The effects of sorafenib and sunitinib on bone turnover markers in patients with bone metastases from renal cell carcinoma

Abstract

e16145 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common and associated with poor outcomes. While the multi-tyrosine kinase inhibitors (TKI's) sunitinib and sorafenib have advanced the treatment of metastatic RCC, their efficacy on BM is unknown. Urinary N-telopeptide (uNTX) is a marker of bone turnover measured in nmol/mmol creatinine. Elevated uNTX levels correlate with an increased risk of skeletal related events and mortality in patients receiving bisphosphonates for BM from a range of primaries. In this pilot biomarker study we sought to prospectively evaluate the effects on BM of these multi-TKI's in RCC patients. Methods: Eligible patients had advanced RCC, at least one BM evident on imaging and no bisphosphonate exposure within 4 weeks. UNTX levels (OsteoMark) were measured at; baseline and weeks-1, 4, 8 and 12 after commencing either sunitinib or sorafenib. The primary endpoint was the percentage change (Ch) in uNTX levels from baseline. Serum samples were also collected for KIT and VEGFR-2 (Quantikine). Patients also completed pain (including bone pain) and quality of life questionnaires. Results: The uNTX results on the first 9 patients are presented in the table below (7 received sunitinib and 2 sorafenib). In this group, sVEGFR-2 and sKIT levels fell by week-1 and 4 respectively and at week-12 the mean % changes (95% CI) were -34% (-0.53,-0.14) and -38% (-0.58,-0.18). Conclusions: In patients with BM from RCC and at least moderately elevated uNTX levels at baseline, these multi-TKI's show a significant trend to decrease uNTX levels, but perhaps not as effectively as bone-specific therapies (e.g. bisphosphonates) do in other malignancies. SVEGFR-2 and sKIT levels also fell across the patient group over the same period. This pilot data raises questions about the activity of the multi-TKI's in BM from RCC and further research is needed. [Table: see text] [Table: see text]

Successful Control of Hypercalcemia with Sorafenib, Evocalcet, and Denosumab Combination Therapy for Recurrent Parathyroid Carcinoma

“…Regarding the direct effect of TKIs on bone, Murray et al elegantly reported that sunitinib, a similar TKI to sorafenib, inhibited the osteoclast development and function mediated by macrophage colony-stimulating factor (M-CSF), a differentiating factor for osteoclasts ( 35 ). Furthermore, sorafenib decreased the urinary levels of N-terminal cross-linking telopeptide of type I collagen (NTx), a bone resorption marker, in renal cell carcinoma with bone metastasis ( 36 ). In the present case, the combination of sorafenib and denosumab displayed strong inhibitory effects against osteoclast-induced bone resorption, subsequently enabling calcium management for recurrent PC.…”

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: New and future perspectives for parathyroid carcinoma

“…The major contributor to poor quality of life and mortality in patients is from hypercalcemia. Different mechanisms of TKI's inhibitory effects on bone resorption have been proposed to be direct effects on osteoblasts and osteoclasts (Dewar et al 2005, Sahi et al 2009, Vandyke et al 2010, Aleman et al 2014; indirect actions via different pathways include osteoblast-derived RANKL, VEGF inhibition, PDGFR inhibition, macrophage colony-stimulating factor, SRC kinase, decrease in vitamin D-mediated intestinal calcium absorption, and altered calcium and phosphorus metabolism (Dewar et al 2005, Sahi et al 2009, Vandyke et al 2010, Aleman et al 2014. Sorafenib is such a multitarget TKI with anti-angiogenesis effect achieved by inactivating VEGFR-2, VEGFR-3, PDGFR-β, FGF receptor 1, c-Kit, Flt-3, and RET (http://hcp.nexavar-us.com/ mechanism-of-action/).…”

Renal cell carcinoma bone metastases: clinical advances

“…A prospective pilot study specifically designed to assess the effect of the anti-VEGFR multi-TKIs has recently been presented [Sahi et al 2009]. In patients with bone metastases from RCC and at least moderately elevated uNTX levels prior to treatment with sunitinib or sorafenib, there was significant trend to decrease uNTX levels during 12 weeks of therapy, but the fall was not as quick nor as marked as typically seen with bone-specific therapies such as bisphosphonates [Sahi et al 2009].…”