Bone Health in theReproductive Years

Robert LindsayHelen Hayes Hospital

&Columbia University

New York

Competing Interests

• Consultant - Eli Lilly, Amgen, Azelon• Speaker – Eli Lilly, Amgen, Warner-Chilcott• Institutional Research Grants – Eli Lilly, Amgen, Pfizer

This talk will not discuss specific therapeutic agents

Bone Mass by Age

Outline

• Determinants of peak skeletal mass

• Bone mass and its control during premenopausal years

• Interpretation of bone density in young women

• Commonly seen intercurrent problems affecting skeletal status in young women

Outline

• Determinants of peak skeletal mass

Bone growth and peak skeletal mass

• Heredity – 80% of variability in peak bone mass thought to be under genetic control

• 241 SNP’s from 9 genes identified as significantly associated with BMD or fracture– Wnt signaling (LRP5, LRP4, SOST)– RANK, RANK-L, OPG

Richards Annals Internal Medicine 2009

Discovery of the HBM Phenotype

ProbandProband NormalNormal

• Proband was 18-yr-old woman referred toCreighton ORC due to “unusually dense” femur

• Hip and spine density 5 standard deviations above normal population (Z-score)

• All bones were of normal shape

• No history of any type of bone fracture and no indication of adverse effects on health

• 17 out of 37 members of the family exhibited the HBM phenotype

Johnson ML, et al. Am J Hum Genet. 1997;60:1326-32.

Peak Bone Mass

Bone mass reaches a peak at between 18 and 25 Bone mass reaches a peak at between 18 and 25 years of ageyears of age

GeneticsGenetics Allelic variation in several different genes influences Allelic variation in several different genes influences

peak bone masspeak bone mass Endocrine statusEndocrine status

Age of menarcheAge of menarche Use of birth controlUse of birth control Altered menstruation statusAltered menstruation status Altered levels of testosteroneAltered levels of testosterone

Peak Bone Mass

Load bearing physical activity can help increase Load bearing physical activity can help increase bone massbone mass Childhood ExerciseChildhood Exercise Adult ExerciseAdult Exercise Sport Specific ExerciseSport Specific Exercise

Body CompositionBody Composition Nutritional StatusNutritional Status

CalciumCalcium Vitamin DVitamin D Protein Protein Other factorsOther factors

• Relatively high protein intake favors bone growth accrual during childhood1

• In adult women there is a positive association reported between protein intake and BMD 1-3

although several studies report no association 4-7 and excessive intake was related to lower BMD 8.

• Diets moderate in protein (1 to 1.5 g protein/kg) are associated with normal calcium metabolism10.

Protein and Bone Health

1. Chevally 20022. Hirota 1992 6. Mazess 19913. Cooper 1996 7. New 1997

4. Teegarden 1998 8. Nieves 19955. Henderson 1995 9. Anderson 1995

10. Kerstetter 2003

Bone growth and peak skeletal mass

• Nutrition– In utero and early life*– Growth (protein calcium and vitamin D)

• Micronutrients

• Physical Activity (may be maintained into

adulthood**)

*Cooper OI 2011; **Erlandson et al JBMR 2012

Higher Fruit and Vegetable Intake Relates to Greater Estimated % Change BMD

Prynne et al, Am J Clin Nutr, 2006Prynne et al, Am J Clin Nutr, 2006Median=250 gmWHO 2005; 400 gm

0

1

2

3

4

5

6

7

8

fruit fruit & vegetables

spine BMD (% difference)

boys

girls

Physical Activity

• Impact loading increases skeletal strength especially during growth

• These effects are continued into adulthood

• Total body BMC at 11yrs of age 1400g vs 1100g for non-gymnasts and at 25 (retired for 6-14yrs) TB-BMC was 2400g vs 2200 in non-athletes

