Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ.

Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence.

Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone.

Cellular subpopulations in the bone marrow play distinct and unexplored functions in skeletal homeostasis. This study delineated a unique role of osteal macrophages in bone and parathyroid hormone (PTH)-dependent bone anabolism using murine models of targeted myeloid-lineage cell ablation. Depletion of c-fms(+) myeloid lineage cells [via administration of AP20187 in the macrophage Fas-induced apoptosis (MAFIA) mouse model] reduced cortical and trabecular bone mass and attenuated PTH-induced trabecular bone anabolism, supporting the positive function of macrophages in bone homeostasis. Interestingly, using a clodronate liposome model with targeted depletion of mature phagocytic macrophages an opposite effect was found with increased trabecular bone mass and increased PTH-induced anabolism. Apoptotic cells were more numerous in MAFIA versus clodronate-treated mice and flow cytometric analyses of myeloid lineage cells in the bone marrow showed that MAFIA mice had reduced CD68(+) cells, whereas clodronate liposome-treated mice had increased CD68(+) and CD163(+) cells. Clodronate liposomes increased efferocytosis (clearance of apoptotic cells) and gene expression associated with alternatively activated M2 macrophages as well as expression of genes associated with bone formation including Wnt3a, Wnt10b, and Tgfb1. Taken together, depletion of early lineage macrophages resulted in osteopenia with blunted effects of PTH anabolic actions, whereas depletion of differentiated macrophages promoted apoptotic cell clearance and transformed the bone marrow to an osteogenic environment with enhanced PTH anabolism. These data highlight a unique function for osteal macrophages in skeletal homeostasis.

Osteoporosis and Periodontitis.

Osteoporosis and periodontitis are both diseases characterized by bone resorption. Osteoporosis features systemic degenerative bone loss that leads to loss of skeletal cancellous microstructure and subsequent fracture, whereas periodontitis involves local inflammatory bone loss, following an infectious breach of the alveolar cortical bone, and it may result in tooth loss. Most cross-sectional studies have confirmed the association of osteoporosis and periodontitis primarily on radiographic measurements and to a lesser degree on clinical parameters. Multiple shared risk factors include age, genetics, hormonal change, smoking, as well as calcium and vitamin D deficiency. Both diseases could also be risk factors for each other and have a mutual impact that requires concomitant management. Suggested mechanisms underlying the linkage are disruption of the homeostasis concerning bone remodeling, hormonal balance, and inflammation resolution. A mutual interventional approach is emerging with complex treatment interactions. Prevention and management of both diseases require interdisciplinary approaches and warrants future well-controlled longitudinal and interventional studies for evidence-based clinical guidelines.

A skeleton in a huff: insights in etiologies of osteosclerosis.

A 30-yr-old man developed right lower leg pain and a palpable solid mass. Radiographic imaging revealed a periosteal reaction with an exostotic mass arising from the right distal fibula. Generalized skeletal osteosclerosis with periosteal reaction was discovered on a radiographic skeletal survey. A biopsy of the right fibular mass revealed reactive woven bone. The patient was referred to a metabolic bone disease clinic, where laboratory values were consistent with secondary hyperparathyroidism and increased bone turnover. A DXA bone density scan revealed high bone density, with an L1-4 spine Z-score of +9.3, a left femoral neck Z-score of +8.5, and a total hip Z-score of +6.5. A dental exam revealed generalized gingival inflammation, teeth mobility, generalized horizontal alveolar bone loss and widening of the periodontal ligament space, increased bone density around the teeth, and thickening of the radicular lamina dura. An extensive evaluation was performed, with the result of a single test revealing the diagnosis. The differential diagnoses of osteosclerosis affecting the skeleton, teeth, and oral cavity are discussed.

A 30-yr-old man developed, over a short period, pain in his lower right leg accompanied by a hard mass. He also reported weight loss and night sweats for the past 6 months. After evaluation by his primary physician, an X-ray was ordered that reported a bony mass arising from the right fibula bone. A biopsy was performed of the mass, but no evidence of cancer or any other specific abnormality was found. The patient was then referred to a bone disease specialty clinic. Laboratory tests revealed a large increase in how quickly the patient's skeleton was remodeling, affecting the balance of bone formation and removal involved in maintaining a healthy skeleton. A bone density scan reported that the patient had very dense bones. Other unusual changes were also discovered in a dental exam, suggesting bone thickening. After an extensive evaluation, a single blood test revealed the cause of the fibular bone mass and dense bones.

