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1.  Health of workmen in the chromate-producing industry in Britain. 
In a follow-up study of 2715 men who had worked for at least one year at the three chromate-producing factories in Britain between 1948 and 1977 only 298 were lost to follow-up, and the average number of person-years in the study was 16.3. One hundred and sixteen deaths from lung cancer occurred in these men, with only 48.0 expected (O/E = 2.4; p less than 0.001). For men employed at the factory, which is still in operation, the relative risk of lung cancer has decreased from over 3.0 before plant modification to about 1.8 in those who have worked only since plant modification. A multivariate analysis was used in an attempt to unravel the overlapping influence of duration of employment, length of follow-up, plant modification, factory, age at entry to work, and estimated degree of chromate exposure. The major dependent factor appeared to be duration of employment; in addition the analysis suggested that modifications in the plant and work environment had been associated with an appreciable reduction of the excess risk from lung cancer.
PMCID: PMC1008833  PMID: 7236535
2.  HEART DISEASE UNDER WORKMEN'S COMPENSATION 
California Medicine  1960;92(6):418-421.
In expert testimony before the Industrial Accident Commission, all physicians are taken as equally competent. The value of their testimony depends upon the validity of their data and the reasons for the conclusions drawn. In case of conflicting opinion, the referees, who are laymen, must decide on the basis of the testimony. Therefore physicians preparing reports must see that data are complete, that all routine investigative procedures are not only applied but reported, and that the reasons for claiming connection of injury with employment are fully stated. Moreover, other recognized causes of the patient's condition should be considered and ruled out for reasons given.
The increasing number of claims for workmen's compensation in heart disease, and the increasing tendency of insurers to settle rather than contest claims, may actually be harmful to the welfare of persons with heart disease, for it deters employers from hiring them and thus risking higher insurance costs. Physicians concerned with compensation claims must develop more widely acceptable standards that properly separate the inherent risk of heart disease from that incurred through employment for which the employer may reasonably be considered liable.
PMCID: PMC1578120  PMID: 13807236
3.  WORKMEN'S COMPENSATION—Details of Medical Reports 
California Medicine  1957;87(2):85-87.
Attention to details of medical reporting that are required for just settlement of compensation cases can greatly facilitate proper adjudication.
PMCID: PMC1512071  PMID: 13446752
4.  Occupational hearing loss of the workmen of an open cast chromite mines 
Background:
The present work aimed at to describe hearing threshold based on audiometry data of the mine workers based on their age, work station and years of working of an open cast chromite mine in Odisha, India at high fence.
Materials and Methods:
A cross-sectional study of hearing threshold of the subjects of the chromite mine was carried out. Audiometric data of 500 subjects were taken from the hospital of the mines of Sukinda Valley, Jajpur, Odisha, India. The latest audiometry data available during the period 2002 to 2008 was used in the statistical analysis.
Results:
The age group 50-60 years is found to be the most influential age group suffering significant hearing loss on both the ears. Also, the Work Zone area is found to be most significant area affecting hearing loss on both the ears. However, the subjects having experience of 30-35 and 25-30 years have the most significant hearing loss on the left and right ears, respectively.
Conclusion:
The hearing loss is found to be at 6 kHz, thus the working areas of the subjects working at work zone should be regularly rotated in less noisy areas to reduce the exposure duration. High frequency noise protective device should be advocated among all the subjects in general and HEMMs operators in particulars. Regular audiometry test of all the subjects should be performed to identify the hearing loss of the subjects occurring at 6 kHz. It is essential to perform periodic maintenance of all the HEMMs to keep all the vehicles in good condition those are generating noise at dominating frequency of 4 and 6 kHz.
doi:10.4103/0019-5278.99684
PMCID: PMC3482703  PMID: 23112502
Asymmetry hearing loss; dip or notch; high fence; low fence; noise induced hearing loss
5.  Oral bisphosphonate-related osteonecrosis of the jaws in rheumatoid arthritis patients: a critical discussion and two case reports 
Background
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition characterized by the presence of exposed bone in the maxillofacial region. Its pathogenesis is still undetermined, but may be associated with risk factors such as rheumatoid arthritis (RA). The aim of this paper is to report two unpublished cases of BRONJ in patients with RA and to conduct a literature review of similar clinical cases with a view to describe the main issues concerning these patients, including demographic characteristics and therapeutic approaches applied.
