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Journal of Clinical Oncology, Vol 24, No 6 (February 20), 2006: pp. 945-952 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.2465 Osteonecrosis of the Jaw in Multiple Myeloma Patients: Clinical Features and Risk FactorsFrom the University of Maryland Marlene and Stewart Greenebaum Cancer Center; University of Maryland Dental School, Baltimore, MD Address reprint requests to Ashraf Badros, University of Maryland, Greenebaum Cancer Center, 22 S Greene St, Baltimore, MD 21201; e-mail: abadros{at}umm.edu
PURPOSE: To describe the clinical, radiologic, and pathologic features and risk factors for osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients. PATIENTS AND METHODS: A retrospective review of 90 MM patients who had dental assessments, including 22 patients with ONJ. There were 62 men; the median age was 61 years in ONJ patients and 58 years among the rest. Prior MM therapy included thalidomide (n = 67) and stem-cell transplantation (n = 72). Bisphosphonate therapy included zoledronate (n = 34) or pamidronate (n = 17) and pamidronate followed by zoledronate (n = 33). Twenty-seven patients had recent dental extraction, including 12 patients in the ONJ group. Median time from MM diagnosis to ONJ was 8.4 years for the whole group. RESULTS: Patients usually presented with pain. ONJ occurred posterior to the cuspids (n = 20) mostly in the mandible. Debridement and sequestrectomy with primary closure were performed in 14 patients; of these, four patients had major infections and four patients had recurrent ONJ. Bone histology revealed necrosis and osteomyelitis. Microbiology showed actinomycetes (n = 7) and mixed bacteria (n = 9). More than a third of ONJ patients also suffered from long bone fractures (n = 4) and/or avascular necrosis of the hip (n = 4). The variables predictive of developing ONJ were dental extraction (P = .009), treatment with pamidronate/zoledronate (P = .009), longer follow-up time (P = .03), and older age at diagnosis of MM (P = .006). CONCLUSION: ONJ appears to be time-dependent with higher risk after long-term use of bisphosphonates in older MM patients often after dental extractions. No satisfactory therapy is currently available. Trials addressing the benefits/risks of continuing bisphosphonate therapy are needed.
Bone disease affects 70% of multiple myeloma patients and is associated with pain and/or pathologic fractures.1,2 Bone destruction results from dissociation of osteoclast/osteoblast activities favoring bone resorption.3 The myeloma/bone stromal cell interaction produces several proteins that result in bone destruction; MIP-1alpha directly stimulates osteoclast formation and dickkopf 1 (DKK1), an inhibitor of the Wingless-type (Wnt) signaling pathway, which is crucial for osteoblast differentiation leading to reduced bone formation.4,5 Bisphosphonates, pamidronate (Aredia; Novartis, Basel, Switzerland) and zoledronate (Zometa; Novartis), act at sites of active bone remodeling by binding to hydroxyapatite, inhibiting osteoclasts development and migratory activity, inducing cell death, thereby, decreasing bone resorption without affecting bone mineralization.6-8 Monthly infusions of bisphosphonates have been shown to reduce skeletal events and modify the natural history of bone disease in multiple myeloma.9 The benefit was maintained up to 21 to 25 months in many phase II and III clinical trials.10 Although no clinical data support long-term efficacy and benefit beyond 2 years, patients with lytic bone disease continue bisphosphonate therapy indefinitely, a practice endorsed by the American Society of Clinical Oncology.11 Even myeloma patients without bone disease have commonly received bisphosphonates long-term because of a potential antimyeloma effect.12 Osteonecrosis of the jaw (ONJ) results from bone exposure in the oral cavity with subsequent necrosis often following dental procedures or traumatic injuries.13 The etiology is unclear; it has been attributed to reduction/loss of vascular supply and hypercoagulable states as well as infection and osteomyelitis.14-16 Osteoradionecrosis is a clinically similar condition related to external beam radiotherapy and is etiologically linked to changes in the microcirculation induced by ionizing radiation in treatment of oropharyngeal carcinoma.17,18 Since December 2002, there has been increased reporting of ONJ in breast, prostate, and multiple myeloma patients.19-29 The main association in all these reports was the use of bisphosphonates.30 ONJ had significant morbidity because of delayed diagnosis and lack of effective interventions.31,32 This study describes the clinical presentation, pathology, and microbiology of ONJ and analyzes the risk factors for developing this complication in multiple myeloma patients. The report focuses on a single center experience using both medical and dental databases.
