Oral Bisphosphonate-Induced Osteonecrosis: … AND PATIENT-ORIENTED RESEARCH J Oral Maxillofac Surg 65:2397-2410, 2007 Oral Bisphosphonate-Induced Osteonecrosis: Risk Factors, Prediction

BASIC AND PATIENT-ORIENTED RESEARCH

J Oral Maxillofac Surg65:2397-2410, 2007

Oral Bisphosphonate-InducedOsteonecrosis: Risk Factors, Prediction of

Risk Using Serum CTX Testing,Prevention, and Treatment

Robert E. Marx, DDS,* Joseph E. Cillo, Jr, DDS,† andJuan J. Ulloa, DDS‡

Purpose: To assess the risk and time course of oral bisphosphonate-induced osteonecrosis of the jaws.

Materials and Methods: Detailed data from 30 consecutive cases were compared with 116 cases dueto intravenous aminobisphosphonates.

Results: Results in part noted a higher incidence related to alendronate (Fosamax; Merck, WhitehouseStation, NJ), a 94.7% predilection for the posterior mandible, and a 50% occurrence spontaneously, withthe remaining 50% resulting from an oral surgical procedure, mostly tooth removals. Just over 53% ofpatients were taking their oral bisphosphonate for osteopenia, 33.3% for documented osteoporosis, and13.4% for steroid-induced osteoporosis related to 4 or more years of prednisone therapy for anautoimmune condition. There was a direct exponential relationship between the size of the exposedbone and the duration of oral bisphosphonate use. There was also a direct correlation between reportsof pain and clinical evidence of infection. The morning fasting serum C-terminal telopeptide (CTX) testresults were observed to correlate to the duration of oral bisphosphonate use and could indicate arecovery of bone remodeling with increased values if the oral bisphosphonate was discontinued. Astratification of relative risk was seen as CTX values less than 100 pg/mL representing high risk, CTXvalues between 100 pg/mL and 150 pg/mL representing moderate risk, and CTX values above 150 pg/mLrepresenting minimal risk. The CTX values were noted to increase between 25.9 pg/mL to 26.4 pg/mLfor each month of a drug holiday indicating a recovery of bone remodeling and a guideline as to whenoral surgical procedures can be accomplished with the least risk. In addition, drug holidays associatedwith CTX values rising above the 150 pg/mL threshold were observed to correlate to either spontaneousbone healing or a complete healing response after an office-based debridement procedure.

Conclusions: Oral bisphosphonate-induced osteonecrosis is a rare but real entity that is less frequent,less severe, more predictable, and more responsive to treatment than intravenous bisphosphonate-induced osteonecrosis. The morning fasting serum C-terminal telopeptide bone suppression marker is auseful tool for the clinician to assess risks and guide treatment decisions.© 2007 American Association of Oral and Maxillofacial SurgeonsJ Oral Maxillofac Surg 65:2397-2410, 2007

Physicians and dentists are now keenly aware ofbisphosphonate-induced osteonecrosis of the jawsfrom the intravenous nitrogen-containing bisphos-phonates pamidronate (Aredia; Novartis, EastHanover, NJ) and zoledronate (Zometa; Novartis).

Oral nitrogen-containing bisphosphonates alendro-nate (Fosamax; Merck, Whitehouse Station, NJ) andresidronate (Actonel; Procter and Gamble Pharmaceu-ticals, Cincinnati, OH) (and possibly more recentlyintroduced bisphosphonates such as ibandronate

*Professor of Surgery and Chief, Division of Oral and Maxillofacial

Surgery, University of Miami Miller School of Medicine, Miami, FL.

†Attending Surgeon, Oral and Maxillofacial Surgery, Alleghany

General Hospital, Pittsburgh, PA.

‡Fellow in Tumor and Reconstructive Surgery, Division of Oral

and Maxillofacial Surgery, University of Miami Miller School of

Medicine, Miami, FL.

Address correspondence and reprint requests to Dr Marx:

Division of Oral and Maxillofacial Surgery, University of Miami

Miller School of Medicine, 9380 SW 150th St, Suite 190, Miami, FL

33157; e-mail: [email protected]

© 2007 American Association of Oral and Maxillofacial Surgeons

0278-2391/07/6512-0002$32.00/0

doi:10.1016/j.joms.2007.08.003

2397

[Boniva; Roche Laboratories, Basel, Switzerland])demonstrate a risk for osteonecrosis as well. Initialreports of bisphosphonate-induced osteonecrosis ofthe jaws focused on those cases caused by eitherZometa or Aredia used to stabilize metastatic cancerdeposits in bone.1-6 Nevertheless, several of thesepublications also reported a smaller number of casesrelated to oral bisphosphonates used in the treatmentof osteopenia and osteoporosis2,3 and since thenthere have been more publications relating osteone-crosis in patients using oral bisphosphonates.7-9 How-ever, few details were provided and no distinctionsconcerning the incidence, severity, risks, prevention,or treatment outcomes between the intravenousbisphosphonate cases and the oral bisphosphonatecases were even attempted. The purpose of this arti-cle is to present data from 30 cases of oral bisphos-phonate-induced osteonecrosis of the jaws contrast-ing it to the data we have accumulated in 116 cases ofintravenous bisphosphonate-induced osteonecrosiscases related to risk factors, prediction of risk, pre-vention recommendations, and treatment recommen-dations. The purpose of this paper is also to introducethe morning fasting serum C-terminal telopeptide(CTX) bone turnover marker as a useful clinical toolto help assess risk, and guide the clinician’s evalua-tions of nonsurgical treatment response as well as toguide decisions as to when surgery can be accom-plished with the least risk.

Materials and MethodsThirty consecutive cases of exposed bone in the

mandible or maxilla that fit the American Associationof Oral and Maxillofacial Surgeons Task Force defini-tion of bisphosphonate-induced osteonecrosis10 wereprospectively included in this data set. The case def-inition is as follows: the presence of nonhealing ex-posed bone in the maxilla or mandible that has per-sisted for more than 8 weeks in a patient who hasreceived a systemic bisphosphonate but has not re-ceived local radiation therapy.