Methods
Two case reports of BRONJ involving RA patients were discussed
Results
Both patients were aging female taking alendronate for more than 3 years. Lesions were detected in stage II in posterior mandible with no clear trigger agent. The treatment applied consisted of antibiotics, oral rinses with chlorhexidine, drug discontinuation and surgical procedures. Complete healing of the lesions was achieved.
Conclusions
This paper brings to light the necessity for rheumatologists to be aware of the potential risk to their patients of developing BRONJ and to work together with dentists for the prevention and early detection of the lesions. Although some features seem to link RA with oral BRONJ and act as synergistic effects, more studies should be developed to support the scientific bases for this hypothesis.
doi:10.1186/1746-160X-7-7
PMCID: PMC3111349  PMID: 21524309
6.  Oral manifestations of McCune-Albright syndrome 
McCune- Albright Syndrome (MAS) is a rare fibrosseous lesion, characterized by a classic triad of polyostotic fibrous dysplasia (PFD), café –au-lait macules (CALM) and underlying endocrinopathies. We present the oral findings of an interesting case of MAS with relevant review of literature. A 30-year-old male presented to us with swelling of both jaws over a period of two years. Cutaneous examination revealed café - au – lait macule over the back, crossing the midline. Skeletal survey showed expansile, osteolytic, mixed radiolucent- radiopaque lesions in skull and jaw bones. Serum alkaline phosphatase was elevated (388 IU/L), with normal calcium, phosphorus, parathyroid hormone and 25 hydroxy vitamin D levels. Diagnosis of McCune- Albright syndrome was made and he was treated with parenteral bisphosphonates (intravenous Zoledronate 4 mg) and is under follow up for surgical recontouring of the jaws. Early recognition facilitates better treatment and improves prognosis by reducing the morbidity.
doi:10.4103/2230-8210.107878
PMCID: PMC3659890  PMID: 23776876
Albright's syndrome; fibrous dysplasia of the jaws; fibroosseous lesion; polyostotic fibrous dysplasia
7.  Effect of Zoledronate on Oral Wound Healing in Rats 
Purpose
Osteonecrosis of the jaw (ONJ) is a growing concern in patients who receive bisphosphonates which target osteoclasts. Since osteoclasts play multifunctional roles in the bone marrow, their suppression likely affects bone homeostasis and alters wound healing of the jaw. The objective was to delineate the impact of osteoclast suppression in the bone marrow and wound healing of the jaw.
Experimental Design
Zoledronate was administered to senile rats for 14 weeks. A portion of the gingiva was removed to denude the palatal bone. Gene expression in the bone marrow was assessed and histologic sections analyzed to determine the wound healing status.
Results
Angiogenesis-related genes, CD31 and VEGF-A, were not altered by zoledronate. VEGF-C, which plays a role in lymphangiogenesis, was suppressed. There was a decrease in gene expression of Tcirg1 and MMP-13. Bone denudation caused extensive osteocyte death indicative of bone necrosis. In zoledronate-treated rats, the necrotic bone was retained in the wound while, in controls, osteoclastic resorption of the necrotic bone was prominent. Even though large necrotic bone areas existed in zoledronate-treated rats, overlaying soft tissue healed clinically. Immunohistochemical staining showed rich vascularity in the overlaying soft tissue.
