Osteoporosis Therapy: How Long & How Safe? & ONJ Review

Calcium, Vitamin D and Exercise are the foundation for good bone health, though the Women's Health Initiative showed us that it is not enough alone to reduce fractures.1 Calcium (1200mg in supplements or the diet, split up several times a day), plus vitamin D (800 to 1000units a day, all at once if easier) as well as exercise (back extension strengthening, balance and core exercises, and of course, weight-bearing such as walking or jumping, if done safely) all help increase bone mineral density (BMD) and reduce the risk of both falls and fractures.

What we have learned in the last decade from osteoporosis clinical trials is that more vitamin D supplementation (at least 2000units a day) is needed for calcium absorption and fall prevention, which Drs. Bikle2 and Krohn 3 discuss in detail at this meeting, and FDA-approved osteoporotic medical therapy is important for fracture reduction.4,5

We will review data to try to answer the following questions. What fracture risk warrants initiating osteoporotic medical therapy? How long do we continue treatment? And, at what potential cost, both from an economic and safety standpoint, are we willing to take for fracture protection? 6,7,8

Fracture Risk increases with age and with each additional risk factor9 (ie. fracture after 50y/o or steroid use). The medications FDA-approved for osteoporosis all significantly increase BMD and reduce the risk of fracture, yet not to the same degree and few are studied head to head. The bisphosphonates are now the mainstay of osteoporosis therapy and include weekly oral Fosamax (alendronate), and Actonel (risedronate), as well as monthly oral and now also an intravenous injection every 3 months Boniva10,11 (ibandronate). The hormonal therapies include daily oral Evista (raloxifene, a selective estrogen receptor modulator), daily subcutaneous injections, Miacalcin (calcitonin hormone) and Forteo12,13 (teriparatide or parathyroid hormone), and of course estrogen14 yet more often used for menopausal symptoms given their potential cardiovascular and breast risks, which Dr. Walsh reviews at this meeting. 15

All of the above therapies, aside from Forteo, are anti-resorptive agents, reducing bone loss or resorption as well as bone formation, but with a 'positive' balance, BMD increases and fracture reduction is seen. Forteo does the 'opposite' as a bone forming agent and increases bone formation and bone loss or resorption, again due to a 'positive' balance, BMD increases and fractures are reduced.

We would like to have the most precise and accurate bone mineral density measurements which The International Society for Clinical Densitometry Credentialing & Accreditation programs provide for many BMD testing centers. More importantly, though, we need better means of quantifying bone strength, bone quality and differentiating specific fracture site protection in order to assess therapeutic efficacy and determine who warrants short vs. long term therapy.

Long-Term Therapy may make sense for patients at high risk for fracture, where continued medical therapy in low risk patients becomes a more difficult clinical decision. Osteoporossis trials with Fosamax have been as long as 10 years and with Actonel 7 years. Some of these studies have looked at the effects of stopping therapy.16,17,18 Safety of osteoporotic therapy specifically bisphosphonates have come into question recently with claims of 'over-treatment' and 'osteonecrosis of the jaw' (ONJ). These long-term treatment studies as well as the ONJ data will be reviewed, hopefully rebuilding our confidence in the safety and efficacy of our FDA-approved osteoporotic therapies.19,20

Osteonecrosis of the Jaw (ONJ) Review


'Phossy-Jaw' was reported in the media as "Fosi-Jaw" implying a potential risk of Fosamax, yet in the 19th century high dose white phosphorus exposure in manufacturers of matches and explosives was thought to cause a osteochemonecrosis of the jaw. Hellstein et. al.21,22 suggested that ONJ may be similar to this possibly phosphorus-related 'phossy-jaw' seen years ago.

It is important to note that no cases of ONJ have been reported in an osteoporosis trial (human or animal), including long-term toxicity and carcinogenicity trials (over 120,000 person-years total). Nor has a case of ONJ been reported in the intravenous zoledronate (Reclast) multicenter osteoporosis trial, not yet completed. If there is a rare association between osteoporosis doses of bisphosphonates and ONJ it is estimated at 1 case or less per 100,000 patient years on medication, but the ONJ warning is now on all bisphosphonate labels.

