BASIC AND PATIENT-ORIENTED RESEARCH

J Oral Maxillofac Surg 65:2397-2410, 2007

Oral Bisphosphonate-Induced Osteonecrosis: Risk Factors, Prediction of Risk Using Serum CTX Testing, Prevention, and Treatment
Robert E. Marx, DDS,* Joseph E. Cillo, Jr, DDS, and Juan J. Ulloa, DDS
To assess the risk and time course of oral bisphosphonate-induced osteonecrosis of the jaws. Detailed data from 30 consecutive cases were compared with 116 cases due to intravenous aminobisphosphonates. Results: Results in part noted a higher incidence related to alendronate (Fosamax; Merck, Whitehouse Station, NJ), a 94.7% predilection for the posterior mandible, and a 50% occurrence spontaneously, with the remaining 50% resulting from an oral surgical procedure, mostly tooth removals. Just over 53% of patients were taking their oral bisphosphonate for osteopenia, 33.3% for documented osteoporosis, and 13.4% for steroid-induced osteoporosis related to 4 or more years of prednisone therapy for an autoimmune condition. There was a direct exponential relationship between the size of the exposed bone and the duration of oral bisphosphonate use. There was also a direct correlation between reports of pain and clinical evidence of infection. The morning fasting serum C-terminal telopeptide (CTX) test results were observed to correlate to the duration of oral bisphosphonate use and could indicate a recovery of bone remodeling with increased values if the oral bisphosphonate was discontinued. A stratication of relative risk was seen as CTX values less than 100 pg/mL representing high risk, CTX values between 100 pg/mL and 150 pg/mL representing moderate risk, and CTX values above 150 pg/mL representing minimal risk. The CTX values were noted to increase between 25.9 pg/mL to 26.4 pg/mL for each month of a drug holiday indicating a recovery of bone remodeling and a guideline as to when oral surgical procedures can be accomplished with the least risk. In addition, drug holidays associated with CTX values rising above the 150 pg/mL threshold were observed to correlate to either spontaneous bone healing or a complete healing response after an ofce-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 bisphosphonateinduced osteonecrosis. The morning fasting serum C-terminal telopeptide bone suppression marker is a useful tool for the clinician to assess risks and guide treatment decisions. 2007 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 65:2397-2410, 2007
Materials and Methods: Purpose:

Physicians and dentists are now keenly aware of bisphosphonate-induced osteonecrosis of the jaws from the intravenous nitrogen-containing bisphosphonates pamidronate (Aredia; Novartis, East Hanover, NJ) and zoledronate (Zometa; Novartis).
*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.

Oral nitrogen-containing bisphosphonates alendronate (Fosamax; Merck, Whitehouse Station, NJ) and residronate (Actonel; Procter and Gamble Pharmaceuticals, Cincinnati, OH) (and possibly more recently introduced bisphosphonates such as ibandronate
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: rmarx@med.miami.edu
2007 American Association of Oral and Maxillofacial Surgeons

0278-2391/07/6512-0002$32.00/0 doi:10.1016/j.joms.2007.08.003

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2398 [Boniva; Roche Laboratories, Basel, Switzerland]) demonstrate a risk for osteonecrosis as well. Initial reports of bisphosphonate-induced osteonecrosis of the jaws focused on those cases caused by either Zometa or Aredia used to stabilize metastatic cancer deposits in bone.1-6 Nevertheless, several of these publications also reported a smaller number of cases related to oral bisphosphonates used in the treatment of osteopenia and osteoporosis2,3 and since then there have been more publications relating osteonecrosis in patients using oral bisphosphonates.7-9 However, few details were provided and no distinctions concerning the incidence, severity, risks, prevention, or treatment outcomes between the intravenous bisphosphonate cases and the oral bisphosphonate cases were even attempted. The purpose of this article is to present data from 30 cases of oral bisphosphonate-induced osteonecrosis of the jaws contrasting it to the data we have accumulated in 116 cases of intravenous bisphosphonate-induced osteonecrosis cases related to risk factors, prediction of risk, prevention recommendations, and treatment recommendations. The purpose of this paper is also to introduce the morning fasting serum C-terminal telopeptide (CTX) bone turnover marker as a useful clinical tool to help assess risk, and guide the clinicians evaluations of nonsurgical treatment response as well as to guide decisions as to when surgery can be accomplished with the least risk.

ORAL BISPHOSPHONATE-INDUCED OSTEONECROSIS

for a CTX bone turnover marker assessment as part of their regular osteoporosis follow-up. Each patient proceeded to receive nonsurgical management with either 0.12% chlorhexidine initially or 0.12% chlorhexidine combined with an antibiotic; penicillin VK 500 mg 4 times daily if not allergic or Levaquin (OrthoMcNeil Inc, Raritan, NJ) 500 mg once daily if they were allergic to penicillin. The advanced presentation cases and cases refractory to nonsurgical management were resolved with surgical debridements or resections as appropriately guided by the CTX values.

Results
The data concerning the type of oral bisphosphonate, the dose, the frequency, the duration, indications for the bisphosphonate, comorbidities, location, and the size of the exposed bone are presented in Table 1. Twenty-seven cases (90%) resulted from Fosamax use with the mean duration of drug exposure of 5.7 years and 3 from Actonel (10%) use with a mean duration of exposure of 5.0 years. All cases occurred in women at a mean age of 64.8 years. Twenty-eight of the 30 patients took their oral bisphosphonate on a once weekly schedule; Fosamax at 70 mg/wk or Actonel at 35 mg/wk. Two patients took Fosamax 10 mg daily. Sixteen patients (53.3%) were taking their oral bisphosphonate for osteopenia as diagnosed by their prescribing physician and with a bone mineral density (BMD) T-score of greater than -2.5.11 Ten patients (33%) took their oral bisphosphonate for osteoporosis as diagnosed by their prescribing physician and had BMD values relating a T-score of less than -2.5,12 7 others (13.4%) took their bisphosphonates for steroid-induced osteoporosis for which each had concomitantly taken prednisone, and 3 also took methotrexate at varying doses for more than 4 years in treatment of an autoimmune condition. Twenty nine cases (96.7%) occurred in the mandible while only 1 case (3.3%) occurred in the maxilla. Spontaneous bone exposures of the lingual cortex in the molar area occurred in 13 cases (43.4%) (Fig 1). One spontaneous bone exposure (3.3%) occurred at the 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 a mandibular molar tooth and 1 (3.3%) from the removal of several anterior mandibular teeth. Two cases (6.7%) developed as a result of dental implant placements (Fig 3) and another 1 (3.3%) from harvesting a palatal connective tissue graft (Fig 4). Therefore, 15 cases (50%) of oral bisphosphonate-induced osteonecrosis occurred spontaneously without a recognized initiating event and another 15 cases (50%) occurred as the result of an invasive dental procedure.

