BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a significant concern, particularly among patients taking bisphosphonates (BPs), denosumab, and selective estrogen receptor modulators (SERMs) for osteoporosis. Despite the known risks, large-scale cohort studies examining the incidence and severity of MRONJ are lacking. We aimed to ascertain the incidence and risk of MRONJ among these patients, whom we stratified by age groups, medication types, and duration of use.
METHODS: We utilized data from the National Health Insurance Service\'s sample cohort database, focusing on patients aged 40 years and above diagnosed with osteoporosis. The patients were divided into three groups: those prescribed BPs only, those prescribed SERMs only, and those prescribed both.
RESULTS: The overall incidence rate of MRONJ was 0.17%. A significantly higher incidence rate was observed among those taking osteoporosis medications, particularly among females with a relative risk of 4.99 (95% confidence interval, 3.21-7.74). The SERM group also had an incidence rate comparable to that of the BP group. Severity was assessed based on the invasiveness of the treatment methods, with 71.3% undergoing invasive treatment in the medication group.
CONCLUSIONS: This study provides valuable insights into the incidence and severity of MRONJ among a large cohort of patients with osteoporosis. It underscores the need for comprehensive guidance on MRONJ risks across different medication groups and sets the stage for future research focusing on specific populations and treatment outcomes.

Estrogen receptor is an important target in breast cancer. Serotonin receptors (5-HT2A and 5-HT2C , in particular) were investigated for a potential role in development and progression of breast cancer. Ligands that interact with estrogenic receptors influence the emotional state of females. Thus, designing selective estrogen receptor modulator (SERM) analogs with potential serotonergic activity is a plausible approach. The dual ligands can augment cytotoxic effect of SERMs, help in both physical and emotional menopausal symptom relief, enhance cognitive function and support bone health. Herein, we report triarylethylene analogs as potential candidates for treatment of breast cancer. Compound 2e showed (ERα relative β- galactosidase activity = 0.70), 5-HT2A (Ki  = 0.97 µM), and 5-HT2C (Ki  = 3.86 µM). It was more potent on both MCF-7 (GI50  = 0.27 µM) and on MDA-MB-231 (GI50  = 1.86 µM) compared to tamoxifen (TAM). Compound 4e showed 40 times higher antiproliferative activity on MCF-7 and 15 times on MDA-MBA compared to TAM. Compound 4e had higher average potency than TAM on all nine tested cell line panels. Our in-silico model revealed the binding interactions of compounds 2 and 2e in the three receptors; further structural modifications are suggested to optimize binding to the ERα, 5-HT2A , and 5-HT2C .

Background and Objectives: This study aimed to investigate osteoporosis-related treatments and the overall anticancer drug treatment tendencies, with a focus on selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), in Korean patients with breast cancer from 2010 to 2019. Materials and Methods: Data were obtained from the Health Insurance Review and Assessment Service. Patients with breast cancer (International Classification of Diseases, 10th Revision code: C50) as a principal diagnosis at least once from 2010 to 2019 were included. Those with osteoporosis (M80, M81, or M82) as a principal or sub-diagnosis or those who received osteoporosis treatment at least once were categorized as the osteoporosis-related treatment group, and others as the non-osteoporosis-related treatment group. The trends of drug prescriptions and treatment costs in patient groups were evaluated using descriptive statistics. Results: Among all included patients, those aged 45-54 years (40.20%) without osteoporosis treatment and those aged 55-64 years (34.11%) with osteoporosis treatment were the most common. SERM was the most commonly prescribed anticancer drug (29.20%) in the entire patient group, followed by AIs (20.83%). Patients without osteoporosis treatment had the highest prescription rate of SERM (31.48%), and those with osteoporosis treatment had a higher prescription rate of AIs (34.28%). Additionally, SERM and AIs were prescribed most frequently before and after the age of 55 years, respectively, regardless of the presence of treatment. Conclusions: This study found that osteoporosis-related treatment and patient age were associated with anticancer drug prescriptions. The present findings would help clinicians and researchers in the clinical diagnosis and treatment of breast cancer.

