Side Effect Of Bisphosphonate Therapy Research Articles

Bisphosphonates Inhibit Expression of p63 by Oral Keratinocytes

Osteonecrosis of the jaw (ONJ), a side-effect of bisphosphonate therapy, is characterized by exposed bone that fails to heal within eight weeks. Healing time of oral epithelial wounds is decreased in the presence of amino-bisphosphonates; however, the mechanism remains unknown. We examined human tissue from individuals with ONJ and non-bisphosphonate-treated controlindividuals to identify changes in oral epithelium and connective tissue. Oral and intravenous bisphosphonate-treated ONJ sites had reduced numbers of basal epithelial progenitor cells, as demonstrated by a 13.8 ± 1.1% and 31.9 ± 5.8% reduction of p63 expression, respectively. No significant differences in proliferation rates, vessel density, or macrophage number were noted. In vitro treatment of clonal and primary oral keratinocytes with zoledronic acid (ZA) inhibited p63, and expression was rescued by the addition of mevalonate pathway intermediates. In addition, both ZA treatment and p63 shRNA knock-down impaired formation of 3D Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) and closure of an in vitro scratch assay. Analysis of our data suggests that bisphosphonate treatment may delay oral epithelial healing by interfering with p63-positive progenitor cells in the basal layer of the oral epithelium in a mevalonate-pathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone.

Geranylgeraniol – A new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw

Bisphosphonate associated osteonecrosis of the jaw (BP-ONJ) is one of the main side effects of bisphosphonate therapy (BPT). To date, there is no effective therapy of the BP-ONJ. Nitrogen-containing bisphosphonates (N-BPs) are particularly able to inhibit pyrophosphate synthase (FPPS) in the mevalonate pathway (MVP). Consequent of decreased synthesis of the metabolite Geranylgeraniol (GGOH) is believed to largely account for the development of BP-ONJ. Negative effect of N-BPs could be shown, resulting in decreased viability and migration capacity of different cell types of hard and soft tissues such as osteoblasts, fibroblast und endothelial cells. Aim of our in vitro study was to demonstrate that the mevalonate pathway metabolite GGOH could reverse the negative biological effect of N-BPs. Biological effect of GGOH on bisphosphonate-treated human umbilicord vein endothelial cells (HUVEC), fibroblast and osteogenic cells was analyzed by a viability test and measuring the migration capacity in a scratch wound assay as well as a migration assay using Boyden chambers. The morphological cell architecture of the treated cells was analyzed by phallacidin staining. GGOH cell-treatment can rescue the negative effect of bisphosphonates. These results underline the hypothesis that systemic or local treatment with GGOH could lead to new therapeutic strategies for BP-ONJ.

Bisphosphonate-Related Osteonecrosis of the Jaw: Is pH the Missing Part in the Pathogenesis Puzzle?

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of bisphosphonate therapy, primarily diagnosed in patients with cancer and metastatic bone disease and receiving intravenous administrations of nitrogen-containing bisphosphonates. If diagnosis or treatment is delayed, BRONJ can develop to a severe and devastating disease. Numerous studies have focused on BRONJ, with possible pathomechanisms identified to be oversuppression of bone turnover, ischemia due to antiangiogenetic effects, local infections, or soft tissue toxicity. However, the precise pathogenesis largely remains elusive and questions of paramount importance await to be answered, namely 1) Why is only the jaw bone affected? 2) Why and how do the derivatives differ in their potency to induce a BRONJ? and 3) Why and when is BRONJ manifested? The present perspective reflects on existing theories and introduces the hypothesis that local tissue acidosis in the jaw bone offers a conclusive pathogenesis model and may prove to be the missing link in BRONJ.

