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Suominen et al. J Cancer Metastasis Treat 2019;5:14 I http://dx.doi.org/10.20517/2394-4722.2018.64 Page 9 of 13

A

C

B

D

2+
Figure 5. Osteoclasts and blood Ca . Osteoclasts were counted from TRAP stained sections and serum TRACP 5b activity was measured
2+
at three time points (before inoculation of cells, days 17 and 24) as a systemic marker of osteoclast number. Blood Ca was measured
from terminal blood samples for detection of hypercalcemia. A: Representative images of the TRAP staining; B: statistically significant
changes were not observed in the number of osteoclasts at tumor-bone interface; C: serum TRACP 5b was decreased in the ZOL group
already on day 17 and in the ZOL and DOX + ZOL groups on day 24 compared to the control group; D: hypercalcemia was prevented in
the ZOL and DOX + ZOL groups. Data are expressed as mean ± SD, n = 7-8 animals. Scale bars 50 μm, arrows osteoclasts. *Significantly
different from control group (P < 0.05); ***significantly different from control group (P < 0.001); NS: non-significant; TRAP: tartrate
resistant acid phosphatase; TRACP 5b: tartrate resistant acid phosphatase 5b; DOX: doxorubicin; ZOL: zoledronic acid

[3]
established bone metastases . DOX on the other hand did increase the number of apoptotic cells, as
expected. We did not observe any other significant effects with DOX on tumor growth or proliferation
index, which may have been due to a suboptimal dose of DOX. Higher doses of DOX are able to decrease
[25]
tumor burden in the same model . However, the dose in this study was set at a low level to enable
[11]
observation of possible synergistic effects. Likewise, Ottewell et al. used a suboptimal dose of DOX and
observed synergistic effects on tumor volume and number of apoptotic cells in bone. They did not observe
any effects of DOX alone on apoptosis by caspase-3 staining or on tumor burden in the intravenous MDA-