HRT and bone health. Management of osteoporosis and controversial issues. Delfin A. Tan, MD

Transcription

1 Strong Bone Asia V. Osteoporosis in ASEAN (+), Danang, Vietnam, 3 August 2013 Management of osteoporosis and controversial issues HRT and bone health Delfin A. Tan, MD Section of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology St. Luke s Medical Center Quezon City, Philippines

2 Management of osteoporosis and controversial issues: HRT and bone health 2 Outline Part 1 Hormone replacement therapy and osteoporosis: recent history 2 HRT: how effective is it against fracture? 3 The Women s Health Initiative: changing lessons after a decade Tan D HRT for osteoporosis: rebuilding confidence

3 Management of osteoporosis and controversial issues: HRT and bone health 3 HRT and osteoporosis: recent history Part 1

4 Management of osteoporosis and controversial issues: HRT and bone health Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's Health Initiative Investigators. JAMA Jul 17;288(3):

5 Management of osteoporosis and controversial issues: HRT and bone health 5 Hormone replacement therapy for osteoporosis: recent history Before WHI After WHI HRT as firstline therapy HRT downgraded to second-line therapy Benefit for bone mineral density Weiss NS, et al. N Engl J Med Nov 20;303(21): Genant HK, et al. Obstet Gynecol Oct;76(4): Prevents fractures at hip, vertebrae and other sites Rossouw JE, et al; Writing Group for the Women's Health Initiative Investigators. JAMA Jul 17;288(3): Anderson GL, et al; Women's Health Initiative Steering Committee. JAMA Apr 14;291(14): Benefits to bone outweighed by risks Cauley JA, et al; Women's Health Initiative Investigators. JAMA Oct 1;290(13): Jackson RD, et al; Women's Health Initiative Investigators. J Bone Miner Res Jun;21(6):

6 Management of osteoporosis and controversial issues: HRT and bone health Re 3.5 Risks and benefits of estrogen plus progestin in healthy postmenopausal women Major clinical outcomes (HR, 95% CI) with CEE/MPA after a mean of 5.2 years of use (vs. placebo) Coronary Breast cancer Stroke Pulmonary heart disease embolism Colorectal cancer Endometrial cancer Hip fracture Death due to other causes Rossouw JE, et al; Writing Group for the Women's Health Initiative Investigators. JAMA Jul 17;288(3):

7 Management of osteoporosis and controversial issues: HRT and bone health 7 WHI CEE/MPA arm: No increase in CHD outcomes (initial vs final analyses) Cardiovascular endpoints (HR, 95% CI) with CEE/MPA (vs. placebo) Coronary heart disease CHD, revascularization, or angina Initial results Rossouw JE, et al; Writing Group for WHI Investigators. JAMA Jul 17;288(3): Coronary heart disease CHD, revascularization, or angina Congesive heart failure Final results Manson JE, et al; Women s Health Initiative Investigators. N Engl J Med Aug 7;349(6):

8 Management of osteoporosis and controversial issues: HRT and bone health 8 Effects of conjugated equine estrogen in postmenopausal women with hysterectomy 2.5 Major clinical outcomes (HR, 95% CI) with CEE after a mean of 6.8 years of use (vs. placebo) Coronary heart disease 0.59 Breast cancer Stroke Pulmonary embolism Colorectal cancer Hip fracture Anderson GL, et al; Women's Health Initiative Steering Committee. JAMA Apr 14;291(14):

9 Management of osteoporosis and controversial issues: HRT and bone health 9 Excerpts from press conference July 9, 2002 Why the WHI CEE/MPA arm, planned to continue for 8.5 years, was stopped after 5.2 years of follow-up Jacques Rossouw, MD. Acting Director, Women s Health Initiative Women on the estrogen plus progestin therapy had a 26% higher incidence of breast cancer than those taking a placebo. The findings also show a 22% increase in total cardiovascular disease, with a 29% increase in heart attacks, a 41% increase in strokes, and a doubling of the rate of blood clots in the lungs. The have broad applicability. The study found no differences in risk by prior health status, age, or ethnicity.

10 Management of osteoporosis and controversial issues: HRT and bone health 10

11 Management of osteoporosis and controversial issues: HRT and bone health 11 Immediate decline in hormone therapy prescriptions following WHI publication Number of monthly US prescriptions for all forms of hormone therapy October July 2003 Data from the National Prescription Audit Plus, IMS HEALTH WHI Women s Health Initiative WHI July % decline relative to months prior to July 2002 Hersh AL, et al. JAMA Jan 7;291(1):47-53.

12 Management of osteoporosis and controversial issues: HRT and bone health 12 Sustained decline in postmenopausal hormone use in the United States Study 10,107 Women aged 40 years in National Health and Nutrition Examination Survey Results Prevalence of oral postmenopausal hormone use, %, in the United States during Overall Estrogen only Estrogen + progestin Sprague BL, et al. Obstet Gynecol Sep;120(3): Overall Overall Estrogen only Estrogen + progestin

13 Management of osteoporosis and controversial issues: HRT and bone health 13 What is especially worrying about the statements and prescribing encyclicals is the apparent blinkered belief in the infallibility of the WHI. Sturdee D, MacLennan A. Editorial. Climacteric Mar;7(1):1-2.

