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Annals of Internal Medicine
Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws
Sook-Bin Woo, DMD; John W. Hellstein, DDS, MS; and John R. Kalmar, DMD, PhD

Osteonecrosis of the jaws is a recently described adverse side
nate therapy is initiated in these patients to reduce the necessity
effect of bisphosphonate therapy. Patients with multiple myeloma
of subsequent dentoalveolar surgery. Conservative de´bridement of
and metastatic carcinoma to the skeleton who are receiving intra-
necrotic bone, pain control, infection management, use of antimi-
venous, nitrogen-containing bisphosphonates are at greatest risk
crobial oral rinses, and withdrawal of bisphosphonates are pref-
for osteonecrosis of the jaws; these patients represent 94% of
erable to aggressive surgical measures for treating this condition.
published cases. The mandible is more commonly affected than
The degree of risk for osteonecrosis in patients taking oral
the maxilla (2:1 ratio), and 60% of cases are preceded by a dental
bisphosphonates, such as alendronate, for osteoporosis is uncer-
surgical procedure. Oversuppression of bone turnover is probably
tain and warrants careful monitoring.
the primary mechanism for the development of this condition,
although there may be contributing comorbid factors. All sites of

Ann Intern Med. 2006;144:753-761.
potential jaw infection should be eliminated before bisphospho-
For author affiliations, see end of text.
Bisphosphonates are used to treat osteoporosis, Paget ACTIONS OF BISPHOSPHONATES
disease of bone and other metabolic bone diseases, Bisphosphonates are powerful inhibitors of osteoclastic multiple myeloma, and skeletal events associated with met- activity. They are analogues of inorganic pyrophosphates astatic neoplasms. Their primary mechanism of action is with low intestinal absorption, are excreted through the inhibition of osteoclastic resorption of bone. Within the kidneys without metabolic alteration, and have a high af- past 2 years, an increasing body of literature has suggested finity for hydroxyapatite crystals (1, 2). Because they are that bisphosphonate use, especially intravenous prepara- incorporated into the skeleton without being degraded, tions, may be associated with osteonecrosis of the jaws. We they are remarkably persistent drugs; the estimated half-life briefly review the action of bisphosphonates, outline the for alendronate is up to 12 years (3). Alendronate, risedro- clinical manifestations of bisphosphonate-associated osteo- nate, pamidronate, zoledronic acid, and ibandronate, necrosis of the jaws, summarize current treatment strate- which are called aminobisphosphonates, have much higher gies, discuss possible mechanisms of etiopathogenesis, and potency because they contain nitrogen in a side chain suggest avenues of research.
(Table 1).
The nonaminobisphosphonates are metabolized by os- teoclasts to inactive nonhydrolyzable adenosine triphos- phate analogues that are directly cytotoxic to the cell and induce apoptosis (1, 2). The newer aminobisphosphonates We performed MEDLINE and PubMed searches of have 2 actions (4): induction of another adenosine triphos- English- and foreign-language literature (1966 to 31 Janu- phate analogue that induces apoptosis, and inhibition of ary 2006) using the following Medical Subject Headings farnesyl diphosphonate synthase, which is part of the me- (MeSH) and terms: osteonecrosis, avascular necrosis, phos- valonate pathway of cholesterol synthesis. Such inhibition phorous necrosis, bisphosphonates, and diphosphonates. We results in dysregulation of intracellular transport, cytoskel- then crossed the same terms with the terms jaw diseases, etal organization, and cell proliferation, leading to inhibi- myeloma, breast cancer, and metastatic cancer. Other refer- tion of osteoclast function. In addition, aminobisphospho- ences were obtained from citations from retrieved articles.
nates reduce recruitment of osteoclasts and induce Similar terms were used to search abstracts from meetings osteoblasts to produce an osteoclast-inhibiting factor (5, 6).
of the American Society of Clinical Oncology.
