Effect of bisphosphonates on macrophagic THP-1 cell survival in bisphosphonate-related osteonecrosis of the jaw (BRONJ).

OBJECTIVES: Immune deficiency and bacterial infection have been suggested to play a role in the pathophysiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Zoledronate was previously found to promote THP-1 cell death. To examine this hypothesis with all commonly prescribed bisphosphonates, we tested the effect of (nitrogen-containing) ibandronate, risedronate, alendronate, pamidronate, and (non-nitrogen-containing) clodronate on macrophagic THP-1 cells. STUDY DESIGN: Activated THP-1 cells were exposed to .5 to 50 µM of nitrogen-containing bisphosphonates and .5 to 500 µM of clodronate. Cell adherence and survival were assessed in vitro using the xCELLigence real-time monitoring system. Results were confirmed histologically and verified with Live/Dead staining. RESULTS: All bisphosphonates inhibited THP-1 cell adherence and survival dose and time dependently, significant for zoledronate, alendronate, pamidronate, and clodronate in high concentrations (50 µM and 500 µM; P < .05). Low concentrations (0.5 µM) of risedronate, alendronate, and pamidronate prolonged the inflexion points of THP-1 cell survival compared with controls (P < .05). THP-1 cells exhibited no cytomorphologic changes at all concentrations. CONCLUSIONS: Commonly prescribed bisphosphonates inhibit the survival of macrophagic THP-1 cells dose-dependently without altering morphology. This may suggest a local immune dysfunction reflective of individual bisphosphonate potency leading to the pathogenesis of BRONJ.

Altered macrophagic THP-1 cell phagocytosis and migration in bisphosphonate-related osteonecrosis of the jaw (BRONJ).

OBJECTIVES: Local immune dysfunction via macrophages is a proposed aetiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study aimed to clarify the effects of various bisphosphonates on macrophage function using a THP-1 monocytic model to examine migration, phagocytosis, and fibrin structure. MATERIALS AND METHODS: THP-1 cell migration was measured in the presence and absence of zoledronate, ibandronate, risedronate, alendronate, pamidronate (0.5, 5 and 50 µM) and clodronate (125, 250 and 500 µM) using the real-time xCELLigence system. Phagocytosis and actin fibre assays were performed after 72 h with zoledronate, ibandronate, alendronate and clodronate. RESULTS: Time to maximum migration for THP-1 cells was significantly reduced (p < 0.05) for high dosages of zoledronate, ibandronate and alendronate compared to controls. All dosages of clodronate and a low dose of zoledronate exhibited prolonged migrations. Phagocytic capacity was significantly reduced in high dosages of all bisphosphonates and for 5 µM zoledronate and ibandronate (p < 0.05). Low bisphosphonate exposure was accompanied by overcharged phagosoms. Altered appearance in F-actin fibrin structure was observed in bisphosphonate-exposed cells. CONCLUSIONS: All bisphosphonates altered the migration of THP-1 cells dose-dependently. Low doses also prolonged migration and altered cell morphology. These findings support the idea of a disturbed local immune function of macrophages even in jaw bone exposed to low concentrations of bisphosphonate. CLINICAL RELEVANCE: These are the first real-time results for disrupted migration and function of macrophagic THP-1 cells in high doses. Low dosages also demonstrated altered macrophage phagocytosis and cell morphology, suggesting a disturbed local immune function in BRONJ pathogenesis.

3D soft tissue changes in facial morphology in patients with cleft lip and palate and class III mal occlusion under therapy with rapid maxillary expansion and delaire facemask.

AIM: Rapid Maxillary Expansion (RME) and Delaire facemask are a well-established treatment method for patients with cleft lip and palate and Class III malocclusion. Several roentgenocephalometric studies on skeletal effects of this therapy are known. However, there are no systematic studies on soft tissue changes. The aim of this study was to analyze three-dimensionally the soft tissue changes in facial morphology of children with cleft lip and palate and Class III malocclusion under therapy with RME and Delaire facemask. PATIENTS AND METHOD: A prospective longitudinal clinical trial was undertaken. 29 children between 4.1 and 6.4 years were divided into four groups: eight patients with unilateral cleft lip and palate (group 1), six patients with isolated cleft palate (group 2), eight patients with Class III malocclusion (group 3). The mean treatment period with RME and Delaire mask was 8.2 months. Seven untreated children with no need of orthodontic treatment were chosen as the control (group 4). Two 3D images, one at the beginning and one at the end of the study, were generated with the DSP 400((c)) imaging system. Both images were superimposed ten times and measured ten times. RESULTS: We detected significant forward rotation and forward displacement of the soft tissue in the lower midface with the dentoalveolar areas in all patient groups. No significant asymmetric forward displacement of the soft tissue in the maxilla could be verified in the lower or upper midface, not even in the unilateral cleft lip and palate patients. Among the groups, the Class III malocclusion patients showed greater maxillary soft tissue changes. CONCLUSION: The RME and the Delaire facemask demonstrated the greatest effectiveness in the lower midface soft tissue in terms of forward displacement and forward rotation in the cleft lip and palate patients, particularly in the Class III patients. The 3D data allowed us to discriminatively interpret the effects of the orthopedic mask on the entire maxillary complex and maxillary alveolar process. In the unilateral cleft lip and palate patients, there was descriptively both symmetric and asymmetric advancement of the midface soft tissue.