{"paper_id":"75b4afe7-45fb-4c30-bd7a-5b285c754ad0","body_text":"Varghese et al. \nAllergy Asthma Clin Immunol           (2021) 17:58  \nhttps://doi.org/10.1186/s13223-021-00561-2\nCASE REPORT\nEffect of omalizumab for autoimmune \nprogesterone dermatitis refractory to bilateral \noophorectomy: a case report\nAkshay Varghese1* , Terri Paul2, Harold Kim3, Stan Van Uum2, Peter Vadas4 and Alescia Azzola1 \nAbstract \nBackground: Autoimmune progesterone dermatitis (APD) is a rare skin condition caused by sensitivity to \nhigh levels of progesterone secreted during the luteal phase of the menstrual cycle. This may be due to various \npathophysiological mechanisms including a Type I and Type IV hypersensitivity reaction. Here we present the \ncase of a patient with APD whose episodic flares were controlled by the addition of omalizumab, after a bilateral \noophorectomy failed to resolve her symptoms.\nCase Presentation: A 34-year-old female presented to our Endocrine clinic with marked Cushingoid features \nsecondary to high-dose oral prednisone prescribed for APD diagnosed 6 years earlier. She first developed a pruritic \nmaculopapular rash on her arms and legs just after the birth of her second child in 2009. The rash was also associated \nwith headaches and diffuse angioedema. Symptoms occurred for 1–2 weeks, in a cyclical fashion, during the luteal \nphase of each menstrual cycle and subsided within a few days after menses. The severity of symptoms increased as \ntime went on, and flare-ups began to also include dyspnea, nausea, vomiting and abdominal pain. Her symptoms \nimproved with administration of oral prednisone, but she continued to experience breakthrough symptoms. After \nmultiple failed treatment modalities, she elected bilateral oophorectomy in 2018. However, her symptoms of APD \npersisted and she still required high-dose oral prednisone. Her condition was further complicated by vasomotor \nmenopausal symptoms and progressive iatrogenic Cushing’s syndrome. She eventually was started on Omalizumab, \nwhich suppressed further recurrences of APD symptoms and allowed her to wean off prednisone. Vasomotor \nmenopausal symptoms responded well to the addition of conjugated estrogens with bazedoxifene. However, \nher symptoms of diffuse bony pain and arthralgias which started whilst on prednisone have persisted in spite of \ndiscontinuing prednisone.\nConclusions: To our knowledge, this is only the third case of APD which was successfully treated with Omalizumab \nand the first case where a bilateral oophorectomy failed to resolve symptoms of APD in the literature. This case also \ndemonstrates the complications of vasomotor menopausal symptoms secondary to a bilateral oophorectomy, as well \nas the adverse effects of long-term glucocorticoid therapy.\nKeywords: Autoimmune progesterone dermatitis, Bilateral oophorectomy, Omalizumab\n© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, \nadaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and \nthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material \nin this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material \nis not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the \npermitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco \nmmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ \nzero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\nAutoimmune progesterone dermatitis (APD) is a \nrare condition, with a literature review from 2016 \ndocumenting approximately 90 cases [1]. Patients with \nAPD are sensitive to the high levels of progesterone \nsecreted during the luteal phase of the menstrual cycle \nOpen Access\nAllergy, Asthma & Clinical Immunology\n*Correspondence:  avarghese@nosm.ca\n1 Division of Internal Medicine, Northern Ontario School of Medicine, \nSudbury, ON, Canada\nFull list of author information is available at the end of the article\n\nPage 2 of 5Varghese et al. Allergy Asthma Clin Immunol           (2021) 17:58 \n[2]. Depending on whether the reaction is IgE-mediated, \nor T-cell mediated, APD can present in various forms, \nsuch as eczema, folliculitis, and erythema multiforme, but \ncan also progress to more acutely severe manifestations \nsuch as dyspnea and anaphylaxis [2]. Symptom onset is \ntypically 1 week prior to menses and symptoms resolve a \nfew days after the onset of menstruation [3, 4].