Nonhealing Irradiated Bone
Friday, June 12, 2026

return to: Pre-irradiation Dental Evaluation   Hyperbaric Oxygen Therapy

Content created June 2026 by Isabella Phillips, BS and Zaid Al-Qurayshi MBChB, MPH, University of Iowa 

  • Definitions – 

    1. Osteoradionecrosis (ORN): nonhealing radiation-induced ischemic necrosis of bone with associated necrosis of soft tissue

    2. Unrelated to primary tumor necrosis, recurrence, or metastatic disease

  • Background - 

    1. Incidence is estimated to occur in around 2-7% of patients with head and neck cancer, but varies by radiation site and dose with median occurrence 8 months after radiation therapy (Frankart et al, 2021)

      • ORN of the mandible is most common

    2. Pathophysiology (Frankart et al, 2021; Fritz et al, 2025)

      • It is a progressive condition that presents as a spectrum of severity. 

      • Radiation impairs blood vessels, leaving bone vulnerable to hypoxia, tissue breakdown, and chronic nonhealing wounds secondary to endothelial disruption and dysfunction, local inflammation, and bacterial inoculation and infection 

      • There is also description of dysregulation and overactivation of fibroblastic activity and free radical production from the radiation

    3. Symptoms include pain, swelling, trismus, non-healing skin breakdown in the oral cavity, orocutaenous fistulas, pathologic fractures, and visibly exposed necrosed bone

    4. ORN is difficult to treat, therefore prevention is the primary goal. Strategies for risk reduction include:

      • Prophylactic dental extractions 

        • Decrease in ORN from 20% to 4-8% (Fritz et al, 2025)

      • Reduction of radiation as applicable

        • Risk of ORN increases significantly with mandibular doses >60 Gy (Frankart et al, 2021)

      • Oral hygiene

      • Avoidance of alcohol and tobacco 

      • Improve and maintain good nutritional status 

      • Prophylactic HBO; however, the HOPON trial found no benefit for prevention (Shaw et al, 2019)

    5. Classification 

      • There are multiple staging systems that reflect the severity spectrum. Those classification systems rely on a combination of factors related to clinical symptoms, radiographic changes, and pathologic findings. 

      • Common classification systems include Notani classification based on radiographic findings 

        • Grade I – confined to alveolar bone 

        • Grade II – limited to alveolar bone or mandible above inferior dental canal

        • Grade III – full-thickness involvement/below inferior alveolar canal, pathologic fracture, or skin fistula

        • Other classifications include Lyons, Marx, Clayman, CTCAE, RTOG/EORTC, Store and Boysen, Schwartz and Kagan, SOMA

  • Management strategies - 

    1. Treatment can be challenging and often noncurative. Treatment depends on the presenting disease stage and prior failed therapeutic attempts 

    2. Conservative management

      • Close clinical observation and monitoring 

      • Oral hygiene 

      • Antibiotics for local infections

    3. Hyperbaric oxygen therapy 

      • Mechanism of action includes increasing local tissue oxygen tension, and thus improving wound healing (Hyperbaric Oxygen Therapy)

      • Multiple RCT's and systemic reviews suggest there is limited evidence for efficacy of HBO in prevention or treatment in oral cavity ORN (Forner et al, 2022; Shaw et al, 2019; Annane et al, 2004; Sultan et al, 2017) 

    4. Targeted medical therapy (Frankart et al, 2021; Fritz et al, 2025; Pak et al, 2025; Ramirez et al, 2025)

      • PENTO/PENTOCLO, medication regimen composed of 

        • Pentoxifylline: vasodilator with antitumor necrosis factor, anti-inflammatory, antiplatelet aggregation 

        • Tocopherol: vitamin E derivative with antioxidative properties, partial inhibitor of TGFB, reduction of inflammation and tissue fibrosis 

        • Clodronate: bisphosphonate, inhibits osteoclast production and bone resorption (currently unavailable in the United States)

          • Of note, clodronate is a non-nitrogen containing bisphosphonate, which is distinct from nitrogen-containing bisphosphonates (zoledronic acid, alendronate) which are a known cause of osteonecrosis of the jaw, whereas clodronate actually has shown protection against necrotic effects (Adams et al, 2024)

        • PENTOCLO Phase II trial, demonstrated improved bone and tissue healing with prolonged therapy (Delanian et al, 2011) 

        • Retrospective cohort found PENTO to be superior to PENTOCLO (Patel et al, 2021) 

    5. Surgical management 

      • Definitive treatment 

        • Debridement for limited disease 

        • Segmental resection with osteocutaneous free flaps is considered the ultimate treatment for a refractory and advanced ORN

