The inventors have developed methods and reagents for the detection of bone sialoprotein (BSP) in biological samples. The technology relates to the disruption of a serum complex that masks the majority of BSP from established detection systems. Furthermore, there is evidence that there may be a more acidic form of BSP secreted not by normal bone, but only by tumors. Detection of BSP in serum may be a good marker of various bone diseases and a variety of cancers including breast, prostate, lung, and thyroid.