Aminobisphosphonates exert several antitumor effects, We specifically reviewed all case reports and case series including induction of tumor cell apoptosis, inhibition of of patients with bisphosphonate-associated osteonecrosis of tumor cell adhesion to the extracellular matrix, and inhibi- the jaws. We included any report that provided acceptable tion of tumor invasion (4, 7). Bisphosphonates also have documentation of disease and use of bisphosphonates, re-gardless of whether it included information on the sex ofpatients, the site of the lesions, and the bisphosphonate used. Several authors published more than 1 paper describ-ing patients with osteonecrosis. Through direct communi- Print
Key Summary Points . . . . . . . . . . . . 758
cation with these authors, we confirmed that some of thesame patients were included in multiple reports. When this occurred, we used and cited data only from the larger, more recent publication.
Conversion of figures and tables into slides No funding was received for this study.
2006 American College of Physicians 753
Review Bisphosphonates and Osteonecrosis of the Jaws antiangiogenesis properties (8, 9) and can activate ␥␦ T retard fracture healing or slow callus remodeling, it may cells (10, 11). The use of bisphosphonates in patients with not affect bone mineralization or mechanical properties multiple myeloma and metastatic cancer to the bones, such as breast, prostate, lung, and renal cell carcinomas, hasresulted in a statistically significant reduction in skeletal ORAL COMPLICATIONS OF BISPHOSPHONATE THERAPY
complications, including pathologic fractures, spinal cordcompression, hypercalcemia of malignant disease, and the Although oral bisphosphonates may cause oral muco- need for subsequent radiotherapy or surgery to bone (12– sal lesions (purportedly arising from direct contact injury) 14). Intravenous bisphosphonates have improved bioavail- (23, 24), we focus our review on bisphosphonate-associ- ability and do not produce gastrointestinal side effects, re- ated osteonecrosis of the jaw. Table 2 summarizes 368
sulting in better patient adherence. They have become reported cases of bisphosphonate-associated osteonecrosis standard therapy in the management of patients with mul- of the jaw (25–54). Reported cases manifested as exposure tiple myeloma and metastatic cancer.
of portions of the bone of the mandible only (65%), max-illa only (26%), or both (9%). Approximately one third oflesions were painless (27), and there was a slight female POTENTIAL ADVERSE EFFECTS OF BISPHOSPHONATE
predilection in a ratio of 3:2 among all reported cases.
Multifocal or bilateral involvement was slightly more com- In normal bone homeostasis, osteoclastic resorption is mon in the maxilla than in the mandible (31% vs. 23%).
tightly linked to osteoblastic bone deposition and both Most lesions were on the posterior lingual mandible near functions are essential for repair of physiologic microdam- the mylohyoid ridge. Of importance, 60% of cases oc- age. Prolonged use of bisphosphonates may suppress bone curred after a tooth extraction or other dentoalveolar sur- turnover to the point that such microdamage persists and gery and the remaining cases occurred spontaneously. The accumulates (15). The result is hypodynamic bone with latter cases often involved patients wearing dentures, a pos- decreased biomechanical competence. Although osteoblas- sible source of local trauma. Marx and colleagues (27) re- tic function is also reduced during bisphosphonate therapy, ported that 39% of cases that occurred spontaneously were continued mineralization yields a hard, brittle bone with located on bony exostoses that were easily traumatized.
an osteopetrotic appearance and an increased risk for frac- There is 1 case report of dental implant failure associated ture (16 –18). Thus, some experts caution that the benefits with bisphosphonate use (55).
of prolonged use of bisphosphonates must be carefully Most patients (94%) were treated with intravenous weighed against the potential negative effects of oversup- bisphosphonates (primarily pamidronate and zoledronic pression of bone metabolism (1, 19, 20). Other experts acid), and most patients (85%) had multiple myeloma or argue that although long-term use of bisphosphonates may metastatic breast cancer (Table 3). The remaining patients
Table 1. Bisphosphonate Formulations*
Generic Name
Brand Name
Manufacturer and Location
Dosage Forms
FDA Approval
Etidronate disodium Procter & Gamble Pharmaceuticals, 200- and 400-mg tablets Clodronate disodium Schering AG, Berlin, Germany 400- and 800-mg tablets; 60 mg/mL Tiludronate disodium Sanofi-Synthelabo Inc., New York, Alendronate sodium Merck & Co. Inc., Whitehouse 5-, 10-, 35-, 40-, and 70-mg tablets; Station, New Jersey 70 mg/75 mL oral solution Alendronate sodium Merck & Co. Inc., Whitehouse 70-mg and 2800-U cholecalciferol Station, New Jersey Pamidronate disodium Novartis Pharmaceuticals, East 30-, 60-, and 90-mg vials† Hanover, New Jersey Risedronate sodium Procter & Gamble Pharmaceuticals, 5-, 30-, and 35-mg tablets Risedronate sodium Actonel with calcium Procter & Gamble Pharmaceuticals, 35-mg and 500-mg calcium tablets Novartis Pharmaceuticals, East Hanover, New Jersey Ibandronate sodium Roche Laboratories Inc., Nutley, * This table shows the most common brand names. Generic forms, other names, and other doses may be available outside the United States. Clodronate is included becauseof its common use in Canada and Europe. FDA ⫽ Food and Drug Administration.
