Medication-Related Osteonecrosis of the Jaw and Dental Implants Failures: A Systematic Review

Osteonecrosis of the jaw (ONJ) is an oral lesion characterized by exposure of necrotic bone in the maxillofacial region, persisting for more than 8 weeks, first described by Marx in 2003.¹  Etiology of the disease is unknown and the pathogenesis seems to be multifactorial.²  Though occurrence could be spontaneous,³  treatment with bisphosphonates (BPs) was highly correlated with ONJ. Particularly, bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-known adverse side effect of long-term BP treatment without previous history of radiation therapy to the jaws.^1,4  Recently, other non-BP drugs seemed to be related to the development of ONJ;⁵  therefore, additional and revised definitions of the pathology were proposed: according to Ikebe,⁶  newly developed molecule-targeting drugs, such as denosumab (a monoclonal antibody acting on receptor activator of nuclear factor kappa-B ligand or RANKL of osteoclast), bevacizumab (a monoclonal antibody targeting vascular endothelial growth factor or VEGF), and sunitinib (a multikinase inhibitor) would cause drug-related ONJ or “drug-related osteoclastic disease of the jaw.” Schipmann et al ⁷  proposed a definition of ONJ, in relation with bone resorption inhibitor treatment: “osteopathology associated with bone resorption inhibitor therapy (BRIOJ).” Moreover, an increasing number of reports have shown an association between the use of antiresorptive medication (ARM; bisphosphonates, human monoclonal antibody against nuclear factor-kappa B ligand (RANKL), and cathepsin K inhibitors) and osteonecrosis of the jaw, that was defined as “antiresorptive agent-induced osteonecrosis of the jaws (ARONJ).”⁸  The latest position paper of American Association of Oral and Maxillofacial Surgeons (AAOMS)⁹  defined “medication-related osteonecrosis of the jaw (MRONJ)” as exposed, unhealed necrotic bone caused by current or previous treatment with antiresorptive or antiangiogenic agents.

ONJ lesions are localized in the jaw bone matrix, mainly in the mandible than in the maxilla (2:1 ratio),⁴  due to the great vascularization, high bone turnover rate, high risk of surgical trauma, and local infections of jaws.^2,3  Moreover, BPs possessed a strong affinity to the hydroxyapatite, and 80% of the administered drugs were accumulated into the bones⁶  and released over time, from months to years.

Several systemic and local risk factors were correlated with the high frequency of ONJ development.²  Time of exposure, drug potency, and way of administration were considered drug-related risk factors,⁴  particularly, intravenous (IV) administration in the treatment of multiple myeloma and bone metastases, expose a risk of ONJ development 100 times higher than oral administration for treatment of osteopenia, osteoporosis, and Paget's disease.⁹  Furthermore, oral and maxillofacial surgery are considered the major local risk factors for ONJ occurrence, mainly in cancer patients treated with intravenous BPs or antiresorptive agents. Though this correlation was unanimously accepted, the possibility to perform tooth extractions and dental implants placement in BP- or antiresorptive agent-users has been widely debated in the literature. Regarding dentoalveolar surgery in patients undergoing intravenous antiresorptive therapy, current opinion contraindicates implant surgery according to the position paper of the American Association of Oral and Maxillofacial Surgeons.⁹  Although dentoalveolar surgery performed on patients receiving oral antiresorptive treatment seems not to be contraindicated,⁹  the presence of comorbidities, such as diabetes, use of glucocorticoids,⁶  use of antiangiogenic drugs, and time of exposure >4 years, should be taken into account,^9,10  since the risk of ONJ development appears to increase.

Nevertheless, there is no strong evidence supporting safe use of BPs or other antiresorptive agents prior, during, or after dentoalveolar surgery, and more data are needed to determinate the real risk of ONJ development, in both cancer and noncancer patients, which is, to date, still unknown.⁹ 

Of key importance is to define whether BPs and antiresorptive agents in general should be considered as “risk factors” in implant dentistry and dentoalveolar surgery fields, and how the type of drugs, time of exposure, and way of administration strictly related to the type of patient (cancer or not) are involved in the development and progression of osteonecrosis.

