Bilal Al-Nawas

Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate.

BACKGROUND In addition to other treatments, patients with prostate cancer (pCA) and bone metastasis receive bisphosphonates. Since 2003, a previously unknown side-effect of bisphosphonates-bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ)-has been described, and frequency has since increased. An exact incidence is still unknown. OBJECTIVES The aim of this study was to assess the incidence and additional factors in the development of BP-ONJ. DESIGN, SETTING, AND PARTICIPANTS From July 2006 to October 2007, patients with advanced pCA and osseous metastasis receiving bisphosphonate therapy in the Department of Urology or Haematology and Oncology at the Johannes-Gutenberg-University Mainz, Germany, received a dental examination. In all, 43 patients were included. MEASUREMENTS Patients were checked for exposed bone, osteonecrosis, mucosal defects, inflammation, and oral hygiene. Further points were the applied bisphosphonate, co-medication, the duration of application, and possible trigger factors for BP-ONJ. RESULTS AND LIMITATIONS Eight of 43 patients developed BP-ONJ (18.6%). All patients had received zoledronate at least 14 times. Two patients had received bondronate, and one patient had received pamidronate before switching to zoledronate. All patients had had a previous tooth extraction or a denture pressure sore, and all patients had received additional chemotherapy and corticosteroids. CONCLUSIONS The reason for this relatively high incidence compared to other studies might be the prospective study design and thorough dental examination. In studies with such small numbers as have been published to date, nondetection or nonreported cases of BP-ONJ have an influence on the outcome. The incidence of BP-ONJ in patients with pCA might be an underestimated problem.

Influence of bisphosphonates on endothelial cells, fibroblasts, and osteogenic cells

Bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is a side effect primarily in patients receiving highly potent nitrogen-containing bisphosphonates. The exact etiopathology is unknown. In addition to reduced bone remodeling, there may also be an impact on soft tissues. The impact of nitrogen- (ibandronate, pamidronate, zoledronate) and non-nitrogen-containing bisphosphonates (clodronate) on human umbilicord vein endothelial cells (HUVEC), fibroblasts and osteogenic cells was analyzed employing cell viability testing and a scratch wound assay. The impact on the cell morphology of vital-stained osteogenic cells was investigated by cell visualization (confocal laser scanning microscopy). Pamidronate and zoledronate had the greatest negative impact on all cell lines, whereas the impact of ibandronate and clodronate was less distinct. The effect of clodronate on HUVEC and fibroblasts was particularly marginal. BP-ONJ could be a multifactorial event with multicellular impairments. This might result in altered wound healing. The increased impact of the highly potent bisphosphonates, particularly on non-bone cells, may explain the higher occurrence of BP-ONJ.

Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro.

Bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is one of the main side effects in patients treated with bisphosphonates for metastasis to the bone or osteoporosis. BP-ONJ usually occurs in patients treated with highly potent nitrogen-containing bisphosphonates. The exact mechanism of action and etiopathology is still unknown. In addition to inhibition of bone remodelling, an anti-angiogenetic effect has become the focus of research. The aim of these study was to investigate the effect of different bisphosphonates on human umbilicord vein endothelial cells (HUVEC) and endothelial progenitor cells (EPC), which play an important role in angiogenesis. Using varying concentrations, the impact of one non-nitrogen-containing bisphosphonate (clodronate) and three nitrogen-containing bisphosphonates (ibandronate, pamidronate and zoledronate) on HUVEC and EPC was analysed. The biologic behaviour of HUVEC after incubation with different bisphosphonates was measured in a Boyden migration assay as well as in a 3D angiogenesis assay. The number of apoptotic cells was measured by Tunnel assay. To underline the importance of neoangiogenesis in the context of BP-ONJ, we measured the EPC number after incubation with different bisphosphonates in vitro. HUVEC and EPC were significantly influenced by bisphosphonates at different concentrations compared with the non-treated control groups. The nitrogen-containing bisphosphonates pamidronate and zoledronate had the greatest impact on the cells, whereas clodronate followed by ibandronate was less distinct on cell function. These results underline the hypothesis that inhibited angiogenesis induced by bisphosphonates might be of relevance in the development and maintenance of BP-ONJ. The increased impact by highly potent bisphosphonates on HUVEC and EPC may explain the high prevalence of BP-ONJ in patients undergoing this treatment.

Incidence of Bisphosphonate-associated Osteonecrosis of the Jaws in Breast Cancer Patients

Bisphosphonate‐associated osteonecrosis of the jaws (BP‐ONJ) is a relatively new disease. The aim of this study was to evaluate the prevalence of BP‐ONJ in breast cancer patients with osseous metastasis and bisphosphonate therapy.

