Complication Of Bisphosphonate Therapy Research Articles

Medication-related osteonecrosis of the jaw after dental clearance: Prevalence in an oncology center

ObjectiveMedication-related osteonecrosis of the jaw (MRONJ), a complication of bisphosphonate therapy, has significant morbidity. This study aimed to determine the prevalence of MRONJ and compare its risks among patients who received antiresorptive or antiangiogenic therapy in King Fahad Medical City. Study designIn this retrospective study, the sample comprised data of all patients referred for dental treatment before antiresorptive and antiangiogenic therapy between 2008 and 2018. All patients were classified as at risk or having stage 0, stage 1, stage 2, or stage 3 MRONJ. ResultsThe sample comprised 622 patients, including 358 (249 IV route, 34 oral route, and 75 subcutaneous route) who fulfilled the inclusion criteria and 25 in stage ≥ 0. Greater risk was observed in the intravenous group (8.82%) than in the oral and subcutaneous groups (2.94% and 2.67%, respectively). The overall prevalence rate was 6%. Patients with no history of dentoalveolar surgery had an MRONJ rate of 1.03%, whereas patients who underwent dentoalveolar surgery > 3 weeks before a lower MRONJ rate of 0.96%. Patients who underwent dentoalveolar surgery < 3 weeks before starting medication, and those who underwent surgery after starting the medication had higher MRONJ rates (21.42%, and 35.85%, respectively). The risk of spontaneously developing MRONJ was low. ConclusionRisk of developing MRONJ was found to be higher when dentoalveolar procedures performed within 3 week before starting antiresorptive medications.

Atypical fracture of the femur in a patient with postmenopausal osteoporosis after four injections of zoledronic acid

Bisphosphonates are one of the most effective medications widely used in the treatment of osteoporosis. In the last 15 years, descriptions, and observations of unusual low-energy femoral fractures with atypical localization for osteoporosis after prolonged use of these drugs have been published.&#x0D; A 78-year-old patient applied to the osteoporosis center. She received parenteral bisphosphonate therapy for severe osteoporosis for 4 years. In 2017, a spontaneous fracture of the middle third of the femoral shaft was registered (the fracture occurred while walking). Regarding the fracture, metal osteosynthesis with a plate was performed. Subsequently, there was a delayed consolidation of the fracture with the formation of a false joint and the need for repeated surgical intervention. Examination of the patient revealed vitamin D deficiency, and significant negative trend in densitometry.&#x0D; A feature of this case is poor fracture consolidation and long-term uncompensated vitamin D deficiency. Physicians should be aware of this rare but serious complication of bisphosphonate therapy, as it requires discontinuation of antiresorptive drugs and the appointment of bone anabolic therapy for osteoporosis, which, in addition to treating the underlying disease, also promotes consolidation fracture.

Non-Invasive Physical Plasma Treatment after Tooth Extraction in a Patient on Antiresorptive Medication Promotes Tissue Regeneration

Postoperative tissue regeneration can be negatively affected by bisphosphonate administration, especially in patients with oncologic diseases. A serious complication of bisphosphonate therapy is the medication-related osteonecrosis of the jaw (MRONJ), which can be observed mainly after dental surgery. MRONJ is a progressive destruction of the bone that requires patients to stay in hospital for extended periods of time. For this reason, primary wound closure is particularly important in surgical procedures. In the case of wound dehiscence, there is a very high risk for MRONJ. In recent years, non-invasive physical plasma (NIPP) has become known for improving wound healing on the one hand, but also for its promising efficacy in cancer therapy on the other hand. We report on a 63-year-old patient with a history of multiple myeloma and receiving zoledronate, who developed wound dehiscence after tooth extraction. NIPP treatment resulted in complete epithelialization of the entire wound dehiscence. In conclusion, the use of NIPP in patients receiving antiresorptive drugs seems to support tissue regeneration and thus could be an important tool for the prevention of MRONJ.

Cloud-Based Multicenter Data Collection and Epidemiologic Analysis of Bisphosphonate-Related Osteonecrosis of the Jaws in a Central European Population.

