Follow-up Bone Mineral Density Testing: 2023 Official Positions of the International Society for Clinical Densitometry.

Dual-energy X-ray absorptiometry (DXA) is the gold standard method for measuring bone mineral density (BMD) which is most strongly associated with fracture risk. BMD is therefore the basis for the World Health Organization's densitometric definition of osteoporosis. The International Society for Clinical Densitometry (ISCD) promotes best densitometry practices and its official positions reflect critical review of current evidence by domain experts. This document reports new official positions regarding follow-up DXA examinations based on a systematic review of literature published through December 2022. Adoption of official positions requires consensus agreement from an expert panel following a modified RAND protocol. Unless explicitly altered by the new position statements, prior ISCD official positions remain in force. This update reflects increased consideration of the clinical context prompting repeat examination. Follow-up DXA should be performed with pre-defined objectives when the results would have an impact on patient management. Testing intervals should be individualized according to the patient's age, sex, fracture risk and treatment history. Incident fractures and therapeutic approach are key considerations. Appropriately ordered and interpreted follow-up DXA examinations support diagnostic and therapeutic decision making, thereby contributing to excellent clinical care. Future research should address the complementary roles of clinical findings, imaging and laboratory testing to guide management.

Executive Summary of the 2023 Adult Position Development Conference of the International Society for Clinical Densitometry: DXA Reporting, Follow-up BMD Testing and Trabecular Bone Score Application and Reporting.

After 15 months of preparation by task force chairs and teams, ISCD's 9th Position Development Conference (PDC) convened in Northbrook, IL, USA on March 28th and 29th, 2023 to approve new ISCD Official Positions in the topic areas of DXA Reporting, Follow-up BMD Testing and TBS Application and Reporting. Three teams of participants work to bring the PDC to fruition: the Steering Committee, Task Forces and Chairs, and the Expert Panel. To reach agreement on draft Official Positions, the PDC follows a scripted process with the UCLA/RAND Appropriateness Method (UCLA/RAM) as its foundation. Multiple rounds of data review, public debate and voting resulted in 32 new or modified Official Positions. Six companion position papers are also published along with this Executive Summary, serving as the detailed substantiation for the Official Positions. This Executive Summary reviews the personnel groups, activities and products of the 2023 PDC, with the entirety of the updated 2023 Official Positions presented in Appendix A. New Official Positions are highlighted in bold.

Effects of two different paradigms of electrical stimulation exercise on cardio-metabolic risk factors after spinal cord injury. A randomized clinical trial.

Objective: To examine the combined effects of neuromuscular electrical stimulation-resistance training (NMES-RT) and functional electrical stimulation-lower extremity cycling (FES-LEC) compared to passive movement training (PMT) and FES-LEC in adults with SCI on (1) oxygen uptake (VO2), insulin sensitivity and glucose disposal in adults with SCI; (2) Metabolic and inflammatory biomarkers; (3) skeletal muscle, intramuscular fat (IMF) and visceral adipose tissue (VAT) cross-sectional areas (CSAs). Materials and methods: Thirty-three participants with chronic SCI (AIS A-C) were randomized to 24 weeks of NMES-RT + FES or PMT + FES. The NMES-RT + FES group underwent 12 weeks of evoked surface NMES-RT using ankle weights followed by an additional 12 weeks of progressive FES-LEC. The control group, PMT + FES performed 12 weeks of passive leg extension movements followed by an additional 12 weeks of FES-LEC. Measurements were performed at baseline (BL; week 0), post-intervention 1 (P1; week 13) and post-intervention 2 (P2; week 25) and included FES-VO2 measurements, insulin sensitivity and glucose effectiveness using the intravenous glucose tolerance test; anthropometrics and whole and regional body composition assessment using dual energy x-ray absorptiometry (DXA) and magnetic resonance imaging to measure muscle, IMF and VAT CSAs. Results: Twenty-seven participants completed both phases of the study. NMES-RT + FES group showed a trend of a greater VO2 peak in P1 [p = 0.08; but not in P2 (p = 0.25)] compared to PMT + FES. There was a time effect of both groups in leg VO2 peak. Neither intervention elicited significant changes in insulin, glucose, or inflammatory biomarkers. There were modest changes in leg lean mass following PMT + FES group. Robust hypertrophy of whole thigh muscle CSA, absolute thigh muscle CSA and knee extensor CSA were noted in the NMES-RT + FES group compared to PMT + FES at P1. PMT + FES resulted in muscle hypertrophy at P2. NMES-RT + FES resulted in a decrease in total VAT CSA at P1. Conclusion: NMES-RT yielded a greater peak leg VO2 and decrease in total VAT compared to PMT. The addition of 12 weeks of FES-LEC in both groups modestly impacted leg VO2 peak. The addition of FES-LEC to NMES-RT did not yield additional increases in muscle CSA, suggesting a ceiling effect on signaling pathways following NMES-RT. Clinical trial registration: identifier NCT02660073.

