Osteonecrosis of the jaw (ONJ), previously an entity associated with radiation therapy to the head and neck, has been observed in patients treated with bisphosphonates. Patients with metastatic breast cancer and myelomatous bone disease, commonly treated with high-potency nitrogen-containing bisphosphonates for a prolonged period of time, have the greatest risk of ONJ development. The reported frequency of ONJ ranges from 0.6% to 6.2% in breast cancer and from 1.7% to 15% in patients with multiple myeloma. Osteonecrosis of the jaw has also been observed in patients with other cancers such as prostate cancer and in benign bone disorders such as osteoporosis and Paget's disease in which the incidence is low. Risk factors associated with the development of ONJ include dental extractions, length of bisphosphonate treatment, and the type of bisphosphonate used. In this review, we summarize the reported incidence and risk factors associated with ONJ.

Introduction Patients diagnosed with lymphoma are at high risk of developing osteoporosis. When treated with alkylating agents or corticosteroids, especially if the patient develops hypogonadism, the risk is further increased. Osteoporotic bone cannot easily be restored to normal levels of strength; thus, prevention of bony loss is crucial. The percentage of healthy patients with osteoporosis dramatically increases with advanced age, suggesting that progressive bone loss is common, even without the above-mentioned cancer-related factors. Pamidronate can reduce the risk of bone loss and vertebral fractures in patients with lymphoma receiving chemotherapy. Zoledronic acid, a bisphosphonate approximately 100-fold more potent than pamidronate, has not been evaluated in patients with lymphoma. Urinary N-telopeptide cross-linked collagen type I (NTx), a marker of bone resorption, has early predictive value for long-term bony outcomes in patients treated with bisphosphonates. Bone-specific alkaline phosphatase (AP), a marker of bone formation, also correlates with response to bisphosphonate therapy. We have conducted a phase III trial to evaluate the effect of zoledronic acid on the change in bone mineral density (BMD) in patients with untreated lymphoma undergoing chemotherapy. We report the striking number of untreated lymphoma patients who present with osteopenia and thus would be at significant risk for future bone-related sequelae. Patients and Methods All patients with newly diagnosed lymphoma seen at our institution from 2005 to 2009 were evaluated for protocol eligibility. Exclusion criteria included bone fractures, BMD T-scores worse than −2.0, creatinine clearance < 60 mL/min, dental problems, and recent steroid or bisphosphonate use. Patients on study were stratified as male, premenopausal female, or postmenopausal female. Accrued patients were randomized to receive either: (1) oral calcium and vitamin D (Ca + D), or (2) Ca + D and 4 mg zoledronic acid intravenously (I.V.) at baseline and at 6 months. Urine NTx and bone-specific AP levels were measured at baseline, 3, 6, 9, and 12 months. Results To date, 46 patients have completed the study and have evaluable data. Patient characteristics include 27 male, 4 premenopausal female, 15 postmenopausal female, median age of 62 years (range, 33-80 years). Twenty-one patients had indolent lymphoma (18 follicular, 1 follicular center, 2 small lymphocytic), 19 had large B-cell lymphoma (17 diffuse large B-cell, 2 primary mediastinal B-cell lymphoma), 3 patients had Hodgkin lymphoma, 2 patients had mantle cell lymphoma, and 1 patient had Waldenström macroglobulinemia. Twenty-two patients (48% of all patients) had osteopenia at baseline enrollment in the trial, including 15 men (56% of men) and 7 women (37% of women). We have previously reported our significant findings of stable T scores in the zoledronic treatment group at all locations during the 12-month observation, and the T-scores of the control group decreased at every location evaluated (location: L1-4, P = .004; L neck, P = .001; L hip, P = .118; R neck, P = .009; R hip, P = .04). We have also reported our significant findings of the bone markers urine NTx and BSAP decreasing in the zoledronic acid treatment group and increasing in the control group. The bone makers were similar at baseline in both groups, and demonstrated early response at 3 months for BSAP and 6 months for urine NTx. Conclusions Treatment with zoledronic acid in newly-diagnosed lymphoma patients prevents the bone mineral density loss commonly seen in this population. Bone mass lost is difficult to restore, thus necessitating effective prevention strategies. Urine NTx and bone-specific AP levels demonstrate early response to bisphosphonate therapy, which may allow for early intervention and potentially prevention of further bone loss. With improving long-term survival for lymphoma patients, the need to address survivorship issues will prove more relevant to avoid preventable morbidity. We found a much-larger-than-expected portion of men with osteopenia at baseline. The etiology of the baseline low bone mass is unknown, but further evaluation of this finding in future trials is warranted to determine the significance. The portion of all lymphoma patients with baseline osteopenia in our trial, prior to any therapy, is striking and argues for baseline screening of all patients.

