Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis

A potential side effect associated with bisphosphonates, a class of drugs used in the treatment of osteoporosis, Paget's disease and metastatic bone disease, is osteonecrosis of the jaw (ONJ). The incidence of ONJ in the general population is unknown; this rare condition also may occur in patients not receiving bisphosphonates. Case reports have discussed ONJ development in patients with multiple myeloma or metastatic breast cancer receiving bisphosphonates as palliation for bone metastases. These patients are also receiving chemotherapeutic agents that might impair the immune system and affect angiogenesis. The incidence or prevalence of ONJ in patients taking bisphosphonates for osteoporosis seems to be very rare. No causative relationship has been unequivocally demonstrated between ONJ and bisphosphonate therapy. A majority of ONJ occurs after tooth extraction. Furthermore, the underlying risk of developing ONJ may be increased in osteoporotic patients by comorbid diseases. Treatment for ONJ is generally conservative.     

Avascular necrosis of the proximal carpal row of the wrist. A possible complication of bisphosphonate administration

Reports of coexisting osteonecrosis of more than one carpal bone are rare. We report an osteonecrosis of the entire proximal carpal row of the wrist, started briefly after intravenous bisphosphonate administration. The use of bisphosphonates for the treatment of osteoporosis is increasing. Osteonecrosis of the jaw (ONJ) is one of the known adverse effects during chronic treatment with bisphosphonates. This case is reported to make clinicians aware of a possible causative link between bisphosphonate use and osteonecrosis of other bones.     

Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome

Summary Osteonecrosis of the jaw (ONJ) is a well-known devastating side effect of bisphosphonate therapy for cancer. Several ONJ cases of patients using oral bisphosphonates have been reported in the literature. The present study analyzed the clinical features, predisposing factors, and treatment outcome of 11 patients with oral bisphosphonates-related ONJ. Introduction and hypothesis Osteonecrosis of the jaw (ONJ) is a well-known side effect of parenteral bisphosphonates therapy. Although ONJ has been reported in patients using oral bisphosphonates, documentation of this entity is sparse. It was hypothesized that the clinical features, predisposing factors, and treatment outcome of this population are different from those of oncologic patients. Methods This retrospective bi-central study involved 98 ONJ patients, 13 of whom were treated with oral bisphosphonates. Two patients were excluded because of previous use of intravenous bisphosphonates. The profiles of 11 patients were analyzed. Results The mean duration of alendronate use before developing ONJ was 4.1 years. ONJ was triggered by dental surgery in 9 patients and by ill-fitted dentures in 2. Heavy smokers were the most recalcitrant subjects. Among the nine patients with at least 6 months of follow-up, ONJ healed completely in three, partially in four, and not at all in two. Conclusions ONJ is a rare devastating side effect of oral bisphosphonates associated with patient morbidity and high financial burden. Clinicians must be aware of this entity and inform patients of the risks of dental surgery. The synergistic effect of smoking in the pathogenesis of ONJ should be further investigated.     

Children and adolescents treated with neridronate for osteogenesis imperfecta show no evidence of any osteonecrosis of the jaw

Over recent years, several reports have been published on unusual cases of osteonecrosis of the jaw (ONJ) in adults using second- and third-generation nitrogen-containing bisphosphonates such as pamidronate, alendronate, risedronate and zoledronate, but no case has ever been reported either in children or in adult patients taking neridronate. Children and adolescents affected by osteogenesis imperfecta (OI) could belong to a high-risk group for ONJ because bone fragility in OI is associated with a connective tissue malfunction. The purpose of this study is to evaluate the incidence of ONJ in a pediatric population treated with neridronate for OI. A total of 102 pediatric patients with OI who received neridronate infusions for a mean of 6.81 years (SD ± 3.06 years) were clinically assessed for possible ONJ. Eligibility criteria for participation included patients between 1.2 and 24 years old who received cyclical neridronate infusions for at least 1 year. All the patients were reviewed to determine duration, dosage and cumulative dose of their bisphosphonate therapy and were examined clinically to assess their oral health status. We have not demonstrated any occurrence of ONJ in our patients. In conclusion, at the moment insufficient data are available to prove a greater risk of ONJ in children with OI than in children affected by other forms of bone fragility. However, cases may emerge in future because the risk of ONJ seems to be related to the cumulative dose and the duration of therapy.     