Testosterone and long pulse width stimulation (TLPS) for denervated muscles after spinal cord injury: a study protocol of randomised clinical trial.

INTRODUCTION: Long pulse width stimulation (LPWS; 120-150 ms) has the potential to stimulate denervated muscles and to restore muscle size in denervated people with spinal cord injury (SCI). We will determine if testosterone treatment (TT)+LPWS would increase skeletal muscle size, leg lean mass and improve overall metabolic health in persons with SCI with denervation. We hypothesise that the 1-year TT+LPWS will upregulate protein synthesis pathways, downregulate protein degradation pathways and increase overall mitochondrial health. METHODS AND ANALYSIS: Twenty-four male participants (aged 18-70 years with chronic SCI) with denervation of both knee extensor muscles and tolerance to the LPWS paradigm will be randomised into either TT+neuromuscular electrical stimulation via telehealth or TT+LPWS. The training sessions will be twice weekly for 1 year. Measurements will be conducted 1 week prior training (baseline; week 0), 6 months following training (postintervention 1) and 1 week after the end of 1 year of training (postintervention 2). Measurements will include body composition assessment using anthropometry, dual X-ray absorptiometry and MRI to measure size of different muscle groups. Metabolic profile will include measuring of basal metabolic rate, followed by blood drawn to measure fasting biomarkers similar to hemoglobin A1c, lipid panels, C reactive protein, interleukin-6 and free fatty acids and then intravenous glucose tolerance test to test for insulin sensitivity and glucose effectiveness. Finally, muscle biopsy will be captured to measure protein expression and intracellular signalling; and mitochondrial electron transport chain function. The participants will fill out 3 days dietary record to monitor their energy intake on a weekly basis. ETHICS AND DISSEMINATION: The study was approved by Institutional Review Board of the McGuire Research Institute (ID # 02189). Dissemination plans will include the Veteran Health Administration and its practitioners, the national SCI/D services office, the general healthcare community and the veteran population, as well as the entire SCI community via submitting quarterly letters or peer-review articles. TRIAL REGISTRATION NUMBER: NCT03345576.

Effects of dose de-escalation following testosterone treatment and evoked resistance exercise on body composition, metabolic profile, and neuromuscular parameters in persons with spinal cord injury.

The dose de-escalation (DD) effects of testosterone and evoked resistance training (RT) on body composition, cardiometabolic, and neuromuscular variables were investigated. Thirteen men with chronic complete spinal cord injury (SCI) were followed for additional 16 weeks after receiving either testosterone treatment only (TT) or TT+RT. During the 16-week DD period, the TT+RT group underwent a program of once weekly electrical stimulation with gradually decreasing ankle weights and testosterone patches of 2 mg day-1 (TT+RT group). The TT only group did not receive any intervention throughout the detraining period (no-TT group). Body composition was tested using anthropometrics, dual energy X-ray absorptiometry, and magnetic resonance imaging. After an overnight fast, basal metabolic rate (BMR), lipid panel, serum testosterone, inflammatory biomarkers, glucose effectiveness, and insulin sensitivity were measured. Finally, peak isometric and isokinetic torques were measured only in the TT+RT group. All measurements were conducted at the beginning and at the end of DD. Absolute thigh muscle cross-sectional areas (CSAs) demonstrated interaction effects (p < 0.05) between the TT+RT (-8.15%, -6.5%) and no-TT (2.3%, 4.4%) groups. Similarly, absolute knee extensor muscle CSA demonstrated interaction effects (p < 0.05) between the TT+RT (-11%, -7.0%) and no-TT (2.6%, 3.8%) groups. There was a trend (p = 0.07) of increasing visceral adipose tissue (VAT) CSAs in the TT+RT (18%) and in the no-TT (16% cm2 ) groups. There was an interaction (p = 0.005) between TT+RT (decreased by 3.7%) and no-TT groups (increased by 9.0%) in BMR. No interactions were evident between groups over time for biomarkers related to carbohydrate, lipid metabolism, or inflammation. Finally, there were no changes (p > 0.05) in peak isometric or isokinetic torques and rise time following 16 weeks of the DD period in the TT+RT group. TT+RT during 16 weeks of DD was minimally effective at preventing detraining relative to no-TT on muscle size, BMR, and VAT. However, neuromuscular gains were successfully maintained.