Patients with lymphoma are at high risk of osteoporosis. The majority have osteopenia at baseline, and the risk increases when treated with alkylating agents or corticosteroids. We conducted a randomized phase III trial to evaluate the effect of zoledronic acid on bone mineral density (BMD) in patients with lymphoma undergoing chemotherapy.

Abstract Abstract 3922 Poster Board III-858 Abstract: Patients diagnosed with lymphoma are at high risk of developing osteoporosis. We have shown previously that the majority of newly diagnosed patients are osteopenic or osteoporotic prior to receiving chemotherapy. When treated with alkylating agents or corticosteroids, especially if the patient develops hypogonadism, the risk is further increased. Osteoporotic bone cannot easily be restored to normal levels of strength, thus prevention of bony loss is crucial. Pamidronate can reduce the risk of bone loss and vertebral fractures in lymphoma patients receiving chemotherapy. Zoledronic acid, a bisphosphonate approximately 100-fold more potent than pamidronate, has not been evaluated in lymphoma patients. We have conducted a phase III trial to evaluate the effect of zoledronic acid on the change in bone mineral density (BMD) in patients with untreated lymphoma undergoing chemotherapy. Urinary N-telopeptide cross-linked collagen type I (NTx), a marker of bone resorption, has early predictive value for long term bony outcomes in patients treated with bisphosphonates. Bone specific alkaline phosphatase (AP), a marker of bone formation, also correlates with response to bisphosphonate therapy. We report the change in urine NTx and bone specific AP levels in lymphoma patients treated with zoledronic acid. Methods All newly diagnosed lymphoma patients seen at our institution from 2005 – 2009 were evaluated for protocol eligibility. Exclusion criteria included bone fractures, BMD T-scores worse than –2.0, creatinine clearance less than 60 mL/min, dental problems, and recent steroid or bisphosphonate use. Patients on study were stratified as male, pre-menopausal female, or post-menopausal female. Accrued patients were randomized to receive either: 1) oral calcium and vitamin D (Ca+D) or 2) Ca+D and 4 mg zoledronic acid IV at baseline and at 6 months. Urine NTx and bone specific AP levels were measured at baseline, 3, 6, 9, and 12 months. Results To date, 33 patients have completed the study and have evaluable data. Patient characteristics include: 17 male, 4 pre-menopausal female, 12 post-menopausal female, median age 62 (range 33 – 80). Seventeen patients had osteopenia upon enrollment. Patients that received zoledronic acid had stable median T-scores at all locations during the 12 month observation, whereas the T-scores of the control group decreased at every location evaluated (Location: L1-4, p=0.004; L Neck, p= 0.001; L Hip, p=0.118; R Neck, p=0.009; R Hip, p=0.040). Each group had a similar baseline level of urine NTx and bone specific AP. At 6 months, the urine NTx decreased significantly in the zoledronic acid-treated group compared to urine NTx levels in the control group which increased (p<0.001). The separation between groups remained constant throughout the evaluation period (12 months, p<0.001). The bone specific AP level decreased in the zoledronic acid group by 3 months, and remained below baseline levels at 12 months. The control group had increases in bone specific AP levels throughout the 12 month period (6 months, p=0.001; 12 months, p<0.001). Conclusions Treatment with zoledronic acid in newly-diagnosed lymphoma patients prevents the bone mineral density loss commonly seen in this population. Bone mass lost is difficult to restore, thus necessitating effective prevention strategies. Urine NTx and bone specific AP levels demonstrate early response to bisphosphonate therapy. The ability to predict response to bisphosphonates at 6 months may allow for early intervention, potentially preventing further bone loss. Our study demonstrates the bone markers urine NTx and bone specific AP are significantly associated with bone health in lymphoma patients receiving chemotherapy. Disclosures: Thompson: Novartis: Research Funding. Toth:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hagemeister:Novartis: Research Funding.

