ORAL & Implantology - Anno II - N. 4/2009

case

rep

ort

26

Introduction

The bisphosphonates represent an important class ofdrugs, which are useful for the treatment of meta-bolic and oncologic pathology involving the appa-ratus of the skeleton. Their mechanism of action isbased on the capability of blocking the bones reab-sorption mediated from the osteoclasts. Common-ly these molecules are incorporated inside the os-teoclasts determining a serious functional alterationto the cellular apoptpsis. The most common bis-phosphonates used in therapy are: alendronate,risendronate, ibandronate, zolendronate andpamidronate. The first three are used for the pre-vention and the treatment of the osteoporosis and aretaken per mouth whereas pamidronate and zole-dronate have an essential role in the prevention ofthe bony complications and in the treatment of se-

vere hypercalcemia associated to multiple myelomaor to bony metastasis followed to mammary or pro-static carcinoma and are generally taken intra-venous.Since 2003, the year when the first case of os-teonecrosis associated to the use of bisphosphonatesappeared (1), it’s now happening more often to no-tice a similar collateral effect as a consequence ofbony traumatisms, like a simple dental extraction,in patients treated with these kind of drugs. The os-teonecrosis can be linked to a wide variety of localand systemic factors like emoglobino-pathologies,presence of antibodies anti cardiolipin and defectsof fibrinolytic, gas embolisms, alcoholism, systemicerythematous lupus and corticosteroid therapies, ca-pable of compromise the vascularization of the bone. Before then, described for the first time by Marx andStern in 2002, the osteonecrosis of the maxillariescaused by bisphosphonates was defined as a conditionthat involves the presence of bony exposition in

OSTEONECROSIS CAUSEDBY BISPHOSPHONATES: A CLINICAL CASED. SPINELLI, G. DE VICO, M. BONINO, A. BARLATTANI JR, P. BOLLERO, A. BARLATTANI

University of Rome “Tor Vergata”, School of Dentistry, President: Prof. A. Barlattani

SUMMARYOsteonecrosis caused by Bisphosphonates: a clini-cal caseThe osteonecrosis of the maxillares caused by bisphos-phonates (OMB) either wrongly known or not reconised inearlier times became nowadays very important among thedentists and maxillo-facials surgeons because of the po-tential serious consequences that might bring in the oralcave of the patients, who are suffering already for theirbase condition. The goal of our work was to verify if a deeptreatment and an attentive observation with a close follow-up can bring to the resolution of serious cases of os-tenecrosis of the maxillares by bisphosphonantes. Al-though without a statistic value our case report put the ba-sis for a chance to execute wider casistic studies.

Key words: osteonecrosis, bisphosphonates.

RIASSUNTOOsteonecrosi da Bifosfonati: presentazione di un casoclinicoL’osteonecrosi dei mascellari da bifosfonati (OMB) dappri-ma misconosciuta o non riconosciuta è divenuta attual-mente di preminente importanza tra i clinici odontoiatri emaxillo-facciali per le potenziali gravi conseguenze chepuò avere nel cavo orale dei pazienti, spesso già seria-mente sofferenti per la loro condizione di base. L’obiettivodel nostro lavoro è stato quello di verificare se un appro-fondito trattamento ed un’osservazione scrupolosa con unserrato follow-up possono portare alla risoluzione di casianche gravi di osteonecrosi dei mascellari da bifosfonati.Pur non avendo valore statistico il nostro case report ponele basi della possibilità di eseguire studi casisitici più ampi.

Parole chiave: osteonecrosi, bifosfonati.

© CIC

Ediz

ioni In

terna

ziona

li

mandibular or maxillary site, which persists frommore than 8 weeks in a patient which took or is tak-ing bisphosphonates and with negative anamnesis forradiotherapy of maxillaries. The same illness wasprobably observed more than 100 hundreds years agoas “industrial occupational” illness, called chemicalosteonecrosis by phosphor or “phossy jaw”. As re-ported, the miners of the factories producing match-es in USA and UK developed persistent bony ex-position just in the oral cave, linked to the time theywere spending in the miners and factories (22). Consequently for this class of drugs it became nec-essary to do an accurate pharmacological anamne-sis (present, past or future), in order to reduce themost the risk of post-traumatic osteonecrosis of max-illaries, doing at the same time a preventive actionwhich can avoid a such dramatic possibility.

