Selective Androgen Receptor Modulators-Transformative Drugs or Heralds of the Next Drug Epidemic?

This Viewpoint examines whether selective androgen receptor modulators have the potential to be transformative drugs or whether they herald the next drug epidemic.

IGF-1 axis changes with ADT and docetaxel in metastatic prostate cancer.

Androgen deprivation therapy (ADT) forms the cornerstone of treatment in locally advanced and metastatic prostate cancer (PCa). Since the growth hormone-insulin-like growth factor (GH-IGF-1) axis has been implicated in prostate tumorigenesis, we aimed to evaluate the association between IGF-1 and its binding proteins on outcomes in men with metastatic PCa treated with ADT, with or without docetaxel (D). We analyzed serum samples for IGF-1 and its family proteins from baseline, 6 months post-randomization, and at the time of progression in men enrolled to receive ADT +/- D in the phase 3 CHAARTED trial. The key outcomes were time to the development of castrate-resistant prostate cancer and overall survival (OS). About 560 patients had samples available for analysis. At 6 months, significant increases in IGF-BP1 (mean Δ+27.4%, P = 0.033), IGF-BP3 (mean Δ+10.3%, P < 0.001), and IGF-BP4 (mean Δ+31.1%, P < 0.001) were seen in the ADT + D group, while the ADT group showed an increase in IGF-BP3 (mean Δ+5.5%, P = 0.015). A higher IGF-1:IGF-BP1 ratio at baseline and after 6 months was associated with improved OS in both the ADT (baseline: hazard ratio (HR) = 0.77, P = 0.026; 6 months: HR = 0.83, P = 0.036) and ADT + D groups (baseline: HR = 0.78, P = 0.04; 6 months: HR = 0.81, P = 0.018). Patients with a log10IGF-1:IGF-BP1 ratio >1.3 at baseline had improved OS when meta-analyzed with data from a prior cohort (HR = 0.71). A higher baseline and 6-month IGF-1:IGF-BP1 ratio was associated with better OS. Further exploration of the IGF-1 axis will be important to assess its role as a predictive biomarker and to target this axis in therapeutic trials.

Cardiovascular Safety of Testosterone-Replacement Therapy.

BACKGROUND: The cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo. RESULTS: The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group. CONCLUSIONS: In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.).

Male Reproduction and Aging.

Recent publications of well-conducted population studies have informed us that the syndromic prevalence of age-related low testosterone, also known as late-onset hypogonadism, is quite low. Several well-conducted trials in middle-aged and older men with age-related decline in testosterone levels have revealed that efficacy of testosterone therapy is modest with improvement in sexual function, mood, volumetric bone density, and anemia. Although select older men might benefit from testosterone therapy, its effect on prostate cancer risk and major adverse cardiovascular events remains unclear. The results of the ongoing TRAVERSE trial will likely provide important insights into these risks.

Gaining metabolic insight in older men undergoing androgen deprivation therapy for prostate cancer (the ADT & Metabolism Study): Protocol of a longitudinal, observational, cohort study.

Androgen deprivation therapy (ADT), a cornerstone of treatment for patients with locally advanced and metastatic prostate cancer, is associated with many adverse effects, including osteoporosis, sexual dysfunction, fatigue, and vasomotor symptoms. It is also associated with loss of muscle mass and increased adiposity. This change in body composition is likely the inciting event in the development of insulin resistance, an independent risk factor for diabetes mellitus and cardiovascular disease. Although the occurrence of insulin resistance during ADT has been reported, it remains unclear whether this insulin resistance is primarily hepatic or muscular. Similarly, the mechanisms that lead to insulin resistance also remain unknown. The ADT & Metabolism Study was designed to address these knowledge gaps, as the elucidation of the predominant site of insulin resistance will allow prevention strategies and the use of targeted, tissue-specific insulin-sensitizing agents in patients undergoing ADT. This prospective, mechanistic, single-center, 24-week, observational cohort study will enroll treatment-naïve adult men with prostate cancer about to undergo surgical or medical ADT for at least 24 weeks (ADT group; n = 50) and a control group of men who had undergone radical prostatectomy and are in remission (non-ADT group, n = 25). The primary outcome is to determine the site of insulin resistance (skeletal muscle or liver) using frequent sampling oral glucose tolerance test at baseline and 12 and 24 weeks after commencement of ADT (ADT group) or after enrollment in the study (non-ADT group). Secondary outcomes will assess changes in hepatic and intramyocellular fat (using magnetic resonance spectroscopy), inflammatory markers, adipokines, free fatty acids, and changes in body composition (assessed using dual-energy x-ray absorptiometry) and their correlation with the development of insulin resistance. Exploratory outcomes will include changes in muscle performance, physical function, physical activity, vitality, and sexual drive.

