Platelet-rich plasma is a concentrate of growth factors and osteoconductive proteins, which can play a major role in bone biology by accelerating and enhancing bone repair and regeneration. This paper describes the results of using platelet-rich plasma in the management of bisphosphonate-associated necrosis of the jaw. Eight patients with a diagnosis of bisphosphonate-associated necrosis of the jaw were surgically treated for debridement and removal of necrotic bone, followed by application of autologous platelet concentrate enriched with growth factors and primary suture of the wound. Patients underwent periodic clinical and radiological follow-up examinations. All patients showed clinical improvement and oral lesions resolved 2–4 weeks after treatment. After an average 14-month follow up period, patients remained asymptomatic. Although not conclusive, the combination of necrotic-bone curettage and platelet-rich-plasma to treat refractory osteonecrosis of the jaw yielded promising results.
In a letter to the Editor of the Journal of Oral and Maxillofacial Surgery , submitted in 2003, Marx et al. reported 36 cases of infected necrotic bone closely resembling osteoradionecrosis (ORN) in patients who had undergone maxillary surgery, particularly, tooth exodontia. Marx proposed the bone dehiscence detected could be due to avascular necrosis secondary to intravenous administration of bisphosphonates (BPs). Also in 2003, Carter and Gross reported on five new cases of maxillary osteonecrosis. In 2004, Ruggiero et al. described 63 new cases of avascular necrosis of the jaw whose clinical characteristics were similar to those reported by Marx et al. Hellstein and Marek also published an article reporting on 28 cases of osteochemonecrosis and coined the term bis-phossy jaw.
Although some of the cases reported were asymptomatic, most of them presented common signs and symptoms: frequent histories of unhealed exodontia, painful or non-painful exposed bone, soft-tissue inflammation, purulent exudates, inflammation, and oral-cutaneous fistula. Even though the aetiopathogenesis of this entity remains unknown, the American Association of Oral and Maxillofacial Surgeons (AAOMS) named it bisphosphonate-related osteonecrosis of the jaw (BRONJ), the American Academy of Oral Medicine named it bisphosphonate-associated osteonecrosis of the jaw (BAONJ), and more recently, some authors named it bisphosphonate-induced osteonecrosis of the jaw (BIONJ). The authors will use BRONJ throughout this study.
Since the mechanism triggering BRONJ remains unknown, both diagnosis and treatment are determined by clinical criteria based on expert consensus. Guidelines for management of patients with this condition are also based on expert opinions; thus treatment is usually selected on an empirical basis. Some authors have proposed an approach based on surgical debridement and reconstruction, combined with the use of platelet-rich plasma (PRP) produced from the patient’s autologous blood rich in growth factors.
Recently, a technological classification was published, providing an overview of available systems classified based on three main parameters: fibrin density, leucocyte content and degree of procedure standardization. Dohan Ehrenfest et al. grouped the platelet concentrates in four categories, based on their leucocyte and fibrin content: pure platelet-rich plasma (P-PRP; e.g. cell separator PRP; Vivostat PRF or Anitua’s PRGF); leucocyte and platelet-rich plasma (L-PRP; e.g. Curasan, Regen, Plateltex, SmartPReP, PCCS, Magellan or GPS PRP); pure platelet-rich fibrin (P-PRF; e.g. Fibrinet); and leucocyte and platelet-rich fibrin (L-PRF; e.g. Choukroun’s PRF).
The authors chose the SmartPReP system because the supplying company allowed them to keep the material on deposit, and to pay only for that which was used. In addition, L-PRP was considered to be more suitable than other types of platelet concentrates because of its leucocyte content and its potential effects on proliferation, differentiation, immunity and infection.
In this study, the authors analyse the effectiveness of, and the reasons for, using L-PRP (automated system SmartPReP by Harvest Corp (Plymouth, USA)) to treat BRONJ.
Materials and methods
This prospective descriptive study was carried out at the Stomatology and Oral Maxillofacial Surgery Department between March 2007 and December 2009. Inclusion criteria were based on the AAOMS criteria (1, current or prior BP treatment; 2, presence of exposed necrotic bone in the maxillofacial region for more than 8 weeks; 3, no radiation to the jaws); later modified by Bagán et al. to include the presence of fistulas, even without exposed necrotic bone, as an incipient BRONJ stage. Patients with neoplastic involvement of the jaw were excluded.
