Abstract
Nitrogen-containing bisphosphonates are widely used for treating diverse bone pathologies. They are anticatabolic drugs that act on osteoclasts inhibiting bone resorption. It remains unknown whether the mechanism of action is by decreasing osteoclast number, impairing osteoclast function, or whether they continue to effectively inhibit bone resorption despite the increase in osteoclast number. There is increasing evidence that bisphosphonates also act on bone marrow cells like macrophages and monocytes. The present work sought to evaluate the dynamics of preosteoclast fusion and possible changes in medullary macrophage number in bisphosphonate-treated animals. Healthy female Wistar rats received olpadronate, alendronate, or vehicle during 5 weeks, and 5-bromo-2-deoxyuridine (BrdU) on day 7, 28, or 34 of the experiment. Histomorphometric studies were performed to study femurs and evaluate: number of nuclei per osteoclast (N.Nu/Oc); number of BrdU-positive nuclei (N.Nu BrdU+/Oc); percentage of BrdU-positive nuclei per osteoclast (%Nu.BrdU+/Oc); medullary macrophage number (mac/mm2) and correlation between N.Nu/Oc and mac/mm2. Results showed bisphosphonate-treated animals exhibited increased N.Nu/Oc, caused by an increase in preosteoclast fusion rate and evidenced by higher N.Nu BrdU+/Oc, and significantly decreased mac/mm2. Considering the common origin of osteoclasts and macrophages, the increased demand for precursors of the osteoclast lineage may occur at the expense of macrophage lineage precursors.
Highlights
Bisphosphonates, especially nitrogen-containing bisphosphonates, are the first-choice drugs in the pharmacological treatment of osteoporosis and other less prevalent bone pathologies
It is well documented that these anticatabolic drugs exert their action by partly inhibiting bone resorption caused by osteoclasts, either by decreasing the number of osteoclasts, altering recruitment, and/or stimulating apoptosis, [1,2,3,4,5,6,7], after which the apoptotic remains are phagocytosed by neighboring macrophages in bone marrow microenvironment
The results of the present work show that animals treated with both the bisphosphonates exhibited a significant decrease in the number of medullary macrophages as compared to shams
Summary
Bisphosphonates, especially nitrogen-containing bisphosphonates, are the first-choice drugs in the pharmacological treatment of osteoporosis and other less prevalent bone pathologies. It is well documented that these anticatabolic drugs exert their action by partly inhibiting bone resorption caused by osteoclasts, either by decreasing the number of osteoclasts, altering recruitment, and/or stimulating apoptosis, [1,2,3,4,5,6,7], after which the apoptotic remains are phagocytosed by neighboring macrophages in bone marrow microenvironment. There are reports indicating that the number of osteoclasts remains unchanged in spite of the significant increase in bone volume [8, 9]. A number of studies including our research group have observed a significant increase in the number of osteoclasts [10,11,12,13,14,15,16,17,18]. It has been reported that macrophages and monocytes are affected by bisphosphonate administration and the acute phase of the adverse reaction as well as the antitumor effects could be associated with the action of bisphosphonates on these cells [21]
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