14 Management of osteoporosis and controversial issues: HRT and bone health 14 HRT: how effective is it against fracture? Part 2

15 Management of osteoporosis and controversial issues: HRT and bone health 15 Study 16,608 Postmenopausal women aged 50 to79 years with intact uterus treated with CE mg + MPA 2.5 mg per day or placebo Hormone replacement therapy reduces all osteoporotic fractures Risk (HR, 95% CI) of fracture with conjugated estrogens + medroxyprogesterone acetate for 5.6 years vs placebo Hip fracture Vertebral fracture Lower arm/wrist fracture Total fracture Continued

16 Management of osteoporosis and controversial issues: HRT and bone health 16 Hormone replacement therapy reduces all osteoporotic fractures* continued Antifracture effects of estrogen + progestin (RR, 95% CI) by years since menopause Number of women whose fractures were prevented over a 5-yr period of use: 21.8 women per 1000 per 5 year <10 years 10 to 19 years 20 years *Fractures refer to hip, vertebral, and other osteoporotic fractures except those of the ribs, chest/sternum, skull/face, fingers, toes, and cervical vertebrae. Cauley JA, et al; Women's Health Initiative Investigators. JAMA Oct 1;290(13):

17 Management of osteoporosis and controversial issues: HRT and bone health 17 Study Estrogen-alone therapy reduces all osteoporotic fractures Postmenopausal women years of age with hysterectomy randomized to conjugated estrogens mg/day (n=5310) or placebo (n=5429), followed for 7.1 years Jackson RD, et al. Women's Health Initiative Investigators. J Bone Miner Res Jun;21(6): Risk (HR, 95% CI) of fracture with conjugated equine estrogens for 6.8 years vs placebo Hip fracture Clinical vertebral fracture Wrist/lower arm fracture Total fracture

18 Management of osteoporosis and controversial issues: HRT and bone health 18 In the Women s Health Initiative A standard dose of conjugated estrogen with or without medroxyprogesterone acetate significantly reduced the risk of all fractures in a population of postmenopausal women, average age 63 years, not selected for osteoporosis by BMD. These results are particularly impressive. Lindsay R. Endocrine Aug;24(3):

19 Management of osteoporosis and controversial issues: HRT and bone health 19 Antifracture efficacy of currently available therapies for postmenopausal osteoporosis Relative reductions in risk of osteoporotic fractures with currently available therapies versus hormone therapy, % Vertebral fracture Hip fracture Vertebral fracture Hip fracture Vertebral fracture Hip fracture All available therapies Estrogen + progestin Estrogen alone Modified from Reginster JY. Drugs Jan 1;71(1): doi: /

20 Management of osteoporosis and controversial issues: HRT and bone health 20 Study of Osteoporotic Fractures: long-term reduction of fractures in estrogen users Study Results 8816 Women age 65 years followed for 10 years Probability of nonvertebral fractures (adjusted for age and weight) 373 Women had taken estrogen continuously with average of 24 years at start of study 19.6 % Estrogen remained beneficial for 34 years Nelson HD, et al; Study of Osteoporotic Fractures Research Group. Arch Intern Med Nov 11;162(20):

21 Management of osteoporosis and controversial issues: HRT and bone health 21 Incidence of fractures increased after publication of WHI and HERS results Study Claims database for multiple healthcare plans including cohort of women aged 40 to 69 years Rate of use/1000 women Year 2000 Year Hormone therapy* Other bonemodifying drugs** Incidence of fracture/10,000 women Year 2000 Year Osteoporotic fractures Estimated additional fractures in All US women aged 40 to 69 years Radius and ulna 57,681 Rib 27,211 Vertebral 9,964 Pelvic 3,828 Hip 2,160 Total 100,844 WHI Women s Health Initiative. HERS Heart and Estrogen/progestin Replacement Study. *Estrogen, estrogen + progestin, other hormones. **Bisphosphonates, selective estrogen receptor modulators, and calcitonin. Islam S, et al. Menopause Jan-Feb;16(1):77-83.

22 Management of osteoporosis and controversial issues: HRT and bone health 22 Women who discontinued postmenopausal hormone therapy has increased hip fracture risk Study 80,955 Postmenopausal women using hormone therapy as of July 2002 were followed through December 2008 in the Southern California Kaiser Permanente health management organization Hip fracture risk (HR, 95% CI) over 6.5 years with HRT discontinuation vs HRT continuation Overall, after age- and raceadjustment Karim R, et al. Menopause Nov;18(11): years after HT cessation Longer duration of HRT cessation 1 Linearly correlated with lower bone mineral density (β estimate [SE]) = [0.003] T-score SD unit per year of HRT cessation; P<0.0001) 2 Hip fracture risk increased incrementally (P trend < )

23 Management of osteoporosis and controversial issues: HRT and bone health 23 The WHI: changing lessons after a decade Part 4

