The potential improvement in management of patients

The potential improvement in management of patients can be evidenced by a paper comparing baseline symptom severity over two time frames by Khan et al.[17]. Baseline edmonton symptom assessment system (ESAS) scores reported by patients seen from 2006 to 2009 were found to exhibit significant improvement for most items, as compared to values taken from 1999 to 2002. The largest magnitude of difference in symptom severity was found in depression, with a median score for depression of 0.0 from 2006 to 2009 compared to 2.0 from 1999 to 2002 [17]. Similar decreases were also seen in pain, fatigue and sense of wellbeing. A probable cause for these items may be the increased referral to palliative care. An increased trend in palliative care has been exhibited and may significantly reduce the symptom severity of patients at risk of bone metastases, especially when coupled with the aforementioned early incorporation in disease trajectory [18]. It is for this reason, palliative treatment has gained increasing support as a vital component of comprehensive cancer care, with ASCO resolving to induct palliative care as routine by 2020 [19]. The heterogeneity in reporting SRE outcomes limits the comparison of studies using bone targeted agents. More phase III data are available than what have been presented herein (Table 3). Unfortunately, due to varying endpoint definitions in the literature, we are unable to include additional studies which may have strengthened our findings. Heterogeneity may also arise from the differences in histology between primary breast, prostate, myeloma, lung, renal and arginase inhibitors cancers, however our results indicate that regardless of history or the different drug mechanisms SMR values are decreasing significantly. Our findings may further be confounded by the variability of the included studies themselves. Certain studies reported extended follow-up periods, while others were published after a predetermined endpoint. Depending on the time frame in which data were captured, this may inflate or deflate true SMR rates. As observed in the data presented, studies on patients with primary renal cell carcinoma generally reported greater SMRs than other cancers, which may have influenced our findings.
Acknowledgements
Introduction Osteonecrosis of the jaw (ONJ) is an adverse event reported in patients receiving BPs and RANKL inhibitors such as denosumab [1–9]. ONJ is defined as the persistence of exposed bone in the oral cavity, despite an adequate treatment for six weeks, without local evidence of malignancy and no prior radiotherapy to the affected region [10]. However, ONJ may present with the non-exposed variant of ONJ. The pooled risk estimated incidence of ONJ, in BPs users, is 2,4% [11–14]. In RCTs comparing zoledronic acid and denosumab in 5677 patients who underwent screening dental procedure, 89 ONJ cases were reported of which 52 in the denosumab group [8,11–13]. Factors adversely influencing bone remodelling are considered to be pivotal in the pathophysiology of the ONJ and preclinical data shows that the bone turnover is higher in the jaws with respect to other skeletal areas [10,15–17]. The presence of chronic periodontal pathologies, the duration and type of BP therapy, tooth extractions, the use of dental appliances, denture traumatisms, invasive dental surgery during the course of BP therapy, poor oral hygiene, concurrent disease (e.g. diabetes, peripheral vasculopathy) and the concomitant use of chemotherapy, antiretroviral therapies, thalidomide, and corticosteroids or the presence of anaemia are considered putative additional risk factors [1–5,18,19]. In a retrospective analysis of 567 cases Vescovi et al. [20] studied the differences between the non surgery-triggered vs surgery-triggered variants bisphosphonate-related osteonecrosis of the jaws. In 205 cases (36.2%) of ONJ no surgery was performed as against 362 cases (63.8%) of post-local invasive procedure forms including tooth extraction in 361 cases and implant placement in one case only.