity

is

likely

to

weaken

rather

than

strengthen

the

associations

found

Recall

is

also

subject

to

errors

and

was

not

validated

in

any

of

these

cohorts

This

is

particularly

problematic

in

the

elderly

In

addition

the

validity

of

self-reported

alcohol

intake

is

notoriously

unreliable

-LSB-

-RSB-

Indeed

alcohol

consumption

was

significantly

less

in

both

men

and

women

than

that

assessed

in

the

UK

-LSB-

-RSB-

Given

that

these

studies

were

prospective

however

much

of

this

error

-LRB-

with

the

exception

of

alcohol

intake

-RRB-

should

be

random

giving

rise

to

non-directional

misclassification

Thus

the

associations

may

actually

be

stronger

than

reported

here

Any

underestimate

may

have

limited

consequences

for

case-finding

since

the

populations

to

be

tested

are

similar

to

the

populations

interrogated

Biases

that

arise

have

more

significance

where

causality

is

inferred

A

further

limitation

is

that

several

of

the

clinical

risk

factors

identified

take

no

account

of

dose-response

but

give

risk

ratios

for

an

average

dose

or

exposure

By

contrast

there

is

good

evidence

that

the

risk

associated

with

excess

alcohol

consumption

and

the

use

of

glucocorticoids

is

dose-responsive

-LSB-

-RSB-

In

addition

the

risk

of

fracture

increases

progressively

with

the

number

of

prior

fractures

-LSB-

-RSB-

These

limitations

are

nearly

all

conservative

It

should

be

acknowledged

that

there

are

many

other

risk

factors

that

might

be

considered

for

incorporation

into

assessment

algorithms

These

include

BMD

at

other

skeletal

sites

ultrasonography

quantitative

computed

tomography

and

the

biochemical

indices

of

bone

turnover

The

available

information

was

too

sparse

to

provide

a

meta-analytic

framework

but

they

should

be

incorporated

into

risk

assessment

algorithms

when

they

are

more

adequately

characterised

Notwithstanding

the

present

model

provides

a

mechanism

to

enhance

patient

assessment

by

the

integration

of

clinical

risk

factors

alone

and/or

in

combination

with

BMD

The

application

of

this

methodology

to

clinical

practice

will

demand

a

consideration

of

the

fracture

probability

at

which

to

intervene

both

for

treatment

-LRB-

an

intervention

threshold

-RRB-

and

for

BMD

testing

-LRB-

assessment

thresholds

-RRB-

These

are

currently

being

developed

for

the

UK

based

on

cost-effectiveness

analyses

-LSB-

-RSB-

Intervention

thresholds

developed

for

the

United

Kingdom

may

not

be

applicable

to

other

countries

The

probability

of

fracture

varies

markedly

in

different

countries

-LSB-

-RSB-

For

countries

with

low

hip

fracture

rates

as

found

in

developing

countries

the

relative

risk

at

which

intervention

is

cost-effective

will

be

higher

though

the

absolute

risk

at

which

intervention

is

cost-effective

would

not

change

assuming

comparable

costs

Intervention

thresholds

would

however

change

with

differences

in

costs

particularly

fracture

costs

which

vary

markedly

world

wide

There

is

also

the

issue

of

affordability

or

willingness

to

pay

for

a

strategy

The

gross

domestic

product

-LRB-

GDP

-RRB-

per

capita

provides

an

index

of

affordability

The

GDP

varies

markedly

in

different

regions

of

the

world

In

the

UK

the

GDP

per

capita

is

estimated

at

US$

in

as

compared

with

US$

in

Turkey

Thus

for

the

same

fracture

risk

and

the

same

costs

treatment

will

be

less

affordable

-LRB-

at

least

to

health

services

-RRB-

in

Turkey

than

in

the

UK

Nevertheless

individuals

in

Turkey

rather

than

society

as

a

whole

may

be

willing

to

pay

United

Kingdom

prices

for

health

care

There

is

also

a

marked

heterogeneity

in

the

proportion

of

GDP

devoted

to

health

care

and

in

the

proportion

of

the

population

at

risk

from

osteoporotic

fracture

-LRB-

i.e.

