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Possible Association between Diabetes and Bisphosphonate-Related Jaw Osteonecrosis

Department of Internal Medicine B and the Diabetes Center (M.K., E.L., I.R.), Hebrew University-Hadassah Medical Center, Departments of Oral and Maxillofacial Surgery (E.R.) and Oral Medicine (S.E.), Hebrew University-Hadassah School of Dental Medicine, and Department of Hematology (B.A., S.E.), Hadassah Medical Center, Jerusalem 91120, Israel; and Department of Oral Pathology and Oral Medicine (N.Y.), The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Address all correspondence and requests for reprints to: Mogher Khamaisi, M.D., Ph.D., Department of Internal Medicine B and the Diabetes Center, Hebrew University-Hadassah Medical Center, Kiryat Hadassah, P.O. Box 12000, Jerusalem 91120, Israel. E-mail: murir{at}hadassah.org.il; or mogher{at}bgumail.bgu.ac.il.

	Abstract

Top Abstract Introduction Patients and Methods Results and Discussion References

 
Context: Bisphosphonate-related osteonecrosis (BON) of the jaws is a newly identified condition for which the exact mechanism involved in its pathogenesis remains obscure.

Objective: The objective of the study was to evaluate whether diabetes mellitus (DM) may be a contributing factor in the development of BON.

Design: From 2004 to 2006, 31 patients were diagnosed with BON. The diagnosis of BON was based on the medical and dental history of each patient as well as the observation of clinical signs and symptoms of this pathological process. DM was based on two consecutive fasting blood glucose levels above 7 mmol/liter.

Setting: The study was completed in the Hebrew University-Hadassah Hospital referral center.

Results: Of the 31 patients with BON, 18 (58%) were found to have DM or impaired fasting glucose. The proportion of diabetic patients was much higher than expected relative to the incidence of DM in the general population (14%) and compared with the proportion of diabetic patients in a control group of oncological patients treated with bisphosphonates and without BON (12%) (P = 0.00003).

Conclusions: This finding indicates that DM may be a risk factor for BON and that DM patients treated with bisphosphonates should be carefully monitored. We discuss here the bone metabolic pathways characteristic of DM patients and the way in which these pathways can augment the effects of bisphosphonates.

	Introduction

Top Abstract Introduction Patients and Methods Results and Discussion References

 
BISPHOSPHONATES ARE COMMONLY prescribed for the treatment of hypercalcemia associated with breast and prostate cancers; osteolysis associated with metastatic bone disease, especially multiple myeloma; Paget disease; and for the treatment and prevention of postmenopausal corticosteroid-induced osteoporosis (1). Since late 2003, there have been reports in the literature of a possible association between bisphosphonate use and the appearance of avascular necrosis of the jaw (2, 3). Marx (4) and co-workers described a group of 36 American patients who received either pamidronate or zoledronate iv for the management of bone disease associated with metastatic cancer, multiple myeloma and osteoporosis and who subsequently developed avascular necrosis of the jaws. In the majority of patients, the latter condition developed after dental extraction, but in about 30% of cases, it apparently occurred spontaneously.

Bisphosphonate-related osteomyelitis (BON) and necrosis of the jaw possibly results from the inability of hypodynamic and hypovascular bone to meet an increased demand for repair and remodeling owing to physiological stress (mastication), iatrogenic trauma (tooth extraction or denture-induced local injury), or tooth infection in an environment that is both trauma intense and bacteria laden. Coexisting factors may include the use of other medications with antiangiogenic properties such as glucocorticoids, diabetes mellitus (DM), irradiation of the jawbone, peripheral vascular disease, and hyperviscosity syndrome (5).

The pathogenesis of BON and its connection to treatment with high-potency bisphosphonates is unclear. Chronic treatment with zoledronic acid has been implicated as a greater contributor to the development of BON than pamidronate (6, 7). This may be due to its greater potency, as demonstrated by larger reductions in collagen type-I degradation products (N-telopeptide) (8). In addition, the antiangiogenic activity of zoledronic acid that may lead to impairment of blood supply has also been implicated in the development of BON. In a prospective series of 252 patients treated with bisphosphonates, the incidence of BON was highest among patients with myeloma, and the risk increased with duration of exposure, use of zoledronic acid, and oral trauma (either dental procedures or wearing dentures). The incidence of BON was 1.5% among patients treated with these agents for 4–12 months, rising to 7.7% after treatment for 37–48 months (6).

The current study was conducted to examine the possibility that DM has a role in the development of BON in patients treated with bisphosponates. We report here on a group of 19 BON patients with concurrent diabetes-related diagnoses [type 2 DM, impaired fasting glucose (IFG) and previous gestational diabetes]. This study presents the incidence of DM in BON patients, compared with DM incidence in a control group.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results and Discussion References

 
Bisphosphonate therapy has been used in our medical center for the last few years. From 2004 to 2006, 31 patients were diagnosed with BON. According to the position paper of the American Academy of Oral Medicine, the diagnosis of BON was based on the medical and dental history of each patient as well as the observation of clinical signs and symptoms of this pathological process (9). Accordingly, diagnosis was based on the patients’ medical history (bisphosphonate treatment), clinical evaluation (pain, bone exposure, purulent secretion or swelling), and histopathological evaluation when available (10).