Clinical and epidemiologicalaspects

In the 70-80% of the cases, the osteonecrosis of themaxillaries caused by bisphosphonates is manifestingwith a missed healing or with a late process of heal-ing of the maxilla or the mandible after a dental ex-traction or after any other kind of oral surgery (2). The early steps of the pathology consists of the miss-ing of symptoms and absence of radiological alter-ationsi; in this phase the pain can be caused by someinfections of the portions of the bone that is exposed.In the 25-40% of the cases, the osteonecrosis of themaxilliares happens on his own without any corre-lation to particular traumas (3). In these cases the firstand most common symptoms is manifested with abad sensation in the mouth with pareshesia and sore-ness. It happens then a gradual alteration of the oralmucosa with a formation of persistent ulcers. In thisphase it can be manifested a strong pain caused byinfection of the portion of the bone which is necro-tised inducted by the oral bacterial flora. Since thesesymptoms arrive before the proper osteonecrosis,their identification is essential to the goals of the pre-vention. Normally, the mandible and the maxilla arethe only bones involved in the osteonecrosis causedby bisphosphates; in the 70% of cases the effect ismanifesting principally in the mandible, at the lev-

el of the region of the molars, whereas in the 30%of the cases the osteonecrosis is manifested in theposterior maxillaries region; just in very few casesthe alterations involves both the bones (4). The in-volving of the maxilla represents a noticeable dif-ference between the osteonecrosis cuased by bis-phosphonates and the osteoradionecrosis, a form ofosteonecrosis which is secondary at radiotherapy forthe treatment of the carcinoma in the head and theneck. In the 95% of the cases this form of os-teonecrosis involves just the mandible (5).It is not still clarified who are the patients which arethe most on a risk for the osteonecrosis of the max-illa. Till now, the complication was observed prin-cipally in the patients with tumors treated with bis-phosphonates intravenous. The cancer and the useof the chemiotherapies for systemic way are in factconsidered the most important co-morbose condi-tions. There were reported some cases of patientswhich have manifested osteonecrosis not linked tocancer; among these, 19 manifested osteoporosis (17were treated with alendronate, 1 with risedronate and1 with alendronate and zoledronate) and 9 were af-fected from Paget disease (4 were treated with al-endronate, 4 with pamidronate and 1 withpamidronate and alendronate). Anyway, it is with any probability a bad valuationof what is the real importance of this complicationin patients treated with bishosphonates taken bymouth. In fact, in a recent review made by the Amer-ican Dental Association, the cases of osteonecrosisassociated at the oral use of bisphosphonates on aworldwide level resulted 170 for the alendronate, 12for the risedronate and 1 for the ibandronate. For what it concerns about the patients treated withbisphosphonates taken by mouth the two factorswhich add more risk for the development of os-teonecrosis are the following: the duration of the treat-ment and the association at the same time with cor-ticosteroids and in particular with the prednisone (19). In relation to the type of dental procedures, in 60%of cases of osteonecrosis is manifesting after den-tal extractions (6). Cases of osteonecrosis were no-ticed on holders of removable incongruous prosthesis,of traumas on bony exostosis, after the surgeon pro-cedures for the insertion of the implants (7). Therewere even some cases of post-endodontics os-teonecrosis (8).

