AGD - Academy of General Dentistry

Osteoporosis is a major public health problem. Oral bisphosphonates are effective for reducing the risk of osteoporotic fractures and are an important treatment option for patients at risk for this condition. Osteonecrosis of the jaw (ONJ) is uncommon among cancer patients who are receiving high-dose intravenous bisphosphonates and rarely is seen among patients who are taking oral bisphosphonates for osteoporosis. Dentists play an important role in discussing the implications of the overall dental and medical treatment plans with both patients and physicians. The low risk of ONJ with oral bisphosphonates should be balanced against the benefits of osteoporosis therapy.

Bisphosphonates reduce bone loss associated with diseases such as osteoporosis, Paget’s disease, multiple myeloma, and metastatic bone disease.1 In recent years, case reports involving osteonecrosis of the jaw (ONJ) subsequent to the use of these agents have brought this issue to the attention of dentists. While it is important that dentists are aware of ONJ, they also must consider their patients’ overall health status together with their dental health. Dentists should be aware of their patients’ risk of fractures (and the ensuing morbidity and mortality) and work with the treating physicians to balance the risks and benefits of bisphosphonate therapy.

There are important differences in ONJ incidence with low-dose oral bisphosphonate therapy compared with high-dose intravenous bisphos-phonate therapy; the incidence of ONJ with oral bisphosphonate use is very low.2 This article reviews data on ONJ associated with the use of bisphosphonates from a multidisciplinary perspective and discusses the importance of balancing the low risk of ONJ with the need to prevent osteoporotic fractures.

Bone tissue is remodeled constantly as a result of a coordinated process of resorption involving osteoclasts and formation by osteoblasts. As people age, the balance of bone remodeling changes in favor of resorption. For women, this process accelerates around the time of menopause. This imbalance between resorption and formation leads to a loss of bone mass, which may result in compromised bone strength (osteoporosis), predisposing individuals to an increased risk of fractures of the hip, spine, and other skeletal sites.3 It is a common misconception that osteoporosis is an inevitable part of aging; in fact, the disease can be prevented and treated.4

Osteoporosis represents a significant public health problem, one that will increase as the world population ages.5 It has been estimated that 55% of those in the U.S. who are 50 or older are at risk; 10 million Americans have osteoporosis and 34 million have low bone mass, which puts them at increased risk for the condition.6 Osteoporosis is responsible for more than 1.5 million fractures in the U.S. annually and it has been calculated that 1 in 2 women and 1 in 4 men aged 50 or over will suffer an osteoporosis-related fracture in her or his lifetime.6

The negative impact of osteoporosis on the lives of affected individuals is dramatic. According to Jonnell et al, 22% of those who suffer an osteoporosis-related hip fracture will die within one year.7 Patients who survive are unlikely to regain pre-fracture levels of mobility and independence; approximately 50% of these patients remained unable to walk independently one year after their hip fracture and approximately 70% of all hip fracture survivors have difficulty with activities of daily living (for example, dressing, personal hygiene, and food preparation).8-10 Many hip fracture patients require some form of long-term care; 10% become dependent (that is, they remain in the community but need help with daily living activities) and 19% will be admitted to a nursing home (accounting for approximately 140,000 nursing home admissions annually in the U.S.).5

Vertebral fractures can result in back pain, height loss, and kyphosis, producing morbidity and mortality rates similar to those for hip fractures.8 The problems associated with hip and vertebral fractures are not limited to physical disability. Reduced functioning and ongoing physical deformity can result in psychological symptoms such as depression, deterioration in interpersonal relationships and social roles, social isolation, loss of independence, and a reduction in health-related quality of life.11-13

Osteoporosis is a costly disease. Burge et al estimated that more than 2 million osteoporotic fractures were diagnosed in the U.S. in 2005, resulting in direct costs (for example, hospital and outpatient costs) of $16.9 billion.14 Nonvertebral fractures (that is, those that occur at skeletal locations other than the spine) accounted for 73% of these fractures and 94% of costs; hip fractures in particular accounted for 14% of fractures and 72% of costs.14 Annual fractures and costs are projected to grow to more than 3 million fractures, totalling $25.3 billion in direct costs by 2025.14 In addition to direct costs, indirect costs are substantial and include lost productivity, which can impact patients and family caregivers.

