New important data on ospemifene
Steven R. Goldstein, MD, CCD, NCMP, FACOG, FRCOG
Professor of Obstetrics and Gynecology
New York University School of Medicine
Director of Gynecological Ultrasound
Co-Director of Bone Densitometry and Body Composition
Department of Obstetrics and Gynecology
New York University Medical Center
New York, New York
ENDOMETRIAL SAFETY
There is a boxed warning in the ospemifene label that says, “in the uterus, ospemifene has estrogenic agonistic effects.”1 Despite the fact that ospemifene is not an estrogen (it’s a SERM), it goes on to state, “there is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogen.” This statement actually caused The Medical Letter to initially suggest that patients receiving ospemifene also should receive a pro-gestational agent (something they later retracted).2,3 In trying to understand why the labeling might possibly be worded in such a way, one has to review the actual data and understand the error the FDA made in response to that poorly named entity, “weakly proliferative endometrium.” If one combines any proliferative endometrium (weakly + actively + disordered) in the clinical trial, 86.1 per 1000 in the ospemifene-treated patients (versus 13.3 per 1000 for those taking placebo) had any one of the proliferative types. The problem is that actively proliferating endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression, whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with just an occasional mitotic figure in just a few of the nuclei of each gland. Furthermore, at 1 year, the incidence of active proliferation with ospemifene was 1%.4 Compare this finding with the Uterine Safety Study for raloxifene—both doses of that agent had an incidence of active proliferation at 1 year of 3%.2
Furthermore, that study had an estrogen-only arm in which, at endpoint, the incidence of endometrial proliferation was 39% and hyperplasia, 23%!5 Thus, it is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen.
Ospemifene, an oral SERM for dyspareunia of menopause: Is it being underutilized?
This activity was planned for obstetricians and gynecologists and women’s health care providers.
Activity Information
Date of Original Release: February 1, 2019
Date Credits Expire: January 31, 2022
This activity is supported by an educational grant from Duchesnay.
CME credit is awarded upon successful completion of the posttest and evaluation.
To access posttest and evaluation, visit www.worldclasscme.com/nonestrogenoraltherapy
World Class CME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
World Class CME designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Faculty
Program Director
Steven R. Goldstein, MD, CCD, NCMP, FACOG
Professor of Obstetrics and Gynecology
New York University School of Medicine
Director of Gynecological Ultrasound
Co-Director of Bone Densitometry and Body Composition
Department of Obstetrics and Gynecology
New York University Medical Center
New York, New York
Author
James A. Simon, MD, CCD, NCMP, IF, FACOG
Clinical Professor
George Washington University School of Medicine
President and Medical Director
IntimMedicine Specialists®
Washington, District of Columbia
Learning Objectives
At the conclusion of this activity, the participant will be able to:
- Understand the pathophysiology of dyspareunia due to vulvovaginal atrophy (VVA) of menopause.
- Appreciate the underrecognition and undertreatment of dyspareunia due to VVA.
- Discuss efficacy results of randomized placebo controlled trials of ospemifene.
- Understand the adverse events associated with ospemifene.
- Appreciate the safety data of ospemifine as well as other oral selective estrogen receptor modulators and estrogens.