Treatment of lymphoma with alkylating agents and steroids is known to cause bone loss and increased fracture risk. These effects result from multiple causes including systemic lymphoma-related cytokine activity, steroid-mediated bone loss, and therapy-induced hypogonadism. Furthermore, over half of all untreated lymphoma patients are either osteopenic or osteoporotic at the time of diagnosis.1,2 Pamidronate is known to reduce bone loss and risk of vertebral fractures in lymphoma patients undergoing chemotherapy. However, the effects of the more potent bisphosphonate zoledronic acid in this setting are unknown. Therefore, we report on an ongoing phase III trial designed to evaluate the effect of zoledronic acid on the change in bone mineral density (BMD) in patients with newly-diagnosed lymphoma undergoing chemotherapy. In total, 72 patients will be randomized to either the control arm consisting of therapy with calcium carbonate (1200 mg orally per day) plus vitamin D (400 mg orally per day), or the bisphosphonate arm consisting of therapy with calcium carbonate and vitamin D as in the control arm plus zoledronic acid (4 mg IV given at baseline and at 6 months). The primary endpoint of the study is to compare the absolute change between the baseline and 12-month measures of BMD at the lumbar spine and femoral necks. Thus far, 97 patients have been screened for enrollment. Twenty-four patients (24.7%) failed screening due to periodontal disease, a predetermined exclusion criterion of the study. Twenty-three patients have been randomized to the control arm, and 18 patients have been randomized to the bisphosphonate arm. To date, 11 patients in the control arm and 7 patients in the bisphosphonate arm have completed the one-year follow up period including baseline and one-year BMD evaluations. In comparing the change in BMD at one year of patients in the control arm to that of patients in the bisphosphonate arm, the average change in T scores at the lumber spine was −0.482 vs. 0, at the left femoral neck was −0.218 vs. 0.057, and at the right femoral neck was −0.309 vs. 0.243, respectively. There have been no therapy-related serious adverse events in either arm of the study. In addition, no occurrences of osteonecrosis of the jaw have been noted. In conclusion, treatment with the bisphosphonate zoledronic acid in combination with calcium carbonate and vitamin D supplementation appears to provide prevention of bone loss or improvement in the BMD of patients with lymphoma undergoing chemotherapy. Given the large number of patients with below-average BMD prior to therapy and the known deleterious effects of lymphoma therapy on bone density, baseline BMD evaluation may be warranted in all lymphoma patients. In addition, the unexpectedly high rate of periodontal disease in this patient population further supports the need for careful dental evaluation prior to the consideration of bisphosphonate therapy given the well-described, albeit rare, risk of osteonecrosis of the jaw from zoledronic acid.

Introduction: Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. The incidence and risk factors associated with this disorder have not been clearly defined.Materials and Methods: We conducted a retrospective analysis of 4019 patients treated with intravenous bisphosphonates between 1996 and 2004. Our goals were to estimate the frequency, understand the clinical presentation, and identify risk factors associated with ONJ development.Results: Sixteen of 1338 patients with breast cancer (1.2%) and 13 of 548 patients with multiple myeloma (2.4%) developed ONJ. The median dose and duration of treatment with pamidronate or zoledronic acid were significantly higher in patients with ONJ (p < 0.0001). Multivariate Cox proportional hazards regression analysis identified treatment with zoledronic acid (hazards ratio [HR], 15.01; 95 % CI: 2.41-93.48; p = 0.0037), treatment with pamidronate followed by zoledronic acid (HR, 4.00; 95 % CI: 0.86-18.70; p = 0.078), and dental extractions (HR, 53.19; 95% CI: 18.20-155.46; p < 0.0001) as significant risks for ONJ in breast cancer. In multiple myeloma, dental extractions (HR, 9.78; 95 % CI: 3.07-31.14; p = 0.0001) and osteoporosis (HR, 6.11; 95% Cl: 1.56-23.98; p = 0.0095) were significant risk factors while controlling for bisphosphonate therapy. Thirteen of 29 patients were followed for a median of 17.1 mo (range, 7-67 mo); lesions healed in 3 patients during this period.Conclusions: ONJ is an uncommon but long-lasting disorder that occurs mainly in breast cancer and multiple myeloma patients treated with intravenous bisphosphonates. High cumulative doses of bisphosphonates, poor oral health, and dental extractions may be significant risk factors for ONJ development. ONJ resolved in 23% of patients with conservative therapy.

