Factors influencing peak bone mass

Nicholas HarveyMA MB BChir PhD FRCP

Professor of Rheumatology and Clinical EpidemiologyMRC Lifecourse Epidemiology Unit, University of Southampton

Outline

MRC Lifecourse Epidemiology Unit, University of SouthamptonDirector: Professor Cyrus Cooper

• Overview

• Relevance of PBM

• Determinants of PBM

• Conclusions

Bone mass(g/Ca)

Age (yr)

1500 -

1000 -

500 -

0 -0 20 40 60 80 100

Peak bone mass predicts risk of osteoporosisHernandez et al., OI 2003

Maternal lifestyle, body build, 25(OH)D during pregnancyGodfrey et al., JBMR 2001Javaid et al., Lancet 2006Harvey et al., JDOHAD 2012

Postnatal nutrition, body composition and PAHarvey et al., BJN 2009Cole et al., Bone 2012Harvey et al., OI 2012

Developmental origins of osteoporotic fracture

Poor early growth, reduced adult BMC, increased risk hip fractureCooper et al., JBMR 1995Cooper et al., OI 2001Javaid et al., OI 2011

Harvey, Dennison, Cooper JBMR 2014; 29(9):1917-25

Maximize peak Reduce fracture risk

Risk factors for low PBM

• Population level– Nutrition, physical activity, smoking, alcohol

• Chronic disease– Malabsorption, Inflammation, Endocrine,

Musculoskeletal, any!– Malignancy– Genetic– Medications

Growth, timing of exposure and PBM

• Long-term trajectory vs transient deviation?

• Linear growth or BMD

Miss B.P.

• 25 year old lab technician, Porton Down• GP referral after 2 wrist fractures• Crohn’s disease since age 8 years

– Prednisolone, azathrioprine– CRP 54, ESR 71– DXA Z-score: LS -3.2; LFN -2.3– Vegan, elite cycle training, smoker, no

alcohol

Inflammation, malabsorption and BMD

Laasko et al., CTI 2012; 91:121-130

Childhood calcium, vitamin D and BMD

Modest effect on LS BMD and TBMD when 25(OH)D<35nmol/l

Winzenberg et al., BMJ 2011;342:c7254Winzenberg et al., BMJ 2006: doi:10.1136/bmj.38950.561400.55

Vitamin D

Calcium

WB BMC

Childhood physical activity, BMD and fracture

4 yr BMC and habitual PA

Harvey et al., Osteoporos Int. 2012;23:121-30

Clark et al., J Bone Miner Res. 2008;23:1012-1022

Greater physical activity (impact) associated with greater BMDBut… also with more fractures

Miss B.P., continued

• Mentions has had weight issues since childhood acute lymphoblastic leukaemia

• Amenorrhea

• BMI 16kg/m2

• Keen to start a family

pQCT volumetric BMD in ALL

p=0.03

p=0.002

RADI

IUS

TIBI

A

p=0.09

p=0.71

TRABECULAR CORTICAL

Kohler, Moon et al., Bone. 2012 Oct;51(4):765-70

Anorexia Nervosa and BMDMean difference LS BMD eating disorder vs control

Robinson et al., Osteoporos Int. 2016; 27:1953-1966

Adolescent AN:Reduced trabecular vBMDIncreased cortical vBMDReduced muscle CSADiVasta et al., Osteoporos Int. 2016 ePub

MalnutritionLow oestrogen? Excessive PA

Miss B.P., continued

• Volunteers further information– Deprived intra-uterine life

– Parents smoked and “never went outdoors”

– “always on bottom centile”

Late pregnancy maternal 25(OH)-vitamin D, venous umbilical cord calcium and nine year WBBMC

Mean (95% CI)Pearson r (p) continuous data

Maternal 25 (OH)-Vit D (ng/ml)

r=0.20p=0.008

<11 -20 >200

0.9

1.0

1.1

1.2

1.3

Child

hood

who

le b

ody

BMC

(kg)

Child

hood

who

le b

ody

BMC

(kg)

r=0.19p=0.02

Umbilical cord Ca2+

corrected for albumin (mmol/L)

<2.7 -2.8 >2.80.00.9

1.0

1.1

1.2

1.3

1.4

Javaid et al, Lancet 2006

875

880

885

890

895

900

905

910

915

Bone

are

a (c

m2)

0.505

0.51

0.515

0.52

0.525

0.53

0.535

0.54

0.545

0.55

0.555

Bone

min

eral

con

tent

(kg)

0.576

0.582

0.588

0.594

0.600

0.606

Bone

min

eral

den

sity

(g/c

m2)

<25 ≥25 <25 ≥25 <25 ≥25

Maternal 25(OH)D (nmol/l)

P=0.016 P=0.015 P=0.046

Maternal late pregnancy 25(OH)D status and offspring whole body less head bone mineral at 6-7 years

Southampton Women’s Survey

Moon et al, Osteoporosis International 2015, 26(4):1449-51

N=1004, shown as mean±95% CI

Expected differences in whole body bone mineralisation at age 20 years for every 10nmol/l maternal 25(OH)D

Western Australia Pregnancy (Raine) Cohort

Model 1: adjusted for season of blood sampling, sex and age at DXAModel 2: Model 1 + maternal education, parity, ethnicity, maternal height and pre-pregnancy weight

Model 3: Model 2 + offspring height, lean mass and fat mass at 20 years

Zhu et al, J Bone Miner Res. 2014;29(5):1088-95

N=341, shown as mean±95% CI

BMC BA BMD

Antenatal vitamin D supplementation increases offspring BMC in winter births

p=0.004

5060

70W

hole

bod

y BM

C (g

)

Placebo 1000 IU/d

Winter

p=0.44

5060

70

Placebo 1000 IU/d

Spring

p=0.73

5060

70

Placebo 1000 IU/d

Summer

p=0.2150

6070

Placebo 1000 IU/d

Autumn

Mean (95% CI) p interaction=0.04

p interaction = 0.04

Cooper, Harvey et al., Lancet DE 2016

6 year follow-up now funded by Arthritis Research UK

Determinants of 25(OH)D response to cholecalciferol supplementationMoon, Harvey, Cooper et al., JCEM 2016 (in press)

Tracking of 25(OH)D across gestationMoon et al., AJCN 2015; 102:1081-7

Genetic determinants of 25(OH)D response

Neonatal BMC (g)

Conclusions

• Determinants of PBM many and varied– From conception onwards

• Considerations– Chronic vs transient– Lifestyle vs morbidity– Size vs BMD

• In younger adults with OP, consider low PBM vs loss

Acknowledgements• MRC LEU Cyrus Cooper (Director and Professor

of Rheumatology),Elaine Dennison, Avan Aihie Sayer, Chris Holroyd, Mark Edwards, Becca Moon, Beth Curtis, Janis Baird, Caroline Fall, Clive Osmond, Sian Robinson, Keith Godfrey, Hazel Inskip

• Osteoporosis Centre, SGH Pat Taylor, Gill Pearson

• Bone & Joint Laboratories Richard Oreffo, Stuart Lanham

• Institute of Developmental Sciences/ EpiGenMark Hanson, Peter Gluckman,

Graham Burdge, Karen Lillycrop, Jane Cleal, Jo Slater-Jefferies

• Botnar Research Centre, Oxford Nigel Arden, Kassim Javaid,

Richie Gill, Andy Price, Andy Carr

Factors influencing peak bone mass

Nicholas HarveyMA MB BChir PhD FRCP

Professor of Rheumatology and Clinical EpidemiologyMRC Lifecourse Epidemiology Unit, University of Southampton