Erlandson et al JBMR 2012Corrected for height, weight, menarchal age

Milk and Cheese

Supplementation

Cadogan et al, BMJ 1997

Cheng 2007Cheng 2007

Milk Intake Versus Soda Intake

Parameter and Treatment

Baseline After 10 days Treatment

PTH, pmol/l

Milk 4.9 + 1.2 5.3 + 1.5 P =0.046

Cola 5.1 + 1.2 5.9 + 0.9

Osteocalcin, µg/l

Milk 45.3 + 13.7 36.8 + 11.8 P =<0.001

Cola 44.5 + 19.6 50.6 + 17.1

CTX, µg/l

Milk 0.8 + 0.3 0.6 + 0.2 P =<0.001

Cola 0.8 + 0.4 0.9 + 0.3

NTX, nmol

BCE/mmol creatinine

Milk 62.1 + 19.2 47.3 + 15.5 P = <0.001

Cola 61.8 + 22.8 66.3 + 17.1

Bone Turnover Responses to 10-day Intervention with 2.5 Liters of Milk or

Cola Respectively in Young Men

Kristensen et al, Osteoporos Int 2005Kristensen et al, Osteoporos Int 2005

Lumbar spine L2–L4 Lumbar spine L2–L4 BMC and BMD in 192 BMC and BMD in 192 adolescent girls. BMC adolescent girls. BMC and BMD values (and BMD values (zz score)score)

Esterle L, OI 2009 Esterle L, OI 2009

Vitamin D Intake and Bone Mass in Children:

• Vitamin D Supplementation in Infancy (400 IU/d) for median 12 months vs. BMD age 7-9 1

• In 168 Finnish girls age 14-16, those with 25(OH)D <25nmol/L had lower radial BMD.2

• A cross sectional study in young Finnish men age 18-20 found approximately 4% difference in BMD between high vs low serum 25(OH)D3.

1. Zamoraa 1999. 2. Cheng 2003. 3. Valimaki 2004

Impact of Menstrual Function On Bone Mass and Size

Contraception in teenagers

• May impede final skeletal growth perhaps by suppressing IGF-1

Soyka et al. JCEM 1999

Impact of OC on Bone Size and Mass

Contraception in adults

• Bone remodeling is controlled by estrogen (in both genders)

• At any age loss of ovarian estrogen production increases bone remodeling and eventually loss of architecture and mass

• In adults in combination OC products there is usually sufficient synthetic estrogen to protect the skeleton

Contraception in adults

• OC use does not seem to change BMD in women 20-40yrs

• OC use after 40 may retard the pre and perimenopausal acceleration of bone loss

Progestin Contraception

• Depot MPA – most studies suggest some deterioration in BMD in young women

• But positive effects on BMD suggested for norethisterone, L-norgestrel, and oral MPA

FN BMD (adjusted)

FN BMD change (adjusted)

Calcium

Diet only (mg) 0.172 0.229

Total calcium (mg) 0.164 0.203

Phosphorous (mg) 0.160 0.244

Potassium (mg) 0.182 0.160

Magnesium (mg) 0.167 0.199

Zinc (mg) 0.081 0.057

Folate (mg) 0.095 0.131

Vitamin C (mg) 0.195 0.199

Correlations Between Nutrients and BMD and BMD Change

McDonald et al, Am J Clin Nutr 2004McDonald et al, Am J Clin Nutr 2004n=146 perimenopausal n=146 perimenopausal

Vitamin D Intake and Bone Mass in Children

In a 3-year longitudinal study of 171 peripubertal girls, there was a significant association between the baseline concentration of 25(OH)D and 3-year change in BMD of the lumbar spine and femoral neck.

Lehtonen-Veromaa, et al Am J Clin Nutr 2002

Engage in Regular Physical Activity

Bass et al, JBMR, 2007Bass et al, JBMR, 2007

Interaction Between Exercise and Calcium on gain in Tibia-Fibula BMC (g/ 8.5 months)

Interaction Between Calcium and Exercise

Cortical Thickness for EachLevel of Exercise and Milk Intake

L

L

L L

M

MM

M

H

H

H H

1 to 31 to 3 4 to 64 to 6 7 to 107 to 10 > 11> 110.00.0

5.05.0

5.55.5

6.06.0

6.56.5

7.07.0

Hours of Exercise/WeekHours of Exercise/Week

L LOW(glasses/day)

<1 milk (glasses/day)

M 1 to 2 milk MEDIUM 1 to 2 milk (glasses/day)

H > = 3 milk HIGH > 3 milk (glasses/day)

CorticalCorticalThicknessThickness

(mm)(mm)

Interaction Between Calcium, Vitamin D Intake and Exercise

Recker 1992Lohman 1995Prince 1995Specker 1996Stear 2003Jones 1998Rowlands 2004 Lloyd 2004Courteix, 2005Cussler 2005Ianc 2006Bass 2007