Resolution of Osteonecrosis of the Jaw After Teriparatide [Recombinant Human PTH-(1-34)] Therapy

To the Editor: Although exceedingly rare in the population with postmenopausal osteoporosis, osteonecrosis of the jaw (ONJ) has a significant impact on the morbidity of the unfortunate patients who develop it. Currently recommended treatments have proven to be suboptimal, as many patients remain unresponsive. We describe the second case of teriparatide therapy for treatment of ONJ that was unresponsive to conventional therapies. Bisphosphonates are one of the most prescribed drugs in North America, with over 17 million prescriptions per year1. There are several different indications for the use of bisphosphonates, and several forms are available, including an intravenous (IV) form (i.e., pamidronate and zoledronate) in the treatment of hypercalcemia in malignant diseases of bone such as multiple myeloma and breast cancer metastasis to the bone. IV bisphosphonates are also used in the pediatric population to treat osteogenesis imperfecta and idiopathic juvenile arthritis. Finally, the most common indication for bisphosphonates is in the treatment of osteoporosis, where an oral form is typically used (e.g., alendronate, risedronate). Osteonecrosis of the jaw (ONJ) is a serious side effect of bisphosphonate therapy that has only been recently recognized. Since first described by Marx, et al in 2003, where 36 oncologic patients taking pamidronate or zoledronate presented with osteonecrosis of the jaw2, hundreds of cases have been reported in cancer patients treated with IV bisphosphonates; but more recently, cases have also been reported in patients with osteoporosis treated with oral bisphosphonates. Based on current literature, 94% of patients with reported bisphosphonate-induced ONJ were treated with an IV form, while the remaining 6% were treated with an oral bisphosphonate3. The estimated incidence of ONJ in patients receiving IV bisphosphonate therapy in the setting of multiple myeloma ranges from 4.5 to 12.8%4, and from 1.2 to 12.0% in the … Address reprint requests to Dr. Adachi. E-mail: jd.adachi{at}sympatico.ca

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

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. The long-term safety of oral bisphosphonates is clinically important considering the rare but potentially serious complications such as bisphosphonate-related osteonecrosis of the jaw (BRONJ) versus the effect of reducing and preventing osteoporotic fracture. The incidence of BRONJ is known to be low among patients treated with oral bisphosphonates around the world. However, the prevalence in those taking oral bisphosphonates for osteoporosis in Asian populations is unknown. Moreover, a recent article, showing that the majority of reported patients who received alendronate were Asian American, raised concern about the prevalence of oral BRONJ in Asian populations. The objective of this study was to investigate the estimated prevalence, clinical characteristics, and treatment outcome of oral BRONJ in Asian populations. From October 2005 to December 2008, a retrospective review of medical charts identified 24 patients receiving oral bisphosphonates diagnosed as BRONJ at the Department of Oral and Maxillofacial Surgery, Yonsei University Dental Hospital, Seoul, South Korea. The estimated prevalence of oral BRONJ was 0.05-0.07%. The average oral bisphosphonate treatment duration was 43.1 months (range, 5-120 months). Treatment with oral antibiotics and/or surgery including sequestrectomy or alveolectomy showed relatively favorable results. The prevalence of oral BRONJ in Korea is similar to that reported previously in Western populations. We suggest that recognition of BRONJ and appropriate management pre- and post-dental surgery might reduce the frequency of BRONJ among patients receiving oral bisphosphonates.

