PGO Scientific journal

Since the first cases of drug-induced osteonecrosis of the jaws were reported for the first time in 2003, several publications have tried to understand the aetiopathogenesis and course of this pathology in order to work on its prevention and establish treatment protocols. When concomitant with a defect in bone metabolism, conventional treatments of debridement and elimination of bone sequestration are very unpredictable as they imply a new bone defect in the treated area. This is why the latest trends are more oriented towards the use of regenerative techniques, among which the use of fibrin-rich plasma (PRF) stands out.

Since 2003, various cases have been reported in which an association has been established between the use of a certain group of drugs, bisphosphonates, and the appearance of bone lesions in the jaws, known as bisphosphonate osteonecrosis of the jaws (ONJ). The first reference we find in the literature is a letter to the editor sent in the same year by the author Marx to the Journal Oral Maxillofacial Surgery, which reports 36 cases suggesting this relationship and the need for further studies. Since then, several publications have come to light that have also shown such an association with other antiresorptive drugs such as Denosumab and with angiogenesis inhibitors. As a result, the AAOMS, American Association of Oral and Maxillofacial Surgeons, changed the name to medication-related osteonecrosis of the jaws (MRONJ) ¹.

Antiresorptive and anti-angiogenic drugs

Bisphosphonates (BP) are drugs that act as analogues of inorganic pyrophosphate (Ppi). Ppi regulates bone mineralisation by being able to inhibit calcification through binding to hydroxyapatite crystals². More recently, it has been suggested that bisphosphonates also function to limit both osteoblast and osteocyte apoptosis^3,4. In addition to inhibiting osteoclasts, it is known to inhibit fibroblast proliferation by inhibiting the expression of the growth factor TGF-B ⁵.

They are mainly used for the treatment of diseases involving bone resorption such as osteoporosis or various metastatic diseases such as Paget’s disease, breast cancer or hypercalcaemia of malignancy⁶. They can be administered orally or intravenously. Oral BPs include alendronate (Fosamax), Risedronate (Actonel) and Ibandronate (Boniva), and the most commonly used intravenous BPs are Pamidronate, Ibandronate and zoledronic acid (Reclast, Zometa).

Due to their pharmacological characteristics these drugs are rapidly cleared from the bloodstream to bind to hydroxyapatite in the bone matrix at sites of bone remodelling. This high affinity for bone mineral allows bisphosphonates to achieve a high local concentration throughout the skeleton leading to an alteration in osteoclast-mediated bone resorption ^3,7.

Although the use of bisphosphonates and the development of ONM have been associated in several publications, a direct causal relationship has not yet been identified as their mechanism of action is not fully understood. Different risk factors have also been proposed.

Angiogenesis inhibitors have shown efficacy in treating cancerous or tumour pathologies at the gastrointestinal level. Angiogenesis is a process involving the growth, migration and differentiation of endothelial cells to form new blood vessels via vascular endothelial growth factor (VEGF). This drug therefore limits scarring.

Denosumab is a mononuclear antibody that acts as an inhibitor of the ligand called RANK-L by preventing it from binding to RANK (a receptor found on osteoblasts), preventing the activation of osteoclasts and increasing bone density. It is mainly used for osteoporosis. By indirectly interfering with osteoclast activity and not directly binding to the bone matrix, it has been observed that when treatment is discontinued for six months, the risk of osteonecrosis decreases¹. The average time to onset of adverse effects is longer for Denosumab compared to zoledronic acid, although they also reflect that the severity of ONJ is greater in cases treated with zoledronic acid ⁹.

Medication-induced osteonecrosis of the jaws

Description

Osteonecrosis of the jaws (ONJ) is a rare but serious pathology and can affect both arches, although it is more common in the mandible. It manifests as one or more necrotic bone lesions, usually exposed in the oral cavity and persisting for at least 8 weeks ¹⁰.

ONJ is a pathology defined by the following clinical criteria determined by the AAOMS Position Paper in 2014: ¹

• Current or previous treatment with anti-resorptive or anti-angiogenic drugs.
• Necrotic exposed bone with or without the presence of an intraoral or extraoral fistula in the maxillofacial region and more than 8 weeks of evolution.
• No history of radiotherapy to the jaws or metastatic disease at the maxillofacial level (which can lead to chemical or physical osteonecrosis).