The American College of Rheumatology provided a Summary in 2006 of 'ONJ and Bisphosphonates' through their 'Hotline' stating that 'Hotline' reflects the views of the authors and does not represent a position statement of the American College of Rheumatology, www.rheumatology.org. Other ONJ reviews can be found at www.ASBMR.org (American Society of Bone and Mineral Research), www.AACE.com (American Assoc. of Clinical Endocrinologists), www.nof.org (National Osteoporosis Foundation), www.ADA.org (American Dental Assoc.), and www.aaoms.org (American Assoc. of Oral and Maxillofacial Surgeons).

"Bisphosphonate-Associated Osteonecrosis of the Jaw"

Hotline Authors: Bart L. Clarke, MD, Metabolic Bone Disease Core Group, Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Department of Medicine, Rochester, MN; Sree Koka, DDS, PhD, Department of Dental Specialties, Mayo Clinic and Mayo Foundation, Rochester, MN. Hotline Editors: A. Kavanaugh, MD; E. L. Matteson, MD, MPH. Disclosures: Dr. Clarke: Consultant for Merck, and Confidentiality Agreement with Amgen. Dr. Koka: Nothing to disclose. Dr. Kavanaugh: Nothing to disclose. Dr. Matteson: Drug trials, and/or consultant, and/or confidential agreements and/or study and/or educational grants from Genentech, Amgen, Centocor, Biogen-Idec, Abbott, Wyeth, Regeneron, Takeda, Glaxo-Smith-Klein, Hoffmann-LaRoche, Human Genome Sciences, Immunex, Protein Design Laboratories, Nastech, Pharmacia & Upjohn, Schering.

Bisphosphonate-Associated Osteonecrosis of the Jaw (ONJ) has recently been recognized as an uncommon but severe adverse event associated with oral or intravenous bisphosphonate therapy in humans. Letters, case reports, and small case series published in the oncology, dental, and maxillofacial surgery literature since September 2003 describe ONJ as typically causing jaw pain, more often in the mandible than the maxilla, with associated exposed bone.23-26

How common is ONJ? In a systematic review of 368 cases of bisphosphonate-associated ONJ published between 1966 and January 31, 2006, Woo et al.27 found most cases (94%) occurred in patients treated with intravenous bisphosphonates with 65% of cases affected the mandible, 26% the maxilla, and 9% both mandible and maxilla. About 2/3 of the lesions were painful at diagnosis, with the remaining one-third painless, and 60% of cases occurred in women. Multifocal or bilateral involvement was more common in the maxilla than the mandible, with most lesions occurring on the posterior lingual mandible near the mylohyoid ridge. 60% occurred after oral surgery for dental extraction or other dentoalveolar surgery, whereas the remainder occurred spontaneously, some in patients wearing dentures.

Most (85%) cases had multiple myeloma or breast cancer metastatic to the skeleton. Patients receiving intravenous bisphosphonates for cancer were most often treated with one or more of the potent nitrogen-containing intravenous bisphosphonates, i.e., zoledronic acid or pamidronate, typically once a month for several years. Some patients developed ONJ within 4 months of starting therapy, but the median duration of therapy before diagnosis ranged from 22 to 39 months, with the mean duration ranging from 9 to 14 months. The highest risk of ONJ appears to be associated with frequent, typically monthly, infusions of intravenous zoledronic acid, which has been widely used in patients with myeloma, breast cancer, and prostate cancer in recent years.

What is the clinical presentation of ONJ? ONJ typically appears as an intra-oral lesion with areas of exposed yellow-white hard bone with smooth or ragged borders, sometimes with associated extra-oral or intra-oral sinus tracts.28 Painful ulcers may be present in the soft tissues adjacent to the ragged bony margins of the lesion. Dental x-rays may be unremarkable in early cases, but advanced cases demonstrate poorly defined areas of moth-eaten radiolucencies, with or without radio-opaque bone sequestra. Pathological jaw fractures have occurred in some cases. In its most severe form, ONJ may cause loss of a significant part of the mandible or maxilla.