Perspective: Assessing the Clinical Utility of Serum CTX in Postmenopausal Osteoporosis and Its Use in Predicting Risk of Osteonecrosis of the Jaw

Bone turnover markers (BTMs) have become increasingly important in the management of postmenopausal osteoporosis (PMO). In bisphosphonate‐treated women with PMO, BTMs can provide early indications of treatment efficacy, are predictors of BMD response and fracture risk reduction, and are potentially useful for monitoring patient compliance. The bone resorption marker serum C‐telopeptide cross‐link of type 1 collagen (sCTX) has shown high sensitivity and specificity for the detection of increased bone resorption. Recently, sCTX has been singled out as a potential indicator of risk of osteonecrosis of the jaw (ONJ) in patients receiving oral bisphosphonates who require oral surgery. However, whether BTMs are capable of predicting ONJ risk and whether sCTX is usable for this purpose are controversial questions. This article presents an overview of the current literature regarding critical issues affecting the clinical utility of BTMs (including variability and reference ranges) and the current applications of BTMs in PMO management, with a focus on sCTX. Last, the appropriateness of using sCTX to predict ONJ risk in women receiving oral bisphosphonates for PMO is evaluated.     

Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research.

ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force.INTRODUCTION: The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder. MATERIALS AND METHODS: A multidisciplinary expert group reviewed all pertinent published data on bisphosphonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed. RESULTS AND CONCLUSIONS: A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patient-treatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1-10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined.     

Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review

The use of bisphosphonate drugs has been popularised in the late 20th century for the management of many conditions associated with abnormalities of bone turnover, particularly metastatic and haematogenous malignancy and osteopenia. The increase in indications for the use of bisphosphonates was supported by what was thought to be a very good safety profile. However in 2003 cases of osteonecrosis related to the use of bisphosphonates were first described. The pathogenesis, and with this the explanation of why it only appears to affect the maxillofacial skeleton, and the best way of managing this problem remains unknown. In this review we examine the process of identification of this pathology and the development of guidelines from medical societies and professional bodies on the management of patients before commencing bisphosphonate therapy, requiring dental treatment whilst on therapy, or with a diagnosis of bisphosphonate associated osteonecrosis of the jaws.     

Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases.

PURPOSE: In recent years, numerous cases of bisphosphonate-associated osteonecrosis of the jaw have been reported involving both intravenous and oral therapy regimens. The majority of these cases have involved intravenous bisphosphonates. Subsequently, drug manufacturers and the US Food and Drug Administration issued warnings about possible bisphosphonate-associated osteonecrosis of the jaw. The American Dental Association and the American Association of Oral and Maxillofacial Surgeons assembled expert panels to formulate treatment guidelines. Both panels differentiated between patients receiving bisphosphonates intravenously and those receiving the drugs orally. However, the recommendations were based on limited data, especially with regard to patients taking oral bisphosphonates. We wanted to ascertain the extent to which bisphosphonate-associated necrosis of the jaw has occurred in our dental implant patients. We also wanted to determine whether there was any indication that the bisphosphonate therapy affected the overall success of the implants as defined by Albrektsson and Zarb. PATIENTS AND METHODS: We identified 1,319 female patients over the age of 40 who had received dental implants at Montefiore Medical Center between January 1998 and December 2006. A survey about bisphosphonate therapy was mailed to all 1,319 patients. Responses were received from 458 patients of whom 115 reported that they had taken oral bisphosphonates. None had received intravenous bisphosphonates. All 115 patients were contacted and informed about the risk of bisphosphonate-associated osteonecrosis of the jaw. Seventy-two patients returned to the clinic for follow-up clinical and radiological evaluation. RESULTS: A total of 468 implants were placed in the 115 patients who reported that they had received oral bisphosphonate therapy. There is no evidence of bisphosphonate-associated osteonecrosis of the jaw in any of the patients evaluated in the clinic and those contacted by phone or e-mail reported no symptoms. Of the 468 implants, all but 2 integrated fully and meet criteria for establishing implant success. Implant success rates were comparable for patients receiving oral bisphosphonate therapy and those not receiving oral bisphosphonate therapy. CONCLUSIONS: Guidelines for treatment of dental patients receiving intravenous bisphosphonate treatments should be different than for patients taking the oral formulations of these medications. In this study, oral bisphosphonate therapy did not appear to significantly affect implant success. Implant surgery on patients receiving bisphosphonate therapy did not result in bisphosphonate-associated osteonecrosis of the jaw. Nevertheless, sufficient evidence exists to suggest that all patients undergoing implant placement should be questioned about bisphosphonate therapy including the drug taken, the dosage, and length of treatment prior to surgery. For patients having a history of oral bisphosphonate treatment exceeding 3 years and those having concomitant treatment with prednisone, additional testing and alternate treatment options should be considered.     

