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| 2. |
- Omar, Omar, et al.
(författare)
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The stimulation of an osteogenic response by classical monocyte activation.
- 2011
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Ingår i: Biomaterials. - : Elsevier BV. - 1878-5905 .- 0142-9612. ; 32:32, s. 8190-8204
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Tidskriftsartikel (refereegranskat)abstract
- The monocyte/macrophage system plays a central role in host defense, wound healing and immune regulation at biomaterial surfaces. Monocytes can be classically and alternatively activated, and can be stimulated differently in response to variations in biomaterial surface properties. In this study, human monocytes, cultured on polystyrene surfaces (Ps), were activated either classically, by lipopolysaccharide (LPS), or alternatively, by interleukin-4 (IL-4). Monocytes were also cultured on anodically oxidized (Ox) and machined (Ma) titanium surfaces, with and without LPS stimulation. Cells were cultured for 1 and 3 days and their conditioned media (CM) were collected. The osteogenic response of hMSCs to the monocyte CM was determined by analyzing the gene expression of key osteogenic markers. The CM from classically activated monocytes increased the hMSCs expression of runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP). Furthermore, CM from monocytes cultured on Ox surface resulted in a modest increase of the expression of bone morphogenetic protein-2 (BMP-2). LPS stimulation of the surface-seeded monocytes overwhelmed the effect of the surface properties and resulted in significant upregulation of BMP-2 and Runx2 for all samples. The results show that human monocytes, cultured on different surfaces and/or under different activation pathways, communicate pro-osteogenic signals to hMSCs. The signals involve regulation of autologous BMP-2 in the hMSCs. The classical activation results in profound and prolonged osteogenic effect compared to the effect of the investigated surface properties.
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| 3. |
- Shah, Furqan A., et al.
(författare)
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Micrometer-Sized Magnesium Whitlockite Crystals in Micropetrosis of Bisphosphonate-Exposed Human Alveolar Bone
- 2017
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6984 .- 1530-6992. ; 17:10, s. 6210-6216
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Tidskriftsartikel (refereegranskat)abstract
- Osteocytes are contained within spaces called lacunae and play a central role in bone remodelling. Administered frequently to prevent osteoporotic fractures, antiresorptive agents such as bi-sphosphonates suppress osteocyte apoptosis and may be localized within osteocyte lacunae. Bisphosphonates also reduce osteoclast viability and thereby hinder the repair of damaged tissue. Osteocyte lacunae contribute to toughening mechanisms. Following osteocyte apoptosis, the lacunar space undergoes mineralization, termed "micropetrosis". Hypermineralized lacunae are believed to increase bone fragility. Using nanoanalytical electron microscopy with complementary spectroscopic and crystallographic experiments, postapoptotic mineralization of osteocyte lacunae in bisphosphonate-exposed human bone was investigated. We report an unprecedented presence of similar to 80 nm to similar to 3 mu m wide, distinctly faceted, magnesium whitlockite [Ca18Mg2(HPO4)(2)(PO4)(12)] crystals and consequently altered local nanomechanical properties. These findings have broad implications on the role of therapeutic agents in driving biomineralization and shed new insights into a possible relationship between bisphosphonate exposure, availability of intracellular magnesium, and pathological calcification inside lacunae.
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| 4. |
- Acquavella, J., et al.
(författare)
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Design and methods for a Scandinavian pharmacovigilance study of osteonecrosis of the jaw and serious infections among cancer patients treated with antiresorptive agents for the prevention of skeletal-related events
- 2016
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Ingår i: Clinical Epidemiology. - 1179-1349. ; 8, s. 267-272
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Osteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post-authorization safety study of cancer patients treated with antiresorptive therapies. Methods: As part of a comprehensive pharmacovigilance plan, developed with regulators' input, the study will estimate incidence of ONJ and of serious infections among adult cancer patients with bone metastases treated with denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously, adjusted for renal function). Patients will be identified using routinely collected data combined with medical chart review in Denmark, Sweden, and Norway. Followup will extend from the first administration of antiresorptive treatment to the earliest of death, loss-to-follow-up, or 5 years after therapy initiation. Results will be reported for three treatment cohorts: denosumab-naive patients, zoledronic acid-naive patients, and patients who switch from bisphosphonate treatment to denosumab. ONJ cases will be identified in three newly established national ONJ databases and adjudicated by the committee that functioned during the XGEVA (R) clinical trials program. Conclusion: This study will provide a real world counterpart to the clinical trial-estimated risks for ONJ and serious infections for cancer patients initiating denosumab or zoledronic acid. The establishment of ONJ databases in the three Scandinavian countries will have potential benefits outside this study for the elucidation of ONJ risk factors and the evaluation of ONJ treatment strategies.
