Ospemifene
Ospemifene (Osphena) is the only oral, non-estrogen FDA-approved treatment for moderate-to-severe dyspareunia and vaginal dryness due to menopause. As a third-generation selective estrogen receptor modulator (SERM), it exerts tissue-specific effects — agonist on vaginal and bone tissue, antagonist on breast tissue, and weak agonist on endometrium — making it a unique option for GSM patients who cannot or prefer not to use vaginal preparations.[1][2][3] Beyond the dyspareunia/dryness indications, a growing body of prospective evidence supports its role in overactive bladder and urge urinary incontinence in postmenopausal women with concurrent VVA.[4][5][6]
For related classes, see Vaginal and topical estrogen, Vaginal DHEA, Preoperative hormonal priming, and the clinical GSM article.
Mechanism and tissue-selective SERM profile
Ospemifene is a triphenylethylene derivative (structurally related to tamoxifen and toremifene) with tissue-selective ER modulation:[3]
| Tissue | ER effect | Clinical implication |
|---|---|---|
| Vaginal epithelium | Agonist | Epithelial maturation, ↑ superficial cells, ↓ pH, lubrication[3] |
| Bone | Agonist | ↓ bone-turnover markers; bone-biomarker profile comparable to raloxifene[7][8] |
| Breast | Antagonist | Preclinical anti-proliferative on breast tissue[9] |
| Endometrium | Weak agonist | Mild thickening; no hyperplasia or cancer in trials up to 52 weeks[10] |
| Cardiovascular / lipids | Mixed | ↑ HDL, ↓ LDL; neutral on triglycerides[11] |
Pharmacokinetics[12]
- Absorption — must be taken with food — a high-fat meal increases Cmax and AUC 2.3× and 1.7× vs fasting
- Protein binding >99% (clinically relevant for drug interactions)
- Volume of distribution 448 L
- Metabolism — primarily CYP3A4 and CYP2C9 (CYP2C19 minor); major metabolite 4-hydroxyospemifene
- Half-life ~26 hours; steady state achieved in ~1 week
- Elimination ~75% fecal, ~7% urinary
FDA-approved indications and dosing
| Element | Details |
|---|---|
| Brand | Osphena[12] |
| FDA indications | (1) Moderate-to-severe dyspareunia of menopause; (2) moderate-to-severe vaginal dryness of menopause (added 2019) |
| Dose | 60 mg PO once daily with food |
| Generic | None as of 2026 |
Contraindications and boxed warning
FDA boxed warning[12]
- Endometrial cancer — estrogen-agonist effect on the endometrium; increased risk of endometrial cancer with unopposed estrogens; evaluate any undiagnosed persistent or recurring abnormal genital bleeding
- Cardiovascular disorders — stroke and DVT risk warnings extrapolated from WHI estrogen-alone data. In ospemifene trials (up to 15 months):
- Thromboembolic stroke: 1.13 per 1,000 woman-years (vs 3.15 placebo)
- Hemorrhagic stroke: 3.39 per 1,000 woman-years (vs 0 placebo)
- DVT: 2.26 per 1,000 woman-years (2 cases) vs 3.15 per 1,000 woman-years (1 case) placebo
Contraindications[12]
- Undiagnosed abnormal genital bleeding
- Estrogen-dependent neoplasia
- Active DVT / PE or history of these
- Active arterial thromboembolic disease (stroke, MI) or history
- Hypersensitivity to ospemifene
- Known or suspected pregnancy
Drug interactions
| Interacting drug | Mechanism | Effect | Clinical action |
|---|---|---|---|
| Fluconazole | Moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor | ↑ AUC 2.7×, ↑ Cmax 1.7× | Do not co-administer[12] |
| Rifampin | Strong CYP3A / moderate CYP2C9-2C19 inducer | ↓ AUC 58%, ↓ Cmax 51% | Do not co-administer (loss of clinical effect)[12] |
| Ketoconazole | Strong CYP3A inhibitor | ↑ AUC 1.4×, ↑ Cmax 1.5× | Use with caution |
| Omeprazole | Moderate CYP2C19 inhibitor | ↑ AUC 1.17×, ↑ Cmax 1.20× | No dose adjustment needed |
| Warfarin | Protein-binding displacement (ospemifene >99% bound) | No effect on single-dose warfarin PK; chronic INR/PT not studied | Monitor if co-administered |
| Estrogens / other SERMs | Pharmacodynamic | Safety not studied | Do not co-administer |
| Highly protein-bound drugs | Displacement | May alter exposure of either drug | Use with caution |
The fluconazole interaction is particularly relevant in urogynecologic practice — fluconazole is commonly prescribed for VVC in the same patient population.[2]
Pivotal efficacy data
Approval rested on three 12-week efficacy trials + one 52-week safety trial, total 2,516 postmenopausal women (1,416 ospemifene / 1,100 placebo).[12] All four coprimary endpoints met (superficial cells, parabasal cells, vaginal pH, most bothersome symptom).