ORAL & Implantology - Anno II - N. 4/2009 27

case report

© CIC

Ediz

ioni In

terna

ziona

li

Patogenetic mechanism

In the past, the bisphosphonates were called diphos-phonates: the modification of the terms sometimescaused confusion. The bisphosphonates are linkedto the complex pyrophosphates, which were used asanti-tartar agents in the toothpastes and as os-teospecific radionuclides in bone scintigraphy withmedium of contrast. The affinity for the sites of the active bone changeis clear by looking the increment of the uptake onthe plates of coltura, in the neoplastic localisations,in the bone grafts and in the scintographies of nor-mal bones of the superior maxillaries and of themandible. The pyrophosphates are easily degradedwith a process of hydrolysis and then eliminated. Be-cause of a substitution with an atom of carbon of theatom of oxygen in the principal axes of the molecule,the bisphosphonates are totally resistant to the hy-drolytic scission, which is followed by their incre-ment in the bone tissue and their extremely long half-life. Moreover, the substitution of the lateral chainof nitrogen on the central atom of carbon incrementsthe power and probably the toxicity. Till now, it isknown that just the bisohosphonates including ni-trogen can cause the osteonecrosis of the maxillar-ies. The main biological action of all the bisphos-phonates is the inhibition of the reabsorption and ofthe turnover and renovation of the bone tissue, whichnaturally reduce the silky levels of calcium. The anti-osteoclastic and anti-reabsorption action is made bythe effect of inhibition on the osteoclastics, ofwhich the bisphosphonates cause in fact the irre-versible cells death. After the taking one of the oralbisphosphonates with less toxicity by vein or bymouth, the drug links quickly to the mineral crys-tals of the whole bone tissue. After several doses itfill the bone matrix. During the normal bone re-modelling the osteoclastics reabsorb the mineralisedbone tissue and the bisphosphonate is introduced intothe cell; the effect of the drug is similar of the iso-prenoid diphosphates lipids. This isoprenoid lipidsare essential for the enzymes which have a preven-tive function to the apoptosis of the osteoclastis. Onthe microscope you can observe that the osteoclas-

tics lose their usual orletto, they disappear from thebone surface and they have a necrosis. Without thebone reabsorption and the release of the proteins in-ducing the osteogenesis, the fix bone is not removedand the new osteoid substance is not created. The oldbone, then, remains present ahead of its pro-grammed vitality. Since the osteocyte is not an im-mortal cell, it will have a necrosis leaving there anot vital bone. The function of the osteocyte is notthe bone neo-formation (which is function of the os-teoblasta instead), but the acting like a mecca-nocettore in order to maintain the mineral matrix ofthe existent bone. So, if the osteocyte doesn’t pro-vide the control of the normal bone remodelling, amore than enough production of mineral matrix iscreated, which is a factor that contributes to the os-teonecrosis caused by bisphosphonates since this lastones are toxic for the osteoclasts and stop the boneturnover, represent a perfect example of paradox bi-ological situation and with no way out. The incre-ment of the bosphosphonates in the bone, in particularin the maxillaries bones, is not reversible for theirtoxic effect on the osteoclasts, which goes up withevery dose. So, the bone toxicity of the bisphos-phonates depends from both the dose that is takenand the duration of the therapy.The bisphosphonates prevent the bone reabsorptionthrough the inibition of the osteoclastic activity whichhappens with the involvment of different mechanisms(9-10-11-12).Inibition of the development of the osteoclasts bymonocytes. Increment of the apoptosis of osteoclasts. Prevention of the development of the osteoclasts andtheir using from the bone marrow precursors. Stimulation of the factor of inibition of the osteo-clasts. Reduction of the osteoclastic activity through an ef-fect on the cell cytoskeleton. Recently some anti-angiogenetic characteristicswere described for these drugs (13). The result is adeep suppression of the bone turnover and, with thetime passing by, reduction or stopping of the boneremodelling. The bone which becomes fragile willbe incapable to repair the physiological microfrac-tures which are caused every day in the maxilla orthe mandible by the strength the chewing acts aremade with. Dixon and Coll. (21) documented the ve-

ORAL & Implantology - Anno II - N. 4/2009

case

rep

ort

28

© CIC

Ediz

ioni In

terna

ziona

li

locity of the bone remodelling in different sites andthey found that the alveolar crest is remodelled witha velocity which is 10 times superior than the oneof the tibia, 5 times superior to the one of themandible at the level of the mandible canal and 3.5superior to the one of the mandible in the corre-spondence of the inferior border. As result, the alve-olar bones of the maxillaries have a much elevateduptake of bisphosphates which are concentrated inthis point very quickly and in a good quantity. Thisstudy demonstrated as well that the maintaining ofthe alveolar bone structure depends more than anyother corporeal bone of the adult skeleton from theprocesses osteoclastic of reabsorption-rimodellingand renovation. The particular collocation of the os-teonecrosis inducted from bisphosphonates in the oralcavity can be attributed to the exposition of these bonestructures to the environment through the gum sul-cus, which can facilitate the infection of the bone andthe progression to osteomyelitis. The particular con-formation of the oral cavity allows to explain whya wide number of cases are associated to dental ex-tractions or to other invasive procedures, which aresituations in which the risk for infection and the ne-cessity of reparations and remodelling of the boneare major.

