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Keywords:

  • thalassaemia major;
  • bisphosphonate induced osteonecrosis of jaw;
  • alendronate

Osteopenia-osteoporosis syndrome (OOS) is a significant cause of bone morbidity that affects 60–80% of thalassaemia major (TM) patients worldwide, causing fracture, bone pain and hospital admissions (Terpos & Voskaridou, 2010; Chatterjee et al, 2012). It is multifactorial in origin and the pathology still poorly understood. It is principally a high bone turnover disease due to transfusional haemosiderosis, chelation therapy (desferrioxamine-induced skeletal dysplasia) and hypogonadotrophic hypogoandism (HH; Chatterjee et al, 2012).

In TM, bisphosphonates are used intravenously (pamidronate, zolendronic acid) or orally (alendronate), with or without sex steroids, with successful outcome of increased bone mass (Terpos & Voskaridou, 2010; Chatterjee et al, 2012). However, bisphosphonates may be associated with a potentially serious side effect, bisphosphonate-related osteonecrosis of the jaw (BONJ), which is well reported in malignant and non-malignant bone diseases (Assael, 2009) but not in TM.

We report for the first time three TM individuals (2 females; 1 male) with OOS presenting with clinical and radiological features of BONJ (Table 1). All 3 had received alendronate 70 mg/week for 4–6 years. Case 2 had received IV pamidronate 60 mg/month for 3 years prior to oral alendronate.

Table 1. Clinical, haematological and dental data of thalassaemia major patients with osteoporosis presenting with non-exposed osteonecrosis of jaw.
PatientAge (years)BONJOral AlendronateIV Pamidronate/monthTooth ExtractionBone ProfileDexa Scan (T-Score)FractureIron OverloadChelationComplications
Clinical StagebX-rayDose (mg)Duration (months)Dose (mg)Duration (months)VDaPTHLSFNTypeNoSerum ferritin (μg/l)Cardiac T2a (ms)Liver T2a, mg/g dw
  1. FN, Femoral neck; LS, lumber spine; HH, Hyogonadotrophic hypogonadism; DFO, Desferrioxamine.

  2. Low VD = <40 nmol/l (Normal range 25–56 nmol/l).

  3. High PTH = >5·8 pmol/l; (1·2–5·8 pmol/l).

  4. a

    VD = Vitamin D 25 (OH)2.

  5. b

    BONJ (Clinical stage zero-) Non-exposed variant of bisphosphonate-related osteonecrosis of the jaw –Jaw pain, gingival swelling, sinus tract.

1520Bone loss with necrosis35048YesLowHigh−1·5−1·5FN12000201DFO, 3 g/kg/4 nights/weekHypertension, Diabetes, nephrocalcinosis, Cholecystectomy, HH
2580Necrosis40040YesLowHigh−3·4−1·4FN, LS2190020·11·5DFO, 2·5 g/kg/5 nights/weekHepatitis C, HH, diabetes
3490Marked necrosis300506024YesLowHigh−3·1−1·6LS1150030·92DFO, 3 g/kg/5 nights/weekHepatitis C, cirrhosis, cholecystectomy, HH

Cases 1 and 2 presented with clinical features of non-exposed BONJ, such as gingival and jaw bone pain with swelling, sinus tract and minimal bone loss whilst the third patient had frank trans-mucosal necrotic bone exposure. All were managed symptomatically with antibiotics and analgesics for infection and pain control. At the 1-year follow-up, there was stable BONJ with no signs of progression in two individuals whilst the third patient experienced severe uncontrolled pain, secondary infection of exposed necrotic bone, and further development of multiple osteonecrotic areas to jawbones.

Although this is the first report of BONJ in TM, BONJ after oral bisphosphonates was first reported in 2003 (Marx, 2003; Koka et al, 2007). BONJ is a potentially severe and a debilitating complication of bisphosphonate. It typically manifests clinically as painful infected areas of necrotic jawbone and can lead to severe chronic pain, facial disfigurement, compromised eating and speech, and reduced quality of life. It is estimated that 8–10% of patients with malignancy taking bisphosphonate can develop BONJ, although the incidence varies widely, from 0–27% (Kühl et al, 2012). Recent reports have shown a much higher frequency of BONJ (4–7·8%; Benlidayi & Guzel, 2013; Otto et al, 2012) in patients taking oral bisphosphonate, such as alendronate sodium. It is difficult to accurately determine the prevalence of BONJ due to the following factors: Firstly, there is wide variation of patients presenting with this pathology. Secondly, the self-limiting nature of the condition and, most importantly, the lack of awareness of physicians caring for TM patients could possibly contribute to its under diagnosis.

Conventionally, BONJ is defined according to the Task force of American Society of Bone and Mineral research as an exposed area of bone in the maxillofacial area which fails to heal within 8 weeks after its identification by a health care professional, in a patient who was currently receiving or had been previously exposed to a bisphosphonate and did not have radiotherapy to the craniofacial area.

All our TM patients fulfilled the criteria of the updated definition of American society of Mineral research for BONJ (Benlidayi & Guzel, 2013), as used at our institution, which states that patients must meet all 3 criteria to be considered for BONJ:

  1. Current or previous treatment with bisphosphonates.
  2. Exposed or otherwise necrotic bone in the maxilla facial region that has persisted more than 8 weeks.
  3. No history of radiation to the jaws.