Di Donato 2019 meta-analysis (6 RCTs)[13]
Ospemifene 60 mg vs placebo at 12 weeks:
- Vaginal pH: SMD −0.96 (95% CI −1.12 to −0.81; p < 0.001)
- Parabasal cells: SMD −1.97 (p < 0.001)
- Superficial cells: SMD +1.74 (p < 0.001)
- Dyspareunia: SMD −0.51 (p < 0.001)
- Dryness: SMD −0.52 (p < 0.001)
Simon 2023 network meta-analysis[14]
Across all comparators, post-treatment endometrial thickness with ospemifene remained under the 4 mm clinical threshold for concerning endometrial pathology; no endometrial carcinoma or atypical hyperplasia in trials up to 52 weeks.
Urogynecologic applications beyond dyspareunia
Overactive bladder and urge urinary incontinence — the strongest off-label signal
| Study | n | Design | Finding |
|---|---|---|---|
| Schiavi 2017 | 46 | Prospective 12 wk | Detrusor overactivity 39% → 13% (p = 0.04); voids/day 9.57 → 6.63; urgency episodes 5.63 → 1.44; nocturia 3.17 → 1.11; UUI 0.85 → 0.33 (all p ≤ 0.003)[4] |
| Schiavi 2018 | 105 | Prospective 12 wk | OAB-Q 55.34 → 23.22 (p < 0.0001); FSFI significantly improved; PGI-I 90.5% total success rate[5] |
| Novara 2020 | 25 | Prospective 12 wk (first-line-refractory OAB) | Significant reduction in micturition, nocturia, urgency, incontinence; bladder-wall thickness decreased; UDI-6 and OAB-Q improved[6] |
| Russo 2023 | 40 | Prospective 12 wk with urodynamics | Cystometric capacity, compliance, and verbal sensory threshold improved; daily voids, UUI, and nocturia decreased; ICIQ-UI SF and ICIQ-OAB improved[15] |
Novara 2020 is particularly notable — the study enrolled women with OAB refractory to first-line antimuscarinic or β₃-agonist therapy, suggesting ospemifene may serve as a second-line adjunct before escalating to botulinum toxin or neuromodulation in postmenopausal women with concurrent VVA.[6]
Mechanism: ospemifene's estrogen-agonist effect on the lower urinary tract restores urethral and trigonal mucosal integrity, improves periurethral blood flow, and reduces detrusor sensitivity — a similar effect profile to vaginal estrogen achieved via oral dosing.[4][15]
Recurrent UTI prevention — not a primary indication
Unlike vaginal estrogen, ospemifene has not been specifically studied for rUTI prevention. The 2023 JAMA review notes that none of the FDA-approved GSM therapies (including ospemifene) are approved for reducing rUTI frequency.[2]
PEONY observational signal (breast cancer survivors, 6 months of ospemifene) — rUTIs decreased by 80% and postcoital cystitis decreased by 90% as secondary outcomes.[16] Hypothesis-generating.