\nAlthough the pathogenesis of the disease is not yet \nfully understood, it has been postulated to involve Type \nI and Type IV hypersensitivity reactions [4]. Progesterone \nhas been noted to stimulate immunoglobulin E (IgE)-\nmediated mast cell degranulation [2, 5]. Additionally, \nprogesterone sensitivity may be also due to cell-mediated \nimmunity, due to prior uptake of progesterone by \nantigen-presenting cells and stimulation of T-helper cells \n[4]. Furthermore, cross-reactivity with other endogenous \nsteroid hormones such as 17-α-hydroxy-progesterone \nmay also be a plausible mechanism for increased \nprogesterone sensitivity in APD patients [1].\nThe diagnosis of APD is based on the unique cyclical \nappearance of symptoms during a menstrual cycle. If \nAPD is IgE-mediated, the diagnosis is confirmed by \na positive wheal and flare response to skin testing with \nprogesterone [6]. Various treatment options have been \ndescribed for APD, including gonadotrophin-releasing \nhormone (GnRH) agonists (suppressing progesterone \nproduction), oral contraceptives, tamoxifen, \nantihistamines, prednisone, dapsone, thalidomide, \nazathioprine and danazol [7–9]. However, if these \ntherapies fail, or cause intolerable side effects, a bilateral \noophorectomy can be performed as a more durable \nsolution [7].\nCase Presentation\nA 34-year-old female with pronounced Cushingoid \nfeatures presented to our Endocrinology clinic in 2018. \nShe had been taking high dose oral prednisone for a \ndiagnosis of severe autoimmune progesterone urticaria, \nrefractory to bilateral oophorectomy.\nA raised pruritic macular erythematous rash initially \nappeared on her arms and legs in 2009, two to three \ndays after the birth of her second child. This rash was \nassociated with headaches, and diffuse angioedema of \nher hands, feet, lips, and eyelids (Fig.  1). The pruritic rash \ncontinued to occur in a cyclical fashion, appearing one \nto two weeks prior to each menses and resolving within \na few days of menstruation onset. Six months after the \npost-partum period, in tandem with the return of her \nmenstrual cycles, her symptoms quickly progressed from \ncyclic urticaria to systemic symptoms such as dyspnea. \nHer flare-ups also coincided with nausea, dizziness, and \nabdominal cramping. All symptoms continued to follow \nthe identical luteal phase cyclical onset of presentation.\nFor several years, she was treated with numerous \nmedications, including first and second generation H1 \nand H2 histamine antagonists, tricyclic antidepressants, \ncalcineurin inhibitor immunosuppressant therapy \nand psoralen and ultraviolet A (PUVA) therapy. \nThese treatments were all unsuccessful in improving \nher symptoms. She was eventually started on oral \nprednisone in doses of up to 100 mg daily. Symptomatic \nimprovement was achieved with corticosteroid use, \nbut pre-menstrual flare-ups would still occur quite \noften. After three years of persistent symptoms, she was \nreferred to an Immunologist who established a likely \ndiagnosis of autoimmune progesterone dermatitis with \npotential catamenial anaphylaxis. This was confirmed \nusing a progesterone skin test. Her serum tryptase at \nbaseline was low at 2.8 Ug/L (3.8–11.4 Ug/L).\nShe was then started on a trial of a low-dose oral \ncontraceptive pill, which contained 0.02  mg ethinyl \nestradiol and 0.1  mg of levonorgestrel, in an attempt to \nbe desensitized to progesterone. High dose prednisone \nwas prescribed for flare-ups. This was an attempt to \nwean her off prednisone. After 6 months, there was still \nno improvement in her symptoms. The reintroduction \nof antihistamine therapy, intensified up to quadruple \ntherapy, as well as a trial of cyclosporine therapy also did \nnot allow for adequate prednisone taper. Gonadotropin-\nreleasing hormone (GnRH) therapy was also \nrecommended. However, the patient declined additional \nmedical therapies. Due to the long-term use of high-dose \nprednisone, she developed Cushingoid features including \nmoon face, violaceous striations, alopecia, and central \nadiposity (Fig. 2—left panel).