Each included patient was asked for a detailed his-tory concerning the oral bisphosphonate used, thedose, the frequency, the duration of bisphosphonatetherapy, comorbidities, and the indication for thebisphosphonate. Each patient was also surveyed con-cerning any initiating event that produced the ex-posed bone, the presence of pain, previous treatmentfor the exposed bone and whether a response wasachieved, and if the bisphosphonate was discontin-ued. Each patient was then given a comprehensiveoral examination noting the size and location of theexposed bone as well as signs of secondary infection.Each patient was also consented and scheduled for afasting morning blood draw of 1 mL of whole blood

for a CTX bone turnover marker assessment as part oftheir regular osteoporosis follow-up. Each patient pro-ceeded to receive nonsurgical management with ei-ther 0.12% chlorhexidine initially or 0.12% chlorhexi-dine combined with an antibiotic; penicillin VK 500mg 4 times daily if not allergic or Levaquin (Ortho-McNeil Inc, Raritan, NJ) 500 mg once daily if theywere allergic to penicillin. The advanced presentationcases and cases refractory to nonsurgical managementwere resolved with surgical debridements or resec-tions as appropriately guided by the CTX values.

ResultsThe data concerning the type of oral bisphospho-

nate, the dose, the frequency, the duration, indica-tions for the bisphosphonate, comorbidities, location,and the size of the exposed bone are presented inTable 1. Twenty-seven cases (90%) resulted fromFosamax use with the mean duration of drug expo-sure of 5.7 years and 3 from Actonel (10%) use with amean duration of exposure of 5.0 years. All casesoccurred in women at a mean age of 64.8 years.Twenty-eight of the 30 patients took their oralbisphosphonate on a once weekly schedule; Fosamaxat 70 mg/wk or Actonel at 35 mg/wk. Two patientstook Fosamax 10 mg daily. Sixteen patients (53.3%)were taking their oral bisphosphonate for osteopeniaas diagnosed by their prescribing physician and witha bone mineral density (BMD) T-score of greater than-2.5.11 Ten patients (33%) took their oral bisphospho-nate for osteoporosis as diagnosed by their prescrib-ing physician and had BMD values relating a T-score ofless than -2.5,12 7 others (13.4%) took their bisphos-phonates for steroid-induced osteoporosis for whicheach had concomitantly taken prednisone, and 3 alsotook methotrexate at varying doses for more than 4years in treatment of an autoimmune condition.

Twenty nine cases (96.7%) occurred in the mandi-ble while only 1 case (3.3%) occurred in the maxilla.Spontaneous bone exposures of the lingual cortex inthe molar area occurred in 13 cases (43.4%) (Fig 1).One spontaneous bone exposure (3.3%) occurred atthe buccal cortex unrelated to a torus and another 1(3.3%) occurred exposing a buccal torus (Fig 2).Eleven cases (36.7%) resulted from an extraction of amandibular molar tooth and 1 (3.3%) from the re-moval of several anterior mandibular teeth. Two cases(6.7%) developed as a result of dental implant place-ments (Fig 3) and another 1 (3.3%) from harvesting apalatal connective tissue graft (Fig 4). Therefore, 15cases (50%) of oral bisphosphonate-induced osteone-crosis occurred spontaneously without a recognizedinitiating event and another 15 cases (50%) occurredas the result of an invasive dental procedure.

2398 ORAL BISPHOSPHONATE-INDUCED OSTEONECROSIS

The length of time patients had taken their oralbisphosphonate ranged from 3.3 years to 10.2 yearswith the composite mean for both Fosamax and Ac-tonel of 5.6 years. This further segregated to a meantime to exposed bone of only 4.25 years for thosepatients who also took prednisone with or withoutmethotrexate and 5.8 years for those who took onlyan oral bisphosphonate (P ! .018).

The data concerning the size of the bone exposure,the presence of pain, and the presence of infection inrelation to the duration of oral bisphosphonate useare presented in Table 2. Nineteen of the 30 patients(63.3%) reported pain associated with their bone ex-posure. The pain was correlated to clinical evidenceof infection (ie, erythema, swelling, drainage, and/orosteolysis) in 18 of the 19 patients (94.7%) who re-

Table 1. ORAL BISPHOSPHONATE-INDUCED OSTEONECROSIS OF THE JAWS

Patient Drug*Dose/

Frequency Indication ComorbiditiesLocation: Mandible (n ! 29);

Maxilla (n ! 1)†Years of

Bisphosphonate Stage

1 Fosamax 70 mg/wk Osteoporosis None 1 cm " 2 cm lingal cortex molar 4.1 I2 Fosamax 70 mg/wk Osteoporosis None 1 cm " 3 cm molar socket 4.4 I3 Fosamax 70 mg/wk Osteopenia None 1 cm " 1 cm molar socket 3.6 I

4 Fosamax 70 mg/wk Osteopenia None1 cm " 3 cm anterior mandibular

sockets 6.4 II5 Actonel 35 mg/wk Osteopenia None 2 cm " 2 cm molar socket 5 I6 Fosamax 70 mg/wk Osteoporosis Rheumatoid

arthritis,prednisone,methotrexate

1 cm " 1 cm lingual cortex 3.4 I

7 Fosamax 70 mg/wk Osteopenia None 1 cm " 2.5 cm buccal cortex molararea

8.4 II

8 Fosamax 10 mg/day

Osteoporosis None 1 cm " 1 cm molar socket 4.4 I

9 Fosamax 70 mg/wk Osteoporosis Systemic lupuserythematosus,prednisone

1 cm " 1 cm molar socket 3.3 II

10 Fosamax 70 mg/wk Osteopenia None 2 cm " 2 cm molar socket 7.3 III11 Fosamax 10 mg/

dayOsteoporosis None 3 cm " 4 cm symphysis 5.5 III

12 Fosamax 70 mg/wk Osteopenia None 1 cm " 1.5 cm lingual cortex 4.9 II13 Fosamax 70 mg/wk Osteoporosis None 1 cm " 1 cm molar area lingual