Sexual function
Schiavi 2018 showed significant improvement in total FSFI and decreased sexual distress in women with VVA and OAB/UUI.[5] The 12-month PEONY study confirmed sustained improvements in lubrication and pain domains; overall FSFI total did not reach significance — likely reflecting the multifactorial nature of sexual dysfunction in this population.[17]
Guideline positioning
- ACOG — ospemifene can be recommended as an alternative to vaginal estrogen for dyspareunia caused by GSM (Level A recommendation)[18]
- AGS Beers Criteria 2023 — lists ospemifene as a GSM-dyspareunia alternative alongside vaginal estrogen, DHEA, and hyaluronic acid[19]
- AAFP 2023 — FDA-approved non-estrogen therapy for vaginal atrophy and dyspareunia[20]
Adverse effects and safety
Pooled safety (6 Phase 2/3 trials; n = 1,242 ospemifene vs n = 958 placebo):[12][21]
| AE | Ospemifene 60 mg | Placebo |
|---|---|---|
| Hot flush | 8.5% | 3.3% |
| UTI | 6.5% | 4.8% |
| Vaginal discharge | 3.8% | 0.3% |
| Muscle spasms | 3.2% | 0.9% |
| Headache | 2.4% | 2.3% |
| Hyperhidrosis | 1.6% | 0.3% |
| Vaginal hemorrhage | 1.0% | 0.2% |
| Night sweats | 1.0% | 0.0% |
| Discontinuation for AEs | 7.6% | 3.8% |
| Serious AEs | 2.6% | 1.8% |
Hot flashes (~8.5%) are the most clinically meaningful AE — counsel patients with pre-existing vasomotor symptoms that ospemifene may worsen hot flashes.[2][21]
Endometrial safety
Constantine 2015 Phase 2/3 pooled analysis (n = 1,242 ospemifene / n = 924 placebo):[10]
- No endometrial cancer in any ospemifene trial
- Endometrial hyperplasia: <1% at 12 months
- Proliferative endometrium: 26.3 per 1,000 women (ospemifene) vs 0 (placebo)
- Uterine polyps: 19.6 vs 8.3 per 1,000 women
Simon 2023 network meta-analysis confirmed endometrial thickness remained under the 4 mm threshold.[14] Progestogen co-administration was not evaluated in trials; FDA label does not mandate it. Long-term (>1 y) endometrial data are limited — counsel patients to report any postmenopausal bleeding.[10][12]
VTE risk — real-world signal favorable
| Source | n | VTE signal |
|---|---|---|
| Clinical trials (up to 15 mo) | Pooled | DVT 2.26 / 1,000 woman-y (2 cases) vs 3.15 / 1,000 (1 case) placebo — trials not powered for VTE[12] |
| Nordstrom 2020 MarketScan 2013–2017 | 8,188 ospemifene | 3.7 per 1,000 person-years VTE |
| Other SERMs | 11,777 | 11.5 per 1,000 person-years |
| Untreated VVA | 220,242 | 11.3 per 1,000 person-years |
Ospemifene's real-world VTE incidence is ~1/3 that of other SERMs and even below untreated VVA, though the FDA contraindication for active or prior DVT/PE/stroke/MI remains.[22]
Perioperative
Per FDA label, discontinue ≥4–6 weeks before high-VTE-risk surgery or during prolonged immobilization.[12]
Bone and lipid effects
Bone
- Phase 3 data show significantly greater decreases in 7 of 9 bone biomarkers vs placebo at 12 weeks, comparable to raloxifene[7][8]
- Maffei 2022 observational 12-month study (n = 128) — stable BMD at total femur and lumbar spine on ospemifene; control group showed significant decline at all sites; bone alkaline phosphatase decreased[23]
- AYSEX real-world 12-month study (n = 100) — no significant change in DXA or bone-resorption markers[24]
- Not FDA-approved for osteoporosis — no fracture-outcome data; biomarker-level evidence only[7]
Lipids
Archer 2017 post-hoc analysis (n = 2,166):[11]
- HDL ↑ 4.4% at 3 mo, 5.1% at 6 mo (vs 0.2% / 1.5% placebo; p < 0.001)
- LDL decrease (p < 0.05)
- Triglycerides neutral (unlike oral estrogens)
