**Conflict of interest**

*Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*

**6.5 Estrogen replacement**

ER+ve breast cancer cells [61].

**7. Conclusion**

survival rates.

**Acknowledgements**

in the nuclei of cancer cells. However, recently 2-ME has been found to activate epigenetically silenced ERβ, resulting in apoptosis of malignant cancer cells [60]. Furthermore, some of the recent reports emphasize the role of mutant ERα gene (*ESR1*) in cancer progression and drug resistance. These mutations have been observed to get accumulated in circulating DNA of bone metastasis patients [32].

Zoledronic acid is a known anti-resorptive agent and exhibits antitumor effects in ER-ve breast cancers. Some of the recent studies emphasize that it's the menopausal status (and not the hormone receptor status) that determines its anticancer efficiency [61]. This differential effect of zoledronic acid in pre- and postmenopausal bone metastasis patients has been suggested to be regulated by bone turnover effect of estrogen. Estrogen inhibits osteoclastogenesis via its direct effect on osteoclast and their precursors. Similarly, zoledronic acid also exhibits pro-apoptotic effects on osteoclasts by inhibiting mevalonate pathway and thus prevents release of growth factors that stimulate tumor growth. But in contrast to estrogen, zoledronic acid also reduces the number and activity of osteoblasts. Therefore, replacement of estrogen with zoledronic acid could be a more effective antitumor therapy in a low-estrogen bone microenvironment. Though administration of zoledronic acid does not alter growth of ER+ve cells at the primary site of tumor, it hampers their dissemination in the bone. As the cells evade the bone microenvironment, zoledronic acid-mediated bone turnover inhibits their proliferation and prevents overt metastases. Thus zoledronic acid could inhibit bone metastases of both ER-ve and

One of the study reports dealing with in vitro microarray data analysis revealed that glucocorticoid was more efficient in controlling osteosarcoma cell growth than 17β estradiol. Glucocorticoid upregulated the expression of tumor suppressor genes resulting in apoptosis and downregulated the oncogenes associated with cell cycle

Primary bone tumors are a rare occurrence, and most of the bone tumors arise due to metastases of breast, prostate, or lung cancers. The bone is the preferred site for metastases because of its highly vascular nature and extensive molecular signaling. A large number of bone tumor cases have been observed in an adolescent population experiencing a growth spurt and hormonal changes. Therefore, the treatment methodologies for bone tumors rarely involve the use of hormones as drugs but rather deal with hormone deprivation or inhibition. Though therapeutic approaches involving deprivation or replacement of hormones negatively affect bone health, the hormonal therapy alone or in combination with chemotherapeutic drugs offers a promising strategy for inhibition of bone tumors and improving the

This article reflects collective intellectual wisdom of the authors. We thank Savitribai Phule Pune University, Pune, India, for providing the necessary infrastructure during the compilation of this chapter. We also thank our colleagues,

whose work has been cited in this article, for their inspiration.

and mitosis, whereas estradiol had an opposite action [62].

**28**

The authors declare no conflict of interest with relation to this study.
