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1. Bisphosphonates in multiple myeloma John Ashcroft
Pinderfields Hospital/University of Leeds
2. * SREs denotes skeletal related events: new lytic lesions, vertebral and non-vertebral fractures, need for radiation or surgery to the bone; p.o. denotes oral administration and iv intravenous administration; NE denotes not evaluated.
† Pamidronate-controlled trial.
‡ In a post-hoc analysis, patients without vertebral fracture at entry survived significantly longer on clodronate (median survival was 23 months longer than in similar patients receiving placebo).
§ Survival in the patients with more advanced disease was significantly increased in the pamidronate group (median survival 21 vs. 14 months; p=0.041 adjusted for baseline serum ß2-microglobulin and Eastern Cooperative Oncology Group performance status).
£ Survival benefit with zoledronic acid over pamidronate for a subgroup of patients who had elevated bone-specific alkaline phosphatase levels baseline.
* SREs denotes skeletal related events: new lytic lesions, vertebral and non-vertebral fractures, need for radiation or surgery to the bone; p.o. denotes oral administration and iv intravenous administration; NE denotes not evaluated.
† Pamidronate-controlled trial.
‡ In a post-hoc analysis, patients without vertebral fracture at entry survived significantly longer on clodronate (median survival was 23 months longer than in similar patients receiving placebo).
§ Survival in the patients with more advanced disease was significantly increased in the pamidronate group (median survival 21 vs. 14 months; p=0.041 adjusted for baseline serum ß2-microglobulin and Eastern Cooperative Oncology Group performance status).
£ Survival benefit with zoledronic acid over pamidronate for a subgroup of patients who had elevated bone-specific alkaline phosphatase levels baseline.
* SREs denotes skeletal related events: new lytic lesions, vertebral and non-vertebral fractures, need for radiation or surgery to the bone; p.o. denotes oral administration and iv intravenous administration; NE denotes not evaluated.
† Pamidronate-controlled trial.
‡ In a post-hoc analysis, patients without vertebral fracture at entry survived significantly longer on clodronate (median survival was 23 months longer than in similar patients receiving placebo).
§ Survival in the patients with more advanced disease was significantly increased in the pamidronate group (median survival 21 vs. 14 months; p=0.041 adjusted for baseline serum ß2-microglobulin and Eastern Cooperative Oncology Group performance status).
£ Survival benefit with zoledronic acid over pamidronate for a subgroup of patients who had elevated bone-specific alkaline phosphatase levels baseline.
* SREs denotes skeletal related events: new lytic lesions, vertebral and non-vertebral fractures, need for radiation or surgery to the bone; p.o. denotes oral administration and iv intravenous administration; NE denotes not evaluated.
† Pamidronate-controlled trial.
‡ In a post-hoc analysis, patients without vertebral fracture at entry survived significantly longer on clodronate (median survival was 23 months longer than in similar patients receiving placebo).
§ Survival in the patients with more advanced disease was significantly increased in the pamidronate group (median survival 21 vs. 14 months; p=0.041 adjusted for baseline serum ß2-microglobulin and Eastern Cooperative Oncology Group performance status).
£ Survival benefit with zoledronic acid over pamidronate for a subgroup of patients who had elevated bone-specific alkaline phosphatase levels baseline.
3. Treatment with bisphosphonates (eg, BONEFOS®) is standard care for patients with malignant bone disease1
BONEFOS® (oral clodronate) 1600 mg/day treatment of multiple myeloma patients is associated with the following compared with placebo:
Significant fewer new vertebral fractures (38% versus 55% with placebo, P = 0.01)2
Significant fewer non-vertebral fractures (7% versus 13% with placebo, P = 0.04)2
A 50% decrease in the proportion of patients with severe hypercalcemia (51% vs 10.1% with placebo, P = 0.06)2 BONEFOS®: Reduces Fractures in Patients With Multiple Myeloma
4. BONEFOS® (oral clodronate) 1600 mg/day treatment of patients with multiple myeloma is associated with the following compared with placebo:
Reduced frequency of back pain1
Improved performance status1 BONEFOS®: Reduces Pain and Improves Performance Status in Patients With Multiple Myeloma
6. Breast cancer and multiple myeloma multiple SRE analysis
7. 2005 guidance Bisphosphonates
Bisphosphonate therapy is recommended for all patients with myeloma requiring chemotherapy, whether or not bone lesions are evident (grade A recommendation; level Ib evidence).