Therefore, the aim of the present systematic review was to assess the scientific literature concerning the implants placement in antiresorptive agent users and the related risk of implants failure and ONJ development.

A search of electronic databases including MEDLINE/PubMed, Scopus, Scholar, and the Cochrane Database of Systematic Reviews was undertaken using a combination of keywords: “BRONJ,” “ONJ,” “ARONJ,” “dental implant” and “oral bisphosphonate(s),” “antiresorptive osteoporosis” and “dental implant,” “antiresorptive osteoporosis” and “dental,” “antiresorptive” and “dental,” and “osteoporosis” and “dental implant.” Papers were selected if the abstract included the term “oral or dental implant” in conjunction with “oral bisphosphonate(s)” and with “osteonecrosis of the jaws.” The following terms: “risedronate,” “etidronate,” “clodronate,” “tiludronate,” “alendronate,” “ibandronate,” “denosumab,” “sunitinib,” and “bevacizumab” were also searched in conjunction with “dental implant.”

Literature search was completed by a hand search, exploring the references cited in all identified publications. No language exclusion criteria were applied; all levels of evidence were considered.

The inclusion criteria for studies selection were as follows: (1) papers published from January 2003 until December 2014, (2) human studies without age limitation, (3) oral or systemic administration of bisphosphonates or antiresorptive agents during or after dental implant placement, and (4) oral rehabilitation with at least 1 dental implant in both jaws per patient.

The exclusion criteria for studies selection were: (1) case reports, case series with <10 patients; (2) studies with <1-year follow-up; and (3) animal studies.

Participants were of any age in treatment with oral or systemic antiresorptive drugs.

Implant placement during or before antiresorptive therapy.

The comparison included implant success and implant failure after placement in patients in therapy with antiresorptive drugs.

The outcome was risk of implant failure or development of osteonecrosis.

Titles and abstracts retrieved from electronic search were screened separately by 2 examiners (R. G. and L. S.). The full text from all papers suitable for inclusion was obtained. Subsequently, all selected papers were independently assessed by both reviewers. Disagreements were solved by discussion among the reviewers. Finally, an evidence table was redacted with the included papers.

After matching results from 2 separated literature searches and removing duplicates, 277 articles were considered suitable for inclusion in the study. After title reading, 58 articles were eligible for abstract reading. Thirty articles were selected for full text reading and a final 10 articles were included in the study (Figure 1). Among selected papers, 7^11–17  were retrospective, 2^18,19  were cross-sectional, and only 1 study was prospective²⁰  (Figure 1 and Table 1).

A total of 17 237 patients in BP therapy were enrolled in the included studies. Age and gender distribution are reported in Table 2. The majority of study population was female since oral antiresorptive drugs were mostly administered in postmenopausal women for the treatment of osteoporosis. The most investigated molecules were alendronate, risedronate, and orally-administered ibandronate.

A total of 30 070 dental implants were placed in the included studies; however, in 2 studies^18,19  the precise number of evaluated implants was not specified (Table 2). Regarding time range between oral antiresorptive drug exposure and dental implant placement, differences were reported by several authors;^11–20  according to Table 2, patients were treated with antiresorptive agents prior to implants placement in a time range between 10 weeks to more than 11 years. In addition, 3 studies^12,13,15  reported that some subjects were treated with antiresorptive drugs even after implant surgery, however, without specifying the timing of postimplant therapy (Table 2).