All data including age, gender, and medical background including DM were obtained from medical records. Diabetic status was confirmed by personal phone interview and diagnostic blood glucose level. In patients for whom no data were available, diagnosis of DM was based on two consecutive fasting blood glucose levels above 7 mmol/liter. IFG was defined as two consecutive fasting blood glucose levels 100 or greater and 7 mmol/liter or less.

The retrospective control group was selected randomly from the pool of hematooncological patients. The patients were from the same medical center and were treated with bisphosphonates during a time period parallel to that of the patients who were diagnosed with BON. The inclusion criteria for the retrospective control group were: 1) treatment with bisphosphonates; 2) underlying hematooncological disease; and 3) no diagnosis of BON. The control group was matched to the BON patients by age, gender, and the underlying disease requiring bisphosphonate treatment.

The incidence of diabetes in the BON and control (non-BON oncological patients) groups was analyzed statistically using a two-tailed paired t test.

The study was approved by the institutional ethics review board.

	Results and Discussion

Top Abstract Introduction Patients and Methods Results and Discussion References

 
Of the 31 patients with BON, 18 (58%) were found to have DM or IFG (Table 1). The patients included 13 females and five males, ranging in age from 47 to 83 yr, with a mean age of 64.8 yr. Patients had been treated with bisphosphonate for breast cancer (seven patients); multiple myeloma (six patients); non-Hodgkin lymphoma (two patients); and rheumatoid arthritis, osteoporosis, and prostate cancer (one patient for each diagnosis). An additional patient had gestational DM and had been treated with bisphophonate for breast cancer.

Fourteen patients were known to have type 2 diabetes before starting bisphosphonate treatment. Of the remaining 17 patients, four were found to have IFG during a retrospective laboratory data search, and 13 had normal fasting blood glucose levels (<5.5 mmol/liter). In addition, one patient had a history of gestational diabetes.

Twelve of the 19 patients of the DM group (including the IFG and gestational diabetes) had received systemic steroids in the past. This number includes a patient who was reported to have received prednisone for only 2 d. Six of the patients were treated with prednisone and six were treated with dexamethasone.

Among the remaining 12 patients suffering from BON but with no diagnosis of DM or IFG, the mean age was 58.75 yr and ranged from 47 to 85 yr. This group included eight females and five males. The most common indications for bisphosphonate therapy were mostly multiple myeloma (five of 12 patients) and cancer (five of 12 patients). The propensity for involvement of the mandibular bone was seen also in BON without DM (69% of cases had mandibular involvement). Only one patient among the non-DM patients had a concurrent diagnosis of hypertension, compared with seven hypertensive patients in the DM group. Seven patients had received steroids.

Of the 33 control patients who were treated with bisphosphonate without developing BON, four (12%) were found to have DM. The patients included 13 females and 20 males, ranging in age from 35 to 79 yr, with a mean age of 63.7 yr. Patients had been treated with bisphosphonate for multiple myeloma (27 patients), diffused large B cell lymphoma (three patients), non-Hodgkin lymphoma, nasopharyngeal carcinoma, and malignant thymoma (one patient for each diagnosis). Eighteen of the 33 control patients had previously been treated with systemic steroids.

The difference in the incidence of DM-related diagnoses between the BON group and the non-BON group (i.e. oncological patients treated with bisphosphonates without BON) was statistically significant (P < 0.001).

Conclusions

The pathogenesis of bisphosphonate-induced osteonecrosis is obscure. The high incidence of jaw osteonecrosis occurring concomitantly with diabetes reported here may have several explanations. Diabetes is generally associated with microvascular ischemia of the bone (11), endothelial cell dysfunction (12), and decreased bone turnover and remodeling (13) as well as induced apoptosis of osteoblasts and osteocytes (14). In vivo and in vitro data uniformly support the concept that new bone formation, as well as bone microarchitectural integrity, is altered in the diabetic state, leading to an increased risk of fragility fracture and inadequate bone regeneration after injury (15). In addition, diabetes is associated with delayed wound healing (16). Bisphosphonates may further exacerbate these states. Recently, it has been shown in a preclinical model in which mice were given high doses of zoledronic acid that bisphosphonate inhibits endothelial cell function and angiogenesis (17), additional processes that are known to be impaired in diabetic patients. However, there is still no evidence in the clinical setting that impaired vascularity occurs.

Decreased cellular reduced glutathione content is a common finding in experimental and human diabetes, in which increased oxidative stress appears to occur. Recently a new nontraumatic rat model was used to investigate the relationship between oxidative stress and the development of osteonecrosis. In this model, glutathione levels were markedly reduced with the prooxidant buthionine sulfoximine. A high rate of osteonecrosis was noted in this animal group. These results suggest that oxidative stress alone may be sufficient to promote the development of osteonecrosis (18). The augmented oxidative stress in the diabetic patients may be one of the explanations for the high incidence of BON in our group of patients.

