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Joint Bone Spine 75 (2008) 34e40

http://france.elsevier.com/direct/BONSOI/

Original article

Thirteen cases of jaw osteonecrosis in patientson bisphosphonate therapy

Marie-Helene Vieillard a,f,*, Jean-Michel Maes b, Guillaume Penel c,f, Thierry Facon d,Leonardo Magro d, Jacques Bonneterre e, Bernard Cortet a,f

a Rheumatology Department, Lille Teaching Hospital, Hospital Roger-Salengro, CHRU de Lille, Rue Emile-Laine, 59037 Lille cedex, Franceb Maxillofacial and Oral Surgery Department, Lille Teaching Hospital, Lille, France

c Odontology Department, Lille Teaching Hospital, Lille, Franced Blood Diseases Unit, Lille Teaching Hospital, Lille, Francee Breast Diseases Unit, Oscar Lambret Center, Lille, France

f IMPRT UFR 114, Group No. 4032, Pathophysiology and Treatment of Calcified Tissues, Dental School Lille, France

Received 3 November 2006; accepted 3 May 2007

Available online 31 August 2007

Abstract

Introduction: We report on our experience with 13 cases of jaw osteonecrosis in patients treated with amino-bisphosphonates.Method: Data were collected by a regional observatory for jaw osteonecrosis in northern France via letters sent to all physicians likely to managepatients with this condition. All study patients were evaluated at a multidisciplinary jaw osteonecrosis clinic between June and December 2005.Results: We identified 13 cases, in 12 women and 1 man, with a mean age of 62.6 years. Intravenous amino-bisphosphonate therapy was givenfor metastatic bone disease from breast cancer in 7 patients and multiple myeloma in 5 patients; the remaining patient was on oral alendronatefor osteoporosis. Mean treatment duration was 24 months. A history of dental extraction was found in 11 (84.6%) patients. The mandible wasinvolved in all 13 patients and the maxillary in 3 (23%) patients. Amino-bisphosphonate therapy was discontinued in all 13 patients. We suggesta classification scheme for the clinical and computed-tomography patterns seen in our patients.Conclusion: Jaw osteonecrosis is a severe complication of amino-bisphosphonate therapy. In addition to the application of published guidelines,we propose discontinuing bisphosphonate therapy whenever possible. We are evaluating our classification scheme to identify early diagnosticcriteria and/or clinical and computed-tomography outcome criteria that would improve the management of patients with jaw osteonecrosis.� 2007 Published by Elsevier Masson SAS.

Keywords: Bisphosphonate; Jaw osteonecrosis; Classification; Vitamin D deficiency; Calcium deficiency

1. Introduction

Several hundred cases of jaw osteonecrosis in patients onbisphosphonate therapy have been reported since 2003 [1e11]. Most of the patients had risk factors for secondary ostei-tis, such as advanced age, glucocorticoid therapy, treatmentwith immunosuppressants, malnutrition, and bone disease

* Corresponding author. Departement Universitaire de Rhumatologie, CHU

Lille, France. Tel.: þ33 03 20 44 44 15; fax: þ33 03 20 44 54 62.

E-mail address: mh-vieillard@chru-lille.fr (M.-H. Vieillard).

1297-319X/$ - see front matter � 2007 Published by Elsevier Masson SAS.

doi:10.1016/j.jbspin.2007.05.003

[12e18]. Whereas primary osteitis of the jaw is rare andpoorly documented, secondary osteitis or osteomyelitis ismore common and better described. The secondary bone le-sions are related to local factors such as dental disease (apicalgranuloma or periodontal disease), invasive procedures, orfractures. Bisphosphonate therapy may increase the risk ofjaw osteonecrosis.

Although bisphosphonates have been used for many yearsto treat a broad range of malignant and nonmalignant diseases,jaw osteonecrosis in patients on bisphosphonate therapy wasnot recognized until recently. Many questions remain regard-ing the pathophysiology and frequency of jaw osteonecrosis,

Fig. 1. Exposed bone and drainage tract to the skin.

35M.-H. Vieillard et al. / Joint Bone Spine 75 (2008) 34e40

as well as the role for bisphosphonate therapy in the genesis ofthe lesions. There is a need for identifying diagnostic criteriaand for defining the optimal management strategy for this pro-tean condition.

We report on our experience with 13 cases of jaw osteonec-rosis in patients on bisphosphonate therapy. Managementstrategies are reviewed. We suggest a classification schemefor the clinical and computed-tomography (CT) patternsseen in our patients. This classification scheme should proveuseful for delineating the presentations of jaw osteonecrosisand monitoring the outcomes.