Materials and Methods

Thirty consecutive cases of exposed bone in the mandible or maxilla that t the American Association of Oral and Maxillofacial Surgeons Task Force denition of bisphosphonate-induced osteonecrosis10 were prospectively included in this data set. The case definition is as follows: the presence of nonhealing exposed bone in the maxilla or mandible that has persisted for more than 8 weeks in a patient who has received a systemic bisphosphonate but has not received local radiation therapy. Each included patient was asked for a detailed history concerning the oral bisphosphonate used, the dose, the frequency, the duration of bisphosphonate therapy, comorbidities, and the indication for the bisphosphonate. Each patient was also surveyed concerning any initiating event that produced the exposed bone, the presence of pain, previous treatment for the exposed bone and whether a response was achieved, and if the bisphosphonate was discontinued. Each patient was then given a comprehensive oral examination noting the size and location of the exposed bone as well as signs of secondary infection. Each patient was also consented and scheduled for a fasting morning blood draw of 1 mL of whole blood

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Table 1. ORAL BISPHOSPHONATE-INDUCED OSTEONECROSIS OF THE JAWS

Patient 1 2 3 4 5 6

Drug*

Dose/ Frequency

Indication

Comorbidities 1 1 1 1

Location: Mandible (n Maxilla (n 1) cm 2 cm 3 cm 1 cm 3 sockets 2 cm 2 1 cm 1 cm cm cm cm

29);

Years of Bisphosphonate Stage 4.1 4.4 3.6 6.4 5 3.4 I I I II I I

Fosamax 70 mg/wk Osteoporosis None Fosamax 70 mg/wk Osteoporosis None Fosamax 70 mg/wk Osteopenia None

lingal cortex molar molar socket molar socket anterior mandibular

7 8 9 10 11 12 13 14 15

16 17

18 19 20 21 22 23 24 25 26 27 28 29 30

Fosamax 70 mg/wk Osteopenia None Actonel 35 mg/wk Osteopenia None cm molar socket cm lingual cortex Fosamax 70 mg/wk Osteoporosis Rheumatoid arthritis, prednisone, methotrexate Fosamax 70 mg/wk Osteopenia None 1 cm 2.5 cm buccal cortex molar area Fosamax 10 mg/ Osteoporosis None 1 cm 1 cm molar socket day Fosamax 70 mg/wk Osteoporosis Systemic lupus 1 cm 1 cm molar socket erythematosus, prednisone Fosamax 70 mg/wk Osteopenia None 2 cm 2 cm molar socket Fosamax 10 mg/ Osteoporosis None 3 cm 4 cm symphysis day Fosamax 70 mg/wk Osteopenia None 1 cm 1.5 cm lingual cortex Fosamax 70 mg/wk Osteoporosis None 1 cm 1 cm molar area lingual cortex Actonel 35 mg/wk Osteoporosis None 1 cm 1 cm molar lingual cortex Fosamax 70 mg/wk Osteoporosis Rheumatoid 3 cm 4 cm molar area palate* arthritis, prednisone, methotrexate Actonel 35 mg/wk Osteopenia None 0.5 cm 0.5 cm lingual cortex Fosamax 70 mg/wk Osteoporosis Rheumatoid 2 cm 2 cm linugal molar arthritis prednisone methotrexate Fosamax 70 mg/wk Osteopenia None 0.5 cm 1 cm lingual molar area Fosamax 70 mg/wk Osteopenia None 2 cm 2 cm molar area Fosamax 70 mg/wk Osteopenia None 2 cm 2 cm molar area buccal torus Fosamax 70 mg/wk Osteoporosis None 1 cm 1 cm lingual molar Fosamax 70 mg/wk Osteopenia None 1 cm 2 cm molar lingual area Fosamax 70 mg/wk Osteoporosis None 1 cm 1 cm molar socket Fosamax 70 mg/wk Osteopenia None 8 cm hemimandible Fosamax 70 mg/wk Osteopenia None 1 cm 1 cm molar socket Fosamax 70 mg/wk Osteopenia None 1 cm 1 cm molar socket Fosamax 70 mg/wk Osteoporosis None 1 cm 1 cm molar socket Fosamax 70 mg/wk Osteoporosis None 7 cm molar bicuspid alveolar crest Fosamax 70 mg/wk Osteopenia None 0.5 cm 0.5 cm lingual cortex Fosamax 70 mg/wk Osteopenia None 0.5 cm 1 cm lingual cortex

8.4 4.4 3.3 7.3 5.5 4.9 8.6 6.2 6.3

II I II III III II II II II

3.8 3.3

I II

3.6 7 9.1 5 8.8 4.1 10.2 4.1 5 5.4 9.3 3.7 3.8

I II I I II II III II II II III I 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.

The length of time patients had taken their oral bisphosphonate ranged from 3.3 years to 10.2 years with the composite mean for both Fosamax and Actonel of 5.6 years. This further segregated to a mean time to exposed bone of only 4.25 years for those patients who also took prednisone with or without methotrexate and 5.8 years for those who took only an oral bisphosphonate (P .018).

