piperidines and tibolone

Several agents have been advocated for breast cancer primary prevention. However, few of them appear effective, the associated severe adverse effects limiting their uptake.. We performed a comprehensive search for randomized controlled trials (RCTs) reporting on the ability of chemoprevention agents (CPAs) to reduce the incidence of primary breast carcinoma. Using network meta-analysis, we ranked CPAs based simultaneously on efficacy and acceptability (an inverse measure of toxicity). All statistical tests were two-sided.. We found 48 eligible RCTs, enrolling 271 161 women randomly assigned to receive either placebo or one of 21 CPAs. Aromatase inhibitors (anastrozole and exemestane, considered a single CPA class because of the lack of between-study heterogeneity; relative risk [RR] = 0.468, 95% confidence interval [CI] = 0.346 to 0.634), arzoxifene (RR = 0.415, 95% CI = 0.253 to 0.682), lasofoxifene (RR = 0.208, 95% CI = 0.079 to 0.544), raloxifene (RR = 0.572, 95% CI = 0.372 to 0.881), tamoxifen (RR = 0.708, 95% CI = 0.595 to 0.842), and tibolone (RR = 0.317, 95% CI = 0.127 to 0.792) were statistically significantly associated with a therapeutic effect, which was restricted to estrogen receptor-positive tumors of postmenopausal women (except for tamoxifen, which is active also during premenopause). Network meta-analysis ranking showed that the new selective estrogen receptor modulators (SERMs) arzoxifene, lasofoxifene, and raloxifene have the best benefit-risk ratio. Aromatase inhibitors and tamoxifen ranked second and third, respectively.. These results provide physicians and health care regulatory agencies with RCT-based evidence on efficacy and acceptability of currently available breast cancer CPAs; at the same time, we pinpoint how much work still remains to be done before pharmacological primary prevention becomes a routine option to reduce the burden of this disease.

Topics: Adult; Aged; Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Middle Aged; Norpregnenes; Piperidines; Postmenopause; Primary Prevention; Pyrrolidines; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Risk Assessment; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Thiophenes

In March, 2010, a group of breast cancer experts met to develop a consensus statement on breast cancer prevention, with a focus on medical and therapeutic interventions. We present the conclusions in this Review. First we agreed that the term chemoprevention is inappropriate and suggested that the term preventive therapy better represents this feature of management. Two selective oestrogen-receptor modulators--tamoxifen and raloxifene--are so far the only medical options approved by the US Food and Drug Administration for preventive therapy. Of these tamoxifen has greater efficacy and can be used in premenopausal women, but raloxifene has fewer side-effects. Two newer drugs in this class, lasofoxifene and arzoxifene, also show efficacy and possibly a better overall risk-benefit profile, but need further assessment. Aromatase inhibitors might be more efficacious, and results of prevention trials are eagerly awaited. Newer agents, notably bisphosphonates and metformin, have shown promise in observational studies and need to be assessed in randomised prevention trials. Other agents, such as aspirin, other non-steroidal anti-inflammatory drugs, COX-2 inhibitors, retinoids, rexinoids, and dietary components have limited effects or are in the early phases of investigation. New contralateral tumours in women with breast cancer might be generally useful as a model for prevention, as has been seen for tamoxifen. If valid such a model would facilitate the design of simpler, cheaper, and better-focused trials for assessing new agents.

Topics: Anastrozole; Androstadienes; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Consensus Development Conferences as Topic; Diphosphonates; Estrogen Receptor Modulators; Expert Testimony; Female; Fenretinide; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metformin; Nitriles; Norpregnenes; Piperidines; Premenopause; Pyrrolidines; Raloxifene Hydrochloride; Retinoids; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Thiophenes; Triazoles

Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason, research continues in search of more effective and more tolerable agents. Arzoxifene and TSE-424 are investigational selective estrogen receptor modulators that have been shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for the prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. Although studies of the effect of isoflavones on bone mineral density have been encouraging, a large multicenter study in Europe recently showed no effect of isoflavones on fractures. The investigational bisphosphonates ibandronate and zoledronic acid may offer the advantage of less frequent dosing. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Finally, the issue of efficacy of statins in bone continues to be debated with no prospective, randomized studies yet to confirm the suggestion of benefit seen in epidemiologic studies.

Topics: Animals; Controlled Clinical Trials as Topic; Diphosphonates; Disease Models, Animal; Evidence-Based Medicine; Fractures, Spontaneous; Glycoproteins; Humans; Ibandronic Acid; Imidazoles; Norpregnenes; Osteoporosis; Osteoprotegerin; Piperidines; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Selective Estrogen Receptor Modulators; Thiophenes; Zoledronic Acid

Topics: Antineoplastic Agents, Hormonal; Cinnamates; Estrogen Antagonists; Female; Genital Neoplasms, Female; Humans; Norpregnenes; Piperidines; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Stilbenes; Tamoxifen; Thiophenes; Toremifene