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EDITORIALS: Basile Nicolas Landis, Michel Richter, Ivan Dojcinovic, and Max Hugentobler Osteonecrosis of the jaw after treatment with bisphosphonates: Is irreversible, so the focus must be on prevention BMJ 2006; 333: 982-983 [Full text]

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Osteonecrosis of the jaw

Prasanna Rao-Balakrishna   (11 November 2006)

why the mandible?

Matthew N S Hunt   (12 November 2006)

Historical Lesson from Occupational Medicine

Eugene R Waclawski   (13 November 2006)

ONJ and bisphosphonates

Mark J Bolland, Andrew Grey, and Ian R Reid   (16 November 2006)

ONJ is not rare after bisphosphonate therapy

Jeffrey R Neilson   (20 November 2006)

A re-newed need to promote awareness of bisphosphonate associated osteonecrosis of the jaw

Israa M Al-Shakarchi, Jonathan L. Jones   (27 September 2007)

Osteonecrosis of the jaw 11 November 2006
Prasanna Rao-Balakrishna, SpR MRI, Manchester Send response to journal: Re: Osteonecrosis of the jaw	The authors have rightly commented on a relatively uncommon but important complication of use of bisphosphonates. This is a timely reminder for all clinicians at a time when the use of these drugs is on the ascent. Bisphosphonates decrease the recruitment of osteoclasts as well as their activity. This results in slowing of the bone turnover thus decreasing bone resorption and bone renewal. They are therefore useful in the prophylaxis and treatment of osteoporosis, Paget's disease, Charcots disease, hypercalcaemia of malignancy and bone metastases in breast cancer. Of the many side effects described, osteonecrosis of the jaw bone seems to be particularly difficult to manage. The fact that it is irreversible makes it important for clinicians to identify as many risk factors for this condition as possible and manage them first before starting Bisphosphonates. This may not always be possible , especially while treating hypercalcaemic states but should certainly be considered before starting treatment for bone prophylaxis. Competing interests: None declared
why the mandible? 12 November 2006
Matthew N S Hunt, GP Willingham Surgery, Cambridge, CB24 5LB Send response to journal: Re: why the mandible?	Fascinating and takes me back to student embryology practicals when we learnt that the mandible ossifies in First Branchial Arch membrane followed by its condylar growth centre. Does this have any connection with its susceptibility to bisphosphonates, or is it more to do with the blood supply not being profuse, or is it something else? Competing interests: None declared
Historical Lesson from Occupational Medicine 13 November 2006
Eugene R Waclawski, Consultant Occupational Physican NHS Greater Glasgow and Clyde, Dykebar Hospital, Paisley PA2 7DE Send response to journal: Re: Historical Lesson from Occupational Medicine	100 years ago the manufacture of matches using yellow phosphorus was subject to an International Convention in Berne (1906) which resulted in substitution of yellow phosphorus for phosphorus sesquisulphide and the control of a disease "phossy jaw". This was an extensive necrosis, usually of the mandible which developed after a latent period of anything up to 5 years after first exposure in those who manufactured matches. Those affected became disfigured and secondary infection was a common cause of death with a 20% case mortality rate (Waldron, 1990). The first case was described in Vienna in 1845 and the first US case in 1851.(Hamilton, 1943). Despite this it took 60 years to ratify an international convention and with legislation, such as the Esch law in the USA (1909), the problem was controlled. It is of interest that the same problem has resurfaced with the use of bisphosphonates. The addition of antibiotics and preventive dental care may reduce the severity of the condition but it is likely that the re- emergence of this condition may only be controlled by restriction of the use of biphosphonates in future. References: 1)Waldron H. (1990). Lecture notes in occupational medicine. Blackwell Scientific Publications, London (4th Edition). 2) Hamilton A. (1943) Exploring the dangerous trades. OEM Press, Beverly, Massachusetts. (OEM edition, 1995). Competing interests: None declared
