BRONJ Review
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MRONJ follows nitrogen-containing bisphosphonates (N-BPs) administration

Metabolic effects of N-BPs :

Effect of N-BPs on Mevalonate Pathway

Underlying Mechanisms and Therapeutic Strategies for Bisphosphonate-Related Osteonecrosis of the Jaw - BRONJ 2017

The inhibition of farnesyl diphosphate synthase (FPP) leads to

• an increase of uphill substrates (IPP)
• a decrease of downhill substrates (cholesterol, CoQ10, farnesylPP and related metabolisms)

The decrease of CoQ10 slows the respiratory chain rate leading to:

• decrease of the intracellular ATP
• decreased heme synthesis rate
  • decrease of eNOS activity
  • decrease of Cytochrome C (with additional impairment of respiratory chain)

The prevalence of BRONJ in patients under N-BPs is around 10?

Median age is high

• median age 77 years, 87% women (Bisphosphonate-related osteonecrosis of the jaw in patients with oral bisphosphonate exposure: clinical course and outcomes. , 2012)
• The prevalence of BPs-associated ONJ is higher between 55-74 years old (Bisphosphonates-induced osteonecrosis of the jaw - epidemiological, clinical and histopathological aspects. 2018)
• 220 women, 17 men; median age 73 years (Prevalence and Risk Factors of Atypical Femoral Fracture Bone Scintigraphic Feature in Patients Experiencing Bisphosphonate-Related Osteonecrosis of the Jaw. 2018)
• The incidence of BRONJ increased with age, was greater in the mandible than the maxilla (Risk factors of osteonecrosis of the jaw after tooth extraction in osteoporotic patients on oral bisphosphonates. 2017

Additional Risk Factors

• Aging
  • Hypothyroidism
    • MANAGEMENT OF ENDOCRINE DISEASE: l-Thyroxine replacement therapy in the frail elderly: a challenge in clinical practice. 2017 : The prevalence of overt and subclinical hypothyroidism is as high as 20%
  • reduction of DHEA synthesis
    • Effects of aging on dehydroepiandrosterone sulfate in relation to fasting insulin levels and body composition assessed by bioimpedance analysis. 1997 : The increased insulin resistance documented throughout aging, with its accompanying hyperinsulinemia, may contribute to the age-related decline in DHEA synthesis.
• Statins that inhibit HMG-CoA reductase
• Glucocorticoids
  • Diabetes and corticosteroid treatment seem to be important contributing factors for BRONJ.(Bisphosphonate related osteonecrosis of the jaws: clinico-pathological investigation and histomorphometric analysis. 2013
  • Concomitant corticosteroid administration or tobacco smoking may prolong the duration for complete remission of BRONJ lesion: Clinical treatment outcomes for 40 patients with bisphosphonates-related osteonecrosis of the jaws. 2012
• Diabetes
  • Diabetes mellitus is an established risk factor associated with bisphosphonate-related osteonecrosis of the jaw / BRONJ: Bisphosphonate induces Osteonecrosis of the Jaw in Diabetic Mice via NLRP3/Caspase-1-Dependent IL-1β Mechanism. 2016
  • of the 46 patients with BRONJ, 31 (67.4%) had diabetes or impaired fasting glucose. (Diabetes microvascular disease and the risk for bisphosphonate-related osteonecrosis of the jaw: a single center study. 2013

Histological findings

• Osteosclerosis
  • Learning from experience. Proposal of a refined definition and staging system for bisphosphonate‐related osteonecrosis of the jaw (BRONJ) 2012
• Vascular congestion
  • Cases and controls did not differ for any study variable except for vascular congestion that was significantly associated with N-BPS use (multivariable OR = 0.24, exact 95% CI 0.10 to 0.57 for cases vs. controls, p = 0.0006). (Exposure to antiresorptive therapy with bisphosphonates does not induce histological changes in human alveolar jawbone)