Radiation-induced xerostomia can result in the rapid onset and progression of dental caries in head and neck cancer patients. Topically applied fluorides have been successfully used to inhibit the formation of dental caries in this population. However, because intensive daily self-application is required, compliance is an issue. The intraoral fluoride-releasing system (IFRS) containing a sodium fluoride core is a newly developed, sustained-release, passive drug delivery system that does not require patient involvement except for periodic replacement, thus reducing the effect of patient compliance on its effectiveness in dental caries prevention. Twenty-two head and neck cancer patients from U. T. M. D. Anderson Cancer Center, with radiation-induced xerostomia, were entered into a pilot study to contrast the daily home use of a 0.4% stannous fluoride-gel-containing tray (control group) to IFRS (study group) with respect to tolerability and adherence, and to obtain information on relative caries preventive efficacy. Participants were stratified on the basis of radiation exposure and randomly assigned to treatment with either IFRS or stannous fluoride gel. Patients in both groups were fitted with two IFRS retainers and also were instructed to use a 1100-ppm fluoride conventional sodium fluoride dentifrice twice daily. The study was conducted as a single-blinded, parallel-cell trial. Pre-existing carious lesions were restored prior to the beginning of the study. The efficacy variable was determined by the mean number of new or recurrent decayed surfaces. Patients were examined for caries 4, 8, 12, 24, 36, and 48 weeks after initiation of treatment. Reports of adverse reactions were based on information volunteered by patients and that were elicited during interviews. At baseline, the resting and stimulated salivary flow rates (g/5 min) were significantly greater in the control group than in the study group (p < 0.05). Patients in the control group had received significantly more radiation than those in the test group (68 Gy vs. 60 Gy; p = 0.047). No marked differences in follow-up new and recurrent caries were found between the stannous fluoride gel control and IFRS groups during the study period. The rate of new or recurrent carious lesions in the group treated with the fluoride gel was slightly lower than in the IFRS group, based on carious lesions at the baseline examination (Poisson mean number of new or recurrent carious lesions for the control group = 0.55 per year vs. 0.83 per year for the study group, p = 0.705; odds ratio of the occurrence of any new or recurrent caries during follow-up for control group vs. the study group = 0.80; p = 0.781). This pilot study revealed that the IFRS was well-tolerated and safe in this study population associated with minimal complications during the duration of this study and was comparable in efficacy to a SnF2 gel in preventing caries development. The IFRS provided similar rates of control for caries formation to a fluoride-gel-containing tray. The IFRS is designed to release a daily dose of 0.12 mg of sodium fluoride, which can be evenly distributed throughout the oral cavity for a single application of 4 months. It would be more convenient than the daily home application of a tray of 0.4% stannous fluoride or 1.1% sodium fluoride gel, and avoids the problem of variable patient compliance. (c) 2006 Elsevier Ltd. All rights reserved.

Purpose This article discusses osteonecrosis of the jaw (ONJ) and offers health care professionals practical guidelines and recommendations for the prevention, diagnosis, and management of ONJ in cancer patients receiving bisphosphonate treatment. Methods A panel of experts representing oral and maxillofacial surgery, oral medicine, endocrinology, and medical oncology was convened to review the literature and clinical evidence, identify risk factors for ONJ, and develop clinical guidelines for the prevention, early diagnosis, and multidisciplinary treatment of ONJ in patients with cancer. The guidelines are based on experience and have not been evaluated within the context of controlled clinical trials. Results ONJ is a clinical entity with many possible etiologies; historically identified risk factors include corticosteroids, chemotherapy, radiotherapy, trauma, infection, and cancer. With emerging concern for potential development of ONJ in patients receiving bisphosphonates, the panel recommends a dental examination before patients begin therapy with intravenous bisphosphonates. Dental treatments and procedures that require bone healing should be completed before initiating intravenous bisphosphonate therapy. Patients should be instructed on the importance of maintaining good oral hygiene and having regular dental assessments. For patients currently receiving bisphosphonates who require dental procedures, there is no evidence to suggest that interrupting bisphosphonate therapy will prevent or lower the risk of ONJ. Frequent clinical assessments and conservative dental management are suggested for these patients. For treatment of patients who develop ONJ, a conservative, nonsurgical approach is strongly recommended. Conclusion An increased awareness of the potential risk of ONJ in patients receiving bisphosphonate therapy is needed. Close coordination between the treating physician and oral surgeon and/or a dental specialist is strongly recommended in making treatment decisions.