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| 5. |
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| 6. |
- Cardemil, Carina, et al.
(författare)
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Jaw Bone Samples From Bisphosphonate-Treated Patients : A Pilot Cohort Study
- 2015
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Ingår i: Clinical Implant Dentistry and Related Research. - : Wiley-Blackwell. - 1523-0899 .- 1708-8208. ; 17, s. E679-E691
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Tidskriftsartikel (refereegranskat)abstract
- Osteonecrosis of the jaw (ONJ) is a severe complication of bisphosphonate treatment. PurposeA detailed characterization of sampled peri-necrotic jawbone from bisphosphonate-treated patients was performed at tissue and cellular level (histological analyses and gene expression). Materials and MethodsAlveolar bone samples were collected from patients with (n=5) and without ONJ (n=5). Healthy patients served as controls (n=10). ResultsThe histological analysis demonstrated low to moderate inflammation, displaying areas of inflammatory infiltrate in the bone marrow. Multinuclear giant cells and osteoclasts were found in both groups. Markers of bone formation (alkaline phosphatase, Col1a1, and osteocalcin), bone resorption (receptor activator of NF-kappaB ligand [RANKL], osteoprotegerin [OPG], tartrate-resistant acid phosphatase, and cathepsin K), inflammation (tumor necrosis factor-alpha, interleukin [IL]-1, and IL-6), angiogenesis (vascular endothelial growth factor A), and apoptosis (Casp3, Casp8, p53, and Smac) were evaluated. Nonparametric statistical tests were used to identify differences between the groups. In patients with ONJ, the expression level of the proinflammatory marker IL-1 was strongly up-regulated compared with controls (p=.040). ConclusionsA down-regulated expression of Casp8 compared with controls was observed (p=.014) in patients treated with bisphosphonates. The RANKL/OPG ratios were similar in the three groups. The results indicate a need to further investigate the molecular mechanisms involved in the course of ONJ related to antiresorptive treatment.
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| 7. |
- Cardemil, Carina, et al.
(författare)
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The effects of a systemic single dose of zoledronic acid on post-implantation bone remodelling and inflammation in an ovariectomised rat model.
- 2013
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Ingår i: Biomaterials. - : Elsevier BV. - 1878-5905 .- 0142-9612. ; 34:5, s. 1546-61
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Tidskriftsartikel (refereegranskat)abstract
- Bisphosphonates reverse the negative effects of ovariectomy on bone, but they have also been associated with adverse processes in human jawbone. The molecular events determining bone regeneration and implant integration in osteoporotic conditions, with and without bisphosphonate treatment, are unclear. In this study, ovariectomised rats, to which a single dose of saline (NaCl) or zoledronic acid (Zol) was administered, received titanium alloy implants in their tibiae and mandibles. An enzyme-linked immunosorbent assay, gene expression analysis and histomorphometry were performed. The results show that ovariectomy, per se, upregulated the expression of genes denoting bone formation in the tibia, bone remodelling in the mandible and apoptosis in the tibia and mandible. Zoledronic acid administration resulted in lower levels of a remodelling marker in serum and downregulated gene expression for inflammation, bone formation, angiogenesis and apoptosis, mainly in the mandible, after 28d of healing. Histomorphometry revealed improved bone-to-implant contact in the tibia, while the opposite was observed in the mandible. The present data show that a systemic single dose of zoledronic acid, in ovariectomised animals, results in site-specific differences in the regulation of genes involved in bone healing and regeneration in association with implant installation. These events occur in parallel with site-specific differences in the rate of osseointegration, indicating diverse tissue responses in the tibia and mandible after zoledronic acid treatment. The zoledronic acid effect on gene expression, during the late phase of healing in the mandible, suggests negative effects by the anti-resorptive agent on osseointegration at that particular site.
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| 8. |
- Dahlgren, Mathias, et al.
(författare)
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Uncertainty managing patients treated with antiresorptive drugs: a cross-sectional study of attitudes and self-reported behavior among dentists in Sweden
- 2020
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Ingår i: Acta Odontologica Scandinavica. - : Informa UK Limited. - 0001-6357 .- 1502-3850. ; 78:2, s. 109-117
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the level of knowledge and attitudes among Swedish general dentists regarding the behavior and management of patients treated with bisphosphonates and denosumab Materials and Methods: A questionnaire was sent to 656 dentists. The web-based survey included questions on demographics, risk perception of osteonecrosis of the jaws (ONJ), the experience of managing patients treated with bisphosphonates and denosumab and requests to acquire new knowledge. Independence and associations were tested using Fisher’s exact test and the chi-square test function. Results: The overall response rate was 57.6%. Most of the dentists, 69.7%, had been in the profession for more than 5years. The criteria for ONJ were not known by 43.2% and 86.9% did not feel comfortable with their current level of knowledge when managing the patients in question. The rest of the respondents felt uncertain and more than 70% were unaware of the different stages of ONJ, when to refer a patient to a specialist and when to prescribe antibiotics. Conclusion: Dentists practicing in Sweden express a strong need for an improved level of knowledge when managing patients treated with bisphosphonates and denosumab. The results demonstrate a need for the necessary advancement of education and clinical training at dental schools in order to prepare dentists to provide safe, modern care within the healthcare sector.