Bisphosphonates are stable analogs of pyrophosphates, which are naturally occurring modulators of bone metabolism.15 The chemical structure of bisphosphonates includes a P-C-P backbone that bestows a strong affinity for bone mineral and provides potent inhibition of bone turnover both in vivo and in vitro.16 Different bisphosphonates were developed by modifying the side chains R1 and R2. There are bisphosphonates that do not contain nitrogen in the R2 side chain, including etidronate (Didronel, P & G Pharmaceuticals, Cincinnati, OH; 800.543.2577), tiludronate (Skelid, Sanofi-Synthelabo, Inc., New York, NY; 800.446.6267), and clodronate (Bonefos, Aventis Pharma Inc., Laval, Quebec; 800.265.7927). Bisphosphonates that contain nitrogen in the R2 chain include alendronate (Fosamax, Merck, Whitehouse Station, NJ; 800.922.1557), pamidronate (Aredia, Novartis Pharmaceuticals, East Hanover, NJ; 800.257.3273), zoledronic acid (Zometa, Novartis Pharmaceuticals), ibandronate (Boniva, Roche Pharmaceuticals, Nutley, NJ; 800.526.6367), and risedronate (Actonel, Aventis Pharmaceuticals, Inc., Bridgewater, NJ; 800.981.2491).

Bisphosphonates inhibit bone resorption by causing osteoclast apoptosis and reducing osteoclastic bone resorption.17 Nitrogen-containing bisphosphonates are not metabolized systemically and are poorly absorbed from oral administration. Of the small amount that is absorbed, 50% is excreted unchanged in the urine and the rest remains bound to bone, acting locally and released slowly over time.

Agents that inhibit bone resorption currently are used most frequently for treating osteoporosis. Alendronate, ibandronate, and risedronate are the bisphosphonates that have been approved by the FDA for the prevention and treatment of osteoporosis. Data from randomized, placebo-controlled clinical trials indicate that all of these agents reduce the risk of vertebral fractures (see Table 1) and that alendronate and risedronate reduce the risk of nonvertebral fractures, including hip fractures.18-26

The main short-term side effects associated with nitrogen-containing bisphosphonates are gastrointestinal intolerance (with oral administration) and a limited acute-phase reaction (consisting of fever, myalgia, and flu-like symptoms) with intravenous administration.1 Concerns have been expressed about the long-term safety of bisphosphonates due to their long half-life, their prolonged reduction of bone turnover, and the potential for reduced bone quality and strength.2,27 Randomized clinical trials designed to examine the efficacy and safety of oral alendronate, risedronate, or ibandronate for treating either osteoporosis or Paget’s disease have never revealed ONJ, nor have trials examining the effect of zoledronic acid on Paget’s disease (which in total amounted to more than 60,000 patient-years of exposure).28 Long-term studies have followed patients treated with risedronate for up to seven years and those treated with alendronate for up to 10 years.29-31 No cases of ONJ were observed in these trials, suggesting that prolonged treatment does not cause a decreased benefit.

ONJ was not reported during clinical trials that administered pamidronate or zoledronic acid intravenously (26 clinical trials of pamidronate involving 1,401 patients and 23 trials of zoledronic acid involving 3,428 patients) but this could be related to the short duration of these trials (both of which lasted one to two years).28

Reports of ONJ first appeared in the literature in 2003 in letters and case reports relating to the use of pamidronate and/or zoledronic acid for the management of oncological conditions, most commonly multiple myeloma and metastatic breast cancer.32-34 Concerns about ONJ also were raised in a retrospective chart review of 63 ONJ cases among patients who had received intravenous bisphosphonates (for the management of metastatic malignancies) or oral bisphosphonates (for osteoporosis).35 In the wake of these reports, the FDA issued a class precaution for all bisphosphonates (including oral formulations).36,37

A systematic review of the scientific literature from 1996–2006 revealed that 368 cases of ONJ subsequent to the use of bisphosphonates had been reported as of January 31, 2006.2 This review provided an insight concerning the location of lesions, underlying diagnoses, type of bisphosphonate therapy, and clinical observations associated with the phenomenon of ONJ.27 Lesion sites, presence of pain, and status regarding tooth extraction or dental surgery among the 368 cases are summarized in Chart 1.2 Most lesions affected the mandible and were located mainly on the posterior lingual surface near the mylohyoid ridge. Nearly one-third of cases were reported to be painless; most were preceded by tooth extraction or another invasive dental procedure. Women were affected slightly more frequently than men (a 3:2 ratio). Chart 2 summarizes the primary diagnoses among these patients while Chart 3 summarizes the types of bisphosphonate therapies that were administered.2 These findings indicate that patients at greatest risk for ONJ are those with multiple myeloma or breast cancer with bone metastases who had received intravenous pamidronate or zoledronic acid; these patients accounted for 94% of published cases.2 Only 15 cases (4.1%) reported ONJ associated with the use of oral bisphosphonates for osteoporosis.2

