Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: Not just a sporadic coincidence – a multi-centre study

Abstract

Introduction

Bisphosphonates (BPs) are powerful drugs that inhibit bone metabolism. Adverse side effects are rare but potentially severe such as bisphosphonate-related osteonecrosis of the jaw (BRONJ). To date, research has primarily focused on the development and progression of BRONJ in cancer patients with bone metastasis, who have received high dosages of BPs intravenously. However, a potential dilemma may arise from a far larger cohort, namely the millions of osteoporosis patients on long-term oral BP therapy.

Patients and methods

This current study assessed 470 cases of BRONJ diagnosed between 2004 and 2008 at eleven different European clinical centres and has resulted in the identification of a considerable cohort of osteoporosis patients suffering from BRONJ. Each patient was clinically examined and a detailed medical history was raised.

Results

In total, 37/470 cases (7.8%) were associated with oral BP therapy due to osteoporosis. The majority (57%) of affected individuals did not have any risk factors for BRONJ as defined by the American Association of Oral and Maxillofacial Surgery. The average duration of BP intake of patients without risk factors was longer and the respective patients were older compared to patients with risk factors, but no statistical significant difference was found. In 78% of patients the duration of oral BP therapy exceeded 3 years prior to BRONJ diagnosis.

Discussion

The results from this study suggest that the relative frequency of osteoporosis patients on oral BPs suffering from BRONJ is higher than previously reported. There is an urgent need to substantiate epidemiological characteristics of BRONJ in large cohorts of individuals.

Introduction

Osteoporosis is a health threat of major public concern. Due to osteoporosis, approximately 50% of women and 20% of men over 50 years of age will suffer from a fragility fracture in their remaining lifetime (Sambrook and Cooper, 2006). Osteoporosis is effectively managed with bisphosphonates (BPs), an antiresorptive drug that can significantly prevent skeletal complications, in particular fractures (Berenson et al., 1996, Black et al., 1996, Black et al., 2006, Cranney et al., 2002, Sambrook and Cooper, 2006). Side effects associated with BP intake are generally rare. However, since 2003 (Marx, 2003, Migliorati, 2003, Wang et al., 2003) bisphosphonate-related osteonecrosis of the jaw (BRONJ) has become a clinical problem of rising importance (Migliorati et al., 2006). BRONJ is defined by (i) trans-mucosal or trans-cutaneous jawbone exposure over a period of 8 weeks, (ii) a positive history of BP administration, and (iii) a negative history for irradiation of the head and neck region (AAOMFS, 2007, Khosla et al., 2007). It is frequently accompanied by a variety of other clinical manifestations such as pain, soft tissue swelling or ulceration, suppuration, intra- or extra-oral sinus tracks, abscess and impairment of nerve functions (Marx, 2003, Abu-Id et al., 2006, Abu-Id et al., 2008, AAOMFS, 2007, Khosla et al., 2007) (Fig. 1). Therapy results of early stages are good (Markose et al., 2009, Otto et al., 2009, Pautke et al., 2009) in particular in cases with oral BP intake (Marx et al., 2007). However, if diagnosis or therapy is delayed, entire parts of the jawbones may have to be removed in severe cases which also necessitate a complex post-surgical rehabilitation (Engroff and Kim, 2007, Mücke et al., 2009, Pautke et al., 2010). This progression has almost exclusively been reported in cancer patients with bone metastasis who received intravenous BP therapy.

Several factors have been suggested to trigger an increased risk of the BRONJ manifestation (AAOMFS, 2007, Khosla et al., 2007), but concrete evidence has been limited to the duration of BP intake, the BP derivate and previous dental procedures (Bamias et al., 2005, Badros et al., 2006, Dimopoulos et al., 2009). Patients subjected to intravenous BP administration are at higher risk of developing a BRONJ with a prevalence of 3–18% (Bamias et al., 2005, Wang et al., 2007, Badros et al., 2008, Boonyapakorn et al., 2008, Kyrgidis et al., 2008, Walter et al., 2008). Preventive dental measures (Dimopoulos et al., 2009) as well as a modified dosing schedule (Corso et al., 2007) can reduce but not eliminate the risk. Dento-alveolar surgeries have been reported to precede a BRONJ manifestation in over 80% of the cases. As a consequence, elective surgical procedures, such as dental implant insertion are contraindicated in these patients (Piesold et al., 2006, Khosla et al., 2007, Ruggiero et al., 2009).

In contrast, studies concerning the risk of BRONJ among users of oral BPs are sparse, limited in total to approximately 200 cases (Abu-Id et al., 2006, Piesold et al., 2006, Marx et al., 2007, Yarom et al., 2007, Hess et al., 2008, King and Umland, 2008, Rizzoli et al., 2008, Hong et al., 2009). Therefore, the association between oral BPs and jaw necrosis has been regarded, by some, as being of negligible clinical significance. For example, neither the American Association of Clinical Endocrinologists (AACE, 2003), the National Osteoporosis Society (McLeod et al., 2007), nor the Joint Organization of the Scientific Societies of Osteology of Germany, Austria and Switzerland (DVO, 2006) provide a recommendation concerning elective invasive dental procedures (e.g. insertion of osteointegrated implants) in osteoporosis patients on oral BP. Moreover, when the issue is addressed, recommendations can be contradictory. The American Society for Bone and Mineral Research sees no contraindication in performing elective alveolar bone surgery in patients on oral BPs (Khosla et al., 2007) whilst the German Association of Oral and Maxillofacial Surgeons recommends to refrain from bone surgery during ongoing oral BP therapy (Piesold et al., 2006). Similarly, the American Association of Oral and Maxillofacial Surgeons, explicitly advises to perform invasive dental surgery only if no further risk factors exist when the BP intake exceeds 3 years (AAOMFS, 2007).

Overall, the association between oral BP and BRONJ has been largely neglected (Pazianas et al., 2007, Pazianas et al., 2008, Rizzoli et al., 2008) notwithstanding the characteristics of this large cohort of individuals. Current figures estimate that over 190 million prescriptions for oral BPs are dispensed worldwide each year (AAOMFS, 2007) and more than 15 million (elective) dental implants operations and other (necessary) dento-alveolar surgical procedures are performed worldwide.

This paper describes a large cohort of patients with osteoporosis who developed BRONJ in association with oral BPs. It aims to (i) examine the association between oral BPs and BRONJ and (ii) increase awareness among osteoporosis-treating physicians who are in the position to monitor and specifically educate patients about preventive measures.