This was a retrospective review of multiple myeloma patients evaluated at University of Maryland Marlene and Stewart Greenebaum Cancer Center and the Dental School at the University of Maryland (both in Baltimore, MD). ONJ patients were included in the study if their complete dental and medical data could be retrieved and verified. The myeloma database (n = 340) included patients referred for a second opinion, those who underwent transplantation and were sent back to their referring physicians and a subset that was closely followed at the University of Maryland (n = 150). A control group was selected if patients had a dental assessment, including oral examination with panoramic radiographs, and were receiving continuous medical care at Greenebaum Cancer Center during the same time period (July 1999 to April 2005), irrespective of the date of diagnosis of myeloma. The institutional review board at the University of Maryland approved the study and granted a waiver to conduct the chart review. The following data were collected for each patient: demographics, myeloma isotype, and the presence or absence of lytic bone disease by radiologic assessment. Panoramic radiographs were assessed for lytic lesions and changes indicative of periapical abscesses and/or advanced periodontal disease. Details of disease status (remission versus relapse) and of multiple myeloma therapy, including the use of thalidomide, dexamethasone, and stem-cell transplantation as well as bisphosphonate therapy, were documented for each patient. In patients treated surgically, the removed bone specimens were pathologically assessed as well as cultured for evaluation of infectious agents. Surgical outcome data, including postoperative complication, infection, use of antibiotics, and recurrence of ONJ, were collected. Associations between independent categorical variables and development of ONJ were assessed with Fisher's exact test. The significance of continuous variables was estimated by Student's t test. Variables were eligible for entry into a logistic regression model if they were associated with ONJ at a P value of less than .2. The backward elimination analysis was used to select prognostic factors for ONJ. This analysis uses a significance level of .2 to retain a variable in the model. Discrimination was assessed by area under the receiver operating characteristic curve that assesses how well the model categorizes patients with ONJ from those without ONJ. SAS (version 9.1; SAS Institute Inc, Cary, NC) was used for the analysis. The Kaplan-Meier method was used to estimate the probability that a multiple myeloma patient will not develop ONJ at least to time t.
The study included 90 multiple myeloma patients; 22 patients had clinical evidence of ONJ. Patients with ONJ included 11 (3%) from a database of 340 patients and 11 of 18 patients referred to the dental school for management of established ONJ; of these, seven patients were excluded because of lack of reliable myeloma therapy data. A previous report included some of these cases.23 Patient characteristics are presented in Table 1. Eighty-four patients received bisphosphonates; of 20 patients without documented lytic bone disease, only six patients did not receive bisphosphonates. One third of the patients were switched from pamidronate to zoledronate after its approval in August 2001. More than 75% of the patients received thalidomide during their disease course for induction and/or maintenance after stem-cell transplantation or at disease relapse. Eighty percent had received high-dose chemotherapy and stem cell support.
Osteonecrosis of the Jaw Of the 22 ONJ patients, four were diagnosed in 2002, eight in 2003, eight in 2004, and two in 2005 (until April 2005). Clinical features of ONJ are presented in Table 2. Patients presented with pain at the affected site; few had asymptomatic exposed bone. Sinus formation with intraorally purulent discharge was seen in three patients and two patients had submental swelling. The areas of exposed bone were usually small 1 to 2 cm and were mainly localized to a single site. The lesions were localized to the mandible (n = 15), mandible and maxilla (n = 5), and maxilla only (n = 2). The majority of the cases of ONJ were seen posterior to the cuspid teeth. Only two patients had the ONJ lesions localized to the anterior mandible and parasymphysis region. Half the cases of ONJ occurred in sites of nonhealing dental extraction and/or other routine dental procedures usually within a few weeks. In the remaining patients, the lesions occurred in the vicinity of healthy teeth, with resultant loss of teeth. Spontaneous ONJ occurred on the lingual surface of the mandible, adjacent or on the mylohyoid ridge. Three cases of ONJ occurred in completely edentulous areas. Teeth adjacent to ONJ exposed bones were often firm but several such sites became loosened late in the disease process. Figure 1 shows examples of various clinical presentations (A, B, and C); D illustrates the extent of bony destruction.
