toremifene and Osteoporosis

Bone health is a significant concern in men with prostate cancer.. To evaluate the effectiveness of drug, supplement, and lifestyle interventions aimed at preventing fracture, improving bone mineral density (BMD), or preventing or delaying osteoporosis in men with nonmetastatic prostate cancer.. Ovid MEDLINE (1946 to 19 January 2017), EMBASE (1980 to 18 January 2017), and the Cochrane Database of Systematic Reviews (19 January 2017).. Randomized trials and systematic reviews of trials that were published in English; involved men with nonmetastatic prostate cancer; and compared bone-targeted therapies with placebo, usual care, or other active treatments.. Two reviewers independently extracted study characteristics and assessed study risk of bias for each outcome.. Two systematic reviews and 28 reports of 27 trials met inclusion criteria. All trials focused on men with nonmetastatic prostate cancer who were initiating or continuing androgen deprivation therapy (ADT). Bisphosphonates were effective in increasing BMD, but no trial was sufficiently powered to detect reduction in fractures. Denosumab improved BMD and reduced the incidence of new radiographic vertebral fractures in 1 high-quality trial. No trials compared calcium or vitamin D versus placebo. Three lifestyle intervention trials did not show a statistically significant difference in change in BMD between exercise and usual care.. Most trials were of moderate quality. Only 2 randomized controlled trials were designed to examine fracture outcomes. Potential harms of treatments were not evaluated.. Both bisphosphonates and denosumab improve BMD in men with nonmetastatic prostate cancer who are receiving ADT. Denosumab also reduces risk for radiographic vertebral fractures, based on 1 trial. More trials studying fracture outcomes are needed in this population.. Program in Evidence-Based Care.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density; Bone Density Conservation Agents; Denosumab; Humans; Male; Osteoporosis; Osteoporotic Fractures; Prostatic Neoplasms; Toremifene

Traditional menopausal hormone therapy containing estrogens/progestin has been associated with an increased risk of breast cancer, and estrogen exposure is known to promote growth and proliferation of a majority of breast cancers. Therefore, it is important for clinicians to consider the breast safety profile of any hormone-based therapy used in postmenopausal women. This review provides an overview of the breast safety and tolerability profiles of currently marketed selective estrogen receptor modulators, antiestrogens, and the first tissue selective estrogen complex combining conjugated estrogens with the selective estrogen receptor modulator bazedoxifene in postmenopausal women. Selective estrogen receptor modulators and antiestrogens act as estrogen receptor antagonists in the breast. Tamoxifen, toremifene, and the selective estrogen receptor degrader fulvestrant are used to treat breast cancer, and tamoxifen and raloxifene protect against breast cancer in high-risk women. Postmenopausal women using selective estrogen receptor modulators for prevention or treatment of osteoporosis (raloxifene, bazedoxifene) can be reassured that these hormonal treatments do not adversely affect their risk of breast cancer and may, in the case of raloxifene, even be protective. There are limited data on breast cancer in women who use ospemifene for dyspareunia. Conjugated estrogens/bazedoxifene use for up to two years did not increase mammographic breast density or breast pain/tenderness, and there was no evidence of an increased risk of breast cancer, suggesting that conjugated estrogens/bazedoxifene has an improved breast safety profile compared with traditional menopausal hormone therapies. Future research will continue to focus on development of selective estrogen receptor modulators and selective estrogen receptor modulator combinations capable of achieving the ideal balance of estrogen receptor agonist and antagonist effects.