What are the risk factors for ONJ? The main risk factors identified to date include cancer, frequent infusions of IV nitrogen-containing bisphosphonates, and dentoalveolar trauma. 29 Risk factors have not been identified in patients receiving oral bisphosphonates for postmenopausal osteoporosis without cancer due to the very small number of published cases.

What about ONJ in patients without cancer, including rheumatic diseases? Although under-reporting is always a potential consideration in pharmacovigilance data, the total number of cases of non-cancer patients with ONJ associated with oral bisphosphonate therapy reported among several million estimated patients who have been exposed to these drugs over the last 20 years appears small. To date, fewer than 20 cases of ONJ have been reported in the medical literature among patients without cancer treated with oral bisphosphonates. The risk of development of ONJ in patients with Paget's disease of bone treated with oral or intravenous bisphosphonates is not known, with only 3 cases reported in this review. None of the reported cases describe bisphosphonate related ONJ in women or men treated with glucocorticoid therapy for rheumatologic disease. The overall risk of ONJ in these patients appears low, but not well quantified.

Which type of bisphosphonate causes ONJ? Most cases of ONJ reported have occurred with intravenous zoledronic acid and pamidronate. The risk of development of ONJ in postmenopausal osteoporotic patients treated with oral bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva) is not known, as only a small number of cases have been reported. Most of these cases are associated with alendronate therapy, likely due to its wider use than other oral bisphosphonates.

The review by Woo et al.27 reported only 15 patients treated for osteoporosis without cancer with any bisphosphonate. Of the 368 total cases of ONJ reported, 18 were associated with oral alendronate, and of these, 15 occurred without exposure to intravenous or other oral bisphosphonates. Thirteen of the alendronate-treated cases occurred in patients treated for osteoporosis without cancer. One case of ONJ was associated with oral risedronate, and one case with oral ibandronate, both in patients treated for osteoporosis without cancer.

How do bisphosphonates cause ONJ? There is no established pathophysiological mechanism by which oral or intravenous bisphosphonates may cause ONJ, although it is hypothesized that suppressed bone turnover caused by potent bisphosphonate therapy leads to accumulation of microdamage, which may eventually lead to microfractures.30,31 Trauma or infection increase demand for bone microdamage repair, which might lead to localized osteonecrosis, although it is not yet clear how exactly this might occur. The antiangiogenic properties of some bisphosphonates32 and other medications and comorbidities may increase the risk of persistence and progression of ONJ.

How can ONJ be prevented? No randomized clinical trials have been published describing either prevention or treatment of ONJ. The American Academy of Oral Medicine (AAOM) guidelines29 call for prevention of ONJ in patients requiring therapy with bisphosphonates by conducting a dental examination and completing any traumatic treatment, such as dental extractions, before starting oral or intravenous bisphosphonate therapy, and avoiding dental trauma in patients who have begun such therapy. Woo et al.33 advised treating active oral infections and obtaining routine dental care before starting nitrogen-containing bisphosphonate therapy, using the least traumatic surgical approach when tooth extraction or other dental surgery is required, and avoiding wide excision of dead bone in patients with ONJ.

How can ONJ be treated? Once ONJ develops, there is no current recognized effective therapy. Dental specialists typically recommend supportive management, with withdrawal of bisphosphonate therapy, avoidance of further dentoalveolar trauma, appropriate use of oral antibiotic rinses, and allowing time for healing. Further aggressive surgery to debride dead bone may exacerbate the condition, but dental gingival flap placement may help stimulate healing.