\nDue to the progressive side effects of prednisone as well \nas persistent symptoms, she elected to undergo a bilateral \noophorectomy at age 34 in June 2018. There was short \nFig. 1 Acute angioedema—patient photograph, consent obtained\n\nPage 3 of 5\nVarghese et al. Allergy Asthma Clin Immunol           (2021) 17:58 \n \nterm relief of symptoms for approximately three weeks. \nUnfortunately, she experienced another flare-up  of \nurticaria with angioedema which  did not subside until \ntreatment with prednisone 50 mg daily was reinstituted.\nUnfortunately, following oophorectomy, her condition \nwas further complicated by vasomotor menopausal \nsymptoms, progressive iatrogenic Cushing’s syndrome \nand unresolved APD.\nDiscussion\nCase Dilemma #1: Refractory APD Following Bilateral \nOphorectomy\nIn our case, the patient had elected to proceed with a \nbilateral oophorectomy after three years of unresolving \nsymptoms despite various treatment modalities. Bilateral \noophorectomy for unresolving APD has been used 19 \ntimes and was found to be successful in all reported cases \n[1, 10–14]. However, in our case, the patient continued \nto have breakthrough episodes of generalized urticaria \nand peripheral swelling. These symptoms were in line \nwith what she was experiencing before her bilateral \noophorectomy. The differential diagnosis may also \ninclude chronic spontaneous urticaria and angioedema \npost-oophorectomy. Although she has not been retested \nusing a medroxyprogesterone skin test since her \nprocedure, the original ADP diagnosis was based on a \npositive skin test and strong clinical features in keeping \nwith this diagnosis. Furthermore, a secondary workup \nfor urticaria was also negative ruling out additional \ninflammatory, vasculitic, rheumatologic, endocrine \nand immunological conditions. Therefore, we believe \nthat it would be unlikely that the underlying etiology \nof her symptoms would change with surgery and we \npresume an adrenal source of progesterone production \npost-oophorectomy. To our knowledge, this is the first \ncase where a bilateral oophorectomy procedure may \nhave failed to resolve symptoms of APD. However, one \npotential publication bias could indeed be a lack of \nreporting of non-responsive cases.\nThree months following bilateral oophorectomy, \nshe presented to our Endocrine clinic for an initial \nconsultation for Cushing syndrome while being treated \nwith 50 mg of daily prednisone. In search of a prednisone \nsparing treatment for her APD, we initiated Omalizumab \n(Xolair) monoclonal antibody therapy. IgE antibodies \nbind to the FcεRI region on the surface of the high-\naffinity IgE receptors, allowing for greater stabilization of \nthe receptors. Cross-linking of IgE or stimulation of the \nhigh-affinity IgE receptor on mast cells leads to release \nof mast cell mediators including histamine. Omalizumab \nworks by decreasing the amount of free IgE antibodies \nin circulation leading to a downregulation of the high-\naffinity IgE receptors on mast cells, thereby inhibiting \nthe release of mast cell mediators [15–17]. Subcutaneous \ninjections of Omalizumab 300mg allowed the patient \nto eliminate the requirement of daily oral prednisone \nover the course of six months with a slow taper. Most \nsignificantly, her ADP flare-ups have resolved. This is \nconsistent with two other case reports which have shown \nimprovement in symptoms of APD with Omalizumab \n[18, 19]. This is the third case for which Omalizumab \nwas used for treatment for APD to our knowledge. We \ncontinue to attempt Omalizumab dose and frequency \nreduction, which she has not tolerated so far.