Topics: Animals; Breast; Breast Neoplasms; Drug Therapy, Combination; Estradiol; Estrogen Antagonists; Estrogens; Estrogens, Conjugated (USP); Female; Fulvestrant; Humans; Indoles; Osteoporosis; Postmenopause; Protective Factors; Raloxifene Hydrochloride; Risk Assessment; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have varying estrogen agonist and antagonist activities in different tissues, most likely due to the receptor conformation changes associated with that SERM's binding and the subsequent effect on transcription. Clinical trials aim to differentiate amongst SERMs on selected target tissues for use in postmenopausal women including effects on breast, bone, cardiovascular venous thrombosis risk, endometrium, vagina, vasomotor symptoms, and brain. This paper describes differences in clinical effects on selected target tissues of SERMs that are approved, discontinued or in development. FDA approved SERMs include tamoxifen and toremifene used for prevention and treatment of breast cancer, raloxifene approved for prevention and treatment of osteoporosis and prevention of invasive breast cancer, and ospemifene approved for treatment of dyspareunia from menopausal vaginal atrophy. The FDA approved first tissue selective estrogen complex (TSEC) a pairing of conjugated equine estrogens with the SERM, bazedoxifene. This pairing reduces the risk of endometrial hyperplasia that can occur with the estrogenic component of the TSEC without the need for a progestogen in women with a uterus. It also allows for the estrogenic benefits on relief of hot flashes and prevention of bone loss without stimulating the breast or the endometrium. In clinical practice, the tissue-selective actions of SERMs, alone or paired with estrogens, allow for individualization in meeting the treatment needs of postmenopausal women by providing targeted tissue effects. This article is part of a Special Issue entitled 'Menopause'.

Topics: Breast Neoplasms; Clinical Trials as Topic; Dyspareunia; Estrogens, Conjugated (USP); Female; Hot Flashes; Humans; Indoles; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause; Pyrrolidines; Raloxifene Hydrochloride; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Toremifene

Toremifene is a triphenylethylene selective estrogen receptor modulator (SERM) that differs from tamoxifen in a single chloride ion addition on a side chain, resulting in a potentially more favorable toxicity profile.. This article reviews the pharmacokinetics of toremifene and its potential use for the treatment of osteoporosis. This article was based on articles found through a literature search containing the terms 'toremifene' and 'SERMs.'. Toremifene can be administered orally with an excellent bioavailability. The overall pharmacokinetic profile is remarkably similar to tamoxifen. Toremifene is highly metabolized in the liver and is eliminated primarily in the feces following enterohepatic circulation. Some of its metabolites retain biological activity. This SERM was approved by the FDA for the treatment of estrogen receptor-positive metastatic breast cancer and is under investigation for its potential skeletal benefits in men on androgen deprivation therapy. Despite the positive preclinical and clinical evidences for the prevention of bone loss and fractures, the chemopreventive effect on prostate cancer remains to be confirmed and an increased risk of venous thromboembolism was evidenced in a large Phase III trial. Thus, additional data are required to establish the full clinical profile of this compound and its potential advantages over antiresorptive agents commonly in use for the treatment of osteoporosis.

Topics: Breast Neoplasms; Clinical Trials, Phase III as Topic; Female; Humans; Liver; Male; Osteoporosis; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Thromboembolism; Toremifene

Osteoporosis is defined as a continuous loss of bone mineral density accompanied by an increased fracture risk in females and males. A fall of estrogen concentrations at the menopause and the consecutive rapid bone loss are an established pathogenic mechanism in female osteoporosis. Males do not have a menopause equivalent during which significant amounts of bone are lost. Several diseases, therapeutic strategies and nutritional deficiencies may also result in bone loss and reduced bone mineral density. Prostate cancer is the most common visceral malignancy in men. Suppression of endogenous androgen production as a therapeutic tool is commonly used in patients with non-metastatic prostate cancer and is associated with significant bone loss and an increased fracture risk. Androgen deprivation therapy is prescribed both for men with locally advanced or high-risk non-metastatic prostate cancer. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density and reduces fracture risk. Denosumab (a monoclonal antibody against RANK ligand) and toremifene (a selective estrogen receptor modulator) recently have been shown to be effective to reduce vertebral fractures in patients with non-metastatic prostate cancer receiving androgen-deprivation therapy. This overview focuses on cancer-treatment-induced bone loss in patients with non-metastatic prostate cancer.