Objective: Bisphosphonate-related osteonecrosis of the jaws is considered to be a rare but severe complication of bisphosphonate therapy. To understand this condition better, data collection is essential. Although the number of scientific papers about this subject is large, to date only a few multicenter reports have been published. Study design: We present a novel cloud-based data collection system for the evaluation of the risk factors of bisphosphonate-related osteonecrosis of the jaws. Web-based questionnaire and database have been set up and made available to voluntary researchers and clinicians in oral and maxillofacial surgery in Hungary and Slovakia. Results: To date, fifteen colleagues from eight maxillofacial units have joined the study. Data of 180 patients have been recorded. Collected data were statistically analysed and evaluated from an epidemiological point of view. Conclusions: Authors consider cloud-based multicenter data collection a useful tool that allows for real-time collaboration between users, facilitates fast data entry and analysis, and thus considerably contributes to widening our knowledge of bisphosphonate-related osteonecrosis of the jaws.

Bisphosphonate-associated Osteonecrosis of the Jaws: a Survey of the Level of Knowledge of Dentists about the Risks of Bisphosphonate Therapy.

Bisphosphonate-associated osteonecrosis of the jaws (BAONJ) is a side effect of treatment with bisphosphonate (BP). Reports of this complication have increased recently. To evaluate the level of knowledge of dentists from Plovdiv, Bulgaria, about possible complications of bisphosphonate therapy of patients in dental practice. Three hundred and twenty-three dental practitioners from Plovdiv, Bulgaria, took part in an anonymous survey containing 25 questions, designed to evaluate the knowledge of dentists about the complications of BP therapy. Oral and maxillofacial surgeons have the best knowledge about the indications and side effects of BP therapy, while dentists with a specialty in Pediatric Dentistry and General Dentistry have insufficient knowledge. Of the respondents, 17.03% are absolutely uninformed about BP and their side effects, and 1/2 declare that they have never had a patient with complications from BP therapy in their practice, probably due to a lack of awareness of the problem. Approximately half of the dentists we surveyed agree to carry out prophylactic examinations of patients receiving BP and know what the prophylactic examination includes. Only 15.48% of the respondents have correctly responded that in order to be treated as clinically healthy, patients should have stopped taking BP for more than 10 years. With the exception of specialists in Oral and Maxillofacial Surgery, dental practitioners in Plovdiv and the region are poorly informed about the complications associated with BP therapy. Therefore, efforts must be made to make these dentists better informed about BAONJ, especially about the methods and means of preventing this condition.

Complications of Bisphosphonate therapy in Dentistry

Complications of Bisphosphonate therapy in Dentistry

Pharmaceutical management of bone catabolism: the bisphosphonates

Background: Conditions associated with catabolism of bone are common and progress sub-clinically with devastating skeletal consequences. Over the past two decades, bisphosphonates have become increasingly popular for the preventative management of the skeleton in these conditions. Methods: Recent literature pertaining to the mechanisms of action, clinical indications and complications of bisphosphonate therapy was retrieved using Google Scholar and Pubmed. Aims of study: To provide an overview of the mechanisms of action, indications, contraindications and complications of the bisphosphonates available for clinical use in South Africa. Results: Despite the availability of alternative management regimens, bisphosphonates remain the pharmaceuticals of choice for the management of hypercalcaemia and generalised catabolic skeletal disorders such as osteoporosis, skeletal metastatic disease, Paget’s disease of bone, glucocorticoid bone disease and osteogenesis imperfecta. Although adverse complications such as tachycardia, bowel and oesophageal irritation, pain, jawbone necrosis and atypical femur fractures are well documented, information remains limited on the long-term effects of bisphosphonate therapy on skeletal health. This manuscript provides an update on the mechanisms of action, principles applied to the selection of the most appropriate management regimen, monitoring of the response and complications of the bisphosphonates marketed in South Africa. Level of evidence: Level 5

Blindness Resulting from Bisphosphonate Related Osteonecrosis of the Skull Base

AbstractBisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare, serious complication of bisphosphonate therapy. We report here a 69-year-old man with a history of multiple myeloma and 5 years of adjuvant zoledronate therapy presenting with loss of light perception, proptosis, ptosis and impaired abduction of the right eye. This patient was found to have developed an unusually severe presentation of osteomyelitis of the skull base in the setting of BRONJ that ultimately led to unilateral blindness. In this extreme case of bisphosphonate-related osteonecrosis of the skull base, we reveal the importance of early identification and treatment of these lesions. This is the first description of BRONJ-induced blindness.

Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious complication of bisphosphonate therapy. The mechanism underlying BRONJ pathogenesis is poorly understood. To determine the effects of zoledronic acid (ZA) and geranylgeraniol (GGOH) on the mevalonate pathway (MVP) in osteoblasts generated from the human mandibular alveolar bone in terms of cell viability/proliferation, migration, apoptosis and gene expression. Primary human osteoblasts (HOBs) isolated from the mandibular alveolar bone were phenotyped. HOBs were cultured with or without ZA and GGOH for up to 72h. Cellular behaviour was examined using a CellTiter-Blue® viability assay, an Ibidi culture-insert migration assay, an Apo-ONE® Homogeneous Caspase-3/7 apoptosis assay and transmission electron microscopy (TEM). Quantitative real-time reverse transcriptase polymerase chain reaction (qRT2-PCR) was used to determine the simultaneous expression of 168 osteogenic and angiogenic genes modulated in the presence of ZA and GGOH. ZA decreased cell viability and migration and induced apoptosis in HOBs. TEM revealed signs of apoptosis in ZA-treated HOBs. However, the co-addition of GGOH ameliorated the effect of ZA and partially restored the cells to the control state. Twenty-eight genes in the osteogenic array and 27 genes in the angiogenic array were significantly regulated in the presence of ZA compared with those in the controls at one or more time points. The cytotoxic effect of ZA on HOBs and its reversal by the addition of GGOH suggests that the effect of ZA on HOBs is mediated via the MVP. The results suggest that GGOH could be used as a possible therapeutic/preventive strategy for BRONJ.

POSIBILITĂŢI TERAPEUTICE COMBINATE ÎN OSTEONECROZA OASELOR MAXILARE STADIUL I

Osteonecrosis of the jaw (ONJ) is a serious complication of bisphosphonate therapy administered to treat conditions such as osteoporosis, Paget’s disease or bone metastases. In this article we present the case of a patient with complex pathology, suffering breast cancer surgery, who performed IV treatment with Zometa for 1 year postoperative. The patient developed ONJ in the mandibular frontal region and has experienced numerous episodes of acute infectious. In the first months of the onset disease were applied non-invasive topical treatments without success, followed by multiple surgeries to remove the pathological tissue by conventional methods. Many relapses led us to the successful adoption of a complex protocol, which combines several modern techniques and technology: piezosurgically bone resection guided by fluorescent light, the use of laser on soft tissue and application of PRF membranes in the residual defect.

Microsurgical reconstruction after bisphosphonate-related osteonecrosis of the jaw: our experience with fibula free flap.

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is the most serious complication of bisphosphonates therapy. Despite that several treatment modalities have been described, aggressive surgical treatment approach with wide bone resection and vascularized microsurgical reconstruction are controversial. The aim of this study was to evaluate the clinical outcome of 8 new cases of BRONJ treated with radical resection and mandibular reconstruction with fibula free flap, to enforce the evidence about the reliability of this treatment option. Retrospective data of 8 patients with BRONJ who underwent segmental mandibulectomy and reconstruction with osteocutaneous fibula free flap from January 2004 to January 2008 were collected, including 6 patients with stage 3 BRONJ and 2 patients with recalcitrant stage 2 BRONJ. All patients were white, with a mean age of 64.7 years (range, 53-77 y), and 62.5% were women. All bisphosphonates were administered intravenously, and all patients had mandibular localization. The mean period of follow-up was 28.9 months. No flap loss or minor complications and no BRONJ recurrence were observed. All patients were able to ambulate pain-free. Despite initial concerns regarding reliability of the mandibular free-flap reconstruction after BRONJ, this method seems to be a safe and feasible option in cancer patients with reasonable life expectancy, with complete BRONJ resolution and life quality improvement. Our findings confirm data previously published by other authors, without complication and with a much longer median follow-up time.