Many ONJ patients had normal radiographs on panoramic views at the site of ONJ, especially at early stages. Classic lytic lesions consistent with bony disease in multiple myeloma were seen in six ONJ patients, none in proximity to the ONJ lesion (Fig 2). Several patients had evidence of osteomyelitis and increased sclerosis with ill-defined margins. Three distinct radiographic findings were noted; a symmetric widening of the periodontal ligament, effacement of the normally distinct borders of inferior alveolar canal, and an onion skin effect mostly in advanced cases, which is commonly associated with Garre's osteomyelitis. This finding is reflective of the localized inflammatory host response and the proliferative activity of the periosteum. Computed tomography scan of the mandible was not routinely done but appears to accurately define the cortical bony destruction at the site of the lesion (Fig 3). Positron emission tomography fusion scans showed nonspecific increased metabolic activity at the site of ONJ with low standardized uptake value suggestion of a superimposed infection. Neither magnetic resonance imaging, when done, nor conventional radiology revealed any abnormalities at the ONJ site.
Before referral to the University of Maryland Dental School, simple sequestrectomy and primary closure had been attempted by community oral surgeons in 10 patients with unsatisfactory results. The mucosa often broke down resulting in recurrent bone exposure and increasing ONJ lesion size. Fourteen patients underwent extensive debridement and sequestrectomy with primary closure; of them, eight patients (57%) had major complications, four patients had severe postoperative infections requiring incision, drainage, and multiple débridements, and two patients required segmental resection and placement of mandibular reconstruction bars. An additional four patients had recurrent ONJ in the same site as well as in adjacent areas where the teeth were removed to achieve adequate closure; multiple subsequent surgeries were needed (three to seven procedures) often with poor results, leaving the patients with significant morbidity. These results prompted us to depart from radical resection as a primary potentially curative therapy and attempt more conservative approaches. To date, six patients have been treated conservatively with antibiotics and removal of sharp areas of bone that might further traumatize adjacent soft tissues. At a median follow-up of 9 months for these six patients (range, 2 to 14), two patients proceeded to radical resection after worsening ONJ lesions and one patient required drainage of a submandibular abscess. Three patients had only minor symptoms despite the presence of nonhealing exposed bony lesions and, to date, none have progressed. Bisphosphonates were stopped in all patients once ONJ was diagnosed; therapy was restarted only after documented healing of the lesions. In recurrent cases, therapy was discontinued permanently; these cases usually had poor outcome with continuous progression of the lesions off bisphosphonates. Histologic examination of surgically removed bone revealed inflammation consistent with osteomyelitis and areas of acellular necrotic bone; three patients showed mixed inflammatory cellular infiltrates (Fig 4). Only one patient had plasma cells on the biopsy suggestive of underlying plasmacytoma. Microbiologically, filamentous organisms consistent with actinomycetes were seen in seven of 20 specimens. Concurrent infectious organisms including Peptostreptococcus, Streptococcus sp, Eikenella, Prevotella, Porphyromonas, and Fusobacterium species were cultured from various specimens in nine patients. The contribution of these organisms to soft tissue infection and osteomyelitis is unclear.
Among ONJ patients, eight patients (36%) had other bone pathology despite the long-term administration of bisphosphonates. Four patients had avascular necrosis of the hip, one before and three after the diagnosis of ONJ. All of them had been on steroids, and those who developed avascular necrosis of the hip after ONJ had been off bisphosphonates. Three patients had pathologic, myeloma-related long-bone fractures; all occurred before ONJ while on bisphosphonate therapy.
Risk Factors for ONJ
Higher probability of developing ONJ was seen in whites versus blacks (Fisher's exact test; P = .038), though the numbers are small for definitive conclusions. There was no significant association between the occurrence of ONJ and sex, use of pamidronate or zoledronate alone (a reflection of time), presence of lytic bony lesions, disease status (remission versus relapse), and the use of thalidomide during induction, maintenance, or for relapsed disease.