Teriparatide and osseous regeneration in the oral cavity.

BACKGROUND: Intermittent administration of teriparatide, a drug composed of the first 34 amino acids of parathyroid hormone, has anabolic effects on bone. Although teriparatide has been evaluated for the treatment of osteoporosis and for the healing of fractures, clinical trials evaluating it for the treatment of osseous conditions of the oral cavity in humans are lacking. METHODS: A total of 40 patients with severe, chronic periodontitis underwent periodontal surgery and received daily injections of teriparatide (20 µg) or placebo, along with oral calcium (1000 mg) and vitamin D (800 IU) supplementation, for 6 weeks. The patients were followed for 1 year. The primary outcome was a radiographic linear measurement of alveolar bone level. Secondary outcomes included clinical variables, bone turnover markers in serum and oral fluid, systemic bone mineral density, and quality of life. RESULTS: Radiographic linear resolution of osseous defects was significantly greater after teriparatide therapy than after placebo beginning at 6 months, with a mean linear gain in bone at 1 year of 29% as compared with 3% (P<0.001). Clinical improvement was greater in patients taking teriparatide than in those taking placebo, with a reduction in periodontal probing depth of 33% versus 20% (2.42 mm vs. 1.32 mm) and a gain in clinical attachment level of 22% versus 7% (1.58 mm vs. 0.42 mm) in target lesions at 1 year (P = 0.02 for both comparisons). No serious adverse events were reported; however, the number of patients in the study was small. No significant differences were noted with respect to the other variables that were assessed. CONCLUSIONS: Teriparatide, as compared with placebo, was associated with improved clinical outcomes, greater resolution of alveolar bone defects, and accelerated osseous wound healing in the oral cavity. Teriparatide may offer therapeutic potential for localized bone defects in the jaw. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00277706 .).

Antiresorptives and osteonecrosis of the jaw.

Osteonecrosis of the jaw (ONJ) is an uncommon condition noted to occur in patients who are receiving osteoclast-targeted antiresorptive therapy. The incidence of ONJ in patients taking oral antiresorptives for the management of osteoporosis is low (approximately 1:100,000), whereas it is higher (∼10%) in patients taking intravenous bisphosphonates for the treatment of metastatic bone diseases. The etiology and pathophysiology of ONJ is unclear. No established preventive or treatment modalities are currently available. Although ONJ is a rare condition, it is imperative for oral care providers to have updated knowledge, as a large number of patients on antiresorptives are seeking oral care. In this comprehensive review, we focus on ONJ and bisphosphonate therapy and dissect the currently available evidence to establish a clinical approach to assess risk, preventive measures, and management of ONJ.

COVID-19 and Dentistry: Biological Considerations, Testing Strategies, Issues, and Regulations.

The COVID-19 pandemic has created a new and demanding work environment for health professionals. This article will focus on the biological issues related to infection and disease, tests developed based on these biological principles, the ways in which these tests are evaluated, and how they can be used to protect both patients, dental professionals, and office affiliates. The article will describe types of COVID-19 testing that may be performed in dental offices, the issue of testing and anxiety, regulations regarding testing that are relevant to dentists, rules for delivery and reimbursement, and strategies for proceeding as a health professional in the current challenging environment. The authors conclude that the devastating effects of the pandemic on public health has facilitated a new role for dentists as public health professionals, with the opportunity for the dental profession to actively expand its participation in improving the health of the public moving forward. Testing will continue as a means of relieving anxiety for the public.

Three-Dimensional Electrodeposition of Calcium Phosphates on Porous Nanofibrous Scaffolds and Their Controlled Release of Calcium for Bone Regeneration.

To mimic the bone matrix of mineralized collagen and to impart microporous structure to facilitate cell migration and bone regeneration, we developed a nanofibrous (NF) polymer scaffold with highly interconnected pores and three-dimensional calcium phosphate coating utilizing an electrodeposition technique. The mineral content, morphology, crystal structure, and chemical composition could be tailored by adjusting the deposition temperature, voltage, and duration. A higher voltage and a higher temperature led to a greater rate of mineralization. Furthermore, nearly linear calcium releasing kinetics was achieved from the mineralized 3D scaffolds. The releasing rate was controlled by varying the initial electrodeposition conditions. A higher deposition voltage and temperature led to slower calcium release, which was associated with the highly crystalline and stoichiometric hydroxyapatite content. This premineralized NF scaffold enhanced bone regeneration over the control scaffold in a subcutaneous implantation model, which was associated with released calcium ions in facilitating osteogenic cell proliferation.