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| 9. |
- Ehrenstein, V., et al.
(författare)
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Osteonecrosis of the jaw among patients with cancer treated with denosumab or zoledronic acid: Results of a regulator-mandated cohort postauthorization safety study in Denmark, Norway, and Sweden
- 2021
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 127:21, s. 4050-4058
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Osteonecrosis of the jaw (ONJ) is an adverse effect of antiresorptive treatment. This study estimated incidence proportions and incidence rates of ONJ in cancer patients with bone metastases from solid tumors treated for the prevention of skeletal-related events in routine clinical practice. METHODS This cohort study in Denmark, Norway, and Sweden in 2011-2018 included 3 treatment cohorts: a denosumab inception cohort (DEIC), a zoledronic acid inception cohort (ZAIC), and a denosumab-switch cohort (DESC). The authors estimated 1- to 5-year incidence proportions and incidence rates of ONJ overall, by cancer site (breast, prostate, or other solid tumor), and by country. ONJ diagnoses were confirmed by adjudication. RESULTS There were 1340 patients in the DEIC, 1352 in the ZAIC, and 408 in the DESC. The median ages of the 3 cohorts were 70, 69, and 70 years, respectively; the proportions of men were 72.6%, 53.8%, and 48.3%, respectively; and the median follow-up was 19.8, 12.9, and 13.3 months, respectively. The 5-year incidence proportions of ONJ were 5.7% (95% confidence interval [CI], 4.4%-7.3%) in the DEIC, 1.4% (95% CI, 0.8%-2.3%) in the ZAIC, and 6.6% (95% CI, 4.2%-10.0%) in the DESC. The corresponding ONJ incidence rates per 100 person-years were 3.0 (95% CI, 2.3-3.7), 1.0 (95% CI, 0.6-1.5), and 4.3 (95% CI, 2.8-6.3). Incidence proportions and incidence rates were highest in patients with prostate cancer and in Denmark. CONCLUSIONS This study provides estimates of the risk of medically confirmed ONJ among patients initiating denosumab or zoledronic acid in routine clinical practice in 3 Scandinavian countries. The results varied by cancer site and by country. LAY SUMMARY Denosumab and zoledronic acid reduce the risk of bone fractures, pain, and surgery in patients with advanced cancers involving bone. Osteonecrosis of the jaw (ONJ)-death of a jawbone-is a known side effect of treatment with denosumab or zoledronic acid. The authors examined almost 2900 denosumab- or zoledronic acid-treated patients with cancer in Denmark, Norway, and Sweden. Over the course of 5 years, ONJ developed in 5.7% of the patients whose initial treatment was denosumab, in 1.4% of the patients whose initial treatment was zoledronic acid, and in 6.6% of the patients who switched from zoledronic acid to denosumab.
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| 10. |
- Larsson Wexell, Cecilia, 1965, et al.
(författare)
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A Case Report on Gardner Syndrome With Dental Implant Treatment and a Long-Term Follow-Up.
- 2019
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Ingår i: Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. - : Elsevier BV. - 1531-5053. ; 77:8, s. 1617-1627
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Tidskriftsartikel (refereegranskat)abstract
- A case of Gardner syndrome (GS) in a 37-year-old woman is presented in which rehabilitation with dental implant treatment was followed for 7years. The course of diagnostics and treatment is followed through an overview of 45 tissue biopsy and cytology samples during a period of 30years. The patient was diagnosed with GS after a routine review of an oral panoramic radiograph presenting with multiple osteomas and multiple unerupted supernumerary teeth. Biopsy results and surgical procedures with histopathologic diagnoses from 1986 to 2016 are presented. Histologic analysis of the sampled jawbone showed a picture similar to an osteoid osteoma. The installed implant was functionally stable, with no clinical or radiographic events observed at yearly visits, for 7years. In 1991, benign tumors appeared; in 2014, multiple adenomas were found in the small intestine and rectum. This case report shows the potential for dental implant treatment in a patient with GS.
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