elderly

people

-RRB-

-LSB-

-RSB-

For

all

these

reasons

it

is

important

to

define

intervention

and

assessment

thresholds

on

a

country

by

country

basis

that

takes

into

account

the

setting

for

service

provision

and

willingness

to

pay

as

well

as

considerations

of

absolute

costs

O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O B I I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I I O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O B I O O O O O O O O O O O O B I I O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

clinical risk factors
fracture probability
osteoporotic fracture


Motor-Skill Learning in Alzheimer 's Disease : A Review with an Eye to the Clinical Practice Since elderly people suffering from dementia want to go on living independently for as long as possible , they need to be able to maintain familiar and learn new practical skills . Although explicit or declarative learning methods are mostly used to train new skills , it is hypothesized that implicit or procedural techniques may be more effective in this population . The present review discusses 23 experimental studies on implicit motor-skill learning in patients with Alzheimer 's disease -LRB- AD -RRB- . All studies found intact implicit motor-learning capacities . Subsequently , it is elaborated how these intact learning abilities can be exploited in the patients ' rehabilitation with respect to the variables ` practice ' and ` feedback . ' Recommendations for future research are provided , and it is concluded that if training programs are adjusted to specific needs and abilities , older people with AD are well able to -LRB- re -RRB- learn practical motor skills , which may enhance their autonomy . Introduction The aging population is growing rapidly and by 2050 the number of elderly people aged 85 years old or older in Europe and North America is estimated to be approximately 19 million -LRB- Román 2002 -RRB- . Since age is a high risk factor for dementia -LRB- Smith and Rush 2006 -RRB- , the expansion of the aging population and thus the number of people suffering from dementia has momentous consequences for national care systems as well as a large economic impact -LRB- Schölzer-Dorenbosch 2005 -RRB- . A way to contain these costly effects is by helping older people to stay independent for as long as possible , implying that the elderly must not stop learning . They apply old skills differently or acquire new skills , like learning how to use a walking aid , which gives rise to the following questions : Are demented elderly people able to learn such new skills ? And are we , health professionals , able to train them ? As yet , psychopharmacological interventions , such as the use of cholinesterase inhibitors , may have some benefit in maintaining autonomy of elderly patients suffering from Alzheimer 's disease -LRB- AD -RRB- , as demonstrated by delayed nursing home placement -LRB- Becker et al. 2006 -RRB- . Recent pharmacological research also shows promising results for cognition : the treatments evaluated produced a moderate positive effect on global cognitive functioning -LRB- Grimley Evans et al. 2004 ; Schölzer-Dorenbosch 2005 ; Takeda et al. 2006 -RRB- . In their 2002 review on the placebo-controlled effects of rivastigmine on the cognition of AD patients , Birks et al. -LRB- 2002 -RRB- reported statistically-significant increases of 0.8 points on the Mini Mental State -LRB- MMS -RRB- Examination and 2.1 points on the Alzheimer 's Disease Assessment Scale -LRB- ADAS-Cog -RRB- . They also found benefits in the patients ' activities of daily living , although the difference with placebo was not significant . Takeda et al. -LRB- 2006 -RRB- also reported reductions in the cognitive impairment of AD patients for donepezil and galantamine , but again , although showing potential , the improvements did not suggest a major difference in the daily lives of the patients . These findings do not negate the importance of non-pharmacological approaches and it is possible that the interactions between medication and non-pharmacological approaches may be the most beneficial in maintaining patient 's autonomy . In their review , Luijpen et al. -LRB- 2003 -RRB- conclude that the effect of non-pharmacological interventions with respect to cognition and affective behavior in dementia is similar to the effect of pharmacological regimens . Non-pharmacological treatments to improve autonomy in this patient population should hence be considered an additional option , especially since rehabilitation is increasingly being advocated as a means to optimize patients ' overall functioning -LRB- De Vreese et al. 2001 -RRB- . Clare -LRB- 2003 -RRB- also concludes that neuropsychological rehabilitation applied in the context of progressive disorders like dementia do yield beneficial results . In the present review we will focus on the ability of Alzheimer 's patients to -LRB- re -RRB- learn practical motor skills . Currently , explicit or declarative learning methods are the starting points in most rehabilitation programs aimed at motor-skill learning in the cognitively unimpaired population -LRB- Van Cranenburg 2004 -RRB- . However , Zanetti et al. -LRB- 2001 -RRB- and