• December 31, 2012 – 13:15

    Zoledronic acid decreases the risk of vertebral fracture in osteoporotic men

    Osteoporotic fractures in men are a major health issue. However, studies involving men with osteoporosis have focused on the surrogate outcomes such as bone mineral density (BMD) and biochemical bone turnover markers (BTM). By contrast, data from randomized, double-blind, clinical trials assessing anti-fracture efficacy in men are lacking. Therefore, the recent multicenter randomized prospective trial assessing the effect of zoledronic on the risk of vertebral fracture in osteoporotic men as a primary end point is of particular interest. Previously, zoledronic acid reduced highly significantly fracture incidence in postmenopausal women and increased BMD in several studies carried out in men with low BMD.

    This study was performed in 1199 men aged 50 to 85. Eligible men without fracture had BMD T-score≤-2.5 at total hip, femoral neck or lumbar spine. Eligible men with fracture had BMD T-score≤-1.5 and one to three vertebral fractures. (T-score was calculated as the number of SDs below or above the mean in young men.) Men were randomly assigned to receive zoledronic acid at a dose of 5 mg or placebo administered as a 15 to 30 minute i.v. infusion at baseline and month 12. All men received daily calcium (1000-1500 mg) and vitamin D (800-1200 IU). Men were followed up for 24 months; almost 90% of men completed the study.

    Vertebral fracture incidence was 67% lower in the zoledronic acid group compared with the placebo group (RR= 0.33, 95% confidence interval: 0.16-0.70, p=0.002). Loss of height was smaller in the zoledronic acid group vs placebo group (2.2 vs 4.5 mm, p=0.002). Zoledronic acid induced a significant increase in BMD at the lumbar spine, total hip and femoral neck. The difference vs the placebo group was statistically significant for all the skeletal sites. Serum levels of bone formation markers (N-terminal propeptide of type I procollagen [PINP], bone-specific alkaline phosphatase) were significantly lower in men who received zoledronic acid than in men who received placebo. Levels of bone resorption markers (serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen) were also significantly lower in men receiving zoledronic acid. The effect of zoledronic acid on the fracture incidence, BMD and BTM levels (except PINP) was similar in men with testosterone levels of >350 ng/dl and in men with testosterone levels of 350 ng/dl or less.

    The most frequent adverse effect of zoledronic acid was the influenza-like syndrome (pyrexia, myalgia, arthralgia, headaches, chills, pain in the extremities). It occurred in 15% of men and subsided spontaneously. No case of osteonecrosis of the jaw and no case of subtrochanteric or atypical fracture were observed. No significant differences were observed between the groups with respect to death, cardiac arrhythmias or renal dysfunction, except for myocardial infarction which was slightly more frequent in the zoledronic acid group. However, the analysis of each case showed that these events were not related to the study drug.

    A key strength of this study was a population that was large enough to detect the anti-fracture efficacy of zoledronic acid in the osteoporotic men in the framework of a placebo-controlled, randomized, prospective trial. Zoledronic acid increased BMD and decreased bone turnover rate. The effect of zoledronic acid was independent of total testosterone levels. The reduction of fracture risk, the increase in BMD, the decrease in bone turnover rate and the safety profile were similar to those found in postmenopausal women treated with zoledronic acid. These results provide support for the value of antiresorptive therapy in osteoporotic men. They may also contribute to a better definition of treatment recommendations of osteoporosis in men.

    Reference: Boonen S et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med 2012, 367:1714-1723.

  • December 28, 2012 – 20:05

    Sex Disparities in Cancer Mortality: The Risks of Being a Man in the US

    A novel descriptive epidemiologic study that will be published in the Journal of Urology is the first study to quantify the differential mortality rates between sexes from non-gender-specific cancers and compare their cancer stage distribution.  This study hypothesized that men die more commonly from their cancers than their female counterparts, even after the increased male incidence is accounted for.

    Between 1975 and 2004, the National Institutes of Health reported the total cancer burden in the US was higher in males compared to females with an incidence ratio of 1.14; when sex-specific cancers were excluded, the ratio increased to 1.77.  Moreover, the yearly male to female cancer mortality ratio was 1.89.

    The authors determined that over the last 10 years, the number of men diagnosed with cancer has consistently been 1.5 times greater than the rate for women.  While the overall mortality rates attributable to cancer have decreased over 10% for both men and women, the mortality rate for men still exceeds that for women, even for the same type of cancer.  While a descriptive study does not explain the reasons for gender differences in oncologic outcomes, previous studies have highlighted differences in modifiable risk factors, differences in healthcare utilization, and intrinsic biological differences between the sexes.  In the US, 27% of men report not being evaluated by a physician within the last year compared to 14% of women. 

