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.     

Oral bisphosphonate-related osteonecrosis of the jaw: the first report in Asia

Summary  

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect of bisphosphonate therapy. The incidence of BRONJ is known to be low among patients treated with oral bisphosphonates. We investigated the prevalence, demographics, clinical manifestations, and treatment outcome of 24 patients with oral BRONJ in Asian populations.     

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.     

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.     

Bisphosphonate-related osteonecrosis of the jaw: position paper from the Allied Task Force Committee of Japanese Society for Bone and Mineral Research, Japan Osteoporosis Society, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology, and Japanese Society of Oral and Maxillofacial Surgeons

Bisphosphonates (BPs) have been widely, efficiently, and safely used for the treatment of osteoporosis, malignant hypercalcemia, bone metastasis of solid cancers, and multiple myeloma bone diseases. Accumulating recent reports describe that surgical dental treatments in patients with cancer or osteoporosis who have been receiving intravenous or oral BPs are associated with osteonecrosis of the jaw (bisphosphonate-related osteonecrosis of the jaw, BRONJ). The accurate incidence, clinical backgrounds, and pathogenesis of BRONJ have been unclear and appropriate approaches for prevention and treatment have not been established to date. To address the current situation of BRONJ in Japan, the “Allied Task Force Committee of Bisphosphonate-Related Osteonecrosis of the Jaw,” consisting of physicians specializing in bone biology, orthopedic surgery, rheumatology, obstetrics/gynecology, and medical oncology and dentists specializing in oral surgery, periodontology, dental radiology, and oral pathology, was organized. The committee attempted to propose a standard position paper for the treatment of BRONJ. The committee expects that this proposal will provide objective and correct scientific information on BRONJ and will serve as a reference for conducting dental procedures for patients receiving BPs and in designing prevention and treatment of BRONJ. However, because this position paper is not based on direct clinical evidence, it should be used as a reference, and a decision on treatment in each case should be made after an extensive discussion among physicians, dentists/oral surgeons, and the patients.     

Jaw avascular osteonecrosis after treatment of multiple myeloma with zoledronate.

PURPOSE: Multiple myeloma, the second most common haematopoietic cancer, which represents the collection of plasma-cell neoplasms that invariably becomes fatal when self-renewing myeloma cells begin unrestrained proliferation. The major clinical manifestation of multiple myeloma is related to the loss of bone through osteolysis. This can lead to pathologic fractures, spinal cord compression, hypercalcaemia, and pain. It is also a major cause of morbidity and mortality in these patients, who frequently require radiation therapy, surgery and analgesic medications. Bisphosphonates are specific inhibitors of osteoclastic activity, and are currently used to prevent bone complications and to treat malignant hypercalcaemia in patients with multiple myeloma, or bone metastases from breast and prostate cancers. Hence, osteonecrosis of the mandible has been reported in three patients from Centro Hospitalar de Vila Nova de Gaia (CHVNG) with multiple myeloma treated for over 18-48 months with intravenous zoledronate, commonly prescribed for multiple myeloma therapy. Although, this report alerts clinicians about the potential complication of bone necrosis in patients receiving bisphosphonate therapy, many questions remain concerning the underlying pathogenesis of this process. PATIENTS AND METHODS: The medical and dental records of three patients with multiple myeloma, who were treated in CHVNG in the past 4 years, were reviewed. These three patients presented exposed bone and osteonecrosis of the mandible, and shared one common clinical feature: all of them were treated with bisphosphonate zoledronate, administered intravenously for long periods. Sequential orthopantomograms (OPGs) and histological evaluation have been analysed from the biopsies of the non healing dental extraction sites of these patients. RESULTS: After a routine dental extraction, these patients developed avascular osteonecrosis of the mandible and secondary bone infection with Actinomyces israelii (actinomycotic osteomyelitis), with no evidence of metastatic disease evaluated by biopsy. In these three described clinical cases, surgical debridment without flap elevation, intensive antibiotherapy and the suspension of the zoledronate treatment allowed a partial recovery of the patients. The purpose of this clinical report is to point out that patients suffering from multiple myeloma can develop bone osteonecrosis induced by treatment with bisphosphonates. Research to determine the mechanism of this dental phenomenon is needed to fully validate and substantiate the possible link between bisphosphonate treatment of multiple myeloma or other cancer diseases and avascular osteonecrosis of the jaws. Until then, clinicians involved in the care of patients at risk should consider this possible complication.     

