The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats

Goss, Paul E.; Qi, Shangle; Josse, Robert G.; Pritzker, Kenneth P.H.; Mendes, Maria; Hu, Haijun; Waldman, Stephen D.; Grynpas, Marc D.

doi:10.1016/j.bone.2003.11.006

Cited by 110 publications

(66 citation statements)

References 44 publications

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“…In two separate studies, Goss et al showed that exemestane treatment prevented the bone loss that normally occurs in animals after ovariectomy, yet this effect was not observed after letrozole treatment (26,27). Exemestane may mediate its protective effect through androgenic effects.…”

Section: Hormonal Therapymentioning

confidence: 99%

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Skeletal Complications of Breast Cancer Therapies

Hirbe

Morgan

Uluçkan

et al. 2006

Clinical Cancer Research

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Nonsurgical treatment options, such as hormonal therapy, chemotherapy, radiation, and bisphosphonate therapy, are undoubtedly improving outcomes for women with breast cancer; however, these therapies also carry significant skeletal side effects. For example, adjuvant hormonal treatments, such as aromatase inhibitors that disrupt the estrogen-skeleton axis, have the potential to cause decreased bone mineral density. Similarly, chemotherapy often induces primary ovarian failure in premenopausal women, resulting in decreased levels of circulating estrogen and subsequent osteopenia. In both cases, women receiving these therapies are at an increased risk for the development of osteoporosis and skeletal fracture. Furthermore, women undergoing radiation therapy to the upper body may have an increased incidence of rib fracture, and those receiving bisphosphonates may be vulnerable to the development of osteonecrosis of the jaw. Therefore, women with breast cancer who are undergoing any of these therapies should be closely monitored for bone mineral loss and advised of skeletal health maintenance strategies. Hormonal TherapyIn adults, the skeleton undergoes complete turnover every 10 years. Bone mass maintenance is a balance between the activity of osteoblasts, which form bone, and osteoclasts, which resorb it. Estrogen plays a key regulatory role in this cycle of bone remodeling by mediating effects through the estrogen receptor (ER) present on several cell types in the bone. Estrogen stimulates osteoblasts to produce osteoprotegerin, a decoy receptor for the receptor of activated nuclear factor-nB (1). Osteoprotegerin blocks the binding of receptor of activated nuclear factor-nB ligand to receptor of activated nuclear factornB on osteoclasts, leading to impaired osteoclast activity and decreased bone resorption. Additionally, estrogen is believed to directly induce apoptosis of bone-resorbing osteoclasts (2, 3). Thus, in premenopausal women, estrogen both inhibits bone remodeling and suppresses bone resorption, contributing to bone strength (Fig. 1). As estrogen levels decline in postmenopausal women, this regulation diminishes and bone resorption increases out of proportion to bone formation, leading to a net loss in bone and weakened bony microarchitecture. Despite the persistence of low levels of circulating estrogen in the postmenopausal state (produced by the conversion of peripheral tissue androgens to estrogen by the aromatase enzyme), bone mass can decrease by as much as 3% yearly in the first 5 years after menopause (4).The ER is expressed by 70% of breast tumors (5), and circulating estrogen can promote the growth of ER-positive tumors. Current breast cancer therapies exploit this relationship either by decreasing circulating estrogen levels or by blocking or down-regulating the receptor itself. Although some of the estrogen-mimicking agents seem to be bone sparing, others that disrupt the estrogen-skeleton axis cause adverse effects on bone remodeling, leading to decreased bone mineral density (BMD)...

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Section: Hormonal Therapymentioning

confidence: 99%

“…Exemestane may mediate its protective effect through androgenic effects. Both exemestane and its metabolite, 17-hydroxyexemestane, are proposed to have androgenic properties (27), and androgens have been previously shown to be important for maintenance of BMD independent of their conversion to estrogen (28).…”

Section: Hormonal Therapymentioning

confidence: 99%

Skeletal Complications of Breast Cancer Therapies

Hirbe

Morgan

Uluçkan

et al. 2006

Clinical Cancer Research

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“…In contrast, there was a sharp increase in bone turnover in those given letrozole over the same time-period. It has been assumed from studies in ovariectomized rats that bone metabolism is protected by the androgenicity of exemestane and its metabolite 17-hydroexemestane (Goss et al 2004).…”

