Is Treating Post-Menopausal Women With Symptomatic Hand Osteoarthritis With Hormone Replacement Therapy Feasible?: Results From The Hope-E Randomised, Placebo-Controlled Feasibility Study

Purpose: Hand osteoarthritis (OA) is more common in women. Hand OA incidence increases further in females around the age of 50, the typical age of menopause. Estrogen-deficient states are associated with increased musculoskeletal pain and inflammation and with increased rates of symptomatic OA. Estrogen replacement and selective estrogen receptor modulators (SERMs) can improve pain and structure in some pre-clinical models of OA associated with estrogen loss, and in exploratory analysis from hormone replacement therapy (HRT) trials. However, no randomised clinical trials (RCTs) of HRT had been performed in symptomatic OA populations, specifically hand OA. By carrying out a RCT feasibility study of a form of HRT (conjugated estrogens (CE)-bazedoxifene) in post-menopausal women with painful hand OA, we set out to determine the feasibility and acceptability of this. We also aimed to generate proof-of concept data on likely outcomes, calculate a sample size and refine methods for a full trial. Method(s): We recruited females aged 40-65 years and 1-10 years after final menstrual period with definite hand OA and >=2 painful hand joints across three primary/secondary care sites and from the community. Medical exclusions included those typical for clinical HRT use. Design was parallel group, double-blind 1:1 randomisation of CE-bazedoxifene or placebo, taken orally once daily for 24 weeks, then tapering for 4 weeks before study end at Week 28. Primary feasibility outcomes were rates of eligible participant identification, recruitment, randomisation, retention, compliance, and likelihood of unblinding. Adverse events (AEs) were collected. Secondary clinical outcomes included the anticipated primary outcome in a full trial of mean hand pain over 14 days prior to each visit, scored on a 0-10 numerical rating scale (NRS) where 10 is worst pain possible, as well as hand function, appearance and menopause symptoms. Progression criteria to a full RCT were: (i) recruitment >=30 participants across all sites in 18 months (or proportionate to time open);(ii) a drop-out rate of <=30% of randomised individuals;and (iii) acceptability to the majority of participants, including acceptable AE rates. All clinical outcomes were analysed on an intention-to-treat basis. Though not powered to detect a treatment difference, change and treatment effects (the difference in the outcome between the two groups) were indicated with 95% CIs, with all models adjusted for clinical subtype of painful hand joint, study site, and baseline values. The sample size for a full trial was estimated using the standard deviation (SD) of week 24 mean hand pain. Result(s): Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. From May 2019 to December 2020, 434 enquiries/referrals were received. Of 96 telephone pre-screens, 35 individuals were potentially eligible and of these, 33 gave consent to participate. Of the remaining, 250/401 (62%) were ineligible, whilst 55/401 (14%) chose not to proceed, with the most common reason being not wanting to take HRT. 28/35 (80% (95%CI 63%,92%)) eligible participants were randomised to study medication. All 28 participants completed all follow-ups with high compliance (100% active, 13/14[93%] placebo) and outcome measure completeness (100%, mean hand pain). All three AE-related treatment withdrawals were on placebo when unblinded. No serious AEs occurred. Participants/investigators were well blinded (participant blinding index 0.50[95%CI 0.25 to 0.75]). All three prespecified progression criteria were therefore met for a full trial. The treatment effect difference over 24 weeks in mean hand pain between active and placebo was -0.71 (95% CI -2.20 to 0.78) (Fig 1A). During tapering/stopping medication, mean hand pain increased by 1.31 points in the active arm compared with 0.17 in the placebo arm, indicating a possible effect of cessation of medication (Fig 1A). Furthermore, 6/13 (46%) participants in the active group reported worsening pain at week 28 compared with week 24, but only 2/12 (17%) were worse on withdrawing placebo (Fig 1B). The sample size for a full trial was estimated as 296 (based on MCID 0.8 on NRS, SD 2.0, 90% power, 10% drop-out, alpha 5%). Conclusion(s): This first study of a RCT of HRT for painful hand OA met its progression criteria, indicating that a full trial of an HRT in this population is feasible and acceptable. Although not powered to detect an effect, there was a trend towards improvement in hand pain on treatment and worsening of hand pain on tapering in the active arm only. This adds to proof-of-concept data in this area, justifying more work.ISRCTN12196200. Funded by Research for Patient Benefit programme, National Institute for Health Research (UK) PB-PG-0416-20023 [Formula presented]Copyright © 2023