The data concerning the size of the bone exposure, the presence of pain, and the presence of infection in relation to the duration of oral bisphosphonate use are presented in Table 2. Nineteen of the 30 patients (63.3%) reported pain associated with their bone exposure. The pain was correlated to clinical evidence of infection (ie, erythema, swelling, drainage, and/or osteolysis) in 18 of the 19 patients (94.7%) who re-

2400

ORAL BISPHOSPHONATE-INDUCED OSTEONECROSIS

FIGURE 3. Bone necrosis resulting from placement of dental implants in a patient who received Fosamax for 5.5 years. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

FIGURE 1. Spontaneous bone exposure of the lingual cortex in the molar area after 4.9 years of Fosamax. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

ported pain. There was also an exponential relationship between the size of the bone exposure and the duration of oral bisphosphonate use (Fig 5). The data concerning the fasting serum CTX bone turnover marker values are presented in Table 3. Seventeen of the 30 patients who presented with an oral bisphosphonate-induced osteonecrosis were still taking their oral bisphosphonate at the time of their presentation. Those 17 patients had CTX values that ranged from 30 pg/mL to 102 pg/mL with a mean of 72.9 pg/mL. After 6 months of discontinuation (drug

holiday) from their oral bisphosphonate the CTX values ranged from 162 pg/mL to 343 pg/mL with a mean of 228.2 pg/mL. This amounted to a mean improvement of 155.3 pg/mL or approximately 25.9 pg/mL per month. Three of these 17 cases were in patients who also received prednisone and methotrexate along with their oral bisphosphonate. Each of these 3 patients exhibited CTX values in the lowest ranges (30 pg/mL, 64 pg/mL, 80 pg/mL) and each improved their CTX slightly below the mean 6 months 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 resolve their osteonecrosis; 3 were resolved with an ofcebased local debridement surgery at CTX values of 291 pg/mL, 299 pg/mL, and 212 pg/mL respectively (Figs 6, 7). The 2 others who had more extensive osteolysis required inpatient management and a mandibular resection to resolve their osteonecrosis at CTX

FIGURE 2. Spontaneous bone exposure of a mandibular buccal torus after 9.1 years of Fosamax. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

FIGURE 4. Bone exposure resulting from a palatal graft harvest after 6.3 years of Fosamax together with the comorbidities of 4 years of prednisone and methotrexate. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

MARX, CILLO, AND ULLOA

2401 healed by 1 year was 175 pg/mL and was 202 pg/mL at 1.5 years. The subgroup of 13 patients that discontinued their oral bisphosphonate (drug holiday) before presenting to our facility were also evaluated with morning fasting serum CTX studies. Their data subset is presented in Table 4 and Figure 13. Their CTX values ranged from 153 pg/mL to 303 pg/mL and correlated to the length of time of their drug holiday. Although no base-line reference points of their CTX values while taking the oral bisphosphonate were available, their improvement of CTX values across this group shows a linear correlation corresponding to a monthly improvement of 26.4 pg/mL per month of drug holiday. This compares favorably with the monthly improvement of 25.9 pg/mL calculated for the subgroup of the 17 patients that were discontinued from the oral bisphosphonate after a baseline CTX value could be obtained.
DATA ANALYSIS

Table 2. MEAN SIZE OF OSTEONECROSIS AND DURATION OF BISPHOSPHONATE EXPOSURE

Duration of Oral BP Use 3 to 4 years 4 to 5 years 5 to 6 years 6 to 7 years More than 7 years

n 8 6 5 3 8

Mean Size of Exposure 0.6cm2 1.5cm2 3.8cm2 4.7cm2 7.9cm2

Pain 2 3 3 2 8

Infection 2 3 3 3 8

Abbreviation: BP, bisphosphonate. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

values of 202 pg/mL and 343 pg/mL respectively (Figs 8-10). Eleven patients experienced resolution of their osteonecrosis without surgery (Figs 11, 12). Five spontaneously sequestered a bone fragment and 6 resorbed their exposed bone, all eventuating into a complete mucosal cover. The mean CTX value for this group was 245.8 pg/mL after a drug holiday of 3 months to 9 months. All 3 patients who had received concomitant prednisone and methotrexate completely healed their exposed bone. However, 1 patient improved with 50% of their original exposed bone covered by healthy-appearing mucosa at 1 year and complete healing by 1.5 years. The CTX values for the 2 that spontaneously healed within 9 months were 204 pg/mL and 196 pg/mL respectively. The CTX value for the prednisone patient that had not
9

Detailed records and data collection from this prospective study of 30 patients generated considerable data. The rst consideration that must be made is that although these 30 patients represent a relatively large series for this rare condition, they represent a very small percentage of patients taking oral bisphosphonates. Although the actual number of individuals taking oral bisphosphonates annually is unknown, Neff13 has related that 13% to 18% of women in the United States over 50 years of age have osteoporosis and that

6 Mean Size cm2

0 1 2 3 4 Duration of Oral Bisphosphonate 5 6 7

FIGURE 5. Mean size of osteonecrosis versus duration of bisphosphonate exposure. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

2402
Table 3. PATIENTS TAKING AN ORAL BISPHOSPHONATE AT TIME OF PRESENTATION

ORAL BISPHOSPHONATE-INDUCED OSTEONECROSIS

Patient 4 7 10 11 15 20 24 28 19 14 22 26 2 12 21 17 13 Mean Score

Duration of CTX BP Years pg/mL 6.4 8.4 7.3 5.5 6.3* 9.1 10.2 9.3 7.0 3.3* 8.8 5.0 4.4 4.9 5.0 3.3* 8.6 102 102 53 88 64 79 33 66 99 30 90 94 72 53 101 80 33 72.9

CTX pg/mL 6 mo After Drug Change Holiday CTX pg/mL 291 199 343 299 204 302 202 232 212 175 162 216 188 194 303 196 162 228.2 189 97 290 211 140 223 169 166 111 145 72 122 116 141 202 116 129 155.3

FIGURE 7. Successful sequestrectomy after a 6 month drug holiday (CTX 299 pg/mL). Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

Abbreviations: BP, bisphosphonate; CTX, C-terminal telopeptide. *Comorbidity of more than 4 years of prednisone. Extensive bone necrosis. Osteonecrosis resolved with ofce debridement surgery at that CTX value. Extensive bone necrosis. Osteonecrosis resolved in patient resection at that CTX value. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

an additional 37% to 50% have osteopenia. Therefore, even though the number of patients receiving oral bisphosphonates is unknown, the number is in the tens of millions. These 30 patients represent only 1 centers experience; the data presented here should not be used to extrapolate prevalence. Ninety percent of our cases were caused by Fosamax and 10% by Actonel. On one hand this higher

incidence related to Fosamax may be biased due to a greater utilization of Fosamax in the public sector. Another possible explanation is dose, potency, absorption, and half life in bone. The weekly dose of Actonel is only 35 mg, while the weekly dose of Fosamax is 70 mg. Fosamax is considered the most potent of the oral bisphosphonates and actually is as potent as the intravenous bisphosphonate Aredia, which can partly explain the higher incidence related to Fosamax.14 Fosamax and other oral bisphosphonates produce a lesser incidence of osteonecrosis and a lesser severity than intravenous bisphosphonates because they are not well-absorbed orally. Both Fosamax and Actonel have a bioavailability of only 0.70% in women and 0.59% in men (a published average bioavailability of 0.64%) under ideal conditions.15,16 In addition, patients often do not take their medications as directed leading to variable absorption rates and a further reduction in bioavailability which may account for the observed variabilities in risk and se-