For established ONJ, Marx et al.26 recommended systemic and topical antibiotic therapy with oral penicillin VK or amoxicillin, concurrent with use of chlorhexidine gluconate 0.12% oral rinses. The authors reported that this palliative regimen is over 90% effective in controlling pain in patients with ONJ, but resolution of lesions did not occur with this regimen. A surgical approach to treat ONJ lesions by means of pedicled flaps may be helpful.34

Current Clinical Practice Until more clinical data become available, it is reasonable to continue oral or intravenous bisphosphonate therapy in patients with appropriate indications, unless ONJ develops. The decision to continue to treat cancer patients with frequent infusions of potent intravenous bisphosphonates should be discussed with each patient's oncologist. Patients contemplating starting therapy with oral or intravenous bisphosphonate therapy for prevention or treatment of postmenopausal or glucocorticoid-induced osteoporosis should be informed of the rare risk of ONJ with oral or infrequent intravenous doses of bisphosphonates. Patients should be informed that caries and periodontal disease may increase the risk of ONJ in patients taking bisphosphonates. Dental examination and treatment should be completed either prior to or as early as possible after beginning bisphosphonate therapy.

Bottom Line: Bisphosphonates (BPs) and ONJ
  1. ONJ is most common in patients with cancer who receive frequent IV infusions of potent nitrogen-containing bisphosphonates (BPs), but rare in postmenopausal women or men with osteoporosis. The actual prevalence or incidence of ONJ in women or men treated with glucocorticoid therapy for rheumatologic disease is not known but appears to be very low.
  2. ONJ may occur during treatment with zoledronic acid, pamidronate, alendronate, risedronate, and ibandronate, but 94% of cases have occurred with intravenous zoledronic acid or pamidronate. These results are derived from combining patients in a meta-analysis. Clinicians should be aware there was considerable heterogeneity amongst patients included (e.g., early RA versus refractory RA, different concomitant therapies, variable comorbidities).
  3. Risk factors for ONJ include cancer, frequent infusions of intravenous nitrogen-containing BPs, and dentoalveolar trauma or infection.
  4. Before beginning therapy with oral or IV BPs, patients should be referred for dental care to address dental issues. BP therapy should not be started until dental issues have resolved.
  5. In patients with established ONJ, treatment with systemic antibiotics and oral antibiotic rinses may help with pain and infrequently may lead to healing. Stopping BP therapy may be prudent, as anecdotal evidence suggests that this may help in some cases. Aggressive dental surgery should generally be avoided.

SUMMARY: Osteoporosis Therapy How Long & How Safe? & ONJ Review

Fracture risk increases with age and risk factors. The optimal duration of medical therapy for postmenopausal women and men with osteoporosis is uncertain, but calcium and vitamin D supplementation as well as exercise to maintain strength and balance are recommended lifelong. We hope that the long awaited 'Absolute Fracture Risk Assessment', once clinically available, will provide us with easier answers to 'When do we start medical therapy for osteoporosis?' and, 'When, if ever do we stop medical therapy for osteoporosis?' Those patients with a high risk for bone loss and fracture need to be identified earlier, treated more aggressively and watched for 'silent' signs of fracture (VFA- vertebral fracture assessment on the BMD DXA machines or by x-ray).

  • Evaluation of pulmonary function and quality of life in women with osteoporosis. Lombardi Jr. I, Oliveria LM, Mayer AF, et al. Osteoporosis International 2005;16:1247-1253

In addition to fracture history, other secondary causes of bone loss which increase risk warrant our special attention. An evaluation to rule out secondary causes should be considered in patients with very low BMD (Z-score -1.0 or lower) or with new fractures.

  • Vitamin D Deficiency and Bone. Aguado et al. SU393; Zhu et al. SU403 ASBMR 2006
  • An RCT of Vitamin D or Placebo on Falls in Elderly Women with Low Vitamin D Status and a Falling History. Zhu et al. presentation 1227 ASBMR 2006
  • Vitamin D Status and Musculoskeletal Health in the Longitudinal Aging Study Amsterdam; Different Thresholds for Different Outcomes. Lips et al. SA302 ASBMR 2006
  • Prevalence of evaluation and treatment of glucocorticoid-induced osteoporosis in men. Cruse LM, Valeriano J, Vasey FB, Carter JD. Journal of Clinical Rheumatology 2006;12(5):221-225
  • Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. van Staa T, Geusens P, Bijlsma J, Leufkens H, Cooper C. Arthritis Rheum 2006;54(10):3104-3112
  • Alendronate for osteoporosis in men with androgen-repleted hypogonadism. Shimon H, Eshed V, Doolman R, et al. Osteoporosis International 2005;16:1591-1596
  • Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture. Yang Y, Lewis J, Epstein S, Metz D. JAMA 2006; 296:2947-2953
  • Statin use and fracture risk. Scranton RE, Young M, et al. Arch Int Med 2005;165:2007-2012
  • Elevated serum levels of soluble receptor activator of nuclear factors-kappa B ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS). Kim HR, Kim HY, Lee SH. Rheumatology 2006;45:1197-1200

