PIs decrease myeloma burden and associated bone destruction in an immunocompetent murine model. 5TGM1-GFP murine myeloma cells were injected into syngeneic C57Bl/KaLwRij mice. After 14 days, mice were randomized into PI treatment groups (n≥7/group) and dosed for an additional 2 weeks. All PIs decreased tumor burden as measured by (a) levels of serum IgG2b (clonotype of 5TGM1 cells) and (b, c) percent of GFP + tumor cells within the BM or spleen upon sacrifice at day 28. (d, e) MicroCT analysis demonstrated that treatment with PIs protected animals from myeloma-induced loss of trabecular bone volume and number. (f) Serum carboxy-terminal telopeptide collagen crosslinks (serum CTX) was significantly decreased and (g) serum N-terminal propeptide of type I procollagen (serum P1NP) was significantly increased in all PI-treated animals compared with vehicle-treated animals. All results are expressed as mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001 versus vehicle or between indicated groups.