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From Brigham and Women's Hospital and Harvard School of Dental Medicine, Boston, Massachusetts; University of Iowa College of Dentistry, Iowa City, Iowa; and The Ohio State University College of Dentistry, Columbus, Ohio.
Note: This is a position paper of the American Academy of Oral and Maxillofacial Pathology.
Grant Support: None.
Potential Financial Conflicts of Interest: Grants received: S.-B. Woo (Novartis).
Requests for Single Reprints: Sook-Bin Woo, DMD, Brigham and Women's Hospital, 45 Francis Street, Boston, MA 02115.
Current Author Addresses: Dr. Woo: Brigham and Women's Hospital, 45 Francis Street, Boston, MA 02115.
Dr. Hellstein: University of Iowa, 356 Dental Science South, Iowa City, IA 52246.
Dr. Kalmar: The Ohio State University, 305 West 12th Avenue, Columbus, OH 43210.
Osteonecrosis of the jaws is a recently described adverse side effect of bisphosphonate therapy. Patients with multiple myeloma and metastatic carcinoma to the skeleton who are receiving intravenous, nitrogen-containing bisphosphonates are at greatest risk for osteonecrosis of the jaws; these patients represent 94% of published cases. The mandible is more commonly affected than the maxilla (2:1 ratio), and 60% of cases are preceded by a dental surgical procedure. Oversuppression of bone turnover is probably the primary mechanism for the development of this condition, although there may be contributing comorbid factors. All sites of potential jaw infection should be eliminated before bisphosphonate therapy is initiated in these patients to reduce the necessity of subsequent dentoalveolar surgery. Conservative dÃ©bridement of necrotic bone, pain control, infection management, use of antimicrobial oral rinses, and withdrawal of bisphosphonates are preferable to aggressive surgical measures for treating this condition. The degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as alendronate, for osteoporosis is uncertain and warrants careful monitoring.
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Woo et al highlight the substantial difference in the risk of osteonecrosis of the jaw (ONJ) between oncology patients receiving high doses of intravenous bisphosphonates and patients with non-malignant skeletal disorders who receive considerably lower doses, yet their recommendations for management of the disorder do not reflect this difference (1). Thus, it is suggested that all patients starting bisphosphonate therapy undergo a comprehensive dental examination and panoramic and intraoral radiographs, followed by surgical treatment of "at -risk" teeth. The strategy proposed by Woo et al is based on the recommended evaluation of patients about to undergo bone marrow transplantation "“ hardly a comparable situation to starting bisphosphonate treatment for osteoporosis. As the same authors acknowledge, there is no evidence base for these recommendations (2).
The incidence of ONJ in osteoporotic patients receiving aminobisphosphonates is uncertain, but no cases were reported in placebo- controlled, randomized trials of alendronate, risedronate and ibandronate that collectively included in excess of 20,000 patients studied over at least two years. If one assumes an incidence of ONJ of 1 in 20,000 patients exposed, and that the (untested) intervention strategy proposed by Woo et al is 100% effective, then 20,000 patients would have to be screened to prevent a single case of ONJ. If the intervention strategy is only 50% effective, then 40,000 patients would need to be screened to prevent a single case of ONJ. Even if there has been considerable under- reporting of the disease in patients with osteoporosis, the number of patients needing to undergo such intervention in order to prevent a case of ONJ is likely to be very high. We suggest that valuable healthcare resources might be better invested in other areas.
We are concerned that the recommendations of expert groups such as the American Dental Association are misleading. They advise that invasive dental procedures should be avoided in patients taking intravenous zoledronate or pamidronate - but do not distinguish those receiving conventional dose treatment for osteoporosis or Paget's disease, from those receiving the very high doses used in malignant disease (3). As Woo et al indicate, ONJ is overwhelmingly a problem for the latter group. It should be noted that the only three cases of ONJ reported in patients with Paget's disease all occurred following exposure to doses of bisphosphonates that exceed those typically used to treat this disorder (4). An excessively conservative approach runs the risk of patients already taking bisphosphonates not getting appropriate dental surgery when they need it, and patients with dental problems not being given treatments of proven efficacy for osteoporosis and Paget's disease.
1. Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753-61
2. 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;136:1658-68.