Several authors^{11,12,14–16,20}  agreed on considering as safe the use of oral bisphosphonates prior or after dental implant surgery (Table 3). Particularly, Bell and Bell¹¹  reported a 95% success rate (5/100 implants failed in 5/100 female patients) without evidence of exposed bone or development of ONJ, and Grant et al¹³  showed that implant success rates in antiresorptive drugs users and nonusers were comparable. In the study of Jeffcoat,²⁰  25 women were rehabilitated with 102 dental implants and 25 BP users women with 108 implants. Success rates were 100% and 99.2% for the 2 groups respectively, without any occurrence of ONJ. Similarly, Koka et al¹⁶  demonstrated an implant survival rate in BP users and BP nonusers of 99.17% and 98.19%, respectively. In addition, Shabestari et al¹⁵  demonstrated that antiresorptive therapy before (7 patients) or after (14 patients) implant placement had no statistically significant influence on peri-implant probing depth, bleeding on probing, and thread exposure. Even Zahid et al¹⁴  showed high implant success rates, 94.11% and 88.46% for the implant-based and subject-based analyses respectively, in patients treated with oral BPs.

Although good clinical results were reported, Zahid et al¹⁴  noted a relationship between BPs and alveolar bone loss around osseointegrated implants, with 13 implants out of 51 exhibiting thread exposure. Moreover, Goss et al¹²  and >Grant et al¹³  reported dental implant failure also when oral bisphosphonate administration started after dental implant surgery. Goss et al¹²  described a relatively low but real risk, ∼1%, when dental implants were placed in patients taking oral bisphosphonates, and Yip et al¹⁷  indicated that women with implant failure (163/490 dental implants) had increased probability of reporting a history of oral bisphosphonates use (9.65%) than controls (4.04%). In the same way, Lazarovici et al¹⁸  showed that the 27 patients included in their study who had developed ONJ after dental implant placement had taken orally administered (41%) or intravenous (59%) bisphosphonates. ONJ occurred in 77.8% of the patients in mean 16.2 months after surgery; moreover, 6 patients developed ONJ 6 months after surgery. Particularly in patients treated with alendronate, zoledronic acid, and pamidronate, ONJ developed after mean periods of 68, 16.4, and 50.2 months, respectively.¹⁸  Martin et al¹⁹  reported 26 implant failures in 16 patients out of 589 patients who had treatment with BPs. Early failures (<1 year after implant placement) were registered for 8 implants, whereas late failures (>1 year after implants placement) were demonstrated in 18 implants. In 2 patients both early and late failures were reported.

All data are reported in Table 3, where follow-up period of dental implants is also shown.

Major risks of ONJ development were definitely related to the use of antiresorptive agents and invasive dental procedures.^3,4 . Indeed, cancer patients undergoing intravenous antiresorptive therapy and also dentoalveolar procedures had a 5- to 21-fold increased risk of ONJ development than the same population who did not undergo dentoalveolar surgery,⁴  whereas oral use of antiresorptive agents seems to have a lower grade risk of ONJ.^2,9,21 

Tooth extraction was a common predisposing event for ONJ occurrence, mainly in cancer subjects in treatment with antiresorptive drugs.²²  Particularly, Saad et al²³  reported a previous history of tooth extraction for 61.8% of cancer patients who developed ONJ. According to the latest position paper of AAOMS,⁹  the current estimate for the risk of ONJ among patients exposed to oral bisphosphonates following tooth extraction is 0.5%; however, this risk increased with the presence of comorbidities and protracted exposure to antiresorptive medications. On the other hand, the correlation between dentoalveolar procedures and risk of ONJ development among patients in treatment with antiresorptive agents is still unknown. Indeed, results of the present systematic review corroborated the absence of univocal data.

This review had included 10 studies (7 retrospective, 2 cross-sectional, 1 prospective), which evaluate the risk of implant failures and ONJ development in patients treated with antiresorptive agents. Even the occurrence of ONJ was reported in just 2 studies,^12,18  incidence of related implant failure seems to be more common, and represents a real side effect of bone resorption inhibition therapy.^13,14,17,19  On the other hand, 6 studies out of 10^{11,13–16,20}  considered as not dangerous the use of oral antiresorptive drugs prior to or after dental implant surgery. Particularly, Jeffcoat²⁰  and Koka et al¹⁶  reported that use of oral BPs should be classified as safe, showing implant survival rates of 100% and 99.17%, respectively, with better results than BP nonusers (survival rates of 99.2% and 98.19%, respectively). In addition, Koka et al¹⁶  concluded that implant survival in postmenopausal BP users was similar to that observed in postmenopausal women with no history of antiresorptive therapy and without any sign of ONJ occurrence and need of predictable “drug holiday.” Moreover, Bell and Bell¹¹  reported that dental implant placement and oral bone grafting appeared to be safe and successful procedures in patients taking oral BPs for osteoporosis.