    6. Prevention is the most effective strategy with multidisciplinary management 

  • Investigational strategies and recent research - 

    1. ALT Fasica Lata Rescue Flap
      • Reconstructive option with potentially similar flap success rates with decreased morbidity attributed to shorter operative times, hospital stays, and tracheotomy (Arianpour et al, 2023; Blunck et al, 2026)
    2. Platelet Rich Fibrin
      • Case reports suggest may be a beneficial adjunct to promote wound healing, tissue regeneration, inflammation, and revascularization (Chen & Chang, 2019)
      • Recent RCTs have not shown benefit in prevention of ORN (Batstone et al, 2012; Macedo et al, 2025)
    3. Photobiomodulation
      • Low level light therapy with suggested analgesic, anti-inflammatory, and wound healing properties through stem cell and osteogenic immune marker upregulation (da Silva et al, 2021; Pak et al, 2025)
    4. Teriparatide
      • Recombinant human parathyroid hormone promoting osteoblastic activity through anabolic effects and has shown complete healing in small case series of osteonecrosis patients (Cha et al, 2018; Pak et al, 2025)
    5. Stem cell therapy
      • Limited clinical translation at this time, but promising preclinical models demonstrating bone volume and density gains via mesenchymal stem cell transplantation (Liu et al, 2026; Mughal et al 2023)

     

  • References

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    Annane D, Depondt J, Aubert P, et al. Hyperbaric oxygen therapy for radionecrosis of the jaw: a randomized, placebo-controlled, double-blind trial from the ORN96 study group. J Clin Oncol. 2004;22(24):4893-4900. doi:10.1200/JCO.2004.09.006

    Arianpour K, Meleca JB, Liu SW, et al. Evaluation of Anterolateral Thigh Fascia Lata Rescue Flap for Mandibular Osteoradionecrosis. JAMA Otolaryngol Head Neck Surg. 2023;149(7):621–627. doi:10.1001/jamaoto.2023.1089

    Batstone MD, Cosson J, Marquart L, Acton C. Platelet rich plasma for the prevention of osteoradionecrosis. A double blinded randomized cross over controlled trial. Int J Oral Maxillofac Surg. 2012;41(1):2-4. doi:10.1016/j.ijom.2011.06.018

    Blunck CK, Havens A, Fritz MA, Prendes BL, Vos DJ, Alvi A, Liu S, Genther DJ, Ciolek PJ. Anterolateral-Thigh Fascia Lata Free Flap Versus Fibula Free Flap for Mandibular Osteoradionecrosis. Laryngoscope. 2026 Jun;136(6):2565-2572. doi: 10.1002/lary.70416. Epub 2026 Feb 8. PMID: 41656581; PMCID: PMC13158826.

    Cha YH, Hong N, Rhee Y, Cha IH. Teriparatide therapy for severe, refractory osteoradionecrosis of the jaw. Osteoporos Int. 2018;29(4):987-992. doi:10.1007/s00198-017-4343-2

    Chen YT, Chang YC. Use of platelet-rich fibrin and surgical approach for combined treatment of osteoradionecrosis: a case report. J Int Med Res. 2019;47(8):3998-4003. doi:10.1177/0300060519862468

    da Silva TMV, Melo TS, de Alencar RC, et al. Photobiomodulation for mucosal repair in patients submitted to dental extraction after head and neck radiation therapy: a double-blind randomized pilot study. Support Care Cancer. 2021;29(3):1347-1354. doi:10.1007/s00520-020-05608-5

    Delanian S, Chatel C, Porcher R, Depondt J, Lefaix JL. Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial. Int J Radiat Oncol Biol Phys. 2011;80(3):832-839. doi:10.1016/j.ijrobp.2010.03.029

    Forner LE, Dieleman FJ, Shaw RJ, et al. Hyperbaric oxygen treatment of mandibular osteoradionecrosis: Combined data from the two randomized clinical trials DAHANCA-21 and NWHHT2009-1. Radiother Oncol. 2022;166:137-144. doi:10.1016/j.radonc.2021.11.021

    Frankart AJ, Frankart MJ, Cervenka B, Tang AL, Krishnan DG, Takiar V. Osteoradionecrosis: Exposing the Evidence Not the Bone. Int J Radiat Oncol Biol Phys. 2021 Apr 1;109(5):1206-1218. doi: 10.1016/j.ijrobp.2020.12.043. Epub 2021 Jan 4. PMID: 33412258.

    Fritz MA, Arianpour K, Liu SW, Lamarre ED, Genther DJ, Ciolek PJ, Byrne PJ, Prendes BL. Managing Mandibular Osteoradionecrosis. Otolaryngol Head Neck Surg. 2025 Feb;172(2):406-418. doi: 10.1002/ohn.990. Epub 2024 Sep 27. PMID: 39327863; PMCID: PMC11773448.

    Liu H, Nie R, Jiang J, Zhang C. Stem cell therapy for osteoradionecrosis of the jaws: mechanisms, advances, and clinical potential. Stem Cells. 2026 Feb 23;44(3):sxaf078. doi: 10.1093/stmcls/sxaf078. PMID: 41389837.

    Macedo DR, Rodrigues JF, de Paulo LFB, de Oliveira GJPL, Soares PBF. Effectiveness of advanced platelet-rich fibrin on post-exodontia socket healing in patients who had undergone head and neck radiation. Support Care Cancer. 2025;33(5):397. Published 2025 Apr 21. doi:10.1007/s00520-025-09428-3

    Mughal A, Aftab M, Shah Vardag AB, Khan Z, Pasha HA, Awan MS. Mesenchymal stem cell therapy for treatment of osteoradionecrosis of mandible in head and neck surgery patients - A way forward into the future with promising clinical Outcomes. J Pak Med Assoc. 2023;73(Suppl 1)(2):S75-S78. doi:10.47391/JPMA.AKUS-12

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