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Current Definition of ONJ

Clinical Features
Exposed bone in maxillofacial area that occurs in association with dental surgery (approximately 75% of the cases) or occurs spontaneously (usually occurs in areas prone to trauma, ie. tori), with no evidence of healing1 Pain can or cannot be present No evidence of healing after 8 weeks of appropriate evaluation and dental care2 No evidence of metastatic disease in the jaw or osteoradionecrosis

Diagnosis of ONJ

1. Ruggiero S, et al. J Oncol Pract. 2006;2:7-14 2. Khosla S, et al. J Bone Miner Res. 2007;22:1479-1491.

Ostenecrosis of the jaw after anticatabolic treatment

Epidemiology of osteonecrosis of the jaw

ONJ in patients with osteoporosis: 0,0028% - 0,0053% ~ 1:19.000 - 1:36.000 No specific recommendations.

ONJ in BP-treated patients with cancer : 1 10% = ~ 1:10 1:100

Etiopathogenesis of ONJ not known

ONJ: Are There any Concerns in Clinical Practice?

Bisphosphonate-associated ONJ Cases in Osteoporosis

ONJ has been reported in approx. 5% of patients with cancer receiving highdose IV bisphosphonates1 The risk of bisphosphonate-related ONJ was estimated to be approx. 1 in < 100,000 patient-treatment years2 Review of 44 case reports/series in 2008 describing 481 patients with bisphosphonate-related ONJ found3: ONJ more common in patients receiving IV bisphosphonates (453 patients, 94.2%) vs. oral bisphosphonates (28 patients, 5.8%) Over 90% of patients who developed ONJ had cancer Approx. 31% of patients had prior use of glucocorticoids 68.8% cases occur after surgical or invasive dental procedures 93 patients (20.7%) developed ONJ spontaneously More recently, ONJ has been reported in cancer patients treated with denosumab1

IV = intravenous 1. Reid IR, Cornish J. Nat Rev Rheumatol. 2011;doi:10.1038/nrrheum.2011.181. 2. Burr DB, et a. J Musculoskelet Neuronal Interact. 2007;7:354355. 3. King AE, et al. Pharmacotherapy. 2008;28:66777.

Atypical femur fractures: Are There Any in Clinical Studies?

ASBMR Task Force on Atypical Femur Fractures: Provisional Case Definition

Main Features Located along the femur from just distal to the lesser trochanter to just proximal to the supracondular flare Associated with no or minimal trauma Transverse or short oblique configuration Non-comminuted Complete fractures must extend through both cortices while incomplete fractures involve only the lateral cortex

Minor Features Periosteal reaction of the lateral cortex (beaking) Increase cortical thickness Prodromal pain Bilateral fractures and symptoms Delayed healing Comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis) Use of pharmaceutical agents (e.g. bisphosphonates, glucocorticoids)

ASBMR = American Society of Bone and Mineral Research. Shane E et al. J Bone Miner Res. 2010.

Subtrochanteric Fractures of the Femur

Watts NB et al. J Clin Endocrinol Metab 2010;95:15551565.

Case Study
September 2008 May 2009 June 2009

Report: Normal

Report: Thickening of the cortex of shaft of left femur; slightly more than on the film in 2008 stress fracture?

CT femur

Epidemiological Data on Atypical Femur Fractures

Atypical fractures can also be seen (with lower frequency) in non-bisphosphonate users Current opinion is that atypical fractures are stress fractures that may appear earlier on bone scan or CT scan Reasons are unknown and may propagate in a small subset of patients

ASBMR = American Society of Bone Mineral Research; CT = computerized tomography. Pazianas M, Abrahamsen B. Bone 2011. 49:103110.

The Absolute Risk of Atypical Fracture among Bisphosphonate Users is Small

Number, n Patients Who Would
Need to Be Treated* Type of fracture Any fracture Any nonvertebral fracture Hip fracture only 35 90 100 29 11

Events per 1000 Patients

Treated for 3 Years

Vertebral fracture



Hypothetical relative risk of subtrochanteric or diaphyseal femur fracture

2.0 1449 0.7

*Estimated numbers of patients who would need to be treated with either zoledronic acid or alendronate in order to prevent one fracture were derived from fracture rates, as compared with placebo in the FIT and HORIZON-PFT;The number of events per 1000 patients treated for 3 years refers to fractures that would be prevented by bisphosphonate treatment. Black DM, et al. N Engl J Med 2010;362:17611771.

Case Reports/Case Series Involving Atypical Fractures of the Femur

A recent systematic review of the literature up to 2010 that identified 141 atypical femoral fractures following bisphosphonate therapy showed:* The bisphosphonate regimen preceding fracture was: Alendronate, n = 119 Risedronate, n = 7 Pamidronate, n = 3 Sequential therapy, n = 7 Unspecified, n = 5 53/120 patients (44%) suffered bilateral fractures Prodromal pain was common (56/88; 64%)

*Bisphosphonate administered at a dosing regimen used for the prevention or treatment of osteoporosis Alendronate/ibandronate, n=4; alendronate/risedronate, n=2; pamidronate/risedronate, n=1. Giusti A, et al. Bone 2010;47:169180.

Post-hoc analysis of baseline characteristics of patients in the HORIZON-RFT study who suffered a low-trauma hip fracture showed that incident subtrochanteric fractures: Are not uncommon Do occur in bisphosphonate-nave patients Secondary analysis of 14,195 patients from the FIT, FLEX and HORIZON-PFT trials showed: No significant increase in risk of subtrochanteric or diaphyseal femur fracture after bisphosphonate treatment The pathophysiology of atypical subtrochanteric or diaphyseal fractures is unclear