Rösler et al. -LRB- 2002 -RRB- claimed that patients with dementia will profit more from implicit or procedural learning methods by showing that their AD cohorts were able to learn to waltz or to use a telephone when an implicit rather than an explicit learning approach was used . In implicit learning , skills are mastered without awareness , often simply by repeated exposure , and can be unconsciously revived from implicit memory -LRB- Buchner and Wippich 1998 -RRB- . The abovementioned studies were all focused on finding the best way to help older people with dementia learn or relearn practical -LRB- motor -RRB- skills , and although the results are encouraging , the patient samples were always small and it remains unclear how much was learned due to a lack of well-defined performance measures . In the first part of our review we looked for corroborating evidence in experimental research for intact implicit motor-learning capacity in cohorts of elderly patients diagnosed with AD . In the second part we will elaborate on how these intact learning abilities can be utilized for their rehabilitation while taking the principles from theories of motor-learning into account . Two of the theories ' core variables , i.e. , practice and feedback -LRB- Schmidt and Wrisberg 2000 -RRB- will be discussed more extensively , also in the light of research exploring these variables in AD . The results will be translated into practical instructions for more targeted rehabilitation training programs for this patient group . Materials and Methods Computerized searches of the literature using the databases of PubMed and PsycLIT were conducted spanning a 20-year period , from 1985 up to and including 2005 . The search terms -LRB- any field -RRB- used were procedural learning , sequence learning , motor-skill learning , or motor learning in combination with Alzheimer 's disease . Only reports published in English were considered . For inclusion in this review the studies had to meet the following criteria : -LRB- a -RRB- a clinical diagnosis of Alzheimer 's disease based on specified and generally accepted criteria ; -LRB- b -RRB- a procedural task with motor responses ; and -LRB- c -RRB- task performance expressed in time or error measures , and not only in fMRI or other imaging data . Ultimately , 23 studies were included in this review . Three studies will only be discussed in the second part of the review since they explicitly examined the role of feedback and type of practice . Experimental Research of Implicit Motor-Skill Learning in Alzheimer 's Disease Implicit Learning Ability The main results of the studies generated by our search of the literature are shown in Table 1 . Four studies using a Maze test in which blindfolded participants had to trace a complex pathway found that the AD patients were able to learn new motor-skills implicitly -LRB- Kuzis et al. 1999 ; Sabe et al. 1995 ; Starkstein et al. 1997 ; Taylor 1998 -RRB- . The nine studies that applied a Rotor-Pursuit task , in which participants had to maintain contact between a hand-held stylus and a rotating spot , also reported preserved learning abilities in their AD samples -LRB- Beatty et al. 1995 ; Deweer et al. 1994 ; Dick et al. 1995 , 2001 ; Heindel et al. 1988 ; Heindel et al. 1989 ; Jacobs et al. 1999 ; Libon et al. 1998 ; Willingham et al. 1997 -RRB- . This is in agreement with the findings of Poe and Seifert -LRB- 1997 -RRB- based on a Puzzle-Assembly task and the results of Rouleau et al. -LRB- 2002 -RRB- involving a Mirror-Tracing task . Also , a Serial Reaction-Time Task -LRB- SRTT -RRB- was used in which participants needed to respond as fast as possible when a stimulus appeared in one of four places by pressing a corresponding response key -LRB- Grafman et al. 1990 ; Knopman and Nissen 1987 ; Knopman 1991 ; Willingham et al. 1997 -RRB- . Again , the AD patients showed implicit learning as reflected by the difference in reaction times -LRB- RTs -RRB- between blocks with a fixed sequence of stimuli presentation -LRB- decreasing RTs -RRB- and a random block -LRB- prolonged RTs -RRB- . However , there are indications that the implicit learning ability in AD patients is affected because they generated inferior outcomes when accuracy was taken into account -LRB- Willingham et al. 1997 -RRB- or when the data were log-transformed because of the unequal variance in RT -LRB- Knopman 1991 -RRB- . Ferraro et al. -LRB- 1993 -RRB- found preserved implicit SRTT learning only in the `` very mildly demented '' group , and less in the `` mildly demented '' group although it is relevant to mention that none of the other studies used such a subtle severity classification . Table 1Summary of results of experimental studies on motor-skill learning in Alzheimer 's diseaseAuthorYearSample size and typesTask -LRB- s -RRB- Amount of learningaResults on learning capacitySabe , L. , et al. 199520 AD with co-morbid depression , 35 AD without co-morbid depression , 14 depressive , non-demented patients , 16 healthy controlsMaze testAD : 19 % Co : 22 % The AD patients showed significant deficits in declarative learning but only a minor -LRB- although statistically significantly -RRB- drop in procedural learning . The AD group with comorbid