Conclusions
Zoledronate therapy impacts bone marrow by suppressing genes associated with lymphoangiogenesis and tissue remodeling, such as VEGF-C and MMP-13. Zoledronate was associated with impaired osseous wound healing but had no effect on angiogenic markers in the bone marrow or soft tissue wound healing. Zoledronate selectively blunts healing in bone but does not effect soft tissue healing in the oral cavity.
doi:10.1158/1078-0432.CCR-10-1614
PMCID: PMC3060285  PMID: 21149614
8.  Is bisphosphonate therapy for benign bone disease associated with impaired dental healing? A case-controlled study 
Background
Bisphosphonates are common first line medications used for the management of benign bone disease. One of the most devastating complications associated with bisphosphonate use is osteonecrosis of the jaws which may be related to duration of exposure and hence cumulative dose, dental interventions, medical co-morbidities or in some circumstances with no identifiable aggravating factor. While jaw osteonecrosis is a devastating outcome which is currently difficult to manage, various forms of delayed dental healing may be a less dramatic and, therefore, poorly-recognised complications of bisphosphonate use for the treatment of osteoporosis. It is hypothesised that long-term (more than 1 year's duration) bisphosphonate use for the treatment of post-menopausal osteoporosis or other benign bone disease is associated with impaired dental healing.
Methods/Design
A case-control study has been chosen to test the hypothesis as the outcome event rate is likely to be very low. A total of 54 cases will be recruited into the study following review of all dental files from oral and maxillofacial surgeons and special needs dentists in Victoria where potential cases of delayed dental healing will be identified. Potential cases will be presented to an independent case adjudication panel to determine if they are definitive delayed dental healing cases. Two hundred and fifteen controls (1:4 cases:controls), matched for age and visit window period, will be selected from those who have attended local community based referring dental practices. The primary outcome will be the incidence of delayed dental healing that occurs either spontaneously or following dental treatment such as extractions, implant placement, or denture use.
Discussion
This study is the largest case-controlled study assessing the link between bisphosphonate use and delayed dental healing in Australia. It will provide invaluable data on the potential link between bisphosphonate use and osteonecrosis of the jaws.
doi:10.1186/1471-2474-12-71
PMCID: PMC3080357  PMID: 21477374
9.  Bisphosphonate-induced Osteonecrosis of the Jaws: Review, Clinical Implications and Case Report 
Head and Neck Pathology  2007;1(2):156-164.
The introduction of bisphosphonates has increased in the last decade following their indication for metastatic bone diseases, osteoporosis, hypercalcaemia of malignancy and Paget’s disease. Although bisphosphonates have been used clinically for more than three decades there have been no documented long-term complications of their effects on the jaws until recently, where there is now growing evidence of the influence of bisphosphonates on osteonecrosis of the jaws. The aim of this paper is to report a case of this newly described complication, to review this phenomenon, including the clinical implications and to reiterate current clinical guidelines for management of patients in which bisphosphonate therapy is indicated. To the best of our knowledge this is the first reported case of bisphosphonate-induced necrosis of the jaw in South Africa.
doi:10.1007/s12105-007-0022-5
PMCID: PMC2807517  PMID: 20614268
Bisphosphonates; Osteonecrosis; Jaws
10.  Association of dental and periodontal status with bisphosphonate-related osteonecrosis of the jaws. A retrospective case controlled study 
Archives of Medical Science : AMS  2014;10(1):117-123.
Introduction
To assess the association of oral hygiene, dental caries, and periodontal status with bisphosphonate-related osteonecrosis of the jaws.
Material and methods
A retrospective case-control study on 81 patients treated for neoplasms with bone metastases. Twenty-nine patients with bone necrosis and 52 controls treated with bisphosphonates were compared using the Oral Hygiene Index, Decay, Missing, Filled Teeth, Community Periodontal Index of Treatment Needs, and Residual Periodontal Bone. The null hypothesis stated that there was no difference in parameters of oral health between patients with and without bone necrosis. Differences of means of above-mentioned variables were compared between the groups with Student's t-test or Mann-Whitney rank sum test and χ2 test. Value of p ≤ 0.05 was considered significant.
Results
Poorer oral hygiene (OHIs 1.94 vs. 1.32; p = 0.065), more advanced dental caries (DMFT 26.85 vs. 22.87; p = 0.05), and more advanced periodontal disease (CPITN: = 0: 21.05% vs. 42.51%; = 1 13.16% vs. 7.29%; = 2: 0% vs. 15.38%; = 3: 65.79% vs. 28.34%; = 4: 0% vs. 6.48%, Residual periodontal bone 73.1% vs. 80.51%; p = 0,001) were characteristic of patients with bisphosphonate related jaw necrosis when compared with control group. An advanced dental caries or periodontal disease required surgical intervention which directly contributed to the development of the bone necrosis.
