Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology
Oral medicineA model for the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw and teriparatide's potential role in its resolution
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:
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the estrogen endocrine pathway that preserves BMD
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the canonical Wnt/β-catenin signaling pathway, a major signaling pathway that facilitates bone formation
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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
References (102)
Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic
J Oral Maxillofac Surg
(2003)- et al.
Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment
J Oral Maxillofac Surg
(2005) - et al.
Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia
J Oral Maxillofac Surg
(2007) - et al.
Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: an institutional inquiry
J Am Dent Assoc
(2009) - et al.
Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment
J Oral Maxillofac Surg
(2007) - et al.
American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update
J Oral Maxillofac Surg
(2009) - et al.
Resolution of bisphosphonate-associated osteonecrosis of the mandible: possible application for intermittent low-dose parathyroid hormone [rhPTH(1-34)]
J Oral Maxillofac Surg
(2007) - et al.
Osteoclast-osteoblast communication
Arch Biochem Biophys
(2008) - et al.
Cellular and molecular mechanisms of bone remodeling
J Biol Chem
(2010) - et al.
Bone remodeling: multiple cellular interactions required for coupling of bone formation and resorption
Semin Cell Dev Biol
(2008)
Is Wnt signalling the final common pathway leading to bone formation?
Mol Cell Endocrinol
Inhibition of glycogen synthase kinase-3beta attenuates glucocorticoid-induced bone loss
Life Sci
Increased circulating Dickkopf-1 in Paget's disease of bone
Clin Biochem
Bisphosphonates: mechanism of action and role in clinical practice
Mayo Clin Proc
Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling
Bone
Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis
Cell Metab
Angiogenic suppression of osteoclasts may play a role in developing bisphosphonate-related osteonecrosis of the jaw
Med Hypotheses
Correlations between biochemical markers of bone turnover and bone density responses in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate
Bone
Bone formation markers in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate
Bone
Molecular and cellular mechanisms of the anabolic effect of intermittent PTH
Bone
Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw—a serial case analysis
J Oral Maxillofac Surg
Osteonecrosis of the jaws induced by anti-RANK ligand therapy
Br J Oral Maxillofac Surg
Effect of parathyroid hormone on release of interleukin 1 and interleukin 6 from cultured mouse osteoblastic cells
Biochem Biophys Res Commun
Coming to grips with bone loss
Science
Osteoporosis treatments and adverse events
Curr Opin Rheumatol
American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw—2009 update
Aust Endod J
Oral bisphosphonate therapy and osteonecrosis of the jaw: what to tell the concerned patient
Int J Prosthodont
Teriparatide therapy for alendronate-associated osteonecrosis of the jaw
N Engl J Med
Resolution of osteonecrosis of the jaw after teriparatide [recombinant human PTH-(1-34)] therapy
J Rheumatol
Successful treatment of advanced bisphosphonate-related osteonecrosis of the mandible with adjunctive teriparatide therapy
Head Neck
Bisphosphonate-associated osteonecrosis of the jaw, with healing after teriparatide: a review of the literature and a case report
Spec Care Dentist
More on the resolution of bisphosphonate-associated osteonecrosis of the jaw
J Rheumatol
Bone microdamage
Osteoporos Int
Bone microdamage: a clinical perspective
Osteoporos Int
Cross-talk among bone cells
Curr Opin Nephrol Hypertens
Bone microdamage and cell apoptosis
Eur Cells Mater
Microdamage and apoptosis
Eur J Morphol
Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone
Am J Physiol, Cell Physiol
Osteocyte: the unrecognized side of bone tissue
Osteoporos Int
Bone modeling and remodeling
Crit Rev Eukaryot Gene Expr
Osteocytes—martyrs for integrity of bone strength
Osteoporos Int
The science and practice of bone health in oncology: managing bone loss and metastasis in patients with solid tumors
J Natl Compr Cancer Netw
Pathogenesis of osteoporosis: concepts, conflicts, and prospects
J Clin Invest
Update on estrogens and the skeleton
J Clin Endocrinol Metab
Biology of RANK, RANKL, and osteoprotegerin
Arthritis Res Ther
Genetics of osteoporosis: accelerating pace in gene identification and validation
Hum Genet
Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoidsPotential mechanisms of their deleterious effects on bone
J Clin Invest
Assessment of fracture risk
Osteoporos Int
New insights in myeloma-induced osteolysis
Leuk Lymphoma
Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma
J Clin Invest
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The effects of mechanically loaded osteocytes and inflammation on bone remodeling in a bisphosphonate-induced environment
2019, BoneCitation Excerpt :A bidirectional interaction occurs between osteoclast ephrinB ligands and osteoblast Eph receptors; this facilitates the transition from resorption to osteoclast attenuation and osteoblast bone formation. Subramanian et al. postulate that when local remodeling synergy is compromised, bone cells are unable to respond to injury (i.e. dental extraction) at the site of the lesion, resulting in BRONJ [87,88]. We are presently working to establish osteoclast-osteoblast co-cultures for the study of bidirectional signaling and have determined culture conditions and densities that enable concurrent functional activity of both cell types (data not shown).
Effects of pH alteration on the pathogenesis of medication-related osteonecrosis of the jaw
2019, BoneCitation Excerpt :In 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) defined MRONJ with the following characteristics in their position paper; (1) current or previous treatment with antiresorptive or antiangiogenic agents; (2) exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for >8 weeks; and (3) no history of radiation therapy to the jaws or obvious metastatic disease to the jaws [31]. Despite the growing number of reports and awareness linking prolonged BPs treatment with ONJ, however, the pathogenesis of this condition is still not well-defined [32,33]. To the best of our knowledge, this is the first in-vivo study inducing pH-altering conditions and determining its role on MRONJ pathogenesis.
Successful treatment of MRONJ in the palatal torus with teriparatide
2018, Journal of Oral and Maxillofacial Surgery, Medicine, and PathologyCitation Excerpt :Although intractable medication-related osteonecrosis of the jaw (MRONJ) (bisphosphonate was administered in this case) was first described by Marx in 2003 [1], there is still no established effective therapy for this condition. However, several recent studies have reported good treatment outcomes after administering the parathyroid hormone (PTH) preparation teriparatide and teriparatide acetate (PTH-A) [2–5]. The use of teriparatide in the treatment of MRONJ is presumed to be effective in improving declining bone turnover of the jaw and in segregating necrotic bone, which are characteristic of MRONJ pathology [3].
Role of nutritional vitamin D in osteoporosis treatment
2018, Clinica Chimica ActaManagement of medication-related osteonecrosis of the jaw according to the clinical grade: An analysis of 19 cases
2018, Revista Espanola de Cirugia Oral y MaxilofacialThe MRONJ Lesion—Dead or Dynamic?
2017, Journal of Oral and Maxillofacial Surgery