Section: Skeletal Effectsmentioning

confidence: 99%

Effects of estrogen deprivation due to breast cancer treatment

Angelopoulos¹,

Barbounis²,

Livadas³

et al. 2004

Endocr Relat Cancer

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Breast cancer is one of the main life-threatening diseases that a woman may have to face during her lifetime. The increasing incidence of breast neoplasia reported over the last few decades has led to widespread screening of women resulting in early diagnosis. One common but challenging question for most doctors, after the surgical excision of the lesion, is determination of the ideal adjuvant therapy for their patients for the achievement of maximum life expectancy with the best quality of life.Since the beginning of the last century, the knowledge that breast cancer arises from hormoneresponsive tissues has long made use of hormone-blocking agents in the beneficial treatment of breast neoplasia. The discovery of new molecules with endocrine actions has rendered the use of adjuvant therapy in a tailor-made pattern too complicated, as these agents have a different mode of action, different adverse effects and probably different indications.The aim of the present review is to clarify these issues, analyzing the mechanism of action of available drugs and their actions on specific areas of uncertainty: cognitive function, cardiovascular system, urogenital tract, bone metabolism, weight gain, hot flushes and premature menopause. Regarding the efficacy of adjuvant therapy, there has been particular focus on the multiple hormonal-induced consequences of each regimen in order to provide the clinician with the available data for choosing the ideal therapy for the patient.

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“…Possibly due to its steroid structure, exemestane may exhibit a unique pharmacology distinct from the nonsteroidal AIs. In two preclinical studies by Goss et al (15,16), exemestane was given to female ovariectomized rats, an animal model of osteoporosis, and found to reduce bone resorption markers and increase BMD and bone strength, whereas lowering serum cholesterol and low-density lipoprotein levels compared with ovariectomized controls. One of these preclinical studies also evaluated the nonsteroidal AI letrozole, but in contrast, found no benefit of letrozole on bone or lipid profiles (16).…”

Section: Introductionmentioning

confidence: 99%

Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen

Ariazi

Leitão

Oprea

et al. 2007

Molecular Cancer Therapeutics

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Aromatase inhibitors (AI) are being evaluated as longterm adjuvant therapies and chemopreventives in breast cancer. However, there are concerns about bone mineral density loss in an estrogen-free environment. Unlike nonsteroidal AIs, the steroidal AI exemestane may exert beneficial effects on bone through its primary metabolite 17-hydroexemestane. We investigated 17-hydroexemestane and observed it bound estrogen receptor A (ERA) very weakly and androgen receptor (AR) strongly. Next, we evaluated 17-hydroexemestane in MCF-7 and T47D breast cancer cells and attributed dependency of its effects on ER or AR using the antiestrogen fulvestrant or the antiandrogen bicalutamide. 17-Hydroexemestane induced proliferation, stimulated cell cycle progression and regulated transcription at high sub-micromolar and micromolar concentrations through ER in both cell lines, but through AR at low nanomolar concentrations selectively in T47D cells. Responses of each cell type to high and low concentrations of the nonaromatizable synthetic androgen R1881 paralleled those of 17-hydroexemestane. 17-Hydroexemestane downregulated ERA protein levels at high concentrations in a cell type -specific manner similarly as 17B-estradiol, and increased AR protein accumulation at low concentrations in both cell types similarly as R1881. Computer docking indicated that the 17B-OH group of 17-hydroexemestane relative to the 17-keto group of exemestane contributed significantly more intermolecular interaction energy toward binding AR than ERA. Molecular modeling also indicated that 17-hydroexemestane interacted with ERA and AR through selective recognition motifs employed by 17B-estradiol and R1881, respectively. We conclude that 17-hydroexemestane exerts biological effects as an androgen. These results may have important implications for long-term maintenance of patients with AIs.

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The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats

Cited by 110 publications

References 44 publications

Skeletal Complications of Breast Cancer Therapies

Skeletal Complications of Breast Cancer Therapies

Effects of estrogen deprivation due to breast cancer treatment

Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen

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