Topics: Aged, 80 and over; Androgen Antagonists; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Bone Density; Bone Density Conservation Agents; Denosumab; Diphosphonates; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Staging; Osteoclasts; Osteoporosis; Osteoporotic Fractures; Prostatic Neoplasms; Randomized Controlled Trials as Topic; RANK Ligand; Selective Estrogen Receptor Modulators; Spinal Fractures; Toremifene

In men, prostate cancer is the most common non-cutaneous malignancy and the second most common cause of cancer death. Skeletal complications occur at various points during the disease course, either due to bone metastases directly, or as an unintended consequence of androgen deprivation therapy (ADT). Bone metastases are associated with pathologic fractures, spinal cord compression, and bone pain and can require narcotics or palliative radiation for pain relief. ADT results in bone loss and fragility fractures. This review describes the biology of bone metastases, skeletal morbidity, and recent advances in bone-targeted therapies to prevent skeletal complications of prostate cancer.

Topics: Androgen Antagonists; Antibodies, Monoclonal, Humanized; Bone Density; Bone Neoplasms; Clinical Trials as Topic; Clodronic Acid; Denosumab; Diphosphonates; Fractures, Spontaneous; Humans; Imidazoles; Male; Osteoclasts; Osteoporosis; Pamidronate; Prostatic Neoplasms; Quality of Life; Samarium; Toremifene; Zoledronic Acid

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Topics: Adult; Anastrozole; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Enzyme Inhibitors; Estrogen Antagonists; Female; Forecasting; Humans; Indoles; Letrozole; Middle Aged; Neoplasm Metastasis; Nitriles; Osteoporosis; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Triazoles

Androgen-deprivation therapy (ADT) is associated with greater risk of incident coronary heart disease and hospital admission for myocardial infarction; treatment-related increases in serum lipids may contribute to greater cardiovascular disease risk. We evaluated the effects of toremifene, a selective estrogen-receptor modulator, on fasting serum lipid levels in men receiving ADT for prostate cancer.. In an ongoing, multicenter, double-blind, placebo-controlled phase III fracture-prevention study, 1,389 men receiving ADT for prostate cancer were randomly assigned to receive toremifene (80 mg/d) or placebo. In this interim analysis of 188 patients, changes in fasting serum lipids from baseline to month 12 were compared between the placebo and toremifene groups.. Changes in serum lipids differed significantly between the groups. Mean (+/- SE) total cholesterol decreased by 1.0% +/- 1.7% from baseline to month 12 in the placebo group and decreased by 8.1% +/- 1.4% in the toremifene group (P = .001 for between group comparison). Low-density lipoprotein (LDL) cholesterol increased by 0.8% +/- 2.5% in the placebo group and decreased by 8.2% +/- 2.5% in the toremifene group (P = .003). In contrast, high-density lipoprotein (HDL) cholesterol decreased by 4.9% +/- 1.2% in the placebo group and increased by 0.5% +/- 2.2% in the toremifene group (P = .018). Triglycerides increased by 6.9% +/- 4.2% in the placebo group and decreased by 13.2% +/- 3.6% in the toremifene group (P = .003).. Toremifene significantly decreased total cholesterol, LDL cholesterol, and triglycerides, and increased HDL cholesterol in men receiving ADT for prostate cancer.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density Conservation Agents; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Fractures, Malunited; Humans; Lipids; Male; Middle Aged; Osteoporosis; Prostatic Neoplasms; Toremifene; Triglycerides

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Bone and Bones; Breast Neoplasms; Cholesterol; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Organ Size; Osteoporosis; Ovariectomy; Raloxifene Hydrochloride; Rats; Rats, Sprague-Dawley; Reference Values; Tamoxifen; Toremifene; Transplantation, Heterologous; Tumor Cells, Cultured; Uterus