To assess the risk of select safety outcomes including endometrial cancer, endometrial hyperplasia, and breast cancer among women using conjugated estrogens/bazedoxifene (CE/BZA) as compared with estrogen/progestin combination hormone therapy (EP).
We conducted a new-user cohort study in five US healthcare claims databases representing more than 92 million women. We included CE/BZA or EP new users from May 1, 2014, to August 30, 2019. EP users were propensity score (PS) matched to users of CE/BZA. Incidence of endometrial cancer, endometrial hyperplasia, breast cancer, and eight additional cancer and cardiovascular outcomes were ascertained using claims-based algorithms. Rate ratios (RR) and differences pooled across databases were estimated using random-effects models.
The study population included 10,596 CE/BZA and 33,818 PS-matched EP new users. Rates of endometrial cancer and endometrial hyperplasia were slightly higher among CE/BZA users (1.6 and 0.4 additional cases per 10,000 person-years), although precision was limited because of small numbers of cases (endometrial cancer: RR, 1.50 [95% confidence interval {CI}, 0.79-2.88]; endometrial hyperplasia: RR, 1.69 [95% CI, 0.51-5.61]). Breast cancer incidence was lower in CE/BZA users (9.1 fewer cases per 10,000 person-years; RR, 0.79; 95% CI, 0.58-1.05). Rates of other outcomes were slightly higher among CE/BZA users, but with confidence intervals compatible with a wider range of possible associations.
CE/BZA users might experience slightly higher rates of endometrial cancer and endometrial hyperplasia, and a lower rate of breast cancer, than EP users in the first years of use.

Little is known about differences in the therapeutic efficacy of denosumab in subjects with and without rheumatoid arthritis (RA). This study compares the changes in bone mineral density (BMD) between RA patients and controls without RA who had been treated with denosumab for 2 years for postmenopausal osteoporosis. A total of 82 RA patients and 64 controls were enrolled, who were refractory to selective estrogen receptor modulators (SERMs) or bisphosphonates and completed the treatment of denosumab 60 mg for 2 years. The efficacy of denosumab in RA patients and controls was assessed using areal BMD (aBMD) and T-score of the lumbar spine, femur neck, and total hip. A general linear model with repeated measures analysis of variance was used to determine differences in aBMD and T-score between 2 study groups. No significant differences in percent changes in aBMD and T-scores by denosumab treatment for 2 years at the lumbar spine, femur neck, and total hip were evident between RA patients and controls (P > .05 of all), except T-score of the total hip (P = .034). Denosumab treatment equally increased aBMD at the lumbar spine and T-scores at the lumbar spine and total hip between RA patients and controls without statistical differences, but RA patients showed less improvement in aBMD at the femur neck (ptime*group = 0.032) and T-scores at the femur neck and total hip than controls (ptime*group = 0.004 of both). Changes in aBMD and T-scores after denosumab treatment in RA patients were not affected by previous use of bisphosphonates or SERMs. Differences of T-score at the femur neck among previous bisphosphonate users and aBMD and T-score at the femur neck and T-scores at the total hip were evident. This study revealed that 2 years of denosumab treatment in female RA patients achieved comparable efficacy on BMD to controls at the lumbar spine, but showed somewhat insufficient improvement at the femur neck and total hip.

Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD.
This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models.
We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n = 52) or placebo (n = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM -2.92; adjusted P = 0.020) and week 12 (LSM -3.12; adjusted P = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P = 0.040), while having negative effects on working memory at week 38 in men (LSM -0.53; adjusted P = 0.026). The number of adverse events was similar between groups.
Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment.

OBJECTIVE: To assess the correlation of different vulvovaginal atrophy therapeutic options with the quality of life of postmenopausal women.
METHODS: The CRETA study is a descriptive, observational, cross-sectional, multicenter study designed to measure, besides treatment satisfaction and adherence, the quality of life of postmenopausal women diagnosed with vulvovaginal atrophy in 29 hospitals and centers across Spain.
METHODS: The study enrolled postmenopausal women currently receiving treatment with vaginal moisturizers, local estrogen therapy or ospemifene. Clinical features and treatment perceptions were collected by self-report questionnaire and quality of life was evaluated using the Cervantes scale.
RESULTS: Among the 752 women included, the ospemifene cohort showed a statistically significant lower global score (44.9 ± 21.7) on the Cervantes scale (and therefore, a better quality of life) than the cohorts treated with moisturizers (52.5 ± 21.6, p = 0.003) or local estrogen therapy (49.2 ± 23.8, p = 0.0473). In the analysis by domains, ospemifene-treated women showed statistically significant better scores in menopause & health and psychological status than moisturizers-treated women (p < 0.05). In the domains of sexuality and couple relations, the score for the quality of life of the ospemifene cohort was statistically significantly better than the scores in either of the cohorts treated with moisturizers (p < 0.001) or local estrogen therapy (p < 0.05).
CONCLUSIONS: Postmenopausal women diagnosed with vulvovaginal atrophy and treated with ospemifene have better quality of life than women treated with vaginal moisturizers or local estrogen therapy. The improvement observed with ospemifene is more remarkable in those aspects related to sex life and couple relations. CLINCIALTRIALS.
UNASSIGNED: NCT04607707.