Skeletal muscle hypertrophy and attenuation of cardio-metabolic risk factors (SHARC) using functional electrical stimulation-lower extremity cycling in persons with spinal cord injury: study protocol for a randomized clinical trial.

BACKGROUND: Persons with spinal cord injury (SCI) are at heightened risks of developing unfavorable cardiometabolic consequences due to physical inactivity. Functional electrical stimulation (FES) and surface neuromuscular electrical stimulation (NMES)-resistance training (RT) have emerged as effective rehabilitation methods that can exercise muscles below the level of injury and attenuate cardio-metabolic risk factors. Our aims are to determine the impact of 12 weeks of NMES + 12 weeks of FES-lower extremity cycling (LEC) compared to 12 weeks of passive movement + 12 weeks of FES-LEC on: (1) oxygen uptake (VO2), insulin sensitivity, and glucose disposal in adults with SCI; (2) skeletal muscle size, intramuscular fat (IMF), and visceral adipose tissue (VAT); and (3) protein expression of energy metabolism, protein molecules involved in insulin signaling, muscle hypertrophy, and oxygen uptake and electron transport chain (ETC) activities. METHODS/DESIGN: Forty-eight persons aged 18-65 years with chronic (> 1 year) SCI/D (AIS A-C) at the C5-L2 levels, equally sub-grouped by cervical or sub-cervical injury levels and time since injury, will be randomized into either the NMES + FES group or Passive + FES (control group). The NMES + FES group will undergo 12 weeks of evoked RT using twice-weekly NMES and ankle weights followed by twice-weekly progressive FES-LEC for an additional 12 weeks. The control group will undergo 12 weeks of passive movement followed by 12 weeks of progressive FES-LEC. Measurements will be performed at baseline (B; week 0), post-intervention 1 (P1; week 13), and post-intervention 2 (P2; week 25), and will include: VO2 measurements, insulin sensitivity, and glucose effectiveness using intravenous glucose tolerance test; magnetic resonance imaging to measure muscle, IMF, and VAT areas; muscle biopsy to measure protein expression and intracellular signaling; and mitochondrial ETC function. DISCUSSION: Training through NMES + RT may evoke muscle hypertrophy and positively impact oxygen uptake, insulin sensitivity, and glucose effectiveness. This may result in beneficial outcomes on metabolic activity, body composition profile, mitochondrial ETC, and intracellular signaling related to insulin action and muscle hypertrophy. In the future, NMES-RT may be added to FES-LEC to improve the workloads achieved in the rehabilitation of persons with SCI and further decrease muscle wasting and cardio-metabolic risks. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02660073 . Registered on 21 Jan 2016.

Low-Dose Testosterone and Evoked Resistance Exercise after Spinal Cord Injury on Cardio-Metabolic Risk Factors: An Open-Label Randomized Clinical Trial.