FIGURE 6. Alveolar bone exposure resulting from tooth extractions after 5.5 years of Fosamax (CTX 88 pg/mL). Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

FIGURE 8. Resection specimen radiograph of an oral bisphosphonate-induced osteonecrosis from a patient with a 10.2 year exposure to Fosamax. Resection accomplished after a 4 month drug holiday (CTX 202 pg/mL). Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

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FIGURE 9. Reconstruction of mandibular defect related to the resection specimen of Figure 8 using a titanium reconstruction plate. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007. FIGURE 11. Spontaneous bone exposure after 5 years of Fosamax (CTX 94 pg/mL).

verity between individuals. Finally, the terminal half life in bone for each oral bisphosphonate is not precisely known. While it is known that the terminal half life in bone is greater than 10 years17 and it has been suggested that Fosamax has a somewhat longer half life in bone than Actonel, this long half life itself precludes an accurate determination beyond this time. Therefore, the difference in the incidence of osteonecrosis between the 3 oral bisphosphonates in use today relates to its accumulation and retention in bone and a clear explanation as to why there are differences may never be completely known. The data clearly indicate that the time over which a patient takes an oral bisphosphonate (accumulation in bone) is the most critical factor. All patients who developed osteonecrosis took an oral bisphosphonate for more than 3 years. Moreover, the data indicate that most cases developed after 5 years or more of drug exposure and that the incidence and severity increased linearly with exposures over 3 years. This is substantially different from osteonecrosis cases

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

caused by intravenous bisphosphonates which requires only a mean of 9.3 months for Zometa and 14.1 months for Aredia to develop exposed bone.2 This faster development of exposed bone is due to the intravenous route which bypasses the low and variable gut absorption of oral bisphosphonates so that after about 40% is cleared in the urine the remainder of the intravenous dose accumulates in bone.18,19 It is likely that the rapid and high dose accumulation in bone from the intravenous bisphosphonates not only induces apoptosis of a large population of osteoclasts but its repeated dosing exhausts the ability of the bone marrow to replenish the osteoclasts from the pool of osteoclast precursors. Comparatively, the

FIGURE 10. Resolution of oral bisphosphonate-induced osteonecrosis after resection and titanium plate reconstruction. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

FIGURE 12. Healing of bone exposure seen in Figure 11 without surgery after a drug holiday of 6 months (CTX 216 pg/mL). Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

2404
Table 4. PATIENTS ON DRUG HOLIDAY AT TIME OF PRESENTATION

ORAL BISPHOSPHONATE-INDUCED OSTEONECROSIS

Patient 1 3 5 6 8 13 16 18 23 25 27 29 30

Drug Holiday Months 2 6 4 12 2 10 8 3 7 8 4 15 6

CTX pg/mL 153 244 206 294 162 303 249 189 216 232 194 303 199

Abbreviation: CTX, C-terminal telopeptide. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

poor absorption of oral bisphosphonates represents only a gradual accumulation in bone and thus may effect the osteoclasts less severely. In addition, their gradual accumulation in bone allows the bone marrow to keep pace with the loss of osteoclasts thus delaying the onset of clinically exposed bone, reducing its severity, and allowing a recovery once the drug is discontinued. It is not unexpected that all patients in this study were women and that the mean age was 64.8 years. These facts are related to the osteopenia/osteoporosis indication for oral bisphosphonates and underscores the fact that oral bisphosphonate-induced osteonecro400

sis of the jaws is mostly a womens health concern and mostly that of postmenopausal women. Even steroid-induced osteoporosis has a prevalence for women because the more common autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus have a strong predilection for women. This differs somewhat from osteonecrosis cases caused by intravenous bisphosphonates due to their indications. That is, a smaller bias toward women is present in this group due to the frequent use of intravenous bisphosphonates for female breast cancers that have developed bony metastasis and that male breast cancer is very rare. However, this is somewhat offset by the remaining indications for intravenous bisphosphonates which include bony metastases mostly from multiple myeloma, and to a lesser extent from lung cancers and prostate cancers all of which have a predilection for men. Despite the bias toward men for these conditions, the incidence of intravenous bisphosphonate-induced osteonecrosis in our database is 70% women. Oral bisphosphonate-induced osteonecrosis developed evenly divided between spontaneous bone exposures and traumatically initiated bone exposures. This contrasts with the experience from intravenous bisphosphonates in which only 25% of cases developed spontaneously. This is most likely due to the fact that the intravenous bisphosphonates accumulate in bone much faster creating a more rapid and more insidious bone turnover suppression. It is also contributed to by the fact that the oral hygiene and periodontal condition was observed to be worse in

350

CTX pg/mL

300

250

200

150

100 0 2 4 6 8 10 12 14 16

Drug Holidays - Months

FIGURE 13. CTX versus duration of drug holiday. Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

