Everyone knows 1/15/2018. Does Osteopenia Warrant Treatment? Osteoporosis Prevention: Is it Ever Warranted?

Transcription

1 /5/8 Wednesday, October, 7 : AM :5 AM Osteoporosis Prevention: Is it Ever Warranted? James A. Simon, MD, CCD, NCMP, IF, FACOG Clinical Professor Department of Ob/Gyn George Washington University Washington, DC Everyone knows A stitch in time, saves nine An ounce of prevention is worth a pound of cure Medical Director Women s Health & Research Consultants Washington, DC James A Simon, MD, Does Osteopenia Warrant Treatment? Bone Mass is Lost in Age-Related Remodeling Menopause-associated rapid bone loss Active bone growth Peak bone mass Less rapid bone loss Bone Mass % Modeling and Remodeling Remodeling Age (years) Simon JA. Does osteopenia warrant treatment? Menopause. 5 Sep-Oct;(5):9-8. Review. Women can lose up to % of their bone mass during the first 5-7 years following menopause. Graph adapted from: Finkelstein JS. Cecil Textbook of Medicine. st ed. 999:-7. NOF Fast Facts at

2 /5/8 Bone Loss Following Discontinuation of HRT is Similar to Bone Loss Following Menopause Number of Years Following Estrogen Cessation Osteoporosis prevention is: Mean Percent Change ± SD from Baseline years -5 years -8 years Post-HRT Bone Loss (N=5) Postmenopausal Bone Loss (N=8) primarily bone loss risk reduction prevention of the first fracture. But who s at risk? Trémollieres FA et al. Osteoporosis Int. ;:85 9. Also see: Simon JA, Wehren LE, Ascott-Evans BH, et. al, Skeletal consequences of hormone therapy discontinuance: a systematic review. Obstet Gynecol Surv. Feb;():5-. For Review.

3 /5/8 Osteoporosis prevention is: Fracture Begets Fracture primarily bone loss risk reduction prevention of the first fracture. Prior Fracture Relative Risk of Future Fractures Wrist Vertebral Hip Wrist..7.9 But who s at risk? Vertebral... Hip NA.5. In this study, a systematic literature review was performed to discern the relative risk of fracture by location of prior and subsequent fracture. NA = not available. Klotzbuecher CM et al. J Bone Miner Res. ;5:7-79.

4 /5/8 Secondary Causes of Osteoporosis Endocrine Thyrotoxicosis Hyperparathyroidsim Diabetes mellitus Hypogonadism Cushing s syndrome Acromegaly GI/Nutritional Malabsorption syndromes Celiac disease Inflammatory bowel disease Malnutrition Chronic liver disease Primary biliary cirrhosis Gastrectomy Vitamin D deficiency Calcium deficiency Alcoholism Renal Chronic renal disease Renal failure Renal tubular acidosis Renal osteodystrophy Transplantation Rheumatologic Connective Tissue Rheumatoid arthritis Lupus Ankylosing Spondylitis Ehlers-Danlos syndrome Marfan syndrome Hematologic Multiple myeloma Leukemia and lymphomas Sickle cell disease National Osteoporosis Foundation. The State of Osteoporosis and Low Bone Mass in the U.S. Washington, DC: National Osteoporosis Foundation; 5. Medications Contributing to Bone Loss Glucocorticoids Aromatase inhibitors Depo-medroxyprogesterone Gonadotropin-releasing hormone agonists Long-term heparin Anticonvulsants Lithium Cancer chemotherapeutic drugs Immunosuppressants (cyclosporine A, tacrolimus) Possible association: Proton pump inhibitors SSRIs/SNRIs Parenteral nutrition National Osteoporosis Foundation. The State of Osteoporosis and Low Bone Mass in the U.S. Washington, DC: National Osteoporosis Foundation; 5. But FRAX is: Spineless! For treatment naïve patients only TBS???