The purpose of the work is to investigate the effects of low-dose testosterone replacement therapy (TRT) and evoked resistance training (RT) on body composition and metabolic variables after spinal cord injury (SCI). Twenty-two individuals with chronic motor complete SCI (ages 18-50 years) were randomly assigned to either TRT+RT (n = 11) or TRT (n = 11) for 16 weeks following a 4 -week delayed entry period. TRT+RT men underwent twice weekly progressive RT using electrical stimulation with ankle weights. TRT was administered via testosterone patches (2-6 mg/day). Body composition was tested using anthropometrics, dual energy x-ray absorptiometry, and magnetic resonance imaging. After an overnight fast, basal metabolic rate (BMR), lipid panel, serum testosterone, adiponectin, inflammatory and anabolic biomarkers (insulin-like growth factor-1 and insulin-like growth factor-binding protein 3 [IGFBP-3]), glucose effectiveness (Sg), and insulin sensitivity (Si) were measured. Total body lean mass (LM; 2.7 kg, p < 0.0001), whole muscle (p < 0.0001), and whole muscle knee extensor cross-sectional areas (CSAs; p < 0.0001) increased in the TRT+RT group, with no changes in the TRT group. Visceral adiposity decreased (p = 0.049) in the TRT group, with a trend in the TRT+RT (p = 0.07) group. There was a trend (p = 0.050) of a 14-17% increase in BMR following TRT+RT. Sg showed a trend (p = 0.07) to improvement by 28.5-31.5% following both interventions. IGFBP-3 increased (p = 0.0001) while IL-6 decreased (p = 0.039) following both interventions, and TRT+RT suppressed adiponectin (p = 0.024). TRT+RT resulted in an increase in LM and whole thigh and knee extensor muscle CSAs, with an increase in BMR and suppressed adiponectin. Low-dose TRT may mediate modest effects on visceral adipose tissue, Sg, IGFBP-3, and IL-6, independent of changes in LM.

Serum testosterone levels may influence body composition and cardiometabolic health in men with spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To establish the association between serum testosterone (T) levels, biomarkers of cardiometabolic health and regional body composition variables after spinal cord injury (SCI). SETTING: Medical research center. METHODS: Metabolic and body composition measurements were collected from thirty-six men with chronic motor complete SCI. Serum T, carbohydrate, and lipid profiles were measured after an overnight fast. Body composition was measured using anthropometrics, dual-energy X-ray absorptiometry, and magnetic resonance imaging. Participants were evenly classified into tertiles based on their serum T levels into low, mid-normal and normal ranges. RESULTS: Low, mid-normal, and normal range serum T were 288.8 ± 84.9 ng/dL, 461.0 ± 52.5 ng/dL and 648.0 ± 53.5 ng/dL, respectively. Low range serum T group had greater total (9.6%, P = 0.04) percentage fat mass and visceral adipose tissue (VAT) area (72%, P = 0.01) compared to normal range serum T group. Serum T was related to the absolute whole thigh muscle area (r = 0.40, P < 0.05) after controlling for body mass index. Serum T was negatively related to fasting plasma glucose (r = -0.46, P = 0.006) and insulin (r = -0.42, P = 0.01), HbA1c (r = -0.39, P = 0.02) and triglycerides (r = -0.36, P = 0.03). CONCLUSION: Men with low serum T have more unfavorable body composition and cardiometabolic health outcomes after SCI. Testosterone replacement therapy may serve as a potential strategy in preventing cardiometabolic disorders after SCI.

Body composition changes with testosterone replacement therapy following spinal cord injury and aging: A mini review.

Context Hypogonadism is a male clinical condition in which the body does not produce enough testosterone. Testosterone plays a key role in maintaining body composition, bone mineral density, sexual function, mood, erythropoiesis, cognition and quality of life. Hypogonadism can occur due to several underlying pathologies during aging and in men with physical disabilities, such as spinal cord injury (SCI). This condition is often under diagnosed and as a result, symptoms undertreated. Methods In this mini-review, we propose that testosterone replacement therapy (TRT) may be a viable strategy to improve lean body mass (LBM) and fat mass (FM) in men with SCI. Evidence Synthesis Supplementing the limited data from SCI cohorts with consistent findings from studies in non-disabled aging men, we present evidence that, relative to placebo, transdermal TRT can increase LBM and reduce FM over 3-36 months. The impact of TRT on bone mineral density and metabolism is also discussed, with particular relevance for persons with SCI. Moreover, the risks of TRT remain controversial and pertinent safety considerations related to transdermal administration are outlined. Conclusion Further research is necessary to help develop clinical guidelines for the specific dose and duration of TRT in persons with SCI. Therefore, we call for more high-quality randomized controlled trials to examine the efficacy and safety of TRT in this population, which experiences an increased risk of cardiometabolic diseases as a result of deleterious body composition changes after injury.

Effects of Testosterone and Evoked Resistance Exercise after Spinal Cord Injury (TEREX-SCI): study protocol for a randomised controlled trial.