The medicalization of testosterone: reinventing the elixir of life.

The pursuit of longevity, which during the Renaissance era was limited to longing for miraculous ways of rejuvenation, such as bathing in the fountain of youth, took a scientific turn in 1889 with the publication of Brown-Sequard's self-experiments with an extract of animal testes, which apparently improved his vitality, physical strength and cognition. This extract, marketed then as the "Elixir of Life", was sold for decades throughout Europe and North America. However, recent replication of Brown-Sequard's experiments demonstrated that such an extract only contains homeopathic concentrations of testosterone that are insufficient to exert any biological effect. Thus, the birth of Andrology began with a placebo effect. Over the past few decades, the quest for compounds that might lead to rejuvenation has regained traction, with testosterone being at the forefront. Though clinical practice guidelines advocate testosterone therapy in men with organic hypogonadism-the only indication approved by the Food and Drug Administration-testosterone continues to be marketed as a wonder drug with rejuvenating effects on sexual function, vitality, and a host of other unproven benefits. Additionally, the epidemic of obesity and diabetes, conditions associated with low testosterone, has further brought testosterone into the limelight. Although the number of testosterone prescriptions written have increased several-fold in the past two decades, carefully conducted randomized trials suggest modest benefits of testosterone therapy. At the same time, safety concerns, particularly in older men, remain valid.

Accurate measurement of total and free testosterone levels for the diagnosis of androgen disorders.

The circulating concentrations of total and free testosterone vary substantially in people over time due to biologic factors as well as due to measurement variation. Accurate measurement of total and free testosterone is essential for making the diagnosis of androgen disorders. Total testosterone should ideally be measured in a fasting state in the morning using a reliable assay, such as liquid chromatography tandem mass spectrometry, in a laboratory that is certified by an accuracy-based benchmark. Free testosterone levels should be measured in men in whom alterations in binding protein concentrations are suspected or in whom total testosterone levels are only slightly above or slightly below the lower limit of the normal male range for testosterone.

Effect of the STRIDE fall injury prevention intervention on falls, fall injuries, and health-related quality of life.

BACKGROUND: Falls are common in older adults and can lead to severe injuries. The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial cluster-randomized 86 primary care practices across 10 health systems to a multifactorial intervention to prevent fall injuries, delivered by registered nurses trained as falls care managers, or enhanced usual care. STRIDE enrolled 5451 community-dwelling older adults age ≥70 at increased fall injury risk. METHODS: We assessed fall-related outcomes via telephone interviews of participants (or proxies) every 4 months. At baseline, 12 and 24 months, we assessed health-related quality of life (HRQOL) using the EQ-5D-5L and EQ-VAS. We used Poisson models to assess intervention effects on falls, fall-related fractures, fall injuries leading to hospital admission, and fall injuries leading to medical attention. We used hierarchical longitudinal linear models to assess HRQOL. RESULTS: For recurrent event models, intervention versus control incidence rate ratios were 0.97 (95% confidence interval [CI], 0.93-1.00; p = 0.048) for falls, 0.93 (95% CI, 0.80-1.08; p = 0.337) for self-reported fractures, 0.89 (95% CI, 0.73-1.07; p = 0.205) for adjudicated fractures, 0.91 (95% CI, 0.77-1.07; p = 0.263) for falls leading to hospital admission, and 0.97 (95% CI, 0.89-1.06; p = 0.477) for falls leading to medical attention. Similar effect sizes (non-significant) were obtained for dichotomous outcomes (e.g., participants with ≥1 events). The difference in least square mean change over time in EQ-5D-5L (intervention minus control) was 0.009 (95% CI, -0.002 to 0.019; p = 0.106) at 12 months and 0.005 (95% CI, -0.006 to 0.015; p = 0.384) at 24 months. CONCLUSIONS: Across a standard set of outcomes typically reported in fall prevention studies, we observed modest improvements, one of which was statistically significant. Future work should focus on patient-, practice-, and organization-level operational strategies to increase the real-world effectiveness of interventions, and improving the ability to detect small but potentially meaningful clinical effects. CLINICALTRIALS: gov identifier: NCT02475850.