cortex8.6 II

14 Actonel 35 mg/wk Osteoporosis None 1 cm " 1 cm molar lingual cortex 6.2 II15 Fosamax 70 mg/wk Osteoporosis Rheumatoid

arthritis,prednisone,methotrexate

3 cm " 4 cm molar area palate* 6.3 II

16 Actonel 35 mg/wk Osteopenia None 0.5 cm " 0.5 cm lingual cortex 3.8 I17 Fosamax 70 mg/wk Osteoporosis Rheumatoid

arthritisprednisonemethotrexate

2 cm " 2 cm linugal molar 3.3 II

18 Fosamax 70 mg/wk Osteopenia None 0.5 cm " 1 cm lingual molar area 3.6 I19 Fosamax 70 mg/wk Osteopenia None 2 cm " 2 cm molar area 7 II20 Fosamax 70 mg/wk Osteopenia None 2 cm " 2 cm molar area buccal

torus9.1 I

21 Fosamax 70 mg/wk Osteoporosis None 1 cm " 1 cm lingual molar 5 I22 Fosamax 70 mg/wk Osteopenia None 1 cm " 2 cm molar lingual area 8.8 II23 Fosamax 70 mg/wk Osteoporosis None 1 cm " 1 cm molar socket 4.1 II24 Fosamax 70 mg/wk Osteopenia None 8 cm hemimandible 10.2 III25 Fosamax 70 mg/wk Osteopenia None 1 cm " 1 cm molar socket 4.1 II26 Fosamax 70 mg/wk Osteopenia None 1 cm " 1 cm molar socket 5 II27 Fosamax 70 mg/wk Osteoporosis None 1 cm " 1 cm molar socket 5.4 II28 Fosamax 70 mg/wk Osteoporosis None 7 cm molar bicuspid alveolar crest 9.3 III29 Fosamax 70 mg/wk Osteopenia None 0.5 cm " 0.5 cm lingual cortex 3.7 I30 Fosamax 70 mg/wk Osteopenia None 0.5 cm " 1 cm lingual cortex 3.8 I

*Fosamax manufactured by Merck, Whitehouse Station, NJ; Actonel manufactured by Procter and Gamble Pharmaceuticals, Cincinnati, OH.†Palate.

Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

MARX, CILLO, AND ULLOA 2399

ported pain. There was also an exponential relation-ship between the size of the bone exposure and theduration of oral bisphosphonate use (Fig 5).

The data concerning the fasting serum CTX boneturnover marker values are presented in Table 3.Seventeen of the 30 patients who presented with anoral bisphosphonate-induced osteonecrosis were stilltaking their oral bisphosphonate at the time of theirpresentation. Those 17 patients had CTX values thatranged from 30 pg/mL to 102 pg/mL with a mean of72.9 pg/mL. After 6 months of discontinuation (“drug

holiday”) from their oral bisphosphonate the CTXvalues ranged from 162 pg/mL to 343 pg/mL with amean of 228.2 pg/mL. This amounted to a meanimprovement of 155.3 pg/mL or approximately 25.9pg/mL per month. Three of these 17 cases were inpatients who also received prednisone and metho-trexate along with their oral bisphosphonate. Each ofthese 3 patients exhibited CTX values in the lowestranges (30 pg/mL, 64 pg/mL, 80 pg/mL) and eachimproved their CTX slightly below the mean 6months improvement level of 155.3 pg/mL (145 pg/mL, 140 pg/mL, 116 pg/mL respectively).

Five of these 17 patients required surgery to resolvetheir osteonecrosis; 3 were resolved with an office-based local debridement surgery at CTX values of 291pg/mL, 299 pg/mL, and 212 pg/mL respectively (Figs6, 7). The 2 others who had more extensive osteo-lysis required inpatient management and a mandibu-lar resection to resolve their osteonecrosis at CTX

FIGURE 1. Spontaneous bone exposure of the lingual cortex in themolar area after 4.9 years of Fosamax.

Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecro-sis. J Oral Maxillofac Surg 2007.

FIGURE 2. Spontaneous bone exposure of a mandibular buccal torusafter 9.1 years of Fosamax.


FIGURE 3. Bone necrosis resulting from placement of dental implantsin a patient who received Fosamax for 5.5 years.


FIGURE 4. Bone exposure resulting from a palatal graft harvest after6.3 years of Fosamax together with the comorbidities of 4 years ofprednisone and methotrexate.



values of 202 pg/mL and 343 pg/mL respectively (Figs8-10).

Eleven patients experienced resolution of their os-teonecrosis without surgery (Figs 11, 12). Five spon-taneously sequestered a bone fragment and 6resorbed their exposed bone, all eventuating into acomplete mucosal cover. The mean CTX value for thisgroup was 245.8 pg/mL after a drug holiday of 3months to 9 months. All 3 patients who had receivedconcomitant prednisone and methotrexate com-pletely healed their exposed bone. However, 1 pa-tient improved with 50% of their original exposedbone covered by healthy-appearing mucosa at 1 yearand complete healing by 1.5 years. The CTX valuesfor the 2 that spontaneously healed within 9 monthswere 204 pg/mL and 196 pg/mL respectively. TheCTX value for the prednisone patient that had not

healed by 1 year was 175 pg/mL and was 202 pg/mLat 1.5 years.

The subgroup of 13 patients that discontinued theiroral bisphosphonate (drug holiday) before presentingto our facility were also evaluated with morning fast-ing serum CTX studies. Their data subset is presentedin Table 4 and Figure 13. Their CTX values rangedfrom 153 pg/mL to 303 pg/mL and correlated to thelength of time of their drug holiday. Although nobase-line reference points of their CTX values whiletaking the oral bisphosphonate were available, theirimprovement of CTX values across this group showsa linear correlation corresponding to a monthly im-provement of 26.4 pg/mL per month of drug holiday.This compares favorably with the monthly improve-ment of 25.9 pg/mL calculated for the subgroup ofthe 17 patients that were discontinued from the oralbisphosphonate after a baseline CTX value could beobtained.