depression showed a similar learning pattern as the non-depressed AD group.GroupxTrial :p < 0.05 Starkstein , S.E. , et al. 199755 AD -LRB- 13 with mild , 12 with severe and 30 without anosognosia -RRB- Maze testAD no : 48 % There was no group difference in declarative learning . As to procedural learning , the patients with severe anosognosia showed a significantly poorer performance whereas the patients with mild or no anosognosia showed no deficits.AD mild : 39 % AD severe : − 16 % -- Taylor , R. 199858 AD , 58 multi-infarct dementiaMaze test -- When age and overall neuropsychological functioning were taken into account , Maze performance was better in the AD patients than in the patients with multi-infarct dementia -- Kuzis , G. , et al. 199915 AD , 15 PD , 10 PD and dementia , 24 healthy controlsMaze testAD : 10 % The AD group showed deficits on all measures of explicit memory . There were no significant between-group differences in the measures of implicit memory between the AD , control , and PD groups.Co : 39 % -- Heidel , W.C. , et al. 198810 AD , 10 HD , 4 amnestic 20 healthy controlsRotor PursuitAD : 147 % The AD patients showed preserved motor-skill learning while the patients with HD showed no motor learning.Co : 115 % GroupxTrial : n.s.Heindel , W.C. et al. 198916 AD , 13 HD , 17 PD , 22 healthy controlsRotor PursuitAD : 101 % The AD patients showed preserved motor-skill learning while the patients with HD showed impaired motor learning.Co : 118 % GroupxTrial : n.s.Beatty , W.W. , et al. 19954 AD , 1 corticbasal degenerationRotor Pursuit -- The AD patients showed preserved motor skill learning -- Deweer , B. , et al. 199413 AD institutionalized , 10 healthy controls , 17 AD out patients , 9 healthy controlsRotor PursuitAD in. : 86 % Explicit memory was severely impaired in the AD patients but they showed normal procedural learning.Co : 48 % GroupxTrial : n.s.AD out : 161 % Co : 139 % GroupxTrial : n.s.Dick , M.B. , et al. 199512 AD , 12 healthy controlsRotor PursuitAD : 47 % Performance significantly improved during the first 40 trials but additional practice provided no further beneficial effects . The AD patients showed minimal retention problems across four retention tests.Co : 81 % GroupxTrial : n.s.Libon , D.J. , et al. 199816 AD , 14 vascular dementiaRotor PursuitAD : 60 % The AD patients obtained a lower score on a verbal-learning task-recognition index and high scores on the Rotor Pursuit . -- Jacobs , D.H. , et al. 199912 AD , 12 healthy controlsRotor PursuitAD : 124 % The AD patients and the controls were able to learn the motor task.Co : 106 % GroupxTrial : p = 0.473 Dick , M.B. , et al. 200118 AD , 18 healthy controlsRotor PursuitAD : 27 % In normal-vision trials no differences in learning between the AD patients and the controls were found.Co : 36 % GroupxTrial : n.s.Dick , M.B. , et al. 200399 AD , 100 healthy controlsRotor PursuitThe AD patients and controls receiving constant practice outperformed those in the blocked and random conditions . The AD patients only benefited from constant practice.Poe , M.K. et al. 19979 AD , 14 healthy controlsPuzzle Assembly -- Even when the subjects had no explicit memory of practicing the task , they all demonstrated savings upon relearning . GroupxTrial : n.s.Rouleau , I. , et al. 200212 AD , 12 healthy controlsMirror TracingAD : 44 % Those AD patients that were able to perform the basic mirror-tracing task did not differ from the controls in level of performance , learning over trails , retention over a delay interval and generalization to other tasksCo : 49 % GroupxTrial : n.s.Knopman , D.S. , et al. 198735 AD , 13 healthy controlsSRTTAD : 22 % The AD patients showed learning of the repeated sequence , although they responded more slowly.Co : 38 % GroupxTrial : n.s.Graftman , J. , et al. 199042 AD , 7 PSP , 44 healthy controlsSRTTAD : 36 % The AD patients and controls showed motor-skill learning while the PSP patients did not . -- Knopman , D. 199116 AD , 17 healthy controlsSRTTAD : 37 % The AD patients showed learning of the sequence but they showed an inferior level of learning when the data were log-transformed . Co : 33 % Ferraro , F.R. , et al. 199327 very mild AD , 15 mild AD , 17 PD , 26 healthy controlsSRTTAD mild : 11 % The very mildly AD patients showed preserved learning comparable with the controls . The mildly AD patients and PD patients showed less implicit learning.AD very mild : 22 % Co : 20 % Willingham , D.B. , et al. 199720 AD , 20 healthy controlsSRTT , Incompatible SRTT , Pursuit Tracking -LRB- randomized and repetitive pattern -RRB- SRTT : The dementia ratings predicted the ability to perform tasks but not the ability to learn them . AD patients can have a performance deficit but they have no general deficit in motor-skill learning.AD : 52 % Co : 60 % GroupXTrial : p > 0.2 Pursuit : AD : 12 % Co : 17 % GroupxTrial : p > 0.2 Hirono , N. , et al. 199736 AD , 19 healthy controlsBi-manual coordinated Tracing taskAD : 37 % Skill learning in those AD patients that completed the tasks was as good as in the controls . Co : 39 % GroupxTrial : p = 0.193 Dick , M.B. , et al. 199623 AD , 22 healthy controlsTossingThe AD patients given constant practice were able to learn and retain the tossing task