2. Methods

We conducted a prospective study between June and De-cember 2005. A letter about the study was sent to all physi-cians likely to see patients with jaw osteonecrosis in theNord Pas-de-Calais region of France (oncologists, hematolo-gists, rheumatologists, urologists, radiotherapists, dental sur-geons, oral surgeons, and maxillofacial surgeons). Allpatients were evaluated at least once at the multidisciplinaryjaw osteonecrosis clinic of the Lille Teaching Hospital to con-firm the diagnosis of jaw osteonecrosis and to collect studydata. The following criteria were used to diagnose jaw osteo-necrosis: lesion exposing the bone that developed either spon-taneously or after a tooth extraction in a non-irradiated region,failure to heal despite appropriate management, bisphospho-nate therapy, and absence of local metastasis or myelomatumor.

During the study period, 16 bisphosphonate-treated patientswere seen at the jaw osteonecrosis clinic. Among them, 3 wereexcluded because a local cause was found (1 case each ofbreast cancer metastasis, myeloma lesion, and chronic peri-odontal infection without osteitis). Of the remaining 13 pa-tients, 7 were referred to the jaw osteonecrosis clinic beforetreatment and 6 were referred after failure of several treat-ments. These 13 patients were included in our jaw osteonecro-sis regional observatory and monitored longitudinally. Foreach patient, the following data were collected: prior medicalhistory, cardiovascular risk factors (hypertension, diabetes, hy-percholesterolemia, history of angina and/or myocardial in-farctions and/or peripheral occlusive arterial disease),tobacco and alcohol consumption, dental status, history oftooth extraction or other dental procedure prior to the diagno-sis of jaw osteonecrosis, reason for bisphosphonate therapy,and time on bisphosphonates. Serum levels of calcium and25-OH-vitamin D and urinary calcium excretion were mea-sured at the first visit. An orthopantomogram and a dentalCT were obtained at the first visit at the jaw osteonecrosisclinic in all 13 patients and later on as dictated by the clinicalcourse in 10 patients.

3. Results

We identified 13 cases, in 12 women and 1 man, witha mean age of 62.6 years. A sinus draining to the skin wasnoted in 2 (15%) patients, a purulent discharge to the oral

cavity in 9 (69%) patients, and exposed bone in 12 patients(Fig. 1). The reason for bisphosphonate therapy was metastaticdisease from breast cancer in 7 patients, myeloma in 5 pa-tients, and osteoporosis in 1 patient.

Table 1 shows the types of bisphosphonates used, treatmentdurations, and cumulative dosages. Bisphosphonate therapywas given intravenously in 12 patients; the remaining patientreceived oral alendronate (10 mg/day then 70 mg/week) forosteoporosis. At the time of the diagnosis of jaw osteonecrosis,10 patients were taking zoledronic acid, 2 patients were takingpamidronate, and 1 patient was taking alendronate.

Mean time from treatment initiation to the diagnosis of jawosteonecrosis was 26.2 months in the patients given only zole-dronic acid, 26 months in the patient who received only pa-midronate, 46 months in the patient given clodronatefollowed by pamidronate, and 29 months in the patients givenpamidronate followed by zoledronic acid. Overall, mean timefrom bisphosphonate initiation to symptom onset was 17.8months (median, 13 months; range, 5e48 months) in the pa-tients treated intravenously (Table 2). Mean cumulative timefrom the initiation of intravenous treatment (zoledronic acidand/or pamidronate) to symptom onset in the patients givenseveral amino-bisphosphonates was 24.3 months (median, 19months; range, 11e59 months). In the patient treated with

Table 1

Underlying diseases, types of bisphosphonates, treatment durations, and cumulative dosages in 13 patients with jaw osteonecrosis

Underlying

disease

BP Time on

tt, mo

Total

dose, mg

BP Time on

tt, mo

Total

dose, mg

BP Time on

tt, mo

Total

dose, mg

BP Time on

tt, mo

Total

dose, mg

Osteoporosis AL 60 18 200

BM PAM 26 2340BM ZOL 10 40

BM ZOL 13 52

MM ZOL 20 80

BM ZOL 33 132BM ZOL 21 84

BM ZOL 60 240

26.2 105MM CLO 7 218 400 PAM 61 5490

MM PAM 44 3960 ZOL 24 96

BM CLO 14 386 400 PAM 4 360 ZOL 11 48

MM CLO 27 1 454 400 PAM 5 450 ZOL 15 60MM CLO 15 468 000 PAM 15 1350 ZOL 19 76

Mean 15.75 631 800 25.8 2325 22.6 90,8 60 18 200

The bisphosphonate used at the diagnosis of jaw osteonecrosis is underlined.

