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Page 6 of 12 Mansinho et al. J Cancer Metastasis Treat 2021;7:44 https://dx.doi.org/10.20517/2394-4722.2021.88

Table 2. Treatments for bone metastasis in mRCC
Bone targeted agents
Bisphosponates
Denosumab
Systemic therapy
TKI (sunitinib, cabozantinib)
IO (nivolumab, pembrolizumab)
Local treatments
Stereotactic ablative radiotherapy
Surgery

patients with BM under active systemic therapy. In this trial, significant SRE and pain reduction was
observed [46,47] .

More recently, the third-generation nitrogenous BP zoledronic acid was compared with pamidronate, also
[48]
in the breast cancer with BM setting, with no significant differences . Zoledronic acid was further
compared with ibandronate in the ZICE trial, a positive non-inferiority study that placed ibandronate as an
alternative for patients for whom frequent hospital visits are not ideal .
[49]
Data on BP efficacy in solid tumors other than breast and prostate are scarce. Zoledronic acid was evaluated
in a placebo-controlled trial of 773 patients with other tumors and BM and shown to reduce SRE incidence
and increase time to first SRE .
[50]

In the mRCC setting, a phase II trial randomized 30 patients in a 1:1 ratio to receive everolimus alone or
everolimus and zoledronic acid . Despite everolimus no longer being the standard mRCC treatment,
[51]
zoledronate may have an important role in delaying time to SREs. This was supported by a recent meta-
analysis showing that zoledronic acid reduced SRE risk by 68% (HR = 0.32, 95%CI: 0.19-0.55) compared
with placebo or no zoledronic acid .
[52]

The BTA denosumab, a fully humanized anti-RANKL monoclonal antibody, emerged from research on key
bone remodeling mediators . Denosumab can be an alternative for patients with renal disfunction or other
[53]
conditions, limiting the use of zoledronic acid. In a pivotal phase III trial, denosumab was non-inferior to
zoledronic acid in delaying time to first SRE in various advanced tumors (HR = 0.84, 95%CI: 0.71-0.98) .
[54]
Additionally, a meta-analysis including 5723 patients from three trials found that denosumab significantly
improved time to first SRE by a median of 8.21 months and reduced the risk of a first SRE by 17% compared
with zoledronic acid (HR = 0.83, 95%CI: 0.76-0.90, P < 0.001) . Data regarding use of denosumab in
[55]
urological cancers were also presented at ASCO 2013 , in a study including urological patients of the
[56]
20050244 trial and prostate cancer patients of the 2005103 trial. In total, 85 mRCC patients were
randomized to zoledronic acid and 70 to denosumab in the 20050244 trial, which reported a trend in
lowering the time to occurrence of first on-study SRE with denosumab (HR = 0.71, 95%CI: 0.43-1.17).

It should be noted that there is an added risk of osteonecrosis of the jaw (ONJ) with cumulative exposure to
denosumab and BPs . Therefore, physicians should consider a full dental examination in patients planned
[57]
to start these agents, and any necessary oral health intervention should be done before starting therapy.
Additionally, frequent clinical assessment of the oral mucosa should be a priority. Particular attention
should be given when administering BTAs concomitantly with other therapies, as anti-angiogenic TKIs