Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism.
OBJECTIVE
Osteonecrosis of the jaw has been reported in patients receiving high doses of intravenous nitrogen-containing bisphosphonates (N-BPs) because of malignant disease. The exact pathomechanisms have been elusive and questions of paramount importance remain unanswered. Recent studies have indicated toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Multipotent stem cells play an important role in the processes of wound healing and bone regeneration, which seem to be especially impaired in the jaws of patients receiving high doses of N-BPs. Therefore, the aim of the present study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH levels on the mesenchymal stem cells in vitro.


METHODS
The effect of 2 N-BPs (zoledronate and ibandronate) and 1 non-N-BP (clodronate) on immortalized mesenchymal stem cells was tested at different concentrations, reflecting 1, 3, and 6 months and 1, 3, 5, and 10 years of exposure to standard oncology doses of the 2 N-BPs and equimolar concentrations of clodronate at different pH values (7.4, 7.0, 6.7, and 6.3). Cell viability and activity were analyzed using a WST assay. Cell motility was investigated using scratch wound assays and visualized using time-lapse microscopy.


RESULTS
Both types of bisphosphonates revealed remarkable differences. Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and an acidic milieu led to a significant decrease in cell viability and activity (P < .01), with more pronounced effects for zoledronate. Equimolar concentrations of clodronate did not affect the cell survival or activity significantly, apart from the effect of pH reduction itself, which was also detectable in the patients in the control group who did not receive bisphosphonates.


CONCLUSIONS
Our results have shown that high concentrations of N-BPs and a local acidic milieu, which is commonly present in infections of the jaw, might play a key role in the pathogenesis of osteonecrosis of the jaw in patients receiving high doses of N-BPs for malignant diseases. Also the potency of N-BPs might be different, suggesting a greater risk of osteonecrosis of the jaw with zoledronate.
Otto
Sven
S
Department of Oral- and, Maxillofacial Surgery, Ludwig-Maximilians-University, Munich, Germany. Sven.Otto@med.uni-muenchen.de
Pautke
Christoph
C
Opelz
Christine
C
Westphal
Ines
I
Drosse
Inga
I
Schwager
Joanna
J
Bauss
Frieder
F
Ehrenfeld
Michael
M
Schieker
Matthias
M
D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000145:classification; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004002:Clodronic Acid / Q000008:administration & dosage / Q000009:adverse effects; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects* / Q000145:classification; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000077557:Ibandronic Acid; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects; D007571:Jaw Diseases / Q000139:chemically induced* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000473:pathology; D010020:Osteonecrosis / Q000139:chemically induced* / Q000473:pathology; D013997:Time Factors; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005456:Fluorescent Dyes; D007093:Imidazoles; D004002:Clodronic Acid; D000077211:Zoledronic Acid; D000077557:Ibandronic Acid