The Spanish Society of Oral and Maxillofacial Surgery, SECOM, defines that this bone exposure can appear spontaneously but more frequently it is usually secondary to a local trauma such as an exodontia. Hence the importance of a good anamnesis before any intervention. It may be asymptomatic and self-limiting in size, or it may be accompanied by pain, inflammation, tooth mobility, erythema and suppuration, and even bone sequestrations ⁸.

Stages

Depending on the evolution of the lesion and its clinical manifestations, different stages can be distinguished, which will also determine our therapeutic guidelines. The AAOMS classically contemplated three stages, however in the last update in 2014 they described a stage “0” in which necrotic bone is not observed, either because it is an initial lesion or because it is a more advanced stage in the healing process.

SECOM recommends biopsy of the exposed bone if there is any suspicion that the origin of the lesion is related to the pathology that led to the use of these drugs, as these are usually tumour or cancer pathologies.

The following table provides a summary of the clinical features and salient characteristics of the stages mentioned above:

Etiopathogenesis

Although ONJ was reported almost 20 years ago, the aetiopathogenesis is not entirely clear. Hypotheses include not only inhibition of osteoclastic bone resorption and remodelling, but concomitant factors such as inflammation and infection, inhibition of angiogenesis, soft tissue toxicity and immune dysfunction. The AAOMS therefore postulates that the aetiopathogenesis is multifactorial ^1:

1) Inhibition of bone resorption and osteoclastic bone remodelling

Inhibition of osteoclast differentiation and function, as well as stimulation of osteoclast apoptosis, leads to decreased bone resorption and bone remodelling.

2) Inflammation / Infection

Early studies indicated the possible role of inflammatory or infectious processes in the development of ONJ, with Actinomyces bacteria being found in several biopsies.

3) Inhibition of angiogenesis

Osteonecrosis is classically considered to be a disruption in vascular supply or avascular necrosis.

4) Bisphosphonate toxicity

The importance of the dose, the time of treatment, especially at intravenous level, has been observed in different studies. In the case of oral BPs, fewer cases have been reported.

According to the Spanish Society of Oral and Maxillofacial Surgery (SECOM), osteonecrosis usually occurs in patients who have taken oral BPs for more than three years, with a mean duration of use of 5.6 years. In contrast, the time of use of patients with osteonecrosis in relation to IV BPs can be less than 1 year (9.3 months for Zoledronic acid and 14.1 months for Pamidronate) ⁸.

Maxillary affectation

Among other questions about this pathology is the fact that it mainly manifests itself at the maxillary level and not in other bone regions of the body. It is stipulated that because the alveolar bone is undergoing continuous remodelling, bisphosphonates accumulate more at this level.

The increased remodelling activity at the maxillary level is explained by masticatory forces: “During the process of mastication, compressive forces are distributed to the base of the teeth, and in particular to the lamina dura, which tends to respond to these forces by modifying its remodelling. When high concentrations of BP are present, this remodelling is inhibited, with a consequent increase in bone density. In the case of surgical intervention involving the jaw (extractions, implants), or in the presence of significant periodontal disease or severe localised inflammation, BP’s administered at high doses also spread to the involved tooth area. This situation results in an abnormal accumulation of BP in a limited area, reaching concentrations sufficient to inactivate not only osteoclasts, but also osteoblasts and osteocytes” ¹².

Clinical approach: prevention and treatment protocol

There are different therapeutic options to control ONM depending on the stage of the lesion, such as conservative treatment, minimally invasive surgical treatment or invasive treatment for more extensive lesions, which would involve subsequent reconstruction. In addition to surgical techniques, adjuvant techniques that promote healing have been compiled in the literature.

The prevention of this type of pathology is the main approach now that it is known in the scientific community and is supported by different studies. It is therefore necessary to emphasise the importance of taking a good clinical history and anamnesis. Communication with other professionals (oncologists, gynaecologists, urologists…) will be the key to avoid the appearance of this pathology. SECOM advises prior dental assessment of the patient before starting treatment with BP⁸. The aim is to eliminate any risk factors: to clean up, eliminate caries and foci of infection and eliminate teeth with a doubtful prognosis. It is advisable to wait a prudent period of time after exodontia (15-20 days) to begin treatment and not to carry out implant treatment if the osseointegration period is expected to coincide with the administration of bisphosphonates.