A Double‐Blind Randomized Controlled Trial (RCT) of Titanium‐13Zirconium versus Titanium Grade IV Small‐Diameter Bone Level Implants in Edentulous Mandibles – Results from a 1‐Year Observation Period

BACKGROUND The use of endosseous dental implants has become common practice for the rehabilitation of edentulous patients, and a two-implant overdenture has been recommended as the standard of care. The use of small-diameter implants may extend treatment options and reduce the necessity for bone augmentation. However, the mechanical strength of titanium is limited, so titanium alloys with greater tensile and fatigue strength may be preferable. PURPOSE This randomized, controlled, double-blind, multicenter study investigated in a split-mouth model whether small-diameter implants made from Titanium-13Zirconium alloy (TiZr, Roxolid™) perform at least as well as Titanium Grade IV implants. METHODS AND MATERIALS Patients with an edentulous mandible received one TiZr and one Ti Grade IV small-diameter bone level implant (3.3 mm, SLActive®) in the interforaminal region. The site distribution was randomized and double-blinded. Outcome measures included change in radiological peri-implant bone level from surgery to 12 months post-insertion (primary), implant survival, success, soft tissue conditions, and safety (secondary). RESULTS Of 91 treated patients, 87 were available for the 12-month follow-up. Peri-implant bone level change (-0.3 ± 0.5 mm vs -0.3 ± 0.6 mm), plaque, and sulcus bleeding indices were not significantly different between TiZr and Ti Grade IV implants. Implant survival rates were 98.9 percent and 97.8 percent, success rates were 96.6 percent and 94.4 percent, respectively. Nineteen minor and no serious adverse events were related to the study devices. CONCLUSION This study confirms that TiZr small-diameter bone level implants provide at least the same outcomes after 12 months as Ti Grade IV bone level implants. The improved mechanical properties of TiZr implants may extend implant therapy to more challenging clinical situations.

Systematic Review on Success of Narrow-Diameter Dental Implants

PURPOSE The aim of this systematic review was to determine the survival and success rates of narrow-diameter implants (NDI) in different clinical indications compared to standard diameter implants. MATERIALS AND METHODS Implant diameters were categorized into categories 1 (< 3.0 mm), 2 (3.00 to 3.25 mm), and 3 (3.30 to 3.50 mm). Retro- and prospective studies with more than 10 patients and a follow-up time of 1 year or more were included. RESULTS A literature search from 1995 to 2012 revealed 10 articles reporting on implant diameters < 3 mm (Category 1), 12 articles reporting on implant diameters 3 to 3.25 mm (Category 2), and 16 articles reporting on implant diameters 3.3 to 3.5 mm (Category 3). The quality of the studies was mostly low with a high risk of bias. Dental implants < 3.0 mm (mini-implants) were one-piece in the edentulous arch and non-loaded frontal region with survival rates between 90.9% and 100%. For dental implants with a diameter between 3.0 and 3.25 mm, most were two-piece implants inserted into narrow tooth gaps without loading and in the frontal region. Survival rates for these implants ranged between 93.8% and 100%. Implants of 3.3 to 3.5 mm were two-piece and were also used in the load-bearing posterior region. Survival rates were between 88.9% and 100%, and success rates ranged between 91.4% and 97.6%. A meta-analysis was conducted for NDI (3.3 to 3.5 mm), which showed no statistically significant difference in implant survival compared to conventional implants with an odds ratio of 1.16 (0.7 to 1.69). CONCLUSIONS Narrow-diameter implants of 3.3 to 3.5 mm are well documented in all indications including load-bearing posterior regions. Smaller implants of 3.0 to 3.25 mm in diameter are well documented only for single-tooth non-load-bearing regions. Mini-implants < 3.0 mm in diameter are only documented for the edentulous arch and single-tooth non-load-bearing regions, and success rates are not available. Long-term follow-up times > 1 year and information on patient specific risk factors (bruxism, restoration type) are also missing.

Bisphosphonates affect migration ability and cell viability of HUVEC, fibroblasts and osteoblasts in vitro

OBJECTIVES Bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) is a side effect in patients being treated with bisphosphonates. The bisphosphonates most often associated with BP-ONJ are the highly potent nitrogen-containing bisphosphonates, e.g. pamidronate or zoledronate. In terms of BP-ONJ aetiology, several theories are being discussed: inhibition of bone remodelling, effect on soft tissues, and antiangiogenic effect of bisphosphonates. The aim of this in vitro study was to investigate the effect of different potent bisphosphonates on osteoblasts, fibroblasts and human umbilicord vein endothelial cells (HUVEC). MATERIALS AND METHODS Three nitrogen-containing bisphosphonates (ibandronate, pamidronate and zoledronate) and one non-nitrogen-containing bisphosphonate (clodronate) were compared concerning their potency on apoptosis induction (tunel), cell viability (calcein assay) and migration potency (boyden chamber) on osteoblasts, fibroblasts and HUVEC. RESULTS   The nitrogen-containing bisphosphonates, particularly pamidronate and zoledronate, affect cell viability, cell migration and the induction of apoptosis of osteoblasts, fibroblasts and HUVEC. CONCLUSIONS These results support the theory that BP-ONJ is a multifactorially caused disease because several cell lines of the oral cavity which are responsible for integrity and wound healing are negatively affected by nitrogen-containing bisphosphonates. Perioperative interruption of bisphosphonate application during dental surgical procedures--if possible--might be feasible to promote better wound healing.

