Page 129 - Haematologica August 2018

OTSSP167 has activity in myeloma bone disease
OTSSP167 decreases osteoclast activity and restores osteoblast activity in multiple myeloma-bearing mice
Because of the lack of an anti-myeloma effect with an OTSSP167 dose of 7.5 mg/kg/2d, we performed immunohistomorphometry on the bones of mice from this cohort. The increase in osteoclast surface observed in MM-bearing mice was completely prevented after OTSSP167 treatment (Figure 6A and 6D). Together with an increase in osteoclast activity, osteoblast surface was
suppressed in MM-bearing mice and OTSSP167 restored osteoblast surface levels to those observed in naive mice (Figure 6B and 6E). Finally, given the effect of OTSSP167 on osteoblast collagen deposition and mineralizing activ- ity in vitro, we analyzed osteoid and found that OTSSP167 increased osteoid surface in MM-bearing mice (Figure 6C and 6F). In addition, osteoid thickness was reduced in OTSSP167-treated MM-bearing mice (Figure 6G).
A
BCDE
Figure 5. Preclinical activity of OTSSP167 in multiple myeloma bone disease. A) Representative 3D-reconstructions of distal femurs of naive or 5TGM.1 MM-bearing mice treated with vehicle solution or various dosing schedules of OTSSP167. Upper panels show a frontal view. Lower panels show a frontal section of the frontal view. Cortical bone is colored white, trabecular bone is colored green. B) Quantification of the number of cortical perforations with a diameter of at least 50 μm. CTAn analysis was performed and C) trabecular bone volume (Tb.BV/TV), D) trabecular number (Tb.N), E) Superimposition of tumor load data (red line, relative to vehicle-treated MM-bearing mice) and Tb.BV/TV (black bars, relative to naive mice) in the different mouse cohorts. All data are represented as mean +/- standard error. All statistical differences are reported versus vehicle-treated mice. No difference between the different dosing schedules was observed. *:P<0.05, **:P<0.01, ***:P<0.001.
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