DATA ANALYSISDetailed records and data collection from this pro-

spective study of 30 patients generated considerabledata. The first consideration that must be made is thatalthough these 30 patients represent a relatively largeseries for this rare condition, they represent a verysmall percentage of patients taking oral bisphospho-nates. Although the actual number of individuals tak-ing oral bisphosphonates annually is unknown, Neff13

has related that 13% to 18% of women in the UnitedStates over 50 years of age have osteoporosis and that

Table 2. MEAN SIZE OF OSTEONECROSIS ANDDURATION OF BISPHOSPHONATE EXPOSURE

Duration of OralBP Use n

Mean Sizeof Exposure Pain Infection

3 to 4 years 8 0.6cm2 2 24 to 5 years 6 1.5cm2 3 35 to 6 years 5 3.8cm2 3 36 to 7 years 3 4.7cm2 2 3More than 7 years 8 7.9cm2 8 8

Abbreviation: BP, bisphosphonate.


0

1

2

3

4

5

6

7

8

9

1 2 3 4 5 6 7

Duration of Oral Bisphosphonate

Mea

n S

ize

cm2

FIGURE 5. Mean size of osteonecrosis versus duration of bisphosphonate exposure.



an additional 37% to 50% have osteopenia. Therefore,even though the number of patients receiving oralbisphosphonates is unknown, the number is in thetens of millions. These 30 patients represent only 1center’s experience; the data presented here shouldnot be used to extrapolate prevalence.

Ninety percent of our cases were caused by Fosa-max and 10% by Actonel. On one hand this higher

incidence related to Fosamax may be biased due to agreater utilization of Fosamax in the public sector.Another possible explanation is dose, potency, ab-sorption, and half life in bone. The weekly dose ofActonel is only 35 mg, while the weekly dose ofFosamax is 70 mg. Fosamax is considered the mostpotent of the oral bisphosphonates and actually is aspotent as the intravenous bisphosphonate Aredia,which can partly explain the higher incidence relatedto Fosamax.14 Fosamax and other oral bisphospho-nates produce a lesser incidence of osteonecrosis anda lesser severity than intravenous bisphosphonatesbecause they are not well-absorbed orally. Both Fosa-max and Actonel have a bioavailability of only 0.70%in women and 0.59% in men (a published averagebioavailability of 0.64%) under ideal conditions.15,16

In addition, patients often do not take their medica-tions as directed leading to variable absorption ratesand a further reduction in bioavailability which mayaccount for the observed variabilities in risk and se-

FIGURE 6. Alveolar bone exposure resulting from tooth extractionsafter 5.5 years of Fosamax (CTX 88 pg/mL).


FIGURE 7. Successful sequestrectomy after a 6 month drug holiday(CTX 299 pg/mL).


FIGURE 8. Resection specimen radiograph of an oral bisphospho-nate-induced osteonecrosis from a patient with a 10.2 year exposureto Fosamax. Resection accomplished after a 4 month drug holiday(CTX 202 pg/mL).


Table 3. PATIENTS TAKING AN ORALBISPHOSPHONATE AT TIME OF PRESENTATION

Patient

Durationof

BP YearsCTX

pg/mL

CTX pg/mL6 mo

After DrugHoliday

ChangeCTX pg/mL

4 6.4† 102 291† 1897 8.4 102 199 97

10 7.3‡ 53 343‡ 29011 5.5† 88 299† 21115 6.3* 64 204 14020 9.1 79 302 22324 10.2‡ 33 202‡ 16928 9.3 66 232 16619 7.0† 99 212† 11114 3.3* 30 175 14522 8.8 90 162 7226 5.0 94 216 1222 4.4 72 188 116

12 4.9 53 194 14121 5.0 101 303 20217 3.3* 80 196 11613 8.6 33 162 129

Mean Score — 72.9 228.2 155.3

Abbreviations: BP, bisphosphonate; CTX, C-terminal telopeptide.*Comorbidity of more than 4 years of prednisone.†Extensive bone necrosis. Osteonecrosis resolved with office

debridement surgery at that CTX value.‡Extensive bone necrosis. Osteonecrosis resolved in patient re-

section at that CTX value.



verity between individuals. Finally, the terminal halflife in bone for each oral bisphosphonate is not pre-cisely known. While it is known that the terminal halflife in bone is greater than 10 years17 and it has beensuggested that Fosamax has a somewhat longer halflife in bone than Actonel, this long half life itselfprecludes an accurate determination beyond thistime. Therefore, the difference in the incidence ofosteonecrosis between the 3 oral bisphosphonates inuse today relates to its accumulation and retention inbone and a clear explanation as to why there aredifferences may never be completely known.

The data clearly indicate that the time over which apatient takes an oral bisphosphonate (accumulationin bone) is the most critical factor. All patients whodeveloped osteonecrosis took an oral bisphosphonatefor more than 3 years. Moreover, the data indicatethat most cases developed after 5 years or more ofdrug exposure and that the incidence and severityincreased linearly with exposures over 3 years. This issubstantially different from osteonecrosis cases

caused by intravenous bisphosphonates which re-quires only a mean of 9.3 months for Zometa and 14.1months for Aredia to develop exposed bone.2 Thisfaster development of exposed bone is due to theintravenous route which bypasses the low and vari-able gut absorption of oral bisphosphonates so thatafter about 40% is cleared in the urine the remainderof the intravenous dose accumulates in bone.18,19 It islikely that the rapid and high dose accumulation inbone from the intravenous bisphosphonates not onlyinduces apoptosis of a large population of osteoclastsbut its repeated dosing exhausts the ability of thebone marrow to replenish the osteoclasts from thepool of osteoclast precursors. Comparatively, the

FIGURE 9. Reconstruction of mandibular defect related to the resec-tion specimen of Figure 8 using a titanium reconstruction plate.


FIGURE 10. Resolution of oral bisphosphonate-induced osteonecro-sis after resection and titanium plate reconstruction.


FIGURE 11. Spontaneous bone exposure after 5 years of Fosamax(CTX 94 pg/mL).