Use in breast cancer survivors — regulatory divergence
| Source | Position |
|---|---|
| FDA label | "Should not be used in women with known or suspected breast cancer"; estrogen-dependent neoplasia contraindicated[12] |
| EMA (Europe) | Approved for use after breast cancer in women who have completed all treatment[18] |
| NCCN Survivorship 2026 | "Currently ospemifene is contraindicated in survivors with a history of estrogen-dependent cancers"[25] |
| ACOG 2021 clinical consensus | FDA warning is "controversial"; post-approval data have not demonstrated increased recurrence; recommend clinician-patient shared decision-making[18] |
Supporting clinical data
- Preclinical — antagonist activity in breast tissue; anti-proliferative effects[18][26]
- PEONY 6-month (n = 64 breast cancer survivors) — significant improvement in VVA symptoms and treatment satisfaction; decreased rUTIs and cystitis; no safety signals[16]
- PEONY 12-month (n = 385 overall; 145 ospemifene incl. breast cancer survivors) — sustained efficacy; ospemifene users had ~3× higher odds of clinically relevant satisfaction improvement vs local estrogen (OR 2.85; 95% CI 1.33–6.11)[17]
Bottom line: the breast-antagonist profile and emerging real-world data are encouraging; the FDA contraindication remains; the European approval provides regulatory precedent for use after breast-cancer treatment completion. Shared decision-making with oncology is essential.[16][18][27]
Long-term efficacy and adherence
AYSEX 12-month real-world (n = 100)[24]
- Significant improvement in all VHI domains sustained at 12 months
- Only 1 patient remained with vaginal atrophy at 12 months (vs 100% at baseline)
- Significant improvement in sexual function and QoL
- No significant change in endometrial thickness, mammography, or bone health
PEONY 12-month (n = 385; 145 ospemifene / 240 local estrogen)[17]
- 75.9% ospemifene completion at 12 months (vs 78.7% local estrogen) — comparable adherence
- Treatment satisfaction 7.02 at 3 mo → 8.32 at 12 mo (p < 0.001)
- Favorable OR vs local estrogen for satisfaction improvement
Practical prescribing
| Parameter | Recommendation |
|---|---|
| Ideal candidate | Postmenopausal woman with moderate-to-severe dyspareunia or dryness who prefers oral therapy over vaginal application[12] |
| Dose | 60 mg PO daily with food (absorption is food-dependent)[12] |
| Onset | Significant improvement by 4–6 wk; full effect by 12 wk[2] |
| Duration | Indefinite; per FDA label, shortest duration consistent with treatment goals[12] |
| Progestogen | Not mandated; no hyperplasia / cancer at 52 wk; evaluate any abnormal bleeding[12] |
| Monitoring | Evaluate postmenopausal bleeding; no routine endometrial surveillance needed unless symptomatic[12] |
| Avoid in | Active / history of DVT-PE-stroke-MI; estrogen-dependent neoplasia; concurrent fluconazole or rifampin; pregnancy[12] |
| Perioperative | Discontinue 4–6 wk before high-VTE-risk surgery[12] |
| Counsel about | Hot flashes ~8.5%; vaginal discharge ~4%; take with food[21] |
| Breast cancer survivors | FDA-contraindicated; EMA-approved post-treatment; shared decision-making with oncology[18] |
| Cost | Brand-name only; ~$200–300/month uninsured |
Comparative summary — ospemifene vs vaginal estrogen vs vaginal DHEA
| Feature | Ospemifene (oral SERM) | Vaginal estrogen | Vaginal DHEA (prasterone) |
|---|---|---|---|
| Route | Oral | Vaginal (cream, insert, ring) | Vaginal insert |
| Dosing frequency | Daily with food | 2×/wk or 90-day ring | Daily at bedtime |