Technetium-99 Conjugated with Methylene Diphosphonate Ameliorates Ovariectomy-Induced Osteoporotic Phenotype without Causing Osteonecrosis in the Jaw

Technetium-99 conjugated with methylene diphosphonate (⁹⁹Tc-MDP) is a novel bisphosphonate derivative without radioactivity and has been successfully used to treat arthritis in China for years. Since bisphosphonate therapy has the potential to induce bisphosphonate-related osteonecrosis of the jaw (BRONJ), we examined whether ⁹⁹Tc-MDP represents a new class of bisphosphonate for antiresorptive therapy to ameliorate estrogen deficiency-induced bone resorption with less risk of causing BRONJ. We showed that ⁹⁹Tc-MDP-treated, ovariectomized (OVX) mice had significantly improved bone mineral density and trabecular bone volume in comparison to the untreated OVX group by inhibiting osteoclasts and enhancing osteogenic differentiation of bone marrow mesenchymal stem cells. To determine the potential of inducing BRONJ, ⁹⁹Tc-MDP/dexamethasone (Dex) or zoledronate/Dex was administered into C57BL/6J mice via the tail vein, followed by extraction of maxillary first molars. Interestingly, ⁹⁹Tc-MDP treatment showed less risk to induce osteonecrosis in the maxillary bones compared to zoledronate treatment group, partially because ⁹⁹Tc-MDP neither suppressed adaptive regulatory T cells nor activated the inflammatory T-helper-producing interleukin-17 cells. Taken together, our findings demonstrate that ⁹⁹Tc-MDP therapy may be a promising approach in the treatment of osteoporosis with less risk of causing BRONJ.     

A pilot case–control study on the alveolar bone density measurement in risk assessment for bisphosphonate-related osteonecrosis of the jaw

Summary

Alveolar bone mineral density (BMD) measured by radiography standardized by aluminum step wedge pasted on the film and digitized by a computer system was significantly higher around osteonecrosis lesions than in control cases in a pilot case–control study. High alveolar bone density appears useful as a local risk factor for bisphosphonate-related osteonecrosis of the jaw (BRONJ).

Introduction

In an attempt to find a reliable test method predicting the occurrence of BRONJ in addition to various risk factors suggested, an increase of alveolar bone density near the necrotic lesions was found by computerized radiogrammetry using dental films pasted with an aluminum step wedge (Bone Right?, Dentalgraphic?Com Company, Himeji) in six cases of BRONJ.

Methods

The bone mineral density surrounding the osteonecrosis lesions showed distinctly higher density in BRONJ cases compared with age-matched controls. In one subject on bisphosphonate treatment in whom two extractions were simultaneously carried out, BRONJ occurred only at the location with extremely high alveolar bone density, but not at the other site with normal density.

Conclusion

This method may be useful in detecting a rise of alveolar BMD frequently occurring near the necrotic lesion in subjects with impending risk for BRONJ.     

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.     

Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice

Nitrogen-containing bisphosphonates such as zoledronic acid (ZOL) and pamidronate have been widely and successfully used for the treatment of cancer patients with bone metastases and/or hypercalcemia. Accumulating recent reports have shown that cancer patients who have received these bisphosphonates occasionally manifest bisphosphonate-related osteonecrosis of the jaw (BRONJ) following dental treatments, including tooth extraction. However, little is known about the pathogenesis of BRONJ to date. Here, to understand the underlying pathogenesis of BRONJ, we examined the effects of ZOL on wound healing of the tooth extraction socket using a mouse tooth extraction model. Histomorphometrical analysis revealed that the amount of new bone and the numbers of blood vessels in the socket were significantly decreased in ZOL-treated mice compared to control mice. Consistent with these results, ZOL significantly inhibited angiogenesis induced by vascular endothelial growth factor in vivo and the proliferation of endothelial cells in culture in a dose-dependent manner. In contrast, etidronate, a non-nitrogen-containing bisphosphonate, showed no effects on osteogenesis and angiogenesis in the socket. ZOL also suppressed the migration of oral epithelial cells, which is a crucial step for tooth socket closure. In addition, ZOL promoted the adherence of Streptococcus mutans to hydroxyapatite and the proliferation of oral bacteria obtained from healthy individuals, suggesting that ZOL may increase the bacterial infection. In conclusion, our data suggest that ZOL delays wound healing of the tooth extraction socket by inhibiting osteogenesis and angiogenesis. Our data also suggest that ZOL alters oral bacterial behaviors. These actions of ZOL may be relevant to the pathogenesis of BRONJ.     

Bisphosphonate related osteonecrosis of the jaw: A minipig large animal model

Bisphosphonate related osteonecrosis of the jaw (BRONJ) is rare but potentially severe, and the etiopathology and risk factors are poorly defined. To date, it has not been possible to induce BRONJ in a large animal model, a shortfall this study aims to redress.Ten two-year-old adult Göttingen minipigs were split into two groups. Five pigs (group 1) were administered intravenously a weekly dose of a bisphosphonate (zoledonate 0.05 mg/kg body weight, approximating the oncologic dose in humans) and five pigs (group 2) served as controls. After 6 weeks, tooth extractions were performed in the upper and lower jaw (both groups) and the bisphosphonate administration continued for a further 10 weeks (group 1 only). Clinical and blood parameters were monitored throughout the entire experiment; thereafter, the jaw-bones were subjected to macroscopic, radiological (CT) and histological investigations.Whilst the extraction sites in the control group healed within two weeks, all animals in the bisphosphonate group exhibited exposed bone and impaired wound healing, indicators that are synonymous of macroscopically advanced osteonecrosis. Radiological and in particular histological investigations confirmed the presence of BRONJ in the animals from group 1.This paper demonstrates that the administration of bisphosphonates, in combination with tooth extractions, induces BRONJ in a minipig model. The ability to study BRONJ in miniature pigs, animals with a bone structure not dissimilar to humans, may improve our knowledgebase regarding the etiopathology, the prophylaxis and potentially uncover new therapies of BRONJ.     

Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

In recent years, atypical femoral fractures and osteonecrosis of the jaw have emerged as potential complications of long-term bisphosphonate therapy; osteonecrosis of the jaw has also been reported in patients receiving high doses of denosumab. The pathophysiology of both conditions is poorly defined, and the underlying mechanisms are likely to differ. The initiation of atypical fractures in the lateral femoral shaft suggests that reduced tensile strength, possibly secondary to alterations in the material properties of bone resulting from low bone turnover, may be an important pathogenetic factor. Osteonecrosis of the jaw is characterised by infection, inflammation, bone resorption and bone necrosis, but the sequence in which these occur has not been established. However, the observation that bone resorption occurs in close proximity to microbial structures suggests that infection may be the most important trigger, often as a result of dental disease. Other possible pathogenetic factors include suppression of bone turnover, altered immune status and adverse effects of bisphosphonates on the oral mucosa.     