    In summary, the authors concluded that men develop and die more often from cancers that should affect men and women equally.  However, the number of men diagnosed with non-gender-specific cancer is 50% higher than the number of women diagnosed with cancer.  After controlling for higher male incidence of cancers, men have a 12.6% higher mortality rate than women for the same types of cancer.

    Reference: Najari BB, Rink M, Li PS, Karakiewicz PI, Scherr DS, Shabsigh R, Meryn S, Schlegel PN, Shariat SF.  Sex disparities in cancer mortality: the risks of being a man in the US.  J Urol 2012, doi:10.1016/j.juro.2012.11.153.

  • December 16, 2012 – 19:59

    Using MRI to Validate Scoring System for Prostate Cancer

    Until recently, wide variations in acquisition protocols and the lack of robust diagnostic criteria make magnetic resonance imaging (MRI) detection of prostate cancer (PCa) one of the most challenging fields in radiology and urology.  A recent trial sought to validate the recently proposed European Society of Urogenital Radiology (ESUR) scoring system for multiparametric MRI (mpMRI) of the prostate, taking advantage of the development of MRI/transrectal ultrasonography (TRUS) fusion technology to evaluate the predictive values of the ESUR scoring system in a cohort of 129 consecutive patients with a total of 1514 cores.

    A prospective study from May to November 2011, 129 consecutive patients with a history of negative TRUS-guided biopsies of the prostate were referred for repeat biopsies. A total of 129 consecutive patients (mean age: 64.7 ± 6.9 yr [range: 47–79]) were enrolled for repeat biopsies (mean number of prior biopsy sessions: 1.3 ± 0.7 [range: 1–4]). Digital rectal examination (DRE) was unremarkable in 107 patients and suspicious in 22 patients (nodule smaller than half a lobe). Mean prostate-specific antigen (PSA) at biopsy was 9.6 ± 5.9 ng/ml (range: 2.7–40.0), and prostate volume (MRI estimate) was 51.1 ± 28.1 cm3 (range: 12–192).  A threshold of ESUR-S (EUR Score Sum) ≥ 9 exhibited the following characteristics: sensitivity: 73.5%; specificity: 81.5%; positive predictive value: 38.2%; negative predictive value: 95.2%; and accuracy: 80.4%.

    Although this trial was not designed to compare repeat biopsy strategies, more targeted cores than random systematic cores were found to be positive for cancer (36.3% compared with 4.9%, p < 0.00001).  Given the inherent challenges of choosing patients for repeat biopsy, the ESUR scoring system was shown to provide clinically relevant stratification of the risk of showing PCa in a given location.  Although the ESUR system was based on literature evidence and consensus, it still lacked validation in a real-life setting.  Only a few cancers were detected solely by random core biopsy specimens, as opposed to the larger yield of cores targeted at mpMRI-suspicious locations.  The validation of the ESUR scoring system and precise targeting of TRUS-guided biopsies now provide convincing leverage in the challenging field of PCa diagnosis.

    Reference: Portalez D, Mozur P, Cornud F, et al.  Validation of the European Society of Urogenital Radiology Scoring System for Prostate Cancer Diagnosis on Multiparametric Magnetic Resonance Imaging in a Cohort of Repeat Biopsy Patients.  Eur J Urol 2012;62:986-996.

  • December 15, 2012 – 21:58

    Bone Microarchitecture and Obese Men

    Obesity has long been considered to be “protective” against osteoporosis, largely due to mechanical loading and adipocyte-derived hormones.  More recent evidence implicates the accumulation of abdominal and visceral fat with bone loss in middle-aged men.  Obesity dysregulates the GH/IGF-1 and HPG axes, both of which are important regulators of bone homeostasis.  Testosterone, which promotes bone mineral density (BMD) and muscle mass, is often reduced in obese men, whereas estrogen levels increase proportionally to body weight.

    A recent study sought to determine hormonal and body composition predictors of bone microarchitecture in young and healthy men with abdominal obesity.  The authors hypothesized that obese men with significant abdominal adiposity would have impaired bone microarchitecture and strength and increased bone marrow fat associated with dysregulation of the GH/IGF-1 and gonadal steroid axes.  This cross-sectional study evaluated 35 men mean age 33.8 years and mean body mass index 36.5 kg/m2.