SHBG, Bone Mineral Density, and Physical Function Among Injection Drug Users With and Without HIV and HCV.

CONTEXT: Sex hormone-binding globulin (SHBG) is a glycoprotein that regulates the bioavailability of sex hormones and is higher in people with HIV (PWH) and hepatitis C virus (HCV). SHBG is associated with aging-related diseases, including osteoporosis and frailty in the general population. However, the relationship between SHBG concentration and bone mineral density (BMD) and physical function among PWH and HCV is unclear. OBJECTIVE: This study aimed to evaluate the association between chronic infection with HIV and HCV and SHBG, and to assess the relationship of circulating SHBG concentrations with low BMD, physical function impairment, and frailty. METHODS: A cross-sectional study was conducted of 278 HCV-exposed (HCV antibody positive) adults enrolled with and without HIV and HCV from the AIDS Linked to the IntraVenous Experience cohort study into 4 groups: HCV-/HIV-, HCV-/HIV+, HCV+/HIV-, and HCV+/HIV+. We evaluated the association between SHBG concentrations and grip strength, gait speed, Short Physical Performance Battery score, frailty (Fried Frailty Phenotype), and BMD (lumbar spine, total hip, and femoral neck T-score) by using adjusted multivariable regression stratified by sex. RESULTS: SHBG concentrations were higher in women, in those with HIV RNA greater than 400 copies/mL (P = .02) and HCV RNA greater than 15 IU/mL (P < .001). In adjusted models, higher SHBG concentrations among women were statistically significantly associated with lower grip strength (-0.43 [95% CI, -0.77 to -0.081] kg/10 nmol/L, P < .05), higher odds of frailty (odds ratio, 1.49 [95% CI, 1.07 to 2.08], P < .05), and lower T-scores at the lumbar spine (-0.070 [95% CI, -0.15 to -0.001] SD/10 nmol/L T-score BMD, P < .05). Similar associations were not observed among men. CONCLUSION: Higher SHBG concentrations are associated with the presence of HIV and HCV viremia. Among women, but not men, higher SHBG concentrations were associated with lower grip strength, higher odds of frailty, and lower lumbar spine BMD. The underlying mechanisms of these associations require further investigation.

Testosterone Therapy With Subcutaneous Injections: A Safe, Practical, and Reasonable Option.

CONTEXT: Injections with intramuscular (IM) testosterone esters have been available for almost 8 decades and not only result in predictable serum testosterone levels but are also the most inexpensive modality. However, they are difficult to self-administer and associated with some discomfort. Recently, subcutaneous (SC) administration of testosterone esters has gained popularity, as self-administration is easier with this route. Available data, though limited, support the feasibility of this route. Here we review the pharmacokinetics and safety of SC testosterone therapy with both long- and ultralong-acting testosterone esters. In addition, we provide guidance for clinicians on how to counsel and manage their patients who opt for the SC route. EVIDENCE ACQUISITION: Systematic review of available literature on SC testosterone administration including clinical trials, case series, and case reports. We also review the pharmacology of testosterone absorption after SC administration. EVIDENCE SYNTHESIS: Available evidence, though limited, suggests that SC testosterone therapy in doses similar to those given via IM route results in comparable pharmacokinetics and mean serum testosterone levels. With appropriate training, patients should be able to safely self-administer testosterone esters SC with relative ease and less discomfort compared with the IM route. CONCLUSION: Although studies directly comparing the safety of SC vs IM administration of testosterone esters are desirable, clinicians should consider discussing the SC route with their patients because it is easier to self-administer and has the potential to improve patient adherence.

Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: Rationale and design of the TRAVERSE study.

BACKGROUND: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately-powered randomized trial. METHODS: The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated major adverse CV event endpoints have occurred to assess whether the 95% (2-sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. RESULTS: As of July 1, 2021, 5,076 subjects had been randomized. CONCLUSIONS: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.

A Selective Androgen Receptor Modulator (OPK-88004) in Prostate Cancer Survivors: A Randomized Trial.

