Nonexposed Bisphosphonate-Related Osteonecrosis of the Jaws: Another Clinical Variant?

Junquera, Luís; Gallego, Lorena

doi:10.1016/j.joms.2008.02.012

Cited by 104 publications

(76 citation statements)

References 7 publications

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“…Thus, the unexplained manifestations leading to dental extraction would be the first clinical sign of underlying bone necrosis. Interestingly, cases of bisphosphonaterelated ONJ without bone exposure were recently reported [45,46]. However, a subclinical infectious origin cannot be totally excluded even if, when mucosal closure was achieved, to protect the bone from the septic oral environment, bone necrosis frequently continued to spread.…”

Section: Discussionmentioning

confidence: 99%

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Lesclous

Najm

Carrel

et al. 2009

Bone

194

140

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Osteonecrosis of the jaw (ONJ) can be associated with nitrogen-containing bisphosphonates (NBPs) therapy. Various mechanisms of NBP-associated ONJ have been proposed and there is currently no consensus of the underlying pathogenesis. The detailed medical and dental histories of 30 ONJ patients treated with NBPs for malignant diseases (24) or osteoporosis (6) were analyzed. The necrotic bone was resected and analyzed histologically after demineralization. In 10 patients the perinecrotic bone was also resected and processed without demineralization. Alveolar bone samples from 5 healthy patients were used as controls. In 14 ONJ patients, serial technetium-99m-methylene diphosphonate scintigraphic scans were also available and confronted to the other data. Strong radionuclide uptake was detected in some patients several months before clinical diagnosis of ONJ. The medullary spaces of the necrotic bone were filled with bacterial aggregates. In the perinecrotic bone, the bacteria-free bone marrow characteristically showed an inflammatory reaction. The number of medullary inflammatory cells taken as an index of inflammation allowed us to discriminate two inflammation grades in the ONJ samples. Low-grade inflammation, characterized by marrow fibrosis and low inflammatory cells infiltration, increased numbers of TRAP + monoand multineacleated cells was seen in patients with bone exposure b 2 cm 2 . High-grade inflammation, associated with larger lesions, showed amounts of tartrate-resistant acid phosphatase + /calcitonin receptor − mono-and multinucleated cells, osteocyte apoptosis, hypervascularization and high inflammatory cell infiltration. The clinical extent of ONJ was statistically linked to the numbers of inflammatory cell. Taken together these data suggest that bone necrosis precedes clinical onset and is an inflammation-associated process. We hypothesize that from an initial focus, bone damage spreads centrifugally, both deeper into the jaw and towards the mucosa before the oral bone exposure and the clinical diagnosis of ONJ.

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Section: Discussionmentioning

confidence: 99%

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Lesclous

Najm

Carrel

et al. 2009

Bone

194

140

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“…A total of 96 patients (29.8%) presented jawbone manifestations that fulfilled the description of presumed nonexposed variant of bisphosphonate-associated osteonecrosis of the jaws, as described in previous reports. 2,[14][15][16] Relevant clinical features included: 1) jaw pain, 2) jaw bone enlargement/gingival swelling, and 3) sinus tract, which could not be related to dental disease or another local or systemic disorder other than osteonecrosis.…”

Section: Methodsmentioning

confidence: 99%

“…[1][2][3]13 More recently, however, there have been reports suggesting that bisphosphonate-associated osteonecrosis of the jaw, especially in its early stages, can manifest signs and symptoms in absence of bone exposure. 2,[14][15][16] Jaw bone pain, sinus tract and gingival/bone swelling in the absence of obvious dental or jawbone disease other than osteonecrosis have occasionally been reported weeks or months before the onset of frank bone exposure. [14][15][16] Transient, early-stage "possible bisphosphonate-associated osteonecrosis of the jaws" and a "nonexposed variant of osteonecrosis" have been proposed as terms for describing this manifestation.…”

mentioning

confidence: 99%

“…2,[14][15][16] Jaw bone pain, sinus tract and gingival/bone swelling in the absence of obvious dental or jawbone disease other than osteonecrosis have occasionally been reported weeks or months before the onset of frank bone exposure. [14][15][16] Transient, early-stage "possible bisphosphonate-associated osteonecrosis of the jaws" and a "nonexposed variant of osteonecrosis" have been proposed as terms for describing this manifestation. 2,[14][15][16] There remain, however, few studies describing in detail such clinical features and little evidence regarding their frequency and natural history.…”

mentioning

confidence: 99%

“…[14][15][16] Transient, early-stage "possible bisphosphonate-associated osteonecrosis of the jaws" and a "nonexposed variant of osteonecrosis" have been proposed as terms for describing this manifestation. 2,[14][15][16] There remain, however, few studies describing in detail such clinical features and little evidence regarding their frequency and natural history.…”

mentioning

confidence: 99%

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Nonexposed Variant of Bisphosphonate-associated Osteonecrosis of the Jaw: A Case Series