similarly well as the controls . The AD patients showed less improvement when practicing at various distances.Dick , M.B. , et al. 200658 AD , 58 healthy controlsTossingThe AD patients showed significant improvements under constant practice only . None of the practice conditions facilitated intermediate transfer in the AD patients whereas constant practice did benefit them on tests assessing near transfer.AD = Alzheimer 's disease ; HD = Huntington 's disease ; PD = Parkinson 's disease ; PSP = Progressive supranuclear palsy.aexpressed as a percentage of the difference score between the last and first trial with respect to the score on the first trial . The GroupxTrial interaction for the AD and Co group is also reported when available . Thus , irrespective of the task used , the studies assessing implicit motor-skill learning in AD we reviewed yielded positive outcomes . Indeed , in their 1997 study , Hirono and colleagues found that patients with mild AD were able to acquire motor and perceptual as well as cognitive skills in various procedural learning tasks . It should be noted that in all studies the patients that could not perform the task were eliminated from the analyses . Yet , a failure to perform the prescribed task need not necessarily be related to learning problems . Willingham et al. -LRB- 1997 -RRB- attributed the phenomenon to other causes like the complexity of the instructions given or the type of skill to be performed . These factors may differ across tasks , which might explain their finding that the ability to complete one task did not predict the rate of improvement in another task . They conclude that AD patients have a performance deficit and not a generalized deficit in motor learning . Performance and Amount of Learning From the above discussion of results we can presume that at least a subgroup of AD patients show preserved implicit learning abilities , but to what extent ? Here , two aspects in motor learning should be differentiated , i.e. , overall performance level and amount of learning -LRB- e.g. , the increment in Total Time on Target in the Rotor-Pursuit task -RRB- . All the studies found preserved motor-skill learning in AD patients although their overall performance levels in terms of reaction and movement time were always inferior to those of the controls . However , when we take the level of learning into account , the results are less consistent . Some of the results were not reported with enough detail to show unambiguously the amount of learning the AD patients showed compared to the controls -LRB- Poe and Seifert 1997 -RRB- . Some comparative studies did not include a healthy control group in addition to the patient groups -LRB- Beatty et al. 1995 ; Grafman et al. 1990 ; Libon et al. 1998 ; Starkstein et al. 1997 ; Taylor 1998 -RRB- , preventing patient-control comparisons from being made . The AD patients in the SRTT studies showed the same amount of learning -LRB- decrease in RT during the blocks with the fixed sequence -RRB- as the normal controls -LRB- Ferraro et al. 1993 ; Knopman and Nissen 1987 ; Knopman 1991 ; Willingham et al. 1997 -RRB- . In the nine studies that used a Rotor-Pursuit or Tracking task there were also no patient-control differences in amount of learning -LRB- Deweer et al. 1994 ; Dick et al. 1995 , 2001 ; Heindel et al. 1988 ; Heindel et al. 1989 ; Hirono et al. 1997 ; Jacobs et al. 1999 ; Rouleau et al. 2002 ; Willingham et al. 1997 -RRB- . Two of the studies using a Maze test reported learning abilities in the AD group but less improvement across trials compared to the controls , -LRB- Kuzis et al. 1999 ; Sabe et al. 1995 -RRB- findings which are perhaps explainable by the use of a task without visual feedback . Taken together , the reviewed studies all showed preserved implicit motor-skill learning in AD patients regardless of the task used . Their performance levels , however , never reached the levels of the healthy controls , demonstrated by their prolonged reaction and movement times . The AD patients ' level of learning also differed depending on the task to be performed . Visual feedback appears to have a positive effect on their learning pace . They also seem to experience more problems with implicit learning when performing the SRTT , a task that involves two learning processes . The subjects have to master both spatial and motor regularities -LRB- Mayr 1996 -RRB- , and it is the learning of spatial regularities that may be compromised in AD patients , a process that is less implicated in the Rotor-Pursuit task in which normal implicit learning for the patients was found . Training Patients with Alzheimer 's Disease : Variables in Motor Learning The studies discussed provide evidence that AD patients can learn new motor skills in an implicit way . It is therefore worthwhile to establish what would be the best way to train them . In the next section we will give a brief account of the two variables practice and feedback that play a role in -LRB- re -RRB- training motor skills . We will subsequently discuss the variables in relation to the findings reported in the relevant AD studies and conclude by making recommendations of how to enhance the acquisition of new motor skills in this population . We