FIGURE 12. Healing of bone exposure seen in Figure 11 withoutsurgery after a drug holiday of 6 months (CTX 216 pg/mL).



poor absorption of oral bisphosphonates representsonly a gradual accumulation in bone and thus mayeffect the osteoclasts less severely. In addition, theirgradual accumulation in bone allows the bone mar-row to keep pace with the loss of osteoclasts thusdelaying the onset of clinically exposed bone, reduc-ing its severity, and allowing a recovery once the drugis discontinued.

It is not unexpected that all patients in this studywere women and that the mean age was 64.8 years.These facts are related to the osteopenia/osteoporosisindication for oral bisphosphonates and underscoresthe fact that oral bisphosphonate-induced osteonecro-

sis of the jaws is mostly a women’s health concernand mostly that of postmenopausal women. Even ste-roid-induced osteoporosis has a prevalence forwomen because the more common autoimmune dis-eases such as rheumatoid arthritis and systemic lupuserythematosus have a strong predilection for women.This differs somewhat from osteonecrosis casescaused by intravenous bisphosphonates due to theirindications. That is, a smaller bias toward women ispresent in this group due to the frequent use ofintravenous bisphosphonates for female breast can-cers that have developed bony metastasis and thatmale breast cancer is very rare. However, this is some-what offset by the remaining indications for intrave-nous bisphosphonates which include bony metasta-ses mostly from multiple myeloma, and to a lesserextent from lung cancers and prostate cancers all ofwhich have a predilection for men. Despite the biastoward men for these conditions, the incidence ofintravenous bisphosphonate-induced osteonecrosis inour database is 70% women.

Oral bisphosphonate-induced osteonecrosis devel-oped evenly divided between spontaneous bone ex-posures and traumatically initiated bone exposures.This contrasts with the experience from intravenousbisphosphonates in which only 25% of cases devel-oped spontaneously. This is most likely due to the factthat the intravenous bisphosphonates accumulate inbone much faster creating a more rapid and moreinsidious bone turnover suppression. It is also con-tributed to by the fact that the oral hygiene andperiodontal condition was observed to be worse in

Table 4. PATIENTS ON “DRUG HOLIDAY” AT TIMEOF PRESENTATION

Patient Drug Holiday Months CTX pg/mL

1 2 1533 6 2445 4 2066 12 2948 2 162

13 10 30316 8 24918 3 18923 7 21625 8 23227 4 19429 15 30330 6 199

Abbreviation: CTX, C-terminal telopeptide.


100

150

200

250

300

350

400

0 2 4 6 8 10 12 14 16

Drug Holidays - Months

CT

X p

g/m

L

FIGURE 13. CTX versus duration of drug holiday.



the intravenous bisphosphonate group. This in turn isrelated to the bone marrow and immune suppressionof their chemotherapy and the practical fact thatmany cancer patients experience fatigue and nauseawhich compromises their ability to maintain plaquecontrol. Of particular note is a significant difference inlocation of the exposed bone. While the intravenousbisphosphonates have shown a 25% incidence in themaxilla, only 1 (3.3%) of our 30 cases occurred in themaxilla as compared to 29 of the 30 cases (96.7%)occurring in the mandible. Furthermore, only 2 casesof the 29 cases of mandibular osteonecrosis occurredin the anterior region (6.4%). The remaining 27 cases(93.1%) occurred in the molar region of the mandibleas either a spontaneous exposure of mostly lingualcortical bone or as the result of a molar tooth removal.While the molar region of the mandible is also themost common location for an intravenous bisphos-phonate-induced osteonecrosis it is not at the strik-ingly high predilection as now documented in oralbisphosphonate-induced osteonecrosis (41.2% to93.7%).

The predilection for the molar area in general andthe mandibular molar area specifically is common toall types of bisphosphonates by virtue of their basicmechanism of action. Because all bisphosphonatescause reversible and/or irreversible osteoclast dys-function they slow down and may even halt boneresorption altogether.20,21 This antiresorptive effect istherapeutic up to a point as proven by their ability toresist cancer-related bone resorption and to slowdown the loss of bone mass and even increase bonemass in osteopenia and osteoporosis. However, be-yond the therapeutic range of any drug lurks toxicity.Too great of an accumulation of a bisphosphonate inbone will cause a significant shut down in bone turn-over. That is, by inhibition of osteoclasts bone re-newal is prevented. This is due to the known role ofthe osteoclast as a cell which resorbs old bone con-taining dead or old osteocytes and microfractures andin doing so releases cytokines such as bone morpho-genetic protein and insulin-like growth factors 1 and 2which induce new bone formation. This new bone ismore cellular and less mineral and more elastic. As itages, this bone will also become less cellular, moremineralized, less elastic and will then die off to be-come resorbed itself and be replaced by yet anothergeneration of bone. Therefore, the rate of bone turn-over in any bone directly relates to its vulnerability tobisphosphonates. The mandibular alveolar bone turn-over rate is 10 times that of long bones like thetibia.22-24 This is the most likely explanation for theexclusive preponderance for bisphosphonate-induced osteonecrosis to occur in the jaws. In addi-tion, the rate of alveolar bone turnover at the crest istwice the rate of the bone turnover about the man-

dibular canal and 3 to 5 times that of the bone aboutthe inferior border.22 This explains why both intrave-nous bisphosphonates and oral bisphosphonates ex-posed bone begins in the alveolar bone. It is apparentthat occlusal or denture-related compression on thealveolar bone which is greatest in the molar regionand creates a more active bone turnover produces agreater vulnerability to drugs that affect osteoclastfunction over a prolonged period.

The presence of pain correlated directly to evi-dence of infection confirming the concept that non-vital bone by itself is deinnervated and nonpainful.The pain arises from secondary infections which pro-voke an inflammatory response that elaborates themediators of pain. This is identical to the associationof pain from the exposed bone caused by the intra-venous bisphosphonates. Although not specificallystudied, in those cases in which bone debridementswere accomplished, the micro-organisms most fre-quently noted were actinomyces, moraxella, andeikenella species (Fig 14) as is also seen in the ex-posed bone removed from intravenous bisphospho-nate-induced osteonecrosis.

