am 10.45 lindsay bone health
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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