Prevalence of bisphosphonate associated osteonecrosis of the jaws in multiple myeloma patients

BackgroundBisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is an adverse effect of bisphosphonate treatment with varying reported incidence rates.MethodsIn two neighboring German cities, prevalence and additional factors of the development of BP-ONJ in multiple myeloma patients with bisphosphonates therapy were recorded using a retrospective (RS) and cross-sectional study (CSS) design. For the RS, all patients treated from Jan. 2000 - Feb. 2006 were contacted by letter. In the CSS, all patients treated from Oct. 2006 - Mar. 2008 had a physical and dental examination. Additionally, a literature review was conducted to evaluate all articles reporting on BP-ONJ prevalence. PubMed search terms were: bisphosphonat, diphosphonate, osteonecrosis, prevalence and incidence.ResultsIn the RS, data from 81 of 161 patients could be obtained; four patients (4.9%) developed BP-ONJ. In the CSS, 16 of 78 patients (20.5%) developed BP-ONJ. All patients with BP-ONJ had received zoledronate; 12 of these had had additional bisphosphonates. All except one had an additional trigger factor (tooth extraction [n = 14], dental surgical procedure [n = 2], sharp mylohyoid ridge [n = 3]).ConclusionThe prevalence of BP-ONJ may have been underestimated to date. The oral examination of all patients in this CSS might explain the higher prevalence, since even early asymptomatic stages of BP-ONJ and previously unnoticed symptomatic BP-ONJ were recorded. Since nearly all patients with BP-ONJ had an additional trigger factor, oral hygiene and dental care might help to reduce BP-ONJ incidence.

Submicron Scale-Structured Hydrophilic Titanium Surfaces Promote Early Osteogenic Gene Response for Cell Adhesion and Cell Differentiation

BACKGROUND AND PURPOSE Titanium (Ti) surface roughness and surface hydrophilicity are key factors to regulate osteogenic cell responses during dental implant healing. In detail, specific integrin-mediated interactions with the extracellular environment trigger relevant osteogenic cell responses like differentiation and matrix synthesis via transcriptions factors. Aim of this study was to monitor surface-dependent osteogenic cell adhesion dynamics, proliferation, and specific osteogenic cell differentiation over a period of 7 days. MATERIALS AND METHODS Ti disks were manufactured to present smooth pretreatment (PT) surfaces and rough sandblasted/acid-etched (SLA) surfaces. Further processing to isolate the uncontaminated TiO(2) surface from contact with atmosphere provided a highly hydrophilic surface without alteration of the surface topography (modSLA). Tissue culture polystyrene (TCPS) served as control. Human osteogenic cells were cultivated on the respective substrates. After 24 hours, 48 hours, 72 hours, and 7 days, cell morphology on the Ti substrates was visualized by scanning transmission electron microscopy. As a marker of cellular proliferation, cell count was assessed. For the analysis of cell adhesion and differentiation, specific gene expression levels of the integrin subunits β1 and αv, runx-2, collagen type Iα (COL), alkaline phosphatase (AP), and osteocalcin (OC) were obtained by real-time RT-PCR for the respective time points. Data were normalized to internal controls. RESULTS TCPS and PT surfaces preserved a rather immature, dividing osteogenic phenotype (high proliferation rates, low integrin levels, and low specific osteogenic cell differentiation). SLA and especially modSLA surfaces promoted both cell adhesion as well as the maturation of osteogenic precursors into post-mitotic osteoblasts. In detail, during the first 48 hours, modSLA resulted in lowest cell proliferation rates but exhibited highest levels of the investigated integrins, runx-2, COL, AP, and OC. CONCLUSION Our results revealed a strong synergistic effect between submicron-scale roughness and surface hydrophilicity on early osteogenic cell adhesion and maturation.

The influence of bisphosphonates on viability, migration, and apoptosis of human oral keratinocytes—in vitro study

Bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) is one of the most often seen side effects in patients treated with bisphosphonates, presenting clinically as a non-healing wound. One theory of BP-ONJ etiology describes a negative effect on soft tissues, especially on keratinocytes, which play an important role in oral wound healing and oral soft tissue regeneration. A high cell viability of keratinocytes, which can migrate to the affected location, is essential for wound healing. The aim of this in vitro study was to investigate the effect of differently potent bisphosphonates on human oral keratinocytes (HOK).Three nitrogen-containing bisphosphonates (ibandronate, pamidronate, and zoledronate) and one non-nitrogen-containing bisphosphonate (clodronate) were compared concerning their potency on cell viability (calcein assay and MTT assay), migration ability (Boyden chamber migration assay and scratch wound proliferation assay), and apoptosis (TUNEL assay) of HOK.The nitrogen-containing bisphosphonates, particulary highly potent pamidronate and zoledronate preparations, had a strong negative influence on cell viability, migration ability, and apoptosis of HOK. The non-nitrogen-containing clodronate even increased cell viability in higher concentrations.This study demonstrates that bisphosphonates have a strong influence on HOK on different cellular levels like cell viability, migration ability, and apoptosis rate. The results support the theory that BP-ONJ is a multifactorially caused disease.Furthermore, this in vitro study confirms the theory that perioperative interruption of bisphosphonate application during dental surgical procedures might be feasible to promote better tissue regeneration and wound healing.