BM, bone metastases; MM, multiple myeloma; mg, milligram; mo, months; BP, bisphosphonate; CLO, clodronate; AL, alendronate; ZOL, zoledronic acid; PAM,

pamidronate; and tt, treatment.

Table 2

Median and mean times from initiation of intravenous amino-bisphosphonate

therapy to symptom onset

Bisphosphonate Time from IV

treatment initiation

(bold type)

Time from IV

amino-BP treatment

initiation

PAM 11 11

ZOL 5 5

ZOL 11 11

ZOL 14 14

ZOL 24 24

ZOL 21 21

ZOL 48 48

CLOþ PAM 41 41

PAMþZOL 15 59

CLOþ PAMþZOL 2 15

CLOþ PAMþZOL 12 17

CLOþ PAMþZOL 10 25

Median time 13 19

Mean time 17.8 24.25

PAM, pamidronate; ZOL, zoledronic acid; CLO, clodronate; IV, intravenous;

and amino-BP, amino-bisphosphonate.

36 M.-H. Vieillard et al. / Joint Bone Spine 75 (2008) 34e40

oral alendronate for osteoporosis, the symptoms started 60months after treatment initiation.

None of the patients had chronic alcohol abuse, 4 (31%)were smokers or ex-smokers, 8 (61.5%) had a past or presenthistory of glucocorticoid therapy, 10 (77%) had a history ofchemotherapy, and 5 (38.5%) had received radiation therapyto fields that did not include the jaw or maxillary bones. All7 women with breast cancer had a past or present history ofhormone therapy. At least 1 cardiovascular risk factor wasidentified in 8 (61.5%) patients. The dental status was poorin 9 (69%) patients, and 3 (23%) patients were edentulous.A recent history of tooth extraction before the diagnosis ofjaw osteonecrosis was identified in 11 (84.6%) patients.

Urinary calcium excretion was less than 100 mg/24 h (thelower limit of the normal range at our laboratory) in 10(80%) patients. Serum vitamin D was less than 20 ng/L in 8(60%) patients. Hypercalcemia was not a feature in any ofthe patients. In addition to the jaw involvement, the maxillarywas involved in 3 (23%) patients. CT showed bony sequestersin 6 (46%) patients (Fig. 2) and a double-contour image in 7(54%) patients (Fig. 3).

Surgery was performed in 12 patients. The procedure con-sisted in curettage in 11 patients, including 6 who had removalof a bony sequester. In the remaining patient, partial resectionof the mandible was required. In most of these cases, surgerywas performed early in the course of jaw osteonecrosis, priorto inclusion in our observatory. Histological studies of the op-erative specimens confirmed the diagnosis.

Penicillin therapy was used in all 13 patients. CT findings(Fig. 3) and the appearance during surgery suggested infectionaround the bone, between the sclerotic cortex and periostealbony appositions. Hyperbaric oxygen therapy was used preop-eratively in 1 patient with severe suppuration that failed to re-spond to antibiotic therapy; after surgery, the lesion healed andno further suppuration occurred. Amino-bisphosphonate

therapy was stopped initially in 12 patients and after 1 yearin 1 patient with progressive jaw osteonecrosis. Clodronatewas substituted for the amino-bisphosphonate in 3 patients.

Mean follow-up duration was 13.8 months (range, 1e44months). Patients were seen at 3-month intervals for examina-tion of the oral cavity and, when clinically indicated, dentalCT. The course of the jaw lesions was unfavorable in 8(61.5%) patients. Healing of the jaw lesions occurred in the re-maining 5 patients; however, follow-up was less than 2 monthsin 3 of these patients. Time to healing in the remaining 2 pa-tients was 4 months.

In 1 patient who took zoledronic acid for 13 months and un-derwent surgical treatment to remove a bony sequester 12months after treatment discontinuation, vascularization of

Fig. 2. Mandible. Marked bony sclerosis with formation of a bony sequester

(arrow).

37M.-H. Vieillard et al. / Joint Bone Spine 75 (2008) 34e40

the newly formed peripheral periosteal bone was noted duringsurgery (Fig. 4).