P.065 Osteonecrosis: a severe side effect of bisphosphonate therapy

P.065 Osteonecrosis: a severe side effect of bisphosphonate therapy

POSTMARKETING SURVEILLANCE RATES OF UVEITIS AND SCLERITIS WITH BISPHOSPHONATES AMONG A NATIONAL VETERAN COHORT

Uveitis and scleritis are the most serious ocular side effects of bisphosphonate therapy. The purpose of this study was to determine the 6-month rates of uveitis/scleritis following dispensing of bisphosphonates in a large veteran cohort. Two national databases (clinical and pharmacy) for fiscal year (FY) 2006 were linked to identify new diagnoses of uveitis/scleritis following the initial dispensing of bisphosphonate drugs. New diagnoses in FY 2006 were identified using International Classification of Diseases, Version 9, Clinical Modification (ICD-9-CM), in a cohort of veterans without a previous diagnosis of uveitis or scleritis using a look-back period to FY 2005. The new diagnoses were temporally aligned with initial dispensing of bisphosphonates and the rates of new cases were calculated for 1-month and 6-month time intervals. There were 7.9 new cases of uveitis/scleritis per 10,000 individuals with a newly dispensed bisphosphonate that occurred within 180 days. The relative risk of uveitis/scleritis for 6 months was 1.23 (95% confidence interval: 0.85-1.79) compared to veterans not exposed to the medications. The rates of uveitis/scleritis did not differ significantly based on route of administration (oral or parenteral) or after age adjustment. Just over a third of the diagnoses were scleritis. Nearly 43% of patients with uveitis/scleritis after bisphosphonate use had a systemic diagnosis commonly associated with inflammation of the uveal tract or sclera. The 30-day and 6-month rates of uveitis/scleritis following the dispensing of a bisphosphonate drug are low and do not differ significantly from rates recorded for veterans not dispensed these drugs.

A Case of Intravenous Pamidronate-Related Osteonecrosis of the Jaw in a Patient with Waldenstrom's Macroglobulinemia

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare, but serious, side effect of bisphosphonate therapy that produces significant morbidity in affected patients. It is characterized by poor wound healing and spontaneous intra-oral soft tissue breakdown, which lead to exposure of necrotic maxillary and mandibular bone. We report a case of BRONJ in 56-year-old man who visited Ajou University Hospital Dental Clinic in March 2007. He had been diagnosed with Waldenstrom's macroglobulinemia in 2005 and had been treated with chemotherapeutic agents, along with concomitant pamidronate injections (45 mg monthly). The patient had clinical features of bisphosphonate-related osteonecrosis of the mandible precipitated by tooth extraction. The patient had multiple systemic risk factors, including extended duration of intravenous pamidronate therapy, chemotherapy, and glucocorticoid therapy for his malignancy. In the 6 months prior to presentation, curettage and debridement were performed repeatedly, but there was no improvement in the mandibular lesion. The patient was referred to the Endocrinology Clinic and was diagnosed with BRONJ. We discontinued pamidronate and started conservative care. BRONJ should be considered in the differential diagnosis when patients complain of poor oral wound healing or have recurrent exposure of necrotic maxillary and mandibular bone. (J Korean Endocr Soc 23:210~214, 2008)

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

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. 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. 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. 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. 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.

Bisphosphonate-induced osteonecrosis of the jaw: Incidence and risk factors in patients with breast cancer and gynecological malignancies

1113 Background: Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. They are successfully used in conditions of increased bone turnover such as osteoporosis or bone metastases. Since 2003 multiple cases of bisphosphonate-induced osteonecrosis of the jaw (ONJ) were reported. Our purpose was to describe the incidence and risk factors of ONJ in patients with breast cancer or gynecological malignancies. Patients and Methods: ONJ was assessed retrospectively for all patients with breast cancer or gynecological malignancies treated with bisphosphonates at the Department of Gynecology and Obstetrics, University Hospital Tuebingen during April 1999 until May 2006. Results: 10 of 310 (3%) patients with breast cancer or gynecological malignancies developed ONJ while receiving bisphosphonate therapy. All patients with ONJ were treated for bone metastases. Except one all patients with ONJ had a history of recent dental procedures. All patients had received zoledronic acid as part of their bisphosphonate regimen. In 4 of 10 patients this was the only bisphosphonate given. The remaining 6 patients had received at least one of the other bisphosphonates (alendronate, ibandronate, clodronate or pamidronate) before or after zoledronic acid therapy during their course of disease. Time of exposure to bisphosphonates and the number of treatment cycles were significant risk factors for the development of ONJ (p<0.001). In patients diagnosed with ONJ the mean number of treatment cycles was 27 ±18 cycles (median: 21 cycles, range 6–62 cycles) and the mean duration of bisphosphonate therapy was 29 ±20 months (median: 22 months, range 1–67 months). In contrast, the mean number of treatment cycles in patients without manifestation of ONJ was 11 ±12 cycles (median: 6 cycles, range 1–90 cycles). The mean duration of therapy was 12 months (median: 7 months, range 1–81 months). Conclusion: Osteonecrosis of the jaw is regarded a major side effect of bisphosphonate therapy. Length of exposure to bisphosphonates and the number of treatment cycles seem to be the most important risk factors for the development of ONJ. In addition, recent dental procedures favours the development of an ONJ. No significant financial relationships to disclose.

