1. Bone Health in the
Reproductive Years
Robert Lindsay
Helen Hayes Hospital
&
Columbia University
New York

2. 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

3. Bone Mass by Age

4. 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

5. Outline
• Determinants of peak skeletal mass

6. 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

7. Discovery of the HBM Phenotype
• Proband was 18-yr-old
woman referred to
Creighton 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
Proband Normal • 17 out of 37 members of the
family exhibited the HBM
Johnson ML, et al. Am J Hum Genet. 1997;60:1326-32. phenotype

8. Peak Bone Mass
 Bone mass reaches a peak at between 18 and 25
years of age
 Genetics
 Allelic variation in several different genes influences
peak bone mass
 Endocrine status
 Age of menarche
 Use of birth control
 Altered menstruation status
 Altered levels of testosterone

9. Peak Bone Mass
 Load bearing physical activity can help increase
bone mass
 Childhood Exercise
 Adult Exercise
 Sport Specific Exercise
 Body Composition
 Nutritional Status
 Calcium
 Vitamin D
 Protein
 Other factors

10. Protein and Bone Health
• 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.
1. Chevally 2002
2. Hirota 1992 6. Mazess 1991
3. Cooper 1996 7. New 1997
4. Teegarden 1998 8. Nieves 1995
5. Henderson 1995 9. Anderson 1995
10. Kerstetter 2003

11. 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

12. Higher Fruit and Vegetable Intake Relates
to Greater Estimated % Change BMD
8
7
6
5
boys
4
girls
3
2
spine BMD (% difference)
1
0
fruit fruit & vegetables
Median=250 gm Prynne et al, Am J Clin Nutr, 2006
WHO 2005; 400 gm

13. 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
Corrected for height, weight,
Erlandson et al JBMR 2012 menarchal age

14. Milk and Cheese
Supplementation
Cadogan et al, BMJ 1997
Cheng 2007

15. Milk Intake Versus Soda
Intake

16. Bone Turnover Responses to 10-day
Intervention with 2.5 Liters of Milk or
Cola Respectively in Young Men
Parameter and Baseline After 10 days Treatment
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
Kristensen et al, Osteoporos Int 2005

17. Lumbar spine L2–L4
BMC and BMD in 192
adolescent girls. BMC
and BMD values (z
score)
Esterle L, OI 2009

18. 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

19. Impact of Menstrual
Function On Bone Mass and Size

20. Contraception in teenagers
• May impede final skeletal growth perhaps
by suppressing IGF-1
Soyka et al. JCEM 1999

21. Impact of OC on Bone
Size and Mass

22. 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

23. 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

24. 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

25. Correlations Between Nutrients and
BMD and BMD Change
FN BMD FN BMD
(adjusted) 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
n=146 perimenopausal
McDonald et al, Am J Clin Nutr 2004

26. 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

27. Engage in Regular Physical
Activity
Interaction Between Exercise and Calcium
on gain in Tibia-Fibula BMC (g/ 8.5 months)
Bass et al, JBMR, 2007

28. Interaction Between Calcium and
Exercise
Cortical Thickness for Each
Level of Exercise and Milk Intake
7.0
7.0
6.5
6.5 H M
H
Cortical H M
Cortical M L LOW <1 milk (glasses/day)
L L (glasses/day)
Thickness 6.0
Thickness 6.0 L
M
(mm)
(mm) M 1 to 2
MEDIUM 1 to 2 milk (glasses/day)
H milk
L
5.5
5.5
H HIGHmilk > 3 milk (glasses/day)
>=3
5.0
5.0
0.0
0.0
1 to 3 4 to 6 7 to 10 > 11
Hours of Exercise/Week
Hours of Exercise/Week

29. Interaction Between Calcium,
Vitamin D Intake and Exercise
Recker 1992
Lohman 1995
Prince 1995
Specker 1996
Stear 2003
Jones 1998
Rowlands 2004
Lloyd 2004
Courteix, 2005
Cussler 2005
Ianc 2006
Bass 2007

30. Lifestyle Variables for
Male Cadets prior to entry

31. Milk Exercise
Interaction- Males

32. PEAK BONE MASS GRAPH
Healy et al, Peak Bone Mass Osteoporisis International (2000) 11:985-1009

33. Effect of Pregnancy on Bone Remodeling
Bone Resorption Bone Formation
Weeks of Gestation
Black et al, 2000

34. The Bone Strength Framework
BONE
STRENGTH
BONE STRUCTURE BONE MATERIAL
STATIC e.g. Architecture e.g. crystal size
Shape collagen quality
BMD BMD
DYNAMIC OPTIMAL LEVEL OF BONE REMODELING

35. Metabolically vs Mechanically
Driven Remodeling
Bone Turnover Rate
Metabolically
driven remodeling
(Excess)
? Optimum
Mechanically
driven remodeling
(Essential)

36. Outline
• Interpretation of bone density in young
women

37. 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

38. PLEASE – PLEASE - PLEASE
CAN WE KILL OSTEOPENIA!
When talking about young women!

39. 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)

40. 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

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

42. 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?

43. 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?

44. 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?

46. 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 .92
Number

47. Bone Quality Is Maximized When Turnover
Is Within the Physiological Window
Physiological
Bone Quality Window
Bone Turnover
Too little turnover: Aging bone, unrepaired Too much turnover:
micro-cracks, hyper-mineralized Under-mineralized, stress risers

48. Functions of Bone Remodeling
Repair of Microdamage
(Bone 28:524-531, 2001)

49. FATIGUE CRACKS :
MECHANICAL STRESS RISERS
www.tam.uiuc.edu

50. Co-Morbidities
• Any chronic disease that interferes with
activity, nutrition or ovarian function can
negatively impact on the skeleton

51. 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

52. Drugs that affect the skeleton
• Steroids
• Psychotropic Medications
• Diabetes treatment
• PPI’s
• Anticonvulsants
• Aromatase Inhibitors
• GnRH agonists
• Chemotherapeutic agents
• Etc, etc,

53. 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

54. 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