Increased prevalence of bisphosphonate‐related osteonecrosis of the jaw with vitamin D deficiency in rats

Necrotic bone exposure in the oral cavity has recently been reported in patients treated with nitrogen‐containing bisphosphonates as part of their therapeutic regimen for multiple myeloma or metastatic cancers to bone. It has been postulated that systemic conditions associated with cancer patients combined with tooth extraction may increase the risk of osteonecrosis of the jaw (ONJ). The objective of this study was to establish an animal model of bisphosphonate‐related ONJ by testing the combination of these risk factors. The generation of ONJ lesions in rats resembling human disease was achieved under the confluence of intravenous injection of zoledronate (ZOL; 35 µg/kg every 2 weeks), maxillary molar extraction, and vitamin D deficiency [VitD(?)]. The prevalence of ONJ in the VitD(?)/ZOL group was 66.7%, which was significantly higher (p < .05, Fisher exact test) than the control (0%), VitD(?) (0%), and ZOL alone (14.3%) groups. Similar to human patients, rat ONJ lesions prolonged the oral exposure of necrotic bone sequestra and were uniquely associated with pseudoepitheliomatous hyperplasia. The number of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick‐end label–positive (TUNEL⁺) osteoclasts significantly increased on the surface of post–tooth extraction alveolar bone of the VitD(?)/ZOL group, where sustained inflammation was depicted by [¹⁸F]fluorodeoxyglucose micro‐positron emission tomography (µPET). ONJ lesions were found to be associated with dense accumulation of mixed inflammatory/immune cells. These cells, composed of neutrophils and lymphocytes, appeared to juxtapose apoptotic osteoclasts. It is suggested that the pathophysiologic mechanism(s) underpinning ONJ may involve the interaction between bisphosphonates and compromised vitamin D functions in the realm of skeletal homeostasis and innate immunity. © 2010 American Society for Bone and Mineral Research     

Bisphosphonates and jaw osteonecrosis: the UAMS experience.

BACKGROUND: Over the past year at least 10 case series and several case reports on osteonecrosis of the jaw (ONJ) have been published with most found in the oral surgery literature. This clinical entity is largely unknown to head and neck surgeons. METHODS: Retrospective chart review. RESULTS: A total of 479 charts were reviewed, identifying 25 individuals meeting inclusion criteria. Mean age was 63.4 (standard deviation, 9.9) years; 40% were female. Multiple myeloma was the most common comorbidity. Twenty-five patients were treated with bisphosphonates for 4.4 years (range, 1 to 8 years); most commonly pamidronate before ONJ diagnosis. Forty-two percent (10) took steroids within the month before diagnosis. Fifty-two percent (11) underwent dental work before developing ONJ. CONCLUSION: These data reflect the importance of awareness of the possibility of ONJ with bisphosphonate therapy.     

Epidemiology and pathogenesis of osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) is defined as exposed bone in the oral cavity that persists despite appropriate therapy. Over the past decade, ONJ has been reported in about 5% of patients with cancer receiving high-dose intravenous bisphosphonates, and more recently in similar patients treated with denosumab, another potent inhibitor of osteoclastic bone resorption. The condition has also been described in patients treated with bisphosphonates for benign diseases, such as osteoporosis, but whether bisphosphonates or denosumab increase the incidence above that seen in untreated patients of comparable age and frailty is yet to be established. The pathogenesis of ONJ is uncertain: the toxic effects of bisphosphonates in a wide variety of cells could increase susceptibility to infections in the oral cavity or impair mucosal healing, and denosumab might interfere with monocyte and macrophage function. Local osteolysis is an important defense against infection on bone surfaces that is blocked by both bisphosphonates and denosumab. Preventive dentistry prior to high-dose antiresorptive therapy is a critical measure in cancer patients, but is not usually justified in patients with osteoporosis. The management of established ONJ lesions is problematic: the greatest success seems to come from vigorous antimicrobial therapy with judicious use of surgical debridement.     