The accepted incidence of DM in a matched-age population in developed countries is less than 14% (19, 20). This fact emphasizes the unusually high incidence of DM or IFG found among patients suffering from BON.

Clearly, the study presented here has limitations due to its retrospective nature. However, we deem these data valuable because there has been to date no report of DM as a potential risk factor for BON. This poses a challenge to be pursued in a prospective study, including quantitative analysis of bisphosphonates treatment, concomitant medications, severity of BON, and glycemic levels.

We want by this report to alert clinicians to the potential relationship between DM and bone necrosis in patients receiving bisphosphonate therapy. Further research is needed to understand the pathogenesis of the disease and its relation to diabetes, including correlative studies between the severity of BON and glycemic control.

	Acknowledgments

 
We thank Dr. Cheryl Balshayi for editorial assistance and Wafi Hamed (Department of Oral Medicine, Hebrew University) for his help in collecting the data.

	Footnotes

 
This work was supported by the Russell Berrie Foundation and D-Cure, Diabetes Care in Israel.

Disclosure Statement: The authors have nothing to disclose.

First Published Online December 19, 2006

Abbreviations: BON, Bisphosphonate-related osteonecrosis; DM, diabetes mellitus; IFG, impaired fasting glucose.

Received September 19, 2006.

Accepted December 11, 2006.

	References

Top Abstract Introduction Patients and Methods Results and Discussion References

 

1. Lindsay RCF 2001 Osteoporosis. In: Braunwald EFA, Kasper DL, Hauser SL, Long DL, Jameson JL, eds. Harrison’s principles of internal medicine. New York: McGraw-Hill; 2226–2237
2. Pogrel MA 2004 Bisphosphonates and bone necrosis. J Oral Maxillofac Surg 62:391–392[Medline]
3. Wang J, Goodger NM, Pogrel MA 2003 Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 61:1104–1107[CrossRef][Medline]
4. Marx RE 2003 Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117[CrossRef][Medline]
5. Woo SB, Hande K, Richardson PG 2005 Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 353:99–102[Free Full Text]
6. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, Dimopoulos MA 2005 Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–8587[Abstract/Free Full Text]
7. Durie BG, Katz M, Crowley J 2005 Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 353:99–102[Free Full Text]
8. Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, Apffelstaedt J, Hussein M, Coleman RE, Reitsma DJ, Seaman JJ, Chen BL, Ambros Y 2001 Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 7:377–387[Medline]
9. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB 2005 Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 136:1658–1668[Abstract/Free Full Text]
10. 2002 Osteomyelitis. In: Neville BW, Damm DD, Allen CM, Bougout JE, eds. Oral and maxillofacial pathology. 2nd ed. Philadelphia: W. B. Saunders Co.
11. Hill SL, Holtzman GI, Buse R 1999 The effects of peripheral vascular disease with osteomyelitis in the diabetic foot. Am J Surg 177:282–286[CrossRef][Medline]
12. Sorensen VR, Mathiesen ER, Clausen P, Flyvbjerg A, Feldt-Rasmussen B 2005 Impaired vascular function during short-term poor glycaemic control in type 1 diabetic patients. Diabet Med 22:871–876[CrossRef][Medline]
13. Carnevale V, Romagnoli E, D’Erasmo E 2004 Skeletal involvement in patients with diabetes mellitus. Diabetes Metab Res Rev 20:196–204[CrossRef][Medline]
14. Kumeda Y 2006 Bone metabolic abnormality in diabetes, especially about osteoblast dysfunction. Clin Calcium 16:17–25
15. Thrailkill KM, Lumpkin CK, Bunn RC, Kemp SF, Fowlkes JL 2005 Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab 289:E735–E745
16. Stegeman CA 2005 Oral manifestations of diabetes. Home Health Nurse 23:233–240
17. Yamagishi S, Abe R, Inagaki Y, Nakamura K, Sugawara H, Inokuma D, Nakamura H, Shimizu T, Takeuchi M, Yoshimura A, Bucala R, Shimizu H, Imaizumi T 2004 Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling. Am J Pathol 165:1865–1874[Abstract/Free Full Text]
18. Ichiseki T, Ueda Y, Katsuda S, Kitamura K, Kaneuji A, Matsumoto T 2005 Oxidative stress by glutathione depletion induces osteonecrosis in rats. Rheumatology (Oxf) 45:287–290
19. Varas-Lorenzo C, Rueda de Castro AM, Maguire A, Miret M 2006 Prevalence of glucose metabolism abnormalities and cardiovascular co-morbidity in the U.S. elderly adult population. Pharmacoepidemiol Drug Saf 15:317–326[CrossRef][Medline]
20. Forouhi NG, Merrick D, Goyder E, Ferguson BA, Abbas J, Lachowycz K, Wild SH 2006 Diabetes prevalence in England, 2001—estimates from an epidemiological model. Diabet Med 23:189–197[CrossRef][Medline]

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khamaisi, M. Articles by Elad, S. Search for Related Content PubMed PubMed Citation Articles by Khamaisi, M. Articles by Elad, S. Related Collections Calcium and Bone Metabolism Diabetes and Insulin