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  • Finasteride The effects of zoledronic acid are most likely d

    2019-06-24

    The effects of zoledronic Finasteride are most likely due to impairment of the tumour-driven alterations to the bone microenvironment. This may render the bone marrow cavity unfavourable for metastatic growth, potentially redirecting tumour cells to other sites, including the periosteal surface. Whereas combination therapy substantially reduced tumour growth inside the bone marrow cavity, growth in the periosteum was unaffected. There is preclinical evidence that bisphosphonate treatment exhibits stronger anti-tumour effects in the bone marrow cavity compared to the extraosseous bone-associated soft tissue when given alone or in combination with cytotoxic agents. Studies investigating the effects of bisphosphonates as a single agent have reported either no effect on extraosseous tumour growth after pamidronate or olpadronate treatment [22] or increased bone-associated soft tissue tumours Finasteride after risedronate [23] or the third generation bisphosphonate YH529 [24]. Collectively the data from these studies suggest that the bisphosphonate-induced inhibition of bone remodelling may redirect tumour growth to extraosseous sites. We have previously shown that doxorubicin given 24h after zoledronic acid induced significantly increased levels of tumour cell apoptosis and reduced proliferation in intraosseous parts of large MDA-MB-231/B02 tumours, whereas the extraosseous parts of the same tumour were unaffected [16]. The present data are in agreement with these reports, showing that a single dose of combination treatment effectively reduced tumour growth inside the bone marrow cavity, but did not eliminate extraosseous tumour growth. Importantly, the tumour colonies growing along the periosteal surface were not part of a large, intraosseous tumour spilling through osteolytic lesions but were separate tumour colonies. This could suggest that during the process of tumour cell dissemination, the cells seed to multiple sites but remain dormant until triggered to proliferate or that cells previously settled in the bone marrow cavity disseminated to other sites at relatively early stages of tumour progression (prior to day 15). There are few and opposing published reports relating to the effects of bisphosphonates on the cells of the periosteum, with the majority of studies focusing on characterisation of endosteal bone surfaces [25]. Risedronate and alendronate are reported to inhibit periosteal osteoblast activity independently of bone resorption [26]. In contrast, risedronate, alendronate or zoledronic acid were found to have no significant effect on periosteal bone formation in oestrogen-deficient rats [27]. The role of the periosteal microenvironment in development and progression of bone metastasis, as well as in response to therapy, therefore remains to be established. Our data suggest that development of improved therapeutic interventions must include control of tumour colonisation of periosteal sites, in addition to growth in the bone marrow cavity. Studies of therapeutic agents in xenograft models of bone metastases are often limited to assessment of tumour burden (by imaging) and gross bone integrity (by μCT). To fully understand the effects of therapeutic interventions, we also characterised the treatment-induced changes of the key cell populations in the host bone microenvironment. In the absence of tumour, a single dose of zoledronic acid, given alone or in combination with doxorubicin, caused a significant reduction of both osteoclast and osteoblast numbers on day 15. Surprisingly, the effect on osteoblasts was the most pronounced, indicating that zoledronic acid either caused inhibition of osteoblast development, induction of osteoblast apoptosis, or both. Further studies specifically designed to distinguish between these options are needed. Evidence that bisphosphonates can be internalised by osteoblasts in vivo is reported by Idris et al. [28] who detected unprenylated Rap1a in bone forming cells derived from mouse calvaria 24h after administration of 0.1mg/kg alendronate. In agreement with this, Orriss et al. [29] demonstrated that zoledronic acid affects osteoblast development and function in vitro. Although the literature is frequently questioning the in vivo effect of bisphosphonates on cells other than osteoclasts [30,31], the data shown in the present study support that a single, clinically achievable dose of zoledronic acid clearly affects osteoblasts. However, we were unable to determine whether the observed effects were due to zoledronic acid affecting osteoblasts directly, or whether the effects were downstream of the osteoclast effects. Well-recognised feedback loops exist between these cell types as a part of normal bone homoeostasis. As the anti-resorptive effect of zoledronic acid is evident soon after administration of a single dose [32] it is most likely that the effects on actively resorbing osteoclasts precede the osteoblast effects.