We continue to question our inability (~18%) to provide Post-Fracture Care as well as we do Post-MI and Post-Stroke Care, and the poor compliance of patients to lifestyle changes and medications despite strong encouragement from providers.

  • Adherence, persistence, concordance: do we provide optimal management to our patients with osteoporosis. Cortet B, Benichou O. Joint Bone Spine 2006

The Medicare cuts in BMD reimbursement will have both positive and negative effects on these goals, but no doubt, many BMD centers will close their doors not able to pay their overhead, and quality BMD DXA testing will be more difficult to find for our patients. For more information regarding this legislation see 'Update on the Deficit Reduction Act of 2005 (DRA) and Its Potential Effect on DXA Imaging' at http://www.iscd.org/visitors/positions/LegislativeAlert.cfm. More advanced bone quality testing (ie. DXA Hip Structure Analysis, micro-MRI, nano-CT) will hopefully be clinically available in the near future, yet will surely be very expensive.

  • Fracture Reduction Affects Medicare Economics: Impact of increased osteoporosis diagnosis and treatment. King AB, Saag KG, Burge RT. Osteo Int 2005;16:1545-1557

Lastly, exciting new osteoporosis therapies are on the horizon which will give us more choices for treatment and create more questions as to length of treatment and safety.

  • Monthly Risedronate (Actonel). Thompson et al. SA363; Ste-Marie et al SA361 ASBMR 2006
  • Daily oral Balicatib, Cathepsin-K Inhib. Presentations by Papanastasiou; Adami ASBMR 2006
  • Enhanced diurnal PTH secretion after Balicatib administration may contribute not only to inhibition of bone resorption but also stim of bone formation. Itabashi et al. ASBMR 2006
  • Denosumab in postmenopausal women with low bone mineral density. McClung MR, Lewiecki EM, Cohen SB, et al. New England Journal of Medicine 2006;354(8):821-831
  • RANK Ligand inhibition with Denosumab for the management of osteoporosis. Lewiecki EM. Expert Opinion on Biological Therapy 2006;6(10):1041-1050
  • Denosumab: a promising drug for the prevention and treatment of osteoporosis. Lewiecki EM. Womens Health 2006;2(4):517-525
  • Osteoimmunology: interplay between the immune system and bone metabolism. Walsh MC, Kim N, Kadono Y, et al. Annual Review of Immunology 2006;24:2.1-2.31
  • Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5 (G171V) to modulate Wnt activity. Ellies DL, Viviano B, McCarthy J, et al. JBMR 2006;21(11):1738-1749
  • Time to Onset of Effect With Single-Dose Zoledronic Acid (Reclast) 5 mg IV vs. Weekly Oral Alendronate (Fosamax). Saag K, et al. presentation ASBMR 2006
  • Patient Preference Between Once-a-Week ALN vs. Once-a-Year Zoledronic Acid (Reclast). Lindsay R, et al. presentation; and Omizo et al. SU329 ASBMR 2006

REFERENCES:

  1. Jackson et al. Calcium plus Vitamin D Supplementation and The Risk of Fractures. Results From the Women's Health Initiative Randomized Trial NEJM 2006; 453;669-83
  2. Daniel Bikle, MD presentation, Spokane Society of Internal Medicine, Update in Internal Medicine 2007, 2/23 430-530pm, "Vitamin D & Non-Skeletal Benefits"
  3. Kelly Krohn, MD presentation, Spokane Society of Internal Medicine, Update in Internal Medicine 2007, 2/24 1030-1130am, "Vitamin D & Balance"
  4. Kleerekoper M, Osteoporosis prevention and therapy: preserving and building strength through bone quality. Osteoporosis International 2006;17:1707-1715
  5. Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Menopause 2006;13:340-367
  6. Borgstrom F, Johnell O, Kanis JA, Jonsson B, Rehnberg C, At what hip fracture risk is it cost-effective to treat?: International intervention thresholds for the treatment of osteoporosis. Osteoporosis Int 2006;17:1459-1471
  7. van Geel ACM, Guesens PP, Nagtzaam IF, et al. Timing and risk factors for clinical fractures among postmenopausal women: a 5-year prospective study. BMC Med 2006
  8. Whyte MP, The long and the short of bone therapy. NEJM 2006;354(8):860-863
  9. Siris ES, Brenneman SK, Barrett-Connor E, et al. The effect of age and bone mineral density on the absolute, excess, and relative risk of fracture in postmenopausal women aged 50-99: results from the NORA. Osteoporosis International 2006;17(4):565-574
  10. Felsenberg D, Miller P, Armbrecht G, et al. Oral ibandronate significantly reduces the risk of vertebral fractures of greater severity after 1, 2, and 3 years in postmenopausal women with osteoporosis. Bone 2005;37:651-654
  11. Delmas PD et al. Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the dosing intravenous administration study. Arthritis Rheum 2006;54: 1838-1846
  12. Delmas PD, Licata AA, et al. Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover. Bone 2006
  13. Chen P, Miller PD, Delmas PD, Misurski DA, Krege JH Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated postmenopausal women with osteoporosis. JBMR 2006;21(11):1785-1790
  14. Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: The Women's Health Initiative Randomized Trial. JBMR 2006;21(6):816-828
  15. Judith Walsh, MD presentation, Spokane Society of Internal Medicine, Update in Internal Medicine 2007, 2/23 1-2pm, "Women's Health Review"
  16. Greenspan SL, Emkey RD, Bone HG et al. Significant differential effects of alendronate, estrogen or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. Ann Int Med 2002;137(11):875-883
  17. Ensrud KE, Barrett-Connor EL, Schwartz A, et al, for the Fracture Intervention Trial Long-Term Extension Research Group. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial Long-Term Extension (FLEX). JBMR 2004;19:1259-1269.
  18. Black D, Schwartz A, Ensrud K, et al. Effects of Continuing or Stopping Alendronate After 5 Years of Treatment: The Fracture Intervention Trial Long-Term Extension (FLEX). JAMA 2006;296(24):2889
  19. Colon-Emeric. Ten vs Five Years of Bisphosphonate Treatment for Postmenopausal Osteoporosis: Enough of a Good Thing. JAMA 2006;296(24):2968-2969
  20. Zoehrer R, et al. Effects of 3- and 5-Year Treatment With Risedronate on Bone Mineralization Density Distribution in Triple Biopsies of the Iliac Crest in Postmenopausal Women. JBMR 2006;21:1106-1112
  21. Hellstein JW, Marek CL. Bisphosphonate osteochem-onecrosis (bis- phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 2005;63:682-9
  22. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61:1115
  23. ACR References for "ONJ & Bisphosphonates"

  24. Bamias et al, J Clin Oncol 2005 ;23:8580-8587
  25. Migliorati CA. Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol. 2003;21:4253-4254
  26. 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
  27. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/ osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg. 2005; 63:1567-1575
  28. Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753-761
  29. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;24:945
  30. Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004. Professional Education Material. East Hanover, NJ: Novartis, 2004
  31. Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Oppermann U. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci USA. 2006;103:7829-7834
  32. Fleisch H. Bisphosphonates: mechanisms of action. Endo Rev 1998;19:80-100
  33. Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, Castronovo V, Green JR. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302:1055-1061
  34. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc. 2005;136:1658-1668
  35. Kademani D, Koka S, Lacy MQ, Rajkumar SV. Primary surgical therapy for osteo-necrosis of the jaw secondary to bisphosphonate therapy. Mayo Clinic Proceedings, 2006
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