BACKGROUND: Androgen deficiency is common among prostate cancer survivors, but many guidelines consider history of prostate cancer a contraindication for testosterone replacement. We determined the safety and efficacy of a selective androgen receptor modulator (OPK-88004) in symptomatic, testosterone-deficient men who had undergone radical prostatectomy for low-grade, organ-confined prostate cancer. METHODS: In this placebo-controlled, randomized, double-blind trial, 114 men, ≥19 years of age, who had undergone radical prostatectomy for low-grade, organ-localized prostate cancer, undetectable PSA (<0.1 ng/mL) for ≥2 years after radical prostatectomy and testosterone deficiency were randomized in stages to placebo or 1, 5, or 15 mg OPK-88004 daily for 12 weeks. Outcomes included PSA recurrence, sexual activity, sexual desire, erectile function, body composition, muscle strength and physical function measures, mood, fatigue, and bone markers. RESULTS: Participants were on average 67.5 years of age and had severe sexual dysfunction (mean erectile function and sexual desire domain scores 7.3 and 14.6, respectively). No participant experienced PSA recurrence or erythrocytosis. OPK-88004 was associated with a dose-related increase in whole-body (P < 0.001) and appendicular (P < 0.001) lean mass and a significantly greater decrease in percent body fat (P < 0.001) and serum alkaline phosphatase (P < 0.001) than placebo. Changes in sexual activity, sexual desire, erectile function, mood, fatigue, physical performance, and bone markers did not differ among groups (P = 0.73). CONCLUSIONS: Administration of OPK-88004 was safe and not associated with PSA recurrence in androgen-deficient men who had undergone radical prostatectomy for organ-confined prostate cancer. OPK-88004 increased lean body mass and decreased fat mass but did not improve sexual symptoms or physical performance.

Longitudinal Changes in Sex Hormone-Binding Globulin in Men With HIV.

BACKGROUND: Sex hormone-binding globulin (SHBG) is a glycoprotein that regulates sex hormone bioavailability and increases with age in the general population. SHBG concentrations are higher in people with HIV, a population in whom accelerated aging has been hypothesized. It is unclear whether longitudinal changes in SHBG increase over time and differ by HIV serostatus. METHODS: In a longitudinal study, SHBG was measured in 182 men with HIV (MWH) and 267 men without HIV (seronegative) from the Multicenter AIDS Cohort Study and matched for age, race, site, and time, with ≥2 SHBG serum samples over the 10 years after HAART initiation. Multivariable linear mixed-effects regression models were used to evaluate whether log-transformed SHBG [ln(SHBG)] and its rate of change differed by HIV serostatus. RESULTS: At baseline, the mean age in MWH was similar to that in HIV-seronegative men (51 ± 5 vs 49 ± 6 years). However, SHBG mean values were higher in MWH compared with those in HIV-seronegative men (65.6 ± 48.8 vs. 45.4 ± 22 nmol/L, P < 0.001). In a fully adjusted model, SHBG increased over time and at a faster rate in MWH compared with that in HIV-seronegative men: [2.0%/year (95% CI: 1.4 to 2.7) vs 1.3%/year (95% CI: 0.8 to 1.8), respectively, P = 0.038]. Among MWH, higher SHBG concentrations were significantly associated with lower CD4+ T-cell count [ß= -0.02 (95% CI: -0.03 to -0.0002), P < 0.05], fewer cumulative years on zidovudine [ß = -0.027 (95% CI: -0.045 to -0.009), P < 0.001], and greater cumulative years on nonnucleoside reverse transcriptase inhibitors drugs [ß = 0.022 (95% CI: 0.0006 to 0.04), P < 0.05]. CONCLUSIONS: Aging-related increases in SHBG were faster in MWH compared with those in HIV-seronegative men and were related to poorer immunologic status and antiretroviral medication exposure. The mechanisms and consequences of these findings require further investigation.

Effect of Protein Intake on Visceral Abdominal Fat and Metabolic Biomarkers in Older Men With Functional Limitations: Results From a Randomized Clinical Trial.