MARX, CILLO, AND ULLOA

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the intravenous bisphosphonate group. This in turn is related to the bone marrow and immune suppression of their chemotherapy and the practical fact that many cancer patients experience fatigue and nausea which compromises their ability to maintain plaque control. Of particular note is a signicant difference in location of the exposed bone. While the intravenous bisphosphonates have shown a 25% incidence in the maxilla, only 1 (3.3%) of our 30 cases occurred in the maxilla as compared to 29 of the 30 cases (96.7%) occurring in the mandible. Furthermore, only 2 cases of the 29 cases of mandibular osteonecrosis occurred in the anterior region (6.4%). The remaining 27 cases (93.1%) occurred in the molar region of the mandible as either a spontaneous exposure of mostly lingual cortical bone or as the result of a molar tooth removal. While the molar region of the mandible is also the most common location for an intravenous bisphosphonate-induced osteonecrosis it is not at the strikingly high predilection as now documented in oral bisphosphonate-induced osteonecrosis (41.2% to 93.7%). The predilection for the molar area in general and the mandibular molar area specically is common to all types of bisphosphonates by virtue of their basic mechanism of action. Because all bisphosphonates cause reversible and/or irreversible osteoclast dysfunction they slow down and may even halt bone resorption altogether.20,21 This antiresorptive effect is therapeutic up to a point as proven by their ability to resist cancer-related bone resorption and to slow down the loss of bone mass and even increase bone mass in osteopenia and osteoporosis. However, beyond the therapeutic range of any drug lurks toxicity. Too great of an accumulation of a bisphosphonate in bone will cause a signicant shut down in bone turnover. That is, by inhibition of osteoclasts bone renewal is prevented. This is due to the known role of the osteoclast as a cell which resorbs old bone containing dead or old osteocytes and microfractures and in doing so releases cytokines such as bone morphogenetic protein and insulin-like growth factors 1 and 2 which induce new bone formation. This new bone is more cellular and less mineral and more elastic. As it ages, this bone will also become less cellular, more mineralized, less elastic and will then die off to become resorbed itself and be replaced by yet another generation of bone. Therefore, the rate of bone turnover in any bone directly relates to its vulnerability to bisphosphonates. The mandibular alveolar bone turnover rate is 10 times that of long bones like the tibia.22-24 This is the most likely explanation for the exclusive preponderance for bisphosphonateinduced osteonecrosis to occur in the jaws. In addition, the rate of alveolar bone turnover at the crest is twice the rate of the bone turnover about the man-

FIGURE 14. Actinomyces colony and nonvital bone obtained from a patient with oral bisphosphonate-induced osteonecrosis. (Hematoxylin and eosin stain; 10.) Marx, Cillo, and Ulloa. Oral Bisphosphonate-Induced Osteonecrosis. J Oral Maxillofac Surg 2007.

dibular canal and 3 to 5 times that of the bone about the inferior border.22 This explains why both intravenous bisphosphonates and oral bisphosphonates exposed bone begins in the alveolar bone. It is apparent that occlusal or denture-related compression on the alveolar bone which is greatest in the molar region and creates a more active bone turnover produces a greater vulnerability to drugs that affect osteoclast function over a prolonged period. The presence of pain correlated directly to evidence of infection conrming the concept that nonvital bone by itself is deinnervated and nonpainful. The pain arises from secondary infections which provoke an inammatory response that elaborates the mediators of pain. This is identical to the association of pain from the exposed bone caused by the intravenous bisphosphonates. Although not specically studied, in those cases in which bone debridements were accomplished, the micro-organisms most frequently noted were actinomyces, moraxella, and eikenella species (Fig 14) as is also seen in the exposed bone removed from intravenous bisphosphonate-induced osteonecrosis. The size of the bone exposure, pain, and infection, and the requirement to accomplish surgery all directly correlated to the length of time the patient had been taking the oral bisphosphonate (Table 2, Fig 5). This is particularly noted by the observation that the 3 patients who required an ofce-based debridement had taken Fosamax 6.4 years, 7 years, and 7.2 years respectively and the patients with the most extensive bone involvement requiring a resection had taken Fosamax for 7.3 years and 10.2 years respectively. In fact, the slope of the curve in Figure 5 which plots the square surface area of bone exposure against the

2406 length of time the patient had been taking the oral bisphosphonate is that of an exponential relationship with the largest bone exposures occurring after 5 years of drug use. Although these correlations were also noted in cases of osteonecrosis due to intravenous bisphosphonates they are less clear due to the many more comorbidities associated in the intravenous bisphosphonate patients.
THE C-TERMINAL TELOPEPTIDE DATA ANALYSIS

ORAL BISPHOSPHONATE-INDUCED OSTEONECROSIS

The morning fasting serum CTX test measures a surrogate marker of bone turnover. It is one of several known serum and urine tests that measures a breakdown product of bone resorption.25-27 The CTX specically measures a specic crosslink peptide of type I collagen in bone. Type I collagen is the structural organic component of bone and accounts for 98% of the total protein in bone. The serum CTX is considered to best correlate to bone turnover28 and was chosen due to the fact that a single laboratory (Quest Diagnostics Nichols East Lab in San Juan Capistrano, California) performs this test under standard conditions. The telopeptide fragment in question is cleaved from the main crosslink chains of collagen by the osteoclast during bone resorption. Its level in the serum is therefore proportional to the amount of osteoclastic resorption occurring at the time the blood is drawn. Even though laboratory normal ranges are said to be between 50 pg/mL and 450 pg/mL, this normal range is not accurate related to the osteoporosis population. Actual normal values are usually well over 300 pg/mL and are most commonly 400 pg/mL to 550 pg/mL in patients not taking bisphosphonates. Lower values represent varying degrees of suppression of normal bone turnover sometimes also called bone remodeling or bone renewal. The most controlled CTX data are seen in the group of 17 patients in which we accomplished a CTX test before their oral bisphosphonate was discontinued which is referred to as a drug holiday. These data are seen in Table 3 and Figure 13. This data subset demonstrates that the individuals who were still taking their oral bisphosphonate and had osteonecrosis also had severe suppression of bone turnover: mean CTX of 72.9 pg/mL. In addition, all 17 patients had CTX values less than 110 pg/mL. Even with a CTX day to day variability of 25% as published by Rosen et al28 and allowing for an additional margin of patient variability, one can say that all cases had CTX values less than 150 pg/mL. Although some of the more severe cases had very low CTX values there were too few cases to suggest a correlation between clinical severity and the CTX value. Of clinical importance, the 6-month drug holiday showed a direct and signicant improvement in the CTX values in every patient. This improvement corre-