Malnutrition due to bisphosphonate-related osteonecrosis of the jaw in a chronic dialysis patient: case report

Abstract

Adequate nutrition is imperative for a successful outcome in dialysis patients. Excellent oral hygiene and an efficient mastication can help to correct several metabolic and endocrine disturbances as well as delay initiation of dialysis in patients with chronic renal failure. However, concerns exist about the risk of malnutrition and protein depletion. On the other hand, intravenous bisphosphonates are the current standard of care for the treatment of hypercalcemia of malignancy and for the prevention of skeletal complications associated with bone metastases. Recently, retrospective case studies have reported an association between long-term bisphosphonate therapy and osteonecrosis of the jaws. This complication occurs either spontaneously or after minor dento-alveolar surgery including extraction of teeth. A malnourished dialysis patient who showed the typical clinical features of bisphosphonate-related osteonecrosis of the jaw (BRONJ) without any obvious radiological changes in his panoramic radiograph is reported. To minimize the risk of BRONJ, patients initiated on bisphosphonates should optimize routine dental care and have their baseline oral health evaluated by both clinical and radiographic examinations before initiation of bisphosphonate therapy.     

Long‐term Treatment with Intravenous Bisphosphonates in Metastatic Breast Cancer: A Retrospective Study

Bisphosphonates are important therapies used to reduce the risk of skeletal‐related events in patients with bone metastases from breast cancer (BC). This retrospective cohort study evaluated the incidence of osteonecrosis of the jaw (ONJ) and renal impairment in women (n = 221) with bone metastases from BC treated with intravenous bisphosphonates from January 1999 to June 2008. In the long‐term cohort, 159 patients received pamidronate (n = 9), zoledronic acid (n = 110), or both (n = 40) for ≥24 months. The comparator group consisted of patients treated with intravenous bisphosphonates for 12–23 months (n = 62). After 39 months' median follow‐up, six of 159 patients developed ONJ (3.8%; median 38.5 treatment cycles and 44 months' exposure) in the long‐term cohort. Of patients who developed ONJ, 50% resumed intravenous bisphosphonates after a 12‐month treatment holiday. Renal impairment developed in 19 patients in the long‐term cohort (11.9%; median 26 treatment cycles and 26 months' exposure). Of these 19 patients, 11 (57.9%) recovered baseline renal function and seven (36.7%) showed partial recovery. After modification of the intravenous bisphosphonate regimen, 17 of 19 patients (89.4%) resumed therapy. Of the 62 patients in the comparator cohort, one patient developed ONJ (1.6%) and six developed renal impairment (9.7%). Similar incidence rates of ONJ and renal impairment were observed for the long‐term and comparator cohorts. Times to ONJ or renal impairment also were similar across intravenous bisphosphonate type. Long‐term (≥24 months) intravenous bisphosphonate use in metastatic BC is well tolerated, with low incidences of ONJ and renal impairment.     

Lip Ulceration Associated with Intravenous Administration of Zoledronic Acid: Report of a Case

Although osteonecrosis of the jaw is a well-known adverse reaction of bisphosphonates (BPs), random cases of oral mucosal ulceration after per os administration of BP-aledronate have been attributed to prolonged mucosal irritation. This report, for the first time, describes the mucosal ulceration related to intravenous use of zoledronic acid (ZA). A 52-year-old female patient presented with painful ulcers on both cutaneous/mucosal surfaces of the lower lip and a 2-month history of osteonecrosis of the mandible beside the right lower canine. Her medical record included intravenous administration of ZA for 10 months for primary breast cancer metastatic to bone. Examination of the peripheral blood showed severe anemia and a slightly increased white blood cell count, due to urinary tract infection by E. coli, but no evidence of a viral infection. The treatment of anemia and E. coli infection did not improve the labial ulcers. Biopsy from the mucosal lesion revealed a non-specific ulceration with moderate inflammatory infiltration. There was no evidence of infection or malignancy. ZA administration was discontinued and within 3 months the lesions were resolved after treatment with systemic antibiotics (amoxicillin), vitamins A and E, chlorexidine and H₂O₂ (hydrogen peroxide) solutions and local pantothenic acid/vitamin A creams. Recurrence was detected a month after ZA re-administration. Nevertheless, after new treatment, the patient was free of oral/skin lesions 18 months later. This case, which is the first report of ulceration associated with intravenous administration of bisphosphonates, suggests that systemic mechanisms may be implicated in BP-induced oral mucosal ulceration. Furthermore, ZA appears to cause the same oral mucosal manifestations as alendronate. This emphasizes the need for oral examination in all cases of BP therapy, whether per os or intravenously administrated.     

