Rheumatology 2015;54:17551756 doi:10.1093/rheumatology/kev094 Advance Access publication 14 April 2015
RHEUMATOLOGY
Osteonecrosis of the jaws All are equal, but some are more equal than others
for osteoporosis have a risk of developing osteonecrosis of 4 in 10 000 [4]. Therefore the risk of developing osteonecrosis seems to be similar no matter which treatment the patient receives. The signs and symptoms of the condition are also the same, which include pain, swelling, bad taste and exposed bone, ranging from minimal to extensive areas. Some cases can result in pathological fractures. The pharmacology of denosumab and bisphosphonates differs, especially in one important respect: denosumab is a fully human mAb that inhibits RANK ligand [4]. Importantly, as a mAb it is not incorporated into the skeleton like bisphosphonates, which bind to hydroxyapatite crystals. Consequently denosumab’s effects should, in theory, be reversed if the patient develops osteonecrosis of the jaws, as the osteoclasts return to normal function 6 months after the drug has been discontinued [6]. Therefore, in theory, withdrawal of the drug should aid in the treatment of these cases of MRONJ. In the FREEDOM trial, it was reported that the cases that developed in patients treated with denosumab resolved either between the 6-monthly injections or after discontinuation of the drug [4]. This is further supported by several case reports that have also shown resolution of denosumab-related osteonecrosis of the jaws following a drug holiday, with very little need for surgical intervention [6, 7]. In our experience, this outcome is rarely achievable with patients who have been taking bisphosphonates. Only 25% of cases are cured and almost as many suffer a progressive form of osteonecrosis [1]. The washout time for bisphosphonates varies depending on the duration of treatment and the type of bisphosphonate given, but due to the binding to hydroxyapatite, it is likely to be much longer. Denosumab can significantly increase BMD in postmenopausal women [8]. The incidence of other adverse events is comparable to that of oral bisphosphonates [9]. The main disadvantage, however, is cost. The estimated annual cost of denosumab treatment is £366, while the cost of annual treatment with non-proprietary alendronic acid, the most commonly prescribed oral bisphosphonate in the UK [2], is £10.92 [10]. The cost of alendronic acid fails to take into account the cost of hospital appointments for patients who develop osteonecrosis and the cost of long-term i.v. antibiotics, along with the support network required, which is a significant difference. The cost of denosumab compares more favourably with branded bisphosphonates, such as fosamax and strontium ranelate, at £296.40 and £353, respectively [10].
! The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://rheumatology.oxfordjournals.org/ by guest on November 14, 2015
Medication-related osteonecrosis of the jaws is a rare side effect of certain drugs. While osteonecrosis can be debilitating and frequently the outcome is stabilization rather than cure of the disorder, the benefits of bisphosphonates outweigh the risks [1]. It has been more than a decade since the first cases of osteonecrosis of the jaws were recognized in patients taking bisphosphonates [2]. Despite this, the pathogenesis of the condition in patients taking these drugs is not fully understood [2]. There are several theories about how bisphosphonates may cause this condition. These include a reduction in the rate of remodelling of the jaws, inhibition of angiogenesis, soft tissue toxicity and dysfunction of the immune system [2]. A national study published by the Faculty of General Dental Practice in 2012 [1] showed that dental extraction was considered the initiating factor in 73% of cases [1]. In 5% of cases, dental infection was the initiating factor; however, 17% of cases occurred spontaneously [1]. Recently, due to other medications giving rise to osteonecrosis of the jaws, there has been a change in the nomenclature from bisphosphonate-related osteonecrosis of the jaw to medication-related osteonecrosis of the jaw (MRONJ) [2]. Although many medications can cause the same condition, the outcome can vary. The national study found that the prevalence of osteonecrosis of the jaws was between 1 in 1000 and 1 in 10 000 for patients taking oral bisphosphonates for osteoporosis [1]. Another study in California surveyed 8572 patients and found the prevalence to be 1 in 1000 [3]. Other studies have shown no cases of osteonecrosis in the control group [4]. These figures are the population risk for all patients taking bisphosphonates and thus do not represent the individual risk to patients developing this condition following a dental extraction. The risk of patients developing MRONJ following an extraction has been shown to be more than three times higher [5]. A study in Australia estimated the risk for a patient taking once-weekly bisphosphonates to be 1 in 296 following a dental extraction [5]. Attempting to assess a patient’s risk of developing MRONJ is very complicated, as the duration of treatment and the therapeutic indicators are also important in assessing the risk [2]. The longer the duration, the greater the risk of developing MRONJ [2]. Bisphosphonates provided for the treatment of malignancy present a greater risk than those provided for the treatment of osteoporotic changes [2]. Although there is less evidence regarding denosumab, a RANK ligand inhibitor, some trials have shown that patients who receive 60 mg s.c. on a 6-monthly basis
EDITORIAL
Editorial
Editorial
Patients who would benefit most from denosumab are those who have yet to start treatment. The patients who have already received bisphosphonate treatment still carry a risk of the more difficult to treat form of the condition due to the skeletally bound reservoir. This reservoir will not reduce over time as the denosumab will inhibit bone turnover. Research into the possible side effects of denosumab treatment and their prevalence still requires further work; however, the current evidence and the drug’s pharmacology indicate it to be a promising, if expensive, drug. Although the risk of MRONJ related to bisphosphonates is small, the effect on a patient’s quality of life can be severe, especially with the increased patient longevity that these drugs afford. The importance of a dental review before starting patients on either of these treatments should also not be underestimated, as the most common time for patients to develop MRONJ is after a dental extraction [1].