\nCase Dilemma #2: Complications Of Early Menopause \nSecondary To A Bilateral Ophorectomy Procedure\nFollowing her bilateral oophorectomy as well as chronic \nprednisone use, our patient was at risk for symptomatic \nearly menopause and premature osteoporosis. As she \nhad not responded to progesterone desensitization in the \npast, typical hormone replacement therapy, consisting of \nestrogen and progesterone, could not be considered. In \naddition, her uterus remained in situ, therefore treatment \nwith unopposed estrogen would have put her at risk for \nendometrial hyperplasia and subsequent malignancy \n[20]. In hindsight, consideration of hysterectomy in \naddition to the bilateral oophorectomy would have \nnegated the requirement of progesterone and allow \nfor estradiol monotherapy. A hysterectomy may still \nbe considered for the future. Unfortunately, estradiol \nmonotherapy was not possible for our patient. As a \nresult, we started the patient on the combination of \nconjugated estrogens with bazedoxifene. Several large \nPhase 3 trials have shown this combination to be effective \nin reducing vasomotor menopausal symptoms, as well \nas maintaining bone health and reducing the risk of \nFig. 2 Iatrogenic cushing’s syndrome (left panel—at the time of \nXolair initiation), followed by drastic weight loss off prednisone (right \npanel—approximately one year steroid free), patient photograph, \nconsent obtained\n\nPage 4 of 5Varghese et al. Allergy Asthma Clin Immunol           (2021) 17:58 \nendometrial hyperplasia for post-menopausal women \nbetween 40 and 65 years of age with an intact uterus [21–\n23]. Initiation of this treatment resulted in immediate \nvasomotor symptom relief.\nCase Dilemma #3: The Consequences Of Long‑Term Use Of \nHigh Dose Oral Prednisone\nOur patient was on sporadic prednisone since 2008. \nFollowing her bilateral oophorectomy in June 2018, \nshe was taking prednisone 50  mg daily for three \nmonths prior to our initial consultation. Despite APD \nsymptom improvement, long-term glucocorticoid \nusage has a myriad of possible adverse side effects, \nincluding lowered bone mass, myopathy, hyperglycemia, \nCushing’s syndrome, and iatrogenic adrenal insufficiency \n[24]. In fact, our patient suffered from most of these \ncomplications.\nAs expected, she developed significant Cushingoid \nfeatures including a significant weight gain of 70 lbs over \nfour years, depression, proximal muscle wasting, moon \nface, easy bruising and dorsoclavicular adiposity. She has \nregained muscle mass and lost 35  lbs since prednisone \ndiscontinuation with resolution of the Cushingoid \nfeatures (Fig. 2—right panel).\nOur patient’s chronic use of glucocorticoid coupled \nwith her bilateral oophorectomy puts her at significant \nrisk for low bone mass and early development of \nosteoporosis. In August 2018, her bone mineral density \nshowed lumbar spine osteopenia (T-Score of Lumbar \nSpine: −  1.1, Z-Score of Lumbar Spine: −  2.0, T-Score \nof Femoral Neck: −  0.8, Z-Score of Femoral Neck: \n− 1.1, T-Score of Total Hip: − 0.5 and Z-Score of Total \nHip: −  0.9) and she was started on Calcium, Vitamin \nD supplements, as well as conjugated estrogens with \nbazedoxifene.\nFurthermore, it was postulated that she had an \nepisode of prednisone-induced adrenal insufficiency \nfollowing a quick taper of daily oral prednisone, \nresulting in an episode of severe atypical chest pain, \nmuscle aches, and nausea. Along with these symptoms, \nher  fasting AM cortisol level was 86 mmol/L (135–\n537  mmol/L)  roughly  48  hour after  prednisone \ndiscontinuation. Due to iatrogenic adrenal suppression, \nthe steroid taper occurred very slowly over the course of \n6  months. Since this time, the patient has remained off  \nsteroids and is asymptomatic with cortisol levels within \nphysiological range.\nThroughout the many years of glucocorticoid therapy, \nshe began to develop diffuse indeterminate bone pain \nand arthralgias which persist to this day. Multiple \nimaging modalities were ordered, which revealed no \nbone abnormalities. Muscle and joint pain have been \nreported with conjugated estrogens with bazedoxifene \n[25], however transient discontinuation of conjugated \nestrogens with bazedoxifene did not improve symptoms. \nOmalizumab serum sickness and other possible \nrheumatological conditions were also ruled out by her \nImmunologist. The cause of the symptoms remains \ninconclusive, but they are improving with physiotherapy.