The AAOMS proposes using the following staging categories: Stage 1, exposed/necrotic bone in patients who are asymptomatic and have no evidence of infection; Stage 2, exposed/necrotic bone in patients with pain and clinical evidence of infection; Stage 3, exposed/necrotic bone in patients with pain, infection, and one or more of the following: pathologic fracture, extra-oral fistula, or osteolysis extending to the inferior border.
Eight patients were selected in stage 2 (six female and two male), aged 66 years on average. Their underlying diseases were: multiple myeloma (50%), breast cancer (25%) and osteoporosis (25%). Patients were selected according to their clinical stage and the size of their radiographic bone lesions (which had to be smaller than 3 cm). After providing informed consent, the patients underwent surgical debridement of necrotic bone (removal of necrotic bone and curettage of the underlying bone) and received autologous platelet concentrate enriched with growth factors, produced by the system SmartPReP 2 – Harvest ® .
SmartPReP is a multifunction system with a specific collection and separation kit requiring little manipulation when used. This two-chamber device is designed to transfer automatically the upper layers (PPP and buffy coat) into the second chamber based on variations in weight and centrifugation speed. The centrifuge can also be used to concentrate stem cells from bone marrow aspirates.
This system produces viable platelet levels four-fold or more over baseline and can be used to accelerate wound healing, enhance management of graft material, improve graft fixation on surgical areas and optimize healing of bone and soft tissue. Additionally, it offers quick results, high yields, and reliable outcomes with reduced variability, compared to other systems.
L-PRP is prepared with the patients’ autologous blood through activation of a platelet concentrate. The authors used the APC-20 Procedure Pack, which produces 3 ml of autologous platelet concentrate (APC + ); 20 ml of blood are centrifuged to separate the three blood components: erythrocyte layer, platelet-rich plasma and platelet-poor plasma. Activation consists of mixing autologous thrombin with plasma in a 1:3 proportion (1 ml thrombin:3 ml plasma). The result is 3 ml of platelet-rich fibrin, easy-to-handle gel.
Once the L-PRP was placed, primary wound suture was carried out. Patients were prescribed amoxicillin-clavulanic acid (875 mg every 8 h for 7–10 days), exhaustive oral hygiene, mouthwash with chlorhexidine 0.12%, and a follow-up visit 2 weeks later, to have the suture removed. Follow-up visits were scheduled 4, 6, 10 and 14 weeks after surgery.
The authors used PRP in the surgical treatment of the eight BRONJ patients selected. Two of them were treated bilaterally, although in different sessions. Table 1 shows the main data corresponding to these patients. None of them were smokers, although four women were former smokers; six patients (75%) had good dental hygiene habits; the most frequent concomitant disease was non-insulin-dependent diabetes mellitus (NIDDM), which affected six patients (75%). Additionally, six patients (75%) were undergoing chemotherapy treatment and five patients (62.5%) were undergoing corticosteroid treatment ( Table 1 ).
|N||Gender||Age||Diagnosis||Bisphosphonate||Adm. route||Dose (mg)||Frequency (days)||Total administered dose (mg)||Risk factors||Trigger factor||Location|
|4||Female||55||Breast neoplasia||Zoledronate||IV||4||28||96||NIDDM||Prosthesis||Mandible bilateral|
|5||Male||68||Multiple myeloma||Zoledronate||IV||4||28||164||NIDDM corticosteroid||Multiple exodontia||Mandible bilateral|
Regarding the onset of BRONJ, the initial symptom was inflammation in four patients (50%), pain in three patients (37.5%) and exposed bone in one patient (12.5%). The most frequent signs and symptoms were: exposed bone in seven patients (87.5%), suppuration in seven patients (87.5%), pain in six patients (75%), bone loss in five patients (62.5%) and tooth loss in two patients (25%).
The patients’ panoramic radiographs in the first visit showed radiolucent areas associated with BRONJ lesions in all of them, and radiopaque areas associated with bone sequestration in 60% of cases. The average lesion size was 2 cm (1.2–3 cm); cases of extensive lesions or extra-oral fistulas were excluded because the potential side effects of the treatment were not known.
As part of the therapeutic approach, which was based on local oral surgery, the authors used autologous platelet concentrate enriched with growth factors produced with the SmartPReP 2 – Harvest ® system. All patients were treated by the same surgical team. All of the patients showed improvement and oral lesions resolved 2–4 weeks after surgery.
When examining the patients, the panoramic radiograph showed radiolucent areas associated with bone loss. The margins were clear and there was no evidence of bone sequestration ( Fig. 1 ). Patients continued to be monitored and remained asymptomatic showing no exposed bone after an average 14-month follow up period (range 12–26 months).