Pharmacology Watch
Can Calcium and Vitamin D Prevent Hip Fractures?
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It has been a tough few months for marketers of vitamins and herbal products. Calcium plus vitamin D, saw palmetto, and glucosamine/chondroitin have all been the subject of studies that have questioned their efficacy. The calcium plus vitamin D results are possibly the most disappointing. In further data from the Women's Health Initiative study, 36,282 postmenopausal women ages 50 to 79 were randomly assigned to receive 1000 milligrams of elemental calcium with 400 IU of vitamin D3 or placebo, with the end point being prevention of hip and other fractures. After 7 years of follow-up, bone density was slightly higher, but there was no reduction in hip fractures in women who took calcium plus vitamin D (hazard ratio, 0.88 for hip fracture [95% CI, 0.72 to 1.08]). There was also no reduction in clinical spine fractures (HR, 0.90 [0.74 to 1.10]) or total fractures (HR, 0.96 [0.91 to 1.02]). Calcium plus vitamin D did result in a higher risk of kidney stones (HR, 1.17 [1.02 to 1.34]).
The authors conclude that among healthy postmenopausal women, calcium plus vitamin D supplementation did not significantly reduce hip fractures or reduce risks of kidney stones (N Engl J Med. 2006;354:669-683). In an accompanying editorial, Joel Finkelstein, MD, points out that many women who take calcium plus vitamin D "believe that they are completely protected against the development of osteoporosis. This study should help correct this important misconception and allow more women to receive optimal therapy for bone health." He also points out that women should not abandon calcium and vitamin D, neither should they rely on it alone as prevention against osteoporotic fractures (N Engl J Med. 2006;354:750-752 [correction published N Engl J Med. 2006;354:1102]).
Treatment of Benign Prostatic Hyperplasia
Saw palmetto is used by over 2 million men to treat symptoms of benign prostatic hyperplasia (BPH). Now, a new study suggests that it is ineffective. The study, funded by the National Institutes of Health and the National Center for Complementary and Alternative Medicine, looked at 225 men over the age of 49 with moderate-to-severe symptoms of BPH who were randomized to one year of saw palmetto extract 160 mg twice a day or placebo. The primary outcomes were changes in American Urological Association Symptom Index and maximal urinary flow rates. Prostate size, the residual urinary volume after voiding, quality of life, laboratory values, and adverse effects were also measured. After one year, there were no significant differences between patients treated with saw palmetto or placebo in any of the outcomes. There was also no difference in adverse effects. The authors conclude that saw palmetto does not improve symptoms or objective measures of BPH (N Engl J Med. 2006;354:557-566). An accompanying editorial welcomes the scientific rigor of placebo-controlled trials applied to dietary supplements, which are generally not held to standards of safety and efficacy. The authors call for similar studies for other commonly used herbal products (N Engl J Med. 2006;354:632-634).
Treatment of Osteoarthritis of the Knee
Glucosamine and chondroitin sulfate is used by millions to treat osteoarthritis. In another study supported by the NCCAM, along with the National Institute of Arthritis and Musculoskeletal and Skin Diseases, 1583 patients with osteoarthritis of the knee were randomized to 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, combination of glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Acetaminophen was allowed as rescue analgesia. The primary outcome was a 20% decrease in the pain from baseline at week 24. Glucosamine and conference sulfate were no better than placebo in reducing the pain by 20%, except for combined therapy (glucosamine plus chondroitin) in patients with moderate-to-severe pain at baseline (79.2% response vs 54.3% response placebo, P = 0.002). Adverse events were no different in all groups. The authors conclude that overall glucosamine chondroitin did not reduce pain effectively in patients with osteoarthritis of the knee, except in the subgroup of patients with moderate-to-severe knee pain (N Engl J Med. 2006;354:795-808). An accompanying editorial recommends telling patients that neither glucosamine nor chondroid alone has been shown to be more effective than placebo in treating knee pain. They suggest that glucosamine sulfate plus chondroitin sulfate may be tried in patients with moderate-to-severe knee pain, but should be discontinued after 3 months if there is no benefit (N Engl J Med. 2006;354:858-860).
Refractory Asthma and TNF—Connection?
Refractory asthma is a condition with a high mortality rate and limited treatment options. A new study suggests that the tumor necrosis factor (TNF) axis is up-regulated in refractory asthma, creating the possibility of treating refractory asthma with TNF inhibitors. Researchers from the United Kingdom measured markers of TNF alpha activity in 10 patients with refractory asthma, 10 patients with mild/moderate asthma, and 10 controls subjects. Patients with refractory asthma increased expression of TNF alpha markers compared to those with mild-to-moderate asthma and controls. Study subjects with refractory asthma were subsequently randomized to receive the TNF alpha receptor etanercept 25 mg twice weekly in a placebo-controlled, double-blind, crossover pilot study. Ten weeks of treatment with etanercept was associated with a significant increase in concentration of methacholine required to provoke a 20% decrease in FEV1 (P = 0.05), an improvement in asthma related quality-of-life score (P = 0 .02), and a 0.32 liter increase in post bronchodilator FEV1 (P = 0.01) compared to placebo. The authors suggest that the TNF alpha axis is upregulated in refractory asthma, and that etanercept may be beneficial in these patients (N Engl J Med. 2006;354:697-708). An accompanying editorial reports that several studies of TNF inhibitors in patients with refractory asthma are ongoing, suggesting that we soon should have an answer as to whether these agents are effective for treating this difficult clinical entity (N Engl J Med. 2006;354:754-758).
FDA Actions
The FDA has approved anidulafungin, Pfizer's new anti-fungal for the treatment of candidemia. The drug is a new molecular entity that is given intravenously. It is approved for a variety of Candida infections including esophagitis, sepsis, abdominal abscesses, and peritonitis. It will be marketed by Pfizer as Eraxis.
The FDA has approved lubiprostone for the treatment of chronic idiopathic constipation in adults. The drug is a selective chloride channel activator that increases intestinal fluid secretion and motility. The drug will be marketed by Sucampo Pharmaceuticals as Amitiza.
CV Therapeutics has received approval to market ranolazine, the first of a new class of agents for the treatment of chronic angina. The drug is an orally available extended-release anti-anginal drug that acts without reducing heart rate or blood pressure. The drug's mechanism of action has not been fully characterized, but it is felt that it works by affecting changes in cardiac metabolism. Because ranolazine prolongs QT interval, it should be reserved for patients who have not achieved adequate response with other anti-anginal drugs, and should be used in combinations with amlodipine, beta-blockers, or nitrates. CV Therapeutics will market ranolazine as Ranexa.
The FDA has approved an oral vaccine for the prevention of rotavirus gastroenteritis in infants and children. The oral vaccine should be initiated in infants 6 to 12 weeks old, with 2 subsequent doses of 4 to 10 week intervals. The vaccine should be completed before the child reaches 32 weeks of age. Based on clinical trials, the vaccine appears to be 98% effective for preventing gastritis caused by targeted rotavirus serotypes, and 74% effective at preventing gastroenteritis of any severity. Rotavirus vaccine will be marketed by Merck as RotaTeq.
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? Please call: (404) 262-5416. E-mail: [email protected].
It has been a tough few months for marketers of vitamins and herbal products. Calcium plus vitamin D, saw palmetto, and glucosamine/chondroitin have all been the subject of studies that have questioned their efficacy.Subscribe Now for Access
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