At present, there currently is no universally accepted definition of ONJ. The manifestations are similar to those of osteoradionecrosis (ORN); one key difference is that involvement of the mandible occurs in approximately 25% of ONJ patients but is extremely rare with ORN.2,38 Clinical signs include the bone and oral mucosa failing to heal within six to eight weeks, jaw pain or numbness, soft tissue swelling and infection, loose teeth, and exposed bone in the oral cavity.1,33-35,39 A clear understanding of ONJ is complicated further by the fact that affected patients often have serious co-morbidities (for example, advanced malignancies, coagulopathy, and diabetes) for which they may receive chemotherapy, corticosteroids, or immunosuppressive agents.40

Although ONJ is a source of growing concern among patients and health care professionals, the findings must be kept in perspective. It is important to distinguish between patients receiving high-dose intravenous bisphosphonates for malignancies and patients receiving low-dose oral bisphosphonates for osteoporosis. A 2004 Web-based survey by the International Myeloma Foundation studied 1,203 patients with myeloma or breast cancer who had received high-dose intravenous bisphosphonates.41 At 36 months, the rate of ONJ was 4% for patients taking pamidronate and 10% for those who had received zoledronic acid.41 The occurrence of ONJ in patients taking low-dose oral bisphosphonates for osteoporosis remains rare, with an incidence estimated at 0.7 cases per 100,000 person-years of exposure or 1:160,000 patients.42 However, the background rate of ONJ is unknown, making it difficult to assess whether the relative risk associated with oral bisphosphonates exceeds that of ONJ in the general population.38

The pathophysiology of ONJ remains unclear. Effects of bisphosphonates that might play a role in the development of ONJ include suppression of bone turnover, reduction in blood flow, direct toxic effects on mucosa, and anti-angiogenic effects. It has been suggested that the oral cavity’s normally high resistance to infection and healing ability stems from high blood flow within the jawbones; as a result, disturbing this blood flow (that is, localized vascular insufficiency) might play an important role in ONJ.35 This suggestion is supported by the fact that bisphosphonates have demonstrated anti-angiogenic effects both in vitro and in animal studies.43 It is possible that these anti-angiogenic effects (in combination with immunosuppression, underlying co-morbid conditions, and further infection) could lead to slow healing; however, additional research is needed to clarify the pathologic mechanisms involved.

Two randomized, placebo-controlled studies have been conducted to prospectively assess the safety of oral bisphosphonates on alveolar bone in patients with periodontal disease.44 The first study evaluated the effects of alendronate and placebo on safety and alveolar bone height by studying 335 patients with moderate-to-severe periodontal disease over a two-year period.44 In the second study, 25 individuals with osteoporosis receiving dental implants and alendronate or rised-ronate were compared with 25 matched patients who had received dental implants and placebo.44 Patients in the test group had been receiving bisphosphonates for a mean period of three years prior to implant placement. The patients remained on therapy for at least another three years. The implant success for both groups was more than 99%.44

No cases of ONJ were observed in either study; in addition, the bisphosphonate-treated groups in the first study demonstrated no adverse events among the patients who required tooth extraction. By contrast, patients taking bisphosphonates gained bone around the teeth, lost 43% fewer teeth than control patients, and showed a trend toward lower incidence of infection. The authors concluded that oral bisphosphonates do not pose a risk to alveolar bone compared with placebo.45

The ADA, the American Association of Oral and Maxillofacial Surgeons (AAOMS), and the American Society for Bone and Mineral Research (ASBMR) all have developed recommendations for the prevention, recognition, and management of ONJ.36,39,42,45 However, the lack of studies concerning the prevention and treatment of ONJ means that current recommendations are based on clinical experience and expert opinion rather than on evidence from prospective trials.40

