Regina Landesberg

American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws—2009 Update

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) adversely affects the quality of life, producing significant morbidity in afflicted patients. Strategies for the treatment of patients with, or at risk of, BRONJ were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws (Position Paper) and approved by the Board of Trustees in September 2006. 1 The Position Paper was developed by a Task Force appointed by the Board and composed of clinicians with extensive experience in caring for these patients and basic science researchers. The knowledge base and experience in addressing BRONJ has expanded, necessitating modifications and refinements to the original Position Paper. The Task Force was reconvened in August 2008 to review the 2006 recommendations, appraise the current published data, and revise the Position Paper and recommendations, where indicated. This update contains revisions to the diagnosis and staging and management strategies and highlights the status of basic science research. AAOMS considers it vitally important that this information be disseminated to other dental and medical specialties.

Quantification of growth factor levels using a simplified method of platelet-rich plasma gel preparation.

PURPOSE This study compared two methods of preparing platelet-rich plasma (PRP) gel and the levels of PDGF and TGFbeta in each preparation. MATERIALS AND METHODS Platelet-rich plasma gel was prepared by centrifugation and clotted using the ITA gelling agent (Natrex Technologies Inc, Greenville, NC) or by the addition of thrombin and calcium chloride. The levels of platelet-derived growth factor (PDGF) and transforming growth factor beta (TGFbeta) generated by clot formation were assayed by enzyme-linked immunoassay (ELISA). RESULTS Both methods of preparation yielded PRP gel in less than 30 minutes. However, the ITA preparation did not require thrombin to achieve adequate gel formation. The levels of PDGF and TGFbeta were similar regardless of which method was used for initiation of clot formation. CONCLUSION Use of ITA for gel preparation is equivalent to using calcium chloride and thrombin, without the need for special equipment and the risk of coagulopathy.

Inhibition of Oral Mucosal Cell Wound Healing by Bisphosphonates

PURPOSE Bisphosphonates (BPs) are a widely used class of drugs that are effective in the treatment and prevention of osteoporosis, hypercalcemia of malignancy, and bone metastases associated with multiple myeloma, breast cancer, and other solid tumors. In the past several years there have been numerous reports describing the occurrence of osteonecrosis of the jaws (ONJ) associated with these drugs. Whether the ONJ lesion initiates in the oral mucosa or derives from the underlying bone is not well understood. In this report we describe the effect of pamidronate, a second-generation BP, on oral mucosal cells. MATERIALS AND METHODS Murine oral keratinocytes were isolated and exposed to pamidronate at a range of clinically relevant doses. Cellular proliferation was measured using a MTS/PMS reagent-based kit and wound healing was examined with a scratch assay. To determine whether oral keratinocytes undergo apoptosis following exposure to pamidronate, TUNEL, caspase-3, and DAPI apoptosis assays were performed. RESULTS We show that BP pretreatment of oral mucosal cells inhibits proliferation and wound healing at clinically relevant doses, and that this inhibition is not due to cellular apoptosis. CONCLUSIONS To our knowledge this is the first report investigating the effect of nitrogen-containing BPs on oral mucosal cells. This study suggests that BPs inhibit oral keratinocyte wound healing which may play a significant role in the initiation of ONJ.

American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw - 2009 update.

0 isphosphonate-related osteonecrosis of the jaw BRONJ) adversely affects the quality of life, producing ignificant morbidity in afflicted patients. Strategies for he treatment of patients with, or at risk of, BRONJ were et forth in the American Association of Oral and axillofacial Surgeons (AAOMS) Position Paper on isphosphonate-Related Osteonecrosis of the Jaws Position Paper) and approved by the Board of Trustes in September 2006. The Position Paper was eveloped by a Task Force appointed by the Board nd composed of clinicians with extensive experince in caring for these patients and basic science esearchers. The knowledge base and experience in ddressing BRONJ has expanded, necessitating modfications and refinements to the original Position aper. The Task Force was reconvened in August 2008 to

Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis

A potential side effect associated with bisphosphonates, a class of drugs used in the treatment of osteoporosis, Pagets disease and metastatic bone disease, is osteonecrosis of the jaw (ONJ). The incidence of ONJ in the general population is unknown; this rare condition also may occur in patients not receiving bisphosphonates. Case reports have discussed ONJ development in patients with multiple myeloma or metastatic breast cancer receiving bisphosphonates as palliation for bone metastases. These patients are also receiving chemotherapeutic agents that might impair the immune system and affect angiogenesis. The incidence or prevalence of ONJ in patients taking bisphosphonates for osteoporosis seems to be very rare. No causative relationship has been unequivocally demonstrated between ONJ and bisphosphonate therapy. A majority of ONJ occurs after tooth extraction. Furthermore, the underlying risk of developing ONJ may be increased in osteoporotic patients by comorbid diseases. Treatment for ONJ is generally conservative.