INTRODUCTION: Individuals with spinal cord injury (SCI) are at a lifelong risk of obesity and chronic metabolic disorders including insulin resistance and dyslipidemia. Within a few weeks of injury, there is a significant decline in whole body fat-free mass, particularly lower extremity skeletal muscle mass, and subsequent increase in fat mass (FM). This is accompanied by a decrease in anabolic hormones including testosterone. Testosterone replacement therapy (TRT) has been shown to increase skeletal muscle mass and improve metabolic profile. Additionally, resistance training (RT) has been shown to increase lean mass and reduce metabolic disturbances in SCI and other clinical populations. METHODS AND ANALYSIS: 26 individuals with chronic, motor complete SCI between 18 and 50 years old were randomly assigned to a RT+TRT group (n=13) or a TRT group (n=13). 22 participants completed the initial 16-week training phase of the study and 4 participants withdrew. 12 participants of the 22 completed 16 weeks of detraining. The TRT was provided via transdermal testosterone patches (4-6 mg/day). The RT+TRT group had 16 weeks of supervised unilateral progressive RT using surface neuromuscular electrical stimulation with ankle weights. This study will investigate the effects of evoked RT+TRT or TRT alone on body composition (muscle cross-sectional area, visceral adipose tissue, %FM) and metabolic profile (glucose and lipid metabolism) in individuals with motor complete SCI. Findings from this study may help in designing exercise therapies to alleviate the deterioration in body composition after SCI and decrease the incidence of metabolic disorders in this clinical population. ETHICS AND DISSEMINATION: The study is currently approved by the McGuire VA Medical Center and Virginia Commonwealth University. All participants read and signed approved consent forms. Results will be submitted to peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: Pre-result, NCT01652040.

Disruption in bone marrow fat may attenuate testosterone action on muscle size after spinal cord injury: a case report.

BACKGROUND: Mesenchymal stem cells can be differentiated into muscle satellite cells. Testosterone replacement therapy (TRT) promotes the differentiation of satellite cells into muscle cells. CASE REPORT: A 31-year-old male with a T4 complete chronic spinal cord injury (SCI) had fixation for a mid-shaft fracture of the left femur. The participant received transdermal testosterone patches (4 mg/day) daily for 16 weeks. Skeletal muscle and yellow bone marrow adiposity cross-sectional areas (CSAs) of both thighs were measured using magnetic resonance imaging. CLINICAL REHABILITATION IMPACT: The yellow bone marrow CSA was 67-69% lower in the left femur compared to the right femur. Following intervention, a discrepancy was noted between the whole skeletal muscle CSAs of the right (+13%) and left (+6%) thighs. The right knee extensor CSA increased by 7% with no changes in the left CSA. Disruption in bone marrow fat may attenuate the systemic effects of TRT on muscle size.

Military Deployment May Increase the Risk for Traumatic Brain Injury Following Deployment.

OBJECTIVE: To compare rates of traumatic brain injury (TBI) diagnosis before and after overseas military deployment. DESIGN: We conducted a retrospective examination of a cohort of 119 353 active duty US military service members (Army, Navy, Air Force, and Marines) whose first lifetime overseas deployment began at any time between January 1, 2011, and December 31, 2011, and lasted at least for 30 days. For this cohort, TBI diagnoses were examined during the 76 weeks prior to deployment, during deployment, and 76 weeks following the end of deployment. MAIN MEASURES: 4-week rates of TBI diagnosis. RESULTS: The risk of being diagnosed with TBI within 4 weeks after returning from deployment was 8.4 times higher than the average risk before deployment. The risk gradually decreased thereafter up to 40 weeks postdeployment. However, during the 41 to 76 weeks following deployment, risk stabilized but remained on average 1.7 times higher than before deployment. CONCLUSION: An increased rate of TBI diagnosis following deployment was identified, which may be partly due to delayed diagnosis of TBIs that occurred while service members were deployed. Also, the increased rate may partly be due to riskier behaviors of service members following deployment that results in an increased occurrence of TBIs.

Frequency of Dietary Recalls, Nutritional Assessment, and Body Composition Assessment in Men With Chronic Spinal Cord Injury.