will first , however , briefly address the existing views on the presence or absence of distinguishable learning stages in explicit and implicit learning . Generally , with explicit learning people tend to pass through three stages in the acquisition of motor skills -LRB- Fitts and Posner 1967 -RRB- . The first is the cognitive stage in which the focus is on understanding the task and developing strategies to perform it , requiring cognitive activity such as attention and executive functions . The second phase is the associative stage : the learner has selected the best strategy and now begins to refine the skill . Here , cognitive aspects are less important . And finally , there is the autonomous stage in which the skill becomes automatic , requiring a low degree of attention . Variables such as practice and feedback can be structured differently to enhance learning at each stage . Feedback in the cognitive stage , for example , may need to be more specific and applied more frequently to enhance learning , while feedback may be weaned toward the third stage of learning -LRB- Tse and Spaulding 1998 -RRB- . In implicit learning , on the other hand , there is no clear distinction between these three stages . It has been proposed that in implicit learning the three stages might overlap or be ordered differently . There is support for a parallel development of implicit and explicit knowledge in learning -LRB- Willingham and Goedert-Eschmann 1999 -RRB- . Practice : Theory and Outcome Studies with AD Patients The principle , `` The more you practice , the more you learn , '' implies that the amount of practice should be maximized in therapy . But does more practice indeed improve the performance in AD patients ? Dick et al. -LRB- 1995 -RRB- found that on the Rotor Pursuit both the AD and control group had reached their optimal performance after 40 trials because subsequent practice failed to yield any additional augmenting effect . It would be interesting to determine whether this also holds for other tasks like the Maze test in which , relative to the controls , an inferior amount of learning was observed for AD patients -LRB- Kuzis et al. 1999 ; Sabe et al. 1995 -RRB- . Since fatigue also plays a role in learning , the next question is how to alternate practice with rest to maximize learning in patients . Schmidt and Wrisberg -LRB- 2000 -RRB- distinguish two types of practice . In ` massed practice , ' the greater proportion of the sessions is dedicated to training , while in ` distributed practice ' the duration of rest equals or is greater than that of practice . To date , the effects of alternating these two training methods in the generally older AD patient group still requires further investigation . Another factor that merits closer attention in the context of training programs for AD patients is whether the task should be learned as a whole or per constituent component . Training the components of a task separately before combining them into the whole pattern can be effective if the task itself can be naturally divided into components that reflect the inherent goal of the task -LRB- Schmidt 1988 -RRB- . For example , learning to drive a car can be easily divided into the components `` learning to shift gear '' and `` learning to steer , '' which can be trained individually . Learning to reach and grasp an item , on the other hand , does not lend itself well for phased training since reaching and grasping are integral components of a single , continuous movement . The amount of variation in the practice session -LRB- s -RRB- is also a topic for further study . Task variables like the beanbag 's weight and throwing distance in the Tossing task can be practiced in a random design so that the weight and distance can be varied systematically . Alternatively , they can be offered in a blocked design in which only one task variable per block is practiced repetitively . Another option is to use a constant design in which only one combination of task variables is trained . Note that over time , the connotation of the two terms has shifted : random and blocked practice now refer to the rehearsal of several distinct skills whereas varied and constant practice implies the rehearsal of different variations of the same skill -LRB- Schmidt and Wrisberg 2000 -RRB- . Nevertheless , in our report we will use the ` old ' terms -LRB- random , blocked and constant -RRB- in their original meanings since these were terms and interpretations used in the reviewed literature . Early evidence suggests that random practice might be most effective for the acquisition and generalizability of a motor skill , whereas during the acquisition of a specific motor skill , performance benefits most from blocked practice -LRB- Schmidt 1988 -RRB- . All available studies reviewed on this matter -LRB- Dick et al. 1996 , 2000 , 2003 -RRB- show that AD patients learn best under constant practice conditions . According to Dick and his 1996 team , humans use their episodic memory of the training trials to accurately perform a task while learning a skill . They suggest that because AD patients experience problems with episodic memory , constant practice is more effective because repeated running of the same motor program