Are 5-α Reductase Inhibitors Associated with Hip Fractures?

Pharmacology Watch

In the issue: 5-α reductase inhibitors and hip fracture in men; the effects of drug-reimbursement policy on outcomes; new guidelines for type 2 diabetes; beta-blocker-associated brady-cardia is linked to CVD events; FDA Updates.

Do 5-α reductase inhibitors affect bone density in men? These drugs, which include finasteride (Proscar®) and dutasteride (Avodart®), have been used for more than a decade to treat benign prostatic hyperplasia (BPH). The drugs block the conversion of testosterone to dihydrotestosterone, the more powerful androgenic agent, which is responsible for secondary sex characteristics, but also adverse effects such as BPH, acne, and male pattern baldness. The 5-α reductase inhibitors shrink prostatic tissue and improve BPH symptoms over time and also can be associated with erectile dysfunction and gynecomastia. Recently researchers looked at the correlation between use of finasteride and bone health, which is highly dependent on steroid pathways. Researchers from Kaiser Permanente in Southern California performed a population-based case-control study of 7076 men age 45 and older with incident hip fractures over a 10-year period. Control patients were 7076 men without hip fracture. The rate of BPH was the same in both groups. There was no suggestion of a dose-response relationship between exposure to 5-α reductase inhibitors and hip fracture (P = 0.12). Interestingly, there was slightly higher rate of a-blocker use in the hip fracture group. The authors conclude that exposure to 5-α reductase inhibitors is not associated with increased risk of hip fracture; in fact, there was a trend toward a protective effect. The increased risk associated with exposure to α-blockers (which can cause orthostasis) needs further investigation (Jacobsen SA, et al. Association between 5-alpha reductase inhibition and risk of hip fracture. JAMA 2008;300:1660-1664).

Effect of drug-reimbursement policy on health care outcomes

Researchers recently looked at clopidogrel use and health outcomes for cardiac patients before and after a Canadian provincial government changed its prior-authorization policy for medications to a more liberal limited-use policy. Researchers looked at all patients 65 years or older with acute myocardial infarction who underwent PCI with stenting. The primary outcome was composite rate of death, recurrent acute myocardial infarction, PCI, and coronary artery bypass grafting at one year. After the change in benefits, the rate of clopidogrel use for 30 days after hospitalization increased from 35% to 88% and the mean time to first dispensing of clopidogrel decreased from 9 days to 0 days. The one-year composite cardiovascular outcome decreased from 15% in the prior-authorization group to 11% in the limited-use group (P = 0.02). The authors conclude that removal of prior-authorization leads to improvement in timely access to clopidogrel after coronary stenting and improved cardiovascular outcomes (Jackevicius CA, et al. Cardiovascular outcomes after a change in prescription policy for clopidogrel. N Engl J Med 2008;359:1802-1810).

Updated guidelines for type 2 diabetes

The American Diabetes Association and the European Association for the Study of Diabetes have updated their treatment guidelines and algorithms for the treatment of type 2 diabetes. Published simultaneously in Diabetes Care and the European journal Diabetologia, the guidelines update the initial August 2006 guideline and the January 2008 update to reflect safety issues surrounding the thiazolidinediones (TZDs) and also introduces new classes of medications to the algorithm. Retained as step 1 therapy are lifestyle interventions and metformin. Step 2 therapy includes insulin and sulfonylureas, while TZDs have been dropped as initial therapy. Of the two TZDs, only pioglitazone (Actosä) is recommended by the guideline. Safety concerns regarding rosiglitazone (Avandia®) have resulted in the guideline group to state: "…given that other options are now recommended, the consensus group members unanimously advised against using rosiglitazone." The GLP-1 agonist exenatide (Byetta®) is elevated to tier 2 with the guideline pointing out the advantage of weight loss associated with the drug, but also noting it is given by two injections per day, has frequent GI side effects, is very expensive, and does not have an established long-term safety history. Other drugs newly mentioned in the guideline include the a-glucosidase inhibitors (starch blockers), acarbose (Precoseä) and miglitol (Glyset®); the glinides, repaglinide (Prandin®) and nateglinide (Starlix®); the amylin agonist primlintide (Symlin®); and the DPP-4 inhibitor sitagliptin (Januvia®) (Nathan DM, et al. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm of the initiation and adjustment of therapy. Diabetes Care 2009;32:1-11; Available at: http://care.diabetesjournals.org/misc/dv08-9025.pdf).

Beta-blockers and hypertension

Beta-blockers have come under increasing fire for treatment of hypertension. Now a new study links beta-blocker-associated bradycardia with increased risk of cardiovascular events. Researchers from Columbia University performed a meta-analysis of 9 randomized controlled trials evaluating beta-blockers for hypertension and from which heart rate data were reported. The compiled studies included more than 34,000 patients taking beta-blockers and more than 30,000 on other antihypertensive agents, as well as nearly 4000 patients receiving placebo. Lower heart rate associated with beta-blocker use was linked to a greater risk for all-cause mortality (r = -0.51; P < 0.0001) and cardiovascular mortality (r = -0.61; P < 0.001). There was also a statistically significant increase in myocardial infarction, stroke, and heart failure associated with lower heart rates. The authors conclude that in contrast to patients with myocardial infarction and heart failure, beta-blocker-associated reduction in heart rate increases the risk for cardiovascular events and death for hypertensive patients. The authors even suggest that beta-blockers may no longer be indicated for treatment of hypertension in the absence of compelling indications (Bangalore S, et al. Relation of beta-blocker-induced heart rate lowering and cardioprotection in hypertension. J Am Coll Cardiol 2008;52:1482-1489).

FDA Updates

The FDA has approved a new selective a-blocker for the treatment of benign prostatic hyperplasia. Silodosin is an a-1 receptor blocker with high affinity for prostate, bladder, and urethra. It will be marketed in an 8 mg dose to be given once daily; however, 4 mg should be used in men with hepatic or renal impairment. Silodosin will be marketed by Watson Pharmaceuticals as Rapaflo™.

The FDA will investigate a report for the Institute of Safe Medication Practices regarding varenicline (Chantix®), Pfizer's smoking cessation drug. For the second straight quarter, varenicline accounted for more reported serious injuries than any other prescription drug with a total of 1001 new cases reported to ISMP, including 50 deaths. The FDA has previously issued a Public Health Alert about psychiatric side effects from the drug, but the new report sites numerous cases involving vehicular or other accidents, or syncope with a high potential to cause accidents. The federal government has already taken action to ban airline pilots and military missile crews from using the drug. Sales of varenicline have dropped sharply this year as a result of these reports.


This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: paula.cousins@ahcmedia.com.