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Bisphosphonate-related osteonecrosis of the jaws is caused by dental procedures that violate oral epithelium; this is no longer a mysterious disease

Published:November 18, 2013DOI:https://doi.org/10.1016/j.oooo.2013.09.076
      To the Editor:
      Regarding the article “Bisphosphonate related osteonecrosis of the jaws: spontaneous or dental origin?,”
      • Pichardo S.E.
      • van Merkesteyn J.P.
      Bisphosphonate related osteonecrosis of the jaws: spontaneous or dental origin?.
      the authors Sarina E. C. Pichardo and J. P. Richard van Merkesteyn should be commended for a landmark discovery. They have answered the question posed in the title of their article—it can be concluded that bisphosphonate-related osteonecrosis of the jaws is caused by dental procedures. This malady is not spontaneous or mysterious; it occurs with invasive, and usually elective, dental surgical procedures. This fact has largely been overlooked, as epidemiologic studies in populations who have not had dental surgery are often cited as proof that bisphosphonate-related osteonecrosis of the jaws (BRONJ) is very rare.
      • Lo J.C.
      • O'Ryan F.S.
      • Gordon N.P.
      • et al.
      Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure.
      For example, the American Dental Association states that the incidence of this malady is only 0.10%.
      • Hellstein J.W.
      • Adler R.A.
      • Edwards B.
      • et al.
      Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs.
      However, when one looks at the incidence of BRONJ in populations of patients who have taken oral bisphosphonates before dental surgery, the incidence is far higher.
      • Sedghizadeh P.P.
      • Stanley K.
      • Caligiuri M.
      • Hofkes S.
      • Lowry B.
      • Shuler C.F.
      Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: an institutional inquiry.
      The authors state that the “precise mechanism of BRONJ remains unclear.” Perhaps this statement should be directed to dentists and dental surgeons alone. It is now apparent from the work of one of their colleagues from Leiden, Serge Cremers, along with his distinguished colleagues in the United States, that bisphosphonates inhibit cell migration necessary for healing.
      • Landesberg R.
      • Cozin M.
      • Cremers S.
      • et al.
      Inhibition of oral mucosal cell wound healing by bisphosphonates.
      The cause is inhibition of prenylation of small GTPases that are essential to intracellular processes required for cytoskeletal organization in cell function. This has been known for over 10 years.
      • Dunford J.E.
      • Thompson K.
      • Coxon F.P.
      • et al.
      Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.
      Cremers et al. modeled bisphosphonate accumulation in bone at the very same university as these 2 distinguished researchers. His work with Landesberg discovered a toxic threshold for bisphosphonate concentration in epithelial cells. Our work, published in Triple O,
      • Sedghizadeh P.P.
      • Jones A.C.
      • LaVallee C.
      • et al.
      Population pharmacokinetic and pharmacodynamic modeling for assessing risk of bisphosphonate-related osteonecrosis of the jaw.
      • Schaudinn C.
      • Gorur A.
      • Webster P.
      • et al.
      Quantification by energy dispersive x-ray spectroscopy of alendronate in the diseased jaw bone of patients with bisphosphonate-related jaw osteonecrosis.
      created a predictive model for toxic accumulation based on the work of Cremers et al.
      • Cremers S.
      • Sparidans R.
      • den H.J.
      • Hamdy N.
      • Vermeij P.
      • Papapoulos S.
      A pharmacokinetic and pharmacodynamic model for intravenous bisphosphonate (pamidronate) in osteoporosis.
      ; this model verified that a 0.1mM concentration of bisphosphonate in bone predicted BRONJ. With our model of accumulation, it is possible to predict when a patient has accumulated a toxic concentration of bisphosphonate—one that would predict the induction of BRONJ after the violation of the oral epithelium by dental surgery.
      One more small point deserves attention. In the opening paragraph it is incorrectly stated that bisphosphonates “further growth and metastasizing in bone.” Bisphosphonates actually inhibit bone growth by osteoblastic inhibition and inhibit metastatic tumor growth by inhibiting the osteoclastic activity and intracellular processes of cancer cells required for expansion in bone lesions.
      Dentists who elect to perform invasive dental procedures on patients who have received bisphosphonates should recognize this very significant article for establishing a clear case for iatrogenesis. In this sense, BRONJ is of “dental origin.” Such adverse consequences may be avoided by abstaining from invasive dentoalveolar surgery when possible in patients predicted to have bisphosphonate concentrations in bone exceeding the toxic threshold (>0.1mM).

      References

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        Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs.
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        Population pharmacokinetic and pharmacodynamic modeling for assessing risk of bisphosphonate-related osteonecrosis of the jaw.
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      Linked Article

      • Bisphosphonate-related osteonecrosis of the jaws of dental origin
        Oral Surgery, Oral Medicine, Oral Pathology and Oral RadiologyVol. 117Issue 3
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          With reference to the Letter to the Editor regarding the article “Bisphosphonate-related osteonecrosis of the jaws: spontaneous or dental origin?”1 we would like to thank the authors for their kind words, opinions, and suggestions. We agree with the authors on BRONJ being of dental origin, caused not only by dental procedures but also by dental pathology, as our article states.
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      • Bisphosphonate related osteonecrosis of the jaws: spontaneous or dental origin?
        Oral Surgery, Oral Medicine, Oral Pathology and Oral RadiologyVol. 116Issue 3
        • Preview
          Bisphosphonates are frequently used worldwide mostly in osteoporosis and skeletal bone metastases. However, a serious side-effect is bisphosphonate related osteonecrosis of the jaws (BRONJ). The mechanism behind BRONJ remains unclear. In literature several origins are suggested. Presence of the teeth in the jaws may play an important role. Therefore in this study 45 patients were analyzed retrospectively.
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