Oral medicine
A model for the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw and teriparatide's potential role in its resolution

https://doi.org/10.1016/j.tripleo.2011.04.020Get rights and content

Objective

The objective of this study was to present a comprehensive model for the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw (BON).

Study design

Review of PubMed literature relevant to BON, bisphosphonates (BPs), and bone remodeling.

Results

Six case reports of spontaneous resolution of BON lesions following administration of teriparatide (Forteo; Eli Lilly and Co., Indianapolis, IN) were identified. These reports suggest that osteoanabolic therapies may hold promise in BON management. Here we propose that BON pathogenesis is multifactorial and is the combined result of attenuated osteoblastic activity (owing to the patient's underlying disease, e.g., osteoporosis or multiple myeloma), BP-mediated osteoclast toxicity, and the resultant compromised osteoblast-osteoclast interactions during bone remodeling. Consequently, a vicious cycle of ineffective local remodeling results in the persistence of defective bone, compromised tissue perfusion, and if unresolved, ultimately leads to necrosis.

Conclusions

Our model for BON pathogenesis advocates for earlier therapeutic intervention in BON. The biological rationale for teriparatide's efficacy in BON justifies further investigation.

Section snippets

1. Role of the underlying disease- suppression of osteoblast function

Bone diseases that warrant clinical management with BPs are all reflective of an underlying imbalance between bone formation and resorption, with a net excess of uncompensated resorption.29, 30

Bone homeostasis involves 3 key biological pathways:

  • the estrogen endocrine pathway that preserves BMD

  • the canonical Wnt/β-catenin signaling pathway, a major signaling pathway that facilitates bone formation

  • the receptor activator of NF-κβ ligand/receptor activator of NF-κβ/osteoprotegerin (RANKL/RANK/OPG)

Model for the Pathogenesis of BON

Our model of the pathogenesis of BON as an outcome of ineffective remodeling is based on the current accepted model of bone remodeling that involves the complex multidirectional communication or crosstalk between OBs, OCs, osteocytes, and bone-lining cells. Our model also accounts for the reports of resolution of BON incidentally noted upon treatment with teriparatide.

We believe that BON is the result of a failed local remodeling process (Fig. 1A). Persistent bone defects from ineffective

Teriparatide and the Resolution of BON Lesions

Recently, 6 independent case reports have documented the ability of a drug called teriparatide to affect clinical resolution of BON lesions (summarized in Table I).11, 12, 13, 14, 15, 16 The initial reports were coincidental observations made in patients whose osteoporosis medications were switched from BPs to teriparatide because of BON resulting from BP therapy. Among these patients, one was on intravenous BPs before developing BON,13 whereas the remainder were originally on oral BPs. Within

The Strengths and Weaknesses of Our Model for BON's Multifactorial Pathogenesis

Our model for BON pathogenesis is consistent with existing evidence on BON. We regard BON as a dynamic lesion, with ongoing but ineffective remodeling, in an attempt to eliminate and repair defective bone. There is increasing evidence for active bone remodeling in BON lesions, contradictory to the theory that BON is the direct result of low bone turnover following treatment with BPs. The earliest evidence for active remodeling in BON came from histopathological studies of BON lesions that

Conclusions

We present here a model for the pathogenesis of BON. We hypothesize that ineffective remodeling in BON is multifactorial. The combined effects of compromised bone formation that accompanies the primary disease and inhibition of bone resorption by bisphosphonates creates a “perfect storm” setting in a subset of patients who eventually develop BON, when unable to maintain bone homeostasis or repair bone injury. Measuring the relative balance between markers of bone formation and resorption may be

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