The exact pathology and cause of BONJ in TM is unclear. High risk factors include older age, drug dose, duration, potency and local risk factors (infection, tooth extraction, prosthesis; Otto et al, 2012). Life style issues and systemic co-morbid factors include smoking, immunosuppression, anaemia, diabetes and steroids (Assael, 2009). BONJ is more common after IV use, but can also occur after oral therapy, especially with nitrogen-containing bisphosphonates (Benlidayi & Guzel, 2013). 0·06% of long-term users of oral bisphosphonates were reported to have BONJ. It can also occur after 122 weeks of alendronate (70 mg/week).

It is plausible that, in our 3 TM patients, BONJ was precipitated by co-morbid conditions including chronic ill health, infection and dental extraction. All our patients were of Mediterranean origin, which could also be an additional contributor, as hypothesized before (Fedele et al, 2010). We propose that the cumulative dose and long half-life of bisphosphonate aggravated the pre-existing bone remodelling disorder of TM in these cases.

Although many cases BONJ are self-limiting or may resolve with symptomatic treatment (Benlidayi & Guzel, 2013), the literature suggests that those with systemic diseases or co-morbidity take longer time to heal (Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws & American Association of Oral & Maxillofacial Surgeons, 2007). This is especially important in TM patients who have multisystem disease and intrinsic bone remodelling disorders including diabetes. Therefore a high index of suspicion is required and awareness for BONJ in TM patients on bisphosphonates so that prompt diagnosis can be made by oral medicine experts for vigilance and early intervention.

Use of biochemical collagen bone markers (serum telopeptide cross-link of type 1 collagen), osteocalcin and parathyroid hormone, have all been proposed as predictive markers for BONJ although their value remains controversial (Benlidayi & Guzel, 2013). Our recent prospective case-controlled study showed that there was a decline in biochemical bone markers concomitant with improved bone density following bisphosphonate therapy in TM (Chatterjee et al, 2012). To the best of our knowledge none of the patients in that study had BONJ or subsequently developed it.

Currently, unlike for cancer patients, there are no known guidelines for oral medical check-ups in TM with OOS treated by bisphosphonates. Given that 70–80% of adult patients with TM have OOS and that bisphosphonate is an important armamentarium in its management, a high index for suspicion is critical for early diagnosis of BONJ. We recommend that all TM patients undergoing bisphosphonate therapy should have regular specialist dental check ups prior to and during treatment.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. Authors' contributions
  4. Conflict of interest
  5. References

We wish to thank Dr Navdeep Kumar, Dr Roger Davies, and Prof Stephen Porter for offering dental care to the patients, and the members of Reproductive Medicine, IFWH and Haematology for their assistance in this study.

Authors' contributions

  1. Top of page
  2. Acknowledgements
  3. Authors' contributions
  4. Conflict of interest
  5. References

RC and RB wrote the paper. SF contributed on the oral medicine component of the paper and JBP and FS provided haematological input. All authors approved of the final version of the manuscript.

Conflict of interest

  1. Top of page
  2. Acknowledgements
  3. Authors' contributions
  4. Conflict of interest
  5. References

The authors have no conflict of interest to declare.

References

  1. Top of page
  2. Acknowledgements
  3. Authors' contributions
  4. Conflict of interest
  5. References
  • Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws and American Association of Oral and Maxillofacial Surgeons (2007) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. Journal of Oral and Maxillofacial Surgery, 65, 369376.
  • Assael, L.A. (2009) Oral bisphosphonates as a cause of bisphosphonate-related osteonecrosis of the jaws: clinical findings, assessment of risks, and preventive strategies. Journal of Oral and Maxillofacial Surgery, 67, 3543.
  • Benlidayi, C. & Guzel, R. (2013) Oral bisphosphonate related osteonecrosis of the jaw: a challenging adverse effect. ISRN Rheumatology, 2013, 215034215040.
  • Chatterjee, R., Shah, F.S., Davis, B.A., Byers, M., Sooranna, S., Bajoria, R., Pringle, J. & Porter, J.B. (2012) Prospective study of histomorphometry, biochemical bone markers and bone densitometric response to pamidronate in β-thalassaemia presenting with osteopenia-osteoporosis syndrome. British Journal of Haematology, 159, 462471.
  • Fedele, S., Porter, S.R., D'Aiuto, F., Aljohani, S., Vescovi, P., Manfredi, M., Arduino, P.G., Broccoletti, R., Musciotto, A., Di Fede, O., Lazarovici, T.S., Campisi, G. & Yarom, N. (2010) Non exposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. American Journal of Medicine, 123, 10601064.
  • Koka, S., Clarke, B.L., Amin, S., Gertz, M. & Ruggiero, S.L. (2007) Oral bisphosphonate therapy and osteonecrosis of the jaw: what to tell the concerned patient. The International Journal of Prosthodontics, 20, 115122.
  • Kühl, S., Walter, C., Acham, S., Pfeffer, R. & Lambrecht, J.T. (2012) Bisphosphonate-related osteonecrosis of the jaws–a review. Oral Oncology, 48, 938947.
  • Marx, R.E. (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. Journal of Oral and Maxillofacial Surgery, 61, 11151117.
  • Otto, S., Schreyer, C., Hafner, S., Mast, G., Ehrenfeld, M., Stürzenbaum, S. & Pautke, C. (2012) Bisphosphonate-related osteonecrosis of the jaws - characteristics, risk factors, clinical features, localization and impact on oncological treatment. Journal of Cranio-Maxillo-Facial Surgery, 40, 303309.
  • Terpos, E. & Voskaridou, E. (2010) Treatment options for thalassemia patients with osteoporosis. Annals of the New York Academy of Sciences, 1202, 237243.