    A high degree of visceral adipose tissue was found to be inversely associated with mechanical properties of bone, whereas bone marrow fat was inversely associated with cortical parameters.  Free estradiol was positively correlated with total bone density and free testosterone was positively associated with trabecular thickness yet inversely associated with trabecular number. 

    The authors concluded that visceral adipose tissue and bone marrow fat are negative predictors and muscle mass is a positive predictor of bone microarchitecture and mechanical properties in obese men.  Testosterone, estradiol, and GH are positive determinants of trabecular microarchitecture, and IGF-I is a positive determinant of cortical microarchitecture.  This supports the notion that VAT is detrimental to bone and that decreased GH and testosterone, characteristic of male obesity, may exert deleterious effects on microarchitecture, whereas higher estradiol may be protective.  Limitations of this study include a small number of test subjects, cross-sectional study design (limits ability to prove causality), and since the study was limited to obese men, the resultant data cannot be extrapolated to normal-weight men or women.  Larger studies across male and female populations are necessary to draw more substantial conclusions regarding these relationships.

    Reference: Bredella MA, Lin E, Gerweck, AV, et al.  Determinants of bone microarchitecture and mechanical properties in obese men.  J Clin Endo Metab 2012;97(11):4115-4122.

  • December 10, 2012 – 13:55

    Viagra on the Internet: Is It Real?

    The rate of availability of counterfeit medications is increasing dramatically worldwide, a substantial portion of which is attributable to the purchase of medications via the Internet.  A recent study sought to assess the requirement for prescription, cost, origin, and content of medications sold via the Internet and purporting to be the PDE5 inhibitor sildenafil citrate (VIAGRA®, Pfizer Inc, New York, NY, USA).

    The World Health Organization (WHO) estimates that medicines purchased over the Internet from sites that conceal their physical address are counterfeit ≥ 50% of the time.  In a European study, 62% of medicines ordered via the Internet and without a prescription were substandard or counterfeit.  In an analysis of samples seized worldwide for suspicion of being counterfeit Viagra, 83% of the samples ordered via the Internet were found to be counterfeit.  Recreational users and abusers of PDE5 inhibitor medication also report using the Internet as a source channel.

    In this trial, Pfizer monitored top search results for the query “buy Viagra” on two leading Internet search engines in March 2011.  Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer.  Tablets received were assessed for chemical composition.  No website examined required a prescription for purchase or a health screening survey; 90% offered illegal “generic Viagra.”  Cost per tablet ranged from $3.28–$33.00.  Shipment origins of purchases were Hong Kong (N = 11), the United States (N = 6), and the United Kingdom (N = 2) as well as Canada, China, and India (N = 1 each).  Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address.  

    Of 22 sample tablets examined, 17 (77%) were counterfeit, 4 (18%) were authentic, and 1 (5%) was an illegal generic. Counterfeit tablets were analyzed for sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra, and contents varied between 30% and 50% of the label claim.  Contaminants such as talcum powder, commercial paint, printer ink, and other active pharmaceutical entities have been found in counterfeit Viagra.  Although non-genuine “fillers” were not further assessed in this study, filler ingredients are associated with significant risk because they generally comprise the majority of tablet weight.

    This study provides additional evidence that online sites claiming to sell authentic Viagra are not often legitimate. Besides the health risks possible from ingesting counterfeit products, credit card fraud and identity theft are also concerns with Internet ordering of medications.  There is evidence that Web sites that illegally supply POM without a prescription manipulate web searching to preferentially direct consumers to their fraudulent sites.  Consumers should use extreme caution when purchasing Viagra, as well as any other medications, via the Internet.

    Reference: Campbell N, Clark JP, Stecher VJ, Goldstein I.  Internet-ordered Viagra (sildenafil citrate) is rarely genuine.  J Sex Med 2012;9(11):2943-2951.

  • October 30, 2012 – 21:50

    Recent review on the erectile dysfunction in Lancet

    This paper describes several aspects of erectile dysfunction (ED). The ED incidence increases with age and the number of older men is on the rise due to the increasing life expectancy. Therefore, the number of men with ED increases and ED became a problem of public health. Vasculogenic ED is particularly important. Symptomatic cardiovascular diseases (CVD), such as ischemic heart disease or hypertension, are often associated with ED. It is partly related to cardiovascular risk factors (smoking, sedentary lifestyle, obesity, diabetes, dyslipidaemia) and to medications (thiazides, b-blockers, quinidine, amiodrone). In men aged <60 without known CVD, ED may be a marker of cardiovascular status. A man in his forties who reports an onset of ED should be considered a “cardiac patient” until proven otherwise.