Bisphosphonate-associated osteonecrosis of the jaws in lung cancer patients

Osteonecrosis of the jaw (ONJ) can occur as a complication of bisphosphonate therapy. This condition has been described in cancer patients and its development has been associated with prolonged exposure to high doses of bisphosphonates. Bad dental hygiene, a history of prosthesis or dental extraction, chemotherapy, corticosteroids, and radiation therapy of the head and neck are reported risk factors. In the initial stages it may be asymptomatic, but the patient subsequently develops severe pain and progressive exposed bone. The authors describe three cases of ONJ in lung cancer patients after prolonged exposure to bisphosphonates and there were known risk factors. ONJ can seriously affect the quality of life of cancer patients. An early diagnosis may reduce or avoid the consequences of progressive bone lesion.

Osteonecrose da mandíbula associada aos bifosfonatos em doentes com cancro do pulmão

Osteonecrosis of the jaw (ONJ) can occur as a complication of bisphosphonate therapy. This condition has been described in cancer patients and its development has been associated with prolonged exposure to high doses of bisphosphonates. Bad dental hygiene, a history of prosthesis or dental extraction, chemotherapy, corticosteroids, and radiation therapy of the head and neck are risk factors reported. In the initial stages it may be asymptomatic, but the patient subsequently develops severe pain and progressive exposed bone. The authors describe three cases of ONJ in lung cancer patients after prolonged exposure to bisphosphonates and there were known risk factors. ONJ can seriously affect the quality of life of cancer patients. An early diagnosis may reduce or avoid the consequences of progressive bone lesion.

Bisphosphonate and Osteonecrosis of the Jaw: The Oral Surgeon's Perspective

Bisphosphonates (BPs) are an important class of drugs, useful in the treatment of some metabolic and oncologic skeletal diseases. BPs have shown a sure effectiveness in the treatment and in the palliative care of such pathologies; on the other hand, an avascular osteonecrosis of the jaws (B-ONJ = Bisphosphonate OsteoNecrosis of the Jaw) has recently been reported as an adverse effect not only of BP intravenous infusions, but also of their prolonged oral administration. B-ONJ normally follows a dental extraction or other surgical procedure in the oral cavity, but it also can develop spontaneously. In the latter case, some systemic risk factors, such as comorbidities and co-therapies or jaw anatomical conditions, can play a leading role in the onset of this pathologic condition. B-ONJ is an uncommon but potentially serious complication of BP therapy that can gravely affect the patient's quality of life, producing significant morbidity. To date, no therapies are completely effective and predictable in the treatment of B-ONJ, therefore prevention should be strongly promoted by sharing knowledge in the involved medical community.