† Drug is administered intravenously.
754 16 May 2006 Annals of Internal Medicine Volume 144 • Number 10
Bisphosphonates and Osteonecrosis of the Jaws Review Table 2. Reports of Cases of Bisphosphonate-Associated Osteonecrosis of the Jaws*
Study, Year
Myeloma (n ⫽ 29) Mandible (n ⫽ 39) Pamidronate (n ⫽ 34) Breast cancer (n ⫽ 21) Maxilla (n ⫽ 23) Zoledronic acid (n ⫽ 9) Prostate cancer (n ⫽ 3) Both (n ⫽ 1) Pamidronate and zoledronic acid Lung cancer (n ⫽ 1) (n ⫽ 13) Uterine leiomyosarcoma Alendronate (n ⫽ 5) Risedronate (n ⫽ 1) Leukemia (n ⫽ 1) Alendronate and zoledronic acid Osteoporosis (n ⫽ 7) Breast cancer (n ⫽ 9) Mandible (n ⫽ 6) Intravenous forms, not specified Myeloma (n ⫽ 4) Maxilla (n ⫽ 5)Both (n ⫽ 2) Myeloma (n ⫽ 62) Mandible (n ⫽ 81) Zoledronic acid (n ⫽ 48) Breast cancer (n ⫽ 50) Maxilla (n ⫽ 33) Pamidronate and zoledronic acid Prostate cancer (n ⫽ 4) Both (n ⫽ 5) (n ⫽ 36) Osteoporosis (n ⫽ 3) Pamidronate (n ⫽ 32)Alendronate (n ⫽ 3) Migliorati et al., Breast cancer (n ⫽ 10) Mandible (n ⫽ 8) Zoledronic acid (n ⫽ 8) Myeloma (n ⫽ 3) Maxilla (n ⫽ 2) Pamidronate and zoledronic acid Prostate cancer (n ⫽ 2) Both (n ⫽ 1) Ovarian cancer (n ⫽ 1) Unknown (n ⫽ 7) Pamidronate (n ⫽ 3) Ovarian/breast cancer Alendronate (n ⫽ 1) Osteoporosis (n ⫽ 1) Purcell and Boyd, Breast cancer (n ⫽ 5) Mandible (n ⫽ 4) Zoledronic acid (n ⫽ 9) Prostate cancer (n ⫽ 4) Maxilla (n ⫽ 2) Pamidronate (n ⫽ 2) Myeloma (n ⫽ 3) Unknown (n ⫽ 7) Pamidronate and zoledronic acid Osteoporosis (n ⫽ 1) Alendronate (n ⫽ 1) Breast cancer (n ⫽ 10) Mandible (n ⫽ 11) Zoledronic acid (n ⫽ 9) Myeloma (n ⫽ 9) Maxilla (n ⫽ 1) Pamidronate and zoledronic acid Prostate cancer (n ⫽ 1) Both (n ⫽ 8) Pamidronate (n ⫽ 5) Breast cancer (n ⫽ 6) Mandible (n ⫽ 8) Pamidronate and zoledronic acid Myeloma (n ⫽ 4) Maxilla (n ⫽ 3) Prostate cancer (n ⫽ 1) Both (n ⫽ 1) Pamidronate (n ⫽ 4) Lung cancer (n ⫽ 1) Zoledronic acid (n ⫽ 3) Myeloma (n ⫽ 11) Mandible (n ⫽ 14) Pamidronate and zoledronic acid Prostate cancer (n ⫽ 3) Maxilla (n ⫽ 3) Breast cancer (n ⫽ 2) Zoledronic acid (n ⫽ 7) Zoledronic acid and ibanronate Breast cancer (n ⫽ 3) Mandible (n ⫽ 8) Zoledronic acid (n ⫽ 4) Myeloma (n ⫽ 7) Maxilla (n ⫽ 2) Pamidronate (n ⫽ 4) Lung cancer (n ⫽ 1) Both (n ⫽ 1) Pamidronate and zoledronic acid Zarychanski et al., Myeloma (n ⫽ 10) Mandible (n ⫽ 10) Pamidronate (n ⫽ 12) Breast cancer (n ⫽ 1) Maxilla (n ⫽ 1) Renal cancer (n ⫽ 1) Both (n ⫽ 1) Summary of studies Myeloma (n ⫽ 29) Mandible (n ⫽ 30) Zoledronic acid (n ⫽ 27) Breast cancer (n ⫽ 26) Maxilla (n ⫽ 14) Pamidronate and zoledronic acid Prostate cancer (n ⫽ 5) Both (n ⫽ 9) (n ⫽ 21) Paget disease (n ⫽ 3) Pamidronate (n ⫽14) Osteoporosis (n ⫽ 3) (n ⫽ 17) Alendronate (n ⫽ 5) Lung cancer (n ⫽ 2) Alendronate and zoledronic acid Lymphoma (n ⫽ 1) Mesothelioma (n ⫽ 1) Pamidronate, zoledronic acid, and alendronate (n ⫽ 1) Oral ibandronate (n ⫽ 1) * NS ⫽ not stated.
