Abstract
ABSTRACTMultiple 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.
Highlights
Multiple myeloma is a cancer of plasma cells which frequently causes severe bone destruction and debilitating bone pain, resulting in substantially diminished functional capacity and quality of life [1, 2]
Treatment of primary murine calvarial osteoblast-like cells (Ob-LC) with recombinant TGF 1 (rTGF 1) resulted in a 5β% (p≤0.001) and 58% (p≤0.01) reduction in alkaline phosphatase (Alp) at 7 and 14 days, respectively, which was prevented upon treatment with 1D11 at both time points (p≤0.01) (Figure 1a i-ii)
In the studies presented here, we have shown for the first time that the bone anabolic 1D11, when administered in combination with the antiresorptive zoledronic acid (Zol), provided a therapeutic strategy for both the prevention, but more importantly, in the treatment of myeloma-induced bone disease
Summary
Multiple myeloma is a cancer of plasma cells which frequently causes severe bone destruction and debilitating bone pain, resulting in substantially diminished functional capacity and quality of life [1, 2]. Osteoblast inhibitors such as dickkopf-1 (Dkk-1) [12, 13], activin A [14, 15] and sclerostin [16, 17] are upregulated in patient sera resulting in a decrease in bone formation. Overall, this imbalance of bone remodelling results in severe bone loss. Whilst Zol and other antiresorptives are effective at inhibiting osteoclastic bone resorption they do virtually nothing to repair existing bone damage, and as a result bone remains weak and at risk of fracture
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