Zoledronate but not denosumab suppresses macrophagic differentiation of THP-1 cells. An aetiologic model of bisphosphonate-related osteonecrosis of the jaw (BRONJ).

OBJECTIVES: Bisphosphonates and denosumab are antiresorptive drugs used for the treatment of osteoporosis and oncological tumors. A severe side effect is osteonecrosis of the jaw. Monocyte/macrophage dysfunction is considered to play a distinct role in osteonecrosis. THP-1 monocytic cells were used in this study to elucidate the influence of zoledronate and denosumab on phorbol-12-myrisate-13-acetate (PMA)-induced macrophage differentiation and function in real-time. MATERIALS AND METHODS: Macrophagic differentiation of the THP-1 suspension cells was measured by cell adherence in the presence or absence of different concentrations of zoledronate (0.5, 5, 50 µM) and denosumab (1, 10, 20, 40 µg/mL) using the real-time xCELLigence system. Additionally, a live/dead staining was performed by fluorescence microscopy. RESULTS: THP-1 cells demonstrated a regular initial PMA-induced differentiation to macrophages by live measurements of cell adherence and by an increase in CD68 surface expression as detected by flow cytometry. The addition of zoledronate led to cell detachment of the THP-1-derived macrophages in a dose-dependent manner in contrast to denosumab. Cell detachment was based on cell death as confirmed by live/dead staining, revealing elevated numbers of dead cells following addition of high zoledronate concentrations. However, denosumab did not deteriorate THP-1 cell viability. CONCLUSION: Our results demonstrate that zoledronate but not denosumab suppresses monocytic THP-1 cell viability after macrophagic differentiation dose-dependently. CLINICAL RELEVANCE: This is the first real-time study providing evidence for a dose-dependent immunosuppressive effect of zoledronate in contrast to denosumab on local macrophages.

Implementing a superimposition and measurement model for 3D sagittal analysis of therapy-induced changes in facial soft tissue: a pilot study.

AIM: 3D digital surface photogrammetry is an objective means of documenting the quantitative evaluation of facial morphology. However, there are no standardized superimposition and measurement systems for surveying soft tissue changes. The aim of this study was to present a superimposition and measurement model for three-dimensional analysis of therapy-induced sagittal changes in facial soft tissue and to ascertain its applicability based on the reproducibility of 3D landmark positions. PATIENTS AND METHOD: Twenty-nine children were examined (eight with cleft lip and palate, six with cleft palate, eight with Class III malocclusion and seven healthy controls, between 4.1 and 6.4 years). The mean time between examinations was 8.2 months for the patients and 8 months for the control group. Data was acquired with the DSP 400((c))imaging system. A mathematical model with seven superimposition points was developed. Two 3D images, one at the beginning and the other at the end of the examination, were generated. Both images were superimposed ten times. Ten landmarks for evaluating the soft tissue changes were geometrically defined on the superimposition image, put in place ten times, and measured. The landmarks' reproducibility was calculated via statistical intraoperator analysis. Measurement error was identified using the root mean square error (RMSE). RESULTS: The superimposition points were easy to locate and the landmarks well definable. All midface landmarks proved to be highly reproducible with an RMSE under 0.50 mm. The lower face landmarks demonstrated good reproducibility with an RMSE under 1 mm. The midface landmarks' precision fell below the range of accuracy, while the lower face landmarks' precision fell within the optoelectronic scanner device's range of accuracy (0.50-1 mm). CONCLUSIONS: As an accurate, non-invasive, millisecond-fast, non-ionizing and ad infinitum repeatable procedure, 3D digital surface photogrammetry is very well suited for clinical and scientific application in orthodontics. We developed a reliable superimposition and measurement model with 3D digital surface photogrammetry. This new capturing and measurement system provides a simple means of determining 3D changes in facial soft tissue. Our landmarks proved to be highly reproducible for the midface while revealing good reproducibility for the lower face.