Changes in dispensing of anti-osteoporotic drugs during COVID-19 pandemic

Care of osteoporosis patients during COVID-19 pandemic is challenging. Due to lockdowns and restrictions, the management of osteoporosis has changed. Diagnosis of osteoporosis decreased and the influence of COVID-19 on drug prescriptions and dispensing is currently unclear. Therefore, the aim of the study was to assess the dispensing of anti-osteoporotic drugs during the Covid19 pandemic. Methods This study was a nationwide retrospective register-based observational study which included all patients in Austria aged >= 50 who received at least one prescription for anti-osteoporotic drug between January 2016 and November 2020. Pseudonymized individual-level patients' data were obtained from social insurance authorities and the Federal Ministry of Labour, Social Affairs, Health and Consumer Protection in Austria. Anti-osteoporotic agents were divided into: (i) oral bisphosphonates, (ii) intravenous bisphosphonates, (iii) selective estrogen receptor modulators (SERMs), (iv) teriparatide (TPTD) and (v) Denosumab (DMAB). We used interrupted time series analysis with autoregressive integrated moving average models (ARIMA) for the prediction of drug dispensing. Results There were 2,884,627 dispensing of anti-osteoporotic drugs by 318,573 patients between 2016-2020. The mean monthly prescriptions for oral bisphosphonates (-14.5 %) and SERMs (-12.9 %) decreased during COVID-19 pandemic, compared to the non-COVID-19 period. The dispensing for intravenous bisphosphonates (1.7 %) and teriparatide (9.5 %) increased during COVID- 19. The prescriptions for DMAB decreased during the first lock-down in March and April 2020 (24 %), however increased by 29.1 % for the total observation time. The ARIMA model for alendronate showed, that the estimated step change was minus 1443 dispensing (95 % CI - 2870 to - 17), while the estimated change in slope was minus 29 dispensing per month (95 % CI - 327 to 270). Thus, there were 1472 (1443 + 29) fewer dispensing in March 2020 than predicted had the lockdown not occurred. Discussion The total number of prescriptions dispensed to patients treated with anti-osteoporotic medications declined rapidly during the first COVID-19 lockdown. The largest drops in absolute terms were observed for ibandronate, followed by alendronate, denosumab, zolendronic acid and risendronate. The observed decrease of DMAB during the first lockdown, was compensated in the following months. Current evidence suggests no need for discontinuation of anti-osteoporotic drugs during COVID-19 pandemic, nor because of vaccination. Taking into account the massive treatment gap for osteoporosis, and the related fracture risk, clinicians should continue treatment, even in times of pandemics.

HAND OSTEOARTHRITIS: INVESTIGATING PAIN EFFECTS in A RANDOMISED PLACEBO-CONTROLLED FEASIBILITY STUDY of ESTROGEN-CONTAINING THERAPY (HOPE-E): REPORT on the PRIMARY FEASIBILITY OUTCOMES

