For this week’s Article of the Week relates to a presentation made by Petere Croucher on the osteocyte-specific protein sclerostin at the most recent MSAG meeting. It is an article published this month in Blood on the use of sclerostin to increase bone mass and reduce the incidence of fractures in multiple myeloma.
Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma is based on the hypothesis that although bisphosphonates like zoledronic acid are effective in preventing bone resorption in multiple myeloma, the use of bone anabolic agents such as anti-sclerostin antibodies may be more effective in protecting bone mass and preventing fractures. Sclerostin is a protein which acts via the Wnt pathway, an important pathway which when inhibited by soluble Wnt antagonists (expressed by myeloma cells) contributes to the development of bone disease in myeloma.
This study included a total of 630 patients with untreated myeloma, 82 patients with relapsed myeloma and 54 different myeloma cell lines. SOST (the gene which encodes sclerostin) and DKK1 (a Wnt antagonist expressed by myeloma cells) gene expression and sclerostin protein were measured. Additionally, an animal model was created by injecting mice with human myeloma cells. These mice were then injected with either anti-sclerostin antibody, phosphate buffered saline or zoledronic acid. Bioluminescent imaging for whole body tumour was then performed and bone marrow tumour burden was measured via flow cytometry. The femur and lumbar vertebrae of the mice were also imaged in a micro CT scanner and compression testing was performed on L4 vertebrae.
In terms of general bone mineral density loss, the study found that injecting anti-sclerostin antibody increased trabecular bone volume and trabecular number in non-myeloma-bearing mice, mice injected with murine myeloma cells and mice injected with human myeloma cells alike. Anti-sclerostin antibody was shown to prevent the myeloma-induced bone loss and increased trabecular and cortical bone thickness in both the femur and vertebra in myeloma-bearing mice (both murine and human). Histomorphometric analysis of mice injected with murine myeloma cells found that the myeloma cells induced an increased osteoclast number and decreased osteoblast number consistent with the uncoupling of bone resorption and formation that occurs in patients with myeloma. Treatment with anti-sclerostin antibody was shown to increase both the osteoblast number as well as the proportion of endosteal surfaces occupied with osteoblasts compared with controls. However, anti-sclerostin antibody did not appear to affect osteoclast number or osteoclastic resorption. The authors then went on to measure mineral apposition rate (MAR) and bone formation rate (BFR) of osteoblasts using two time-separated calcein labels. They demonstrated that both MAR and BFR were suppressed by murine myeloma cells but that this suppression was prevented by anti-sclerostin antibodies, normalising bone formation to the same levels as seen in controls.
In examining the effect of anti-sclerostin antibody on the development of lytic lesions, the authors injected a line of murine myeloma cells known to induce the development of osteolytic lesions in mouse models. The authors demonstrated that treatment with anti-sclerostin antibody in these mice reduced the number of osteolytic bone lesions in the femurs of these mice. In this same mouse model a similar effect on generalised bone loss was seen with anti-sclerostin antibody preventing the decrease in femoral trabecular and cortical bone seen in myeloma-bearing mice compared to controls.
In order to examine the effect of anti-sclerostin antibody on fracture risk, the authors performed biomechanics compression testing of L4 vertebrae from murine myeloma cell mouse models as well as human myeloma cell models. Anti-sclerostin antibody increased the maximum load to failure sustained by L4 vertebrae in all models including control mice. In the human myeloma cell model anti-sclerostin antibodies increased the maximum load to failure back up to the levels measured in healthy control mice.
Finally, the authors went on to assess the use of zoledronic acid in combination with anti-sclerostin antibody. In their murine myeloma cell injected mouse model they compared treatment with anti-sclerostin antibodies alone, zoledronic acid alone and both treatments in combination. The authors found that anti-sclerostin antibody and zoledronic acid alone both prevents bone loss in the femur and the vertebrae. However, when both treatments were used in combination the authors demonstrated a fourfold increase in trabecular bone volume when compared with placebo treated mice. The combination treatment demonstrated increased trabecular thickness compared to zoledronic acid alone, whereas it demonstrated increased trabecular number when compared to anti-sclerostin antibodies alone. Overall, the combination treatment demonstrated 37% greater increase in vertebral bone volume than anti-sclerostin antibody alone and 97% greater increase than zoledronic acid alone. Additionally, the authors found that maximum load to failure in the L4 vertebrae of the mouse model was increased by both anti-sclerostin antibody alone as well as combination therapy but not by zoledronic acid alone.
In summary this study demonstrates the enormous potential for the use of anti-sclerostin antibody in preventing myeloma-induced generalised bone loss, osteolytic lesions and increased fracture risk. It also demonstrates that the use of anti-sclerostin antibody and zoledronic acid in combination appears to have an additive effect and is superior to zoledronic acid alone and likely equivalent or superior to anti-sclerostin antibody alone (at least in preventing fractures). These findings appear to indicate that an increase in bone-formation has the predominant effect on bone strength and that bone-anabolic agents should be an important area for development of new agents in the management of myeloma-induced bone disease.