Osteonecrosis of the jaw or maxilla (ONJM) is a rare but clinically significant disorder recently reviewed in a large retrospective study by our group (Hoff et al, 27th ASBMR Meeting 2005, Presentation #1218). A subset of the ONJM patients with breast cancer or myeloma was followed at the University of Texas M.D. Anderson Cancer Center (UTMDACC) dental clinic. This analysis describes the natural history of ONJM in this subset. Thirteen of 29 ONJM patients treated with intravenous bisphosphonates (IVBP) at UTMDACC and 1 ONJM patient treated elsewhere were evaluated in the dental clinic for more than 6 months (myeloma, n=7; breast cancer, n=7). Measurement of the maximum length of exposed bone was documented at each visit. Each patient received a standard regimen of conservative dental care with debridement only when indicated. All patients received zoledronic acid (mean cumulative dose 80mg; range 24–152mg) and 10 patients also received pamidronate (mean cumulative dose 1665mg; range 90–2700mg). This subset was followed for a median duration of 18.2 months (range: 7.1–67.3 months). The mean length of exposed bone at initial evaluation was 11 mm (range: 2–29 mm). The lesion from baseline to the most recent clinic visit progressed in 7 patients (50%), remained stable in 2 (14%), regressed in 2 (14%), and resolved in 3 (21%). Persistent ONJ was seen if IVBP was stopped (n=8), decreased in frequency (n=1), or continued at the same dose/frequency (n=2) (Graphs 1, 2). Complete resolution occurred in 3 multiple myeloma patients; IVBP was decreased in one and discontinued in 2 of the resolved cases (heavy lines on Graph 1). Our experience shows that ONJM is a disorder with slow resolution in most patients, lasting as long as 5 years. In the oncologic setting where there is clear benefit of bisphosphonate therapy, studies to optimize the dosing regimen may be needed.

BACKGROUND: Lymphoma treatment with alkylating agents and steroids can cause premature osteoporosis, increasing the risk of vertebral and hip fracture. Mechanisms of bone loss may include local microenvironment lymphoma-related cytokine activity, steroid-mediated bone loss, and hypogonadism from chemotherapy. The bisphosphonate pamidronate every three months has been found to reduce bone loss and the risk of new vertebral fractures in lymphoma patients receiving chemotherapy; however, the more potent bisphosphonate, zoledronic acid, has not been evaluated in this patient population. We are conducting a randomized study of zoledronic acid in untreated non-Hodgkin’s lymphoma (NHL) patients to study chemotherapy induced bone loss and improve NHL survivorship. While this trial is still accruing patients, we report the abnormal baseline bone mineral density (BMD) and endocrine characteristics found in patients screened for this study. METHODS: We report the preliminary baseline endocrine characteristics for this ongoing bone health research study. Untreated NHL patients were screened for BMD and endocrine studies including vitamin D levels, testosterone, and bone turnover markers. Patients on the study were stratified as male, female (pre-menopausal), and female (post-menopausal). Exclusion criteria included bone fractures, BMD T-scores worse than −2.0, creatinine clearance less than 60 mL/min, dental problems, and prior steroid or bisphosphonate use. Patients accrued to the study are randomized to receive either: 1) oral calcium and vitamin D (Ca+D) or 2) Ca+D and 4 mg zoledronic acid IV at baseline and at 6 months. RESULTS: Patient characteristics included: 49 male, 35 female (10 pre-menopausal), median age 61 (range: 18–87). Of 84 patients screened for BMD to date, patients had the following abnormalities: 12/84 (14%) had osteoporosis and 47/84 (56%) had osteopenia or osteoporosis. Of 20 patients who consented to the trial and who were evaluated with additional studies, 10 were excluded due to the following: 3/20 hypovitaminosis D, 1/20 with prior steroid use, 1/20 low testosterone, 1/20 prior HRT, 1/20 with bone disease, 2/20 required dental extractions, and 1/20 treatment changed to chemotherapy without steroids. Patients with osteoporosis or T score worse than −2.0 were evaluated by their primary oncologist for treatment with bisphosphonates. Patients with other abnormal studies were further evaluated and treated by specialists in endocrinology and dentistry. CONCLUSIONS: Baseline testing of BMD and endocrine studies revealed osteopenia or osteoporosis in 56% of untreated NHL patients. Hypovitaminosis D or low testosterone was found in a smaller number of tested patients. While these patients were excluded from the remainder of the study and referred for further evaluation, patients should benefit from having these underlying problems addressed. Our ongoing clinical trial will address the potential role of zoledronic acid in preserving bone density for survivors of NHL. This trial was funded by Novartis. ClinicalTrials.gov Identifier: NCT00352846.