Conflict of interest disclosure
Steven R. Goldstein, MD
Consultant: Cook Ob/Gyn, Cooper Surgical, IBSA, PfizerGYN Advisory Board: AbbVie, Allergan, AMAG, Shionogi, TherapeuticsMD
Speakers Bureau: AMAG, Duchesnay, TherapeuticsMDEquipment Loan: GE Ultrasound
James A. Simon, MD
Advisory Board/Consultant: AbbVie, Inc. (North Chicago, IL), Allergan, Plc (Parsippany, NJ), AMAG Pharmaceuticals, Inc. (Waltham, MA), Amgen (Thousand Oaks, CA), Ascend Therapeutics (Herndon, VA), Bayer HealthCare Pharmaceuticals Inc. (Whippany, NJ), CEEK Enterprises, LLC. (Cambridge, MA), Covance Inc., (Princeton, NJ), Millendo Therapeutics, Inc. (Ann Arbor, MI), Mitsubishi Tanabe Pharma Development America, Inc. (Jersey City, NJ), ObsEva SA (Geneva, Switzerland), Radius Health, Inc. (Waltham, MA), Sanofi S.A. (Paris, France), Sebela Pharmaceuticals, Inc. (Roswell, GA), Shionogi Inc. (Florham Park, NJ), Symbiotec Pharmalab (Indore, India), TherapeuticsMD (Boca Raton, FL), Valeant Pharmaceuticals (Laval, Canada) Speaker: AMAG Pharmaceuticals, Inc., Duchesnay USA (Rosemont, PA), Novo Nordisk (Bagsvrerd, Denmark), Shionogi Inc., Valeant Pharmaceuticals (Laval, Canada)Grants/Research: AbbVie, Inc., Allergan, Plc, Agile Therapeutics (Princeton, NJ), Bayer Healthcare LLC. (Tarrytown, NY), Dornier MedTech (Munich, Germany), Endoceutics, Inc. (Quebec, Canada), GTx, Inc. (Memphis, TN), Ipsen (Paris, France), Myovant Sciences (Basel, Switzerland), New England Research Institute, Inc. (Watertown, MA), ObsEva SA (Geneva, Switzerland), Palatin Technologies (Cranbury, NJ), Symbio Research, Inc. (Port Jefferson, NY), TherapeuticsMD, Tissue Genesis (Honolulu, HI) Stock Shareholder: Pharmaceuticals (Columbus, OH)
No disclosures to declare
Heidi M. Wilson, Course Director
References
- Osphena [package insert]. Florham Park, NJ: Shionogi Inc.; 2018.
- Ospemifene (Osphena) for dyspareunia. Med Lett Drugs Ther. 2013;55(1420):55-56.
- Addendum. Ospemifene (Osphena) for dyspareunia (Med Lett Drugs Ther2013;55:55). Med Lett Drugs Ther. 2013;55(1427):84.
- Goldstein SR, Bachmann G, Lin V, et al. Endometrial safety profile of ospe-mifene 60 mg when used for long-term treatment of vulvar and vaginal atrophy for up to 1 year (abstract). Climacteric. 2011;14(suppl 1):S57.
- Goldstein SR, Scheele WH, Rajagopalan SK, et al. A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet Gynecol. 2000;95(1):95-103.
- Qu Q, Zheng H, Dahllund J, et al. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology. 2000;141(2):809-820.
- Eigeliene N, Kangas L, Hellmer C, et al. Effects of ospemifene, a novel selective estrogen-receptor modulator, on human breast tissue ex vivo. Menopause. 2016;23(7):719-730.
- Kangas L. Unkila M. Tissue selectivity of ospemifene: pharmacologic pro-file and clinical implications. Steroids. 2013;78(12-13):1273-1280.
- Constantine GD, Kagan R, Miller PD. Effects of ospemifene on bone parameters including clinical biomarkers in postmenopausal women. Menopause. 2016;23(6):638-644.
- Gerdhem P, Ivaska KK, Alatalo SL, et al. Biochemical markers of bone metabolism and prediction of fracture in elderly women. J Bone Miner Res. 2004;19(3):386-393.
- Schiavi MC, Zullo MA, Faiano P, et al. Retrospective analysis in 46 women with vulvovaginal treated with ospemifene for 12 weeks: improvement in overactive bladder symptoms. Gynecol Endocrinol. 2017;33(12):942-945.
- Schiavi MC, Di Pinto A, Sciuga V, et al. Prevention of recurrent lower urinary tract infections in postmenopausal women with genitourinary syndrome: outcome after 6 months of treatment with ospemifene. Gynecol Endocrinol. 2018;34(2):140-143.
- Brostrøm S, Lose G. Oestrogen for prevention of recurrent urinary tract infections in postmenopausal women—a survey of a Cochrane review. [in Danish] Ugeskr Laeger. 2009;171(36):2568-2571.