5 Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007;65: 41523.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
6 O’Halloran M, Boyd NM, Smith A. Denosumab and osteonecrosis of the jaws he pharmacology, pathogenesis and a report of two cases. Aust Dent J 2014;59: 5169.
Jamie Toole1 1 Oral Surgery Department, Royal Victoria Hospitals, Belfast, UK Revised version accepted 20 February 2015 Correspondence to: Jamie Toole, Oral Surgery Department, Royal Victoria Hospitals, 274 Grosvenor Road, Belfast BT12 6BA, UK. E-mail: [email protected]
References 1 Faculty of General Dental Practice (UK). National study on avascular necrosis of the jaws. London, UK: Faculty of General Dental Practice, 2012.
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3 Lo JC, O’Ryan FS, Gordon NP et al. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 2010;68: 24353. 4 Papapoulos S, Chapurlat R, Libanati C et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 2012;27: 694701.
7 Malan J, Ettinger K, Naumann E, Beirne OR. The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral surgery, oral medicine, oral pathology and oral radiology. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:6716. 8 Scott LJ. Denosumab: a review of its use in postmenopausal women with osteoporosis. Drugs Aging 2014;31: 55576. 9 Zhou Z, Chen C, Zhang J et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol 2014;7:211322. 10 Joint Formulary Committee. British National Formulary. 68th edn. London, UK: British Medical Association and the Royal Pharmaceutical Society of Great Britain, 2014.
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ by guest on November 14, 2015
Disclosure statement: The author has declared no conflicts of interest.
2 Ruggiero SL, Dodson TB, Fantasia J et al. Medication-related osteonecrosis of the jaw—2014 update. Position paper. Rosemont, IL, USA: American Association of Oral and Maxillofacial Surgeons, 2014.
RHEUMATOLOGY
Osteonecrosis of the jaws All are equal, but some are more equal than others
for osteoporosis have a risk of developing osteonecrosis of 4 in 10 000 [4]. Therefore the risk of developing osteonecrosis seems to be similar no matter which treatment the patient receives. The signs and symptoms of the condition are also the same, which include pain, swelling, bad taste and exposed bone, ranging from minimal to extensive areas. Some cases can result in pathological fractures. The pharmacology of denosumab and bisphosphonates differs, especially in one important respect: denosumab is a fully human mAb that inhibits RANK ligand [4]. Importantly, as a mAb it is not incorporated into the skeleton like bisphosphonates, which bind to hydroxyapatite crystals. Consequently denosumab’s effects should, in theory, be reversed if the patient develops osteonecrosis of the jaws, as the osteoclasts return to normal function 6 months after the drug has been discontinued [6]. Therefore, in theory, withdrawal of the drug should aid in the treatment of these cases of MRONJ. In the FREEDOM trial, it was reported that the cases that developed in patients treated with denosumab resolved either between the 6-monthly injections or after discontinuation of the drug [4]. This is further supported by several case reports that have also shown resolution of denosumab-related osteonecrosis of the jaws following a drug holiday, with very little need for surgical intervention [6, 7]. In our experience, this outcome is rarely achievable with patients who have been taking bisphosphonates. Only 25% of cases are cured and almost as many suffer a progressive form of osteonecrosis [1]. The washout time for bisphosphonates varies depending on the duration of treatment and the type of bisphosphonate given, but due to the binding to hydroxyapatite, it is likely to be much longer. Denosumab can significantly increase BMD in postmenopausal women [8]. The incidence of other adverse events is comparable to that of oral bisphosphonates [9]. The main disadvantage, however, is cost. The estimated annual cost of denosumab treatment is £366, while the cost of annual treatment with non-proprietary alendronic acid, the most commonly prescribed oral bisphosphonate in the UK [2], is £10.92 [10]. The cost of alendronic acid fails to take into account the cost of hospital appointments for patients who develop osteonecrosis and the cost of long-term i.v. antibiotics, along with the support network required, which is a significant difference. The cost of denosumab compares more favourably with branded bisphosphonates, such as fosamax and strontium ranelate, at £296.40 and £353, respectively [10].