Tables 3 and 4 show the various clinical and CT patternsseen during the 7-month study period. Based on these patterns,we defined various stages of the disease and we monitored thecourse in our patients.

4. Discussion

The frequency of jaw osteonecrosis among patients treatedwith bisphosphonates has ranged across studies from 1% to8% [19e21]. In a retrospective study of 4000 patients, jawosteonecrosis occurred in 0.83% of cases overall, 1.2% of pa-tients with breast cancer, and 2.8% of patients with myeloma.In the only prospective study reported to date, the frequency ofjaw osteonecrosis was 6.7% [20].

Although maxillofacial and oral surgeons are familiar withradiation-induced osteonecrosis of the mandibular and maxil-lary bones and with osteomyelitis or osteitis secondary to

Fig. 3. Mandible of a patient on bisphosphonate therapy. Sclerosis of trabec-

ular bone and double-contour image (black arrow) separated from the cortex

by a thin lucent line (white arrow), corresponding to the site of infection.

Fig. 4. (a) Computed-tomography of the mandible showing a double-contour

image and a bony sequester. (b) Intraoperative findings: the peripheral bone

is well vascularized and a bony sequester is visible deep in the lesion. (c)

Bony sequester removed from the lesion.

infection or trauma, the pathophysiology of jaw osteonecrosisin patients taking bisphosphonate therapy remains enigmatic.Similar clinical and surgical findings were reported in the19th century in match-factory workers exposed to white phos-phorus (as opposed to red phosphorous) [22]. White phospho-rus may accumulate in the oral cavity, either because the jawbones are highly exposed or because they exhibit specific met-abolic characteristics [23]. Bisphosphonate accumulation inthe jaw bones may be related to bone turnover stimulationby chewing or to continuous bony remodeling around the peri-odontal ligaments [24]. However, no objective data are avail-able to substantiate these hypotheses. Other distinctivecharacteristics of the jaw bones [25] include a membranous or-igin, high density and low vascularity of the mandibular cor-tex, and a paucity of red marrow. In addition, reduced blood

Table 3

Clinical patterns in patients with jaw osteonecrosis

Classification Clinical features

A No exposed bone

A bis No exposed bone; presence of suppuration and/or drainage

tract

B Exposed bone

C Exposed boneþ suppuration

D Exposed boneþ suppurationþ drainage tract to the skin

s Pain, heaviness, dysesthesia, numbing of the jaw

as No symptoms

38 M.-H. Vieillard et al. / Joint Bone Spine 75 (2008) 34e40

flow and bony remodeling due to bisphosphonate therapy mayimpair healing after tooth extraction or trauma. Finally, an ex-perimental study in rats showed lower blood flows in the skulland mandible compared to the pelvis, tibia, and fibula [26].

Paradoxically, bisphosphonates are used to treat primary os-teomyelitis of the jaw [27e30] and avascular osteonecrosis ofthe femoral head [31]. Their effects on blood vessels [32,33]may modify the relationship between blood supply and boneremodeling. The life span of osteoclasts and osteocytes hasbeen estimated at about 150 days [24]. By inhibiting osteoclastactivity, bisphosphonates may prevent the resorption of themineral matrix and, therefore, the release of growth factorsand cytokines contained in the matrix. The result is failure ofinduction of new osteoblasts from stem cells, loss of osteoncells, osteon necrosis, and involution of intra-osseous bloodvessels. The resulting avascular bone cannot heal if a spontane-ous or induced break occurs in the overlying mucosa [24].

Osteonecrosis of the jaws is a feature of several rare bonediseases including osteopetrosis [34,35] and pyknodysostosis[36e39], which are characterized by diffuse osteosclerosis.Thus, osteonecrosis may occur when remodeling of the jawbones is inadequate for genetic, constitutional, or iatrogenicreasons. Should this be the case, resorption-inhibiting drugsthat will be introduced in the future would be expected to in-duce jaw osteonecrosis in high-risk patients.

Both osteopetrosis and bisphosphonate therapies are char-acterized by diffuse bony sclerosis. However, osteonecrosis as-sociated with bisphosphonate therapy is confined to the jaws.This fact suggests a role for local triggering factors, whichmay be traumatic or infectious in nature. Immunosuppressantsand glucocorticoids promote the development of infections. Inour experience, infection occurs between the sclerotic cortex

Table 4

Computed-tomography patterns in patients with jaw osteonecrosis

Computed-tomography findings

0 No osteosclerosis

I Osteosclerosis

II Osteosclerosisþ double-contour

III Osteosclerosisþ sequester with

no double-contour

IV Osteosclerosisþ sequesterþ double-contour

L Limited involvement

(confined to one side)

E Extensive involvement

(extension to the other side)

and bony appositions produced by the hypertrophic perios-teum. Infection at this site corresponds to the double-contourimages seen by CT (Fig. 3). The sclerotic bone is hard, avas-cular, and low in trabeculae, mimicking the appearance of os-teopetrotic bone [2,23,24].

