With the strength data and the various architectural measures quantified we then use logistic regression models to examine the relative contribution of each of the elements to overall bone strength. Shown here are some of the results. If we use a simple one variable model, bone volume can explain about 76% of the observed strength. Used singly the various trabecular elements account formore than 60% of the strength. Trabecular thickness is shown here. Other single elements also show comparable results. IF we begin to use multiple variable models we can account for a larger and larger fraction of the observed strength. Trabecular separation and thickness together can account for about 80% of observed bone strength. And the combination of bone volume, the standard deviation of trabecular separation and trabecular number (which is essentially a way to describe how many trabeculae there are and how they are spaced) can explain over 90% of the observed strength.
I’ve talked about a lot different things in the last 30 minutes
Am 10.45 lindsay bone health
Bone Health in theReproductive Years Robert Lindsay Helen 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
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
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 • 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 HBMJohnson ML, et al. Am J Hum Genet. 1997;60:1326-32. phenotype
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
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
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
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 8 7 6 5 boys 4 girls 3 2 spine BMD (% difference) 1 0 fruit fruit & vegetablesMedian=250 gm Prynne et al, Am J Clin Nutr, 2006WHO 2005; 400 gm
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
Milk and CheeseSupplementation Cadogan et al, BMJ 1997 Cheng 2007
Bone Turnover Responses to 10-dayIntervention 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
Lumbar spine L2–L4BMC and BMD in 192adolescent girls. BMCand BMD values (zscore)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 MenstrualFunction On Bone Mass and Size
Contraception in teenagers• May impede final skeletal growth perhaps by suppressing IGF-1 Soyka et al. JCEM 1999
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
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
Vitamin D Intake and Bone Mass in ChildrenIn a 3-year longitudinalstudy of 171 peripubertalgirls, there was asignificant associationbetween the baselineconcentration of 25(OH)Dand 3-year change in BMDof the lumbar spine andfemoral neck. Lehtonen-Veromaa, et al Am J Clin Nutr 2002
Engage in Regular Physical ActivityInteraction Between Exercise and Calciumon gain in Tibia-Fibula BMC (g/ 8.5 months) Bass et al, JBMR, 2007
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 6.0Thickness 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
Interaction Between Calcium,Vitamin D Intake and ExerciseRecker 1992Lohman 1995Prince 1995Specker 1996Stear 2003Jones 1998Rowlands 2004Lloyd 2004Courteix, 2005Cussler 2005Ianc 2006Bass 2007
Lifestyle Variables forMale Cadets prior to entry
PEAK BONE MASS GRAPH Healy et al, Peak Bone Mass Osteoporisis International (2000) 11:985-1009
Effect of Pregnancy on Bone Remodeling Bone Resorption Bone Formation Weeks of Gestation Black et al, 2000
The Bone Strength Framework BONE STRENGTH BONE STRUCTURE BONE MATERIALSTATIC e.g. Architecture e.g. crystal size Shape collagen quality BMD BMDDYNAMIC OPTIMAL LEVEL OF BONE REMODELING
Metabolically vs Mechanically Driven Remodeling Bone Turnover Rate Metabolically driven remodeling (Excess) ? Optimum Mechanically driven remodeling (Essential)
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 - PLEASECAN 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?
Bone Quality Is Maximized When Turnover Is Within the Physiological Window Physiological Bone Quality Window Bone TurnoverToo little turnover: Aging bone, unrepaired Too much turnover:micro-cracks, hyper-mineralized Under-mineralized, stress risers
Functions of Bone Remodeling Repair of Microdamage (Bone 28:524-531, 2001)
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