! The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://rheumatology.oxfordjournals.org/ by guest on November 14, 2015
Medication-related osteonecrosis of the jaws is a rare side effect of certain drugs. While osteonecrosis can be debilitating and frequently the outcome is stabilization rather than cure of the disorder, the benefits of bisphosphonates outweigh the risks [1]. It has been more than a decade since the first cases of osteonecrosis of the jaws were recognized in patients taking bisphosphonates [2]. Despite this, the pathogenesis of the condition in patients taking these drugs is not fully understood [2]. There are several theories about how bisphosphonates may cause this condition. These include a reduction in the rate of remodelling of the jaws, inhibition of angiogenesis, soft tissue toxicity and dysfunction of the immune system [2]. A national study published by the Faculty of General Dental Practice in 2012 [1] showed that dental extraction was considered the initiating factor in 73% of cases [1]. In 5% of cases, dental infection was the initiating factor; however, 17% of cases occurred spontaneously [1]. Recently, due to other medications giving rise to osteonecrosis of the jaws, there has been a change in the nomenclature from bisphosphonate-related osteonecrosis of the jaw to medication-related osteonecrosis of the jaw (MRONJ) [2]. Although many medications can cause the same condition, the outcome can vary. The national study found that the prevalence of osteonecrosis of the jaws was between 1 in 1000 and 1 in 10 000 for patients taking oral bisphosphonates for osteoporosis [1]. Another study in California surveyed 8572 patients and found the prevalence to be 1 in 1000 [3]. Other studies have shown no cases of osteonecrosis in the control group [4]. These figures are the population risk for all patients taking bisphosphonates and thus do not represent the individual risk to patients developing this condition following a dental extraction. The risk of patients developing MRONJ following an extraction has been shown to be more than three times higher [5]. A study in Australia estimated the risk for a patient taking once-weekly bisphosphonates to be 1 in 296 following a dental extraction [5]. Attempting to assess a patient’s risk of developing MRONJ is very complicated, as the duration of treatment and the therapeutic indicators are also important in assessing the risk [2]. The longer the duration, the greater the risk of developing MRONJ [2]. Bisphosphonates provided for the treatment of malignancy present a greater risk than those provided for the treatment of osteoporotic changes [2]. Although there is less evidence regarding denosumab, a RANK ligand inhibitor, some trials have shown that patients who receive 60 mg s.c. on a 6-monthly basis
EDITORIAL
Editorial
Editorial
Patients who would benefit most from denosumab are those who have yet to start treatment. The patients who have already received bisphosphonate treatment still carry a risk of the more difficult to treat form of the condition due to the skeletally bound reservoir. This reservoir will not reduce over time as the denosumab will inhibit bone turnover. Research into the possible side effects of denosumab treatment and their prevalence still requires further work; however, the current evidence and the drug’s pharmacology indicate it to be a promising, if expensive, drug. Although the risk of MRONJ related to bisphosphonates is small, the effect on a patient’s quality of life can be severe, especially with the increased patient longevity that these drugs afford. The importance of a dental review before starting patients on either of these treatments should also not be underestimated, as the most common time for patients to develop MRONJ is after a dental extraction [1].
5 Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007;65: 41523.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
6 O’Halloran M, Boyd NM, Smith A. Denosumab and osteonecrosis of the jaws he pharmacology, pathogenesis and a report of two cases. Aust Dent J 2014;59: 5169.
Jamie Toole1 1 Oral Surgery Department, Royal Victoria Hospitals, Belfast, UK Revised version accepted 20 February 2015 Correspondence to: Jamie Toole, Oral Surgery Department, Royal Victoria Hospitals, 274 Grosvenor Road, Belfast BT12 6BA, UK. E-mail: [email protected]
References 1 Faculty of General Dental Practice (UK). National study on avascular necrosis of the jaws. London, UK: Faculty of General Dental Practice, 2012.
1756
3 Lo JC, O’Ryan FS, Gordon NP et al. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 2010;68: 24353. 4 Papapoulos S, Chapurlat R, Libanati C et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 2012;27: 694701.
7 Malan J, Ettinger K, Naumann E, Beirne OR. The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral surgery, oral medicine, oral pathology and oral radiology. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:6716. 8 Scott LJ. Denosumab: a review of its use in postmenopausal women with osteoporosis. Drugs Aging 2014;31: 55576. 9 Zhou Z, Chen C, Zhang J et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol 2014;7:211322. 10 Joint Formulary Committee. British National Formulary. 68th edn. London, UK: British Medical Association and the Royal Pharmaceutical Society of Great Britain, 2014.
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ by guest on November 14, 2015
Disclosure statement: The author has declared no conflicts of interest.
2 Ruggiero SL, Dodson TB, Fantasia J et al. Medication-related osteonecrosis of the jaw—2014 update. Position paper. Rosemont, IL, USA: American Association of Oral and Maxillofacial Surgeons, 2014.