5 /5/8 N.O.R.A. Study Participants, physicians participated., postmenopausal women aged 5 and older not previously assessed for, or diagnosed with, osteoporosis. Primary care physicians were recruited from states and the District of Columbia between September 997 and March 999. Siris ES et al. JAMA. ; 8:85 8. Population BMD Distribution, Fracture Rates, and Number of Women With Fractures Fracture per Person-Years 5 BMD distribution Fracture rate No. of women with fractures >..5 to..5 to..5 to..5 to. <.5. to.5. to.5. to.5. to.5. to.5 BMD T-Scores (Peripheral) Adapted from Siris ES, et al. Arch Intern Med. ;: No. of Women With Fractures Universal Prevention and Treatment Strategies Prevention Counsel all patients on risk reduction Adequate calcium Adequate vitamin D Weight-bearing exercise and muscular strengthening exercises Avoidance of smoking and excessive alcohol intake Fall prevention Gait and balance training Minimize/adjust dosages of drugs with sedative effects Anchor rugs, minimize clutter, remove loose wires, etc. 5

6 /5/8 Pharmacologic Prevention Options: Guidelines and Position Statements Key points from the 7 Position Statement of The North American Menopause Society 7 FDA-approved indications for hormone therapy First-line therapy for relief of vasomotor symptoms in appropriate candidates To prevent bone loss and reduce fractures in postmenopausal women at elevated risk of osteoporosis or fractures For women with hypogonadism, primary ovarian insufficiency, or premature surgical menopause without contraindication, hormone therapy is recommended for health benefits until the average age of menopause Low-dose vaginal estrogen therapy is recommended first line for isolated genitourinary syndrome of menopause to treat symptoms of vulvovaginal atrophy The 7 hormone therapy position statement of The North American Menopause Society. Menopause. 7;(7): Hormone therapy and bone and joints Hormone therapy effectively prevents postmenopause osteoporosis and fractures Women in the estrogen-alone and estrogen-progestogen therapy overall cohorts in the Women s Health Initiative (WHI) had significant % reductions in hip fracture After treatment discontinuation in the WHI, beneficial effects on bone dissipated rapidly, but no rebound was seen Women in the WHI showed less joint pain or stiffness The 7 hormone therapy position statement of The North American Menopause Society. Menopause. 7;(7):

7 /5/8 Hormone therapy and early menopause and primary ovarian insufficiency Data regarding hormone therapy in women aged older than 5 years should not be extrapolated to younger postmenopausal women Observational studies suggest benefits outweigh risks on bone, heart, cognition, vulvovaginal atrophy/ genitourinary syndrome of menopause, sexual function, and mood Hormone therapy recommended until at least median age of menopause (5 y) Younger women may require higher doses for symptom relief or protection against bone loss ACOG NOF NAMS AACE All recommend estrogen therapy as FDA-approved medication for prevention of postmenopausal osteoporosis. The 7 hormone therapy position statement of The North American Menopause Society. Menopause. 7;(7): American College of Physician (ACP) Guidelines Conversely, the 7 ACP Guidelines recommend: Against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women. Based on moderate-quality evidence showing no difference in reduced fracture with estrogen treatment of postmenopausal women with established osteoporosis 7 American College of Physician Guidelines The American Academy of Family Physicians (AAFP) also endorses the ACP guideline against menopausal estrogen therapy as: Not only did estrogen treatment show a lack of benefit, but it has been associated with serious harms Ultimately, based on the ACP and the U.S. Preventive Services Task Force (USPSTF): Family physicians won't need to update how they approach prescribing hormone replacement medications.. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. 7;(): AAFP Endorses ACP Guideline on Treating Osteoporosis. May 7. Don't Use Estrogen/Progestin Therapy for Chronic Conditions in Postmenopausal Women: USPSTF Draft Recommendation. May 7 7