When treating ONJ, the objectives are to eliminate pain, control infection of the hard and soft tissues, minimize the occurrence or progression of bone necrosis, and, ultimately, to heal the lesion.36 Table 2 outlines the staging and treatment recommendations for bisphosphonate-related ONJ developed by the AAOMS.36 The recommendations from the AAOMS Expert Panel highlight the need for a nonsurgical approach if possible and provide suggestions for specific antibiotic regimens.39

As the efficacy of treatment is limited, preventing ONJ remains important.40 For patients who are taking or considering bisphos-phonate therapy, the approach for preventing ONJ is determined largely by the type of bisphosphonate therapy. Patients for whom intravenous bisphosphonate therapy is indicated require preventive measures that may impact treatment plans.36,39 Given the apparently low risk of ONJ among patients receiving oral bisphosphonates for osteoporosis, it seems likely that all that these patients require is the maintenance of good oral hygiene and the same level of dental care that is recommended for the general population.28 Some health care professionals recommend dental evaluation before initiating bisphosphonate therapy, including examining dentures to ensure proper fit.39,40

It also has been proposed that dentists limit dental surgery to that required for good dental health and only when nonsurgical therapies are not appropriate or are ineffective.28,39 Given the bisphosphonates’ long half-life, stopping bisphosphonate therapy for several weeks before and after dentoalveolar surgery is unlikely to reduce the already low risk of ONJ in this patient population, although it may be a safe approach. Table 3 outlines steps that general dentists can take to ensure the best of both dental and medical care relating to oral bisphosphonate therapy and the prevention of ONJ.29,41

Osteoporosis is a debilitating disease, exceedingly prevalent in the U.S. aging population. Oral bisphosphonate therapy is the first-line treatment option for patients who require osteoporosis treatment and is highly effective in preventing fractures. ONJ is a rare complication in individuals taking oral bisphosphonates. Given the significance of bisphosphonates in the treatment of patients with osteoporosis, it is important that the dentist and the physician weigh the risks and benefits attendant on its use. Based on the current evidence, therapy with low-dose bisphosphonates should not be viewed as a barrier to dental treatment delivered via customary protocols. If the patient’s history discloses no special contraindications (notably the high-dose bisphosphonates used for cancer chemotherapy), oral bisphos-phonate therapy poses a very low risk of ONJ and is highly effective for preventing fractures in patients who require osteoporosis treatment. However, if there is any doubt concerning risk factors in an individual patient, the physician and dentist should collaborate closely in treatment planning and subsequent monitoring.

The authors received editorial/writing support in the preparation of this manuscript funded by The Alliance for Better Bone Health (Procter & Gamble Pharmaceuticals and sanofi-aventis U.S., Inc). However, the authors were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of this article.

Dr. Jeffcoat is Dean and Professor of Periodontics, University of Pennsylvania School of Dental Medicine in Philadelphia. Dr. Watts is a professor of Internal Medicine, University of Cincinnati College of Medicine, and Director of the University of Cincinnati Bone Health and Osteoporosis Center.

1. Bilezikian JP. Osteonecrosis of the jaw—Do bisphosphonates pose a risk? N Engl J Med 2006;355:2278-2281.

2. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.

3. Miller RG. Osteoporosis in postmenopausal women. Therapy options across a wide range of risk for fracture. Geriatrics 2006;61:24-30.

4. 8 Common myths about osteoporosis. Available at: www.nof.org/osteoporosis/8%20common%20myths.pdf. Accessed December 11, 2006.

5. Melton LJ 3rd. Adverse outcomes of osteoporotic fractures in the general population. J Bone Miner Res 2003;18:1139-1141.

6. Fast facts. Available at: http://www.nof.org/osteoporosis/diseasefacts.htm. Accessed December 11, 2006.

7. Johnell O, Kanis JA, Oden A, Sernbo I, Redlund-Johnell I, Petterson C, De Laet C, Jonsson B. Mortality after osteoporotic fractures. Osteo-poros Int 2004;15:38-42.

8. Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med 1997;103(2A):12S-17S.

9. Koot VC, Peeters PH, de Jong JR, Clevers GJ, van der Werken C. Functional results after treatment of hip fracture: A multicentre, prospective study in 215 patients. Eur J Surg 2000;166: 480-485.

10. Pasco JA, Sanders KM, Hoekstra FM, Henry MJ, Nicholson GC, Kotowicz MA. The human cost of fracture. Osteoporos Int 2005;16:2046-2052.

