Interdisciplinary Management of Bisphosphonate-Related Osteonecrosis of the Jaw

Review Article

Austin J Dent. 2021; 8(1): 1153.

Interdisciplinary Management of Bisphosphonate-Related Osteonecrosis of the Jaw

Szymacha K, Bielecka-Kowalska N* and Lewkowicz N

Department of Oral Mucosal and Periodontal Diseases, Medical University of Lodz, Poland

*Corresponding author: Natalia Bielecka-Kowalska, Department of Oral Mucosal and Periodontal Diseases Medical University of Lodz, Lodz, ul. Pomorska 251, 92- 217, Poland

Received: February 27, 2021; Accepted: March 18, 2021; Published: March 25, 2021


Bisphosphonate (BP) Related Osteonecrosis of the Jaw (BRONJ) is one of the frequently occurring adverse reaction of BP intake, which is indicated in management of osteoporosis, Paget disease, multiple myeloma, and hypercalcemia in malignancies. The risk of osteonecrosis of the jaw relates to dose and duration of the therapy and the route of administration (i.e. more often BRONJ occurs in patients undergoing intravenous BPs therapy). At present, the management of BRONJ is a dilemma. No effective treatment has yet been developed. There is currently no gold standard of treatment for BRONJ. However, nowadays new alternative methods appear to be a promising modality of BRONJ treatment in early stages of the disease, while being safe and welltolerated, i.e. hyperbaric therapy, ozone therapy, use of platelet rich fibrine and platelet rich plasma, photodynamic therapy, low level laser therapy.

Keywords: Osteoporosis; Bisphosphonates; Osteonecrosis of the jaw; BRONJ; BPs; BPT


BP: Bisohosphonate; BRONJ: Bisphosphonate Related Osteonecrosis of the Jaw; BMD: Bone Mineral Density; ALN: Alendronate; RIS: Risedronate; IBN: Ibandronate; SREs: Skeletal- Related Events; RANKL: Receptor Activator for Nuclear Factor κB Ligand; ONJ: Osteonecrosis of the Jaw; AAOMS: American Association of Oral and Maxillofacial Surgeons; MRONJ: Medication- Related Osteonecrosis of the Jaw; CTX: Plasma Terminal Telopeptide C; NTX: N-Terminal Telopeptide; PRF: Platelet Rich Fibrin; PRP: Platelet Rich Plasma; LLLT: Low-Level Laser Therapy


Bisphosphonates (BPs) are currently widely used; however, recently recognized relationship of BPs with an array of pathologic conditions of skeletal disorders has brought increased scrutiny to the current broad use of BPs therapy. BPs are recommended primarily for diseases of osteoclast-mediated bone excessive bone loss due to osteoporosis, Paget disease of the bone, multiple myeloma, and hypercalcemia in malignancies. The therapy brings many positive clinical effects, but it is not without risk of significant adverse effects. Long standing clinical observations have revealed the association of this group of drugs with the osteonecrosis of the jaw [1].

Characteristics of Bisphosphonates

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption, their mechanism of action is based on inhibiting osteoclast differentiation and blocking their activity. BPs have been shown to increase Bone Mineral Density (BMD), reduce bone turnover markers, and reduce the risk of osteoporotic fractures [2].

The BPs are divided due to their chemical structure and potency. The first-generation bisphosphonates (etidronate, clodronate) are characterized by short alkyl-side chains, and are no longer of clinical use. Second-generation BPs, such as alendronate and pamidronate, have amino-terminal groups and are known as aminobisphosphonates. Risedronate, a third-generation bisphosphonate, has a cyclic side chain. The antiresorptive properties increase approximately ten-fold between generations. Newer bisphosphonates, such as ibandronate, zoledronate, olpadronate and incandronate, are even more potent [3].

According to the American Society for Bone and Mineral Research, BPs are the most commonly used medications for prevention and treatment of postmenopausal osteoporosis in women and osteoporosis in men. They are also widely used in the treatment of inflammatory joint diseases and rheumatoid arthritis [4]. Between 2005 and 2009, approximately 150 million prescriptions were dispensed in the United States for the oral BPs Alendronate (ALN), Risedronate (RIS), or Ibandronate (IBN), and 5.1 million patients over the age of 55 years received a prescription for these drugs in 2008 [5].

The BPs are well tolerated in long-term treatment for over 3 years. In the patients with rheumatoid diseases, the preferred route of administration is intravenous injection [6-8]. Almost all (~94%) cases of BRONJ occur in patients receiving intravenous bisphosphonate as compared to oral bisphosphonates [9].

Bisphosphonates are widely utilized in cancer treatment by lowering the risk of bone loss associated with cancer therapy and the risk of disease recurrence, by managing hypercalcemia and by minimizing the risk of bone incidents in conditions with bone metastases.

The presence of such metastases is associated with increased skeletal morbidity due to Skeletal-Related Events (SREs), including radiation therapy to alleviate pain or prevent fracture, surgery to bone, pathological fracture and spinal cord compression, and also bone pain and hypercalcemia [10]. BPs are used in cases of breast cancer, prostate cancer, and multiple myeloma [11-13]. Less frequent indications are congenital osteogenesis imperfecta in children and Paget’s disease [2,5,9]. Bisphosphonate treatment does not completely effective in the treatment of SREs. Recently, a new antiresorptive drug was introduced on the market, denosumab. It is indicated in prevention of skeletal-related events in patients with bone metastases from solid tumors, for the treatment of postmenopausal osteoporosis and for treatment of cancer-induced bone loss in prostate or breast cancer patients, however, denosumab is not recommended for the prevention of SREs in patients with multiple myeloma [14]. Denosumab is a human monoclonal antibody that binds and inhibits the protein Receptor Activator for Nuclear factor κB Ligand (RANKL), an essential mediator in osteoclast formation, function and survival [10]. It exerts a strong antiresorptive effect, which is useful in cancer and osteoporosis patients in reducing skeletal related events. Due to the shorter half-life and lack of covalent bonding to the bone, it was expected that denosumab would have a similar therapeutic effect as BPs but with reduced profile of adverse effects, thus preventing cases of Osteonecrosis of the Jaw (ONJ). However, in 2010, several reports emerged describing the occurrence of ONJ in the patients being treated with denosumab [15-17].

The pathogenesis of BRONJ is not thoroughly understood and is undoubtedly multifactorial. Chronic pain and microtrauma of the jaws inhibit the healing process and as consequence prohibit bone resorption and its apposition. Some authors suggest that the microtraumas may not be fully recovered due to bisphosphonate inhibition of osteoclast-mediated bone resorption [2,9]. Osteoblasts develop brittle bones and the blood flow reduces due to the antiangiogenic effects of bisphosphonates, which all together contribute to necrosis or prevent bone healing.

In addition, bacteria-rich oral cavity environment facilitates infection, contributing to bone pain and inflammation.

Diagnosis of BRONJ

According to American Association of Oral and Maxillofacial Surgeons (AAOMS), the diagnosis of BRONJ is considered when all the following components are fulfilled [18,19]:

• Current or previous treatment with antiresorptive or antiangiogenic agents,

• Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for longer than 8 weeks,

• No history of radiotherapy to the jaws or metastatic disease to the jaws (Figure 1).