† Sex was not reported for 9 patients in these studies.
were taking oral bisphosphonates for osteoporosis or Paget present (Figure 3). Painful ulcers may develop in soft tis-
disease of bone (25, 27–29, 40, 50, 51).
sues that impinge on the ragged bony margins.
Clinically, intraoral lesions appear as areas of exposed Results of radiographic evaluation may be negative in yellow-white, hard bone with smooth or ragged borders early cases. Although some investigators have noted subtle (Figures 1 and 2). Extraoral or intraoral sinus tracts may be
changes, such as widening of the periodontal ligament, 16 May 2006 Annals of Internal Medicine Volume 144 • Number 10 755
Review Bisphosphonates and Osteonecrosis of the Jaws the jaws are the type and total dose of bisphosphonate and Table 3. Primary Diagnoses and Types of Bisphosphonates
history of trauma, dental surgery, or dental infection.
in Reported Cases of Osteonecrosis of the Jaws
Ninety-four percent of patients with osteonecrosis receivedpamidronate or zoledronic acid. The doses for oncologic Patients, n (%)*
indications are often up to 12 times higher than those used for osteoporosis (13, 59). Of interest, clodronate, a non- Metastatic breast cancer aminobisphosphonate, has not been implicated in the de- Metastatic prostate cancer velopment of osteonecrosis (60). The risk for osteonecrosis of the jaws is substantially higher for patients taking Other metastatic disease† Paget disease of bone zoledronic acid and increases over time, probably because of the long half-life of these drugs. Although oral lesionsmay develop after as few as 4 months of bisphosphonate therapy, the median duration of drug use ranged from 22 to 39 months (32, 38, 48) and the mean ranged from 9 to Pamidronate and zoledronic acid 14 months (27, 33). The cumulative hazard was 1% within Alendronate and zoledronic acid the first year and 21% at 3 years of treatment with zoledronic acid. In contrast, it was 0% in the first year and 4% in the third year for patients receiving pamidronate Ibandronate and zoledronic acid Pamidronate, zoledronic acid, and alendronate alone or with subsequent zoledronic acid (32). Another study showed that 10% of 211 patients receivingzoledronic acid developed osteonecrosis compared with 4% Intravenous bisphosphonates, not specified
of 413 patients receiving pamidronate (61).
Patients with osteoporosis
A few cases have been reported in patients taking alen- Receiving alendronate dronate (10 mg/d) for osteoporosis (25, 27–29, 50, 51).
