Epidemiology: Life trajectories of

lean, fat and bone mass

Cyrus Cooper OBE, DL, FMedSci

Professor of Rheumatology and Director, MRC Lifecourse Epidemiology Unit, University of Southampton;

and Professor of Epidemiology, University of Oxford, UK

President, International Osteoporosis Foundation

Conflict of interest statement: CC has received lecture fees and consulting honoraria from Amgen, MSD, Eli Lilly, Procter & Gamble, Aventis, GSK/Roche, Novartis, Nycomed, Radius, Servier, UCB and Wyeth Pharmaceuticals.

AGS/NIA Osteoporosis and Soft Tissue Disorders, Bethesda; March 2019

Body composition trajectories throughout the lifecourse

MRC Lifecourse Epidemiology Unit, University of Southampton

• Bone mass trajectory through lifecourse

• Implications for prevention from conception to old age

• Linkage in trajectories of bone, muscle and fat

Institute of Musculoskeletal Science, University of Oxford

Bone mass across the lifecourse: gain and loss

Bone mass

(g, Ca)

Age (yr)

1500 -

1000 -

500 -

0 - 0 20 40 60 80 100

Peak bone mass

Determinants of peak bone mass

Determinants of bone loss and fracture risk

PEAK BONE MASS RATE OF BONE LOSS Gene Menopause Dietary Ca/D Nutrition Body mass Physical activity Physical activity Smoking Diseases Hormonal status Alcohol Drugs (GC)

Peak 50% Loss rate 50%

Bone mass

Target those with a low

bone density

Bone mass

Move entire distribution by

intervening in everyone

Mean

-1SD +1SD

Preventive strategies: High-risk and population

approaches

Cooper C, et al. Trends Endocrinol Metab 1992;3:224–9.

Screening based on clinical risk factors and FRAX leads to reduced risk of hip fracture

Control

Screening

HR = 0.72; 95%CI 0.59-0.89

Shepstone L et al Lancet 2018; 391: 741-7

Lifecourse determinants of health and disease:

A conceptual framework M

EC

HA

NIS

MS

Developmental plastic responses Epigenetic processes

Childhood body composition and development

Infant feeding and illnesses

Infant body composition & development Weight gain and catch-up growth

Young women’s diet, body composition, physical activity, education and lifestyle before and during pregnancy

Childhood diet, physical activity, lifestyle and education

Vulnerability to chronic disease in later life

Work, lifestyle and health behaviours in adulthood

Retirement and ageing

Gluckman, Hanson, Cooper et al New Engl J Med 2008; 359: 61-73

Vitamin D supplementation increases offspring BMC in winter births by eliminating steep winter decline in

maternal vitamin D status: MAVIDOS Trial

p=0.004

50

60

70

Whole

body B

MC (

g)

Placebo 1000 IU/d

Winter

p=0.44

50

60

70

Placebo 1000 IU/d

Spring

p=0.73

50

60

70

Placebo 1000 IU/d

Summer

p=0.21

50

60

70

Placebo 1000 IU/d

Autumn

Mean (95% CI) p interaction=0.04

Cooper C et al Lancet Diabetes Endocrinol 2016; 4: 393-402

winter

spring

summer

autumn

25

35

45

55

65

75

25(O

H)D

(nm

ol/

l)

14 34Gestation (weeks)

-1-.

50

.5

Diffe

ren

ce in

RX

RA

1 (

SD

) (9

5%

CI)

RX

RA

1

RX

RA

2

RX

RA

3

RX

RA

4

RX

RA

5

RX

RA

8

RX

RA

9

RX

RA

10

RX

RA

11

RX

RA

12

RX

RA

13

RX

RA

14

1000 IU/d vs. Placebo

Gestational vitamin D supplementation leads to reduced perinatal RXRA methylation

(MAVIDOS)

Curtis E et al J Bone Miner Res 2019; 34: 231-40

DNA methylation

Prevention of fragility fracture throughout the lifecourse

Conclusions

• Population/individual mortality and morbidity burden attributable to osteoporotic fracture established

• Risk assessment well validated through FRAX, and widely incorporated in international treatment guidelines

• Effectiveness of FRAX-based programmes for treatment targeting demonstrable and cost-effective (MRC SCOOP)

• Secondary preventive strategies well designed, widely available and cost-effective

• Novel approaches point at prevention throughout the lifecourse

Sarcopenia

Components: • Muscle mass • Muscle strength • Physical performance

“A syndrome characterised by progressive, generalised loss of skeletal muscle mass and strength with the risk of adverse outcomes such as physical disability, poor quality of life and death.”

Cruz-Jentoft A et al Age Ageing 2019; 48: 16-31

ICD-10 Registration 2016

Novel approaches to definition: • EWGSOP-2 • SDOC (FNIH-2)

Muscle strength across the lifecourse

PLoS ONE 2014; 9(12): e113637; Age and Ageing 2017; 46: 407-16; Calcif Tissue Int 2018; 102: 53-63

Cross-cohort centile curves for grip strength.

12 population studies in Great Britain; 60,803 observations from 49,964 participants (26,687

female)

Peak 45% Loss rate 55%

Annual percentage change in muscle

function and body composition: HealthABC

Boxes show median, lower quartile and upper quartile

Median (LQ, UQ)

-2.0 (-3.7, -0.6)

-1.5 (-2.9, 0.0)

-0.4 (-1.0, 0.1)

-0.7 (-1.4, -0.1)

-0.4 (-1.9, 1.1)

-0.5 (-1.1, 0.0)

Westbury L et al ICFSR (2019)

Relationships between conditional change measures

Measures Grip

strength

Walking

speed

Lean

mass ALM Fat mass

Walking speed 0.16

P-value <0.001

Lean mass 0.24 0.08

P-value <0.001 0.002

ALM 0.24 0.08 0.89

P-value <0.001 0.004 <0.001

Fat mass 0.11 0.06 0.55 0.46

P-value <0.001 0.039 <0.001 <0.001

Hip BMD 0.22 0.21 0.42 0.34 0.39

P-value <0.001 <0.001 <0.001 <0.001 <0.001

ALM: Appendicular lean mass; Correlations where r>0.3 are in red

Westbury L et al ICFSR (2019)

Proportion of variance at Year 10 explained by

baseline level and change since baseline

Conditional change measures were derived for each characteristic

0% 20% 40% 60% 80% 100%

Hip BMD

Fat mass

ALM

Lean mass

Walking speed

Grip strength

Variance explained

0% 20% 40% 60% 80% 100%

Men Women

Baseline Change

Westbury L et al ICFSR (2019)

• All indices of body composition and muscle function show significant age-related declines

• Among muscle indices, proportionate declines over 10 years greatest for gait speed, then grip strength and lean mass

• Latent trajectory models identify subgroups with more pronounced differences in levels of characteristics, as compared with rates of loss

• Trajectories of change in indices of body composition (lean mass, ALM, fat mass and hip BMD), more strongly correlated with each other, than between these and gait speed or grip strength

• Extension to studying trajectories in multiple cohorts

• Findings support a lifecourse approach to preventive strategies, rather than purely a focus on environmental influences in later life

Conclusions

Bauer J et al ICFSR (2019)

Linked Pathophysiologic Entity: Osteosarcopenic Obesity?

With thanks to all at Southampton, Oxford and Health ABC