Conservative treatment: Conservative treatment is advised for all stages of ONJ. So far there is no universally accepted protocol for the treatment of ONJ. Conventional treatment consists of debridement of the exposed area and closure with mobilisation of the mucoperiosteal flap, 0.12% chlorhexidine mouthwash and analgesic and antibiotic treatment (amoxicillin 500 mg with clavulanic acid 125 mg (every 8 hours for 7 days) or metronidazole 500 mg (every 8-12 hours for 7 days) or ciprofloxacin 500 mg (every 12 hours for 7 days)).

Surgical treatment: Aimed at removing necrotic bone tissue, preferably in a minimally invasive manner. The extent will depend on the size of the lesion. It is indicated for stages I, II and III.

Adjuvant treatments: Along with surgical techniques, the use of different therapies have been studied to promote tissue healing as it is compromised in ONJ. These therapies include the use of teriperatide, hyperbaric oxygen, ozone or fibrin-rich plasma.

Some authors even propose a drug-holiday for a period of time, 3 months before the intervention and 3 months after, to promote healing, however there is much controversy on this point as it is not always possible and there is no literature to support it. In principle, discontinuation of treatment would only be beneficial in the case of intravenous bisphosphonates and in the long term ^1,8,13.

The condition of bone metabolism results in difficult prediction of treatment, especially surgical treatment. This has led to the exploration of other techniques to try to improve healing. This is where the application of the Fibrin Rich Plasma (FRP) application technique comes in.

A systematic literature search was carried out in bibliographic databases such as Pubmed and Scielo during the first months of 2020. A search was also carried out for specific articles based on the references of the first articles obtained. On the other hand, information has been consulted in the reference associations that study this pathology; Sociedad Española De Cirugía Oral Y Maxilofacial (SECOM) and American Association of Oral and Maxillofacial Surgeons (AAOMS). Finally, some of the articles used have been contributed by other colleagues in the profession.

The search was carried out using the descriptors listed in the following table. Due to the large volume of articles obtained, different filters were applied to select them.

In order to understand the relationship between bisphosphonates and osteonecrosis and thus lay the foundations for the work, a search was carried out using the descriptors “bisphosphonate AND Jaw AND osteonecrosis”. However, this resulted in 2761 articles. After applying the filters “free full text” + “5 years” + “review” the results were reduced to a total of 63 articles. From these, a manual selection of articles was made after reading the abstract.

The search “Platelet-rich fibrin AND osteonecrosis” returned 27 articles, a similar search “Platelet-rich fibrin AND bisphosphonate” returned 24 articles, which were the same as the previous search.

Of these 27 articles, 4 were discarded when “Jaw” was added as a descriptor. The same happened when adding “Jaw” to the search for “Platelet-rich fibrin AND bisphosphonate”; the 24 articles were reduced to 21.

A total of 29 references were used to develop the different points to be addressed in this work.

Since 2003, the association between the use of antiresorptive drugs such as bisphosphonates, Denosumab and anti-angiogenic drugs and the risk of suffering osteonecrosis of the jaws spontaneously or, more frequently, after dental surgery, has been reported in the literature.

However, the mechanism of action by which this occurs is still unknown. Authors such as Landesberg argue that “the pathophysiology is not well defined and is likely to be multifactorial in nature. While it is likely that this condition is associated with BP use, a causal effect has not yet been demonstrated. The unique anatomy, biomechanical forces and microbial environment of the oral cavity may explain why ONJ lesions show a preference for the craniofacial region. In addition, it seems likely that immunosuppression and impaired wound healing play a role in the development of ONJ” ¹⁴.

The management of this pathology is the most controversial point found in the literature. In general, the line of treatment to be followed is conservative and palliative of the symptoms. Surgical treatment is determined by the stage of the lesion. On this point, studies such as the one by Bermúdez-Bejarano¹⁵ analysed the protocols of 47 articles and the study by Díaz-Reverand ¹⁶ with 19 clinical cases, set out different protocols to analyse and determine which treatment plan is the most appropriate depending on the stage. Both studies conclude that the protocols that included adjuvant therapies to surgery gave better results.