3. American Dental Association: Osteonecrosis of the jaw www.ada.org/prof/resources/topics/osteonecrosis.asp accessed 20.5.06
4. Carter G, Goss AW, Doecke C. Bisphosphonates and osteonecrosis of the jaw: a possible association. Med J Aust. 2005;182:413-5.
Little is known about etiopathogenesis of osteonecrosis of the jaws (ONJ) associated to bisphosphonate treatment. As the comprehensive review by Woo et al pointed out (1), it is commonly believed that bone turnover suppression and angiogenesis reduction in local bone microenvironment induced by these drugs could affect the quality of jaw bone during growth and healing. In case of trauma, this microenvironment derangement may promote the development of a non-healing wound and osteonecrosis, leaving the lesion prone to infection that can progress to osteomyelitis. Due to the great frequency of traumatic jaw lesions and the wide spread use of bisphosphonates in clinical oncology, however, it is somewhat surprising that this unfavourable event occurs so rarely. The potency of bisphosphonates employed and the treatment duration are recognized risk factors, but as Woo et al admitted, many exceptions have been observed. The careful identification of predictive factors is of course of paramount importance.
The potent osteoclast inhibition induced by bisphosphonates leads to hypocalcemia and hyperparathyroidism, therefore concomitant administration of calcium and vitamin D is mandatory. This metabolic derangement is usually asymptomatic and occurs transiently (2). In some cases, however, it may persist for a long time despite calcium and vitamin D supplementation at recommended doses. In these patients hypovitaminosis D often co-exist suggesting inadequate supplementation (3). Relative hypovitaminosis D and continuous exposure to elevated PTH levels obstaculate bone repair and may contribute to ONJ. In a case control study recently published, we have observed that long term persistence of low serum calcium levels and high serum parathyroid hormone levels during zoledronic acid treatment was significantly associated to ONJ onset (4). The monthly profile of serum calcium and parathyroid hormone (PTH) levels in 13 patients undergoing ONJ after zoledronic acid was compared to that obtained in 40 bone metastatic patients who did not. Patients destined to develop ONJ had lower calcium levels and higher PTH levels than controls at all time point considered. A single institution experience analyzed the ONJ frequency in a consecutive series of breast and prostate cancer patients with bone metastases submitted to zoledronic acid (5). The results showed a greater ONJ frequency in prostate cancer patients (5.6% vs 1.6%, respectively). These data provide indirect confirmation to our data. Secondary hyperparathyroisidm, in fact, is more frequent in bone metastatic prostate cancer patients than breast cancer patients and this condition could be worsened by bisphosphonate administration.
2. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003; 98: 1735-44.
3. Maalouf NM, Heller HJ, Odvina CV, Kim PJ, Sakhaee K. Bisphosphonate-induced hypocalcemia: report of 3 cases and review of literature. Endocr Pract. 2006; 12: 48-53.
4. Ardine M, Generali D, Donadio M, et al Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw? Ann Oncol. 2006 in press.
5. Ortega C, Faggiuolo R, Vormola R, Montemurro F, Nanni D, Goia F, Aglietta M. Jaw complications in breast and prostate cancer patients treated with zoledronic acid. Acta Oncol. 2006; 45: 216-17.