Treatment should be continued for at least 2 years (grade A recommendation; level Ib evidence); it is current practice to continue treatment indefinitely although there are a few reported data on longer-term use.
Oral clodronate (1600 mg/d or equivalent dosage according to formulation), intravenous pamidronate, and intravenous zoledronic acid (grade A recommendation; level Ib evidence) may be used. Monthly i.v. pamidronate 90 mg and zoledronic acid 4 mg are equivalent in efficacy (grade A recommendation; level Ib evidence). The choice of therapy will depend on patient and physician preference.
8. 2005 guidance (2) Bisphosphonates Doses, infusion times and frequencies should be as recommended by the manufacturer, and renal function should be monitored. Creatinine should be checked before each zoledronic acid infusion.
Special caution is required with all bisphosphonates in patients with moderate to severe renal failure; zoledronic acid should not be used if creatinine is >265 µmol/l.
There are insufficient data to make a recommendation for the use of bisphosphonates in patients with asymptomatic myeloma.
9. Proposed 2008 guidance
10. Vertebroplasty/Kyphoplasty/Spinal cord compression Further studies available demonstrating similar efficacy in myeloma as osteoporosis.
Less cement leak, lower complication rates, some restoration of vertebral height
11. Prevalence of ONJ ONJ is an uncommon condition, with an estimated incidence of 1-10%1-3
The true incidence is unknown, as current estimates rely on case reports and retrospective analyses4
ONJ has been reported in patients taking long-term bisphosphonate therapy3
Most cases have developed in patients with multiple myeloma or metastatic cancer; however, ONJ has also been identified in patients with osteoporosis5
There are many risk factors, including tumour burden, poor blood circulation, diabetes mellitus, and the patients overall health6
Landis BN, Richter M, Dojcinovic I et al. Osteonecrosis of the jaw after treatment with bisphosphonates: Is irreversible, so the focus must be on prevention. BMJ 2006;333:982-983.
Durie BGM, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99-102.
Bamias A, Kastritis E, Bamia C et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol 2005;23:8580-8587.
Sanna G, Preda L, Bruschini R et al. Bisphosphonates and jaw osteonecrosis in patients with advanced breast cancer. Ann Oncol 2006;17:1512-1216.
Woo S, Preda L, Bruschini R et al. Systematic review: Bisphosphonates and osteonecrosis of the jaw. Ann Intern Med 2006;144:753-761.
Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 2005;136:1658-1668.
ONJ is an uncommon condition, with an estimated incidence of 1-10%1-3
The true incidence is unknown, as current estimates rely on case reports and retrospective analyses4
ONJ has been reported in patients taking long-term bisphosphonate therapy3
Most cases have developed in patients with multiple myeloma or metastatic cancer; however, ONJ has also been identified in patients with osteoporosis5
There are many risk factors, including tumour burden, poor blood circulation, diabetes mellitus, and the patients overall health6
Landis BN, Richter M, Dojcinovic I et al. Osteonecrosis of the jaw after treatment with bisphosphonates: Is irreversible, so the focus must be on prevention. BMJ 2006;333:982-983.
Durie BGM, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99-102.
Bamias A, Kastritis E, Bamia C et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol 2005;23:8580-8587.
Sanna G, Preda L, Bruschini R et al. Bisphosphonates and jaw osteonecrosis in patients with advanced breast cancer. Ann Oncol 2006;17:1512-1216.
Woo S, Preda L, Bruschini R et al. Systematic review: Bisphosphonates and osteonecrosis of the jaw. Ann Intern Med 2006;144:753-761.
Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 2005;136:1658-1668.
12. MDACC Retrospective Chart Review: Results 4,019 patient charts were reviewed; 31 patients were excluded: 25 with insufficient information and 6 seen in dental clinic but not in MDACC pharmacy database
3,994 patients were included in final analysis: 29 cases of ONJ were identified
Overall: 29/3,994 (0.73%)
Breast cancer: 16/1,338 (1.2%)
Multiple myeloma: 13/548
Site of ONJ involvement: mandible (70% of cases) and maxilla (30% of cases)
Of 29 ONJ cases, 72% presented with exposed bone without pain
ONJ was not identified in the following patient groups treated with IV bisphosphonates: metastatic bone disease from cancers other than breast or myeloma, osteoporosis, hypercalcemia of malignancy, or Paget’s disease
Risk factors in MM incl zol/pam, osteoporosis and dental extractions
13. ONJ: Other Retrospective Reviews
University of Maryland: review of 90 multiple myeloma patients who had dental evaluation1
22 patients with ONJ
ONJ diagnosed in 11/340 patients followed with multiple myeloma (ONJ frequency 3%)
Another 11 patients with multiple myeloma referred to dental school for management of ONJ
Risk factors: dental extraction, pamidronate and/or zoledronic acid, and longer follow-up time
University of Athens: 252 oncology patients treated with bisphosphonates = 6 months since 19972
13/17 (76%) patients had dental extraction within 1 year before ONJ
Length of exposure seems to be a risk factor for ONJ
ONJ developed in 17 (6.7%) patients overall; frequencies ranged from 2.9% in breast cancer to 9.9% in multiple myeloma patients
Despite the inherent weakness of retrospective reviews, and the much larger sample size of the MDACC review compared to the two reviews above, the reported frequencies of ONJ are similar, except for the increased frequency seen in MM patients in the Greek review.
University of Athens study (Bamias, et al JCO 23: 8580, 2005)
University of Maryland study (Badros, et al JCO 24: 945, 2006)Despite the inherent weakness of retrospective reviews, and the much larger sample size of the MDACC review compared to the two reviews above, the reported frequencies of ONJ are similar, except for the increased frequency seen in MM patients in the Greek review.
University of Athens study (Bamias, et al JCO 23: 8580, 2005)
University of Maryland study (Badros, et al JCO 24: 945, 2006)
14. Preventive Measures Active oral infections must be treated before bisphosphonate therapy begins to eliminate all potential sites of infection2,3
Medical information, including a complete review of all medical diagnoses, history of cancer, and oral complications, should be used to guide the dentist in developing a treatment plan based on the patient’s dental needs and medical health3
Once bisphosphonate therapy is initiated, patients are encouraged to seek appropriate dental maintenance care approximately every 6 months or more frequently, where appropriate1
After bisphosphonate treatment has commenced, surgical procedures are not recommended, and patients are advised to undergo endodontic therapy with appropriate local and systemic antibiotics2
If there is no possible alternative, then surgery and dental extractions must be performed with minimal bone manipulation, the appropriate local and systemic antibiotics, and have follow-up to ensure healing2
Weitzman R, Sauter N, Eriksen EF et al. Critical review: Updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients – May 2006. Crit Rev Oncol/Hematol 2007;62:148-152.
Woo S, Preda L, Bruschini R et al. Systematic review: Bisphosphonates and osteonecrosis of the jaw. Ann Intern Med 2006;144:753-761.
Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 2005;136:1658-1668.Active oral infections must be treated before bisphosphonate therapy begins to eliminate all potential sites of infection2,3
Medical information, including a complete review of all medical diagnoses, history of cancer, and oral complications, should be used to guide the dentist in developing a treatment plan based on the patient’s dental needs and medical health3
Once bisphosphonate therapy is initiated, patients are encouraged to seek appropriate dental maintenance care approximately every 6 months or more frequently, where appropriate1
After bisphosphonate treatment has commenced, surgical procedures are not recommended, and patients are advised to undergo endodontic therapy with appropriate local and systemic antibiotics2
If there is no possible alternative, then surgery and dental extractions must be performed with minimal bone manipulation, the appropriate local and systemic antibiotics, and have follow-up to ensure healing2
Weitzman R, Sauter N, Eriksen EF et al. Critical review: Updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients – May 2006. Crit Rev Oncol/Hematol 2007;62:148-152.