At this point there are different adjuvant therapies to improve the outcome of the treatment. Among the options are:

–Ozone: induces the formation of bone sequestration, improves vascularisation of the underlying bone and stimulates the formation of granulation tissues. Agrillo reports in a sample of 94 patients treated with ozone a complete resolution with decrease of symptoms in 57 patients (60%); in 28 cases (30%) a marked reduction of lesions was observed, with improvement of symptoms, while in 9 patients (10%) only a partial cure of symptoms was achieved without any result with the lesion. The disadvantage of this therapy is that it requires application at least twice a week, which prolongs the healing time ¹⁷.

–Hyperbaric oxygen: application of oxygen in a pressurised chamber for the treatment of lesions and infections. Since osteonecrosis occurs with oxygen deficiency in the exposed area, this treatment would be indicated. However, authors such as Khan and Ceponis, in a review carried out in 2017, conclude that there is a lack of clinical evidence on this therapy and point out its limitations due to the need to select the patient, the number of sessions required and the economic cost^{18, 19}.

– Teriparatide: a technique in which the hormone teriparatide is administered subcutaneously. It is also used in the treatment of osteoporosis. Author Pelaz conducted a study comparing teriparatide with the use of FRP. He determined that its use is limited as it is contraindicated in patients with metastatic cancer due to its involvement in promoting metastasis and that its effect has a low level of scientific evidence. Although it used a small sample size, it was observed that FRP offers better results compared to teriparatide ²⁰.

– Fibrin-rich plasma (FRP): this seems to be the most advanced adjuvant therapy and the one most reflected in the literature, as it stands out for promoting regeneration rather than healing like the other therapies mentioned above.

New treatment techniques: Fibrin Rich Plasma (FRP)

In 2001, the fibrin-rich plasma (FRP) technique was developed by Choukroun. FRP is a blood clot optimised by centrifugation. Centrifugation within a specific glass tube leads to the activation of the physiological coagulation cascade and thus to the formation of a fibrin clot enriched with cells within the peripheral blood, i.e. platelets and leukocytes²¹.

It is a process that is still being developed and applied today in different areas of medicine. This clot has a trimolecular fibrin structure that houses the platelets. The platelets contain growth factors that promote both the repair and regeneration of soft and hard tissues. It is used as an autologous biomaterial that also provides strength and stability as a graft. It can be combined with other types of biomaterials acting synergistically and serving as a structural support for them (membrane).

The FRP technique is obtained after the collection of venous blood usually from the cubital vein in the forearm. This is immediately centrifuged at 3000 RPM for 10 minutes or 2700 RPM for 12 minutes ²². At this point different protocols have been postulated that would give different characteristics to the clot obtained. This technique does not require the use of anticoagulants (bovine thrombin), as is the case with other platelet concentrates, such as platelet-rich plasma (PRP) and plasma rich in growth factors (PRGF) ²³.

After centrifugation of the tubes with the blood sample, three different layers are clearly visible:

• At the top of the tube is the acellular plasma.
• Below this we find the platelet fibrin. This is the most important part of the treatment. It contains platelets with growth factors, leukocytes and matrix proteins.
• At the bottom of the collection tube is the red blood cell clot.

Compared to a normal clot, we find that an optimised clot has 94% platelets compared to 6% in a natural clot. The presence of red blood cells is decreased from 93% in a normal clot to 5% in the FRP. White cells are present in both types of clot at a concentration of 1% ²⁴.

This results in a reduction of recovery time by promoting regeneration phenomena through the following growth factors present in the clot:

• PDGD – Platelet derived growth factor; induces mitogenesis of endothelial cells and osteoblasts, important role in angiogenesis.
• TGF-B, transforming growth factor beta, activates fibroblasts and pre-osteoblasts by inducing their mitosis and promotes their differentiation into mature functional osteoblasts. Continued secretion induces osteoblasts to deposit bone matrix and fibroblasts to deposit collagenous matrix ²⁴.
• VEGF, Vascular Endothelial Growth Factor, promotes angiogenesis.