Cell‐based immunotherapy with mesenchymal stem cells cures bisphosphonate‐related osteonecrosis of the jaw–like disease in mice

Patients on high‐dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate‐related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of BRONJ‐like disease that recapitulates major clinical and radiographic manifestations of the human disease, including characteristic features of an open alveolar socket, exposed necrotic bone or sequestra, increased inflammatory infiltrates, osseous sclerosis, and radiopaque alveolar bone. We show that administration of zoledronate, a potent aminobisphosphonate, and dexamethasone, an immunosuppressant drug, causes BRONJ‐like disease in mice in part by suppressing the adaptive regulatory T cells, Tregs, and activating the inflammatory T‐helper‐producing interleukin 17 cells, Th17. Most interestingly, we demonstrate that systemic infusion with mesenchymal stem cells (MSCs) prevents and cures BRONJ‐like disease possibly via induction of peripheral tolerance, shown as an inhibition of Th17 and increase in Treg cells. The suppressed Tregs/Th17 ratio in zoledronate‐ and dexamethasone‐treated mice is restored in mice undergoing salvage therapy with Tregs. These findings provide evidence of an immunity‐based mechanism of BRONJ‐like disease and support the rationale for in vivo immunomodulatory therapy using Tregs or MSCs to treat BRONJ. © 2010 American Society for Bone and Mineral Research     

Bisphosphonate-related osteonecrosis of the jaws: legal liability from the perspective of the prescribing physician

Recently, it has been reported that patients administered with bisphosphonates (BP), in particular cancer patients receiving intravenous amino-bisphosphonates, as well as patients taking oral BP for prevention/treatment of diseases of altered bone turnover, may be affected by a significant adverse reaction—BP-related osteonecrosis of the jaws (BRONJ). This condition may cause high morbidity and detriment of quality of life. Its treatment is complex and often unsatisfactory, and prevention strategies may have limited effectiveness, if any; thus, BRONJ may become a source of litigation in the near future. Although most cases seem to be triggered by invasive dental procedures and oral health care providers are more exposed to malpractice claims and legal actions pursuant to BRONJ, the attribution of liability requires caution. In fact, types of possible negligence claims against oral health care providers have already been highlighted. However, according to the medico-legal methodology, since BRONJ is an adverse reaction to BP administration, the attribution of liability, if any, requires a comprehensive consideration of the chain of events and figures acting before, and potentially related to BRONJ. The physician prescribing BP at the start of this chain has specific duties which we are going to address, and breaching these duties may set the stage for potential liability claims.     

Prevalence and Risk Factors of Bisphosphonate-Associated Osteonecrosis of the Jaw in Prostate Cancer Patients with Advanced Disease Treated with Zoledronate

Background

In addition to other treatments, patients with prostate cancer (pCA) and bone metastasis receive bisphosphonates. Since 2003, a previously unknown side-effect of bisphosphonates—bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ)—has been described, and frequency has since increased. An exact incidence is still unknown.

Objectives

The aim of this study was to assess the incidence and additional factors in the development of BP-ONJ.

Design, setting, and participants

From July 2006 to October 2007, patients with advanced pCA and osseous metastasis receiving bisphosphonate therapy in the Department of Urology or Haematology and Oncology at the Johannes-Gutenberg-University Mainz, Germany, received a dental examination. In all, 43 patients were included.

Measurements

Patients were checked for exposed bone, osteonecrosis, mucosal defects, inflammation, and oral hygiene. Further points were the applied bisphosphonate, co-medication, the duration of application, and possible trigger factors for BP-ONJ.

Results and limitations

Eight of 43 patients developed BP-ONJ (18.6%). All patients had received zoledronate at least 14 times. Two patients had received bondronate, and one patient had received pamidronate before switching to zoledronate. All patients had had a previous tooth extraction or a denture pressure sore, and all patients had received additional chemotherapy and corticosteroids.

Conclusions

The reason for this relatively high incidence compared to other studies might be the prospective study design and thorough dental examination. In studies with such small numbers as have been published to date, nondetection or nonreported cases of BP-ONJ have an influence on the outcome. The incidence of BP-ONJ in patients with pCA might be an underestimated problem.     

