Recently emerging data suggest that lower

Recently emerging data suggest that lower frequency of IV bisphosphonates in metastatic breast cancer has the same efficacy as monthly regimen [48]. ONJ on the other hand can be extremely symptomatic with a severely detrimental effect on quality of life. A case-control study based on risk factors for ONJ confirms that ONJ is associated with the duration of bisphosphonate treatment. A higher risk of ONJ began within 2 years of bisphosphonate treatment and increased four-fold 2 years later, showing that even less potent bisphosphonates remain linked to ONJ after brief treatment therapy [25]. There are several reports that long term discontinuation of IV bisphosphonates in patients with ONJ may be beneficial in stabilizing established sites of osteonecrosis and provide improvement of clinical symptoms [5,46]. However, there have been some cases of spontaneous resolution during ongoing monthly bisphosphonate therapy [28,29]. Moreover, Wilde et al. [60] reported favorable outcome with surgical treatment of ONJ irrespective of whether bisphosphonates were discontinued or not. In another report, the patients who developed ONJ after dental procedures safely restarted bisphosphonate therapy, but those who developed ONJ without a predisposing cause were at increased risk of recurrence after initial healing, especially when these agents were reintroduced [76]. Since bisphosphonates are incorporated into the mineral matrix of bone, it is unknown as to whether or not stopping bisphosphonate therapy would be beneficial in managing ONJ [7]. Nevertheless, stopping the bisphosphonate would remove any acute influences on the red and soft tissues, and could potentially improve the healing process. [5,31]. Therefore decisions around bisphosphonate withdrawal and reintroduction after ONJ are complex and should be made using a multidisciplinary team including oncologist, oral and maxillo-fascial surgeon and patient and based on weighing the severity of ONJ symptoms against the benefits from ongoing bisphosphonate therapy including patients\' overall prognosis and symptoms of bone metastases [46].
Discussion We simply have to accept that while there is growing data on incidence and risk factors of ONJ, the current data about the prevention and treatment of ONJ is relatively poor and is based mainly on case reports, case-controlled series, retrospective studies and expert opinions. Ongoing prospective trials in metastatic and adjuvant (D-CARE trial, http://www.clinicaltrials.gov/ct2/show/NCT01077154) settings with accurate ONJ monitoring will help us answer many more questions about the prevention and management of this condition. In particular strategy looking at de-escalating regimens in patients with bone metastases that can reduce exposure of the jaw to bisphosphonates and therefore reduced risk of ONJ and improve patient care [48].
Introduction Bone metastases are a major cause of cancer-related pain and can result in pathological fractures, paralysis and life-threatening hypercalcaemia. Less than 20% of patients survive for five years after the discovery of bone metastasis [1–4]. In other types of cancers, such as liver and lung malignancies, the incidence of bone metastasis has increased in recent years, possibly due to the effect of improved treatment regimens on life expectancy [5,6]. Metastasis of tumour cells to bone depends on a complex cascade of events which includes the detachment of individual cancer cells from the primary tumour site; invasion into the vasculature; migration and adherence to distant capillaries within the bone; extravasation and initial survival within the new environment; proliferation to micrometastases; recruitment of blood supply to the tumour for further expansion; and invasion beyond the adjacent tissues [3,4,7]. The ability of cancer cells to survive and expand in the bone marrow cavity has long been based on the “seed and soil” theory: In 1889, Sir James Paget proposed that bone acts as a fertile environment (‘soil’) for cancer cell (‘seed’) colonization and growth [8]. Many years later, Mundy and colleagues greatly broadened our understanding of the mechanisms that govern the growth of bone metastases by developing a concept widely known as the “vicious cycle” [7,9–11]. This theory elegantly explains how cancer metastases, once established in bone, modify their immediate environment to support their own survival and growth. Thus, tumour-derived factors such as parathyroid hormone-related protein (PTHrP) up-regulate the expression of Receptor Activator of Nuclear Factor KB Ligand (RANKL) by cells of the osteoblast lineage (i.e., osteoblast precursors, osteoblasts and osteocytes). RANKL then binds to the Receptor Activator of Nuclear Factor KB (RANK) on osteoclasts and osteoclast precursors to increase osteoclast recruitment and formation, and to activate bone resorption. Accelerated bone resorption then triggers the release of growth factors embedded in the bone matrix, which in turn act on cancer cells to promote their further growth [7,10,12] (Fig. 1). This model has been extremely useful in elucidating some of the mechanisms that support and maintain established cancer metastases in bone. It is, however, less clear how individual cancer cells survive and proliferate within the bone environment at the very early stages of colonisation, i.e., before reaching a critical mass that allows them to manipulate resident bone cells in a significant way. We would therefore predict that additional mechanisms are at work at the early stages of bone metastases that involve more direct signalling pathways than those described by the classical vicious pathway.