BACKGROUND: It remains controversial whether high protein diets improve cardiometabolic profile. We investigated whether increasing protein intake to 1.3 g/kg/day in functionally limited older adults with usual protein intake ≤RDA (0.8 g/kg/day) improves visceral fat accumulation and serum cardiovascular risk markers more than the recommended daily allowance (RDA). METHODS: The Optimizing Protein Intake in Older Men Trial was a placebo-controlled, randomized trial in which 92 functionally limited men, ≥65 years, with usual protein intake ≤RDA were randomized for 6 months to: 0.8 g/kg/day protein plus placebo; 1.3 g/kg/day protein plus placebo; 0.8 g/kg/day protein plus testosterone enanthate 100 mg weekly; or 1.3 g/kg/day protein plus testosterone enanthate 100 mg weekly. In this substudy, metabolic and inflammatory serum markers were measured in 77 men, and visceral adipose tissue (VAT) was assessed using dual-energy x-ray absorptiometry in 56 men. RESULTS: Treatment groups were similar in their baseline characteristics. Randomization to 1.3 g/kg/day protein group was associated with greater reduction in VAT compared to 0.8 g/kg/day group (between-group difference: -17.3 cm2, 95% confidence interval [CI]: -29.7 to -4.8 cm2, p = .008), regardless of whether they received testosterone or placebo. Changes in fasting glucose, fasting insulin, HOMA-IR, leptin, adiponectin, IL-6, and hs-CRP did not differ between the 0.8 versus 1.3 g/kg/day protein groups regardless of testosterone use. CONCLUSIONS: Protein intake >RDA decreased VAT in functionally limited older men but did not improve cardiovascular disease risk markers. CLINICAL TRIALS REGISTRATION NUMBER: NCT01275365.

Risk of Dementia and Depression in Young and Middle-aged Men Presenting with Nonmetastatic Prostate Cancer Treated with Androgen Deprivation Therapy.

BACKGROUND: Previous studies have found an association between androgen deprivation therapy (ADT) and an increased risk of dementia and depression in elderly men. This association remains controversial, and little is known about the effects of ADT in younger men. OBJECTIVE: To examine the association between the receipt of ADT and these outcomes in young men aged 40-64 yr presenting with nonmetastatic prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: For this observational study, we identified 9117 men aged 40-64 yr diagnosed with localized PCa between 2007 and 2014, without a pre-existing neurocognitive diagnosis, using the TRICARE military database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier curves were fitted to compare ADT versus no ADT. We also performed a subgroup analysis in patients undergoing ADT for ≥12 mo. The association between ADT and new-onset dementia or depression was evaluated using inverse-probability-of treatment-weight-adjusted Cox proportional hazards regression analysis. RESULTS AND LIMITATIONS: Patients receiving ADT had a significantly higher incidence of depression (30.2 vs 15.8 per 1000 person years) and dementia (17.9 vs 7.5 per 1000 person years). The risk of developing either outcome was higher in the ADT cohort (depression: hazard ratio [HR] 2.07, p < 0.001; dementia: HR 1.70, p = 0.052). Additionally, there was a dose-response relationship between the duration of ADT and either outcome. CONCLUSIONS: In our cohort of young men with PCa, the receipt of ADT was associated with an increased risk of developing dementia and depression. Long-term use of ADT was associated with the highest risk of neurocognitive outcomes. PATIENT SUMMARY: In this study, we looked at the risk of dementia and depression in patients <65 yr of age undergoing androgen deprivation therapy (ADT) for prostate cancer. We found that these patients had a higher risk of dementia and depression than those who did not undergo ADT.

Effect of a Multifactorial Fall Injury Prevention Intervention on Patient Well-Being: The STRIDE Study.

BACKGROUND/OBJECTIVES: In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, a multifactorial intervention was associated with a nonsignificant 8% reduction in time to first serious fall injury but a significant 10% reduction in time to first self-reported fall injury relative to enhanced usual care. The effect of the intervention on other outcomes important to patients has not yet been reported. We aimed to evaluate the effect of the intervention on patient well-being including concern about falling, anxiety, depression, physical function, and disability. DESIGN: Pragmatic cluster-randomized trial of 5,451 community-living persons at high risk for serious fall injuries. SETTING: A total of 86 primary care practices within 10 U.S. healthcare systems. PARTICIPANTS: A random subsample of 743 persons aged 75 and older. MEASUREMENTS: The well-being measures, assessed at baseline, 12 months, and 24 months, included a modified version of the Fall Efficacy Scale, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scales, and Late-Life Function and Disability Instrument. RESULTS: Participants in the intervention (n = 384) and control groups (n = 359) were comparable in age: mean (standard deviation) of 81.9 (4.7) versus 81.8 (5.0) years. Mean scores were similar between groups at 12 and 24 months for concern about falling, physical function, and disability, whereas the intervention group's mean scores on anxiety and depression were .7 points lower (i.e., better) at 12 months and .6 to .8 points lower at 24 months. For each of these outcomes, differences between the groups' adjusted least square mean changes from baseline to 12 and 24 months, respectively, were quantitatively small. The overall difference in means between groups over 2 years was statistically significant only for depression, favoring the intervention: -1.19 (99% confidence interval, -2.36 to -.02), with 3.5 points representing a minimally important difference. CONCLUSIONS: STRIDE's multifactorial intervention to reduce fall injuries was not associated with clinically meaningful improvements in patient well-being.

