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Updated: Nov 19, 2025
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Zoledronate Causes a Systemic Shift of Macrophage Polarization towards M1 In Vivo
Manuel Weber1, Andi Homm1, Stefan Müller1
1Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
Background:
Immunomodulatory properties of bisphosphonates (BP) are suggested to contribute to the development of medication-associated osteonecrosis of the jaw (MRONJ). Furthermore, bisphosphonate-derived immune modulation might contribute to the anti-metastatic effect observed in breast cancer patients. Macrophages are potential candidates for the mediation of immunomodulatory effects of bisphosphonates. The study aimed to investigate the influence of bisphosphonates alone and in combination with surgical trauma on systemic macrophage polarization (M1 vs. M2) using an in vivo rat model.
Methods:
A total of 120 animals were divided into four groups. Groups 2 and 4 were treated with 8 × 40 μg/kg body weight of the BP Zoledronate i.p. (week 0-7). Groups 3 and 4 were exposed to surgical trauma (week 8, tooth extraction + tibia fracture), whereas in Group 1 neither medication nor surgical trauma was applied. After 8, 10, 12 and 16 weeks, skin, lung and spleen were immunohistochemically examined for macrophage polarization via expression analysis of CD68, CD163 and iNOS using a tissue microarray (TMA).
Results:
A significant shift of macrophage polarization towards M1 was observed in skin, spleen and lung tissue of animals, with and without surgical trauma, treated with BP when compared to those without BP application. Surgical trauma did not cause a significant increase towards M1 polarization.
Conclusions:
BP application leads to a systemic pro-inflammatory situation in vivo, independent of surgical trauma, as evidenced by the shift in macrophage polarization towards M1 in various somatic tissues. This provides a possible explanation for the clinically observed anti-tumor effect of bisphosphonates and might also contribute to pathogenesis of MRONJ.
Insights
Bisphosphonates (BP) induce a systemic pro-inflammatory response by shifting macrophage polarization towards M1, independent of surgical trauma. This finding may explain BP's anti-tumor effects and contribute to understanding medication-associated osteonecrosis of the jaw (MRONJ).
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Bisphosphonates (BP) exhibit immunomodulatory properties potentially linked to medication-associated osteonecrosis of the jaw (MRONJ) and anti-metastatic effects in breast cancer.
- Macrophages are key mediators of BP's immunomodulatory effects.
Purpose of the Study:
- To investigate the impact of bisphosphonates (BP) alone and with surgical trauma on systemic macrophage polarization (M1 vs. M2) in an in vivo rat model.
Main Methods:
- 120 rats were divided into four groups: control, BP only, surgical trauma only, and BP with surgical trauma.
- BP (Zoledronate) was administered intraperitoneally for 7 weeks.
- Macrophage polarization was assessed via immunohistochemistry (CD68, CD163, iNOS) in skin, lung, and spleen at 8, 10, 12, and 16 weeks.
Main Results:
- Bisphosphonate treatment significantly shifted macrophage polarization towards M1 in skin, spleen, and lung tissues, irrespective of surgical trauma.
- Surgical trauma alone did not significantly increase M1 polarization.
Conclusions:
- Bisphosphonate administration induces a systemic pro-inflammatory state characterized by M1 macrophage polarization across multiple tissues.
- This pro-inflammatory shift may contribute to the observed anti-tumor effects of bisphosphonates and the pathogenesis of MRONJ.