OBJECTIVES: To assess different frequencies of dietary recalls while evaluating caloric intake and the percentage of macronutrients in men with spinal cord injury (SCI) and to examine the relations between caloric intake or percentage of macronutrients and assessment of whole and regional body composition using dual-energy x-ray absorptiometry. DESIGN: Cross-sectional and longitudinal. SETTING: Laboratory and hospital. PARTICIPANTS: Men with chronic (>1 y postinjury) motor complete SCI (N=16). INTERVENTIONS: Participants were asked to turn in a 5-day dietary recall on a weekly basis for 4 weeks. The averages of 5-, 3-, and 1-day dietary recalls for caloric intake and percentage of macronutrients (carbohydrates, fat, protein) were calculated. Body composition was evaluated using whole-body dual-energy x-ray absorptiometry. After overnight fast, basal metabolic rate (BMR) was evaluated using indirect calorimetry and total energy expenditure (TEE) was estimated. MAIN OUTCOME MEASURES: Caloric intake, percentage of macronutrients, BMR, and body composition. RESULTS: Caloric intake and percentage of macronutrients were not different after using 5-, 3-, and 1-day dietary recalls (P>.05). Caloric intake was significantly lower than TEE (P<.05). The percentage of fat accounted for 29% to 34% of the whole and regional body fat mass (P=.037 and P=.022). The percentage of carbohydrates was positively related to the percentage of whole-body lean mass (r=.54; P=.037) and negatively related to the percentage of fat mass. CONCLUSIONS: The frequency of dietary recalls does not vary while evaluating caloric intake and macronutrients. Total caloric intake was significantly lower than the measured BMR and TEE. Percentages of dietary fat and carbohydrates are related to changes in body composition after SCI.

Opioid endocrinopathy.

OBJECTIVE: The use of prescription opioids has increased dramatically over the past 20 years. Opioids appear to affect multiple endocrine pathways leading to abnormal levels of different hormones such as testosterone, cortisol, and prolactin (PRL). In this article, we review the current data regarding opioid effects on the hypothalamus, pituitary, and bone metabolism. METHODS: We conducted a PubMed search for articles regarding opioids and each of the following subjects: testosterone, estrogen, cortisol, thyroid, growth hormone (GH), and bone. Most articles were primary source studies conducted between 1980 and 2014. Articles were included if studies were conducted within the time period, published in English, and available as full-length articles. Case reports were reviewed, but controlled studies were given more weight. RESULTS: Opioids appear to affect each of the pituitary hormone pathways in addition to altering bone metabolism. The most commonly reported and substantial effect was hypogonadism in both sexes; however, suppression of the adrenal axis may be more common than initially thought. Although some studies report a change in thyroid and GH levels, overall effects have not been thoroughly studied. There is some evidence for increased fracture risk, possibly mediated by hypogonadism and fall risk. CONCLUSION: More research is needed to determine which opioids are more likely to cause endocrine dysfunction and which patients need to be screened and treated. Also unknown is the length of time to the development of hormonal changes after starting opioid therapy and if cessation of opioid therapy can normalize hormone levels.

Clinical utility of denosumab for treatment of bone loss in men and women.

While most older patients with osteoporosis are treated with antiresorptive bisphosphonates such as alendronate, risedronate, ibandronate, and zoledronic acid, such drugs have side effects, remain in bone for extended periods, and lead to poor adherence to chronic treatment. Denosumab is a humanized monoclonal antibody and antiresorptive agent that works by decreasing the activity of the receptor activator of nuclear factor kappa B ligand. In major trials in postmenopausal women, denosumab increased bone mineral density by dual energy x-ray absorptiometry in the spine, hip, and distal third of the radius and decreased vertebral, nonvertebral, and hip fractures. Denosumab is administered by subcutaneous injection every six months, suggesting that adherence may be improved with such therapy. In addition, pharmacokinetic studies measuring bone turnover markers imply that the antiresorptive effect diminishes more quickly over time. Whether these properties will lead to fewer long-term side effects needs to be proven. Denosumab has also been studied in men with prostate cancer treated with androgen deprivation therapy. These men, at high risk for fracture, also have increases in spine, hip, and forearm dual energy x-ray absorptiometry, as well as fewer morphologic vertebral fractures on x-ray. Denosumab is approved for postmenopausal women with osteoporosis in the US and Europe and for men on androgen deprivation therapy in Europe.