Conclusions
Dental and periodontal disease can lead to bisphosphonate-related osteonecrosis of the jaw. Oncologic patients treated with bisphosphonates should be offered preventive care to reduce dental plaque, calculus, dental caries, and periodontal disease.
doi:10.5114/aoms.2014.40738
PMCID: PMC3953981  PMID: 24701224
necrosis; jaw; dental status; periodontal status; oral health
11.  Histology of the Oral Mucosa in Patients With BRONJ at III Stage: A Microscopic Study Proves the Unsuitability of Local Mucosal Flaps 
Background
Bisphosphonate Osteonecrosis of the Jaw (BRONJ) is a newly recognized condition reported in patients treated with aminobisphosphonates (BF). BRONJ is defined as the presence of exposed necrotic alveolar bone that does not resolve over a period of 8 weeks in a patient taking bisphosphonates who has not had radiotherapy to the jaw. Treatment protocols have been outlined, but trials and outcomes of treatment and long-term follow-up data are not yet available. In 2004 an expert panel outlined recommendations for the management of bisphosphonate-associated osteonecrosis of the jaws. Through the histological study of the oral mucosa over the bone necrosis and around the osteonecrosis area in 8 patients affected by BRONJ at III stage, the authors highlight the inappropriateness of the local mucosal flaps to cover the losses of substance of the jaw, BF-related.
Methods
Mucosa tissue was taken from 8 patients, affected by BRONJ, III stage. The samples taken from the mucosa around and over the osteonecrosis area were fixed with formalin and an ematossilina-eosin dichromatic coloring was carried out.
Results
The samples of mucosa showed pathognomonic signs of cell suffering that prove that in these patients using local mucosa flaps is inappropriate.
Conclusions
The authors suggest that only a well vascularized flap as free flap must be used to cover the osteonecrosis area in patients with BRONJ stage III. Because of the structural instability of the mucosa in patients suffering of osteonecrosis Bf related the local flaps are prone to ulceration and to relapse.
doi:10.4021/jocmr1253e
PMCID: PMC3564564  PMID: 23390472
Osteonecrosis of the jaw; Bisphosphonates; Aminobisphosphonates
12.  Increased human defensine levels hint at an inflammatory etiology of bisphosphonate-associated osteonecrosis of the jaw: An immunohistological study 
Background
Human β-defensins (hBD) are antimicrobial peptides that are an integral part of bone innate immunity. Recently, it could be shown that expression of hBD-1, -2 and -3 were upregulated in cases of osteomyelitis of the jaws. In order to gain insight into the possible impairment of hBD metabolism in bisphosphonate-associated osteonecrosis of the jaws (BONJ), the present exploratory study was designed so as to determine the qualitative and quantitative expression of afore mentioned hBDs in BONJ and infected osteoradionecrosis (ORN), both of which represent inflammatory bone diseases.
Methods
Bone samples were collected from patients with BONJ (n = 20) and ORN (n = 20). Non-infected healthy bone samples (n = 20) were included as controls. Immunohistological staining in an autostainer was carried out by the (Strept-ABC)-method against hBD-1,-2,-3. Specific positive vs. negative cell reaction of osteocytes (labeling index) near the border of bony resection was determined and counted for quantitative analysis. Number of vital osteocytes vs. empty osteocytes lacunae was compared between groups.
Results
hBD-1,-2 and -3 could be detected in BONJ as well as ORN and healthy bone samples. Immunoreactivity against hBD-2 and -3 was significantly higher in BONJ than in ORN and healthy jaw bone samples. Number of empty osteocyte lacunae was significantly higher in ORN compared with BONJ (P = 0.001).