Background: There is an unmet need for new treatments for hand osteoarthri-tis (OA). Symptomatic hand OA is more common in women and its incidence increases round the age of menopause. Pre-clinical, epidemiological and post hoc studies in Hormone Replacement Therapy (HRT) trials implicate estrogen defciency as of likely importance in OA aetiopathogenesis. No clinical trials of HRT have been carried out in hand OA to date. The licensed HRT Duavive (conjugated estrogens + SERM bazedoxifene) was selected on its potential for efficacy and tolerability. Objectives: We set out to determine the feasibility and acceptability of this form of HRT in post-menopausal women with hand OA, to generate proof of concept data and refne methods for a full study. Methods: ISRCTN12196200. Females aged 40-65 yrs and 1-10yrs after fnal menstrual period with hand OA fulflling ACR criteria and 2+ painful hand joints were recruited. Eligibility incorporated best practice for HRT prescription but did not require menopausal symptoms. Recruitment was at 3 sites in primary/secondary care, including directly from the community. Design was parallel group, double-blind 1:1 randomisation of Duavive or placebo, orally once daily for 24 weeks, then weaning for 4 weeks before stopping. Routes and rates of recruitment and the acceptability of randomisation, medication (compliance, retention), and proposed outcomes were measured, and the likelihood of unblinding. Measures related to hand pain and function, menopause symptoms and joint appearance. Patient and Public Involvement actively informed study rationale, design and materials. An end of study questionnaire and 2 participant focus groups provided further acceptability data. Results: Recruitment was for 12/possible 18 months, interrupted due to COVID-19. Some study procedures were modifed to allow reopening whilst collecting all primary outcomes. 434 enquiries/referrals were received, leading to 96 telephone pre-screens, of which 33 gave written informed consent and attended face to face screening. 28/33 screened (85%) were eligible and randomised. The highest number of randomisations was from study web presence (n=7) followed by SMS text from GP surgeries (n=5). Of 401 not proceeding, 250 (62%) were ineligible, most commonly due to contraindicated medication, followed by medical contraindication, whilst 55 (14%) decided not to take part, for reasons including not wanting to take a hormone-based drug or difficulty attending study visits. Retention and compliance were excellent. All 28 participants completed all study follow ups, with only 3 withdrawals from treatment due to AEs, 2 of these at week 24 and all in the placebo arm. There were no serious AEs. High levels of completeness of all study outcome measures were achieved. Bang's blinding index suggested that participants/investigators were well blinded. There were overall high/good levels of satisfaction with taking part in the study. 26/28 (92%) would recommend taking part to others with hand OA (irrespective of study arm). Many found the fexibility offered by a combination of remote and face to face visits (due to the pandemic) attractive. Additional insights from focus groups were to include hand stiffness as well as pain measures but to reduce the overall number of questions. Conclusion: Despite COVID-19 and a reduced recruitment period, this study recruited sufficient numbers to assess feasibility outcomes. Randomisation of eligible people and retention rates were high. A mixture of remote and face to face visits due to COVID-19 probably improved recruitment and retention and was supported by participants, who were generally satisfed with the study design and medication. The study provided useful insight and improvements that would be incorporated into a future study. Overall, this feasibility study showed that with clear messaging on eligibility and a defned recruitment strategy, recruitment and retention to a study testing this treatment is possible.

Inhibition of estrogen receptor signaling as a strategy for radiosensitization of ER+ breast cancers

Purpose: The estrogen receptor (ER) is expressed in over 80% of breast tumors and has been shown to be a significant driver of breast cancer (BC) pathogenesis and therefore a target of effective first-line therapies. While both ionizing radiation (RT) and endocrine therapies (ET) are used for the treatment of ER+ BC, the effect of ET on tumor radiosensitization remains unclear, with concerns it may be radioprotective based on G1 cell arrest with ET treatment. Here we assessed the efficacy and mechanism of ER-mediated radiosensitization using various pharmacologic approaches in ER+ BC. Methods: Radiosensitization with ER inhibitors (tamoxifen [TAM], fulvestrant [FULV], AZD9496) was assessed using clonogenic survival assays. DNA damage was assessed by the neutral comet assay. Efficiency of homologous recombination (HR) or non-homologous end joining (NHEJ) as well as changes in cell cycle, apoptosis, and senescence were assessed. The efficacy of TAM with RT in vivo was assessed with an MCF-7 xenograft model. Results: The selective estrogen receptor modulator TAM radiosensitized ER+ MCF-7 (enhancement ratio [enhR]: 1.14-1.50) and T47D (enhR: 1.33-1.60) cells but not ER-negative SUM-159 cells (enhR: 0.99-1.02). The selective estrogen receptor degrader (SERD) FULV had similar radiosensitization effects in MCF-7 (enhR: 1.33-1.76) and T47D cells (enhR: 0.97-2.81) with no radiosensitization observed in SUM-159 cells (enhR: 1.01-1.03). The novel oral SERD AZD9496 radiosensitized MCF-7 cells (enhR: 1.36-1.56). MCF-7 cells treated with TAM and RT had an increase in dsDNA breaks compared to RT alone as measured by the comet assay (p<0.05) and a decrease in NHEJ-mediated repair with TAM (p<0.05). No changes were observed in HR-mediated repair by Rad51 foci or a reporter (p=NS). RT alone and in combination with TAM or FULV induced similar levels of cell cycle arrest, suggesting that radiosensitization with the combination therapy is cell-cycle independent. There were no significant changes in apoptosis with TAM, FULV, RT, or the combination (p=NS). Although TAM or FULV did induce senescence, ET with RT increased senescence induction (p<0.05). In vivo, combination RT and TAM led to a significant delay in days to tumor doubling (control: 17, TAM: 40, RT: 32, TAM+RT: undefined;p<0.0001), and a significant difference in tumor growth between mice treated with TAM or RT alone compared combination treatment, with no increased toxicities or skin lesions from the combination treatment. Conclusion: Our data suggest that TAM, FULV, or AZD9496 can radiosensitize ER+ breast tumors, and these agents with RT may be more effective for radiosensitization. This work also supports further clinical investigation of the timing of RT for patients receiving ET, including using ET during RT, especially as initiating ET prior to RT has been increasingly utilized as a bridging therapy followed by concurrent ET+RT during the COVID-19 pandemic.