Fedele

Porter

D’Aiuto

et al. 2010

The American Journal of Medicine

218

150

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PURPOSE:To report a case series of patients with the nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw-a form of jaw osteonecrosis that does not manifest with necrotic bone exposure/ mucosal fenestration. METHODS: Among 332 individuals referred to 5 clinical centers in Europe because of development of jawbone abnormalities after or during exposure to bisphosphonates, we identified a total of 96 patients who presented with the nonexposed variant of osteonecrosis. Relevant data were obtained via clinical notes; radiological investigations; patients' history, and referral letters. RESULTS:The most common clinical feature of nonexposed osteonecrosis was jaw bone pain (88/96; 91.6%); followed by sinus tract (51%), bone enlargement (36.4%); and gingival swelling (17.7%). No radiological abnormalities were identified in 29.1% (28/96) of patients. In 53.1% (51/96) of the patients; nonexposed osteonecrosis subsequently evolved into frank bone exposure within 4.6 months (mean; 95% confidence interval; 3.6-5.6). CONCLUSIONS: Clinicians should be highly vigilant to identify individuals with nonexposed osteonecrosis, as the impact on epidemiological data and clinical trial design could be potentially significant. Although the present case series represents approximately 30% of all patients with bisphosphonates-associated osteonecrosis observed at the study centers, further population-based prospective studies are needed to obtain robust epidemiological figures.

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Periapical Disease and Bisphosphonates Induce Osteonecrosis of the Jaws in Mice

Kang

Cheong

Chaichanasakul

et al. 2013

Journal of Bone and Mineral Research

103

142

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Osteonecrosis of the jaw (ONJ) is a well-recognized complication of antiresorptive medications, such as bisphosphonates (BPs). Although ONJ is most common after tooth extractions in patients receiving high dose BPs, many patients do not experience oral trauma. Animal models utilizing tooth extractions and high BP doses recapitulate several clinical, radiographic and histologic findings of ONJ. We and others have reported on rat models of ONJ utilizing experimental dental disease in the absence of tooth extraction. These models emphasize the importance of dental infection/inflammation for ONJ development. Here, we extend our original report in the rat, and present a mouse model of ONJ in the presence of dental disease. Mice were injected with high dose zoledronic acid and pulpal exposure of mandibular molars was performed to induce periapical disease. After 8 weeks, quantitative and qualitative radiographic and histologic analyses of mouse mandibles were executed. Periapical lesions were larger in vehicle- vs. BP treated mice. Importantly, radiographic features resembling clinical ONJ, including thickening of the lamina dura, periosteal bone deposition and increased trabecular density, were seen in the drilled site of BP treated animals. Histologically, osteonecrosis, periosteal thickening, periosteal bone apposition, epithelial migration and bone exposure were present in the BP treated animals in the presence of periapical disease. No difference in TRAP+ cell numbers was observed, but round, detached, and removed from the bone surface cells were present in BP animals. Although 88% of the BP animals showed areas of osteonecrosis in the dental disease site, only 33% developed bone exposure, suggesting that osteonecrosis precedes bone exposure. Our data further emphasize the importance of dental disease in ONJ development, provide qualitative and quantitative measures of ONJ, and present a novel mouse ONJ model in the absence of tooth extraction that should be useful in further exploring ONJ pathophysiological mechanisms.

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Nonexposed Bisphosphonate-Related Osteonecrosis of the Jaws: Another Clinical Variant?

Cited by 104 publications

References 7 publications

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Nonexposed Variant of Bisphosphonate-associated Osteonecrosis of the Jaw: A Case Series

Periapical Disease and Bisphosphonates Induce Osteonecrosis of the Jaws in Mice

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