Woo S, Preda L, Bruschini R et al. Systematic review: Bisphosphonates and osteonecrosis of the jaw. Ann Intern Med 2006;144:753-761.
Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 2005;136:1658-1668.
15. Prevention and Management Strategies: Before Treatment Currently there are no effective treatments for ONJ;2 therefore, prevention is of paramount importance3
A retrospective review of 813 consecutive cancer patients with bone metastases treated with bisphosphonates was conducted1
The routine application of preventive measures before starting and during treatment with bisphosphonates led to a 75% reduction in the incidence on ONJ1
Strategies for the prevention and management of bisphosphonate-related ONJ have been published, and are based primarily on eliminating the active sites of infection before bisphosphonate therapy commences, and good oral hygiene during treatment3,4
Before commencing bisphosphonate treatment, the recommended dental consultation should include a comprehensive introral and extraoral examination, including a panoramic jaw radiograph to detect any potential dental and periodontal infections5,6,7
The risk of ONJ needs to be balanced against the benefit of therapy8
A risk benefit profile should be considered for each individual patient before starting long-term bisphosphonate treatment3
Patients should be made aware of the small potential risk of developing ONJ. Furthermore, all patients should be educated in regards to dental health and the timely reporting of any symptoms, such as bleeding, pain or unusual feeling in the teeth or gums3,5,6
Ripamonti C, Maniezzo M, Cislaghi E et al. Application of preventive measures minimizes the occurrence of the osteonecrosis of the jaw (ONJ) in solid tumors patients (pts) with bone metastases treated with bisphosphonates (BPs): A single institution series. Presented at San Antonio Breast Cancer Symposium, December 13-16 2007, Texas, USA. Abstract 2056.
Shenker NG. Bisphosphonates and osteonecrosis of the jaw. Rheumatology 2007;46:1049-1051.
Capsoni F, Longhi M, Weinstein R. Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist’s role. Arthritis Res Ther 2006;8:219.
Weitzman R, Sauter N, Eriksen EF et al. Critical review: Update recommendations for the prevention, diagmnosis, and treatment of osteonecrosis of the jaw in cancer patients – May 2006. Crit Rev Oncol/Hematol 2007;62:148-152.
Woo S, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.
Ruggiero S, Gralow J, Marx RE et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Practice 2006;2:7-14.
Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 2005;136:1658-1668.
Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw. Aust Fam Physician 2006;35:801-803.
Currently there are no effective treatments for ONJ;2 therefore, prevention is of paramount importance3
A retrospective review of 813 consecutive cancer patients with bone metastases treated with bisphosphonates was conducted1
The routine application of preventive measures before starting and during treatment with bisphosphonates led to a 75% reduction in the incidence on ONJ1
Strategies for the prevention and management of bisphosphonate-related ONJ have been published, and are based primarily on eliminating the active sites of infection before bisphosphonate therapy commences, and good oral hygiene during treatment3,4
Before commencing bisphosphonate treatment, the recommended dental consultation should include a comprehensive introral and extraoral examination, including a panoramic jaw radiograph to detect any potential dental and periodontal infections5,6,7
The risk of ONJ needs to be balanced against the benefit of therapy8
A risk benefit profile should be considered for each individual patient before starting long-term bisphosphonate treatment3
Patients should be made aware of the small potential risk of developing ONJ. Furthermore, all patients should be educated in regards to dental health and the timely reporting of any symptoms, such as bleeding, pain or unusual feeling in the teeth or gums3,5,6
Ripamonti C, Maniezzo M, Cislaghi E et al. Application of preventive measures minimizes the occurrence of the osteonecrosis of the jaw (ONJ) in solid tumors patients (pts) with bone metastases treated with bisphosphonates (BPs): A single institution series. Presented at San Antonio Breast Cancer Symposium, December 13-16 2007, Texas, USA. Abstract 2056.