8 /5/8 FDA Approved Medications for Osteoporosis Prevention Pharmacologic Prevention Options Estrogen(s)* Raloxifene Bisphosphonates Alendronate Risedronate Ibandronate *with or without progestogens, bazedoxifene, etc. The Role of HRT in the Prevention of Osteoporosis in Early Menopausal Women Micronized 7β-estradiol Conjugated equine estrogens Ethinyl estradiol Transdermal 7β-estradiol Esterified estrogens Average Bone-Sparing Dose. mg.5 mg 5 μg 5 μg. mg WHI-E+P: Relative and Absolute Risk Women 5 to 79 (mean.5) Years of Age at Baseline Health Event Overall Hazard Ratio Confidence Interval Nominal 95% Adjusted 95% Absolute Risk per, Women/Year CHD-Revised Breast cancer Breast cancer Absolute Benefit per, Women/Year Strokes VTE Colorectal cancer Hip fractures Total fractures New onset diabetes Cauley JA, et al. JAMA ;9:79-8; Chlebowski RT, et al. N Engl J Med ;5:99-; Chlebowski RT, et al. JAMA ;89:-5; Manson JE, et al. N Engl J Med ;9:5-5; Wassertheil-Smoller S, et al. JAMA ; 89:7-8; Margolis KL, et al. Diabetologia ;7:7-87; Writing Group for the Women's Health Initiative Investigators. JAMA ;88:-. 8

9 /5/8 Effect of Estrogen + Progestin Therapy on Fracture Risk in the WHI After 5. Years Placebo (n=8,) E + P (n=8,5) Women s Health Initiative (WHI): Fracture Outcomes No. of women 8 HR =. (.5-.98) HR =. (.-.98) -% -% HRT Placebo % Risk * Hip (.) (.5) - -5 Vertebral (.9) (.5) - - Others** 579 (.) 7 (.7) - -9 Total 5 (.7) 788 (.9) - - Hip Fracture Vertebral Fracture Writing Group for the Women s Health Initiative Investigators. JAMA. ;88:-. *Excess number of cases/, pt-yr.**others=other osteoporotic fractures, excluding fractures of the chest/sternum,skull/face, fingers, toes,and cervical vertebra. JAMA. ; 88 (): -. WHI HRT Study (Number Needed to Treat or Harm*) Event Number Needed To Harm CHD 7 Stroke 5 CV- All (CHD or Stroke) 5 VTE 5 Invasive Breast Cancer 7 Number Needed To Treat Colon Cancer Hip Fracture Vertebral Fracture 87 Event CHD Strokes VTE PE WHI-E: Relative and Absolute Risk Women 5 to 79 (mean ) Years of Age at Baseline Breast cancer Colorectal cancer Hip fractures Total fractures Overall HR New onset diabetes.88 Confidence Intervals 95% Nominal % Adjusted Absolute Risk per, Women/Year 7 Absolute Benefit per, Women/Year Adapted from: Writing Group for the Women s Health Initiative. JAMA. ;88:-. *Based on an average exposure of 5. years, and results are reported only if the event is significant based on 95% nominal CI Women's Health Initiative Steering Committee. JAMA. ;9:7-7. 9

10 /5/8 No. of women 8 Effect of CEE Alone on Fracture Risk in the WHI After 7 Years Placebo (n=5,9) Hip Fracture CEE (n=5,) HR =. (.-.9) HR =. (.-.9) The Women s Health Steering Committee. JAMA. ;9: % -8% Vertebral Fracture The Role of Hormone Replacement Therapy in the Prevention of Osteoporosis Estrogen/Hormone Replacement Therapy is First-Line Therapy Adjusted Mean Change ( SE) in BMD (mg/cm ) Month * * Month -8 * Placebo./.5/.5 /5 / Placebo.5 5 mg NA/ µg EE µg EE *P<.5 vs. baseline; P<.5 vs. placebo. BMD = bone mineral density; EE = ethinyl estradiol; NA = norethindrone acetate. Speroff L et al. JAMA 99;7: Month Change in BMD: Estrogen-Androgen vs CEE Change From Baseline (%) 5 months * months Spine E-A E-A CEE CEE HS.5 mg.5 mg Hip (total) 5 months months * *P<.5 vs CEE. CEE=conjugated equine estrogens; E-A HS=esterified estrogens (.5 mg) + methyltestosterone (.5 mg); E-A=esterified estrogens (.5 mg) + methyltestosterone (.5 mg). Barrett-Connor E, et al. J Reprod Med. 999;:-. E-A E-A CEE CEE HS.5 mg.5 mg Effect of Low-Dose Oral Estrogen Therapy on BMD in Postmenopausal Women Study Estrogen in spine BMD vs. placebo* (%) Ettinger et al, 99 Recker et al, 999 Prestwood et al, Micronized 7- estradiol.5 mg x 8 mo CEE. mg + MPA.5 mg x.5 y Micronized 7- estradiol.5 mg x y (+ intermittent micronized progesterone mg/day x wk every mo) *All subjects received calcium (, mg/day) and vitamin D (, IU/day). P value +. NS +.8 <. +.9 <. Ettinger B, et al. Am J Obstet Gynecol. 99;:79-88; Recker RR, et al. Ann Intern Med. 999;:897-9; Prestwood KM, et al. JAMA. ;9:-8.

