Preventing Bone Loss in Early Postmenopausal Women A CME Slide Library From the Council on Hormone Education

Preventing Bone Loss in Early Postmenopausal Women Section 1: Introduction Section 2: Mechanisms Underlying Menopause-Related Bone Loss Section 3: Prevalence and Consequences of Bone Loss Section 4: Predicting Fracture Risk in Postmenopausal Women Section 5: Prevention of Bone Loss Section 6: Osteoporosis Therapies and Fracture Prevention Section 7:Effect of HT on Fracture Prevention Section 8: Summary and Conclusions

Section 1: Introduction Preventing Bone Loss in Early Postmenopausal Women

Bone Mass by Age and Sex Bone Mass Age (years) Adapted from Finkelstein JS. Cecil Textbook of Medicine. 21st ed. 1999; ©1999 Reprinted with permission from Elsevier. Riggs BL, Melton LJ III. N Engl J Med. 1986;314: MenWomen Menopause-Associated Bone Loss

Change in Spine and Femoral Neck BMD Versus Years Since Menopause Percent per Year Bjarnason NH, et al. Bone. 2002;30: to 44 to 77 to SpineFemur Years Since Menopause

Section 2: Mechanisms Underlying Menopause-Related Bone Loss Preventing Bone Loss in Early Postmenopausal Women

Osteocytes Osteoclasts Reversal Apoptotic Osteoclasts Lining Cells Osteocytes Activation Osteocytes Formation Osteoblasts Osteocytes Resorption Resting Phase Osteoclasts Bone Remodeling Osteoid Lining Cells Osteocytes Preosteoblasts

Estrogen Deficiency Increases Bone Resorption IL = interleukin; TNF = tumor necrosis factor; M-CSF = macrophage colony-stimulating factor; GM-CSF = granulocyte M-CSF; TGF = transforming growth factor ; RANKL = receptor activator of nuclear factor B ligand; OPG = osteoprotegerin. Increased Bone Resorption Monocytes IL-6M-CSFIL-11GM-CSFRANKL Stromal Cells/Pre- osteoblasts Active Osteoclasts IL-1 IL-1 TNF TNF Early Osteoclast Progenitors OPG TGF TGF = RANKM-CSF IL-6, IL-1 IL-6, IL-1TNFRANKL

Estrogen Decreases Bone Resorption E = estrogen. IL-1 IL-1 TNF TNF Decreased Bone Resorption IL-6M-CSFIL-11GM-CSFRANKL Monocytes Stromal Cells/Pre- osteoblasts Active Osteoclasts Early Osteoclast Progenitors OPG TGF OPG TGF E E = RANK EM-CSF IL-6, IL-1 IL-6, IL-1TNFRANKL

Biochemical Markers Predict Early Menopausal Bone Loss Women with markers of resorption or formation within the premenopausal range –Bone loss over 4 years, <1% Women with markers of resorption or formation above the premenopausal range –Bone loss over 4 years, 1.5% to 2.5% Garnero P, et al. J Bone Miner Res. 1999;14:

4-Year Rate of Loss (%) BMD Change: Healthy Postmenopausal Women With Low and High Bone Turnover BMD = bone mineral density; BAP = bone alkaline phosphatase; PICP = C-terminal propeptide of type I collagen; PINP = N-terminal propeptide of type I collagen; NTX = N-telopeptide breakdown products; CTX = C-telopeptide breakdown products; High turnover = bone marker levels above the upper limit of the premenopausal range. Garnero P, et al. J Bone Miner Res. 1999;14: Used with permission. Low TurnoverHigh Turnover Serum Osteocalcin Serum BAP Serum PICP Serum PINP Urinary NTX Urinary CTX Serum CTX P =.0016 P =.06 P =.09 P =.01 P =.005 P =.006 P =.0001

Section 3: Prevalence and Consequences of Bone Loss Preventing Bone Loss in Early Postmenopausal Women

Diagnostic Categories for Osteoporosis in Postmenopausal Women (WHO Criteria) Normal: T-score above –1 Low bone mass (osteopenia): T-score between –1 and –2.5 Osteoporosis: T-score at or below –2.5 WHO = World Health Organization. WHO Study Group. WHO Technical Report Series. 1994;843:5-6.