Conclusion
Under the condition of BONJ an increased expression of hBD-1,-2,-3 is detectable, similarly to the recently described upregulation of defensins in chronically infected jaw bones. It remains still unclear how these findings may relate to the pathoetiology of these diseases and whether this is contributing to the development of BONJ and ORN or simply an after effect of the disease.
doi:10.1186/1479-5876-9-135
PMCID: PMC3163206  PMID: 21843332
antimicrobial peptide; bisphosphonate-associated osteonecrosis; osteoradionecrosis; human beta defensins; innate immunity
13.  Transfer of Antigen-Pulsed Dendritic Cells Induces Specific T-Cell Proliferation and a Therapeutic Effect against Long-Term Helicobacter pylori Infection in Mice  
Infection and Immunity  2006;74(2):984-993.
Helicobacter pylori causes persistent infection of the stomach and results in chronic gastritis and peptic ulcers. Jaws II cells, derived from mouse bone marrow, were pulsed with live or formalin-killed or whole-cell sonicates (WCS) of H. pylori. Representative cell surface molecules were expressed at substantial levels on Jaws II cells, indicating that appropriate maturation of the cells was achieved with the three H. pylori antigens without any significant differences. H. pylori WCS-pulsed Jaws II cells secreted a significant amount of tumor necrosis factor alpha into the culture supernatant. The naïve T cells exposed to the WCS-pulsed Jaws II cells showed significant proliferation and gamma interferon (IFN-γ) and interleukin-10 (IL-10) production in vitro. A 2-log reduction in the number of colonizing bacteria was observed in the mice treated with the WCS-pulsed Jaws II cells; however, no significant reductions were achieved in mice treated with Jaws II cells pulsed with other H. pylori antigens. Up-regulated production of IFN-γ and IL-10 was observed in the stomachs of the mice treated with the WCS-pulsed Jaws II cells, which is consistent with the result obtained in vitro. There were no differences in gastritis scores or H. pylori-specific antibody titers among the mice treated with Jaws II cells pulsed with the three different H. pylori antigens. The results suggest that Th1 cell-mediated immunity in combination with Th2 cell-mediated immunity plays a role in reducing colonizing bacterial numbers in mice with chronic H. pylori infections.
doi:10.1128/IAI.74.2.984-993.2006
PMCID: PMC1360321  PMID: 16428744
14.  Role of platelet-rich-fibrin in enhancing palatal wound healing after free graft 
Contemporary Clinical Dentistry  2012;3(Suppl 2):S240-S243.
Platelet-rich fibrin has long been used as a wound healing therapy in skin wounds and recently evidence has suggested its usage in oral cavity for different treatment procedures. This article proposes an overview of use of platelet-rich fibrin in management of complicated oral wounds. Excessive hemorrhage of the donor area, necrosis of epithelium, and morbidity associated with donor site have been described as the possible complications after harvesting subepithelial connective tissue graft, but little has been mentioned about their management. The article includes a case report of a 45-year-old male patient who showed a delayed wound healing after subepithelial connective tissue graft harvestation, which was treated with platelet-rich fibrin.
doi:10.4103/0976-237X.101105
PMCID: PMC3514941  PMID: 23230372
Delayed; palatal; platelet-rich fibrin; subepithelial connective tissue graft; wound healing
16.  Non-Hodgkins lymphoma of maxilla: A rare entity 
Non-Hodgkin's lymphomas are a group of neoplasms that originate from the cells of the lymphoreticular system. Forty percent of non-Hodgkin's lymphomas arise from extra nodal sites. Non-Hodgkin's lymphomas detected primarily in the bone are quite rare, but among jaw lesions, they are more frequently present in the maxilla than in the mandible. There are no classical characteristic clinical features of lymphomas involving the jaw bones. Swelling, ulcer or discomfort may be present in the region of the lymphoma, or it may mimic a periapical pathology or a benign condition. Extranodal non-Hodgkins lymphoma of the maxilla could present as one of the early manifestation of detrimental diseases. Clinically these types of lymphoma can mimic an inflammatory endo-periodontal lesion with symptoms of pain and local discomfort. The greater the delay in diagnosis subsequently worsens the prognosis. A case of maxillary non-Hodgkin's lymphoma with an unusual presentation is discussed.
doi:10.4103/0975-5950.94485
PMCID: PMC3343395  PMID: 22639517
Non-Hodgkin's lymphoma; maxilla; rare entity
17.  Adjuvant combined ozone therapy for extensive wound over tibia 
Indian Journal of Orthopaedics  2011;45(4):376-379.