Prevention - Therapy

The evaluation of the risk starts from a good anam-nesi, the next level would coincide with the effec-tuation of a scrupulous clinical exam and the analy-sis of radiographic exams. In this specific case, par-ticular attention has to be dedicated to the observa-tion of the molar elements that might present pre-vious signs of toxicity for the bone tissue, like thespread sclerosis of the alveolar bone, of the stronglamina and the opening of the area of the periodontallink. An evident mobility to the dental elements notsecondary to the reabsorption of the alveolar boneand deep algici synthoms without evident odonto-genic link might be dependent to a meaningful ac-tion of toxicity of the bisphosphonate. A thirdmodality for the evaluation of the risk consists of thedosage of the sierologic mark of the bone changing

CTX, which results approximately linked to the sys-temic soppressione of the renovation of the bone tis-sue depending from the action of the bisphosphonate.The inferior values at 100 pg/mL can be associatedto a high risk of osteonecrosis of the maxillaries. TheGeneral Congress of the Osteoporosis of the HIN ar-rived to the conclusion that the marker of the boneturnover can’t substitute the exams finalised to theevaluation of the mineral bone density BMD (20).Before starting the therapy with bisphosphonates or,when it’s not possible, at the maximum within thefirst 3 months at the start of the treatment, it shouldbe made a screening of the mouth and evaluated thepresence of factors of local or systemic risks. So itwill be opportune to take all the elements out withuncertain prognosis, to solve all the problems of in-fective nature through oral igene appointments, roothscailing associated or not to the use of antisepticsolutions. So it will be opportune paying the max-imum attention to the situations that can configurea trauma (control and eventual corrections of re-movable incongruous prosthesis, extraction of teethwhich are partially included) using protocols usuallyapplied on patients which are going to have radio-therapy on head-neck area or a transplantation of bonemarrow. In case the therapy with bisphosphonatesis started from more than 3 months, it is advised tonot proceed by extractions, swapping tem withcanalar therapies and eventual “coronations” or“decoronations” of the compromised elements.Where it’s necessary execute some extraction, it hasto be limit the bone trauma to its maximum puttingat the same time an antibody therapy with wide spec-trum for a long time (es. Amoxicilline per mouth, 2-3 gr per day for 21 days) associated with clorexid-ina 0,12%, twice per day. In the extreme case inwhich the osteonecrosis is already there, the thera-peutic approach can be represented with the takingoff of the portions of necrotic bones (modest se-questrectomie and surgeon curettage) associated toirrigations with antiseptic or antibody solutions. Thesesteps are accompanied with a long systemic antibodytherapy (monotherapy es.: amoxicillina or therapycombined adding tetracycline or metronidazole).Nowadays the iperbaric therapy, instead, didn’t of-fer good results, like it happens instead in the cas-es of osteonecrosis of radiotherapy, because thepatophisiological mechanisms at the base of the two

ORAL & Implantology - Anno II - N. 4/2009 29

case report

© CIC

Ediz

ioni In

terna

ziona

li

illnesses are completely different. A strategy finalisedto the reduction of the incidence of osteonecrosiscaused by bisphosphonates consists of the adoption,by the patient, of a regime of intermittent treatmentof the drug which is indicated for the therapeuticneeds of the patient and that includes an often fol-low-up. It was an evident result that the actual in-dication of the utilisation of bisphosphonates is basedon quantitative evaluations with BMD at the level ofthe femur, basin and lumbar vertebrate bodies; butthe effect of the bisphosphonates in the districts ofmaxillaries bones, since it’s more than in the districtof reference, the result is that the same maxillariesreceive a relative extra-dosage of the drug. In oth-er words a therapeutic dose which is indicated forfemur, basin, vertebrates and long bones would beactually toxic for the maxillaries. With the suspen-sion of the therapy, there can be as well cases of heal-ing and important improvement of the conditions ofbone exposition, indicating the fact that the popu-lation of the precursors of the osteoclasts of the bonemarrow can generally regenerate. The removing op-erations of detritus of osteonecrotic areas, have beensuccessful in cases where there was a suspension ofthe treatment from 6 months to one year.