Third National Health and Nutrition Examination Survey (NHANES III, ) for women 50 years of age. Looker AC, et al. J Bone Miner Res. 1997;12: Prevalence of Low Bone Mass and Osteoporosis in Postmenopausal Women by Ethnicity Population Prevalence of Low Bone Mass (T-score between –1 and –2.5) Prevalence of Osteoporosis (T-score –2.5) Non-Hispanic white African American Mexican American All ethnic groups (total) 42% 28% 37% 40% 17% 8% 12% 16%

Fracture Risk by Ethnicity in US Women 4 out of 10 white women 1 2 out of 10 black women 2 1 Melton LJ III, et al. J Bone Miner Res. 1992;9: Griffin MR, et al. Am J Epidemiol. 1992;136: Melton LJ III. Endocrinol Metab Clin North Am. 2003;32:1-13. Lifetime Risk for Fracture, After Age 50 Years Lower risk in Hispanic women compared with non- Hispanic white; greater than in black women 3 Risk for vertebral fracture in Asian women similar to non-Hispanic whites; hip fracture risk is lower 3

Section 4: Predicting Fracture Risk in Postmenopausal Women Preventing Bone Loss in Early Postmenopausal Women

DXA = dual-energy x-ray absorptiometry; QCT = quantitative computed tomography; pQCT = peripheral quantitative computed tomography; QUS = quantitative ultrasonometry; RA = radiographic absorptiometry. American Association of Clinical Endocrinologists. Endocr Pract. 2003;9: Prediction of Fracture Risk All techniques (DXA, QCT, pQCT, QUS, RA, etc) predict fracture risk Bone loss can best be monitored using DXA of the spine in early postmenopausal women

Predictive Validity of BMC for Fracture BMC = bone mineral content; CHD = coronary heart disease. WHO Study Group. WHO Technical Report Series. 1994;843:46; Neaton JD, Wentworth D. Arch Intern Med. 1992;152: Relative Risk Increasing Total Cholesterol Decreasing BMC Quartile 1Quartile 4Quartile 2Quartile 3 Comparison to Predictive Validity of Cholesterol for Heart Disease

NORA: All Devices Studied Predicted Fracture Risk US = ultrasound; SXA = single-energy x-ray absorptiometry. Fractures during 1-year follow-up in 149,524 postmenopausal Caucasian women. Miller PD, et al. J Bone Miner Res. 2002;17: Used with permission. T-Score

When Measurement of BMD in Women is Inappropriate Healthy premenopausal women Healthy children and adolescents Women initiating HT for menopausal symptom relief –Other osteoporosis therapies should not be initiated without BMD measurement

When to Measure BMD in Women All women 65 years and older Postmenopausal women <65 years of age –If results might influence decisions about intervention –One or more risk factors –History of fracture –Patient requests measurement American Association of Clinical Endocrinologists. Endocr Pract. 2003;9: National Osteoporosis Foundation. Washington, DC: National Osteoporosis Foundation; 2003:1-37.

Risk Factors for Osteoporosis-Related Fractures Non-modifiable Female sex Advanced age Caucasian race History of fracture as an adult Family history of osteoporosis Early or premature menopause Modifiable Low BMD Low body weight/BMI Smoking Low calcium intake Vitamin D deficiency Inadequate physical activity Glucocorticosteroid use Estrogen deficiency High risk for falls American Association of Clinical Endocrinologists. Endocr Pract. 2003;9: National Osteoporosis Foundation. Washington, DC: National Osteoporosis Foundation; 2003:1-37.

Who Should Be Offered Intervention? All women with osteoporosis-related fractures irrespective of BMD All postmenopausal women with a BMD T-score of –2.5 or lower

Who Should Be Considered for Preventive Intervention? Patients with levels of BMD above –2.5 with other risk factors, including –Age –Glucocorticosteroid use –Low body weight/BMI –Smoking –Family history –Early or premature menopause

Hui SL, et al. J Clin Invest. 1988;81: For a Given BMD, Fracture Risk Increases With Age Fracture Risk per 1000 Person-Years Bone Mass (g/cm) Age (years) <45

NORA: Osteoporotic Fracture Rate by Age *Corrected for initial BMD Derived from Siris ES, et al. JAMA. 2001;286: , and Miller PD, et al. J Bone Miner Res. 2002;17:

NORA: Factors Associated With Reduced Risk of Osteoporosis Siris ES, et al. JAMA. 2001;286: Factor Odds Ratio (95% CI) BMI 30 kg/m 2 Current estrogen use Alcohol use ( 14 drinks/week) Former estrogen use Regular exercise 0.16 (0.15–0.17) 0.27 (0.25–0.28) 0.62 (0.54–0.71) 0.77 (0.73–0.80) 0.86 (0.82–0.89)

NORA: Inverse Relationship Between BMD and Fracture Rate BMD T-scores Fracture Rate per 1000 Person-Years > to to to –0.5 –0.5 to –1.0 –1.0 to –1.5 –1.5 to –2.0 –2.0 to –2.5 –2.5 to –3.0 –3.0 to –3.5 < –3.5 Adapted from Siris ES, et al. JAMA. 2001;286: Fracture Rate BMD Distribution

# Fractures NORA: Fracture Rate vs Number of Fractures by T-Score BMD T-scores Fracture Rate per 1000 Person-Years Number of Fractures > to to to –0.5 –0.5 to –1.0 –1.0 to –1.5 –1.5 to –2.0 –2.0 to –2.5 –2.5 to –3.0 –3.0 to –3.5 < –3.5 Adapted from Siris ES, et al. JAMA. 2001;286: Fracture Rate BMD Distribution

Patient A Patient B Gomberg BR, et al. IEEE Trans Med Imaging. 2000;19: Bone Quality: Contribution of Bone Micro-Architecture Two Patients With Similar BMD, Dissimilar Micro-Architecture

Bone Quality: Contribution of Bone Micro-Architecture continued Most plate-likeMost rod-like 60-Year-Old Male68-Year-Old Female 53-Year-Old Female74-Year-Old Female Distal Radius Specimens Gomberg BR, et al. IEEE Trans Med Imaging. 2000;19:

Section 5: Prevention of Bone Loss Preventing Bone Loss in Early Postmenopausal Women

Calcium Supplementation Alone Does Not Prevent Early Postmenopausal Bone Loss Change in BMD After 2 Years (%) Placebo (n = 14) Calcium supplementation = 500 mg/day. *P <.01 vs baseline. Dawson-Hughes B, et al. N Engl J Med. 1990;323: Calcium Citrate (n = 25) Calcium Carbonate (n = 28) Placebo (n = 11) Calcium Citrate (n = 24) Calcium Carbonate (n = 23) * * * SpineFemoral Neck

FDA-Approved for the Prevention of Bone Loss Estrogen Bisphosphonates –Alendronate –Risedronate Raloxifene

Blue area represents placebo-treated population of oophorectomized women. Lindsay R, et al. Lancet. 1976;1: Metacarpal Bone Mineral Content (mg/mm) Years At Oophorectomy 3 Years After Oophorectomy 6 Years After Oophorectomy Effect of Delayed Initiation of HT on Bone Loss

CEE CEE/MPA Changes in Spine BMD With HT Intent-to-treat population only; Womens HOPE = Womens Heart, Osteoporosis, Progestin, Estrogen; CEE = conjugated equine estrogens; MPA = medroxyprogesterone acetate. Lindsay R, et al. JAMA. 2002;287: Used with permission. The Womens HOPE Study

*Adherent participants only (n = 641, age 45 to 64 years). All active treatment groups significant vs placebo; no significant differences were found among active treatment groups. PEPI = Postmenopausal Estrogen/Progestin Interventions; MP = micronized progesterone. Writing Group for the PEPI Trial. JAMA. 1996;276: Used with permission. Different Progestin Regimens Do Not Modify the Impact of Estrogen on BMD Change From Baseline (%)* Baseline12 Months36 Months Baseline12 Months36 Months Spine Hip CEE/MP (cyclic)Placebo CEE Only CEE/MPA (cyclic) CEE/MPA (continuous) The PEPI Trial

Bone Loss Is Uncommon With HT Use Among Adherent Women in the PEPI Trial Only 3% of HT users lost >2% in spinal BMD in the first 12 months vs 41% using placebo Only 1% of HT users lost >2% in spinal BMD after 12 to 36 months vs 16% using placebo Greendale GA, et al. Arch Intern Med. 2000;160:

Section 6: Osteoporosis Therapies and Fracture Prevention Preventing Bone Loss in Early Postmenopausal Women

FDA-Approved for the Treatment of Osteoporosis Bisphosphonates –Alendronate –Ibandronate* –Risedronate Calcitonin Raloxifene Teriparatide *Approved, but not available in the US as of 2/11/04.