Disinfectant and antibacterial properties of ozone are utilized in the treatment of nonhealing or ischemic wounds. We present here a case of 59 years old woman with compartment syndrome following surgical treatment of stress fracture of proximal tibia with extensively infected wound and exposed tibia to about 4/5 of its extent. The knee joint was also infected with active pus draining from a medial wound. At presentation the patient had already taken treatment for 15 days in the form of repeated wound debridements and parenteral antibiotics, which failed to heal the wound and she was advised amputation. Topical ozone therapy twice daily and ozone autohemotherapy once daily were given to the patient along with daily dressings and parenteral antibiotics. Within 5 days, the wound was healthy enough for spilt thickness skin graft to provide biological dressing to the exposed tibia bone. Topical ozone therapy was continued for further 5 days till the knee wound healed. On the 15th day, implant removal, intramedullary nailing, and latissimus dorsi pedicle flap were performed. Both the bone and the soft tissue healed without further complications and at 20 months follow-up, the patient was walking independently with minimal disability.
doi:10.4103/0019-5413.80332
PMCID: PMC3134027  PMID: 21772635
Ozone therapy; autohemotherapy; wound healing
18.  The use of pedicled buccal fat pad combined with sequestrectomy in bisphosphonate-related osteonecrosis of the maxilla 
The use of pedicled buccal fat pad flap (BFP) has proved of value for the closure of oroantral and oronasal communications and is a well-established tool in oral and maxillofacial surgery. Otherwise, the perceived limitations of surgical therapy for bisphosphonate-related osteonecrosis of the jaws (BRONJ) have been widely discussed, and recommendations have largely been made to offer aggressive surgery only to stage 3 patients refractary to conservative management. Oroantral communication may be a common complication after sequestrectomy and bone debridement in upper maxillary BRONJ. We report a case series of stage 3 recalcitrant maxillary BRONJ surgically treated with extensive sequestrectomy and first reconstruction using pedicled BFP. All the cases presented an uneventful postoperative healing was uneventful without dehiscence, infection, necrosis or oroantral communication. We postulate that managing initially the site with BFP and primary closure may ensure a sufficient blood supply and adequate protection for an effective bone-healing response to occur. This technique may represent a mechanic protection and an abundant source of adipose-derived adult stem cells after debridement in upper maxillary BRONJ. We evaluate in this work results, advantages and indications of this technique.
Key words: Buccal fat pad flap, bisphosphonate-related osteonecrosis of the jaws, oroantral communications, sequestrectomy.
doi:10.4317/medoral.17422
PMCID: PMC3448310  PMID: 22143692
19.  Osteonecrosis of the jaw in a Crohn’s disease patient following a course of Bisphosphonate and Adalimumab therapy: a case report 
BMC Gastroenterology  2014;14:6.
Background
Bisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal-related conditions. Bisphosphonate-associated osteonecrosis of the jaw (BRONJ) is a feared side effect which is hard to treat and often affects patient´s quality of life in an extensive manner. Adalimumab (Humira®), a fully human recombinant antibody specific for tumor necrosis factor- α, is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn’s disease.
Case presentation
In March 2013, a 36-year-old female presented with right-sided perimandibular swelling, recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47. She had the medical history of Crohn’s disease for more than one decade with chronic active enterocolitis, fistula disease as well as previous oral manifestation and was currently treated with Adalimumab since September 2008. Due to steroid-induced osteoporosis, diagnosed in 2004, she received oral Bisphosphonates (Risedronate) from 2004 until 2007 followed by two infusions of Zoledronic acid in 2008 and 2009.