Osteonecrosis of the jaw: an update and review of recommendations.

Bisphosphonates have had a very positive impact as therapeutic agents for cancer and osteoporosis, but have also been associated with osteonecrosis of the jaw (ONJ) which has emerged as an idiosyncratic oral complication. Bisphosphonate-associated ONJ has generated wide attention despite its considerably rare occurrence. Many speculations exist as to why bisphosphonates may increase the incidence of ONJ. The American Society for Bone and Mineral Research established a task force on bisphosphonate-associated ONJ and recently released a summary report of their findings. A case definition delineated a confirmed case of ONJ as 'an area of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a health care provider, in a patient who was receiving or had been exposed to a bisphosphonate and had not had radiation therapy to the craniofacial region'. Treatment recommendations have been developed by the American Dental Association, the American Association of Oral and Maxillofacial Surgeons and the American Society for Bone and Mineral Research. Considering the scientific evidence, little is known about the true incidence and pathophysiology, and many questions persist. New epidemiologic studies are surfacing and attempts to ameliorate the condition may shed light on the likely complex etiology. The bones of the oral cavity provide a unique environment relative to blood flow, oral microbiota, bone structure and function. Although little is known of the mechanisms and course of ONJ, even less is known about the spectrum of issues of altered healing that could fall short of defined ONJ.

Case report of implant placement in a patient with Paget's disease on bisphosphonate therapy.

Paget's disease is the second most common bone disease following osteoporosis. Paget's disease is characterized by abnormal resorption and deposition of bone. The most widely used agents to treat Paget's disease are bisphosphonates. Bisphosphonates have been given much attention due to reports of osteonecrosis associated with their use. This case report demonstrates the placement of implants in a patient with Paget's disease on a six-month-course of bisphosphonate therapy. The patient had post-operative complications and a secondary placement but no signs of bisphosphonate-associated osteonecrosis of the jaw (ONJ). Although complications may exist, the placement of implants in a patient with Paget's disease taking bisphosphonates can have a positive outcome.

Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research.

UNLABELLED: ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force. INTRODUCTION: The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder. MATERIALS AND METHODS: A multidisciplinary expert group reviewed all pertinent published data on bisphosphonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed. RESULTS AND CONCLUSIONS: A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patient-treatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1-10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined.

Pulsatile release of parathyroid hormone from an implantable delivery system.

Intermittent (pulsatile) administration of parathyroid hormone (PTH) is known to improve bone micro-architecture, mineral density and strength. Therefore, daily injection of PTH has been clinically used for the treatment of osteoporosis. However, this regimen of administration is not convenient and is not a favorable choice of patients. In this study, an implantable delivery system has been developed to achieve pulsatile release of PTH. A well-defined cylindrical device was first fabricated with a biodegradable polymer, poly(l-lactic acid) (PLLA), using a reverse solid-free form fabrication technique. Three-component polyanhydrides composed of sebacic acid, 1,3-bis(p-carboxyphenoxy) propane and poly(ethylene glycol) were synthesized and used as isolation layers. The polyanhydride isolation layers and PTH-loaded alginate layers were then stacked alternately within the delivery device. The gap between the stacked PTH-releasing core and the device frame was filled with PLLA to seal. Multi-pulse PTH release was achieved using the implantable device. The lag time between two adjacent pulses were modulated by the composition and the film thickness of the polyanhydride. The released PTH was demonstrated to be biologically active using an in vitro assay. Timed sequential release of multiple drugs has also been demonstrated. The implantable device holds promise for both systemic and local therapies.

Effect of long-term oral bisphosphonates on implant wound healing: literature review and a case report.