OPG‐Fc but Not Zoledronic Acid Discontinuation Reverses Osteonecrosis of the Jaws (ONJ) in Mice

Osteonecrosis of the jaws (ONJ) is a significant complication of antiresorptive medications, such as bisphosphonates and denosumab. Antiresorptive discontinuation to promote healing of ONJ lesions remains highly controversial and understudied. Here, we investigated whether antiresorptive discontinuation alters ONJ features in mice, employing the potent bisphosphonate zoledronic acid (ZA) or the receptor activator of NF‐κB ligand (RANKL) inhibitor OPG‐Fc, utilizing previously published ONJ animal models. Mice were treated with vehicle (veh), ZA, or OPG‐Fc for 11 weeks to induce ONJ, and antiresorptives were discontinued for 6 or 10 weeks. Maxillae and mandibles were examined by μCT imaging and histologically. ONJ features in ZA and OPG‐Fc groups included periosteal bone deposition, empty osteocyte lacunae, osteonecrotic areas, and bone exposure, each of which substantially resolved 10 weeks after discontinuing OPG‐Fc but not ZA. Full recovery of tartrate‐resistant acid phosphatase‐positive (TRAP+) osteoclast numbers occurred after discontinuing OPG‐Fc but not ZA. Our data provide the first experimental evidence demonstrating that discontinuation of a RANKL inhibitor, but not a bisphosphonate, reverses features of osteonecrosis in mice. It remains unclear whether antiresorptive discontinuation increases the risk of skeletal‐related events in patients with bone metastases or fracture risk in osteoporosis patients, but these preclinical data may nonetheless help to inform discussions on the rationale for a “drug holiday” in managing the ONJ patient. © 2015 American Society for Bone and Mineral Research.     

Necrosis of the jaws under bisphosphonate therapy

Bisphosphonates are widely used in the treatment of cancer patients with hypercalcemia and bone metastases or in osteoporosis therapy. Current reports have focused on therapy-resistant osteonecrosis of the jaws as a possible side effect of bisphosphonates. Official German drug committees have recently warned about the possibility of these side effects. So far we have experience with 12 patients showing therapy-resistant osteonecrosis of the mandible under bisphosphonate medication, three of whom received oral bisphosphonates for osteoporosis treatment. Presentation of these three cases provides more information on this clinically important side effect of oral bisphosphonate medication, also in osteoporosis therapy.     

Frequency and Risk Factors Associated With Osteonecrosis of the Jaw in Cancer Patients Treated With Intravenous Bisphosphonates

Introduction: Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. The incidence and risk factors associated with this disorder have not been clearly defined. Materials and Methods: We conducted a retrospective analysis of 4019 patients treated with intravenous bisphosphonates between 1996 and 2004. Our goals were to estimate the frequency, understand the clinical presentation, and identify risk factors associated with ONJ development. Results: Sixteen of 1338 patients with breast cancer (1.2%) and 13 of 548 patients with multiple myeloma (2.4%) developed ONJ. The median dose and duration of treatment with pamidronate or zoledronic acid were significantly higher in patients with ONJ (p < 0.0001). Multivariate Cox proportional hazards regression analysis identified treatment with zoledronic acid (hazards ratio [HR], 15.01; 95% CI: 2.41–93.48; p = 0.0037), treatment with pamidronate followed by zoledronic acid (HR, 4.00; 95% CI: 0.86–18.70; p = 0.078), and dental extractions (HR, 53.19; 95% CI: 18.20–155.46; p < 0.0001) as significant risks for ONJ in breast cancer. In multiple myeloma, dental extractions (HR, 9.78; 95% CI: 3.07–31.14; p = 0.0001) and osteoporosis (HR, 6.11; 95% CI: 1.56–23.98; p = 0.0095) were significant risk factors while controlling for bisphosphonate therapy. Thirteen of 29 patients were followed for a median of 17.1 mo (range, 7–67 mo); lesions healed in 3 patients during this period. Conclusions: ONJ is an uncommon but long‐lasting disorder that occurs mainly in breast cancer and multiple myeloma patients treated with intravenous bisphosphonates. High cumulative doses of bisphosphonates, poor oral health, and dental extractions may be significant risk factors for ONJ development. ONJ resolved in 23% of patients with conservative therapy.     