Osteonecrosis of the Jaw and the Role of Bisphosphonates : A Critical Review

Osteonecrosis of the jaw (ONJ), a condition characterized by necrotic exposed bone in the maxillofacial region, has been reported in patients with cancer receiving bisphosphonate therapy, and rarely in patients with postmenopausal osteoporosis or Paget disease of bone receiving such therapy. In the absence of a uniform definition, the American Academy of Oral and Maxillofacial Surgeons (AAOMS), the American Society for Bone and Mineral Research (ASBMR), and other groups have established similar diagnostic criteria for bisphosphonate-related ONJ, which is more commonly reported in patients with advanced malignancies with skeletal metastases who receive higher doses, and is more rarely reported in patients with osteoporosis and Paget disease who receive lower doses. However, a critical review of the literature reveals that the etiology of ONJ remains unknown, and to date no direct causal link to bisphosphonates has been established. Despite an increased awareness of ONJ and recent improvements in preventive strategies, patients and physicians alike continue to express concern about the potential risks of bisphosphonate treatment in both oncologic and nononcologic settings. Although much remains to be learned about this condition, including its true incidence in various patient populations, its pathophysiology, and optimal clinical management, evidence to date suggests that the positive benefits of bisphosphonates in patients with malignant bone disease, osteoporosis, or Paget disease outweigh the relatively small risk of ONJ.

Potential pathophysiological mechanisms in osteonecrosis of the jaw

Bisphosphonates are used in the treatment of hypercalcemia of malignancy, skeletal complications associated with metastastic bone disease, Pagets disease, and osteoporosis. Osteonecrosis of the jaw (ONJ) is a recently described clinical condition that has been associated with the use of nitrogen‐containing bisphosphonates. Reports describing this entity first appeared in the literature in 2003. While there have been significant numbers of case reports and a limited number of retrospective and prospective studies examining risk factors associated with ONJ, the pathophysiology of this condition remains elusive. In this review, we explore proposed mechanisms underlying ONJ development and identify potential areas for future investigation.

Controlled delivery of platelet-rich plasma-derived growth factors for bone formation

Platelet-rich plasma (PRP) represents an autologous source of growth factors essential for bone regeneration. The clinical efficacy of PRP is, however, unpredictable, and this is likely due to the inefficient and inconsistent delivery of PRP-derived growth factors. Previous investigations have shown that current methods of PRP preparation result in a premature release of the relevant bone stimulatory factors. As successful bone regeneration requires multiple factors presented in a physiologic temporal and spatial cascade, the objective of this study is to control the bioavailability of PRP-derived growth factors using a hydrogel carrier system. Specifically, the release of platelet-derived growth factor, transforming growth factor beta-1, and insulin-like growth factor from two types of alginate carriers was compared over time. The effects of the released factors on the growth and alkaline phosphatase (ALP) activity of human osteoblast-like cells were also evaluated. It was found that factor release profiles varied as function of carrier type, and binding of growth factors to the alginate matrix also modulated their release. The bioactivity of released factors was maintained in vitro and they promoted cell proliferation and ALP activity. These results demonstrate the potential of this autologous multifactor delivery system for controlling the bioavailability of PRP-derived factors. Future studies will focus on optimizing this system to increase the clinical efficacy of PRP by matching the distribution and temporal sequencing of PRP-derived factors to the bone healing cascade.

Alternative Indications for Bisphosphonate Therapy

Bisphosphonates are currently used in the treatment of osteoporosis (postmenopausal and steroid-induced), hypercalcemia of malignancy, Pagets disease of bone, multiple myeloma, and skeletally related events associated with metastatic bone disease in breast, prostate, lung, and other cancers. There are, however, numerous other conditions where a decrease in bone remodeling by bisphosphonates might aid in disease management. The focus of this review will be to discuss a select group of conditions for which bisphosphonate therapy may be efficacious. In this review we present several cases where bisphosphonates have been used as a primary or adjunctive treatment for giant cell lesions of the jaws. Use of bisphosphonate therapy for giant cell tumors of the appendicular skeleton, pediatric osteogenesis imperfecta, fibrous dysplasia, Gauchers disease, and osteomyelitis will be discussed. Finally, we will review previous in vivo studies on the use of bisphosphonates to augment integration and to treat osteolysis surrounding failing orthopedic implants.

Phosphaturic mesenchymal tumor, mixed connective tissue variant, of the mandible: Report of a case and review of the literature

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that results in renal phosphate wasting with hypophosphatemia. In most cases, the underlying cause of TIO is a small mesenchymal neoplasm that is often difficult to detect, resulting in delayed diagnosis. One such neoplasm is the phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT), an unusual entity with unique morphologic and biochemical features. Most of these tumors are found at appendicular sites with only rare cases reported in the jaws. We describe a PMTMCT involving the mandible in a patient with a protracted history of osteomalacia. A review of the current literature is provided with emphasis on the clinical and histologic features, etiopathogenesis, and management of PMTMCT in the setting of TIO.