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

further increase ONJ risk when combined with those agents. In a series of 41 patients treated with
denosumab and an anti-angiogenic TKI, ONJ incidence was 17% (contrasting with pivotal denosumab
[58]
trials) . Additionally, a multicenter retrospective study including 44 patients mostly under anti-angiogenic
TKIs and BTAs reported an unexpectedly high number of ONJ cases, which contrasts with literature data
and suggests that the frequency of ONJ in RCC patients may be largely underestimated .
[59]
In addition to bisphosphonates, radioisotopes have also been investigated in this setting. Radium-223 acts as
a calcimimetic, and therefore it has a high affinity to skeletal lesions that typically have an increased bone
turnover. Being an alpha-emitting agent, radium-223 can prevent the progression of bone metastasis by
killing cancer cells and breaking the vicious cycle of bone metastasis, stabilizing the tumoral
[60]
microenvironment. In a study by McKay et al. , the addition of radium-223 to VEGF-targeted therapy in
patients with mRCC and bone metastases was studied. This association produced a significant decrease in
the serum levels of five bone turnover markers, with no limiting toxicity. These data suggest that radium-
223 associated with VEGF-targeted therapy is safe and might be useful in treating mRCC patients, although
we need clinical trial data to see if this approach reduces the rate and incidence of SREs in these patients .
[60]
The RadiCal trial is a phase II randomized protocol that is currently investigating this (SSE as a primary
endpoint), by comparing cabozantinib with radium-223 in combination with cabozantinib (NCT04071223).

Systemic therapy
Systemic treatment options for patients with mRCC include TKIs targeting the vascular endothelial growth
[61]
factor receptor, the mammalian target of rapamycin (mTOR), and other pathways . Additionally,
monoclonal antibodies, such as the anti-VEGF bevacizumab, and immune checkpoint inhibitors, such as
pembrolizumab, nivolumab, and ipilimumab, have yielded positive results, both alone and in
combination [62,63] .

Data regarding BM and systemic therapy is also scarce. Preclinical evidence suggests that sunitinib can
[64]
[64]
inhibit osteoclastic activity . In a study by Shinya et al. , the number of osteoclasts in mice treated with
sunitinib was significantly lower than in the controls, suggesting sunitinib may inhibit osteoclast
maturation. Additionally, a decline in serum and urine levels of amino-terminal telopeptide was seen in
patients with mRCC during the first four weeks of sunitinib treatment, suggesting that it might have
[65]
significant activity in patients with RCC and bone metastasis .
Although there are no prospective clinical data supporting this, two retrospective analyses found that
[66]
sunitinib prolongs OS compared to historical controls and decreases development and time to new bone
[67]
lesions compared to sorafenib .
Cabozantinib is an approved treatment for mRCC, in both first and second line, and has been studied in the
subgroup of BM patients, in the METEOR trial. In this study, the median survival of patients with BM was
20 months in the cabozantinib arm and 12 months in the everolimus arm in the second- or higher-line
setting [68,69] . In a preclinical study, it was shown that doses of cabozantinib below the threshold of
cytotoxicity inhibit osteoclast differentiation and bone resorption activity. Additionally, cabozantinib
downregulated the expression of osteoclast marker genes, and direct cell-to-cell contact between
cabozantinib pre-treated osteoblasts and untreated osteoclasts confirmed the indirect anti-resorptive effect
of cabozantinib . Moreover, recent data from a subgroup analysis of the Checkmate-9ER trial evaluating
[70]
[12]
nivolumab plus cabozantinib confirm an OS and PFS benefit of the combination in BM patients . A
favorable OS trend was also observed in a subgroup analysis of the Checkmate-214 trial , comparing
[9]
nivolumab plus ipilimumab with sunitinib, and in the Checkmate-025 trial , comparing nivolumab with
[71]