Meta-Analysis of Osteoporosis Therapies: Spine BMD HT (2 year) Alendronate, 5 mg (2 or 3 year) Alendronate, 10–40 mg (2–4 year) Risedronate, 5 mg (1.5–3 year) Raloxifene, 60 mg (2–3 year) Calcitonin* (1–5 year) Calcium (2 year) *Doses ranged from 250 to 2800 IU per week; predominantly nasal delivery. Cranney A, et al. Endocr Rev. 2002;23:570-8; Endocrine Rev. 2002;23: Weighted Mean Difference ± 95% CI (% change in BMD)

HT (2 year) Alendronate, 5 mg (2 year) Alendronate, 10–40 mg (2 year) Risedronate, 5 mg (1.5–3 year) Raloxifene, 60 mg (2–3 year) Calcitonin* Calcium Weighted Mean Difference ± 95% CI (% change in BMD) *Doses ranged from 350 to 800 IU per week; predominantly nasal delivery. Cranney A, et al. Endocr Rev. 2002;23:570-8; Endocrine Rev. 2002;23: Meta-Analysis of Osteoporosis Therapies: Total Hip BMD

HT (2 year) Alendronate, 5 mg (2 year) Alendronate, 10–40 mg (2–4 year) Risedronate, 5 mg (1.5 year) Raloxifene, 60 mg (1 year) Calcitonin* Calcium Weighted Mean Difference ± 95% CI (% change in BMD) *Doses ranged from 350 to 800 IU per week; predominantly nasal delivery. Cranney A, et al. Endocr Rev. 2002;23: Endocrine Rev. 2002;23: Meta-Analysis of Osteoporosis Therapies: Forearm BMD

Effect of Treatment and Discontinuation on BMD in Older Postmenopausal Women Change From Baseline (%) *P <.05 compared with baseline measure. P <.05 compared with placebo group. Gallagher JC, et al. J Clin Endocrinol Metab. 2002;87: Copyright 2002, The Endocrine Society. Spine BMDFemoral Neck BMD Month TreatmentFollow-up Change From Baseline (%) Month TreatmentFollow-up PlaceboHT * * * *

Effect of Treatment and Discontinuation on BMD in Older Postmenopausal Women continued Mean Change in BMD (%) Greenspan SL, et al. Ann Intern Med. 2002;137: Used with permission. Lumbar SpineFemoral Neck Month TreatmentFollow-up Mean Change in BMD (%) Month TreatmentFollow-up Placebo/PlaceboCEE/PlaceboAlendronate/Placebo

Section 7: Effect of HT on Fracture Prevention Preventing Bone Loss in Early Postmenopausal Women

Years Fracture-Free Survival P <.05; prospective trial of women aged 45 to 58 yrs in which 21 wrist fractures were documented; HT = 2 mg oral estradiol + 10 days of 1 mg norethisterone. Reprinted from Mosekilde L, et al. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal womenresults of the Danish Osteoporosis Prevention Study. Maturitas. 2000;36: © 2000, with permission from Elsevier Science. HT (n = 502) No HT (n = 504) Danish Osteoporosis Prevention Study: Fracture-Free Survival in Early Postmenopausal Women Wrist Fracture

Meta-Analysis of Osteoporosis Therapies : Nonvertebral Fractures HT* (n = 20,494) Alendronate, 5 mg (n = 8603) Alendronate, 10–40 mg (n = 3723) Risedronate, 2.5–5 mg (n = 12,958) Raloxifene, 60 mg (n = 6961) Calcitonin (n = 6961) Calcium (n = 222) Relative Risk (95% CI) *Includes the Womens Health Initiative (WHI) trial. Estimate from the Prevent Recurrence of Osteoporotic Fractures (PROOF) trial. Cranney A, et al. Endocr Rev. 2002;23: Endocrine Rev. 2002;23: ; Rosen C. Presentation for ASBMR at NIH Scientific Workshop: Menopausal Hormone Therapy, October 23-24, Available at: Accessed 1/18/03.

