Osteoclasts, which are abundant in the bone tissue, are multinuclear cells derived from myeloid lineage [
1,
2]. Osteoclasts are known to initiate physiologic bone remodeling during bone growth, tooth eruption and fracture healing, and also are able to mediate bone loss in pathologic conditions, such as bone cancer metastasis [
3,
4]. Therefore, inhibition of osteoclasts is a potential target for the treatment of bone cancer metastasis.
According to the Global Cancer Statistics 2018, there would have 18.1 million new cancer cases and 9.6 million deaths from cancer worldwide in 2018 [
5]. Increasing global demographic trends and epidemiologic transitions indicate an ever-increasing cancer burden over the coming decades, particularly in low- and middle-income countries, with over 20 million new cancer cases expected annually as early as 2025 [
6]. The bone is the third most common site of metastasis for a wide range of solid tumors including lung, breast, prostate, colorectal, thyroid, gynecologic, and melanoma, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis [
7], because of the close interactions between cancer cells and the bone marrow microenvironment which facilitates the growth of the tumors cells in the bone by providing niche, nutrients and oxygen [
8]. However, the mechanism of bone cancer metastasis is very complex, including various cytokines, growth factors and other molecules involved, leading to activation of different pathways of bone resorption [
9].
Zoledronic acid (ZA, C5H10N2O7P2), also called zoledronate, is the third generation of bisphosphonate (BP) with a history of only 25 years, belonging to nitrogen-containing bisphosphonate (N-BP). BP is a kind of anti-resorptive drug, and has been used clinically for near 50 years [
10], which is stable pyrophosphate analogues, where a carbon atom replaces the central oxygen atom, making the P-C-P backbone non-hydrolysable [
11]. Furthermore, the P-C-P backbone structure allows the BP binding to hydroxyapatite in bone tissue through the chelation of Ca
2+ [
12,
13], this is the reason why BP has high affinity with bone. Once internalized by bone-resorbing osteoclasts [
14], BP affects multiple pathways to lead to effective anti-resorptive activity and induces cell apoptosis [
15,
16]. ZA is the most widely used BP for its potent anti-resorptive activity, in addition, it inhibits the differentiation and apoptosis of osteoclasts [
17‐
19]. It also has anticancer effects [
15,
20], including suppressing metastasis of cancer [
21,
22], inhibiting the angiogenesis [
23], and the synergistic effect with other anticancer drugs [
17,
20,
24]. Here, we want to elaborate the mechanisms of ZA in inhibition of differentiation and apoptosis of osteoclasts, as well as its anticancer effects, which may provide a new strategy for the treatment of cancer, especially cancer with bone metastasis.