A phase 2 randomized, double-blinded, placebo-controlled, multicenter trial evaluating the efficacy and safety of raloxifene for patients with mild to moderate COVID-19.

Background: Current available therapeutic options for Coronavirus Disease-2019 (COVID-19) are primarily focused on treating hospitalized patients, and there is a lack of oral therapeutic options to treat mild to moderate outpatient COVID-19 and prevent clinical progression. Raloxifene was found as a promising molecule to treat COVID-19 due to its activity to modulate the replication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and act as an immunomodulator to decrease proinflammatory cytokines. Methods: This was a phase 2 multicenter, randomized, placebo-controlled trial to evaluate the efficacy and safety of raloxifene in adult patients with mild to moderate COVID-19 between October 2020 to June 2021 in five centers located in Italy. This was a planned 2/3 adaptive study, but due to operational difficulties, the study was discontinued during the phase 2 study segment. Participants were randomized 1:1:1 to receive oral placebo, raloxifene 60 mg, or raloxifene 120 mg by self-administration for a maximum of two weeks. The primary outcomes were the proportion of patients with undetectable SARS-CoV-2 via nasopharyngeal swabs at day 7 and the proportion of patients who did not require supplemental oxygen therapy or mechanical ventilation on day 14. Safety was assessed. The trial is registered (EudraCT 2021-002,476-39, and ClinicalTrials.gov: NCT05172050). Findings: A total of 68 participants were enrolled and randomized to placebo (n = 21), raloxifene 60 mg (n = 24), and raloxifene 120 mg (n = 23). The proportion of participants with undetectable SARS-CoV-2 after seven days of treatment with raloxifene 60 mg [36.8%, 7/19 vs. 0.0%, 0/14] and 120 mg [22.2%, 4/18 vs. 0.0%, 0/14] was better compared to placebo, [risk difference (RD) = 0·37 (95% C.I.:0·09-0·59)] and [RD = 0·22 (95% C.I.: -0·03-0·45)], respectively. There was no evidence of effect for requirement of supplemental oxygen and/or mechanical ventilation with effects for raloxifene 60 mg and raloxifene 120 mg over placebo, [RD = 0·09 (95% C.I.: -0·22-0·37)], and [RD = 0·03 (95% C.I.: -0·28-0·33)], respectively. Raloxifene was well tolerated at both doses, and there was no evidence of any difference in the occurrence of serious adverse events. Interpretation: Raloxifene showed evidence of effect in the primary virologic endpoint in the treatment of early mild to moderate COVID-19 patients shortening the time of viral shedding. The safety profile was consistent with that reported for other indications. Raloxifene may represent a promising pharmacological option to prevent or mitigate COVID-19 disease progression. Funding: The study was funded by Dompé Farmaceutici SpA and supported by the funds from the European Commission - Health and Consumers Directorate General, for the Action under the Emergency Support Instrument- Grant to support clinical testing of repurposed medicines to treat SARS-COV-2 patients (PPPA-ESI-CTRM-2020-SI2.837140), and by the COVID-2020-12,371,675 Ricerca finalizzata and line 1 Ricerca Corrente COVID both funded by Italian Ministry of Health.

Antiviral efficacy of selective estrogen receptor modulators against SARS-CoV-2 infection in vitro and in vivo reveals bazedoxifene acetate as an entry inhibitor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the seventh member of the coronavirus family that can infect humans. Recently, more contagious and pathogenic variants of SARS-CoV-2 have been continuously emerging. Clinical candidates with high efficacy and ready availability are still in urgent need. To identify potent anti-SARS-CoV-2 repurposing drugs, we evaluated the antiviral efficacy of 18 selective estrogen receptor modulators (SERMs) against SARS-CoV-2 infection. Six SERMs exhibited excellent anti-SARS-CoV-2 effects in Vero E6 cells and three human cell lines. Clomifene citrate, tamoxifen, toremifene citrate, and bazedoxifene acetate reduced the weight loss of hamsters challenged with SARS-CoV-2, and reduced hamster pulmonary viral load and interleukin-6 expression when assayed at 4 days postinfection. In particular, bazedoxifene acetate was identified to act on the penetration stage of the postattachment step via altering cholesterol distribution and endosome acidification. And, bazedoxifene acetate inhibited pseudoviruses infection of original SARS-CoV-2, Delta variant, Omicron variant, and SARS-CoV. These results offer critical information supporting bazedoxifene acetate as a promising agent against coronaviruses.