Womens Health Initiative (WHI) Trial

WHI: Baseline Prevalence of Osteoporosis (WHO) by DXA Femoral Neck T-scores Normal (>–1.0) Low Bone Mass (–1.0 to –2.4) E+PPlacebo P =.29 Cauley JA. Available at: Accessed 1/7/04. In 6% of Participants (n = 1024) 32% 58% 10% 35% 53% 12% Osteoporosis ( –2.5 )

Placebo HT WHI Results: Mean Change in BMD During 3 Years of E+P Follow-up (years) Cauley JA, et al. JAMA. 2003;290: Mean Change in BMD From Baseline (%) Total Hip Spine In 6% of Participants (n = 1024)

WHI Results: Fracture Outcomes Hip Vertebral Lower Arm/ Wrist Total Hazard Ratio 95% nCI 95% aCI Adjusted confidence interval reported only for hip fracture. Cauley JA, et al. JAMA. 2003;290:

WHI Results: Effect of E+P in Preventing Fractures Number of Fractures/Year in 10,000 Women Type of Fracture Cauley JA, et al. JAMA. 2003;290:

WHI Results: Effect of E+P on Risk of Hip Fracture Kaplan-Meier Estimate Time (year) Cumulative Hazard for Hip Fracture HR = % nCl = 0.47– % aCI = 0.41–1.10 Placebo E+P Cauley JA, et al. JAMA. 2003;290:

WHI Results: Effect of E+P on Risk of Lower Arm/Wrist Fracture Adjusted confidence interval not reported. Cauley JA, et al. JAMA. 2003;290: Kaplan-Meier Estimate Time (year) Cumulative Hazard for Lower Arm/Wrist Fracture HR = % nCl = 0.59–0.85 Placebo E+P

WHI Results: Effect of E+P on Risk of Vertebral Fracture Adjusted confidence interval not reported. Cauley JA, et al. JAMA. 2003;290: Kaplan-Meier Estimate Time (year) Cumulative Hazard for Vertebral Fracture HR = % nCl = 0.46–0.92 Placebo E+P

Cumulative Hazard for Total Fracture Time (year) WHI Results: Effect of E+P on Risk of Total Fracture Adjusted confidence interval not reported. Cauley JA, et al. JAMA. 2003;290: HR = % nCl = 0.69–0.83 Placebo E+P Kaplan-Meier Estimate

1 Cauley JA, et al. JAMA. 2003;290: Black DM, et al. Osteoporosis Int. 2001;12: WHI: Summary Fracture Risk Score WHI Investigators 1 developed a summary fracture risk score guided by the methods used to develop the FRACTURE Index 2 Predictive validity of FRACTURE Index has been shown 2 Validity of WHI fracture risk score not established –WHI reported fracture risk score showed moderate predictive strength for hip fracture 1

1 Cauley JA, et al. JAMA. 2003;290: Black DM, et al. Osteoporosis Int. 2001;12: WHI: Summary Fracture Risk Score continued Differences between FRACTURE Index and WHI risk score 1,2 –WHI score includes age, prior fracture after age 55 years, current smoking, and BMI 22.4 kg/m 2 –FRACTURE Index includes age, prior fracture after age 50 years, maternal hip fracture after age 50 years, weight 125 lbs, current smoking, use of arms to stand from a chair, and total hip BMD (if available)

HR for Global Index: Stratified by Fracture Risk Scores Highest Middle Lowest Hazard Ratio (95% nCI) Fracture Risk* *Stratified by tertiles of summary fracture risk scores; the WHI Global Index measure and WHI Fracture Risk Score have not been validated. Cauley JA, et al. JAMA. 2003;290:

Summary: WHI Results and Considerations CEE/MPA significantly decreased the risk of hip fractures, vertebral fractures, and all other fractures in a population not specifically selected for being at increased risk of fracture 1 This benefit has not been demonstrated in a similarly low-risk population with any other osteoporosis therapy 1 Cauley JA, et al. JAMA. 2003;290:

Section 8: Summary and Conclusions Preventing Bone Loss in Early Postmenopausal Women

Summary: Prevention of Early Bone Loss Bone loss is most rapid in the years immediately following menopause Women treated with HT to relieve menopausal symptoms do not need another antiresorptive agent HT is the only therapy that has been demonstrated to prevent fractures in women whose risk for osteoporosis is unknown