    The most important part of the diagnosis of ED is history taking. In case of psychogenic ED it helps to establish predisposing, precipitating and maintaining factors. In some cases, it may reveal severe psychosocial disorders necessitating psychiatric therapy. It also helps to identify the presence of factors increasing the risk of ED (lifestyle, concomitant diseases, drugs). The assessment of the patient's opinions on his sexual performance, masculinity, penile length and on his attitude to sex should be a part of history taking. Interviewing the patient's partner is also advisable. Local physical examination permits to assess organic congenital and acquired diseases. Laboratory investigations should comprise fasting blood sugar, lipid profile and testosterone. The patient's cardiovascular risk should be also assessed.

    The therapeutic choice should be based on the specific problems of the patient. Psychosexual therapy (of the patient or of the couple) is recommended in the psychogenic ED. However, the efficacy of this treatment has not been appropriately investigated. Smoking cessation, weight loss and physical exercise improve erectile function and augment the efficacy of other types of therapy. Selective phosphodiesterase type 5 inhibitors (PDE5-Is) are the mainstay of the treatment of ED. However, their efficacy is 65% and they are contraindicated in men with severe CVD or taking some types of drugs. The failure of PDE5-Is may be related to the underlying diseases (e.g. diabetes, severe CVD, hypogonadism). Thus, its management should include the treatment of the underlying disease. Decision on other options (intracavernosal injection, vacuum constrictive device, penile prosthesis) depends on the health status of the patient, his preferences and on the failure or side effects of other therapeutic methods.

    This paper presents useful hints for the management of ED. It will probably elicit a discussion of experts in the field which may be interesting for physicians in charge of patients with ED.

    Reference: Shamloul R, Ghanem H. Erectile dysfunction. Lancet. 2012 Oct 4. pii: S0140-6736(12)60520-0. doi: 10.1016/S0140-6736(12)60520-0.

  • September 29, 2012 – 11:30

    Costs of Hypogonadism

    Prevalence studies have shown that nearly 39% of men over the age of 45 presenting to primary care offices have signs and symptoms of hypogonadism.  While prior studies on male hypogonadism have demonstrated a significant economic and quality-of-life burden, these previous trials have not evaluated the direct or indirect impacts of hypogonadism on healthcare utilization and costs in US men.

    A recent study sought to compare direct healthcare and indirect (disability leave or medical absence) costs between privately insured US men with hypogonadism and controls without hypogonadism.  The study included a sample size of 4,269 employed men ages 35-64 with 2 or more hypogonadism diagnoses.  Employees and controls had a mean age of 51 years. 

    This study demonstrated that men with hypogonadism had higher statistically significant comorbidity rates compared to controls with respect to hyperlipidemia, hypertension, musculoskeletal pain, and human immunodeficiency virus infection, which are directly related to increased financial costs.  Men with hypogonadism had higher inpatient hospitalizations, emergency department visits, and prescription drug use compared to controls.  However, the inpatient and emergency department evaluations did not substantially increase annual medical care utilization.  Men with hypogonadism had higher direct and indirect costs compared to controls, $14,118 versus $5,272, respectively.

    The authors admit that this study has limitations relative to retrospective claims data analysis.  For example, controlling for a comorbid diagnosis of obesity is challenging secondary to infrequency of reporting in billing claims.  Thus, the authors used 2 or more comorbid conditions associated with hypogonadism in the test group.  It is also probable that patients with additional comorbidities are likely to be labeled as having hypogonadism as an incidental results of laboratory evaluation.  Since the analysis in this study examined men who held private insurance, it limits the ability to generalize across populations of hypogonadal men with Medicare or Medicaid.

    Reference: Kaltenboeck A, Foster S, Ivanova J, et al.  The direct and indirect costs among US privately insured employees with hypogonadism.  J Sex Med 2012;9:2438-2447.

  • September 29, 2012 – 11:28

    Do PDE5 Inhibitors Improve Premature Ejaculation?

    Premature ejaculation (PE) remains a highly prevalent and complex syndrome both to define and effectively treat in millions of men worldwide.  While treatment is largely via pharmacotherapy with off-label indications, a recent systematic review sought to investigate the therapeutic role of PDE5 inhibitors.