11 /5/8 Effect of Low-Dose Transdermal Estrogen Therapy on BMD in Postmenopausal Women % Change from baseline in lumbar BMD at years 8 Study (5, 5, and 75 µg/day) Study (5, 75, and µg/day) All P =. 5µg 5µg 75µg µg Dose of transdermal 7- estradiol ULTRA Study: Baseline Characteristics E µg Placebo (n=8) (n=9) means or percent Age, y.8.7 Body mass index Calcium intake, mg/day 7 9 Age at menopause Lumbar spine BMD T-score.. Total hip BMD T-score.89.8 Caucasian 9.8% 9.9% Some college.5%.% Current smoking 7.7%.% Osteoporosis 9.7%.% Reprinted with permission from Delmas PD, et al. Am J Obstet Gynecol. ;8:-. Ettinger B, et al. Obstet Gynecol, September, in press. P values for all comparisons NS ULTRA Study: Change in Median Plasma Estradiol Versus Baseline ULTRA Study: Change in BMD Versus Placebo 9 Median increase on E was approximately.8 pg/ml P<. P<. Lumbar Spine Total Hip Median plasma estradiol (pg/ml) P=. (.7-8.) (.7-8.).7.8 P<. (.5-7.9) (5.-.5) P<. (.7-8.). 8. Baseline year years (.-.9) Placebo E µg Half had E levels <.7; half had >.7 % Change in BMD P=. P<. P<. P<. year years year years Placebo E µg Estradiol measured by RIA with LLD of. pg/ml Adapted from Ettinger B, et al. Obstet Gynecol, September, in press. Adapted from Ettinger B, et al. Obstet Gynecol, September, in press.

12 /5/8 Bone Mass is Lost in Age-Related Remodeling Menopause-associated rapid bone loss Active bone growth Peak bone mass Less rapid bone loss Bone Mass % Average in ULTRA -7y Bisphosphonates Modeling and Remodeling Remodeling Age (years) Women can lose up to % of their bone mass during the first 5-7 years following menopause. Graph adapted from: Finkelstein JS. Cecil Textbook of Medicine. st ed. 999:-7. NOF Fast Facts at EPIC Study Design Alendronate for Osteoporosis Prevention N Study Year 5 PBO 5 PBO ALN ALN ALN.5 PBO 9 9 ALN.5 PBO Exit Study (Year ) 8 ALN 5 9 N Completing Endpoints: BMD: Lumbar spine, total hip, total body and radius by: DXA (QDR-) Bone turnover: Biochemical markers (NTX) Safety: Adverse experiences collected as clinical events at study visits every months Routine laboratory tests every months 5 ALN 5 PBO 8 5 ALN 5 PBO 9 E/P Off therapy 8 *Alendronate manufactured by Merck & Co., Inc., Whitehouse Station, NJ McClung MR, Wasnich RD, Hosking DJ, et al for the Early Postmenopausal Intervention Cohort (EPIC) Study Group. Prevention of Postmenopausal Bone Loss: Six-Year Results from the EPIC Study. J Clin Endocrinol Metab 89: , McClung MR, Wasnich RD, Hosking DJ, et al for the Early Postmenopausal Intervention Cohort (EPIC) Study Group. Prevention of Postmenopausal Bone Loss: Six-Year Results from the EPIC Study. J Clin Endocrinol Metab 89: ,