ONJ and bisphosphonates 16 November 2006
Mark J Bolland, Research Fellow Department of Medicine, University of Auckland, Auckland, New Zealand, Andrew Grey, and Ian R Reid Send response to journal: Re: ONJ and bisphosphonates	The recent editorial by Landis et al.1 has added confusion rather than clarity to the issue of osteonecrosis of the jaw (ONJ) in association with the use of bisphosphonates. In their editorial, Landis and colleagues do not distinguish between the use of very high doses of intravenous bisphosphonates (monthly pamidronate or zoledronate) to treat patients with malignancy, and the use of much lower doses of bisphosphonates (approximately 1/12 of the oncology dose) in the treatment of Paget’s disease or osteoporosis. These two different uses of bisphosphonates have been associated with markedly different risks for ONJ. The authors quote an incidence of 1-10% for ONJ of the jaw in association with bisphosphonates.1 However, they fail to indicate that this estimate relates to people with malignancy treated with high dose intravenous bisphosphonates.2 3 They also refer to ONJ as “avascular osteonecrosis of the jaw”.1 ONJ is not usually termed “avascular” since reduced vascularity has not been proven to be an aetiological factor in ONJ associated with bisphosphonate treatment. Most patients who receive bisphosphonates are prescribed them for osteoporosis, or Paget’s disease. By March 2006, approximately 170 cases worldwide of ONJ in association with alendronate had been reported to the manufacturer (Merck).4 There are few clinical details available for the majority of these cases. In 2004, it was estimated that there had been approximately 20 million patient-years of alendronate treatment for osteoporosis, or Paget’s disease.5 While it is possible that under- reporting of cases of ONJ has occurred, this would have to be very substantial to significantly alter the very low incidence. No cases of ONJ were reported in randomised controlled trials of alendronate, risedronate, zoledronate, and ibandronate in non-malignant skeletal disease that collectively included more than 60,000 patients treated for at least 2 years.6 In the recently completed 3-year trial of annual zoledronate in > 7000 post-menopausal women with osteoporosis, there was 1 case of ONJ in the zoledronate group, and 1 case in the placebo group- interestingly the latter patient had never received any bisphosphonate treatment.7 Therefore, while the incidence of ONJ in patients treated with bisphosphonate for Paget’s disease and osteoporosis is difficult to determine, it is very likely to be less than 1/60,000. The authors recommend that all persons have a specialist dental review prior to starting bisphosphonate therapy,1 in agreement with other dental authorities,2 even though they acknowledge that this approach has not been proven to prevent ONJ. For patients with osteoporosis and Paget’s disease, who appear to have an extremely low risk of ONJ, this intervention (even if it was 100% effective in preventing ONJ) is not likely to be cost-effective, and may lead to unnecessary invasive dental procedures, with attendant morbidity. 1. Landis BN, Richter M, Dojcinovic I, Hugentobler M. Osteonecrosis of the jaw after treatment with bisphosphonates: is irreversible, so the focus must be on prevention. BMJ 2006;333:982-3. 2. Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753 -61. 3. Hoff AO, Toth BB, Altundag K, Guarneri V, Adamus A, Nooka AK, et al. Osteonecrosis of the jaw in patients receiving intravenous bisphosphonate therapy. J Clin Oncol 2006;24 (suppl):8528. 4. American Dental Association. Osteonecrosis of the jaw. 2006; Accessed at 3.7.2006, http://www.ada.org/prof/resources/topics/osteonecrosis.asp 5. Bone HG, Santora AC. N Engl J Med 2004;351:191-2. 6. Shane E, Goldring S, Christakos S, Drezner M, Eisman J, Silverman S, et al. Osteonecrosis of the jaw: more research needed. J Bone Miner Res 2006;21:1503-5. 7. Black DM, Boonen S, Cauley J, Delmas P, Eastell R, Reid IR, et al. Effect of Once-Yearly Infusion of Zoledronic Acid 5 mg on Spine and Hip Fracture Reduction in Postmenopausal Women with Osteoporosis: The HORIZON Pivotal Fracture Trial [abstract]. American Society for Bone and Mineral Research, ASM; 2006; Philidelphia. Abstract 1054. Competing interests: None declared