NEPHROCALCINOSIS: A POTENTIAL COMPLICATION OF BISPHOSPHONATE THERAPY IN CHILDREN

12 September 2011 Dear Editor, Although bisphosphonate therapy is effective in severe childhood osteoporosis, both short and long term side effects occur.1 We have treated a total of 124 children including those with severe Osteogenesis Imperfecta (OI) since 1998, and more recently, patients with other forms of osteoporosis (e.g. juvenile idiopathic osteoporosis or steroid induced) with serious fractures (e.g. vertebral crush fractures). All patients received intravenous pamidronate therapy. The protocols (Table 1) were those used at the Children's Hospital at Westmead at that time. Our protocol included a dietary calcium assessment to ensure a dietary calcium intake of ≥1200 mg/day for at least 1 week after the initial infusion to prevent hypocalcaemia, a known complication of bisphosphonate therapy. Patients were prescribed calcitriol 0.25 mcg twice daily at the time of each pamidronate infusion and for 7 days post-infusion. We present four patients who developed nephrocalcinosis during intravenous pamidronate therapy. None of these patients had nephrocalcinosis prior to commencement of therapy. An 8-year-old boy with severe OI Type 1B and multiple long-bone fractures was treated with intravenous pamidronate and vitamin D as per protocol. His dietary intake of calcium was adequate and baseline vitamin D levels were normal. Early medullary nephrocalcinosis was noted on ultrasound after 3.5 years of pamidronate therapy. Calcitriol therapy was ceased and pamidronate continued. Repeat renal ultrasound after 6 months showed complete resolution of the nephrocalcinosis. A 7-year-old boy with Juvenile Idiopathic Osteoporosis and multiple vertebral compression fractures was referred for continuation of bisphosphonate therapy. He was treated with calcitriol 0.25 mcg (as per protocol) and given supplemental calcium. Mild medullary nephrocalcinosis was identified on renal ultrasound after 2 years of pamidronate therapy. Vitamin D therapy was ceased. Pamidronate therapy was ceased after 3 years of treatment. Renal ultrasound showed complete resolution of nephrocalcinosis after 6 years. A 2-year-old girl with OI Type 1A was commenced on IV pamidronate therapy (total duration 2.5 years) following a history of multiple, atraumatic hip and vertebral fractures. Dietary calcium intake was adequate and baseline vitamin D levels were normal. She was commenced on pamidronate and calcitriol, as per protocol. After 12 months of therapy, she was advised to cease Calcitriol because of concerns arising from Cases 1 and 2 above. Early nephrocalcinosis was noted after 22 months of intravenous bisphosphonate therapy. Follow-up ultrasound after 3 years was normal. A 15-year-old boy with severe ulcerative colitis and steroid induced osteoporosis presented with painful crush fractures of the thoracic spine. Calcium supplementation was commenced. Baseline vitamin D level was normal and vitamin D supplementation was not prescribed. After 12 months of pamidronate therapy ultrasound demonstrated a small area of nephrocalcinosis of the mid pole of the left kidney. The patient admitted taking a natural supplement which contained 320 IU (8 mcg) vitamin D3 per day. Advice was given to cease this supplement and pamidronate therapy was continued. An ultrasound 12 months later was normal. Serum calcium and alkaline phosphatase levels remained normal in all four patients whilst on bisphosphonate therapy. Urinary calcium: creatinine ratio was normal in the four cases presented. Bone turnover markers (urinary pyridinoline and deoxypyridinoline) were measured yearly in all patients on bisphosphonate therapy and remained within the normal range in the four cases. Nephrocalcinosis is defined as a generalised increased solute content (in particular, calcium) within the kidney. Medullary nephrocalcinosis is the typical pattern seen in 98% of cases in humans.2 The diagnosis of nephrocalcinosis is usually made radiologically, using ultrasound, computed tomography or intravenous pyelogram. Risk factors for the development of nephrocalcinosis include; hypercalciuria, vitamin D intoxication, distal renal tubular acidosis, hyperparathyroidism, hyperoxaluria and prematurity.3 The mechanism of development of nephrocalcinosis is likely related to hypercalcaemia and subsequent hypercalciuria. Nephrocalcinosis has not been previously reported following bisphosphonate therapy in children, but has been seen in pamidronate-treated rabbits.4 Vitamin D excess or intoxication can cause severe hypercalcaemia resulting in calcium deposition in the tissues, including nephrocalcinosis.3,5 All of the cases described above were taking vitamin D supplementation in addition to bisphosphonate therapy, either as part of a treatment protocol to prevent hypocalcaemia (Cases 1–3) or as self medication (Case 4). Interestingly, three of the four cases presented were treated with bisphosphonate prior to 2001, when vitamin D supplementation was routine. Since cessation of routine supplementation, only one case has developed nephrocalcinosis and he was found to be inadvertently taking a supplement containing vitamin D. Nephrocalcinosis has been observed in four children treated with both intravenous pamidronate and vitamin D supplementation. Excess Vitamin D has been shown to be a cause of nephrocalcinosis. We suggest that vitamin D supplementation during bisphosphonate therapy may have contributed to the development of nephrocalcinosis. In the presence of normal vitamin D levels, vitamin D supplementation on bisphosphonate therapy may be unnecessary and may be associated with the development of nephrocalcinosis.

Referral patterns from general medical practitioners to dentists prior to the use of oral bisphosphonates in Australia

Introduction: Osteonecrosis of the jaw (ONJ) is a rare but serious complication of bisphosphonate therapy. There is international consensus in recommending dental referral prior to initiating IV bisphosphonates, but no consensus when starting on oral bisphosphonate therapy for the treatment of osteoporosis.