24 Management of osteoporosis and controversial issues: HRT and bone health 24 Women s Health Initiative: misreporting and poorly presented results shrouded benefits of HRT Background Results misinterpreted, exaggerated Re-analysis 2012 HRT is associated with Results generalized to all women Media reacted with shock and terror, women with panic HRT use decreased 40% to 80% Improved quality of life Early use reduced risk of coronary heart disease and death Early use reduced risk of dementia Reduced risk of colorectal cancer Reduced risk of fracture Special edition on Women s Health Initiative and HRT. Climacteric. 2012;15(3):

25 Management of osteoporosis and controversial issues: HRT and bone health 25

26 Management of osteoporosis and controversial issues: HRT and bone health 26 The restrictions placed on HRT as a bone-specific drug by regulatory bodies have not withstood the test of time and are not supported by the data of the WHI.

27 Management of osteoporosis and controversial issues: HRT and bone health 27 HRT early after menopause reduced cardiovascular disease and mortality Study 1006 menopausal women aged years received hormone replacement therapy (n=502) or no treatment (n=504) With intact uterus: daily triphasic estradiol and norethisterone acetate With hysterectomy: estradiol 2 mg Stopped after 11 years, followed for up to 16 years Continued

28 Management of osteoporosis and controversial issues: HRT and bone health 28 HRT early after menopause reduced cardiovascular disease and mortality continued Results 5 4 Risk (HR, 95% CI) after 11 years of hormone replacement therapy started early after menopause (vs. no treatment) to vs 33 P= vs 26 P= vs 39 P= vs 17 P= vs Primary composite endpoint* vs 1 Death Any cancer Breast cancer Deep vein thrombosis 0.77 Stroke *Death, admission to hospital for heart failure, and myocardial infarction. Schierbeck LL, et al. BMJ Oct 9;345:e6409. doi: /bmj.e6409.

29 Management of osteoporosis and controversial issues: HRT and bone health 29 HRT early after menopause reduced cardiovascular disease and mortality continued Results 5 4 Risk (HR, 95% CI) after 11 years of hormone replacement therapy started early after menopause (vs. no treatment) to vs 33 P= vs 26 P= vs 39 P= vs 17 P= vs vs Primary Reduction Deathstill Any present cancer Breast after cancer 16 years; Deep vein no increase Stroke composite thrombosis endpoint* in any cancer. *Death, admission to hospital for heart failure, and myocardial infarction. Schierbeck LL, et al. BMJ Oct 9;345:e6409. doi: /bmj.e6409.

30 Management of osteoporosis and controversial issues: HRT and bone health First paper Changing lessons from WHI trials of menopausal hormone therapy The risk-benefit profile is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases,..this regimen should not be initiated or continued for primary prevention of CHD On timing hypothesis Rossouw JE, et al, Writing Group for the Women's Health Initiative Investigators. JAMA Jul 17;288(3): Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk but this trend test did not meet our criterion for statistical significance. Rossouw JE, et al. JAMA Apr 4;297(13): Continued

31 Management of osteoporosis and controversial issues: HRT and bone health Further analysis Changing lessons from WHI trials of menopausal hormone therapy continued Little support for hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices Reevaluation Prentice RL, et al. Am J Epidemiol Jul 1;170(1): The risk of CHD tended to be reduced in women close to menopause. *and+ shortterm absolute risks of stroke and venous thromboembolism were small. Rossouw JE, et al. Obstet Gynecol Jan;121(1):172-6.

32 Management of osteoporosis and controversial issues: HRT and bone health 32 HRT for osteoporosis: rebuilding confidence Part 5

33 Management of osteoporosis and controversial issues: HRT and bone health 33

34 Management of osteoporosis and controversial issues: HRT and bone health : It is now time to move on 1 Revise stringent guidelines on HRT prescribing 2 Reinstate HRT as first-line intervention for osteoporosis prevention 3 Grant a cardiovascular disease prevention indication for women who commence HRT early

35 Management of osteoporosis and controversial issues: HRT and bone health 35

36 Management of osteoporosis and controversial issues: HRT and bone health 36 In postmenopausal women at risk of fracture and younger than 60 years, or within 10 years of menopause, MHT can be considered as one of the first-line therapies for the prevention and treatment of osteoporosis-related fractures.

37 Management of osteoporosis and controversial issues: HRT and bone health 37

38 Management of osteoporosis and controversial issues: HRT and bone health 38 HRT is the first-line therapeutic intervention for the prevention and treatment of osteoporosis in women with premature ovarian insufficiency and menopausal women below 60 years, particularly those with menopausal symptoms.

39 Management of osteoporosis and controversial issues: HRT and bone health 39

40 Management of osteoporosis and controversial issues: HRT and bone health 40 MHT is effective and appropriate for the prevention of osteoporosis-related fractures in at-risk women before age 60 years or within 10 years after menopause.

41 Management of osteoporosis and controversial issues: HRT and bone health 41 The Global Consensus.. should form the template upon which to rebuild confidence in prescribing menopausal hormone therapy. Editorial: Panay N, Fenton A. Climacteric Apr;16(2):201-2.