Alfredo Berruti is a consultant of Novartis Company
To the editor: Woo et al. have provided a helpful review of bisphosphonates and osteonecrosis of the jaws.(1) However, their paper includes serious misstatements about bisphosphonates and bone. Citing the beagle dog study of Mashiba et al. (2), they state that "prolonged use of bisphosphonates may suppress bone turnover to the point that"¦ microdamage persists and accumulates" resulting in "decreased biomechanical competence." However, they did not mention an earlier study by the same authors showing that the microcracks in the ribs of these beagle dogs had little or no effect on vertebral strength.(2) Woo et al. state further that ""¦continued mineralization yields a hard, brittle bone with an osteopetrotic appearance and an increased risk for fracture." As support for this statement, they cite 3 sources: a paper by Weinstein(3), a single case of osteopetrosis(4) and a series by Odvina et al. of 9 patients with unusual fractures and decreased bone turnover on biopsy.(5) Weinstein's paper is a perspective in which he speculates on the possibility of hypermineralization but he adds "at some very high dose, not yet attainable in clinical practice, bisphosphonates may shut down remodeling"¦ All evidence indicates that these agents can be used for extended periods without fear of fractures in humans."(3) Whyte's case of osteopetrosis was a child who had an unusual but uncharacterized bone disease who then received massive doses of intravenous bisphosphonate.(4) This is clearly not a usual setting of bisphosphonate use. In the report of Odvina et al., the 9 patients who had evidence of suppressed bone remodeling while receiving alendronate were not thoroughly evaluated for other bone diseases before starting bisphosphonates and constituted a very heterogeneous group: 2 of the 9 had been treated with glucocorticoids concurrently and 3 others received combination therapy with estrogen and alendronate. Under any circumstances, these 9 patients represent a miniscule fraction of the millions of patients who have been treated with these agents. In sum, we find the arguments used by Woo and colleagues as the basis for concern about the adverse skeletal effects of long-term bisphosphonate therapy for osteoporosis to be unconvincing. The 7-year data with risedronate(6) and the 10-year data with alendronate(7;8) are reassuring regarding the long-term safety of bisphosphonates in doses used to treat osteoporosis. Nevertheless, we agree that more information is needed about the occurrence of ONJ in patients on oral bisphosphonate therapy, but it is premature to extrapolate the experience with high-dose IV bisphosphonates in patients with cancer to the lower doses used in otherwise healthy adults with osteoporosis.
(1) Woo S-B, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;206:753-61.
(2) Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles . Bone. 2001;28:524-31.
(3) Weinstein RS. Perspective. True Strength. J Bone Miner Res. 2000;15:621-25.
(4) Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003;349:457-63.
(5) Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CYC. Severely suppressed bone tJurnover: A potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294-301.
(6) MellstrÃ¶m DD, SÃ¶rensen OH, Goemaere S, Roux C, Johnson TD, Chines AA. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;75:462-68.
(7) Bone HG, Hosking D, Devogelaer J-P, Tucci JR, Emkey RD, Tonino RP et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. New Engl J Med. 2004;350:1189-99.
(8) Ensrud KE, Barrett-Connor EL, Schwartz A, Santora AC, Bauer DC, Suryawanshi S et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: Results from the Fracture Intervention Trial long-term extension. J Bone Miner Res. 2004;19:1259-69.
Dr Watts is consultant for Eli Lilly, Novartis, Procter & Gamble, Roche and sanofi aventis; receives honoraria for speaking from Procter & Gamble, Roche and sanofi aventis; and receives research support through his university from Amgen, Lilly, Merck, Novartis, Procter & Gamble and sanofi aventis
We congratulate Woo et al.(1) to their review and welcome it to be published in a general medicine journal. Although the oro-maxillo-facial literature has seen an almost exponential increase in reports on new generation bisphosphonates (NGB) induced jaw osteonecrosis during the last three years (1), most general practitioners still barely know about it.
NGB have proved efficacious in oncologic patients with bone affection and there is no doubt about their contribution in improving the life quality in patients with metastatic cancer spread. These patients receive high and intravenous doses of NGB and are thus more prone to get jaw osteonecrosis.
Nevertheless, maxillo-mandibular osteonecrosis in osteoporosis patients receiving NGB are also, and increasingly reported (1, 2). Whether these are isolated examples or cases that herald a wider clinical problem will become clearer within the next years. The occurrence of maxillo- mandibular osteonecrosis considerably depends on the type and the doses of NGB given. As osteoporosis patients are mainly prescribed oral and lower dosed NGB this might prevent them from this complication. NGBs inhibit osteoclast activity, but also have antiangiogenic effects and once incorporated into the bone they are barely degraded (3). Considering the higher life expectancy in osteoporosis patients, even lower NGB doses could lead to protracted occurrence of jaw osteonecrosis (1).
Maxillo-mandibular osteonecrosis is clinically difficult to manage and no curative treatment exists (1, 2). However, recent studies clearly identified poor dental hygiene, periodontal problems and particularly dental extractions during NGB treatment to increase considerably the risk of jaw osteonecrosis. Long-term antibiotic medication, NGB discontinuing and careful surgical debridement may limit the osteonecrosis but never heal this iatrogenic bone pathology. With respect to this complication and potential future medico-legal claims, it might be advised to balance individually the risks and benefits of the NGB treatment (4).