Osteonecrosis of the Jaw (ONJ) in Patients with Multiple Myeloma, Receiving Bisphosphonate Therapy, Is Independent of Renal Function: Single Institute Experience of an Emerging Clinical Problem.

Introduction: Use of bisphosphonate (zoledronic acid and pamidronate) for prevention of pathological fractures is standard of care in multiple myeloma (MM) patients with osteolytic bone lesions. While clinical trials have investigated effectiveness of these agents for up to 2 years of use, clinical practice has incorporated their use indefinitely. With improvement in survival through availability of novel agents in MM patients, the use of bisphosphonate therapy has also prolonged. Recent reports unveiled a new side effect of Bisphosphonate therapy i.e., ONJ, characterized by necrosis of the jawbone with antecedent subluxation or loss of the teeth and ulceration of the gum mucosa. The underlying etiology remains elusive, and in the absence of effective remedy ONJ has raised significant concerns upon the duration of treatment with Bisphosphonate. We investigated the magnitude of this problem among MM patients receiving Biphosphonate therapy at our institute.Methods: We conducted a retrospective review of all patients diagnosed with MM at our institute since 2001 who received bisphosphonate treatment and developed ONJ. Clinical characteristics, prior treatments and renal function prior to development of ONJ were evaluated.Results: Records of 20 pts who developed ONJ were reviewed.The median age of these pts was 57 (range 45–69).Among these, 9 were males, 11 were females. All pts (100%) had stage III MM.11 patients (55%) received 2 or more antimyeloma treatment.14 pts (70%) were on Zoledronic acid, 5 pts (25%) were on Pamidronate, and 1 pt (5%) was first on Zoledronic acid then switched to Pamidronate.Out of those 20 patients, 19 (95%) had normal renal function prior to and after development of ONJ, with Creatinine level range of (0.5–1). Only 1 patient (5%) had decreased renal function prior to development of ONJ, with Creatinine level of 6.6Conclusion: Although the number of patients reported are small, experience at our center with ONJ in MM patients who were on Bisphosphonate failed to show any association with renal function. Interestingly all patients who developed ONJ were stage III MM.There are currently no established guidelines for prevention or treatment of this disorder.

Adjuvant aromatase inhibitors and bone health

Adjuvant hormonal therapy results in substantial improvements in disease-free and overall survival for women with operable breast cancer. Use of an aromatase inhibitor (AI) is expected to replace tamoxifen as standard care for many patients. Aromatase is the enzyme responsible for the final step in estrogen biosynthesis. This is the conversion of the androgens testosterone and androstenedione to the estrogens estrone and estradiol. AIs are potent inhibitors of estrogen production and thus one of the major concerns over their use is their effect on bone health and their potential to increase the incidence of osteoporosis and risk of fracture. The American Society of Clinical Oncology has recognized that these patients are at high risk of developing osteoporosis and has published guidelines to aid in their management. These recommend that all patients have an initial dual-energy X-ray absorptiometry (DEXA) bone scan to assess bone mineral density and are offered calcium and vitamin D supplements as well as lifestyle advice. Patients with osteoporosis should be treated with a bisphosphonate to reduce the incidence of fracture. Osteonecrosis of the jaws is a recently described adverse side-effect of bisphosphonate therapy and has been described in women with metastatic breast cancer. Oversuppression of bone turnover is probably the primary mechanism for the development of this condition. The degree of risk for osteonecrosis with bisphosphonates is uncertain and warrants careful monitoring.