13 /5/8 Lumbar Spine BMD Mean Percent Change from Baseline Stratum Only 9 Total Hip BMD Mean Percent Change from BaselineStratum Only Mean Percent Change - Mean Percent Change Years PBO/PBO/PBO ALN 5 mg/aln 5 mg/ PBO Estrogen/Progestin - Off Therapy - 5 PBO/PBO/PBO Years ALN 5 mg/aln 5 mg/ PBO Estrogen/Progestin - Off Therapy McClung MR, Wasnich RD, Hosking DJ, et al for the Early Postmenopausal Intervention Cohort (EPIC) Study Group. Prevention of Postmenopausal Bone Loss: Six-Year Results from the EPIC Study. J Clin Endocrinol Metab 89: , Resolution of Effect Following Treatment Bone loss resumes after withdrawal of ALN therapy. BMD remains above pretreatment levels. There is a residual benefit of taking ALN 5 mg daily because there is no catch up bone loss. Bone loss resumes when ALN 5 mg daily is discontinued after years but at a rate slower than that following E/P therapy. Effect of Risedronate on Prevention of Bone Loss in Early Postmenopausal Women Assess prevention of bone loss -y Study Women in early postmenopause ( mo, mean = y) Mean age = 5 y Mean lumbar spine T-score = -. Primary endpoint Effect on lumbar spine BMD Secondary endpoint Effect on femoral neck/trochanter BMD McClung MR, Wasnich RD, Hosking DJ, et al for the Early Postmenopausal Intervention Cohort (EPIC) Study Group. Prevention of Postmenopausal Bone Loss: Six-Year Results from the EPIC Study. J Clin Endocrinol Metab 89: , Hooper, et al. Calcified Tissues. 999;(suppl ):S9.

14 /5/8 Risedronate Prevention Trial: Change in BMD From Baseline SERMS: Selective Estrogen Receptor Modulators % Change in BMD - - Placebo * Risedronate 5 mg * * Tamoxifen Raloxifene - Lumbar Spine Femoral Neck Femoral Trochanter *P <.5 vs control. Hooper, et al. Calcified Tissues. 999; (suppl ):S9. Weighing Tamoxifen s Risks/Benefits in Breast Cancer Prevention* Raloxifene for Prevention of Bone Loss Number of Cases Benefits 59 Placebo Tamoxifen 7 7 Risks 7 99 Invasive Noninvasive Fractures Endometrial Vascular Breast Cancer Breast Cancer Cancer Events * Based on the Breast Cancer Prevention Trial s:, women at high-risk of getting breast cancer. Source: National Cancer Institute: NSABP, 998 Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 997 Dec ;7():-7.

15 /5/8 Effect of Raloxifene on Breast Cancer Incidence WHI-E vs Raloxifene in Perspective % of Randomized Patients.5. MORE Trial - Months Median Follow-Up Outcome WHI-E RUTH n=,79 n=, mean age. years 7.5 years mean follow-up.8 years 5. years RR =.5 (95% CI,.-.58)* Placebo./ womanyears.5 Raloxifene.5/ womanyears. Years Since Randomization *P <.. Cummings SR, et al. JAMA. 999;8: No. cases/, women/year of treatment CHD -5-7 Stroke (8) 9 VTE 7 PE DVT Breast cancer -8-8 Bone fracture -5-5 Hsia, et al. Arch Intern Med ;:57-5. Writing Group for the Women's Health Initiative Investigators. JAMA ;9:7-7. Curb JD, et al. Arch Intern Med ;: Stefanick ML, et al. JAMA ;95:7-57. RUTH. New Engl J Med ;55:5-7. Prevention of Osteoporosis in Postmenopausal Women: Summary In making a choice of Rx for prevention, consider the possible extraskeletal effects of osteoporosis agents Antiresorptive drugs prevent bone resorption, enhance BMD, and decrease fracture risk in those at risk of fracture. Current FDA-approved antiresorptive drugs include Bisphosphonates: alendronate, risedronate, ibandronate SERM: raloxifene Estrogen therapy Standard dose E (oral/transdermal), E+P, E+MT in early menopause Transdermal estradiol µg in later menopause 5