11. Silverman SL. Quality-of-life issues in osteoporosis. Curr Rheumatol Rep 2005;7:39-45.

12. Boonen S, Autier P, Barette M, Vanderschueren D, Lips P, Haentjens P. Functional outcome and quality of life following hip fracture in elderly women: A prospective controlled study. Osteoporos Int 2004;15:87-94.

13. Hallberg I, Rosenqvist AM, Kartous L, Lofman O, Wahlstrom O, Toss G. Health-related quality of life after osteoporotic fracture. Osteoporos Int 2004;15:834-841.

14. Burge R, Dawson-Hughes B, Solomon D, Wong J, King A, Tosteson A. Incidence and economic burden of osteoporosis related fractures in the United States, 2005-2025. J Bone Miner Res 2007;22:465-475.

15. Russell RG. Bisphosphonates: From bench to bedside. Ann N Y Acad Sci 2006;1068:367- 401.

16. Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RG, Ebetino FH. Novel insights into actions of bisphosphonates on bone: Differences in interactions with hydroxyapatite. Bone 2006;38:617-627.

17. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001;296:235-242.

18. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996;348:1535-1541.

19. Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, Nevitt MC, Suryawanshi S, Cummings SR; Fracture Intervention Trial. Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 2000;85:4118-4124.

20. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999;282: 1344-1352.

21. Roux C, Seeman E, Eastell R, Adachi J, Jackson RD, Felsenberg D, Songcharoen S, Rizzoli R, Di Munno O, Horlait S, Valent D, Watts NB. Efficacy of risedronate on clinical vertebral fractures within six months. Curr Med Res Opin 2004;20: 433-439.

22. Harrington JT, Ste-Marie LG, Brandi ML, Civitelli R, Fardellone P, Grauer A, Barton I, Boonen S. Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis. Calcif Tissue Int 2004;74:129- 135.

23. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, Adami S, Fogelman I, Diamond T, Eastell R, Meunier PJ, Reginster JY; Hip Intervention Program Study Group. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001;344:333-340.

24. Chesnut CH 3rd, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC, Delmas PD; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004;19: 1241-1249.

25. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: Results from the Fracture Intervention Trial. JAMA 1998;280:2077-2082.

26. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000;11:83-91.

27. Liberman UA. Long-term safety of bisphosphonate therapy for osteoporosis: A review of the evidence. Drugs Aging 2006;23:289-298.

28. Shane E, Goldring S, Christakos S, Drezner M, Eisman J, Silverman S, Pendrys D. Osteonecrosis of the jaw: More research needed. J Bone Miner Res 2006;21:1503-1505.

29. Mellstrom DD, Sorensen OH, Goemaere S, Roux C, Johnson TD, Chines AA. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int 2004;75:462-468.

30. Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA; Alendronate Phase III Osteoporosis Treatment Study Group. Ten years‘ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199.

31. Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: The Fracture Intervention Trial Long-term Extension (FLEX): A randomized trial. JAMA 2006;296:2927-2938.

32. Migliorati CA. Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 2003;21: 4253-4254.

33. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 2003;61: 1104-1107.

34. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 2003;61:1115-1117.

35. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 2004;62:527-534.

36. American Association of Oral and Maxillofacial Surgeons (AAOMS) position paper on bisphosphonate-related osteonecrosis of the jaws. Available at : http://www.aaoms.org/docs/position_papers/osteonecrosis.pdf. Accessed May 12, 2007.

37. MedWatch—Safety information. Available at: http://www.fda.gov/MedWatch/safety/2005/safety05.htm#drugs. Accessed March 12, 2007.

38. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, Meiller T. Osteonecrosis of the jaw in multiple myeloma patients: Clinical features and risk factors. J Clin Oncol 2006;24:945-952.

39. Expert panel recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaws: June 2004. Available at: http://www.ada.org/prof/resources/topics/topics_osteonecrosis_whitepaper.pdf. Accessed May 12, 2007.

40. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis: An American Academy of Oral Medicine position paper. J Am Dent Assoc 2005;136:1658-1668.

41. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99-102.

42. American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: Expert panel recommendations. J Am Dent Assoc 2006;137:1144-1150.

43. Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M, Clezardin P. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002;62:6538-6544.

45. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E. Bisphosphonate-associated osteonecrosis of the jaw: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;July 30 [Epub ahead of print].