In addition to Woo's et al. (1) watchful attitude in osteoporosis patients we strongly emphasize that physicians prescribing NGB should be concerned about the oral and periodontal conditions of their patients. Systematic dental screening before NGB treatment might be expensive and exaggerated but including dental problems into the patient's history, sending them for a specialist workup if necessary and informing the patients that thorough dental hygiene is mandatory, is cheap and not time consuming. These simple measures might prevent a treatment which was intended to increase life quality and lower fracture risks (4) from turning into a clinical nightmare condition in otherwise middle-aged women.
1. Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144(10):753-61.
2. 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(11):1567-75.
3. Lin JH, Russell G, Gertz B. Pharmacokinetics of alendronate: an overview. Int J Clin Pract Suppl. 1999;101:18-26.
4. Schousboe JT, Nyman JA, Kane RL, Ensrud KE. Cost-effectiveness of alendronate therapy for osteopenic postmenopausal women. Ann Intern Med. 2005;142(9):734-41.
5. Farrugia MC, Summerlin DJ, Krowiak E, et al. Osteonecrosis of the mandible or maxilla associated with the use of new generation biphosphonates. Laryngoscope. 2006;116(1):115-120.
In their article Dr. Woo and colleagues review osteonecrosis of the jaw as a common adverse drug reaction (ADR) of bisphosphonates. They are right in suggesting that bisphosphonate-associated osteonecrosis of the jaws results from marked suppression of bone metabolism that leads to microdamage in the jawbones, compromising its biomechanical properties, and that local trauma and infection as co-factors promote the condition.
While we agree entirely with their description of the pathogenesis we would like to point out that the underlying mechanism of action resembles the one's of a known disease. In this context, we propose that the main culprit is the two phosphorus atoms in the bisphosphonate molecule. Regarding the clinical course of the condition, there is a striking similarity with a classical occupational disease, phosphorus necrosis of the jaw, also known as "phossy jaw". It occurs when phosphorus is chronically inhaled by workers in match factories and was first reported in 1844 in Vienna (1). The disease is regarded as the greatest occupational medicine tragedy of industrialized mankind (2).
Similarities with the "phossy jaw" phenomenon exist in both, chemical and clinical respect. The chemical structure of bisphosphonates is a P-C-P configuration with the carbon atom carrying various residues. At the Fourth Annual Meeting of the International Society of Pharmacovigilance in Dublin in November 2004 we have presented our hypothesis together with a review of the until then known cases of bisphosphonate-associated osteonecrosis of the jaw from the German spontaneous reporting system of ADRs (3). We have named the condition "bisphossy jaw" (3).
"Phossy jaw" usually began with toothache and swelling of the gums and jaw (4). In its full blown form it was an extremely painful and disfiguring condition. The onset of the disease was generally quite slow, an average of 5 years being required for the symptoms to develop from first exposure. The lower jaw was more commonly affected than the upper jaw, exactly as seen in the bisphosphonate-associated osteonecrosis (5). Two to three percent of the exposed people developed the condition. Many patients committed suicide because of pain and disfigurement caused by the disease or they died of infections.
By pointing out the extraordinary clinical similarities and the common chemical characteristics between the two entities we want to strengthen the argument that bisphosphonate-associated osteonecrosis of the jaw is mediated through the long-term deposition of phosphate in the bone.
(1) Lesky E. Die Phosphornekrose, klassisches Beispiel einer Berufskrankheit. Wiener klinische Wochenschrift. 1966;37:601-4.
(2) Morgan L, Scott A. Hunter's disease of occupations. 9th ed. London: Arnold; 2000.
(3) Berthold HK, Diel IJ, Gouni-Berthold I. Phossy jaw revisited -- do bisphosphonates cause "bisphossy jaws"? Drug Safety. 2004;27:920.
(4) Miles AEW. Phosphorus necrosis of the jaw: "phossy jaw". British Dental Journal. 1972;133:203-6.
(5) Hughes JPW, Baron R, Buckland H, Cooke MA, Craig JD, Duffield DP et al. Phosphorus necrosis of the jaw: a present-day study. Brit J Industr Med. 1962;19:83-99.