Endocrine therapy treatment radiosensitizes estrogen receptor-positive breast cancers

Purpose: Estrogen receptor (ER) expression is present in over 80% of breast tumors and has been shown to be a significant driver of breast cancer (BC) pathogenesis and therefore a target of first-line therapies for ER-positive (ER+) BC patients. While both ionizing radiation (RT) and endocrine therapies (ET) are used for the treatment of ER+ BC, the sequencing of therapy and the effect of ET on tumor radiosensitization remain unclear. Recently, this question has become much more clinically relevant when many physicians started offering ET as a bridging strategy to surgery and RT during the COVID-19 pandemic. Here we assessed the efficacy and mechanism of ER inhibition in ER+ BC in combination with RT in preclinical models. Methods: Clonogenic survival assays were used to assess radiosensitization. Inhibition of ER signaling was accomplished by treating ER+ MCF-7 and T47D cells with the selective ER modulator (SERM), tamoxifen, or the selective ER degrader (SERD), fulvestrant. The ER-negative SUM-159 cells were used as a negative control. DNA damage was assessed by the neutral comet assay. Efficiency of homologous recombination (HR) was measured by Rad51 foci or a GFP reporter system. Non-homologous end joining (NHEJ) efficiency was assessed with a pEYFP reporter. Cell cycle effects were measured using flow cytometry with propidium iodide (PI) staining. Apoptosis was assessed by annexin V/PI via flow Scytometry. Senescence was measured using β-galactosidase staining. Western blotting was used to quantify expression of proteins and phospho-proteins involved in cell cycle and apoptosis. An MCF-7 xenograft model was used to assess the efficacy of tamoxifen with RT in vivo. Synergy was determined using the fractional tumor volume (FTV) method. Results: ER inhibition with tamoxifen radiosensitized ER+ MCF-7 (10-250 nM, enhR: 1.14-1.50) and T47D (500 nM-2.0 μ M, enhR: 1.33-1.60) cells but not ER-negative SUM-159 cells (500 nM-2.0 μ M, enhR: 0.99-1.02). ER degradation with fulvestrant had similar radiosensitization effects in MCF-7 (1-25 nM, enhR: 1.33-1.76) and T47D cells (0.5-5 nM, enhR: 0.97-2.81) with no radiosensitization observed in SUM-159 cells (1-25 nM, enhR: 1.01-1.03). MCF-7 cells treated with 500 nM tamoxifen and 4 Gy RT had an increase in dsDNA breaks compared to RT alone as measured by the comet assay (p<0.05), and there was a decrease in NHEJ-mediated repair with tamoxifen treatment (p<0.05). No changes were observed in HR-mediated repair by Rad51 foci or an HR reporter (p=NS). RT alone and in combination with tamoxifen and fulvestrant induced similar levels of cell cycle arrest, suggesting that radiosensitization with the combination therapy is a cell-cycle independent effect. In addition, there were no significant changes in apoptosis in MCF-7 or T47D cells with endocrine therapy, RT, or the combination (p=NS). Although treatment with ET did induce senescence in ER+ MCF-7 and T47D cells, the combination treatment of ET with RT induced senescence to a much greater level suggesting this mechanism may contribute to radiosensitization (p<0.05). In vivo, combination RT and tamoxifen led to a significant delay in time to tumor doubling (17 days in control, 40 days with tamoxifen alone, 32 days with RT alone, and undefined with combination;p<0.0001) and a significant difference in tumor growth between mice treated with tamoxifen or RT alone compared to mice treated with tamoxifen and RT with synergy noted with combination treatment (FTV 1.297). Conclusion: Our data suggest that ET can radiosensitize ER+ breast tumors, and ET with RT may be more effective for radiosensitization. Ongoing studies will address concurrent versus sequential ET with RT. This work also supports further clinical investigation of the timing of RT for patients receiving ET, especially as ET prior to RT is increasingly used as a bridging therapy during the COVID-19 pandemic.