Receiving risedronate Receiving alendronate and zoledronic acid One patient had taken alendronate for only 2 years (27).
The concern is that with more women aging and taking * Percentages may not sum to 100% because of rounding.
bisphosphonates for longer periods of time, more cases of † Five patients had lung tumors. Other diseases were leiomyosarcoma, leukemia,ovarian/breast cancer, ovarian cancer, renal cancer, lymphoma, mesothelioma, and osteonecrosis may develop even in patients receiving alen- dronate or ibandronate therapy.
‡ Nine of 11 cases were in the mandible, and 2 of 11 cases were in the maxilla.
The remaining 2 cases were not specified.
Trauma to oral tori is also associated with osteonecro- § All cases were in the mandible.
sis (27) (Figure 2). Furthermore, 60% of patients had
some form of dentoalveolar surgery resulting in nonhealing
of the surgical site and necrosis of bone. Because most
these findings are indistinguishable from chronic periodon- dentoalveolar surgeries are performed to treat dental infec- tal infection, a predisposing factor for osteonecrosis (27).
tion, the contribution of each to the development of osteo- Advanced cases show a moth-eaten, poorly defined radiolu-cency, with or without radio-opaque sequestra. In 1 series,5 of 63 patients developed pathologic jaw fractures (25).
Cultures of exposed bone may identify Actinomyces species, Figure 1. Osteonecrosis of the right mandible after tooth
but care must be taken to distinguish between a true sup- extraction in a patient taking zoledronic acid for metastatic
purative infection and mere surface colonization by Actino- myces, because such organisms are a common componentof dental plaque.
Patients with bisphosphonate-associated osteonecrosis may present similarly to those with osteoradionecrosis ofthe jaws. Osteoradionecrosis is a complication of radiother-apy. It is thought to result from osteocyte and microvascu-lar damage after the jaws are exposed to ionizing radiationand also frequently occurs after tooth extraction (56). Os-teoradionecrosis, however, infrequently involves the max-illa (⬍5% of cases) and is more common in men than inwomen (57, 58).
The most important predisposing factors for the de- velopment of bisphosphonate-associated osteonecrosis of 756 16 May 2006 Annals of Internal Medicine Volume 144 • Number 10
Bisphosphonates and Osteonecrosis of the Jaws Review diseases. Because the teeth are separated from bone by no Figure 2. Osteonecrosis of the palatal torus in a patient with
more than 2 mm of periodontal connective tissue, such osteoporosis taking alendronate.
infections have easy access to the underlying bone. A caseof osteonecrosis in the ear of a patient taking zoledronicacid for multiple myeloma was reported recently (44). Thelesion occurred after removal of exostoses in the externalauditory canal, and the patient had concurrent osteonecro-sis of the maxilla.
We suggest that bisphosphonate-associated osteone- crosis of the jaws results from marked suppression of bonemetabolism that results in accumulation of physiologic mi-crodamage in the jawbones, compromising biomechanicalproperties. Trauma and infection increase demand for os-seous repair that exceeds the capacity of the hypodynamicbone, resulting in localized bone necrosis. The antiangio-genic property of bisphosphonates and other medicationsand the presence of other comorbid factors may promotethe risk for or persistence and progression of this condi-tion.
necrosis is unclear, although it is likely that together theycompound the problem.
Patients with myeloma tend to be prothrombotic and OSTEONECROSIS OF THE JAWS
are often treated with other antiangiogenic agents, such as A Web-based survey conducted by the International glucocorticoids, thalidomide, and the new proteasome in- Myeloma Foundation resulted in 1203 respondents, 904 hibitors, such as bortezomib, in addition to bisphospho- with myeloma and 299 with breast cancer. Seven percent nates (62, 63). Although neither corticosteroids nor thalid- and 4% of patients with myeloma and breast cancer, re- omide has been shown to be associated with additional risk spectively, reported osteonecrosis, and 6% and 8% of pa- for osteonecrosis of the jaws, prospective studies are needed tients with myeloma and breast cancer, respectively, re- to more fully address this issue (32, 61). The impact of ported lesions suspicious for osteonecrosis (61). In a single- local factors, such as smoking, and of underlying medical center study of 252 patients who had received intravenous conditions, such as diabetes or peripheral vascular diseases, bisphosphonates since January 1997, 10% of 111 patients remains to be determined.