Clinically Important Differences for Mobility Measures Derived from the Testosterone Trials.

BACKGROUND/OBJECTIVES: Accurate estimates of clinically important difference (CID) are required for interpreting the clinical importance of treatments to improve physical function, but CID estimates vary in different disease populations. We determined the CID for two common measures of walking ability in mobility-limited older men. DESIGN: Longitudinal, multisite placebo-controlled trial. SETTING/PARTICIPANTS: Men enrolled in the Testosterone Trials who had self-reported mobility limitation and gait speed less than 1.2 m/second (n = 429). Testosterone- and placebo-allocated participants were combined for this study. RESULTS: Mean changes from baseline, adjusting for time-in-intervention and site, were 29.6, 13.2, 12.5, -2.4, and -32.6 m for 6MWD, and 15.4, 7.2, 2.1, -3.4, and -7.2 for PF10 in men who reported their mobility was "very/much better," "little better," "no change," "little worse," or "much worse," respectively. CID estimates using regression, ROC, and eCDF varied from 5.0-29.6 m for 6MWD, and 5.0-15.2 points for PF10. CONCLUSION: CID estimates vary by the population studied and by the method and precision of measurement. Increases of 16 to 30 m for 6MWD and 5 to 15 points for PF10 over 12 months appear to be clinically meaningful in mobility-limited, older hypogonadal men. These CID estimates may be useful in the design of efficacy trials of therapies to improve physical function.

Investigation of Suicidality and Psychological Adverse Events in Patients Treated With Finasteride.

Importance: There is ongoing controversy about the adverse events of finasteride, a drug used in the management of alopecia and benign prostatic hyperplasia (BPH). In 2012, reports started emerging on men who had used finasteride and either attempted or completed suicide. Objective: To investigate the association of suicidality (ideation, attempt, and completed suicide) and psychological adverse events (depression and anxiety) with finasteride use. Design, Setting, and Participants: This pharmacovigilance case-noncase study used disproportionality analysis (case-noncase design) to detect signals of adverse reaction of interest reported with finasteride in VigiBase, the World Health Organization's global database of individual case safety reports. To explore the strength of association, the reporting odds ratio (ROR), a surrogate measure of association used in disproportionality analysis, was used. Extensive sensitivity analyses included stratifying by indication (BPH and alopecia) and age (≤45 and >45 years); comparing finasteride signals with those of drugs with different mechanisms but used for similar indications (minoxidil for alopecia and tamsulosin hydrochloride for BPH); comparing finasteride with a drug with a similar mechanism of action and adverse event profile (dutasteride); and comparing reports of suicidality before and after 2012. Data were obtained in June 2019 and analyzed from January 25 to February 28, 2020. Exposures: Reported finasteride use. Main Outcomes and Measures: Suicidality and psychological adverse events. Results: VigiBase contained 356 reports of suicidality and 2926 reports of psychological adverse events (total of 3282 adverse events of interest) in finasteride users (3206 male [98.9%]; 615 of 868 [70.9%] with data available aged 18-44 years). A significant disproportionality signal for suicidality (ROR, 1.63; 95% CI, 1.47-1.81) and psychological adverse events (ROR, 4.33; 95% CI, 4.17-4.49) in finasteride was identified. In sensitivity analyses, younger patients (ROR, 3.47; 95% CI, 2.90-4.15) and those with alopecia (ROR, 2.06; 95% CI, 1.81-2.34) had significant disproportionality signals for increased suicidality; such signals were not detected in older patients with BPH. Sensitivity analyses also showed that the reports of these adverse events significantly increased after 2012 (ROR, 2.13; 95% CI, 1.91-2.39). Conclusions and Relevance: In this pharmacovigilance case-noncase study, significant RORs of suicidality and psychological adverse events were associated with finasteride use in patients younger than 45 years who used finasteride for alopecia. The sensitivity analyses suggest that these disproportional signals of adverse events may be due to stimulated reporting and/or younger patients being more vulnerable to finasteride's adverse effects.