lated to either spontaneous resolution of the exposed bone, a signicant improvement in the amount of exposed bone, or an uncomplicated healing response after surgery. It was noted that the CTX values improved at an average of 155.3 pg/mL over 6 months or a rate of 25.9 pg/mL each month. This rate of improvement was consistent with the slope of the curve seen in Figure 13 which plots the CTX values against the duration of a drug holiday in the 13-patient subgroup in which the oral bisphosphonate was discontinued at varying times prior to the CTX blood draw. This relationship appeared to be linear and was measured at 26.4 pg/mL per month. These ndings are very signicant because they demonstrate clinical bone recovery and response to a drug holiday. It proves that at least part of the functioning osteoclast population can recover and be re-established from the osteoclast precursors in the bone marrow. This is a clear distinction between the oral bisphosphonate cases and the intravenous bisphosphonate cases in which we mostly observe no improvement or response to local debridement surgery with discontinuation of the intravenous bisphosphonate. Moreover, we have also accomplished over 60 CTX tests in cases of osteonecrosis due to intravenous bisphosphonates and have noted no direct correlations with the size of bone exposure, pain, infection, or severity. Instead, the CTX values more closely correlate with the control of metastatic bone deposits. This reinforces the notion that the intravenous bisphosphonate accumulation in bone is greater than that of the oral bisphosphonates, and that the osteoclast population is less likely to recover due to exhaustion atrophy of the osteoclast precursors in bone. This may also explain why those patients who develop osteonecrosis from an intravenous bisphosphonate in the treatment of multiple myeloma are noted to be more severe, have greater amounts of exposed bone, and are less responsive to treatment than those with metastatic bone deposits from other cancers. That is, the intravenous bisphosphonate suppression of bone marrow osteoclast precursors is added to by the disease itself which replaces much of the normal bone marrow with malignant myeloma cells. The CTX values also noted that prednisone and/or methotrexate used to treat some autoimmune diseases caused a further suppression of bone turnover in the oral bisphosphonate cases and slowed the recovery of bone turnover from the drug holiday. Nevertheless, even in patients with a prednisone comorbidity, the drug holiday was seen to produce a bonehealing response measurable by the CTX values.

Discussion
The data presented in this report concern complications from commonly prescribed drugs in the treatment of a common disease: osteoporosis and its pos-

MARX, CILLO, AND ULLOA

2407 Unfortunately, the BMD only measures bone mass not trabecular bone connectivity or bone elasticity and therefore does not directly or solely correlate with fracture risk.33,34 Because fracture prevention is the goal of the treating physician, the BMD value is only 1 of several factors that are considered in the treatment planning for osteoporosis. Other factors considered are race (Caucasian women are more at risk for fracture than other races), age, diet, exercise, concomitant medications, and family history. Yet the BMD value remains as the most common utilized measure of response to bisphosphonate therapy.35 It is important to note that in a 10-year study by Bone and Hosking et al36 on osteoporosis patients treated with Fosamax, the BMD values improved to a maximum at 3 years and that the group that stopped taking Fosamax at that point experienced no increase in fractures compared with the group that continued taking Fosamax and that their BMD values decreased only slightly over several years. A conrmatory study by Black et al37 noted in a randomized double-blind controlled study of 760 women that once Fosamax had been taken for 5 years, no increase in fractures occurred after another 5 years off the drug. Thus the appropriate utilization of bisphosphonates to prevent fractures will await further dose-accumulation studies. These data combined with the CTX data presented in this report indicate that drug holidays on the order of 4 to 6 months are reasonable, safe, and could be expected to minimize the risk of osteonecrosis (due to the anticipated rise in CTX due to increased osteoclast function) when performing invasive oral surgical procedures in patients taking oral bisphosphonates while also maintaining BMD values and fracture prevention related to the osteoporosis. The efcacy of this concept is supported by the uncomplicated healing and osteonecrosis resolution of the 5 patients in this study who required surgery and the improvement and nonsurgical resolution of the other cases in this study after a 4 month to 9 month drug holiday.
PREVENTION AND TREATMENT RECOMMENDATIONS

sible precursor osteopenia. Oral bisphosphonateinduced osteonecrosis cases are very rare and even though it is anticipated that the number will grow due to improved recognition, further reporting, and more patients receiving these drugs over longer periods of time, it is expected to remain a rare complication. However, patients taking oral bisphosphonates but who do not have osteonecrosis and some who already have exposed bone will still present to many clinicians who must assess the risks of invasive oral procedures, plan prevention strategies, and treat those cases with exposed bone. In doing so the treating dentist or oral and maxillofacial surgeon must consult with the physician treating the osteoporosis and have an understanding of the denitions of osteopenia and osteoporosis as well as the goals and treatment challenges the physician confronts in treating these entities. It is estimated that 14 million women in the United States are currently diagnosed with osteopenia/osteoporosis.13 It is reported that approximately 5% to 15% of patients with untreated osteoporosis eventually develop a nontrauma-related fracture usually of the femoral neck but referred to as a hip fracture or develop compression fractures of the vertebrae, usually the lumbar vertebrae.29-31 These fractures bring about pain and immobility that in this more advanced age group, frequently leads to long term and even permanent disability and sometimes even death. Therefore osteoporosis is a serious disease and a public health problem. The World Health Organization denes osteoporosis based on the dual energy x-ray absorptiometry scan known as a DXA or DEXA scan which measures BMD in mg/cm2.30,32 The reference BMD value is given as an arbitrary normal at the maximum bone mineral density of a population of 22 2-year-old Caucasian women.32 As age and postmenopausal hormonerelated reductions in bone mass occur, it is reected as a lower BMD value or a negative value as compared with this arbitrary norm. Individual BMD values are compared with this arbitrary norm in standard deviations. Within the range of normal is any individual who is less than 1 standard deviation below the norm. Osteopenia is dened as anyone who is between 1 and 2.5 standard deviations below the norm and osteoporosis is dened as anyone who is more than 2.5 standard deviations below the norm. Severe osteoporosis is further dened as an individual who is more than 2.5 standard deviations below the norm and also has a nontraumatic fracture. These standard deviations are referred to as T-scores and are reported as negative numbers (eg, -1, -2.5, etc,) because they represent loss of BMD.

From the data gained from these studies and our clinical experience with both oral and intravenous bisphosphonate-induced osteonecrosis cases, we offer the following recommendations. Prevention Patients rst diagnosed with osteopenia or osteoporosis and are prescribed a bisphosphonate. Because patients taking oral bisphosphonates for less than 3 years have little risk for osteonecrosis, this allows time for the dental team to obtain optimum oral health and repair of the dentition. Similar to the