does not require an intact episodic memory . The second reason why random practice may be less effective is that other cognitive functions that play a role in random practice , like the ability to switch tasks and divide attention , are affected in AD patients . Dick et al. -LRB- 1996 , 2003 -RRB- explained the AD patients ' superior learning performance under constant practice conditions in terms of the schema theory originally developed by Schmidt -LRB- 1975 -RRB- , and likewise propose a more open-loop account of motor control . Schmidt assumes the existence of generalized motor programs -LRB- GMPs -RRB- that are acquired through practice and that define the `` form '' of the action . These GMPs can be altered to meet environmental demands by a closed-loop system using sensory feedback . Schemata , e.g. , for varying weight and distances in tossing , are learned and allow the action to be scaled to the environment -LRB- Schmidt 2003 -RRB- . When they considered their results in terms of this theory , Dick et al. -LRB- 1996 , 2003 -RRB- concluded that AD patients can develop and access a GMP in training situations that emphasize movement consistency . However , they do not form the motor schemas needed to successfully achieve a movement when the environmental demands change because they are unable to encode and to store the different types of information about a motor pattern . There are three other training approaches that can produce the desired learning effect : guidance , observation , and mental practice -LRB- Schmidt 1988 -RRB- . Guidance should only be used at the onset of training because experiments have shown that practice under unguided conditions seems to be more effective for retention and transfer -LRB- Shumway-Cook and Woollacott 1995 -RRB- . Observation conveys information about how a skill should be performed and seems to be especially beneficial for the acquisition of new movement patterns -LRB- Magill 1993 -RRB- . Our automated computer search and an extra search combining the three keywords with Alzheimer dementia both failed to generate any relevant studies that employed one of these training methods . The only study that provided some additional information on the topic is a report by Dick et al. -LRB- 1988 -RRB- which showed that AD patients could recall preselected -LRB- subject-defined -RRB- movements more accurately than constrained -LRB- experimenter-defined -RRB- movements on a linear positioning apparatus . This was explained by the patients ' ability to profit from mental preparation of the movement prior to its execution . Without further systematic investigation , however , it can not be inferred that the ability to profit from mental preparation also means AD patients will profit from mental practice . More research into the effects of all three practice types in AD is needed . Feedback : Theory and Outcome Studies with AD Patients A second crucial variable that influences motor learning is type of feedback . Intrinsic feedback encompasses the sensory information generated by motion , and extrinsic feedback entails information from an external source like a therapist -LRB- Schmidt and Wrisberg 2000 -RRB- . There are various ways to provide extrinsic feedback . It can be delivered during or after the movement , immediately following movement completion or delayed , and in a verbal or a non-verbal fashion . It can contain information on average performance -LRB- summary feedback -RRB- or it may reflect each movement or performance -LRB- constant feedback ; Schmidt 1988 -RRB- . It is generally believed that constant feedback enhances only motor performance , not the level of learning -LRB- Shumway-Cook and Woollacott 1995 -RRB- . With less frequent feedback , learners have to rely more on other cues , which entails more elaborate encoding -LRB- Schmidt 1988 -RRB- . Extrinsic feedback can moreover be divided into ` knowledge of results , ' in which the movement outcome is given in terms of the goal , and ` knowledge of performance , ' so that the feedback concerns the movement pattern itself -LRB- e.g. , in a Tossing task : increase the swing of your arm -RRB- . In almost all studies on motor-skill learning in AD , visual feedback was employed . Only the Maze tasks were administered under blindfolded conditions and the amount of learning in the AD patients proved inferior to the amount found for the controls -LRB- Sabe et al. 1995 ; Kuzis et al. 1999 -RRB- . In most Rotor-Pursuit tasks , the velocity of the target was individualized to equate initial performance . Controls generally tracked at a faster rate than the AD patients -LRB- Deweer et al. 1994 ; Dick et al. 1995 ; Jacobs et al. 1999 ; Libon et al. 1998 -RRB- . Possibly , AD patients can only perform this task at a slower rate because they rely more on visual feedback than controls . Only one study using a Rotor-Pursuit task explicitly examined the role of visual feedback on performance in AD patients , showing a drop in performance when the visibility of the moving target was reduced during the learning phase -LRB- Dick et al. 2001 -RRB- . In contrast to that of the normal controls , the patients ' performance did not improve across trials in the restricted-vision condition . In the