with myeloma and 3% of 46 patients with breast cancerdeveloped osteonecrosis (32). In another study of 124 pa- SUSCEPTIBILITY OF THE JAWS TO OSTEONECROSIS
tients with myeloma or breast cancer who were treated The question often asked is "Why the jaws?" First, the with intravenous bisphosphonates in a dental clinic in a jaw bones are separated from a trauma-intense and micro- cancer center, 4 and 9 patients with myeloma and breast biologically diverse oral environment by thin mucosa andperiosteum. The fragility of this barrier is reflected by thecondition known as lingual mandibular sequestration, Figure 3. Extraoral fistula in a patient with intraoral
which occurs in healthy adults yet resembles mild cases of bisphosphonate-associated osteonecrosis of the jaws (64).
In this condition, 1- to 3-mm slivers of bone are seques-trated in the area of the protuberant mylohyoid ridge withspontaneous resolution. It is thought that minor traumacauses local damage to the thin mucosa and underlyingperiosteum, leading to bone necrosis. Because the posteriorlingual mandible is also a frequent site for osteonecrosis, itseems probable that the hypodynamic bone in patients re-ceiving bisphosphonate therapy may turn this typically in-nocuous process into chronic bone exposure. Trauma tothe periosteum may also serve to initiate osteonecrosis inpatients wearing dentures or dental prostheses or in pa-tients with prominent exostoses.
Second, teeth are readily infected by bacteria that cause caries and periodontal disease, 2 common infectious 16 May 2006 Annals of Internal Medicine Volume 144 • Number 10 757
Review Bisphosphonates and Osteonecrosis of the Jaws Patient management before initiation of therapy with Key Summary Points
aminobisphosphonates is targeted at eliminating active Osteonecrosis of the jaws is strongly associated with the sites of infections to minimize future infections and the use of aminobisphosphonates, and the mechanism of dis- need for future dentoalveolar surgery, such as tooth extrac- ease is probably severe suppression of bone turnover.
tions, to treat such infections. Similar protocols have beenestablished for patients preparing for allogeneic stem-cell Ninety-four percent of patients are treated with zoledronic transplantation and those about to receive radiation to the acid or pamidronate or both; 85% of affected patients head and neck (67, 68).
have multiple myeloma or metastatic breast cancer, and Recommendations for group 1, patients about to be- 4% have osteoporosis.
gin intravenous bisphosphonate therapy, are outlined in
Table 4. It is probably not necessary to delay initiation of
The prevalence of osteonecrosis in patients with cancer is bisphosphonate therapy if dental treatment can be com- 6% to 10% and the prevalence in those taking alendro- pleted within 1 to 2 months. With drug use between 3 and nate for osteoporosis is unknown; osteonecrosis seems to 6 months, patients in group 2 (those receiving intravenous be time- and dose-dependent because of the long half-life aminobisphosphonates who do not have signs of osteone- crosis of the jaws) should be evaluated on a case-by-casebasis. Those who have been receiving intravenous bisphos- More than half of all cases (60%) occur after dentoalveo- phonate therapy for oncologic indications for more than 6 lar surgery (such as tooth extraction) to treat infections, months are at risk for this condition. In group 3, patients and the remaining 40% are probably related to infection, with osteonecrosis of the jaws, there are anecdotal reports denture trauma, or other physical trauma.
of the use of acrylic stents (with or without soft liners) to Preventive strategies include removing all foci of dental cover areas of exposed bone, protect adjacent soft tissues, infection before starting bisphosphonate therapy.
and improve comfort. However, there is a risk that thestent may act as a fomite and that additional trauma may Treatment is directed toward control of pain and infection be caused by the stent itself.
and careful local de´bridement of dead bone, but not wide Reduction of pain and regression or even resolution of excision of lesions.