The age and gender distributions of our patients are conso-nant with previous data [1,2]. The predominance of womenmay be ascribable to the high rate of breast cancer and tothe prolonged survival of patients with this disease, even afterthe development of metastases.

Our diagnostic criteria for jaw osteonecrosis included ex-posure of the bone and absence of another cause such as localmetastasis or myeloma. However, there is no consensus re-garding the definition of jaw osteonecrosis. The severity ofthe symptoms, extent of the lesions, and distribution to oneor both sides varies considerably within and across patients.Patients report a broad range of symptoms, among which dys-esthesia and paresthesia are common. Pain is an inconsistentfeature that is difficult to interpret, as it may originate eitherin the teeth or in the underlying osteonecrotic lesion. Painmay prompt extraction of the tooth before the bone becomesexposed. We suggest a classification scheme (Table 3), whichwill be used to monitor our patients. Stage A is defined as painantedating bony exposure. CT abnormalities such as bonysclerosis may be present in patients with stage A disease.

We are currently evaluating our classification scheme. Atpresent, the prognostic significance of each clinical/CT stageis unknown. Furthermore, the timing of the development ofCT abnormalities remains to be determined. We do not knowwhether the bony sclerosis seen on CT scans on our patients isan early manifestation of jaw osteonecrosis or merely a signof bisphosphonate impregnation. These issues are under study.

Previously described risk factors for jaw osteonecrosis werepresent in most of our patients [1,2,12,17,19,23,24]. Thus,smoking was noted in 31% of patients, glucocorticoid therapyin 61.5%, chemotherapy in 38.5%, and a poor dental status in69%. The high prevalence of cardiovascular risk factors(61.5%) is probably ascribable to the advanced age of the pa-tients. Vitamin D deficiency was a common feature. Vitamin Ddeficiency is prevalent in the general population and consti-tutes a risk factor for periodontal disease [40e42], infectionsand jaw osteonecrosis. Therefore, vitamin D supplementationshould be given when needed.

Amino-bisphosphonates were used on our patients, as inmost of the previously reported cases. One case has been re-ported with risedronate therapy [2] and one with ibandronatetherapy [8]. The non-amino-bisphosphonate clodronate wasassociated with a case in Germany [9], although a pharmacovi-gilance study found no further cases with this drug [43]. In ourstudy and in previous reports [3e12,19], the mean time to thedevelopment of jaw osteonecrosis was 24 months in patientsgiven intravenous amino-bisphosphonate therapy (pamidro-nate and zoledronic acid) and 60 months in the patient treatedwith alendronate. Treatment duration is a risk factor for jawosteonecrosis. Other risk factors may include the potency ofthe bisphosphonate, the cumulative dosage, dental extraction,and underlying disease [19].

Table 5

Position statement issued by the GRIO

Jaw osteonecrosis and bisphosphonate therapy: position statement by the

GRIO (Osteoporosis Research and Information Group)

The first complication of long-term high-dose bisphosphonate therapy used to

treat bone metastases or myeloma was identified recently: jaw osteonecrosis.

Reports of this complication have disconcerted oral and dental surgeons.

The GRIO would like to emphasize a number of points.

� The lesions are confined to the jaw bones, which are exposed to consider-

able loading associated with chewing and to the abundance of microorga-

nisms present in the oral mucosa.

� The frequency of jaw osteonecrosis is difficult to determine: it ranged from

0.8% in pharmacovigilance studies to 10% in retrospective studies with major

sources of bias.

� The overwhelming majority of cases reported to date occurred with pami-

dronate or zoledronic acid, two potent amino-bisphosphonates that inhibit

both osteoclast activity and angiogenesis.

� Patients at risk are patients with malignant osteolytic disease who receive

prolonged intravenous bisphosphonate therapy in high cumulative doses.

� About 15 cases have been reported in patients treated for osteoporosis. This

number is tiny given that several million women are currently treated and

that bisphosphonates have now been used for over 10 years.