Clinical case

The case was represented by a 60 years old, no-smok-er, African woman affected by serious osteoporosisin pharmacologic treatment with alendronate permouth. The objective exam was putting in evidenceon the level of the III quadrant an important dehis-cence of the mandible alveolar mucosa with areasof bone exposition associated to pain and pyrosis(Figs. 1, 2).After ulterior radiographic exams (Figs. 3 and 4) andconsidering the pharmacologic anamnesis positiveto the bisphosphonates it was clear the conclusionof a diagnosis of osteonecrosis of the maxillaries. So,following the pharmacologic protocol coded by Marxand Stern in 2002 it was put under antibody pro-phylaxis and, with the patient in “therapeutic holi-day from the drug”, under a attentive surgery curet-tage of the area of the necrosis (Figs. 6-8) and to the

parallel avulsion of the dental elements involved inthe pathological process (Fig. 10).After a follow up of about 6 months (Figs. 12-14)here was the total healing of the tissues, this resultencouraged our studies to wider cases statistics.

ORAL & Implantology - Anno II - N. 4/2009

case

rep

ort

30

Figure 1Intra-oral view of the osteonecrosis area.

Figure 2Intra-oral view of the osteonecrosis area.

© CIC

Ediz

ioni In

terna

ziona

li

Conclusions

Apparently, the long term bioavailability (14) (it iscalculated that its permanence could arrive till 12years after its suspension) and the sistemic absorpionof the aminobisphosphonates (15) makes useless thesuspension of their treatment in patients who areclearly affected by osteonecrosis of the maxilla. Butit was suggested that, in patients who need to havean oral surgery and, waiting for a protocol of uni-versal work, the suspension of the therapy with bis-phosphonates, when it’s possible, is thought useful

ORAL & Implantology - Anno II - N. 4/2009

31

case report

Figure 55 Intra-oral view after teeth extraction.

Figure 6Is possible to see in the post-extraction sites por-tions of bone in necrosis.

Figure 3Initial Rx panoramic.

Figure 44TC Dentascan.

© CIC

Ediz

ioni In

terna

ziona

li

but not an absolute need (16-17-18). In conclusionthe prevention of the osteonecrosis with bisphos-phonates per mouth needs a strict collaboration be-tween the doctor and the dentists who are taking careof the treatment of the patient. This preventive pro-

ORAL & Implantology - Anno II - N. 4/2009

case

rep

ort

32

Figure 7With more blowups we can see that the bone ne-crosis interests also the lingual bone cortical.

Figure 8Post extraction sites after surgical curettage.

Figure 10Teeth after extraction. Is possible to see bone chipsjoined with the roots.

Figure 9Portion of bone in necrosis we can see the roof ofthe mandibolar tunnel.

© CIC

Ediz

ioni In

terna

ziona

li

tocol starts with the indication, from the doctor, ofthe absuntion of bisphosphonate for the treatmentsof cases of osteopenia, osteoporosis or other con-ditions which present the same indication. It would

be better that the same doctor sent the patient for anodontostomatologyc evaluation before starting thecicle of the assumption of the drug. The dentistryshould then proceed to the execution of a clinical andtotal radiographic exam of the oral cave in order towrite a plan of treatment with the finality of limit-ing the need of making invasive movements. In thecase of an oncologic patient, the doctor could post-pone of two months the assumption of the bispho-sphonates per veins in order to allow the dentist the

ORAL & Implantology - Anno II - N. 4/2009 33

case report

Figure 12Intra-oral view of the state of healing after one month.

Figure 14Rx of control after 6 months. We can see the perfecthealing of the bony woven.

Figure 11Suture of the hut with healing for second intention.

Figure 13Rx panoramic of control after one year.

© CIC

Ediz

ioni In

terna

ziona

li

reduction and/or the elimination of evident factorsof risk. Since these drugs taken by mouth arescarcely absorbed on an intestinal level, they takeplace on a bone level with a major slowness than thesimilar ones taken by vein. The consequence is thefact that the risk of presenting bone exposition is notrelevant before three years of continous therapypassed and the dental treatment plan would be thenmore flexible.