\nConclusions\nThis patient case depicts a complex case of APD which \nbegan following a pregnancy. In contrast to the 19 \npreviously documented cases, a bilateral oophorectomy \ndid not lead to resolution of symptoms. This unique \ncase identifies an additional steroid sparing therapeutic \noption, omalizumab, that can be considered for the \ntreatment of APD. Given the apparent effectiveness of \nOmalizumab, consideration to using this drug should be \ngiven before proceeding on to bilateral oophorectomy \nsurgery for APD.\nThis case also highlights the unique role of conjugated \nestrogens with bazedoxifene for vasomotor menopause \ntreatment in patients with APD post bilateral \noophorectomy if the uterus remains intact. Again, \nperhaps hysterectomy should be considered in future \ncases as it may allow estrogen monotherapy.\nLastly, this case report demonstrates the complications \nof long-term steroid therapy as well as the challenges \nencountered in discontinuing their use. Omalizumab \ntherapy allowed for steroid discontinuation and the \nconjugated estrogens with bazedoxifene allowed \nfor bone protection against steroid induced bone \ndemineralization.\nAbbreviations\nAPD: Autoimmune progesterone dermatitis; IgE: Immunoglobulin E; GnRH: \nGonadotropin releasing hormone; PUVA: Psoralen and ultraviolet A.\nAcknowledgements\nI would like to thank Dr. Paul Greenberger for his assistance in revising a \nsection of the manuscript.\nAuthors’ contributions\nAV drafted the manuscript. AA cared for the patient and was involved \nin revising the manuscript. Additionally, HK, PV, SVU were also involved \nin revising the manuscript. All authors have read and approved the final \nmanuscript.\nFunding\nNone.\nAvailability of data and materials\nThe data use and analyzed during the current study are available from the \ncorresponding author on reasonable request.\nDeclarations\nEthics approval and consent to participate\nAn informed consent form was obtained from the patient to use her data.\n\nPage 5 of 5\nVarghese et al. Allergy Asthma Clin Immunol           (2021) 17:58 \n \n•\n \nfast, convenient online submission\n •\n  \nthorough peer review by experienced researchers in your field\n• \n \nrapid publication on acceptance\n• \n \nsupport for research data, including large and complex data types\n•\n  \ngold Open Access which fosters wider collaboration and increased citations \n \nmaximum visibility for your research: over 100M website views per year •\n  At BMC, research is always in progress.\nLearn more biomedcentral.com/submissions\nReady to submit y our researc hReady to submit y our researc h  ?  Choose BMC and benefit fr om: ?  Choose BMC and benefit fr om: \nConsent for publication\nConsent for publication was obtained from the patient.\nCompeting interests\nHK has been on an advisory board and speaker’s bureau for Novartis Canada. \nAV, TP , SVU, PV and AA have no competing interests to disclose.\nAuthor details\n1 Division of Internal Medicine, Northern Ontario School of Medicine, \nSudbury, ON, Canada. 2 Division of Endocrinology and Metabolism, Schulich \nSchool of Medicine and Dentistry, Western University, London, ON, Canada. \n3 Division of Clinical Immunology and Allergy, Schulich School of Medicine \nand Dentistry, Western University, London, ON, Canada. 4 Division of Clinical \nImmunology and Allergy, St. Michael’s Hospital, University of Toronto, Toronto, \nON, Canada. \nReceived: 12 November 2020   Accepted: 3 June 2021\nReferences\n 1. Nguyen T, Ahmed AR. Autoimmune progesterone dermatitis: update and \ninsights. Autoimmun Rev. 2016;15(2):191–7.\n 2. Mbonile L. Autoimmune progesterone dermatitis: case report with \nhistory of urticaria, petechiae and palpable pinpoint purpura triggered \nby medical abortion. S Afr Med J. 2016;106(4):356–8.\n 3. Snyder JL, Krishnaswamy G. Autoimmune progesterone dermatitis and \nits manifestation as anaphylaxis: a case report and literature review. Ann \nAllergy Asthma Immunol. 2003;90(5):469–77.