    Twenty-nine manuscripts that examined proposed mechanisms of action and 14 manuscripts that reported data from clinical trials were identified and reviewed.  The review identified commonly reported supposed, central, and peripheral mechanisms of action of PDE5 inhibitors, predominantly centered on the role of nitrous oxide (NO) relative to second messenger pathways (e.g. CGMP) in the central nervous system and its relationship to smooth muscle in peripheral tissue.

    Two different meta-analyses were performed including 1) PDE5 inhibitor monotherapy compared to placebo and 2) PDE5 inhibitor + SSRI versus placebo.  The first meta-analysis found a significant effect of the PDE5 inhibitor treatment compared to placebo, while there was greater variability in the results in the group that received combination therapy.  Overall, there was felt to be insufficient clinical evidence to support the use of PDE5 inhibitors in the treatment of PE.

    Reference: Asimakopoulos AD, Miano R, Agro EF, et al.  Does current scientific and clinical evidence support the use of phosphodiesterase type 5 inhibitors for the treatment of premature ejaculation?  A systematic review and meta-analysis.  J Sex Med 2012;9:2404-2416.

  • September 29, 2012 – 11:25

    Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline

    Hypertriglyceridemia is a known risk factor for both cardiovascular disease and pancreatitis. The National Cholesterol Education Program Adult Treatment Panel  (NCEP ATP) III Guidelines from 2001 have recommended screening adults for hypertriglyceridemia as part of a fasting lipid panel at least once every 5 years.  A recent Endocrine Society Task Force convened to review existing guidelines for evaluation and treatment of hypertriglyceridemia. 

    The Task Force recommends the following:

    • Diagnosis of hypertriglyceridemia should be based upon fasting triglyceride levels
    • Measurement of aoplipoprotein B or lipoprotein (a) may be of value
    • Patients with elevated fasting triglycerides should be evaluated for secondary causes of hyperlipidemia including endocrine conditions and medications
    • Patients with primary hypertriglyceridemia should be evaluated for additional cardiovascular risk factors including central obesity, hypertension, impaired glucose metabolism, and liver dysfunction
    • Patients with primary hypertriglyceridemia should be evaluated for a family history of dyslipidemia and cardiovascular disease to assess genetic causes as well as future risk
    • Lifestyle therapy, including dietary counseling and physical activity, should be promoted to achieve weight reduction in obese patients
    • For severe hypertriglyceridemia (> 1000mg/dl), pharmacotherapy should be prescribed along with dietary fat and simple carbohydrate reduction to reduce the risk of pancreatitis
    • Fibrates should be used as first-line agents for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis
    • Fibrates, niacin, and α-3 fatty acids alone or in combination with statins should be considered as treatment options in patients with moderate to severe hypertriglyceridemia
    • Statins should not be used as monotherapy for severe or very severe hypertriglyceridemia, but may be used for treatment of moderate hypertriglyceridemia when indicated to modify cardiovascular risk

    Reference: Berglund L, Brunzell JD, Goldberg AC, et al.  Evaluation and treatment of hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline

  • September 28, 2012 – 11:24

    Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy

    Since the causative link between prostate cancer and androgen dependence was first highlighted in 1941, androgen deprivation has been the mainstay of treatment for men with metastatic prostate disease. Recently, the NCIC Clinical Trials Group convened a phase 3 trial with a primary end point of overall survival to investigate intermittent versus continuous androgen deprivation in men with rising PSA levels after radiotherapy and no evidence of metastatic disease.

    This trial enrolled 1386 men, of whom 690 were randomly assigned to intermittent therapy and 696 to continuous therapy with a mean follow-up of 6.9 years.  In the intermittent therapy group, 35% of men experienced full testosterone recovery, with potential benefits regarding physical function, fatigue, urinary problems, hot flashes, decreased libido, and erectile function.  Median overall survival was 8.8 years and 9.1 years in the intermittent- and continuous-therapy groups, respectively (hazard ratio for death = 1.02).

    Intermittent androgen deprivation was found to be non-inferior (nearly comparable) to continuous therapy with respect to overall survival in men with metastatic prostate cancer.  The authors concluded that this trial raised several provocative issues in that the non-significant increase in deaths from other causes among patients in the continuous-therapy group could not be attributed to any specific non-toxic effects.  However, the cost savings from reduction in drug use in the intermittent-therapy group could have been partially offset by the closer follow-up.  While an intermittent approach to androgen deprivation does not necessarily yield inferior survival, some benefits in quality of life were observed.

    Reference: Crook JM, O'Callaghan CJ, Duncan G, et al.  Intermittent androgen suppression for rising PSA level after radiotherapy.  NEJM 2012;367:895-903.