OBJECTIVE: The combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy is a standard treatment for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC); however, their toxicities and financial burden are major issues, especially for prolonged treatment. We investigated fulvestrant plus palbociclib in patients with HR-positive MBC resistant to fulvestrant monotherapy.
METHODS: Patients who initially received fulvestrant as their first- or second-line endocrine therapy were assigned to group A. Patients with disease progression during fulvestrant monotherapy who subsequently received fulvestrant plus palbociclib were assigned to group B. The primary endpoint was progression-free survival (PFS1) in group B. We set the threshold median PFS of 5 months (null hypothesis).
RESULTS: Between January 2018 and February 2020 we enrolled 167 patients in group A (January 2018-February 2020) from 55 institutions, of whom 72 subsequently received fulvestrant plus palbociclib and were enrolled in group B. The median follow-up was 23.8 and 8.9 months in groups A and B, respectively. The median PFS in group B (combination therapy) was 9.4 (90% confidence interval [CI]: 6.9-11.2) months (p < 0.001). This was 25.7 (90% CI: 21.2-30.3) months in group A (fulvestrant monotherapy). The TTF in group B was 7.2 (90% CI: 5.5-10.4) months. In the post-hoc analysis, the median PFS1 in group B among patients with longer-duration fulvestrant monotherapy (> 1 year) was longer than that of patients with shorter-duration monotherapy (≤ 1 year) (11.3 vs. 7.6 months). No new toxicities were observed.
CONCLUSIONS: Our findings suggest that palbociclib plus fulvestrant after disease progression despite fulvestrant monotherapy is potentially safe and effective in patients with HR-positive/HER2-negative advanced MBC.

BACKGROUND: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.
METHODS: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed.
RESULTS: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported.
CONCLUSIONS: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer.
BACKGROUND: Clinical trial registration NCT03816839.

BACKGROUND: This study aimed to assess the association between pharmacotherapy and secondary hip fracture incidence.
METHODS: The correlation between secondary hip fracture incidence and the presence, type, and medication possession ratio (MPR) of pharmacotherapy was investigated using medical insurance data acquired from the National Database of Health Insurance Claims and Specific Health Checkups of Japan.
RESULTS: Data collected from female patients (n = 1,435,347) were analyzed. The 2-year secondary hip fracture incidence was 3.48% (n = 49,921). Secondary hip fracture was significantly more common in patients without medications (3.80%) than in those with medications (3.00%). Patients receiving selective estrogen receptor modulators (SERMs) had the lowest average age. The crude incidence of secondary hip fracture was the lowest in patients receiving SERMs (n = 2088 [2.52%]), followed by those taking bisphosphonates (n = 11,355 [2.88%]), denosumab (n = 1118 [2.90%]), no medications (n = 32,747 [3.80%]), and parathyroid hormone (PTH: n = 2163 [4.55%]), whereas the age-adjusted incidence was the lowest in patients administered denosumab (2.27%), followed by those taking bisphosphonates (2.47%), SERMs (2.55%), PTH (3.67%), and no medications (3.80%). The mean MPR was the highest in patients taking denosumab (64.9%), followed by those receiving bisphosphonates (58.7%), SERMs (58.2%), and PTH (40.6%) in the no hip fracture group.
CONCLUSIONS: Secondary hip fractures were less likely to occur with medication versus no medication. Differences in the crude incidence of secondary hip fracture based on medications usage might be attributed to background characteristics.