The size of the bone exposure, pain, and infection,and the requirement to accomplish surgery all di-rectly correlated to the length of time the patient hadbeen taking the oral bisphosphonate (Table 2, Fig 5).This is particularly noted by the observation that the3 patients who required an office-based debridementhad taken Fosamax 6.4 years, 7 years, and 7.2 yearsrespectively and the patients with the most extensivebone involvement requiring a resection had takenFosamax for 7.3 years and 10.2 years respectively. Infact, the slope of the curve in Figure 5 which plots thesquare surface area of bone exposure against the

FIGURE 14. Actinomyces colony and nonvital bone obtained from apatient with oral bisphosphonate-induced osteonecrosis. (Hematoxylinand eosin stain; "10.)



length of time the patient had been taking the oralbisphosphonate is that of an exponential relationshipwith the largest bone exposures occurring after 5years of drug use. Although these correlations werealso noted in cases of osteonecrosis due to intrave-nous bisphosphonates they are less clear due to themany more comorbidities associated in the intrave-nous bisphosphonate patients.

THE C-TERMINAL TELOPEPTIDE DATA ANALYSISThe morning fasting serum CTX test measures a

surrogate marker of bone turnover. It is one of severalknown serum and urine tests that measures a break-down product of bone resorption.25-27 The CTX spe-cifically measures a specific crosslink peptide of typeI collagen in bone. Type I collagen is the structuralorganic component of bone and accounts for 98% ofthe total protein in bone. The serum CTX is consid-ered to best correlate to bone turnover28 and waschosen due to the fact that a single laboratory (QuestDiagnostics Nichols East Lab in San Juan Capistrano,California) performs this test under standard condi-tions. The telopeptide fragment in question is cleavedfrom the main crosslink chains of collagen by theosteoclast during bone resorption. Its level in theserum is therefore proportional to the amount ofosteoclastic resorption occurring at the time theblood is drawn. Even though laboratory normalranges are said to be between 50 pg/mL and 450pg/mL, this normal range is not accurate related to theosteoporosis population. Actual normal values areusually well over 300 pg/mL and are most commonly400 pg/mL to 550 pg/mL in patients not takingbisphosphonates. Lower values represent varying de-grees of suppression of normal bone turnover some-times also called bone remodeling or bone renewal.

The most controlled CTX data are seen in the groupof 17 patients in which we accomplished a CTX testbefore their oral bisphosphonate was discontinuedwhich is referred to as a “drug holiday.” These dataare seen in Table 3 and Figure 13. This data subsetdemonstrates that the individuals who were still tak-ing their oral bisphosphonate and had osteonecrosisalso had severe suppression of bone turnover: meanCTX of 72.9 pg/mL. In addition, all 17 patients hadCTX values less than 110 pg/mL. Even with a CTX dayto day variability of 25% as published by Rosen et al28

and allowing for an additional margin of patient vari-ability, one can say that all cases had CTX values lessthan 150 pg/mL. Although some of the more severecases had very low CTX values there were too fewcases to suggest a correlation between clinical sever-ity and the CTX value.

Of clinical importance, the 6-month drug holidayshowed a direct and significant improvement in theCTX values in every patient. This improvement corre-

lated to either spontaneous resolution of the exposedbone, a significant improvement in the amount of ex-posed bone, or an uncomplicated healing response aftersurgery. It was noted that the CTX values improved at anaverage of 155.3 pg/mL over 6 months or a rate of 25.9pg/mL each month. This rate of improvement was con-sistent with the slope of the curve seen in Figure 13which plots the CTX values against the duration of adrug holiday in the 13-patient subgroup in which theoral bisphosphonate was discontinued at varying timesprior to the CTX blood draw. This relationship appearedto be linear and was measured at 26.4 pg/mL per month.These findings are very significant because they demon-strate clinical bone recovery and response to a drugholiday. It proves that at least part of the functioningosteoclast population can recover and be re-establishedfrom the osteoclast precursors in the bone marrow. Thisis a clear distinction between the oral bisphosphonatecases and the intravenous bisphosphonate cases inwhich we mostly observe no improvement or responseto local debridement surgery with discontinuation of theintravenous bisphosphonate. Moreover, we have alsoaccomplished over 60 CTX tests in cases of osteonecro-sis due to intravenous bisphosphonates and have notedno direct correlations with the size of bone exposure,pain, infection, or severity. Instead, the CTX valuesmore closely correlate with the control of metastaticbone deposits. This reinforces the notion that the intra-venous bisphosphonate accumulation in bone is greaterthan that of the oral bisphosphonates, and that theosteoclast population is less likely to recover due toexhaustion atrophy of the osteoclast precursors in bone.This may also explain why those patients who developosteonecrosis from an intravenous bisphosphonate inthe treatment of multiple myeloma are noted to be moresevere, have greater amounts of exposed bone, and areless responsive to treatment than those with metastaticbone deposits from other cancers. That is, the intrave-nous bisphosphonate suppression of bone marrow os-teoclast precursors is added to by the disease itselfwhich replaces much of the normal bone marrow withmalignant myeloma cells.

The CTX values also noted that prednisone and/ormethotrexate used to treat some autoimmune dis-eases caused a further suppression of bone turnoverin the oral bisphosphonate cases and slowed the re-covery of bone turnover from the drug holiday. Nev-ertheless, even in patients with a prednisone comor-bidity, the drug holiday was seen to produce a bone-healing response measurable by the CTX values.

DiscussionThe data presented in this report concern compli-

cations from commonly prescribed drugs in the treat-ment of a common disease: osteoporosis and its pos-


sible precursor osteopenia. Oral bisphosphonate-induced osteonecrosis cases are very rare and eventhough it is anticipated that the number will grow dueto improved recognition, further reporting, and morepatients receiving these drugs over longer periods oftime, it is expected to remain a rare complication.However, patients taking oral bisphosphonates butwho do not have osteonecrosis and some who alreadyhave exposed bone will still present to many clini-cians who must assess the risks of invasive oral pro-cedures, plan prevention strategies, and treat thosecases with exposed bone. In doing so the treatingdentist or oral and maxillofacial surgeon must consultwith the physician treating the osteoporosis and havean understanding of the definitions of osteopenia andosteoporosis as well as the goals and treatment chal-lenges the physician confronts in treating these enti-ties.