lesions of osteonecrosis have been observed in patientstreated with antibiotics and mouth rinses, withdrawal ofbisphosphonates, and removal of loose sequestra (31, 45,48). Extensive resection has not consistently resulted inwound closure and may lead to worsening or progression cancer, respectively, developed osteonecrosis (prevalence of of disease (25, 27). However, even for patients with mul- tiple myeloma who are potential candidates for hematopoi-etic stem-cell transplantation or continued chemotherapy, asymptomatic osteonecrosis may not necessarily pose a Treatment protocols have been outlined, but trials and substantial risk for increased morbidity if there is no evi- outcomes of treatment and long-term follow-up data are dence of active infection, as characterized clinically by pain not yet available (25, 27, 28, 65). In June 2004, an expert and suppuration. Hyperbaric oxygen therapy, given to a panel outlined recommendations for the management of few patients, has only infrequently shown clinical efficacy bisphosphonate-associated osteonecrosis of the jaws (66).
(25, 27, 28, 32, 33, 36, 69).
Because there are no randomized clinical trials that assessmanagement strategies, we propose the following guide-lines based on published literature, our own experience, DISCONTINUATION OF BISPHOSPHONATE THERAPY
and the experience of our colleagues.
Currently, there is no published evidence to support We group patients who are either receiving bisphos- or oppose discontinuation of bisphosphonate therapy once phonate therapy or about to begin therapy into the follow- osteonecrosis develops or before required dental surgery.
ing 3 broad categories: group 1, patients about to begin Because of the long half-life of bisphosphonates, recovery aminobisphosphonate therapy; group 2, patients without of normal osteoclast function and bone turnover after drug osteonecrosis of the jaws who are receiving aminobisphos- withdrawal may be too gradual for this measure to have phonate therapy; and group 3, patients with osteonecrosis clinical significance. It is also unclear what effect, if any, of the jaws. Patients with osteoporosis who are taking oral discontinuation of such therapy would have on overall preparations, such as alendronate, and are at lower risk morbidity and mortality among patients with cancer.
than those receiving intravenous preparations are included Nevertheless, patients may benefit from bisphospho- in group 1. We note that the risks associated with oral nate withdrawal. There have been anecdotal reports of ibandronate, recently approved for the treatment of osteo- healing and complete resolution of existing sites of osteo- porosis, are unknown.
necrosis after several months of therapy cessation. The re- 758 16 May 2006 Annals of Internal Medicine Volume 144 • Number 10
Bisphosphonates and Osteonecrosis of the Jaws Review Table 4. Management Recommendations*
Group 1: patients about to begin Treat active oral infections, eliminate sites at high risk for infection (partially impacted wisdom teeth, nonrestorable teeth, or teeth with substantial periodontal bone loss) Encourage routine dental care Perform biannual oral examination and dental cleaningMinimize periodontal inflammationProvide routine restorative care of carious teethProvide endodontic therapy of nonsalvageable teeth Group 2: patients without osteonecrosis of the jaws Less than 3 months of drug therapy who are receiving intravenous Same as above for group 1 More than 3 months of drug therapy Seek conservative alternatives to surgical procedures (endodontic therapy with or without decoronation, scaling, and de´bridement) with appropriate local and systemic antibiotics Perform extractions and other surgery using minimal bone manipulation with appropriate local and systemic antibiotics; follow up to ensure healing Group 3: patients with osteonecrosis of the jaws Same as above for group 2 with more than 3 months of drug therapyConsider additional imaging studies, such as computed tomography scansPerform conservative removal of dead bone as necessary with minimal trauma to adjacent hard Prescribe oral rinses (0.12% chlorhexidine rinse, hydrogen peroxide)Prescribe systemic antibiotic therapy (monotherapy or combination therapy with ␤-lactam, tetracycline, macrolide, metronidazole, and/or clindamycin) Prescribe systemic analgesics as indicatedPrescribe a soft acrylic stentSuggest discontinuation of bisphosphonate therapy until osteonecrosis heals or underlying disease * Patients receiving or scheduled to begin bisphosphonate therapy should receive a comprehensive dental examination and panoramic and intraoral radiographs. Patientsshould be made aware of osteonecrosis, including its signs, symptoms, and sequelae.
moval of the antiangiogenic effects of the drug on the soft determine what additional risk factors, if any, may predis- tissues and periosteum may play a role in healing. For this pose the patient to the development of osteonecrosis of the reason, discontinuation of oral bisphosphonate therapy for jaws. Such variables as age, sex, medications, preexisting several weeks before and after dentoalveolar surgery may be medical conditions, and individual genetic variations need warranted. Until data from clinical trials are available, the to be examined. Finally, clinical trials should be done to optimal timing and duration of such a drug holiday are determine the most effective treatment protocols for pa- somewhat arbitrary and must be weighed against the risks tients with this condition.
posed by not taking medication. If the patient's underlyingsystemic disease is stable, bisphosphonates can be with-drawn until the area of osteonecrosis heals or until clinical variables indicate disease progression.