\n 4. Prieto-Garcia A, Sloane DE, Gargiulo AR, Feldweg AM, Castells M. \nAutoimmune progesterone dermatitis: clinical presentation and \nmanagement with progesterone desensitization for successful in vitro \nfertilization. Fertilit sterilit. 2011;95(3):1121-e9.\n 5. Camões S, Sampaio J, Rocha J, Tiago P , Lopes C. Autoimmune \nprogesterone dermatitis: case report of an unexpected treatment \nreaction. Australas J Dermatol. 2017;58(3):e132-4.\n 6. Solomon M, Itsekson AM, Lev-Sagie A. Autoimmune progesterone \ndermatitis. Curr Dermatol Rep. 2013;2(4):258–63.\n 7. Medeiros S, Rodrigues-Alves R, Costa M, Afonso A, Rodrigues A, Cardoso \nJ. Autoimmune progesterone dermatitis: treatment with oophorectomy. \nClin Exp Dermatol. 2010;35(3):e12-3.\n 8. Zhang M, Tang X, Zhou H, Liao Q, Han J. Case of autoimmune \nprogesterone dermatitis presenting as necrotic migratory erythema \nsuccessfully controlled by danazol. J Dermatol. 2020;47(2):178–80.\n 9. Le K, Wood G. A case of autoimmune progesterone dermatitis diagnosed \nby progesterone pessary. Australas J Dermatol. 2011;52(2):139–41.\n 10. Whitt W, Stiegler JD, Richardson CT. Autoimmune progesterone \ndermatitis mimicking facial erythromelalgia successfully treated with \nhysterectomy and bilateral salpingo-oophorectomy. JAAD Case Rep. \n2020;6(10):1104–6.\n 11. Galán‐Gutierrez M, Gomez‐Arias PJ, Rodenas‐Herranz T, Ruiz‐Villaverde R. \nAutoimmune progesterone dermatitis: Successful outcome with bilateral \nsalpingo‐oophorectomy. Dermatologic therapy. 2020;33(4):e13520.\n 12. Drayer SM, Laufer LR, Farrell ME. Autoimmune progesterone \ndermatitis presenting as Stevens–Johnson syndrome. Obstet Gynecol. \n2017;130(4):881–4.\n 13. DeRosa I, Bender B, Centilli M. Autoimmune progesterone dermatitis. \nCutis. 2018;4:E12-4.\n 14. Grunnet KM, Powell KS, Miller IA, Davis LS. Autoimmune progesterone \ndermatitis manifesting as mucosal erythema multiforme in the setting of \nHIV infection. JAAD Case Rep. 2017;3(1):22.\n 15. Spector SL, Tan RA. Effect of omalizumab on patients with chronic \nurticaria. Ann Allergy Asthma Immunol. 2007;99(2):190–3.\n 16. Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential \npharmacologic mechanisms of omalizumab in patients with chronic \nspontaneous urticaria. J Allergy Clin Immunol. 2015;135(2):337–42.\n 17. Potaczek DP , Kabesch M. Current concepts of IgE regulation and impact \nof genetic determinants. Clin Exp Allergy. 2012;42(6):852–71.\n 18. Heffler E, Fichera S, Nicolosi G, Crimi N. Anaphylaxis due to progesterone \nhypersensitivity successfully treated with omalizumab. J Allergy Clin \nImmunol Pract. 2017;5(3):852–54.\n 19. Gadoury-Levesque V, Bernstein J. A CASE OF REFRACTORY RECURRENT \nCYCLICAL ANGIOEDEMA AND URTICARIA SUCCESSFULLY TREATED WITH \nMULTIPLE STEPS THERAPY. Ann Allergy Asthma Immunol. 2018;121(5):S85.\n 20. Gompel, A. Progesterone and endometrial cancer. Best Pract Res Clin \nObstet Gynaecol. 2020;69:95–107.\n 21. Pinkerton JV, Utian WH, Constantine GD, Olivier S, Pickar JH. Relief of \nvasomotor symptoms with the tissue-selective estrogen complex \ncontaining bazedoxifene/conjugated estrogens: a randomized, \ncontrolled trial. Menopause. 2009;16(6):1116–24.\n 22. Pinkerton JV, Harvey JA, Lindsay R, Pan K, Chines AA, Mirkin S, Archer DF, \nSMART-5 Investigators. Effects of bazedoxifene/conjugated estrogens on \nthe endometrium and bone: a randomized trial. J Clin Endocrinol Metab. \n2014;99(2):E189-98.\n 23. Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, \nde Villiers TJ, Constantine GD, Chines AA. Efficacy of bazedoxifene in \nreducing new vertebral fracture risk in postmenopausal women with \nosteoporosis: results from a 3-year, randomized, placebo-, and active-\ncontrolled clinical trial. J Bone Miner Res. 2008;23(12):1923–34.\n 24. Oray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster CS. Long-term \nside effects of glucocorticoids. Expert Opin Drug Saf. 2016;15(4):457–65.\n 25. Chaplin S. Duavive HRT: conjugated oestrogens with bazedoxifene. \nPrescriber. 2016;12:53.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in \npublished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}