It is estimated that 14 million women in the UnitedStates are currently diagnosed with osteopenia/osteo-porosis.13 It is reported that approximately 5% to 15%of patients with untreated osteoporosis eventuallydevelop a nontrauma-related fracture usually of thefemoral neck but referred to as a “hip fracture” ordevelop compression fractures of the vertebrae, usu-ally the lumbar vertebrae.29-31 These fractures bringabout pain and immobility that in this more advancedage group, frequently leads to long term and evenpermanent disability and sometimes even death.Therefore osteoporosis is a serious disease and a pub-lic health problem.

The World Health Organization defines osteoporo-sis based on the dual energy x-ray absorptiometryscan known as a DXA or DEXA scan which measuresBMD in mg/cm2.30,32 The reference BMD value isgiven as an arbitrary normal at the maximum bonemineral density of a population of 22 # 2-year-oldCaucasian women.32 As age and postmenopausal hor-mone-related reductions in bone mass occur, it is reflectedas a lower BMD value or a negative value as comparedwith this arbitrary norm. Individual BMD values arecompared with this arbitrary norm in standard devia-tions. Within the range of normal is any individualwho is less than 1 standard deviation below the norm.Osteopenia is defined as anyone who is between 1and 2.5 standard deviations below the norm and os-teoporosis is defined as anyone who is more than 2.5standard deviations below the norm. Severe osteopo-rosis is further defined as an individual who is morethan 2.5 standard deviations below the norm and alsohas a nontraumatic fracture. These standard devia-tions are referred to as T-scores and are reported asnegative numbers (eg, -1, -2.5, etc,) because theyrepresent loss of BMD.

Unfortunately, the BMD only measures bone massnot trabecular bone connectivity or bone elasticityand therefore does not directly or solely correlatewith fracture risk.33,34 Because fracture prevention isthe goal of the treating physician, the BMD value isonly 1 of several factors that are considered in thetreatment planning for osteoporosis. Other factorsconsidered are race (Caucasian women are more atrisk for fracture than other races), age, diet, exercise,concomitant medications, and family history. Yet theBMD value remains as the most common utilizedmeasure of response to bisphosphonate therapy.35 Itis important to note that in a 10-year study by Boneand Hosking et al36 on osteoporosis patients treatedwith Fosamax, the BMD values improved to a maxi-mum at 3 years and that the group that stopped takingFosamax at that point experienced no increase infractures compared with the group that continuedtaking Fosamax and that their BMD values decreasedonly slightly over several years. A confirmatory studyby Black et al37 noted in a randomized double-blindcontrolled study of 760 women that once Fosamaxhad been taken for 5 years, no increase in fracturesoccurred after another 5 years off the drug. Thus theappropriate utilization of bisphosphonates to preventfractures will await further dose-accumulation stud-ies.

These data combined with the CTX data presentedin this report indicate that drug holidays on the orderof 4 to 6 months are reasonable, safe, and could beexpected to minimize the risk of osteonecrosis (dueto the anticipated rise in CTX due to increased oste-oclast function) when performing invasive oral surgi-cal procedures in patients taking oral bisphospho-nates while also maintaining BMD values and fractureprevention related to the osteoporosis. The efficacy ofthis concept is supported by the uncomplicated heal-ing and osteonecrosis resolution of the 5 patients inthis study who required surgery and the improvementand nonsurgical resolution of the other cases in thisstudy after a 4 month to 9 month drug holiday.

PREVENTION AND TREATMENTRECOMMENDATIONSFrom the data gained from these studies and our

clinical experience with both oral and intravenousbisphosphonate-induced osteonecrosis cases, we of-fer the following recommendations.

Prevention

Patients first diagnosed with osteopenia or osteo-porosis and are prescribed a bisphosphonate. Be-cause patients taking oral bisphosphonates for lessthan 3 years have little risk for osteonecrosis, thisallows time for the dental team to obtain optimumoral health and repair of the dentition. Similar to the


recommendations already in place for a patient aboutto receive intravenous bisphosphonates, the treatingphysician is recommended to refer the patient tohis/her dentist for an evaluation, treatment, and mon-itoring program focused on attaining and maintainingoral health. The dental team should accomplish acomplete medical and dental history and a thoroughoral examination. Nonrestorable and abscessed teethshould be removed first, followed by periodontal ther-apy with a recall schedule established. Root canaltherapy if indicated should be accomplished nextfollowed by any indicated restorative dental care andprosthodontic appliances. Little is known concerningorthodontic care at this point, but it is anticipated thatadult orthodontic care is feasible and safe but may beslowed or even stopped during the first 3 years of oralbisphosphonate exposure due to the antiresorptive(antiosteoclastic) effects of the bisphosphonate.38,39

Dental implant placements are also likely safe andwill osseointegrate during this period.40 However,informed consent should be provided as to an in-creased risk for implant failure or osteonecrosis aboutthe implants once the oral bisphosphonate exposureexceeds 3 years.