What can we tell our patients today?

� The risk/benefit ratio of bisphosphonate therapy for bone metastases and

myeloma is clearly favorable, and bisphosphonates should continue to be

used in these indications.

� A careful evaluation of the patient’s oral cavity and dental status should be

performed prior to initiating bisphosphonate therapy for malignant bone

disease.

� The risk is far lower in patients with osteoporosis.

� Nevertheless, patients should be reminded that regular oral hygiene and

dental care is a matter of common sense.

� The recommendations issued by the AFSSAPS should be followed; treatment

should be given for 4e5 years, after which the need for further treatment

should be assessed.

Last updated on September 4, 2006

39M.-H. Vieillard et al. / Joint Bone Spine 75 (2008) 34e40

Amino-bisphosphonate therapy was stopped in 12 of our 13patients. In 3 patients, the non-amino-bisphosphonate clodro-nate was given instead. It has been suggested that treatmentdiscontinuation may be useless, given the persistence overtime of amino-bisphosphonates within bone tissue. However,amino-bisphosphonates may exert short-term effects, most no-tably on the blood vessels. There is no consensus about the ap-propriateness of discontinuing bisphosphonate therapy whenjaw osteonecrosis develops. Neither is there any agreementon the need for, or optimal duration of, interrupting bisphosph-onate therapy when invasive dental procedures are required.Because dental extractions should be avoided during bi-sphosphonate therapy, dental problems should be dealt withbefore treatment initiation.

Neither body weight nor psychological status was evaluatedin our patients. However, the development of jaw osteonecro-sis was followed by appetite loss in 2 patients and recurrentdepression in 1 patient. Thus, jaw osteonecrosis can have ad-verse functional, nutritional, and psychological effects. On theother hand, bisphosphonate therapy reduces the incidence ofbony events, thereby improving the quality of life of the pa-tients. Therefore, the appropriateness of resuming amino-bi-sphosphonate or non-amino-bisphosphonate therapy shouldbe evaluated based on the risk/benefit ratio.

The outcome of jaw osteonecrosis is unpredictable at pres-ent. In our study, in which the mean follow-up was 14 months,no relation was found between the course of the underlyingdisease and the course of the jaw osteonecrosis. In 1 patientwho received zoledronic acid for 13 months then underwentsurgery 1 year after treatment discontinuation, the newlyformed peripheral periosteal bone was seen to be vascularized(Fig. 4). Thus, the resorption of the bisphosphonate-impreg-nated sclerotic bone and its extrusion as a bony sequestermay constitute a healing mechanism. This hypothesis requiresconfirmation.

Few cases of jaw osteonecrosis have been reported in patientstreated for postmenopausal osteoporosis. There have been 170cases with alendronate (0.7 cases/100 000 patient-years), 12cases with risedronate, and 1 case with ibandronate [44]. Withalendronate, jaw osteonecrosis is less severe and occurs aftera longer treatment time (60 months in our patient, which is theusual duration of bisphosphonate therapy for osteoporosis).Nevertheless, guidelines for preventing jaw osteonecrosisshould be carefully followed. More specifically, the patient’sdental status should be evaluated before treatment initiationand monitored at a frequency determined by the dentist ona case-by-case basis. In France, the AFSSAPS (French Agencyfor Food and Healthcare Product Safety) issued recommenda-tions in July 2005 (Table S1; see the supplementary material as-sociated with this article online) and the GRIO (OsteoporosisResearch and Information Group) made a number of comments(Table 5), most notably regarding patients with osteoporosis.

As indicated in published recommendations (www.jopasco.org), the prevention of jaw osteonecrosis requires correction ofvitamin D and calcium deficiencies. In patients with establishedjaw osteonecrosis, we suggest that amino-bisphosphonate ther-apy be discontinued whenever possible. Prospective studies

aimed at elucidating the pathophysiology of jaw osteonecrosisand obtaining accurate data on the risk/benefit ratio ofamino-bisphosphonates are needed. Such data would help todetermine whether changes in the dosage and prescription mo-dalities are in order.

Acknowledgments

We are grateful to the maxillofacial surgeons, hematologists,oncologists, radiation therapists, rheumatologists, urologists,and dental surgeons in the Nord Pas-de-Calais region who arehelping us to centralize data on patients with jaw osteonecrosis.

Supplementary material

Supplementary data (Table S1) associated with this articlecan be found at http://www.sciencedirect.com, and atdoi:10.1016/j.jbspin.2007.05.003.

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