Low-level laser therapy supported teeth extractions of two patients receiving IV zolendronate

BRONJ (bisphosphonate-related osteonecrosis of jaws) is a frequently encountered disease, particularly in the maxillofacial region, and a consequence of bisphosphonate use. Treatment of BRONJ remains controversial, as efficiency of medical and surgical approaches as well as a combination of these methods with supportive treatments have not been clearly demonstrated in the literature. In recent years, laser usage alone or in combination with the main therapy methods, has become popular for the treatment of bisphosphonate-related osteo-necrosis of jaws. In this article, we present the successful management of two dental patients who had high potentials for BRONJ development as a result of chemo and radiotherapy combined with IV zoledronic acid application. Multiple consecutive teeth extractions followed with primary wound closure and LLLT applications were performed under high doses of antibiotics prophylaxis. Satisfactory wound healing in both the surrounding soft and hard tissues was achieved. LLLT application combined with atraumatic surgical interventions under antibiotics prophylaxis is a preferable approach in patients with a risk of BRONJ development. Adjunctive effect of LLLT in addition to careful infection control on preventing BRONJ was reported and concluded.     

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.     

Computerized tomographic findings in bisphosphonate-associated osteonecrosis of the jaw in patients with cancer.

OBJECTIVES: To study bisphosphonate-associated osteonecrosis of the jaw with respect to radiographic, demographic, and clinical features. STUDY DESIGN: Thirty-two patients with painful exposed bone in the jaws subsequent to treatment with bisphosphonates for various neoplastic diseases were examined with both dental panoramic radiograph and multislice spiral computerized tomography (CT). Each case was assessed for the following radiologic signs: structural alteration of trabecular bone, cortical bone erosion, osteosclerosis, small sequestrum, extensive sequestrum, and presence of periosteal new bone. The McNemar, chi2, and Kruskall-Wallis tests were performed to analyze the association between radiologic signs, demographic data, clinical aspects of the lesion, and type and duration of bisphosphonate therapy. Hierarchical cluster analysis was used to group patients into categories on the basis of CT signs and dental panoramic radiograph signs. The agreement between CT and dental panoramic radiograph clusters was analyzed by kappa index. RESULTS: Dental panoramic radiograph proved positive for features of osteonecrosis in 18 cases and CT in 30. Computerized tomography was far superior to dental panoramic radiograph in detecting all the radiologic signs. The cluster analysis applied to CT signs showed a classification of the 32 patients in 4 categories characterized by an increasing number of signs coherent with the clinical extension of the lesions. Structural alteration of trabecular bone and cortical bone erosion, a constant finding in the 30 positive CTs, could be sometimes differentiated only with difficulty from those due to recent extraction. Dental panoramic radiograph missed the correct diagnosis of sequestration in 15 cases. Intense periosteal reaction was often found. The most extensive maxillary lesions were associated with new bone formation in Schneider mucous membrane, never described previously, and oroantral communications. CONCLUSIONS: Dental panoramic radiograph were found to be of limited use in assessing bisphosphonate-associated osteonecrosis of the jaw in patients for whom CT imaging was subsequently ordered.     

On the horizon: can bisphosphonates prevent bone metastases?

Skeletal complications of bone metastases increase the risk of death and undermine patients' functional independence and quality of life. Although bisphosphonates are integral in the treatment regimen of patients with metastatic bone disease and have demonstrated efficacy in delaying the onset and reducing the incidence of skeletal-related events, there is great interest in developing treatments to prevent metastasis to bone. Emerging evidence indicates that the potential benefits of bisphosphonate therapy extend beyond the treatment of metastatic bone lesions. Data from preclinical studies suggest that bisphosphonates may have antitumour activity and may prevent bone metastasis. The mechanisms of these antitumour effects are currently under investigation and may include induction of apoptosis, inhibition of tumour cell invasion and angiogenesis, and tumour growth reduction. Therefore, patients with early-stage disease may benefit from early bisphosphonate therapy, before bone metastasis develops, and investigations are ongoing to determine the clinical utility of bisphosphonates in this setting.     

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.