Shenker NG. Bisphosphonates and osteonecrosis of the jaw. Rheumatology 2007;46:1049-1051.
Capsoni F, Longhi M, Weinstein R. Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist’s role. Arthritis Res Ther 2006;8:219.
Weitzman R, Sauter N, Eriksen EF et al. Critical review: Update recommendations for the prevention, diagmnosis, and treatment of osteonecrosis of the jaw in cancer patients – May 2006. Crit Rev Oncol/Hematol 2007;62:148-152.
Woo S, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.
Ruggiero S, Gralow J, Marx RE et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Practice 2006;2:7-14.
Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 2005;136:1658-1668.
Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw. Aust Fam Physician 2006;35:801-803.
16. Prevention and Management Strategies: During Treatment ONJ can occur during treatment with bisphosphonates; however, preventative measures can lead to a significant reduction in the incidence of ONJ1
A study of 128 patients with multiple myeloma treated with bisphosphonates was undertaken to investigate whether the occurrence of ONJ decreased after implementation of preventative measures1
Patients were stratified into two groups depending on the date preventive measures were implemented1
Overall there were 10 cases of ONJ (8%); 8 cases in group A (23%) and 2 cases in group B (2%). The incidence rate (IR) was 0.560/100 person-month for group A and 0.118/100 person-month for group B, the IR ratio was group A/group B: 4.76 (p=0.029, 95%CI:1.01-22.40)1
The implementation of detailed assessment by experienced specialists of patients with multiple myeloma and dental problems and the avoidance of dental procedures during bisphosphonate treatment results in a significant 5-fold reduction of ONJ1
Along with good oral hygiene, a routine 6-monthly oral examination should be recommended to all patients on bisphosphonates2,3
Patients receiving bisphosphonates should avoid invasive dentistry, or seek alternatives such as endodontic therapy with appropriate local and systemic antibiotics2,3
Any other surgery or extractions performed must be monitored to ensure healing2
Dimopoulos MA, Kastritis E, Bamia C et al. Decreased incidence of osteonecrosis of the jaw (ONJ) in patients with multiple myeloma (MM) treated with Zoledronic acid (ZA) after application of preventive measures. Presented at 49th ASH Annual Meeting, December 8-11 2007, Atlanta, Georgia. Abstract.
Weitzman R, Sauter N, Eriksen EF et al. Critical review: Updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients – May 2006. Crit Rev Oncol/Hematol 2007;62:148-152.
Woo S, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.
Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw. Aust Fam Physician 2006;35:801-803.ONJ can occur during treatment with bisphosphonates; however, preventative measures can lead to a significant reduction in the incidence of ONJ1
A study of 128 patients with multiple myeloma treated with bisphosphonates was undertaken to investigate whether the occurrence of ONJ decreased after implementation of preventative measures1
Patients were stratified into two groups depending on the date preventive measures were implemented1
Overall there were 10 cases of ONJ (8%); 8 cases in group A (23%) and 2 cases in group B (2%). The incidence rate (IR) was 0.560/100 person-month for group A and 0.118/100 person-month for group B, the IR ratio was group A/group B: 4.76 (p=0.029, 95%CI:1.01-22.40)1
The implementation of detailed assessment by experienced specialists of patients with multiple myeloma and dental problems and the avoidance of dental procedures during bisphosphonate treatment results in a significant 5-fold reduction of ONJ1
Along with good oral hygiene, a routine 6-monthly oral examination should be recommended to all patients on bisphosphonates2,3
Patients receiving bisphosphonates should avoid invasive dentistry, or seek alternatives such as endodontic therapy with appropriate local and systemic antibiotics2,3
Any other surgery or extractions performed must be monitored to ensure healing2
Dimopoulos MA, Kastritis E, Bamia C et al. Decreased incidence of osteonecrosis of the jaw (ONJ) in patients with multiple myeloma (MM) treated with Zoledronic acid (ZA) after application of preventive measures. Presented at 49th ASH Annual Meeting, December 8-11 2007, Atlanta, Georgia. Abstract.