Conclusion
This patient with a medical history of Crohn’s disease and gastrointestinal remission under Adalimumab therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti-TNF-α antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity.
doi:10.1186/1471-230X-14-6
PMCID: PMC3890650  PMID: 24400722
Osteonecrosis of the jaw; Bisphosphonate; Adalimumab; Crohn’s disease
20.  EFFECTS OF PAMIDRONATE ON HUMAN ALVEOLAR OSTEOBLASTS IN VITRO 
Purpose
Administration of bisphosphonates has recently been associated with the development of osteonecrotic lesions of the jaw (ONJ). To elucidate the potential contributions of osteogenic cells to the development and regeneration of ONJ, we have isolated primary cells from human alveolar and long/iliac bones, and examined the effects of pamidronate on cell viability, proliferation, osteogenesis and wound healing.
Materials and Methods
Primary human osteoblasts and bone marrow stromal cells were isolated from alveolar and iliac/long bone and marrow tissue. Cellular proliferation, alkaline phosphatase activity, apoptosis (TUNEL, Caspase-3, and DAPI assays) and wound healing in an in vitro scratch assay were assessed after exposure to pamidronate at a range of clinically relevant doses.
Results
Primary alveolar osteoblasts proliferated at significantly higher rates than long/iliac bone osteoblasts in vitro. Upon exposure of alveolar osteoblasts and long/iliac bone marrow stromal cells to pamidronate for more than 72h, we have observed significantly decreased cell viability, proliferation, osteogenesis and in vitro wound healing at ≥6 × 10−5 M pamidronate, with the induction of apoptosis in ~20% of cell population.
Conclusions
The remodeling activity of alveolar bone, indicated by higher proliferation of alveolar osteoblasts, could be negatively affected by exposure to high concentrations of pamidronate over extended periods of time. The absence of anabolic effects of pamidronate on alveolar osteoblasts, and induction of apoptosis in osteogenic cells could negatively affect bone balance at this site, and contribute to osteonecrosis of the jaw.
doi:10.1016/j.joms.2011.05.002
PMCID: PMC3223542  PMID: 21856057
osteonecrosis of the jaw; pamidronate; alveolar osteoblasts; BMSCs; apoptosis
21.  Decayed, Missing, and Filled Teeth Index and Periodontal Health in Osteoporotic Patients Affected by BRONJ: An Observational Study 
Journal of Osteoporosis  2013;2013:231289.
The aim of this paper is to describe the incidence of decayed, missing, and filled teeth (DMFT) and periodontal disease in 32 osteoporotic patients affected by bisphosphonate-related osteonecrosis of the jaw (BRONJ). Moreover, an investigation between the obtained data and 20 patients treated with bisphosphonate drugs and with no evidence of ONJ has been performed. Osteonecrosis of the jaws is a rare complication in a subset of patients receiving bisphosphonate drugs. Based on a growing number of case reports and institutional reviews, this kind of therapy can cause exposed and necrotic bone specifically in the jawbones. From April 2009 to June 2012, 32 osteoporotic patients treated with oral or intravenous (I.V.) bisphosphonates have been recorded. The patients' oral health has been compared with 20 bisphosphonates patients with no ONJ. The incidence of decayed, missing, and filled teeth (DMFT) and periodontal disease was recorded in all patients and student's t-test was applied for comparing the two investigated groups data. Data demonstrated how the poor dental hygiene and periodontal disease of the BRONJ patients' are connected with the occurrence of jawbone necrosis.
doi:10.1155/2013/231289
PMCID: PMC3876686  PMID: 24455411
22.  Multiple Myeloma and Bisphosphonate-Related Osteonecrosis of the Mandible Associated with Dental Implants 
Case Reports in Dentistry  2011;2011:568246.
Multiple myeloma (MM) is a malignant plasma cell disorder and more than 30% of patients with this pathology develop osteolytic lesions in the jaw. Either pamidronate or zoledronic acid is recommended in patients with MM who have one or more lytic lesions. However, bisphosphonate-related osteonecrosis of the jaws (BRONJ) has been described as a complication associated with their use. Otherwise, the use of endosseous implants in oral rehabilitation is a well-established procedure, with good long-term success although systemic factors may affect the bone healing around dental implants. We report the first case reported of MM adjacent to a mandibular dental implant in a patient who developed BRONJ in the same area after intravenous zoledronate treatment. We discuss possible pathogeny of this particular and interesting phenomena.
doi:10.1155/2011/568246
PMCID: PMC3335612  PMID: 22567443
23.  Disparate osteogenic response of mandible and iliac crest bone marrow stromal cells to pamidronate 
Oral diseases  2008;14(5):465-471.