BACKGROUND: Bisphosphonates suppress osteoclast activity, and their intravenous use has been reported in hundreds of cases to be associated with osteonecrosis in the jaw. Little is known of the risks associated with long-term use of oral bisphosphonates despite their use for >10 years by an oral mode of delivery for the treatment of osteopenia, osteoporosis, and Paget's disease of bone. The purpose of this report is to review the literature associated with bisphosphonate use that could impact bone healing and to report a case of bone necrosis in a patient on long-term oral bisphosphonates. METHODS: A Medline search was carried out to find relevant articles from both medical and dental literature between 1960 and 2006. A patient, who had been taking an oral bisphosphonate for >10 years, developed unexplained clinical signs of bone necrosis after routine dental implant placement. This case was followed, documented, and the treatment of the osteonecrosis described. RESULTS: A summary of how bisphosphonates may play a role in wound healing is presented. The compromised healing noted in a patient, who was under long-term oral bisphosphonate use, was successfully treated with systemic antibiotics, local microbial mouthrinse, and aggressive defect management (detoxification and mixture of bone graft and tetracycline). CONCLUSIONS: This case suggests that patients under long-term oral bisphosphonate use should be treated with caution. Well-controlled, prospective clinical trials on the effect of oral bisphosphonates on bone are warranted to determine which patients may be at risk for such complications.

Synthesis and erosion properties of PEG-containing polyanhydrides.

To tailor the erosion rate of polyanhydrides while retaining their surface erosion characteristics, new three-component polyanhydrides of sebacic acid, 1,3-bis(p-carboxyphenoxy)propane and poly(ethylene glycol) were synthesized. The hydrophilicity of the polymer increased and its mechanical strength decreased with increasing PEG content. Correspondingly, the erosion rate increases with increasing PEG content, whereas it decreases with increasing specimen thickness. This indicates that the incorporation of poly(ethylene glycol) into traditional two-component polyanhydrides retains their surface erosion properties while making the erosion rate tunable. The new polyanhydrides hold potential for drug delivery applications.

The Future of Dental Schools in Research Universities and Academic Health Centers.

As a profession, dentistry is at a point of discernible challenge as well as incredible opportunity in a landscape of evolving changes to health care, higher education, and evidence-based decision making. Respecting the past yet driving forward, a well-mapped future course is critical. Orchestrating this course in a collaborative manner is essential for the visibility, well-being, and potentially the existence of the dental profession. The research performed in dental institutions needs to be contemporary, aligned with biomedical science in general, and united with other disciplines. Dentistry is at risk of attrition in the quality of its research and discovery mission if participation with bioscience colleagues in the collaborative generation of new knowledge is underoptimized. A fundamental opportunity dentistry has is to contribute via its position in academic health centers. Rigorous research as to the impact of interprofessional education and collaborative care on population health outcomes provides significant potential for the dental profession to participate and/or lead such evidence-centered efforts. It is imperative that academic dental institutions are part of interdisciplinary and transdisciplinary organizations that move health care into its new day. Strategizing diversity by bringing together people who have different ways of seeing problems to share perspectives, heuristics, interpretations, technologies, and predictive models across disciplines will lead to impactful progress. Academic dental institutions are a natural part of an emphasis on translational research and acceleration of implementing new scientific discoveries. Dentistry needs to remain an essential and integrated component of higher education in the health professions; doing so necessitates deliberate, respectful, and committed change. This article was written as part of the project "Advancing Dental Education in the 21st Century."

The impact of primary hyperparathyroidism on the oral cavity.

CONTEXT: Primary hyperparathyroidism (HPT) is a systemic disease causing bone loss. Periodontal disease is a local inflammatory disease characterized by alveolar bone loss. The older literature records that HPT is associated with loss of radicular lamina dura and brown tumors of the bone, but contemporary studies are lacking. OBJECTIVE: The objective of the study was to determine the effects of HPT on oral bony structures and periodontal disease in a contemporary population. DESIGN: This was a cross-sectional, case-controlled study. SETTING: The study was conducted at the clinics of endocrine surgery and hospital dentistry. PATIENTS AND OTHER PARTICIPANTS: Fifty-nine patients, 39 with HPT and 20 thyroid controls, were included in the study. MAIN OUTCOME MEASURES: Periodontal clinical measures and dental radiographic analyses were used in this study. RESULTS: HPT patients were more likely to have tori and reductions in radicular lamina dura on dental radiographs. Widening of the periodontal ligament space surrounding teeth correlated with serum PTH levels. Panoramic radiographs demonstrated reduced cortical bone thickness at the angle of the mandible in HPT patients but no evidence of brown tumors or other overt pathologies. CONCLUSIONS: Changes in the oral cavity observed in patients with HPT suggested both decreased cortical density and increased likelihood of oral tori. The contemporary oral manifestations of primary HPT are different from those previously reported, and health care providers should be aware of newer, more subtle findings that may be present when treating patients with HPT.

