An Overview of Advancements in the Bone Metastases in Endocrine Cancers: From Molecular Insights to Clinical Applications View PDF

Bone metastases are a common and serious complication of many cancers, including those of endocrine origin [1-5]. These metastases significantly impact patient quality of life, increasing mortality and causing debilitating symptoms like pain and SREs [1-3]. The incidence of bone metastases varies considerably across different cancer types. For instance, prostate and breast cancers exhibit a particularly high propensity for bone metastasis [4], while thyroid cancer, although the most common endocrine malignancy, shows a lower but still significant incidence [6, 7]. Understanding the mechanisms of bone metastasis and developing effective treatment strategies remain critical areas of research.

The incidence of bone metastases at the time of solid tumor diagnosis is substantial [1]. Huang et al. [1] used the surveillance, epidemiology, and end results database to analyze a large population, revealing high bone metastasis rates in prostate cancer (88.74%), breast cancer (53.71%), and renal cancer (38.65%). Other cancers, including those of the genitourinary, lung, and gynecologic systems, also showed significant rates. The overall incidence rate in the entire cohort was 3.73% for breast cancer and 5.69% for prostate cancer [1]. A separate study in a Korean population confirmed high rates of bone metastasis in breast, prostate, and lung cancers [2]. This highlights the global significance of this complication across diverse populations. Further research, such as Agnoli et al. [8] retrospective study on dogs with solid cancer and bone metastases, can offer valuable insights into disease progression and potential treatment strategies applicable to human cancers.

Bone metastasis is a complex, multi-stage process [3-5]. It begins with circulating tumor cells and disseminated tumor cells entering the bone marrow, often establishing a dormant state [3-5]. Later, these cells reactivate, proliferate, and interact with the bone microenvironment, influencing bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, ultimately leading to bone destruction [3-5]. The bone microenvironment itself plays a crucial role, with various cell types (osteoblasts, osteocytes, osteoclasts, adipocytes, and immune cells) engaging in a complex interplay with tumor cells [4, 9]. The specific molecular mechanisms involved vary depending on the primary cancer type [5]. For instance, in prostate cancer, dormancy is modulated by pathways such as CXCR-4/CXCL-12, ANXA2/CXCL12, and GAS6, while breast cancer involves different pathways, including ERK1/2, p38, and MSK1 [5]. Moreover, the role of osteocytes, while initially unclear, is increasingly understood [9]. Studies are revealing both stimulatory and protective effects of osteocytes, highlighting the complexity of their interaction with cancer cells [9, 10]. Sclerostin, a protein produced by osteocytes, has been implicated in regulating bone metastasis in Wnt-responsive breast cancer cells [10].

Accurate and early detection of bone metastases is crucial for effective management. [18F]FDG PET/CT (Positron emission tomography/computed tomography) has been a standard imaging modality; however, newer techniques are emerging. Wu et al. [11] compared the diagnostic performance of [68Ga]Ga-DOTA-FAPI-04 PET/CT with [18F]FDG PET/CT, finding [68Ga]Ga-DOTA-FAPI-04 to be significantly more sensitive in detecting bone metastases across various cancer types, including thyroid and lung cancers. However, the potential for false positives necessitates careful interpretation of results. Treatment strategies for bone metastases aim to alleviate symptoms, prevent SREs, and improve overall survival [3, 12]. BMAs such as bisphosphonates and denosumab are frequently used to reduce bone resorption and prevent fractures [12]. The choice of BMA, treatment duration, and management of side effects remain areas of ongoing discussion [12]. For example, a survey of Italian oncologists revealed variability in practice patterns regarding BMA prescription and sideeffect management [12]. Beyond BMAs, targeted therapies are being explored, with the potential of PLK1 inhibitors showing promise in certain breast cancer subtypes [13]. In endocrine-resistant breast cancer, lasofoxifene, a selective estrogen receptor modulator, has shown efficacy in inhibiting tumor growth and reducing metastasis in preclinical models [14].

Bone metastases in endocrine cancers pose a significant clinical challenge. This review highlights the substantial incidence, complex mechanisms, and diverse treatment approaches associated with this debilitating complication. Continued research is vital to further elucidate the molecular pathways involved, develop improved diagnostic tools, and design more effective therapies to improve patient outcomes. Further studies focusing on specific endocrine cancer types and exploring innovative treatment strategies are warranted.