2408 recommendations already in place for a patient about to receive intravenous bisphosphonates, the treating physician is recommended to refer the patient to his/her dentist for an evaluation, treatment, and monitoring program focused on attaining and maintaining oral health. The dental team should accomplish a complete medical and dental history and a thorough oral examination. Nonrestorable and abscessed teeth should be removed rst, followed by periodontal therapy with a recall schedule established. Root canal therapy if indicated should be accomplished next followed by any indicated restorative dental care and prosthodontic appliances. Little is known concerning orthodontic care at this point, but it is anticipated that adult orthodontic care is feasible and safe but may be slowed or even stopped during the rst 3 years of oral bisphosphonate exposure due to the antiresorptive (antiosteoclastic) effects of the bisphosphonate.38,39 Dental implant placements are also likely safe and will osseointegrate during this period.40 However, informed consent should be provided as to an increased risk for implant failure or osteonecrosis about the implants once the oral bisphosphonate exposure exceeds 3 years. Patients who have been taking an oral bisphosphonate and present for dental treatment. In this group the dentist needs to specically ask the patient the length of time of oral bisphosphonates use as well as the dose, the indication, and the possible use of concomitant steroids or other medications that might affect bone healing. In general, nonsurgical dental procedures such as restorations, dentures, root canal therapy, dental prophylaxis, supragingival scaling, and crowns are safe at all times in bisphosphonateexposed patients. For patients who relate a history of fewer than 3 years of oral bisphosphonate use, bone healing is expected to be uncomplicated. Therefore, a serum CTX is not required prior to an oral surgical procedure but may be used to assess the degree of bone turnover suppression and/or establish a baseline value. However, if the patient relates a history of greater than 3 years of oral bisphosphonate use or fewer than 3 years but with concomitant corticosteroid use or chemotherapy use, a CTX test is highly recommended. If the CTX test is returned with a value of 150 pg/mL or greater, in our experience invasive oral surgical procedures can be accomplished with a minimal risk of osteonecrosis. If the CTX value is less than 150 pg/mL it is recommended to defer the planned surgery and to contact the prescribing physician. It is reasonable to suggest a drug holiday with or without a substitute drug also approved for osteoporosis.36,37 Other drugs with Food and Drug Administration clearance for osteoporosis include raloxifene (Evista; Eli Lilly, Indianapolis, IN),

ORAL BISPHOSPHONATE-INDUCED OSTEONECROSIS

calcitonin salmon (Miacalcin, Novartis), and recombinant human 1-34 parathyroid hormone (rh1-34 PTHForteo, Eli Lilly). A drug holiday of 4 months to 6 months is recommended before a repeat CTX is accomplished. If the repeat CTX value is less than 150 pg/mL, it is recommended to extend the drug holiday with the agreement of the prescribing physician. From the data related to the rate of CTX value improvements during a drug holiday, it is unlikely that a CTX value of 150 pg/mL would require more than a 6 month to 9 month drug holiday. In the rare event that the treating physician feels that a drug holiday from the oral bisphosphonate would worsen the osteoporosis and does not want to consider a nonbisphosphonate alternative osteoporosis treatment, the dental team should modify its treatment plan and discuss the risks and benets to the patient. In this rare situation, elective surgeries such as ridge augmentations, dental implant placements, tooth removals, periodontal surgery, apicoectomies, and even adult orthodontic tooth movements are advised only with caution. Instead, noninvasive dental care should be emphasized. If urgent invasive procedures such as removal of abscessed or severely mobile teeth, incision and drainage of abscesses, or surgery for severe acute periodontitis are necessary, they may be accomplished with the informed consent of the patient and the acceptance of a greater risk for osteonecrosis. Treatment of Oral Bisphosphonate-Induced Osteonecrosis Oral bisphosphonate-induced osteonecrosis is usually less extensive, and more responsive to treatment than intravenous bisphosphonate-induced osteonecrosis. It also correlates well to the serum CTX and is therefore more predictable. For patients who present with exposed bone due to an oral bisphosphonate we recommend that the dental provider contact the prescribing physician and inform him/her of this complication and relate that the exposed bone will worsen with continued oral bisphosphonate use. The oral bisphosphonate should be discontinued by the prescribing physician and either a non-bisphosphonate alternative used or a complete drug holiday started. The dental team should order a morning fasting serum CTX test and begin palliative care. If the exposed bone is painless, maintenance with 0.12% chlorhexidine is all that is initially required. If the patient relates pain and/or clinical evidence of infection is present, antibiotic therapy should be provided in addition to the 0.12% chlorhexidine. Penicillin V-K 500 mg 4 times daily is the drug of choice due to its activity against actinomyces, eikenella, and moraxella species which are the 3 most common species associated with secondary infections in exposed bone due to bisphosphonates. If the patient is allergic to penicillin

MARX, CILLO, AND ULLOA

2409 with minimal risks to this group of individuals while maintaining their control of osteoporosis.

levoaxacin (Levaquin) 500 mg once daily is the best second line drug of choice followed by doxycycline (Vibramycin; Pzer Pharmaceuticals, New York, NY) 100 mg once daily, and zithromycin (Zithromax; Pzer Pharmaceuticals) 250 mg once daily. The antibiotic regimen should extend for 14 days or until the pain is controlled and only restarted if pain returns. In patients refractory to these antibiotics the addition of metronidazole (Flagyl; Searle, Chicago, IL) 500 mg 3 times daily has proven effective. Clindamycin (Cleocin; Pzer Pharmaceuticals) is not recommended due to its absent or low activity against the microorganisms seen in bisphosphonate-induced osteonecrosis cases. The oral and maxillofacial surgeon is urged to resist the temptation to accomplish a local debridement initially. Many cases of oral bisphosphonate-induced osteonecrosis will resolve without surgery during the period of the drug holiday. If the exposed bone becomes mobile or shows radiographic evidence of a sequestrum, then a local debridement can be accomplished with the anticipation of uncomplicated healing provided that the CTX value is greater than 150 pg/mL.
SUMMARY

