Osteonecrosis of the Jaw and the Role of Macrophages

Pazianas, Michael

doi:10.1093/jnci/djq516

Cited by 126 publications

(105 citation statements)

References 72 publications

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“…It has also been proposed that the adverse effects of nitrogen-containing bisphosphonates on macrophage viability may impair the immune response, acting on the mevalonate pathway to induce apoptosis [84,85]. Vitamin D deficiency is associated with reduced macrophage differentiation and decreased production of the antibacterial protein, cathelicidin, and may further suppress the response to infection [86].…”

Section: Altered Immune Statusmentioning

confidence: 99%

Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

Compston

2011

Osteoporos Int

104

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In recent years, atypical femoral fractures and osteonecrosis of the jaw have emerged as potential complications of long-term bisphosphonate therapy; osteonecrosis of the jaw has also been reported in patients receiving high doses of denosumab. The pathophysiology of both conditions is poorly defined, and the underlying mechanisms are likely to differ. The initiation of atypical fractures in the lateral femoral shaft suggests that reduced tensile strength, possibly secondary to alterations in the material properties of bone resulting from low bone turnover, may be an important pathogenetic factor. Osteonecrosis of the jaw is characterised by infection, inflammation, bone resorption and bone necrosis, but the sequence in which these occur has not been established. However, the observation that bone resorption occurs in close proximity to microbial structures suggests that infection may be the most important trigger, often as a result of dental disease. Other possible pathogenetic factors include suppression of bone turnover, altered immune status and adverse effects of bisphosphonates on the oral mucosa.

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Section: Altered Immune Statusmentioning

confidence: 99%

Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

Compston

2011

Osteoporos Int

104

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“…35) Thus, other factors-possibly, infection or impairment of the defense mechanisms against infection-might be the common, and most important, factor leading to the induction of ONJ by N-BPs and denosumab. 28,35,36) We previously reported that lipopolysaccharide (LPS), a potent inflammatory component of the cell walls of Gram-negative bacteria, augments both the production of the inflammatory cytokine IL-1 and the induction of the histamine-forming enzyme histidine decarboxyl- ase. 31,32) Possibly, such an increased production of IL-1 might act in conjunction with that induced by N-BPs (see above a-d).…”

Section: )mentioning

confidence: 99%

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

Kiyama

Tsuchiya

Okada

et al. 2016

Biological & Pharmaceutical Bulletin

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Bisphosphonates (BPs) are used against diseases involving increased bone-resorption. Among BPs, nitrogencontaining BPs (N-BPs) have much stronger anti-bone-resorptive effects than non-nitrogen-containing BPs (non-N-BPs). However, N-BPs carry the risk of inflammatory/necrotic effects, including osteonecrosis of jawbones. When injected into mouse ear-pinnas, N-BPs induce inflammatory/necrotic effects within the ear-pinna. We previously found that (a) the non-N-BPs clodronate and etidronate can reduce such side effects of N-BPs, and (b) phosphonoformate (an inhibitor of the phosphate transporters SLC20 and SLC34) can reduce the inflammatory/necrotic effects of zoledronate (the N-BP with the highest reported risk of side effects). However, it is not clear (i) whether phosphonoformate can reduce the side effects of other N-BPs, too, and (ii) whether other phosphonocarboxylates have such inhibitory effects. Here, using the mouse ear-pinna model, we compared the effects of etidronate, clodronate, and four phosphonocarboxylates on the inflammatory/necrotic effects of N-BPs of the alkyl type (alendronate) or cyclic type (zoledronate and minodronate). Like phosphonoformate, the other three phosphonocarboxylates protected against the inflammatory/necrotic effects of all the N-BPs. The protective potencies were clodronate>etidronate>phosphonoacetate>phosphonoformate> phosphonopropionate>phosphonobutyrate. With a similar order of potencies, these agents reduced the amount of 3 H-alendronate retained within the ear-pinna after its injection therein. The mRNAs of SLC20 and SLC34 were detected in untreated ear-pinnas. These findings suggest that the inhibition of phosphate transporters by phosphonocarboxylates, as well as by etidronate and clodronate, might be a useful preventive strategy against the side effects of both alkyl-and cyclic-type N-BPs.

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“…The direct toxic effects of bisphosphonates on oral mucosa can result in the ability of oral pathogens to pass through defective or severely damaged oral mucosa and infect the bone [120]. Clinically, gastrointestinal intolerability is one of the most recognisable side effects of oral preparations of nitrogen-containing bisphosphonates such as alendronate, risendronate and ibandronate.…”

Section: Direct Toxicity To Oral Mucosal Cellsmentioning

confidence: 99%