Accuracy and consistency of radiographic interpretation among clinical instructors in conjunction with a training program.

There are inaccuracies and inconsistencies of radiographic interpretation among clinical instructors. The purpose of this investigation was to determine if a training program could improve the accuracy and consistency of instructors' ratings of bone loss. A total of thirty-five clinical instructors consisting of periodontal faculty (periodontists and general dentists), dental hygiene faculty, and periodontal graduate students viewed projected digitized radiographic images and quantified bone loss for twenty-five teeth into four descriptive categories. Ratings of bone loss were made immediately before (pretest) and after (post-test 1) initiation of the training program and then again three months later (post-test 2). Ratings were compared to the correct choice categories as determined by direct measurement using the Schei ruler. Overall agreement with the correct choice improved over time (from 64.5 percent to 85.2 percent) with the greatest change from pretest (64.5 percent) to post-test 1 (76.5 percent). Mean and absolute differences improved in three of the four categories, but worsened in one from pretest to post-test 1. This category returned to its original high value at post-test 2. The greatest improvement in consistency among instructors' ratings was seen in one of the four categories, which was "none" (no bone loss). Extension of the training program may further enhance the accuracy and consistency of instructors' radiographic interpretation.

Accuracy and consistency of radiographic interpretation among clinical instructors using two viewing systems.

Accurate and consistent radiographic interpretation among clinical instructors is needed for assessment of teaching, student performance, and patient care. The purpose of this investigation was to determine if the method of radiographic viewing affects accuracy and consistency of instructors' determinations of bone loss. Forty-one clinicians who provide instruction in a dental school clinical teaching program (including periodontists, general dentists, periodontal graduate students, and dental hygienists) quantified bone loss for up to twenty-five teeth into four descriptive categories using a view box for plain film viewing or a projection system for digitized image viewing. Ratings were compared to the correct category as determined by direct measurement using the Schei ruler. Agreement with the correct choice for the view box and projection system was 70.2 percent and 64.5 percent, respectively. The mean difference was better for a projection system due to small rater error by graduate students. Projection system ratings were slightly less consistent than view box ratings. Dental hygiene faculty ratings were the most consistent but least accurate. Although the projection system resulted in slightly reduced accuracy and consistency among instructors, training sessions utilizing a single method for projecting digitized radiographic images have their advantages and may positively influence dental education and patient care by enhancing accuracy and consistency of radiographic interpretation among instructors.

Variation in periodontal diagnosis and treatment planning among clinical instructors.

Consistency in clinical decision making may be necessary for reliable assessment of student performance and teaching effectiveness, yet little has been done to examine variation in periodontal diagnosis and treatment planning among dental school faculty. The purpose of this investigation was to examine variation among faculty in diagnosis and management of common periodontal diseases. Twenty-seven clinical instructors (periodontists, general dentists, dental hygienists, and first- and second-year periodontal graduate students) reviewed three web-based cases and answered a brief questionnaire focusing on radiographic interpretation, periodontal diagnosis, and treatment planning. Response rates for the three cases ranged from 62 percent to 70 percent. Clinical instructors' rating of percent bone loss in the majority of cases varied between three descriptive categories for the same tooth. Greater consistency in periodontal diagnosis was noted within the graduate student group as compared to periodontal and dental hygiene faculty groups. Diagnoses offered for one of the three patients varied between gingivitis and chronic and aggressive periodontitis. Six to nineteen different treatment plans (many with subtle differences) were submitted for each of the three cases. Inter-rater variation was qualitatively more prevalent than intra-rater variation. To our knowledge, this is the first study to document substantial variation among instructors in radiographic interpretation, diagnosis, and treatment planning for common periodontal diseases. Qualitative judgments speculating on the impact of variability among dental school faculty on student performance and patient care can be made but as yet remain unknown. Consistent use of accepted practice guidelines and greater consensus-building opportunities may decrease variation among faculty and enhance dental education.