Thank you to Drs. Berthold and Gouni-Berthold for the comments on "bisphossy jaw". One of us (J. Hellstein) had also noticed the similarities between these two conditions.1
Thank you to Dr. Berutti for bringing attention to the importance of monitoring for hypocalcemia and hyperparathyroidism and administration of calcium and vitamin D as appropriate.2 Such work underscores the many factors that directly or indirectly are involved in the pathogenesis of osteonecrosis of the jaws (ONJ).
We agree with Drs. Grey and Cundy that there is no data on the incidence or prevalence of ONJ in patients taking oral bisphosphonates for osteoporosis. However, the lack of reported cases in the 20,000 patients does not mean that none occurred. Patients who develop what they perceive as oral or dental problems generally seek help from their dentist or oral surgeon and may not have thought to report this to their physicians. Furthermore, since the risk for ONJ seems to be both time and dose dependent, a two-year exposure may be insufficient for disease development in this patient population. Despite their lower overall risk for ONJ, we feel that at this time, patients with osteoporosis should be included in Group 1 since the number of patients taking these drugs for multiple years is growing rapidly.
The recommendations for Group 1 are not particularly costly and are consistent with basic dental care in most industrialized countries. Identifying dental infections via a standard oral examination with radiographs and eliminating such infections is good practice for anyone, not just bisphosphonate users. This would also reduce the need for subsequent jaw surgery, a risk factor for ONJ. Should ONJ prove to be an exceptionally rare complication among oral bisphosphonate users, regardless of time or dose, we agree that the recommendations should be changed.
In response to Dr. Watts, the research by Mashiba et al.3,4 indicated that even though vertebral strength was not compromised, toughness was reduced by 20% in both studies. Toughness has a significant linear relationship with microdamage accumulation and compromises overall biomechanical properties of bone. We agree and that the population at highest risk for ONJ is the oncology population on high dose intravenous therapy. However, the risk for patients with osteoporosis is not zero. As data accrues, we will understand better who is susceptible and what factors help to predict the development of ONJ.
References: 1. Hellstein JM and Marek CL. Bisphosphonate osteochemonecrosis (bis- phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 2005; 63:682-9. 2. Ardine M, Generali D, et al. Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw? Ann Oncol 2006 (electronic format). 3. Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC and Burr DB. Suppressed bone turnover by bisphosphonates increases micro-damage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 2000; 15:613-620. 4. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant sites in beagles. Bone 2001; 28:524-531.
Dr. S. Woo has research supported by Novartis.
Dear Dr. Berthold et al. Thank you for your response. I am well aware of phossy jaw and you may be interested in 1 letter to the editor and 1 article in the Journal of Oral and Maxillofacial Surgery I have written. Submitted in the Summer of 2004 they were eventually published respectively in December 2004 and May 2005.1,2 These two publications outline at length many of the similarities you mentioned in your letter. Additionally, the online archives of the Bulletin Board of Oral Pathology also contains some information on the connection in September of 2004.3 As can be deduced from the titles of the articles I personally like the term "bis-phossy jaw", though many believe it to be too colloquial. I also think that those of us who believe in the uncanny similarities of the 2 diseases will continue to prefer the term in verbal communication.
Unfortunately the current lack of scientific support for the theory and lack of space did not allow us to expand on the subject in our Annals of Internal Medicine article. I personally feel that time will provide a more scientific link. I would not be at all surprised that phossy jaw was working by the same or similar mechanism(s) as our current 21st century problem. However, at this point in time we continue to await more data. I believe we can all agree with the George Santayana quote "those who cannot learn from history are doomed to repeat it."
1) Hellstein JW, Marek CL. Bis-phossy jaw, phossy jaw, and the 21st century: bisphosphonate-associated complications of the jaws. J Oral Maxillofac Surg. 2004 Dec;62(12):1563-5.
2) Hellstein JW, Marek CL.Bisphosphonate osteochemonecrosis (bis- phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg. 2005 May;63(5):682-9.
3) Hellstein JW, Online Bulletin Board of Oral Pathology. http://listserv.acsu.buffalo.edu/cgi- bin/wa?A2=ind0410&L=bboplist&T=0&P=2038
John Hellstein, DDS, MS Clinical Professor University of Iowa
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