However, though the risk of implant failures was considered relatively low, ∼1%,¹²  it is really devastating for the patients. For this reason, Yip et al¹⁷  suggested the discontinuation of oral BPs therapy prior to dentoalveolar surgery, demonstrating that oral BP use was 2.69 times higher in patients who presented implant failures compared with the patients for whom the implants did not fail. Probably, ONJ development should be considered as a late complication^18,19  of implant therapy; however, these data are not yet supported by the scientific literature, where few reports lacking of details are available. Also the present systematic review has many limits due to the heterogeneity of the included papers and the high risk of bias. The majority of the selected studies (7/10) are retrospective with inclusion/exclusion criteria different from each other. Even the sample size and the exposure to drugs are extremely varied ranging from 21¹⁵  to 16 000¹²  patients and from 10 weeks¹²  to more than 11 years,¹¹  respectively. In addition, 3 studies^12,13,15  reported that the bone resorption inhibition therapy was administered also after implant surgery, without specifying the onset and the duration, and in another 3 studies^14,16,17  the period of antiresorptive drug exposure is completely missing. Moreover, the number of implants varies from 46¹⁵  to 28 000¹²  with a widely heterogeneous follow-up period (Table 3) and criteria of implant success. Additional risk factors such as comorbidities, periodontal status, implant type and position, and differences in the type of drugs taken, definitely contribute to the lack of univocal data. According to a recent literature review,²¹  there is a paucity of data regarding the development of ONJ resulting from implant therapy in patients treated with antiresorptive agents; however, authors included just 4 studies in their review and concluded that the placement of dental implants should be considered a safe procedure in patients taking oral BPs for <5 years.²¹ 

Another crucial issue that should be fully investigated is the pathophysiology of ONJ occurrence. Recent findings suggested that the use of antiresorptive medications was not the only cause of disease appearance. Schipmann et al,⁷  proposed the existence of a major infectious component in the development of osteonecrosis due to bone resorption inhibitors therapy; indeed, bacterial invasion by Actinomyces might be a decisive factor in the etiology of the lesion. Moreover, Major Histocompatibility Complex Class II polymorphisms seem to be a genetic risk factor for the development of ONJ,⁸  supporting the hypothesis that inflammation crucially influenced the disease pathogenesis. Furthermore, inhibition of angiogenesis might play a key role in ONJ pathophysiology,^24,25  since a decrease of vascularization is always related to bone necrosis. Histologic examination found peri-implant nonvital demineralized bone with empty osteocyte lacunae, inflammatory cell infiltrate, and few small blood vessels^26,27  around dental implants involved in osteonecrosis lesions.

The clarification of ONJ pathophysiology is of crucial significance in the prevention and treatment of the disease; moreover, the role of the inflammatory response in the occurrence of osteonecrosis should be deeply investigated; further studies are needed to evaluate the role of chronic BPs and antiresorptive therapy in the long-term implant osseointegration maintenance.

Within the limitations of the present systematic review, high quality studies are needed to provide an adequate level of evidence regarding the safety of dentoalveolar surgery during or before bone resorption inhibition therapy, and the increase predisposition to ONJ development. Therefore, antiresorptive agent therapy should be considered a risk factor until further evidence is prospectively obtained.

Abbreviations

AAOMS

American Association of Oral and Maxillofacial Surgeons

ARM

anti-resorptive medication

ARONJ

anti-resorptive agent-induced osteonecrosis of the jaws

BP

bisphosphonates

BRONJ

bisphosphonate-related osteonecrosis of the jaw

IV

intravenous

MRONJ

medication-related osteonecrosis of the jaw

ONJ

osteonecrosis of the jaw

RANKL

human monoclonal antibody against nuclear factor-kappa B ligand