The true incidence of ONJ is unknown. In this series, a 3% incidence in our population of myeloma patients can be arbitrarily increased to 8% if all ONJ cases, including those referred to the dental school, were included. Since the US Food and Drug Administration approval of pamidronate in 1991 for hypercalcemia of malignancy and in 1995 for multiple myeloma and zoledronate in August 2001, approximately 3 million patients have received one or both drugs (1.9 and 1 million, respectively). No cases of ONJ have been reported in 26 trials for pamidronate and 23 trials for zoledronate that enrolled 1,401 and 3,428 patients, respectively. This may be a factor of time as most trials followed patients for a relatively short period (1 to 2 years) or possibly missed diagnosis because of lack of awareness on the part of the patients and health care providers.33 In 2002, nine cases of ONJ in cancer patients receiving intravenous bisphosphonate were reported to the US Food and Drug Administration. In September and November 2003, zoledronate and pamidronate package inserts were updated to include ONJ in the adverse events section, respectively. In September 2004, Novartis issued a warning communication letter to physician regarding ONJ, and in May 2005, a similar letter was sent to the dental community providing guidelines for diagnosis and therapy of ONJ.34,35 The mechanism of action of bisphosphonates remains unclear.36 First generation bisphosphonates are metabolized and incorporated into adenosine triphosphate–generating toxic analogs, inducing osteoclast apoptosis.37 Nitrogen-containing bisphosphonates (pamidronate, alendronate, risedronate, incadronate, zoledronate, and so on) target the intracellular enzyme farnesyl diphosphate synthase, inhibiting the mevalonate pathway resulting in disruption of posttranslational intracellular signaling proteins such as Ras.38 This would alter cytoskeleton organization and cell motility, resulting in osteoclast apoptosis. Nitrogen-containing bisphosphonates are not metabolized; 50% are secreted in the urine unchanged and the rest bind to bone and are slowly released into the circulation. The half-life in the bone could be as long as 10 years.39 Bisphosphonates disrupt the normal bone homeostasis, resulting in impaired healing, especially in bones exposed to constant trauma that may result in necrosis.40 Through inhibition of endothelial proliferation, bisphosphonates may interrupt intraosseous circulation and bone blood flow, contributing to development of ONJ.41,42 It remains unclear which patients are at greatest risk for developing ONJ. ONJ has been mostly reported in cancer patients receiving intravenous bisphosphonates with few reports in osteoporosis patients receiving oral bisphosphonates.43 The recent documented risk of ONJ in multiple myeloma may be linked to improved patient survival with the introduction of novel therapeutics such as thalidomide and bortezomib, allowing prolonged exposure to bisphosphonates.44 Duration of bisphosphonates therapy was the major risk factor for developing ONJ in myeloma patients in a recently published web-based survey.27 Although the circumstantial evidence suggests that with the approval of zoledronate there is an increased incidence of ONJ, the association remains speculative. Another significant factor for ONJ is invasive dental procedures. Theoretically, trauma to the mucosa and exposure of bone and surrounding tissues to microbial flora creates an acidic inflammatory milieu. Bisphosphonates detach from the bone in a low pH environment resulting in further inhibition of osteoclast activity and slowing down clearance of bone debris enhancing the development of localized osteomyelitis.45 As acute exacerbations of bone and soft tissue infections contribute to the symptoms of ONJ, it seems reasonable to administer antimicrobials systemically and as oral rinses. Nevertheless, long-term antibiotics did not prevent progression in established cases of ONJ. New cases of ONJ are being diagnosed with painless exposed bone with no clinical evidence of infection making it unlikely that infection is the initiating event in ONJ. There is also no consensus on management of ONJ. Although surgery is potentially curative when performed by experienced surgeons, postoperative complications were significant and, in many cases, resulted in more bone exposures. Discontinuation of bisphosphonate therapy has not significantly helped to either reverse the presence of ONJ or ameliorate symptoms of established