Nekrosen der Kieferknochen unter Bisphosphonattherapie

Bisphosphonates are widely used in the treatment of cancer patients with hypercalcemia and bone metastases or in osteoporosis therapy. Current reports have focused on therapy-resistant osteonecrosis of the jaws as a possible side effect of bisphosphonates. Official German drug committees have recently warned about the possibility of these side effects. So far we have experience with 12 patients showing therapy-resistant osteonecrosis of the mandible under bisphosphonate medication, three of whom received oral bisphosphonates for osteoporosis treatment. Presentation of these three cases provides more information on this clinically important side effect of oral bisphosphonate medication, also in osteoporosis therapy.     

Mitigating osteonecrosis of the jaw(ONJ) through preventive dental care and understanding of risk factors

It is well established that alterations in phosphate metabolism have a profound effect on hard and soft tissues of the oral cavity. The present-day clinical form of osteonecrosis of the jaw(ONJ) was preceded by phosphorus necrosis of the jaw, ca. 1860. The subsequent removal of yellow phosphorus from matches in the early 20 th century saw a parallel decline in "phossy jaw" until the early 2000 s, when similar reports of unusual jaw bone necrosis began to appear in the literature describing jaw necrosis in patients undergoing chemotherapy and concomitant steroid and bisphosphonate treatment. Today, the potential side effect of ONJ associated with medications that block osteoclast activity(antiresorptive) is well known, though the mechanism remains unclear and the management and outcomes are often unsatisfactory. Much of the existing literature has focused on the continuing concerns of appropriate use of bisphosphonates and other antiresorptive medications, the incomplete or underdeveloped research on ONJ, and the use of drugs with anabolic potential for treatment of osteoporosis. While recognizing that ONJ is a rare occurrence and ONJ-associated medications play an important role in fracture risk reduction in osteoporotic patients, evidence to date suggests that health care providers can lower the risk further by dental evaluations and care prior to initiating antiresorptive therapies and by monitoring dental health during and after treatment. This review describes the current clinical management guidelines for ONJ, the critical role of dental-medical management in mitigating risks, and the current understanding of the effects of predominantly osteoclast-modulating drugs on bone homeostasis.     

Collapsing focal segmental glomerulosclerosis in a liver transplant recipient on alendronate

We describe a case of collapsing focal segmental glomerulosclerosis and severe kidney dysfunction in a liver transplant recipient after the initiation of alendronate for osteopenia. In view of the increasing incidence of chronic kidney disease in long-term liver transplant patients, bisphosphonates need to be used with caution in these patients. The usefulness of bisphosphonates for the prevention of early bone loss after liver transplantation is increasingly reported. However, there is little information on the safety and efficacy of these drugs when used in the later stages of liver transplant, particularly in the presence of chronic kidney disease. Bisphosphonates are excreted unchanged via the kidneys after reaching the systemic circulation. Some cases of severe kidney injury, in particular collapsing focal segmental glomerulosclerosis, have been described that are associated with the use of pamidronate. Alendronate, a widely used bisphosphonate in transplant patients, has not been related to kidney toxicity. We describe a case of collapsing focal segmental glomerulosclerosis and severe kidney dysfunction in a liver transplant recipient soon after the initiation of alendronate for osteopenia. Possible pathogenetic mechanisms are discussed. In view of the increasing incidence of chronic kidney disease in long-term liver transplant patients, bisphosphonate need to be used with caution in patients with a low glomerular filtration rate.