Aggressive cancer therapy places patients at greater risk for oral complications and treatment-related consequences. Unfortunately, prevention and/or treatment of such oral sequelae has become an often overlooked priority of the treatment team. We describe a philosophy of management of the cancer patient that specifically emphasizes the prevention and treatment of oral complications associated with cancer therapy. These concepts and principles are based on treatment protocols and ongoing clinical research at the University of Texas M.D. Anderson Cancer Center in Houston, Texas.

Because mantle field radiotherapy is associated with partial xerostomia in patients with Hodgkin's disease, the purpose of this study was to evaluate their cariogenic microflora before and after completion of radiotherapy. We obtained samples of oral saline solution rinse from 40 patients with Hodgkin's disease before radiotherapy and from 31 patients with Hodgkin's disease who had survived 1 to 24 years after radiotherapy. We also evaluated caries experience and history of fluoride gel use for caries prevention in these patients. Mutans streptococci and lactobacilli levels were significantly higher in the postradiotherapy patients with carious teeth, particularly in those with limited home use of fluoride gels. In the postradiotherapy group, caries parameters were significantly higher (p < 0.05) than in the preradiotherapy group. Within the postradiotherapy group, both caries and microbial parameters tended to be higher in patients who were less compliant about using the recommended 0.4% stannous fluoride "brush-in" technique than in those who used the gel regularly at home. This study indicates that for patients with Hodgkin's disease who receive mantle field irradiation during the management of their disease, a sustained brush-in program with stannous fluoride gel can be of benefit for caries prevention and for limitation of oral levels of cariogenic mutans streptococci.

The cancer patient receiving chemotherapy often suffers severe oral complications related to the administration of antineoplastic drugs. Cancer patients who also have transmucosal or endosseous dental implants pose special problems for medical oncologists and dentists, both when planning for chemotherapy and when providing supportive care during the course of treatment. The relationship between dental implants and cancer chemotherapy is described and complications experienced by implant patients treated with chemotherapy at The University of Texas M.D. Anderson Cancer Center are reviewed. Recommendations on various aspects of management involving implant evaluation and the removal or retention of dental implants are discussed.

Bone marrow transplantations are being used with increasing frequency in the treatment of patients with leukemia and aplastic anemia. The graft-vs.-host disease (GVHD) is a serious complication that affects long-term survivors following bone marrow transplantation. It is the result of an immunologic reaction mounted by the grafted reticuloendothelial cells against the tissues of the recipient, and it affects multiple organ systems. Involvement of the skin and mucosal surfaces of the head and neck region, in particular the oral cavity, occurs in a large number of patients with GVHD. In this report we present four patients with GVHD in whom mucosal lesions and infections of the head and neck region were prominent features. Our observations indicate that the clinical and histological characteristics of these lesions vary according to the time elapsed from the onset of the disease. Therefore, clinical examination of the head and neck region and biopsy of the oral mucosa are important not only in the diagnosis of the GVHD, but also in the evaluation of its progress and response to treatment.