ONJ is not rare after bisphosphonate therapy 20 November 2006
Jeffrey R Neilson, consultant haematologist Russells Hall Hospital, Dudley, DY11 6JG Send response to journal: Re: ONJ is not rare after bisphosphonate therapy	EDITOR- I was surprised to see osteonecrosis of the jaw (ONJ) described as a rare side effect of bisphosphonate therapy by Landis et al, given the incidence quoted in the previous sentence as 1-10%. Given the significant morbidity associated with this difficult to manage condition, I was disappointed that the obvious preventative strategy of avoiding the use of certain bisphosphonates or limiting therapy say 12 months was not mentioned. Zoledronate seems to produce the highest incidence of ONJ, with one study (Bamias et al, 2005)estimating that 21% of patients develop the complication after 3 years. The only phase 3 trial of zoledronate in cancer patients was a non-inferiority study compared with pamidronate, and the study ran for 13 months (ONJ rarely occurs before 12 months). Given the high rate of ONJ with prolonged therapy with zoledronate, I suggest that before continuing it beyond 12 months clinicians are confident about its benefit, as the risks are significant. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol. 2005 Dec 1;23(34):8580-7. Competing interests: None declared
A re-newed need to promote awareness of bisphosphonate associated osteonecrosis of the jaw 27 September 2007
Israa M Al-Shakarchi, ST2 Renal Medicine West London Renal and Transplant Unit, Hammersmith, W12 0HS, Jonathan L. Jones Send response to journal: Re: A re-newed need to promote awareness of bisphosphonate associated osteonecrosis of the jaw	During a discussion with dental colleagues it was interesting to hear that a recent edition of the British Dental Journal (BDJ) focused on the subject of bisphosphonate associated osteonecrosis of the jaw (ONJ) (1-3). ONJ related to bisphosphonates was highlighted last year in an article within the BMJ by Landis et al., who recommended that given the lack of effective treatment, patients should be referred for a specialist dental or maxillofacial opinion prior to commencing bisphoshonate therapy (4). As new cases have emerged, the focus has moved away from highlighting this issue in only specialist journals, and is now being introduced to a wider dental audience within the BDJ. Currently it is suggested that patients should have their dental status assessed prior to receiving bisphosphonate therapy, be informed of the risks prior to treatment, and have their oral hygiene status closely monitored during treatment by a dental practitioner (no longer specifying the need for a specialist opinion) (1&3). Given that thousands of patients are commenced on bisphosphonate therapy within both the primary and secondary care setting, and the growing number of cases of bisphosphonate associated ONJ with no current effective treatment, it seems prudent to now re-promote a greater awareness of this condition within the medical field. By doing so one hopes not only to reduce the incidence of ONJ, but also to promote better communication within differing specialities and to ensure prompt investigation and treatment in those who may already be affected. References 1.Pancholi M, Edwards A, Langton S. Bisphosphonate induced Osteochemonecrosis of the jaw mimicking a tumour. British Dental Journal 2007; 203;2:87-89. 2.Srinivasan D, Shetty S, Ashworth D, Grew N, Millar B. Orofacial pain – a presenting symptom of bisphosphonate associated osteonecrosis of the jaws. British Dental Journal 2007; 203;2:91-92. 3.Malden NJ, Pai AY. Oral bisphosphonate associated osteonecrosis of the jaws: 4.Landis BN, Richter M, Dojcinovic I, Hugentobler M. Osteonecrosis of the jaw after treatment with bisphosphonates. British Medical Journal 2006; 333;2:982-983. Competing interests: None declared