Weitzman R, Sauter N, Eriksen EF et al. Critical review: Updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients – May 2006. Crit Rev Oncol/Hematol 2007;62:148-152.
Woo S, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.
Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw. Aust Fam Physician 2006;35:801-803.
17. Discontinuation of Bisphosphonate Therapy during invasive dental work Recommendations regarding the discontinuation of bisphosphonates have been published1
Once bisphosphonate therapy has begun, patients must maintain good oral hygiene, and visit the dentist regularly1
There are no prospective data to support the idea that discontinuing bisphosphonate therapy will reduce the risk of developing ONJ1
Temporary cessation of treatment maybe considered in some patients requiring dental procedures, but this should be discussed on an individual case-by-case basis1,2
Consideration should be given to continuing therapy in patients who are at a high risk of hypercalcaemia or skeletal-related events, such as those with progressive disease or more than three bone lesions in a solid tumour1
Dental procedure should be non-invasive, with endodontic therapy being preferred to tooth extraction1,2,3
The long half life of bisphosphonates (up to 12 years) may mean that temporary cessation has little overall effect on the amount already incorporated into bone4
The antiangiogenic activity may be reduced by stopping treatment, and this could help with healing of the overlying mucosa and periosteum4,5
Any decision on discontinuing bisphosphonate treatment should be made by the treating clinician on an individual case-by-case analysis, taking into full consideration the risk/benefit analysis1,5
Weitzman R, Sauter N, Eriksen EF et al. Critical review: Updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients – May 2006. Crit Rev Oncol/Hematol 2007;62:148-152.
Capsoni F, Longhi M, Weinstein R. Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist’s role. Arthritis Res Ther 2006;8:219.
Ruggiero S, Gralow J, Marx RE et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Practice 2006;2:7-14.
Woo S, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.
Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw. Aust Fam Physician 2006;35:801-803 Recommendations regarding the discontinuation of bisphosphonates have been published1
Once bisphosphonate therapy has begun, patients must maintain good oral hygiene, and visit the dentist regularly1
There are no prospective data to support the idea that discontinuing bisphosphonate therapy will reduce the risk of developing ONJ1
Temporary cessation of treatment maybe considered in some patients requiring dental procedures, but this should be discussed on an individual case-by-case basis1,2
Consideration should be given to continuing therapy in patients who are at a high risk of hypercalcaemia or skeletal-related events, such as those with progressive disease or more than three bone lesions in a solid tumour1
Dental procedure should be non-invasive, with endodontic therapy being preferred to tooth extraction1,2,3
The long half life of bisphosphonates (up to 12 years) may mean that temporary cessation has little overall effect on the amount already incorporated into bone4
The antiangiogenic activity may be reduced by stopping treatment, and this could help with healing of the overlying mucosa and periosteum4,5
Any decision on discontinuing bisphosphonate treatment should be made by the treating clinician on an individual case-by-case analysis, taking into full consideration the risk/benefit analysis1,5
Weitzman R, Sauter N, Eriksen EF et al. Critical review: Updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients – May 2006. Crit Rev Oncol/Hematol 2007;62:148-152.
Capsoni F, Longhi M, Weinstein R. Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist’s role. Arthritis Res Ther 2006;8:219.
Ruggiero S, Gralow J, Marx RE et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Practice 2006;2:7-14.
Woo S, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.
Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw. Aust Fam Physician 2006;35:801-803
18. Summary ONJ is an uncommon condition, affecting 1-10% of patients taking IV bisphosphonates
It is associated with a number of risk factors, including the agent used, cumulative dose, and oral hygiene
The majority of cases are observed after invasive dental procedures, but it can occur spontaneously
The risk of ONJ needs to be balanced against the benefits of therapy and has influenced present guidelines
ONJ can be effectively managed by an increased level of monitoring and preventative measures
19. BONJ in the guideline The following recommendations are all grade C; level III evidence.
All patients to be stated on long term bisphosphonate should be warned of the risk of BONJ and its predisposing factors. Readily available and easy to read information should be offered at time of diagnosis and discussion of therapeutic options.
All patients to be started on IV bisphosphonate should be referred for a dental opinion and any teeth of poor prognosis extracted before initiation of chemotherapy if possible. Patients on long-term oral bisphosphonates should beware of the potential risk of BONJ. All patients should have regular preventative dental care and maintain excellent oral hygiene.
Invasive dental procedures in patients on IV or long-term oral bisphosphonate should be avoided as much as possible. For patients on IV bisphosphonates specialist opinion should be sought prior to any extractions.
Patients with suspected BONJ should be referred to a clinician with special interest and expertise in the management of this condition.
20. Which agent is best Both zoledronic acid and pamidronate have demonstrated equal efficacy, pamidronate is cheaper but more costly to deliver.
The comparison between sodium clodronate and Zoledronic acid is awaited
Osteonecrosis occurs at the highest levels with Zoledronic acid and very rarely with sodium clodronate
21. Duration of therapy Most guidelines are based on the use of Pamidronate/Zoledronic acid where there is little evidence of benefit beyond two years (Berenson et al 1996/98, Rosen 2001/03)
IMWG suggests sessation of treatment at 1 year in patients with CR/VGPR post autologous transplant with no active bone disease (based on Attal 2006)
Clodronate has evidence of benefit up to four years (Mccloskey 1998)
22. * SREs denotes skeletal related events: new lytic lesions, vertebral and non-vertebral fractures, need for radiation or surgery to the bone; p.o. denotes oral administration and iv intravenous administration; NE denotes not evaluated.
† Pamidronate-controlled trial.
‡ In a post-hoc analysis, patients without vertebral fracture at entry survived significantly longer on clodronate (median survival was 23 months longer than in similar patients receiving placebo).
§ Survival in the patients with more advanced disease was significantly increased in the pamidronate group (median survival 21 vs. 14 months; p=0.041 adjusted for baseline serum ß2-microglobulin and Eastern Cooperative Oncology Group performance status).
£ Survival benefit with zoledronic acid over pamidronate for a subgroup of patients who had elevated bone-specific alkaline phosphatase levels baseline.* SREs denotes skeletal related events: new lytic lesions, vertebral and non-vertebral fractures, need for radiation or surgery to the bone; p.o. denotes oral administration and iv intravenous administration; NE denotes not evaluated.
† Pamidronate-controlled trial.
‡ In a post-hoc analysis, patients without vertebral fracture at entry survived significantly longer on clodronate (median survival was 23 months longer than in similar patients receiving placebo).
§ Survival in the patients with more advanced disease was significantly increased in the pamidronate group (median survival 21 vs. 14 months; p=0.041 adjusted for baseline serum ß2-microglobulin and Eastern Cooperative Oncology Group performance status).
£ Survival benefit with zoledronic acid over pamidronate for a subgroup of patients who had elevated bone-specific alkaline phosphatase levels baseline.
23. Proposed guidance
Bisphosphonate therapy is recommended for all patients with myeloma requiring chemotherapy, whether or not bone lesions are evident (grade A recommendation; level Ib evidence).
Oral clodronate (1600 mg/d or equivalent dosage according to formulation), intravenous pamidronate, and intravenous zoledronic acid (grade A recommendation; level Ib evidence) may be used. Monthly i.v. pamidronate 90 mg and zoledronic acid 4 mg are equivalent in efficacy (grade A recommendation; level Ib evidence). The choice of therapy will depend on patient and physician preference.