Osteonecrosis of the jaws is a newly recognized condi- tion reported in patients treated with bisphosphonates, in particular potent aminobisphosphonates. Most cases have Clinical trials are urgently needed to address many developed in patients with multiple myeloma or metastatic issues. Can alternative dosing schedules reduce the inci- cancer, but the condition has also been identified in pa- dence of osteonecrosis while maintaining the enormous tients with osteoporosis. This article reviews the findings in benefits of these drugs? For example, once the patient's 368 cases, suggests treatment strategies, and outlines re- condition is stabilized, perhaps lower-potency, nonami- search avenues that may help us better understand and nobisphosphonates can be substituted in a maintenance treat this condition.
role (60, 70). Monitoring bone turnover markers may helpclinicians avoid oversuppression (71). A staging system can Note added in proof: An article describing this condi- be developed, possibly including serologic and imaging tion in 22 patients was recently published in the Journal of data, that more accurately determines disease severity; this Clinical Oncology: Badros A, Weikel D, Salama A, could then be used to guide treatment. Establishing criteria Goloubeva O, Schneider A, Rapoport A, et al. Osteone- for the diagnosis of early changes that precede or predict crosis of the jaw in multiple myeloma patients: clinical bone exposures would also be desirable.
features and risk factors. J Clin Oncol. 2006;24:945-52.
Prospective studies are also needed to more precisely [PMID: 16484704].
16 May 2006 Annals of Internal Medicine Volume 144 • Number 10 759
Review Bisphosphonates and Osteonecrosis of the Jaws From Brigham and Women's Hospital and Harvard School of Dental 16. Weinstein RS. True strength. J Bone Miner Res. 2000;15:621-5. [PMID:
Medicine, Boston, Massachusetts; University of Iowa College of Den- tistry, Iowa City, Iowa; and The Ohio State University College of Den- 17. Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphos-
tistry, Columbus, Ohio.
phonate-induced osteopetrosis. N Engl J Med. 2003;349:457-63. [PMID:
18. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY.
Note: This is a position paper of the American Academy of Oral and
Severely suppressed bone turnover: a potential complication of alendronate ther- apy. J Clin Endocrinol Metab. 2005;90:1294-301. [PMID: 15598694]
19. Ott SM. Fractures after long-term alendronate therapy [Letter]. J Clin En-
Grant Support: None.
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Annals of Internal Medicine
Current Author Addresses: Dr. Woo: Brigham and Women's Hospital,
Dr. Kalmar: The Ohio State University, 305 West 12th Avenue, Colum- 45 Francis Street, Boston, MA 02115.
bus, OH 43210.
Dr. Hellstein: University of Iowa, 356 Dental Science South, Iowa City,IA 52246.
W-186 16 May 2006 Annals of Internal Medicine Volume 144 • Number 10


The welfare effects of innovative pharmaceuticals

[Save eerst dit bestand als XXX(titel).doc] The welfare effects A pilot study for the Netherlands Apostolos Tsiachristas Research commissioned by the American Chamber of Commerce Pharma-ceutical Committee © Aarts De Jong Wilms Goudriaan Public Economics bv (APE) and Maastricht University Den Haag, January 2008


Deep Lamellar Keratoplastyby Intracorneal Dissection A Prospective Clinical and Confocal Microscopic Study Giorgio Marchini, MD,1 Leonardo Mastropasqua, MD,2 Emilio Pedrotti, MD,1 Mario Nubile, MD,2Marco Ciancaglini, MD,2 Arianna Sbabo, MD1 To evaluate the clinical findings, visual outcomes, and confocal microscopic corneal features of a