CYP2C8 gene polymorphism and bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma

Osteonecrosis of the jaw is an uncommon but potentially serious complication of bisphosphonate therapy in multiple myeloma. Previous studies showed that the presence of one or two minor alleles of the cytochrome P450, subfamily 2C polypeptide 8 gene (CYP2C8) polymorphism rs1934951 was an independent prognostic marker associated with development of osteonecrosis of the jaw in multiple myeloma patients treated with bisphosphonates. The aim of this study was to validate the frequency of SNP rs193451 in 79 patients with multiple myeloma. In 9 (22%) patients developing osteonecrosis of the jaw, a heterozygous genotype was found, in contrast with those who did not develop osteonecrosis of the jaw (n=4, 11%) or healthy individuals (n=6, 13%). We found no differences in the cumulative risk of developing osteonecrosis of the jaw between patients homozygous and heterozygous for the major allele. We were unable to confirm a significant association between this polymorphism and the risk of developing osteonecrosis of the jaw.

Prevention and treatment of osteonecrosis of the jaw

Purpose: to update recommendations for the prevention and treatment of osteonecrosis of the jaw in patients on bisphophonate therapy. Osteonecrosis of the jaw is a rare and serious complication of bisphosphonate therapy. Also, it is one of the important and growing clinical public health issues, because biphosphonates are now more commonly used than before. Bisphophonates are primarly used in the treat-ment of cancer-related conditions such as bone metastases, hypercalcemia, lytic skeletal lesions. More recently, bisphophonate has been approved for the management of osteoporosis. The etiology and pathogenesis remain unknown, however, two important risk factors have been identified, i.e. the potency and length of bisphos- phonate use, and recent dental intervention. Recommendations: prior to the introduction of bisphosphonate therapy, all patients should undergo complete dental examination, any active oral cavity infec-tion should be treated and the potential sites of new infection removed. During bisphosphonate therapy, patients should strictly comply with oral hygiene and avoid any invasive procedure of the oral cavity.

“Osteonecrosis of the Jaw: Experience of a Single center”.

Abstract 4935 BackgroundBisphosphonates have been proven to be effective in preventing or delaying skeletal complications in multiple myeloma with a significant improvement of the quality of life. Although these agents are usually well tolerated, osteonecrosis of the jaw (ONJ) has been recently associated with the use of bisphophonates. Nevertheless, the true incidence of this complication is not clearly defined. Therefore, we studied the incidence, characteristics and risk factors for the development of ONJ among patients with multiple myeloma treated with biphosphonates in our institution. Patients and methodsFive-hundred and sixteen patients who received biphosphonates (zoledronic acid, pamidronate, bondronate) and had a minimum exposure of 6 months to the drug were included in this analysis. These patients were asked reterospectivly to fill out a form containing several queries, including sex and age, type and time of neoplasia diagnosis, treatment and neoplasia status, odonthoiatric anamnesis, type and duration of therapy with BP, microbial isolation in site of lesion, specific treatment for osteonecrosis, number of patients (pts) affected by MM treated with BP from 2007 to 2009. From this retrospective review thirty-five patients were identified with pain of the jaw. ResultsTwo-hundred of five-hundred and sixteen patients received bondronate, seventy-four patients pamidronate, one-hundred and seventy-four patients zoledronic acid, twenty-three patients oral bisphosphonate and two patients are unable to name the bisphosphonate. Thirty-five patients were identified with pain of the jaw. A total of twenty-five ONJ cases were identified either by histology or estimation of the surgeon among all patients treated and referred to our institute. Five patients had no ONJ, only non-specific pain of the jaw. Five patients have other disease of the jaw (1 patient osteoymelitis; 1 patient cyst of the jaw; 1 patient epulis gigantocellularis, 1 patient granuloma, 1 patient plasmozytoma of the jaw). Ten patients who were diagnosed with ONJ received bondonate, eleven patients pamidonate and thirteen patients zoledronic acid. The majority of the ONJ lesions completely healed in 24 patients. Overall, most of the ONJ lesions were associated with dental procedures and pain was the symptom most frequently reported. ConclusionONJ is a serious complication of bisphosphonate therapy. But with active monitoring for ONJ and early input from dental experts, ONJ has been mild to moderate in severity, had minimal impact on overall quality of life and improved or healed in the majority of patients. These results suggest that with proper management, ONJ is a manageable, infrequent complication that may be associated with a reduced SRE (skeletal-related events) risk and improved overall survival. Length of exposure and the probably the type of biphosphonate used appear to be the most important risk factor for this complication. DisclosuresGoldschmidt:Johnson and Johnson: Research Funding, Speakers Bureau.