Patients who have been taking an oral bisphos-phonate and present for dental treatment. In thisgroup the dentist needs to specifically ask the patientthe length of time of oral bisphosphonates use as wellas the dose, the indication, and the possible use ofconcomitant steroids or other medications that mightaffect bone healing. In general, nonsurgical dentalprocedures such as restorations, dentures, root canaltherapy, dental prophylaxis, supragingival scaling,and crowns are safe at all times in bisphosphonate-exposed patients. For patients who relate a history offewer than 3 years of oral bisphosphonate use, bonehealing is expected to be uncomplicated. Therefore, aserum CTX is not required prior to an oral surgicalprocedure but may be used to assess the degree ofbone turnover suppression and/or establish a baselinevalue. However, if the patient relates a history ofgreater than 3 years of oral bisphosphonate use orfewer than 3 years but with concomitant corticoste-roid use or chemotherapy use, a CTX test is highlyrecommended. If the CTX test is returned with avalue of 150 pg/mL or greater, in our experienceinvasive oral surgical procedures can be accom-plished with a minimal risk of osteonecrosis. If theCTX value is less than 150 pg/mL it is recommendedto defer the planned surgery and to contact the pre-scribing physician. It is reasonable to suggest a drugholiday with or without a substitute drug also ap-proved for osteoporosis.36,37 Other drugs with Foodand Drug Administration clearance for osteoporosisinclude raloxifene (Evista; Eli Lilly, Indianapolis, IN),

calcitonin salmon (Miacalcin, Novartis), and recombi-nant human 1-34 parathyroid hormone (rh1-34 PTH-Forteo, Eli Lilly). A drug holiday of 4 months to 6months is recommended before a repeat CTX is ac-complished. If the repeat CTX value is less than 150pg/mL, it is recommended to extend the drug holidaywith the agreement of the prescribing physician.From the data related to the rate of CTX value im-provements during a drug holiday, it is unlikely that aCTX value of 150 pg/mL would require more than a 6month to 9 month drug holiday. In the rare event thatthe treating physician feels that a drug holiday fromthe oral bisphosphonate would worsen the osteopo-rosis and does not want to consider a nonbisphospho-nate alternative osteoporosis treatment, the dentalteam should modify its treatment plan and discuss therisks and benefits to the patient. In this rare situation,elective surgeries such as ridge augmentations, dentalimplant placements, tooth removals, periodontal sur-gery, apicoectomies, and even adult orthodontictooth movements are advised only with caution. In-stead, noninvasive dental care should be emphasized.If urgent invasive procedures such as removal of ab-scessed or severely mobile teeth, incision and drain-age of abscesses, or surgery for severe acute periodon-titis are necessary, they may be accomplished withthe informed consent of the patient and the accep-tance of a greater risk for osteonecrosis.

Treatment of Oral Bisphosphonate-InducedOsteonecrosisOral bisphosphonate-induced osteonecrosis is usu-

ally less extensive, and more responsive to treatmentthan intravenous bisphosphonate-induced osteone-crosis. It also correlates well to the serum CTX and istherefore more predictable. For patients who presentwith exposed bone due to an oral bisphosphonate werecommend that the dental provider contact the pre-scribing physician and inform him/her of this compli-cation and relate that the exposed bone will worsenwith continued oral bisphosphonate use. The oralbisphosphonate should be discontinued by the pre-scribing physician and either a non-bisphosphonatealternative used or a complete drug holiday started.The dental team should order a morning fasting serumCTX test and begin palliative care. If the exposedbone is painless, maintenance with 0.12% chlorhexi-dine is all that is initially required. If the patient relatespain and/or clinical evidence of infection is present,antibiotic therapy should be provided in addition tothe 0.12% chlorhexidine. Penicillin V-K 500 mg 4times daily is the drug of choice due to its activityagainst actinomyces, eikenella, and moraxella specieswhich are the 3 most common species associatedwith secondary infections in exposed bone due tobisphosphonates. If the patient is allergic to penicillin


levoflaxacin (Levaquin) 500 mg once daily is the bestsecond line drug of choice followed by doxycycline(Vibramycin; Pfizer Pharmaceuticals, New York, NY)100 mg once daily, and zithromycin (Zithromax;Pfizer Pharmaceuticals) 250 mg once daily. The anti-biotic regimen should extend for 14 days or until thepain is controlled and only restarted if pain returns. Inpatients refractory to these antibiotics the addition ofmetronidazole (Flagyl; Searle, Chicago, IL) 500 mg 3times daily has proven effective. Clindamycin (Cleo-cin; Pfizer Pharmaceuticals) is not recommended dueto its absent or low activity against the microorgan-isms seen in bisphosphonate-induced osteonecrosiscases.

The oral and maxillofacial surgeon is urged to resistthe temptation to accomplish a local debridementinitially. Many cases of oral bisphosphonate-inducedosteonecrosis will resolve without surgery during theperiod of the drug holiday. If the exposed bone be-comes mobile or shows radiographic evidence of asequestrum, then a local debridement can be accom-plished with the anticipation of uncomplicated heal-ing provided that the CTX value is greater than 150pg/mL.

SUMMARYOral bisphosphonate-induced osteonecrosis is a

rare but real entity caused by the antiosteoclasticeffects of bisphosphonates which inhibit bone turn-over.

The clinical disease of oral bisphosphonate-inducedosteonecrosis is less frequent, less severe, more pre-dictable, and more responsive to treatment than in-travenous bisphosphonate-induced osteonecrosis.

The comorbidities of prednisone and/or methotrex-ate do not produce osteonecrosis by themselves butalong with a bisphosphonate will cause the osteone-crosis to occur sooner, be more severe, and respondmore slowly to a drug holiday.

The serum morning fasting CTX bone turnovermarker is a straightforward and useful tool to assessthe bone turnover/renewal suppression caused byoral bisphosphonates. Its interpretation of less than100 pg/mL as high risk, 100 pg/mL to 150 pg/mL asmoderate risk, and greater than 150 pg/mL as minimalrisk provides the clinician with a useful assessmenttool to predict risk and guide treatment decisions.

Oral and maxillofacial surgeons as well as all otherdental providers should respect the diagnosis ofosteopenia and osteoporosis but should not be intim-idated by the potential for complications when treat-ment planning for patients taking oral bisphospho-nates. With the ability to assess the suppression ofbisphosphonate-induced bone turnover by CTX mea-surements and the guidelines recommended in thisreport, it is possible to provide comprehensive care

with minimal risks to this group of individuals whilemaintaining their control of osteoporosis.

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Oral Bisphosphonate-Induced Osteonecrosis: … AND PATIENT-ORIENTED RESEARCH J Oral Maxillofac Surg 65:2397-2410, 2007 Oral Bisphosphonate-Induced Osteonecrosis: Risk Factors, Prediction