full-vision condition the patients showed normal learning . It can be tentatively concluded that for AD patients , constant visual feedback is important in learning motor skills , but more research is needed to confirm this hypothesis . We did not find any studies that were concerned with the frequency of external feedback , and whether knowledge of results and knowledge of performance makes a difference in this patient group . Based on the results cited above , it may be hypothesized that both forms of feedback knowledge probably place too much weight on the cognitive abilities in AD patients and therefore contribute little to successful performance . Conclusions and Recommendations People with Alzheimer 's disease are able to implicitly -LRB- re -RRB- learn motor skills to a certain extent and under specific conditions . The experimental research to date shows preserved implicit motor learning irrespective of the task used . Patients are capable of acquiring motor skills without awareness simply by repeated exposure , although their performances will not reach normal levels . This is expressed in their protracted performance relative to that of unimpaired controls . Moreover , extent of learning will differ depending on the task to be mastered . The preserved implicit learning ability in AD can be of use for physical therapists working with this elderly patient group . Physical therapists can call upon neuropsychologists to provide information on their patients ' learning capacities since they have quantitative measures at their disposal to assess a patient 's level of functioning . However , the memory and learning tests currently available in the clinical practice evaluate explicit or declarative memory -LRB- Spaan et al. 2003 -RRB- . In order to get a satisfactory differential picture of the learning capacities in demented patients , implicit -LRB- motor -RRB- learning tasks need to be added to the neuropsychological assessment . The evidence of intact implicit learning in AD further prompted the question how these intact learning abilities can best be translated into rehabilitation programs targeting this patient group . Learning is central in rehabilitation and knowledge of the system under treatment , like the motor system , must be combined with knowledge of how learning principles must be applied to achieve a successful training program -LRB- Baddeley 1993 -RRB- . With respect to patients with dementia , apart from the subtype of dementia and its specific neuropsychological syndrome , the training programs should apply the principles that emerge from theories of learning . The studies we reviewed showed that in -LRB- re -RRB- learning motor skills , constant , or rather frequent and consistent practice is important in AD patients . This way of learning draws less on episodic memory and other cognitive functions compromised in AD patients . These data also suggest that practice under dual-task conditions should also be avoided . Because AD patients have difficulty in generalizing the motor skills learned during the sessions , training has to take place in an environment that closely resembles the one in which the skill is going to be used and presumably with tools used by the AD patient in his or her daily life . If , for instance , an AD patient is trained in the use of a microwave , the device used during the training should be the same as the one available in the patient 's household . The amount of training a patient needs will depend on the task being trained . The role of fatigue is also important in this respect . The effects of massed and distributed practice in this generally older patient group need to be addressed in future investigations . Patients with AD appear to remain dependent upon visual feedback throughout training and performance . Screening and subsequent correction of visual problems or the use of visual aids can be effective in the training process in this group for whom vision problems are very common -LRB- De Winter et al. 2004 -RRB- . The type and point in time when external feedback needs to be given and its effect on learning in AD also warrants attention in future research . In the introduction of our review we asked whether patients with Alzheimer 's disease might have intact motor-skill learning abilities . The answer is twofold . Clearly , AD patients show preserved implicit learning abilities that can be utilized in teaching -LRB- motor -RRB- skills , yet transfer to other skills is minimal . Accordingly , the professionals delivering the training programs should tailor the contents to the particular needs and abilities of this patient group or the individual patient . When the above guidelines are kept in mind and when our knowledge on this topic are widened , non-pharmacological interventions might contribute significantly in helping elderly people suffering from dementia to keep their autonomy . The extent to which pharmacological intervention may enhance these behavioral mechanisms and foster independent living in AD patients has yet to be determined .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

procedural learning
rehabilitation
implicit learning

alzheimer’s disease
motor-skill learning
non-pharmacological interventions