High Body Surface Area (BSA) Is An Independent Risk Factor for Developing Bisphosphonate-Induced Osteonecrosis of the Jaw (ONJ)

Background: Osteolytic bone disease and associated complications of pathological fractures is a major complication in patients with multiple myeloma (MM) and metastatic breast cancer (MBC). This is due to tumor cell mediated increase in osteoclastic activity. Bisphosphonates (BP) are effective in preventing skeletal events associated with osteolytic bone destruction. Improved survival of MM and MBC patients has resulted in prolonged exposure to BP therapy, which is reported to be associated with an increased incidence of osteonecrosis of the jaw (ONJ). ONJ involves destruction and necrosis of the maxillary and/or mandibular bone, etiology of which remains unclear. As treatment is usually not helpful, prevention becomes an important strategy and in this context identification of validated risk factors for development of OJN is critical. Several investigators have reported possible risk factors (including invasive dental procedures, prolonged BP therapy and renal dysfunction) that are associated with increased likelihood of ONJ development. We asked if specific patient biometric profile renders enhanced risk of ONJ development? Thus we investigated patient demographic profiles in a large cohort of patients and correlated with development of ONJ.Methods: Patients with MM or MBC with bone lesions treated with intravenous (iv) BP (zoledronic acid; Zometañ) between November 2002–December 2006 were identified using the RPCI database. Demographic, laboratory biochemical, BP-related and ONJ-related data was collected and compared between cases and controls.Results: Complete data was available for 160 patients, of whom 36 (22.5%) patients had ONJ. The remaining 124 (77.5%) patients served as controls. Of all the patients, 122 (76.2%) had MBC and 38 (23.8%) had MM. Median age for all patients was 58 years (range 35–87) while the median age at diagnosis of ONJ was 59.5 years (range 40–81). The median number of cycles with BP for the control group was 15 (range 1–80) and for the ONJ group was 23.5 (range 1–80). Cumulative median BP dose in the control and ONJ groups was 58 mg (range 2–316 mg) and 94 mg (range 4–297 mg) respectively, while the median body surface area (BSA) amongst the control group was 1.66 m2 (range 0.93–2.4) and in the ONJ group was 1.81 m2 (range 1.44–2.5). Other variables studied between cases and controls included percent deviation from ideal body weight, body mass index (BMI) serum creatinine at baseline, creatinine clearance (CrCl) at baseline and at time of diagnosis of ONJ, baseline serum calcium and baseline serum alkaline phosphatase. Amongst the variables tested, BSA was the only factor that was significantly different between the two groups (p=0.004; Wilcoxon). There was no significant difference between CrCl at baseline and at ONJ diagnosis (p=0.73; Sign test). A logistic regression model showed that BSA was significantly different between the cases and controls on univariate analysis (p=0.009) as well as a multivariate analysis incorporating BSA, cumulative BP dose, age at initiation of BP, BMI and baseline creatinine clearance (p=0.028). Using a normal adult BSA of 1.71 m2 as the cut-off, the odds ratio for developing ONJ was 2.85 times (univariate) and 2.54 times (multivariate) higher in the higher than normal BSA group (BSA 3 1.71 m2) when compared with the lesser BSA group (BSA <1.71 m2).Conclusions: ONJ is a serious complication of BP therapy. Patient's biometric profile has not been implicated as a potential risk factor in ONJ development so far. Our study, for the first time suggests that patient's BSA may be an important and independent risk factor for BP associated ONJ. Our findings warrant further investigation in prospective studies and emphasize close monitoring of patients with high BSA who are on BP treatment with careful periodic assessment of risk-benefit for BP continuation. [Display omitted]