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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Lasofoxifene is a nonsteroidal SERM developed by Pfizer for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy. There is also evidence based on meta-analyses that it can reduce the risk of breast cancer in women. It was approved for the treatment of osteoporosis in postmenopausal women by the FDA (under the name OporiaTM) and by the EMEA (under the name FablynTM) in 2005 and 2009, respectively. The closely related ormeloxifene (also known as centchroman) has an oxygen in its tetrahydronaphthalene ring system and is estrogenic in some parts of the body (e.g., bones) but antiestrogenic in others (e.g., uterus and breasts). It has been available in India for use as a weekly nonhormonal oral contraceptive since the early 1990s and is currently marketed under the trade names SaheliTM or ChhayaTM. However, there is evidence that it may also be effective for dysfunctional uterine bleeding (menorrhagia), mastalgia, fibro-adenoma, and advanced breast cancer.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
In humans, ~72% of the administered dose of lasofoxifene is recovered from the urine and feces, with majority of the dose excreted in the feces, probably via bile (Prakash et al. 2008). The absorption of lasofoxifene is slow, with Tmax values typically exceeding 6 h. The primary metabolic routes of lasofoxifene in humans are direct conjugation (glucuronide and sulfate conjugates) and Phase I oxidation, each accounting for approximately half of the metabolism (Prakash et al. 2008). The primary Phase I metabolites result from hydroxylations on the tetraline moiety and the phenyl rings attached to the tetraline and oxidation on the pyrrolidine moiety. The turnover of lasofoxifene is very slow in human liver microsomes, and only two metabolites are identified as two regioisomers of the catechol metabolite. Further in vitro experiments with recombinant CYPs and selective inhibitors suggested that the oxidative metabolism of lasofoxifene is catalyzed primarily by CYP3A and 2D6 (Prakash et al. 2008). In addition, its glucuronidation is catalyzed by multiple UGTs that are expressed in both the liver (UGT1A1, 1A3, A6, and 1A9) and the intestine (UGT1A8 and 1A10) (Prakash et al. 2008).
Hormonal regulation of the endometrium and the effects of hormonal therapies
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Gulcin Sahin Ersoy, Monica Modi, Myles Alderman, Hugh S. Taylor
Numerous SERMs have been developed to provide tissue-specific estrogen agonist–antagonist effects. Novel SERMs in various stages of clinical development are lasofoxifene, ospemifene, and arzoxifene. Lasofoxifene has been shown to reduce fracture risks and decrease the incidence of breast cancer, but has been associated with endometrial thickening and endometrial polyps (138). Lasofoxifene and ospemifene have beneficial effects on vaginal epithelium (138). Trials using idosifene and levormeloxifene were stropped early because of adverse uterine effects (138).
A patent review of bisphosphonates in treating bone disease
Published in Expert Opinion on Therapeutic Patents, 2019
Teriparatide (recombinant parathyroid hormone) and abaloparatide (a parathyroid hormone-related protein analog) are approved for the treatment of osteoporosis. It should be noted that in animals, abaloparatide caused an increase in the incidence of osteosarcoma [103], and therefore, this agent is not to be used in patients who are at increased risk for osteosarcoma. In addition, a cumulative use of either teriparatide or abaloparatide for more than 2 years during a patient’s lifetime is not recommended. Lasofoxifene, a nonsteroidal selective estrogen receptor modulator, did reduce the risk of vertebral and nonvertebral fracture in postmenopausal women with osteoporosis, but this treatment was also associated with an increased risk of venous thromboembolic events [104]. Development of the cathepsin K inhibitor odanacatib as an osteoporosis drug was abandoned due to an increased risk of strokes. Finally, romosozumab, a monoclonal antibody-targeting sclerostin, was recently approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis. This was accompanied by a black box warning because of the increased risk of myocardial infarction, stroke and cardiovascular death. In addition, treatment is limited to 12 monthly doses. Thus overall, the agents with the best-understood safety profiles continue to be the NBPs and denosumab. Further studies and clinical experience are required to establish the role that the newer drugs such as romosozumab will play in the treatment of bone diseases.
The use of selective estrogen receptor modulators on bone health in men
Published in The Aging Male, 2019
Sok Kuan Wong, Nur-Vaizura Mohamad, Putri Ayu Jayusman, Ahmad Nazrun Shuid, Soelaiman Ima-Nirwana, Kok-Yong Chin
In a study conducted by Ke et al. [37], histomorphometric analysis showed that lasofoxifene had a dose-dependent effect in preventing bone loss induced by aging and orchidectomy in the adult rats. Treatment with 1 µg/kg/day lasofoxifene for 60 days significantly decreased eroded perimeter in ORX rats, but had no effect in other parameters for bone microstructure. Orchidectomized rats treated with 10 µg/kg/day lasofoxifene had significantly higher Tb.Th as well as lower percent labeling perimeter, percent osteoid perimeter, percent eroded perimeter and bone formation rate. Orchidectomized rats treated with 100 µg/kg/day lasofoxifene had greater BV/TV, thickness, wall width, formation period, and resorption period and significantly lower labeling perimeter, osteoid perimeter, eroded perimeter, mineral apposition rate, bone formation rate/BV, bone formation rate/BS and activation frequency compared with ORX controls. These results showed that lasofoxifene prevented bone loss by inhibiting high bone turnover due to androgen deficiency [37]. In the subsequent study, Ke et al. [46] evaluated the long-term (6 months) treatment of lasofoxifene (0.01 mg/kg and 0.1 mg/kg per day) on bone histomorphometry in 15 months old male rats. Age-related increase in Tb.Sp and eroded surface in proximal tibia were completely prevented by lasofoxifene. Apart from that, the age-related decrease in BV/TV, thickness, as well as an increase in osteoclast number and surface in vertebral cancellous bone were prevented by lasofoxifene [46].
Beyond estrogen: advances in tissue selective estrogen complexes and selective estrogen receptor modulators
Published in Climacteric, 2019
Lasofoxifene, a third-generation non-steroidal SERM, was devised to treat osteoporosis53 and VVA54, but was discovered to reduce total and ER-positive breast cancers. The Postmenopausal and Risk-Reduction with Lasofoxifene (PEARL) RCT of 8556 postmenopausal women over 5 years used two doses of lasofoxifene and placebo. With the 0.5 mg/day dose, the incidence of vertebral and non-vertebral fractures was reduced 42% (p < 0.001) and 24% (p = 0.002), respectively, when compared to placebo, with a reduction in the risk of coronary heart disease (32%) and stroke (36%)53. The reduction in heart disease for lasofoxifene 0.5 mg/day during the trial was due to fewer coronary revascularization procedures, unstable angina leading to hospitalization, and new ischemic heart disease55.