| FDA indications | Dyspareunia + vaginal dryness | GSM symptoms | Dyspareunia (US) |
| OAB improvement | Yes (multiple prospective)[4][5][6][15] | Yes | Not studied |
| UTI prevention | Not formally studied (observational signal) | Strong evidence (RR 0.42) | Not studied |
| All-FSFI-domain sexual function | Lubrication + pain; desire/arousal inconsistent | Primarily pain / lubrication | All 6 domains including desire / arousal |
| Systemic absorption | Systemic (oral) | Very low (formulation-dependent) | Ultra-low (below postmenopausal E2) |
| Hot flashes | May worsen (~8.5%) | No effect | No effect |
| Bone effects | Favorable biomarkers (not FDA-approved) | None demonstrated | None demonstrated |
| Lipid effects | ↑HDL, ↓LDL, neutral TG | None | None |
| VTE risk | FDA contraindication (history DVT/PE); real-world favorable | No increased risk | No increased risk |
| Endometrial safety | Mild thickening; no hyperplasia/cancer (52 wk) | No hyperplasia (1 y data) | No hyperplasia (52 wk) |
| Breast cancer survivors | FDA-contraindicated; EMA-approved | First-line hormonal (shared decision) | Second-line (ACOG); favorable pharmacology in AI users |
| Progestogen needed | No | No (low dose) | No |
| Generic | No | Yes (most) | No |
Evidence Summary
| Indication | Evidence level | Key source |
|---|---|---|
| Dyspareunia + vaginal dryness | Level 1 (Phase III + meta) | Di Donato 2019[13]; FDA label[12] |
| Endometrial safety (up to 52 wk) | Level 1 | Constantine 2015[10]; Simon 2023 NMA[14] |
| OAB / UUI improvement | Level 2 (prospective) | Schiavi 2017[4] / 2018[5]; Novara 2020[6]; Russo 2023[15] |
| Bone biomarkers | Level 2–3 | de Villiers 2019[7]; Maffei 2022[23] |
| Lipid effects | Level 2 | Archer 2017[11] |
| VTE in real-world use | Level 3 (PASS) | Nordstrom 2020[22] |
| Long-term efficacy / adherence (12 mo) | Level 3 | AYSEX[24]; PEONY[17] |
| Breast cancer survivors | Level 3 | PEONY[16][17]; ACOG consensus[18] |
Clinical Positioning
- Ospemifene 60 mg daily with food is the only oral, non-estrogen FDA-approved GSM therapy. Take-with-food matters — absorption nearly doubles with a fatty meal.[12]
- Avoid with fluconazole (2.7× AUC) and rifampin (58% AUC loss). The fluconazole interaction collides with common VVC management in the same patient population.[2][12]
- Ospemifene improves OAB / UUI in multiple prospective studies, including in women with first-line-refractory OAB (Novara 2020) — reasonable second-line adjunct before botulinum toxin or neuromodulation in postmenopausal women with concomitant VVA.[6]
- Not an rUTI-prevention agent. Vaginal estrogen retains the AUA-endorsed indication (RR 0.42). The PEONY observational signal is hypothesis-generating only.[16]
- Hot flashes are the dominant tolerance issue (~8.5%) and drive most discontinuations — counsel preemptively, particularly in women with pre-existing vasomotor symptoms.[2][21]
- Endometrial safety through 52 weeks is reassuring — no cancer, <1% hyperplasia, thickness under 4 mm. Long-term (>1 y) endometrial data remain limited; evaluate any postmenopausal bleeding.[10][14]
- Real-world VTE is favorable — Nordstrom 2020 MarketScan showed VTE incidence ~1/3 that of other SERMs and below untreated VVA, but the FDA contraindication for active / prior DVT-PE-stroke-MI remains.[22]
- Discontinue 4–6 weeks before high-VTE-risk surgery or during prolonged immobilization per label.[12]