The fundamentals of this technique attempt to combine and utilise the positive effects of substances involved in the healing process such as platelets, fibrin and leukocytes²¹. The mechanism of action of FRP is therefore precisely the same as that observed in tissue healing and regeneration;

1. Haemostasis; thanks to platelet aggregation, which contains alpha granules, a reservoir of different growth factors. The fibrin clot is also formed in this phase.
2. Inflammatory phase; proteins present in the fibrin induce adhesion of leukocytes to the vascular endothelium. At this stage there is also a phagocytic phenomenon by macrophages and growth factors are released.
3. Proliferative phase; the growth factors released stimulate angiogenesis, increase of collagen, granular and epithelial tissue.
4. Maturation phase; tissue remodelling.

Since the widespread use of FRP membranes in dentistry, several authors have reported their clinical experiences and shown their efficacy.

Ghanatii et al. conducted a literature review in 2017 to evaluate the results and level of scientific evidence of articles published in the last 15 years up to that time related to the use of FRP for bone and soft tissue regeneration in different areas of dentistry and maxillofacial surgery. They selected a total of 72 articles of which 5 of them investigated the effect of FRP in the treatment of ONJ. Two of these studies reported a statistically significant improvement in wound healing compared to the control group. Epithelialisation was observed in the FRP group in 2-4 weeks and in the control group in 2-8 weeks. The remaining 3 case-control studies studied a total of 101 cases, 96 of these patients showed good clinical results; rapid epithelialisation within 4 weeks to 3 months and complete bony closure of the defect (during anti-resorptive treatment or with interrupted treatment prior to surgery). Also within this group, 25 patients were studied with FRP treatment in combination with recombinant human bone morphogenetic protein 2 (rhBMP2) and compared to a control group of 30 patients treated with FRP alone; the results showed statistically significant improvements in healing in the FRP-BMP2 group ²⁵.

According to the literature reviewed, the clinical community requires standardisation of FRP protocols to show the benefit of FRP in the regeneration of osteonecrosis-affected tissues.

Table 1 summarises the main findings of the studies analysed in this review: ^{23,26,27,28,29.}

• ONM develops in susceptible patients due to long-term use of antiresorptive drugs for the treatment of osteoporosis or metastatic disease. This is why it is mostly seen in women around 70 years of age.
• All the cases described take place after a dental intervention and therefore require interceptive treatment, with the exception of the case reported by Pispero et al. which establishes a preventive protocol after assessing the patient’s risk factors.
• Of the six cases studied, two of them had maxillary involvement and the rest affected the mandible, which is consistent with the findings of other authors such as Junquera et al (greater mandibular involvement).
• No great consensus was observed in any of the cases when determining the preoperative guidelines or when using a specific protocol for FRP or lesion follow-up.
• While it is noted that all authors opt for antibiotic and antiseptic treatment prior to treatment of the defect, there is no clear dosing protocol.
• In the FRP protocol collected, two authors used a FRP obtained from 20 ml of blood centrifuged at 3000 rpm for 10 min, two others used 30 ml of blood centrifuged at 2700 rpm for 12 min and two authors did not specify their method.
• Four of the authors used FRP in membrane form alone and the other two combined it with an allograft and RhBMP-2.
• Despite differences in the protocols used, all cases show signs of re-epithelialisation and healing without signs of infection within a few weeks. Some authors also report radiographically observable bone regeneration.

1. Although the use of bisphosphonates and the development of ONJ has been associated in several publications, a direct causal relationship has not yet been identified.
2. The occurrence of osteonecrosis depends on the dose received and the form of administration, with intravenous BPs posing the greatest risk.
3. Some studies showed a toxic BP effect on the oral epithelium with inhibition of normal soft tissue healing.
4. Osteonecrosis can be spontaneous or more frequently after tooth extraction. Interprofessional communication and dental pre-assessment is recommended before starting BP treatment in order to eliminate future risk factors.
5. Treatment in the early stages is always conservative, following an antibiotic, analgesic and antiseptic regimen.
6. In more advanced stages, surgery is required and the prognosis is doubtful.
7. Several studies have evaluated different protocols concluding the benefit of the use of adjuvant therapies in conjunction with surgery. These therapies include the use of ozone, hyperbaric oxygen, teriparatide hormone or PRF.
8. The use of PRF is becoming more and more widespread in dental practice and offers great advantages over the other adjuvant therapies mentioned, as it promotes regeneration rather than healing.
9. Further studies are needed to demonstrate the effectiveness of this method in order to establish protocols for action.

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