References1. Wang J., Goodger NM., Pogrel MA.Osteonecrosis of the

jaw associated with cancer chemotherapy. J OralMaxillofac Surg. 61:1104-1107, 2003

2. Ruggiero SL, et al. Osteonecrosis of the jaws associat-ed with the use of bisphosphonates: a review of 63 cas-es. J Oral Maxillofac Surg 2004, 62:527-534

3. Bagan JV, et al. Jaw osteonecrosis associated with bis-phosphonates: multiple exposed areas and its relation-ship to teeth extractions. Study of 20 cases. Oral Oncol2006, 42:327-329

4. Marx RE, et al. Bisphosphonateinduced exposed bone(osteonecrosis/osteopetrosis) of the jaws: risk factors,recognition, prevention, and treatment. J Oral Maxillo-fac Surg 2005, 63:1567-1575

5. Reuther T, et al. Osteoradionecrosis of the jaws as a sideeffect of radiotherapy of head and neck tumour patientsa report of a thirty year retrospective review. Int J OralMaxillofac Surg 2003, 32:289-295

6. Woo S-B, Hellstein JW, Kalmar JR. Ann Intern Med144:753-761, 2006

7. Stark WJ, Epker BN.Int Faiulure of osseointegrated den-tal implants after disphosphonates therapy for osteo-porosis: a case report. J Oral Maxillofac Surg10:74-78,1995

8. Sarathy AP, Burgeois SI, Goodel GG.Bisphosphonates-induced osteonecrosis of the jaws and endodontic treat-ment: two case report. JOE 31:831-834,2005.

9. Hughes DE, et al. Bisphosphonates promotes apoptosisin murine osteoclasts in vitro and in vivo. J Bone MinerRes 1995,10:1478-1487.

10. Hughes DE, et al. Inhibition of osteoclast-likemcell for-

mation by bisphosphonates in longterm cultures of hu-man bone marrow. J Clin Invest 1989, 83:1930-1935.

11. Vitte C, et al. Bisphosphonates induce osteoblasts to se-crete an inhibitor of osteoclastic mediated resorption. En-docrinology 1996, 137:2324-2333.

12. Sato M, Grasser W: Effects of bisphosphonates on iso-lated ratosteoclasts as examined by reflected light mi-croscopy. J Bone Miner Res 1990, 5:31-40.

13. Santini D, et al. Pamidronate induces modifications ofcirculating angiogenetic factors in cancer patients. ClinCancer Res 2002, 8:1080-1084.

14. Lin HJ, Russel G, Gertz B. Int J clin Pract 101:18-26,1999.

15. Bagger YZ, et al. Alendronate has a residual effect on bonemass in postmenopausal Danish women up to 7 years af-ter treatment withdrawal. Bone 2003, 33:301-307.

16. Merigo E, et al. Jaw bone necrosis without previous den-tal extractions associated with the use of bisphosphonates(pamidronate and zoledronate): a four-case report. J OralPathol Med 2005, 34:613-617.

17. Zarychanski R, et al. Osteonecrosis of the jaw associatedwith pamidronate therapy. Am J Hematol 2006, 81:73-75.

18. Gibbs SD, et al. Bisphosphonateinduced osteonecrosisof the jaw requires early detection and intervention. MedJ Aust 2005, 183:549-550).

19. Reginster J, Minne HW, Sorensen OH, et al. Random-ized trial of the effects of residronate on vertebral frac-tures in women with established postmenopausal os-teoporosis. Osteoporos Int 2000;11:83-91

20. Rosen HN,Moses AC, Garber J, et al. Serum CTX. A newmarker of bone resorption that shows treatment effectmore often than other markers because of low coefficientof variability and large changes with bisphosphonate ther-apy.Calcif Tissue Int 2000;66:100-103.

21. Dixon RB, Tricker NB, Garetto LP. Bone turnover in eld-erly canine mandible and tibia [abstract 2579]. J DentRes1997; 76-336.

22. Marx RE, Stern DS. Oral and Maxillofacial Pathology:A Rationale for Diagnosis and Treatment. Chicago: Quin-tessence, 2002.

Correspondence to:Dott. Dario SpinelliVia Flaminia Vecchia 798 - 00191 RomaE-mail: dariospinelli@hotmail.it

ORAL & Implantology - Anno II - N. 4/2009

case

rep

ort

34

© CIC

Ediz

ioni In

terna

ziona

li