- Breast-cancer policy is jurisdiction-specific. FDA contraindicates; EMA approves after treatment completion; PEONY 12-month data support safety and satisfaction. Shared decision-making with oncology is essential — do not improvise.[18][17]
- Bone and lipid effects are favorable but off-label. Reasonable consideration in the patient who also has low-risk dyslipidemia or borderline bone density, but do not prescribe ospemifene as an osteoporosis drug.[7][11]
- Counsel about 4–6-week onset and 12-week full effect — realistic expectations improve adherence.[2]
See Also
References
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3. Di Carlo C, Cagnacci A, Murina F, et al. "Ospemifene and vulvovaginal atrophy: an update of the clinical profile for post-menopausal women." Expert Opin Pharmacother. 2024;25(11):1541–1554. doi:10.1080/14656566.2024.2391009
4. Schiavi MC, Zullo MA, Faiano P, et al. "Retrospective analysis in 46 women with vulvovaginal atrophy treated with ospemifene for 12 weeks: improvement in overactive bladder symptoms." Gynecol Endocrinol. 2017;33(12):942–945. doi:10.1080/09513590.2017.1323859
5. Schiavi MC, Sciuga V, Giannini A, et al. "Overactive bladder syndrome treatment with ospemifene in menopausal patients with vulvovaginal atrophy: improvement of sexuality?" Gynecol Endocrinol. 2018;34(8):666–669. doi:10.1080/09513590.2018.1441398
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12. US Food and Drug Administration. Osphena (ospemifene) — prescribing information. Updated 2025-02-14.
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15. Russo E, Misasi G, Montt-Guevara MM, Giannini A, Simoncini T. "Effects of ospemifene on overactive bladder in postmenopausal women with vulvovaginal atrophy." Climacteric. 2023;26(3):284–288. doi:10.1080/13697137.2023.2184251
16. Villa P, Cassani C, Nappi RE, et al. "Quality of life and satisfaction with ospemifene for treating vulvovaginal atrophy in breast cancer survivors: six-month results from the PatiEnt SatisfactiON studY (PEONY)." Clin Breast Cancer. 2025. doi:10.1016/j.clbc.2025.08.001
17. Meriggiola MC, Villa P, Cagnacci A, et al. "Treatment of vulvovaginal atrophy is associated with high levels of satisfaction and improves symptom severity and patient-reported outcomes: 12-month results of the PatiEnt SatisfactiON studY (PEONY)." Menopause. 2026. doi:10.1097/GME.0000000000002737
18. American College of Obstetricians and Gynecologists. "Treatment of urogenital symptoms in individuals with a history of estrogen-dependent breast cancer: clinical consensus." Obstet Gynecol. 2021;138(6):950–960. doi:10.1097/AOG.0000000000004601
19. Steinman MA. "Alternative treatments to selected medications in the 2023 American Geriatrics Society Beers Criteria." J Am Geriatr Soc. 2025;73(9):2657–2677. doi:10.1111/jgs.19500
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22. Nordstrom BL, Cai B, De Gregorio F, et al. "Incidence of venous thromboembolism among postmenopausal women prescribed ospemifene, selective estrogen receptor modulators for noncancer indications, or untreated vulvar and vaginal atrophy." Menopause. 2020;27(8):864–871. doi:10.1097/GME.0000000000001552
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24. Pingarrón Santofímia C, Lafuente González P, Guitiérrez Vélez MDC, et al. "Long-term use of ospemifene in clinical practice for vulvo-vaginal atrophy: end results at 12 months of follow-up." Gynecol Endocrinol. 2022;38(7):577–582. doi:10.1080/09513590.2022.2083103
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