References
1. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2003 2. Marx RE, Sawatari Y, Fortin M, et al: Bisphosphonate induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention and treatment. J Oral Maxillofac Surg 63:1567, 2005 3. Ruggerio SL, Mekrota B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527, 2004 4. Purcell PM, Boyd IW: Bisphosphonates and osteonecrosis of the jaw. Med J Aust 182:417, 2005 5. Migliorati CA, Schubert MM, Peterson DE, et al: Bisphosphonate associated osteonecrosis of mandibular and maxillary bone: An emerging oral complication of supportive cancer therapy. Cancer 104:83, 2005 6. Bagan JV, Jimenez Y, Murillo J, et al: Jaw osteonecrosis associated with bisphosphonates multiple exposed areas and its relationship to teeth extractions. Study of 20 cases. Oral Oncol 42:327, 2006 7. Brooks JK, Gilson AJ, Sindler AJ, et al: Osteonecrosis of the jaws associated with use of residronate. Report of 2 new cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103:780, 2007 8. Mavrokoski T, Cheng A, Stein B, et al: Nature and frequency of bisphosphonate associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 65:415, 2007 9. Wynn RL: Oral bisphosphonates and osteonecrosis of the jaw. Gen Dent 55:8, 2007 10. Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369, 2007 11. Varney LF, Parker RA, Vincelette A, et al: Classication of osteoporosis and osteopenia in postmenopausal women in dependent on site-specic analysis. J Clin Densitom 2:275, 1999 12. Leib ES, Lewiecki EM, Binkley N, et al: Ofcial positions of the International Society for Clinical Densitometry. J Clin Densitom 7:1, 2007 13. Neff MJ: Practical guidelines: ACOG releases guidelines for clinical management of osteoporosis. Am Fam Physician 69:1, 2004 14. Licata AA: Discovery, clinical development, and therapeutic uses of bisphosphonate. Ann Pharmacother 39:668, 2005 15. Product information (Fosamax). Whitehouse Station, NJ, Merck Co, 2005 16. Product information (Actonel). Cincinnati, OH, Procter and Gamble Pharmaceuticals, 2005 17. Lasseter KC, Porras AG, Denker A, et al: Pharmacokinetic considerations in determining the terminal elimination halflives of bisphosphonates. Clin Drug Invest 25:107, 2005 18. Product information sheet, Aredia. Pamidronatate sodium for injection, for intravenous infusion. East Hanover, NJ, Novartis AG, 2001 19. Zometa. Zoledronic acid injection product information sheet. East Hanover, NJ, Novartis AG, 2004 20. Rogers MJ, Gordon S, Benford HL, et al: Cellular and molecular mechanisms of action of bisphosphonates. Cancer 88:2961, 2000 21. Adoina CV, Zerwekh JE, Rao S, et al: Severely suppressed bone turnover: A potential complication of Alendronate therapy. J Clin Endocrinol Metab 90:1294, 2005 22. Dixon RB, Tricker ND, Garetto LP: Bone turnover in elderly canine mandibles and tibia. J Dent Res 76 (IADR Abstracts), 1997:2579 23. Viznery A, Baron R: Dynamic histomorphometry of alveolar bone remodeling in the adult rat. Anat Rec 196:191, 1980

Oral bisphosphonate-induced osteonecrosis is a rare but real entity caused by the antiosteoclastic effects of bisphosphonates which inhibit bone turnover. The clinical disease of oral bisphosphonate-induced osteonecrosis is less frequent, less severe, more predictable, and more responsive to treatment than intravenous bisphosphonate-induced osteonecrosis. The comorbidities of prednisone and/or methotrexate do not produce osteonecrosis by themselves but along with a bisphosphonate will cause the osteonecrosis to occur sooner, be more severe, and respond more slowly to a drug holiday. The serum morning fasting CTX bone turnover marker is a straightforward and useful tool to assess the bone turnover/renewal suppression caused by oral bisphosphonates. Its interpretation of less than 100 pg/mL as high risk, 100 pg/mL to 150 pg/mL as moderate risk, and greater than 150 pg/mL as minimal risk provides the clinician with a useful assessment tool to predict risk and guide treatment decisions. Oral and maxillofacial surgeons as well as all other dental providers should respect the diagnosis of osteopenia and osteoporosis but should not be intimidated by the potential for complications when treatment planning for patients taking oral bisphosphonates. With the ability to assess the suppression of bisphosphonate-induced bone turnover by CTX measurements and the guidelines recommended in this report, it is possible to provide comprehensive care

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24. Brunski JB: In vivo bone response to biochemical loading at the bone/dental-implant interface. Adv Dent Res 13:99, 1999 25. Marx RE (ed): Risks, prevention, and management of intravenous bisphosphonate-induced osteonecrosis of the jaws, in History, Etiology, Prevention, and Treatment. Hanover Park, IL, Quintessence Publ, 2006, pp 77-95 26. Garnero P, Delmas PD: Biochemical markers of bone turnover: Applications for osteoporosis. Endocrinol Metab Clin North Am 27:303, 1998 27. Rosen HN, Moses AC, Garber J, et al: Utility of biochemical markers of bone turnover in the follow-up of patients treated with bisphosphonates. Calcif Tissue Int 63:363, 1998 28. Rosen HN, Moses AC, Garber J, et al: Serum CTX. A new marker of bone resorption that shows treatment effect more often than other markers because of low coefcient of variability and large changes with bisphosphonate therapy. Calcif Tissue Int 66:100, 2000 29. US Food and Drug Administration. 2004. FDA publication 041322C. 30. Black DM, Thompson DE, Bauer DC, et al: Fracture Intervention Trial: Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial. FIT Research Group [Erratum in 86:938, 2001]. J Clin Endocrinol Metab 85:4118, 2000 31. Liberman UA, Weiss SR, Broll J, et al: Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 333:1437, 1995

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32. Melton LJ 3rd, Khosla S, Achenbach SJ, et al: Effects of body size and skeletal site on the estimated prevalence of osteoporosis in women and men. Osteoporos Int 11:977, 2000 33. Cummings SR, Karpf DB, Harris F: Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 112:281, 2002 34. Sarkar S, Mitlak BH, Wong M, et al: Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 17:1, 2002 35. Marcus R, Wong M, Heath H 3rd, et al: Antiresorptive treatment of postmenopausal osteoporosis: Comparison of study designs and outcomes in large clinical trials with fracture as an endpoint. Endocr Rev 23:16, 2002 36. Bone HG, Hosking D, Devogelaer JP, et al: Ten years experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189, 2004 37. Black DM, Schwartz AV, Ensrud KE, et al, FLEX Research Group: Effects of continuing or stopping alendronate after 5 years of treatment: The Fracture Intervention Trial Long-term Extension (FLEX): A randomized trial. JAMA 296:2927, 2006 38. Rinchuse DJ, Rinchuse DJ, Sosovicka MF, et al: Orthodontic treatment of patients using bisphosphonates: A report of 2 cases. Am J Orthod Dentofacial Orthop 131:321, 2007 39. Zahorski JJ: Bisphosphonate treatment: An orthodontic concern calling for a proactive approach. Am J Orthod Dentofacial Orthop 131:311, 2007 40. Jeffcoat MK: Safety of oral bisphosphonates: Controlled studies on alveolar bone. Int J Oral Maxillofac Implants 21:349, 2006