cases. In several patients, the condition worsened and recurrences were seen months after stopping bisphosphonate therapy; in fact, two patients developed ONJ 9 and 12 months after bisphosphonates were stopped because of renal insufficiency. Recurrence signals poor prognosis and continuous progression irrespective of bisphosphonate use. In several established ONJ cases (n = 5), bisphosphonates were held until complete healing of the oral lesions was documented. Then, only patients with bone disease restarted therapy, using pamidronate every 3 months; no recurrences of ONJ have been observed. Whether discontinuing bisphosphonates before elective surgical interventions, such as dental extractions, can prevent the development of ONJ requires further investigations. For prevention, an aggressive screening and treatment of dental diseases should occur before bisphosphonate therapy is initiated. Furthermore, the routine administration of bisphosphonates to patients with smoldering myeloma and no bone disease should be limited to clinical studies since, thus far, there are no data to suggest benefit or delayed progression to overt myeloma in this setting.46,47 The development of avascular necrosis of the hip in ONJ patients also raises the possibility that ONJ represents a systemic bone disease with initial manifestation in the jaw and as patients live longer and duration of therapy increases other bones would be affected.48 In conclusion, ONJ is an emerging problem in multiple myeloma patients. It affects older myeloma patients who had received long-term bisphosphonates therapy. Zoledronate use after pamidronate is a major risk factor; although, duration rather than a specific drug appears to be most significant. The enthusiasm for surgery is decreasing, primarily because of its significant morbidity, in favor of conservative management approaches such as debridement and antibiotics. The consequences of ONJ are significant; nevertheless, the incidence is low and justifies the continued use of monthly bisphosphonates that has overall reduced bony events in many patients and significantly improved their quality of life. Beyond 2 years, the benefit/risk of bisphosphonate therapy should be individually discussed until prospective/randomized trials address the optimal duration and frequency of bisphosphonate therapy.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Kyle RA, Gertz MA, Witzig TE, et al: Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78:21-33, 2003 2. Berenson JR: Myeloma bone disease. Best Pract Res Clin Haematol 18:653-672, 2005[Medline] 3. Roodman GD: Pathogenesis of myeloma bone disease. Blood Cells Mol Dis 32:290-292, 2004[CrossRef][Medline] 4. Choi SJ, Cruz JC, Craig F, et al: Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood 96:671-675, 2000 5. Tian E, Zhan F, Walker R, et al: The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349:2483-2494, 2003 6. Licata AA: Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 39:668-677, 2005 7. Boivin G, Meunier PJ: Effects of bisphosphonates on matrix mineralization. J Musculoskelet Neuronal Interact 2:538-543, 2002[Medline] 8. Van Beek ER, Lowik CW, Papapoulos SE: Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: The role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors. Bone 30:64-70, 2002[Medline] 9. Jantunen E: Bisphosphonate therapy in multiple myeloma: Past, present, future. Eur J Haematol 69:257-264, 2002[CrossRef][Medline] 10. Berenson JR, Lichtenstein A, Porter L, et al: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 16:593-602, 1998[Abstract] 11. Berenson JR, Hillner BE, Kyle RA, et al: American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol 20:3719-3736, 2002 12. Clezardin P: The antitumor potential of bisphosphonates. Semin Oncol 29:33-42, 2002[Medline] 13. Assael LA: New foundations in understanding osteonecrosis of the jaws. J Oral Maxillofac Surg 62:125-126, 2004[CrossRef][Medline] 14. Glueck CJ, McMahon RE, Bouquot JE, et al: Heterozygosity for the Leiden mutation of the factor V gene, a common pathoetiology for osteonecrosis of the jaw, with thrombophilia augmented by exogenous estrogens. J Lab Clin Med 130:540-543, 1997[CrossRef][Medline] 15. Kouwabunpat D, Hoffman J, Adler R: Varicella complicated by group A streptococcal sepsis and osteonecrosis. Pediatrics 104:967-969, 1999 16. Mostofi R, Marchmont-Robinson H, Freije S: Spontaneous tooth exfoliation and osteonecrosis following a herpes zoster infection of the fifth cranial nerve. J Oral Maxillofac Surg 45:264-266, 1987[CrossRef][Medline] 17. Thiel HJ: Osteoradionecrosis, I: Etiology, pathogenesis, clinical aspects and risk factors [in German]. Radiobiol Radiother (Berl) 30:397-413, 1989[Medline] 18. Reuther T, Schuster T, Mende U, et al: Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients: A report of a thirty year retrospective review. Int J Oral Maxillofac Surg 32:289-295, 2003[CrossRef][Medline] 19. Carter GD, Goss AN: Bisphosphonates and avascular necrosis of the jaws. Aust Dent J 48:268, 2003[Medline] 20. Migliorati CA: Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 21:4253-4254, 2003 21. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115-1117, 2003[CrossRef][Medline] 22. Ruggiero SL, Mehrotra B: Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med 351:190-192, 2004 23. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527-534, 2004[CrossRef][Medline] 24. Bagan JV, Murillo J, Jimenez Y, et al: Avascular jaw osteonecrosis in association with cancer chemotherapy: Series of 10 cases. J Oral Pathol Med 34:120-123, 2005[CrossRef][Medline] 25. Purcell PM, Boyd IW: Bisphosphonates and osteonecrosis of the jaw. Med J Aust 182:417-418, 2005[Medline] 26. Maerevoet M, Martin C, Duck L: Osteonecrosis of the jaw and bisphosphonates [letter]. N Engl J Med 353:99-102, 2005 27. Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw and bisphosphonates [letter]. N Engl J Med 353:99-102, 2005 28. Woo SB, Hande K, Richardson PG: Osteonecrosis of the jaw and bisphosphonates [letter]. N Engl J Med 353:99-102, 2005 29. Migliorati CA, Schubert MM, Peterson DE, et al: Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: An emerging oral complication of supportive cancer therapy. Cancer 104:83-93, 2005[CrossRef][Medline] 30. Carter G, Goss AN, Doecke C: Bisphosphonates and avascular necrosis of the jaw: A possible association. Med J Aust 182:413-415, 2005[Medline] 31. Schwartz HC: Osteonecrosis of the jaws: A complex group of disorders. J Oral Maxillofac Surg 63:1248-1249, 2005[CrossRef][Medline] 32. Hellstein JW, Marek CL: Bisphosphonate osteochemonecrosis (bis-phossy jaw): Is this phossy jaw of the 21st century? J Oral Maxillofac Surg 63:682-689, 2005[CrossRef][Medline] 33. United States Food and Drug Administration Oncologic Drugs Advisory Committee: Combidex briefing information. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095b1.htm 34. United States Food and Drug Administration: MedWatch. http://www.fda.gov/medwatch/SAFETY/2004/ZometaHCP.pdf 35. United States Food and Drug Administration: MedWatch. http://www.fda.gov/medwatch/safety/2005/zometa_deardentite_5-5-05.pdf 36. Reszka AA, Rodan GA: Mechanism of action of bisphosphonates. Curr Osteoporos Rep 1:45-52, 2003[Medline] 37. Rogers MJ: New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 9:2643-2658, 2003[CrossRef][Medline] 38. Fisher JE, Rodan GA, Reszka AA: In vivo effects of bisphosphonates on the osteoclast mevalonate pathway. Endocrinology 141:4793-4796, 2000 39. Takeyama S, Shinoda H: [Pharmacological actions and pharmacokinetics of bisphosphonates]. Clin Calcium 13:115-121, 2003[Medline] 40. Greenberg MS: Intravenous bisphosphonates and osteonecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 98:259-260, 2004[CrossRef][Medline] 41. Vincenzi B, Santini D, Rocci L, et al: Bisphosphonates: New antiangiogenic molecules in cancer treatment? Ann Oncol 14:806-807, 2003 42. Wood J, Bonjean K, Ruetz S, et al: Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302:1055-1061, 2002 43. Alendronate (Fosamax) and risedronate (Actonel) revisited. Med Lett Drugs Ther 47:33-35, 2005[Medline] 44. Rajkumar SV: Novel approaches to the management of myeloma. Oncology (Williston Park) 19:621-625, 2005[Medline] 45. Hoshino H, Yamazaki K: [Mechanisms of action in bisphosphonates]. Clin Calcium 15:88-92, 2005[Medline] 46. Pecherstorfer M, Seibel MJ, Woitge HW, et al: Bone resorption in multiple myeloma and in monoclonal gammopathy of undetermined significance: Quantification by urinary pyridinium cross-links of collagen. Blood 90:3743-3750, 1997 47. Musto P, Falcone A, Sanpaolo G, et al: Pamidronate for early-stage, untreated myeloma. J Clin Oncol 21:3177-3178, 2003 48. Agarwala S, Jain D, Joshi VR, et al: Efficacy of alendronate, a bisphosphonate, in the treatment of AVN of the hip: A prospective open-label study. Rheumatology (Oxford) 44:352-359, 2005[CrossRef][Medline] Submitted September 19, 2005; accepted November 23, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
