Preventing and Repairing Myeloma Bone Disease by Combining Conventional Antiresorptive Treatment With a Bone Anabolic Agent in Murine Models

Abstract

Multiple myeloma is a plasma cell malignancy, which develops in the bone marrow and frequently leads to severe bone destruction. Current antiresorptive therapies to treat the bone disease do little to repair damaged bone; therefore, new treatment strategies incorporating bone anabolic therapies are urgently required. We hypothesized that combination therapy using the standard of care antiresorptive zoledronic acid (Zol) with a bone anabolic (anti‐TGFβ/1D11) would be more effective at treating myeloma‐induced bone disease than Zol therapy alone. JJN3 myeloma‐bearing mice ( n = 8/group) treated with combined Zol and 1D11 resulted in a 48% increase ( p ≤ 0.001) in trabecular bone volume (BV/TV) compared with Zol alone and a 65% increase ( p ≤ 0.0001) compared with 1D11 alone. Our most significant finding was the substantial repair of U266‐induced osteolytic bone lesions with combination therapy ( n = 8/group), which resulted in a significant reduction in lesion area compared with vehicle ( p ≤ 0.01) or Zol alone ( p ≤ 0.01). These results demonstrate that combined antiresorptive and bone anabolic therapy is significantly more effective at preventing myeloma‐induced bone disease than Zol alone. Furthermore, we demonstrate that combined therapy is able to repair established myelomatous bone lesions. This is a highly translational strategy that could significantly improve bone outcomes and quality of life for patients with myeloma. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

TGFβ Inhibition Stimulates Collagen Maturation to Enhance Bone Repair and Fracture Resistance in a Murine Myeloma Model

“…One‐half of the lesions were completely repaired, and remaining lesions were reduced in size by nearly 60% with SD‐208 treatment + chemotherapy, which was substantially more effective than chemotherapy alone. Similarly, SD‐208 increased trabecular bone volume in long bones, supporting previous studies in naïve mice and with 1D11 in myeloma‐bearing (JJN3, U266, and 5TGM1) mice . Chemotherapy‐treated mice also exhibited lesion repair, reflecting recent observations in patients .…”

“…However, chemotherapy‐driven repair was less effective than when combined with SD‐208. Importantly, by combining SD‐208 with chemotherapy we observed more effective repair within 2 weeks, even without anti‐resorptive therapy and despite administration at a very late disease stage, differing from previous studies treating for longer periods or prior to tumor development . Furthermore, we identified that chemotherapy alleviated not only the tumor‐derived pro‐osteoclastic signals, but also eliminated expression of pro‐osteoclastic PTHrP in osteocytes, which were previously an unidentified source of PTHrP in myeloma.…”

“…The bone effects of SD‐208 were not limited to the U266‐GFP‐luc model, as myeloma bone disease was also reduced with preventative treatment of JJN3‐bearing mice and was more effective than 1D11 at preventing bone lesions. Thus, SD‐208 effectively prevented myeloma bone disease and when administered with chemotherapy rapidly repaired bone lesions across multiple murine models, and was more effective than 1D11 …”

“…Prevention of lesion development has been observed with anti‐TGFβ therapies (1D11 and now SD‐208), an anti‐sclerostin antibody, an anti‐DKK1 antibody, and a soluble decoy receptor for activin A in vivo . Repair of bone lesions was observed with 1D11 in combination with zoledronic acid . Here we show more rapid repair with SD‐208 combined with btz and len, without the use of conventional anti‐resorptives, in a novel U266‐GFP‐luc low tumor phase model.…”

“…Inhibition of TGFβ has both bone anabolic and anti‐resorptive effects in non‐tumor‐bearing mice, leading to increased bone volume and improved bone quality . Similarly, TGFβ inhibition prevented development of myeloma bone disease, and repaired existing bone lesions if administered with the bisphosphonate zoledronic acid …”