OBJECTIVE
Long-term administration of intravenous bisphosphonates like pamidronate is associated with jaw osteonecrosis but axial and appendicular bones are unaffected. Pathogenesis of bisphosphonate-associated jaw osteonecrosis may relate to skeletal-site specific effects of bisphosphonates on osteogenic differentiation of bone marrow stromal cells (BMSCs) of orofacial and axial/appendicular bones. This study evaluated and compared skeletal site-specific osteogenic response of mandible (orofacial bone) and iliac crest (axial bone) human BMSCs to pamidronate.
MATERIALS AND METHODS
Mandible and iliac crest BMSCs from six normal healthy volunteers were established in culture and tested with pamidronate to evaluate and compare cell survival, osteogenic marker alkaline phosphatase, osteoclast differentiation in co-cultures with CD34+ hematopoietic stem cells, gene expression of receptor activator of NFκB ligand (RANKL) and osteoprotegerin, and in vivo bone regeneration.
BRESULTS
Mandible BMSCs were more susceptible to pamidronate than iliac crest BMSCs based on decreased cell survival, lower alkaline phosphatase production and structurally less organized in vivo bone regeneration. Pamidronate promoted higher RANKL gene expression and osteoclast recruitment by mandible BMSCs.
CONCLUSION
Mandible and iliac crest BMSC survival and osteogenic differentiation are disparately affected by pamidronate to favor dysregulated mandible bone homeostasis.
PMCID: PMC2905679  PMID: 18938273
Bisphosphonate; Osteonecrosis; Jaw; Stem cells; Bone
24.  Multiple systemic diseases complicated by bisphosphonate osteonecrosis: a case report 
Annali di Stomatologia  2012;3(2 Suppl):32-36.
Summary
Aims
this work aims at demonstrating that multiple systemic conditions, in association with the development of bisphosphonate associated osteonecrosis of the jaw (ONJ), increase the risk of complications and may lead to hospitalization. For this reason the dental approach to patients with multisystem disease should be carefully managed by a team of specialists.
Case report
a case of mandibular necrosis associated with intake of oral bisphosphonates in a complex systemic context is described.
Results and discussion
many different diseases and systemic conditions may draw the line at oral surgery. Multiple treatments (e.g. antithrombotic, calcium channel blockers, diuretics, antibiotics and bisphosphonates) can alter the normal physiological response to tissue healing.
Conclusions
patients taking bisphosphonates for more than three years (i.e. the term over which the risk of ONJ increases according to the literature, in presence of complex systemic situations, need to be carefully managed during the pre-operative, peri-operative and postoperative phases through a synergistic collaboration among different kind of specialists.
PMCID: PMC3512552  PMID: 23285320
bisphosphonate osteonecrosis; oral surgery; therapeutic approach; CTX
25.  A case of mandible osteonecrosis after a severe periimplant infection 
Dental Research Journal  2012;9(Suppl 2):S233-S236.
The term osteonecrosis has been applied to describe the presence of a persistent inflammation of the mouth, osteomyelitis, delayed healing of extraction sockets, development of sequestra or presence of fistulae from the mouth to the lower skin. Here, we document a case of mandible osteonecrosis that developed in a patient after a severe periimplant infection. Osteonecrosis, severe inflammatory osteolysis, and heavy bacterial colonization were found. Surgical toilette and hyperbaric oxygen therapy permitted complete healing of the case. No complication was recorded in the post-operative period and no further surgery was performed. The clinical follow up and the imaging after one year showed a complete ‘restitution ad integrum’ of the mandible. Although the risk of developing osteonecrosis of the jaw for oral implants is low, the devastating complications still require caution.
doi:10.4103/1735-3327.109768
PMCID: PMC3692181  PMID: 23814591
Hyperbaric oxygen therapy; jaw osteonecrosis; periimplant infection; surgical toilette

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