Treatment should be continued for at least 2 years (grade A recommendation; level Ib evidence); longer term treatment should be at the physicians discretion and should take into account the disease activity and bone disease in individual patients. Consideration should be given to the rising incidence of ONJ with IV pamidronate and zoledronic acid and converting to oral sodium clodronate if clinically appropriate beyond this point
24. Proposed guidance (2) Doses, infusion times and frequencies should be as recommended by the manufacturer, and renal function should be monitored. Creatinine should be checked before each zoledronic acid infusion and dosage altered in accordance with the manufacturers recommendation.
Special caution is required with all bisphosphonates in patients with moderate to severe renal failure; zoledronic acid and pamidronate should not be used if creatinine clearance is <30ml/min
There is at present insufficient data to make a recommendation for the use of bisphosphonates in patients with asymptomatic myeloma
26. Benefits and Risks of Bisphosphonate Treatment Bisphosphonates are given to patients with cancer to help control bone loss resulting from metastatic skeletal lesions1
They reduce skeletal-related events associated with multiple myeloma (such as fractures) and metastatic solid tumours (such as breast, lung and prostate cancers)1
Bisphosphonates are generally well-tolerated, with side effects (such as elevated serum creatinine, transient low-grade fever, and increased bone pain) being uncommon2
Bisphosphonates are associated with a small risk of ONJ, with a 1-10% incidence rate3-5
This risk is associated with both IV and oral bisphosphonates6
Preventative measures can lead to a significant reduction in the incidence of ONJ7
The risk of ONJ needs to be balanced against the benefits of therapy8
Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 2005;136:1658-1668.
Capsoni F, Longhi M, Weinstein R. Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist’s role. Arthritis Res Ther 2006;8:219.
Landis BN, Richter M, Dojcinovic I et al. Osteonecrosis of the jaw after treatment with bisphosphonates: Is irreversible, so the focus must be on prevention. BMJ 2006;333:982-983.
Durie BGM, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99-102.
Bamias A, Kastritis E, Bamia C et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol 2005;23:8580-8587
Woo S, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.
Dimopoulos MA, Kastritis E, Bamia C et al. Decreased incidence of osteonecrosis of the jaw (ONJ) in patients with multiple myeloma (MM) treated with Zoledronic acid (ZA) after application of preventive measures. Presented at 49th ASH Annual Meeting, December 8-11 2007, Atlanta, Georgia. Abstract.
Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw. Aust Fam Physician 2006;35:801-803
Bisphosphonates are given to patients with cancer to help control bone loss resulting from metastatic skeletal lesions1
They reduce skeletal-related events associated with multiple myeloma (such as fractures) and metastatic solid tumours (such as breast, lung and prostate cancers)1
Bisphosphonates are generally well-tolerated, with side effects (such as elevated serum creatinine, transient low-grade fever, and increased bone pain) being uncommon2
Bisphosphonates are associated with a small risk of ONJ, with a 1-10% incidence rate3-5
This risk is associated with both IV and oral bisphosphonates6
Preventative measures can lead to a significant reduction in the incidence of ONJ7
The risk of ONJ needs to be balanced against the benefits of therapy8
Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 2005;136:1658-1668.
Capsoni F, Longhi M, Weinstein R. Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist’s role. Arthritis Res Ther 2006;8:219.
Landis BN, Richter M, Dojcinovic I et al. Osteonecrosis of the jaw after treatment with bisphosphonates: Is irreversible, so the focus must be on prevention. BMJ 2006;333:982-983.
Durie BGM, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99-102.
Bamias A, Kastritis E, Bamia C et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol 2005;23:8580-8587
Woo S, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.
Dimopoulos MA, Kastritis E, Bamia C et al. Decreased incidence of osteonecrosis of the jaw (ONJ) in patients with multiple myeloma (MM) treated with Zoledronic acid (ZA) after application of preventive measures. Presented at 49th ASH Annual Meeting, December 8-11 2007, Atlanta, Georgia. Abstract.
Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw. Aust Fam Physician 2006;35:801-803
27. Can bisphosphonates influence survival in multiple myeloma?