Lifestyle Variables for Male Cadets prior to entry

Milk Exercise Interaction- Males

Effect of Pregnancy on Bone Remodeling

Bone Resorption Bone Formation

Black et al, 2000

Weeks of Gestation

The Bone Strength Framework

BONESTRENGTH

BONE STRUCTUREe.g. Architecture Shape

STATICBONE MATERIALe.g. crystal size

collagen quality

DYNAMIC OPTIMAL LEVEL OF BONE REMODELING

BMD BMD

Metabolically vs Mechanically Driven Remodeling

Bo

ne

Tu

rno

ver

Ra

te

Mechanicallydriven remodeling

(Essential)

Metabolicallydriven remodeling

(Excess)

? Optimum

Outline

• Interpretation of bone density in young women

Bone Density by DXA

• Measures absorption or deflection of x-rays divided by the perceived area of tissue

• Does not measure “density” (gms/cc)• Small people have small bones interpreted by

DXA as low bone density!• In healthy premenopausal women results in the

low BMD range should be considered to be normal (i.e. within the range for 25 year olds)

• The presence of a co-morbidity changes that conclusion and may require further patient assessment

PLEASE – PLEASE - PLEASE

CAN WE KILL OSTEOPENIA!

When talking about young women!

For premenopausal women a negative T-score usually means you are below the population average value!

Being 61 inches means you are below average height – not that you have inchopenia (feetopenia or centimopenia)

BMD Testing in Premenopausal Women

• Generally not necessary or clinically relevant

• May be useful when comorbidities known to affect the skeleton are present (MS, AN Steroid Rx etc)

• May be useful when fractures occur in unusual circumstances i.e. modest trauma

Thank you for referring Ms Smith for bone density evaluation. Her T-score is -2 which increases her risk of fracture by 4 times.

Thank you for referring Ms Smith for bone density evaluation. Her T-score is -2 which increases her risk of fracture by 4 times.

What think you if Ms Smith is 60 inches and 100lbs?

Thank you for referring Ms Smith for bone density evaluation. Her T-score is -2 which increases her risk of fracture by 4 times.

What think you if Ms Smith is 70 inches and 200lbs?

Thank you for referring Ms Smith for bone density evaluation. Her T-score is -2 which increases her risk of fracture by 4 times.

What if she is 70 yrs old?

Predicting Bone Strength From Architecture

Parameter R2

Bone Volume (BV/TV) .76

Trabecular Thickness .63

Tb. Separation + Tb. Thickness .83

Volume+ SD- Tb Separation + Tb Number

.92

Bone Turnover

Too little turnover: Aging bone, unrepaired micro-cracks, hyper-mineralized

Too much turnover:Under-mineralized, stress risers

Bone Quality Is Maximized When Turnover Is Within the Physiological Window

PhysiologicalWindow

Bo

ne Q

ual

ity

Functions of Bone Remodeling Repair of Microdamage

(Bone 28:524-531, 2001)(Bone 28:524-531, 2001)

FATIGUE CRACKS : MECHANICAL STRESS RISERS

www.tam.uiuc.edu

Co-Morbidities

• Any chronic disease that interferes with activity, nutrition or ovarian function can negatively impact on the skeleton

Co-Morbidities

• Any chronic disease that interferes with activity, nutrition or ovarian function can negatively impact on the skeleton

• The classic example is anorexia nervosa

Drugs that affect the skeleton

• Steroids• Psychotropic Medications • Diabetes treatment• PPI’s • Anticonvulsants• Aromatase Inhibitors• GnRH agonists• Chemotherapeutic agents• Etc, etc,

General Recommendations for Osteoporosis

• Maintain Physical Activity – do something you like and make it a social experience

• Eat a good diet – modest amounts of red meat (acid load), but high in fruits and vegetables

• Try to get 1000-1500mg calcium per day (on average) from diet.

• Supplement vitamin D intake • Avoid cigarettes and keep alcohol intake modest

Conclusions

• Try to avoid the overuse of BMD measurements in young persons

• Do not ever tell someone they have osteopenia

• Avoid using osteoporosis medications whenever possible, at least until after menopause

• If fractures are present evaluate and treat