Clinical experiences with bisphopsphonate induced osteochemonecrosis of the jaws.

Bisphosphonates are frequently used drugs in the adjuvant therapy of bone metastases and tumour-induced hypercalcaemia, but also for osteoporosis or Pagets disease. Several publications within the last three years considered osteonecrosis of the jaws to be connected with bisphosphonate therapy. Until today possible treatment strategies contain antibiotics, hyperbaric therapy and operative treatment. The tendency of healing however seems to be extremely poor. All clinicians should be aware of this new kind of side effect of bisphosphonate therapy. 14 patients with this new kind of osteonecrosis were admitted to the department of Cranio-Maxillofacial Surgery of the University Hospital of Zurich. 8 men and 6 women all received bisphosphonates for cancer therapy. A complete analysis of patients' data was performed. Of 14 patients in 7 the underlying disease disease was multiple myeloma. In one patient it was prostate cancer and in all female patients it was breast cancer. All of them had prior dental treatment and showed inflammatory signs and bacterial colonisation with localisation in the upper or lower jaw or in both. The infectious part of the bisphosphonate-induced osteonecrosis (ONJ) is considered to be more important than thought before. We presume that antimicrobial treatment is of utmost importance in the treatment of this kind of osteonecrosis. Patients with current or previous bisphosphonate therapy should be treated multidisciplinary to assure ideal prevention and treatment.

Clinical experiences with bisphopsphonate induced osteochemonecrosis of the jaws.

Bisphosphonates are frequently used drugs in the adjuvant therapy of bone metastases and tumour-induced hypercalcaemia, but also for osteoporosis or Pagets disease. Several publications within the last three years considered osteonecrosis of the jaws to be connected with bisphosphonate therapy. Until today possible treatment strategies contain antibiotics, hyperbaric therapy and operative treatment. The tendency of healing however seems to be extremely poor. All clinicians should be aware of this new kind of side effect of bisphosphonate therapy. 14 patients with this new kind of osteonecrosis were admitted to the department of Cranio-Maxillofacial Surgery of the University Hospital of Zurich. 8 men and 6 women all received bisphosphonates for cancer therapy. A complete analysis of patients' data was performed. Of 14 patients in 7 the underlying disease disease was multiple myeloma. In one patient it was prostate cancer and in all female patients it was breast cancer. All of them had prior dental treatment and showed inflammatory signs and bacterial colonisation with localisation in the upper or lower jaw or in both. The infectious part of the bisphosphonate-induced osteonecrosis (ONJ) is considered to be more important than thought before. We presume that antimicrobial treatment is of utmost importance in the treatment of this kind of osteonecrosis. Patients with current or previous bisphosphonate therapy should be treated multidisciplinary to assure ideal prevention and treatment.

Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws

Osteonecrosis of the jaws is a recently described adverse side effect of bisphosphonate therapy. Patients with multiple myeloma and metastatic carcinoma to the skeleton who are receiving intravenous, nitrogen-containing bisphosphonates are at greatest risk for osteonecrosis of the jaws; these patients represent 94% of published cases. The mandible is more commonly affected than the maxilla (2:1 ratio), and 60% of cases are preceded by a dental surgical procedure. Oversuppression of bone turnover is probably the primary mechanism for the development of this condition, although there may be contributing comorbid factors. All sites of potential jaw infection should be eliminated before bisphosphonate therapy is initiated in these patients to reduce the necessity of subsequent dentoalveolar surgery. Conservative débridement of necrotic bone, pain control, infection management, use of antimicrobial oral rinses, and withdrawal of bisphosphonates are preferable to aggressive surgical measures for treating this condition. The degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as alendronate, for osteoporosis is uncertain and warrants careful monitoring.

Bisphosphonate und Osteonekrosen im Kieferbereich

Since 2003, reports have been published on necrosis of the jaw bones possibly being associated with the administration of bisphosphonates. Bisphosphonates are highly active inhibitors of osteoclasts which have been used prophylactically or symptomatically in the treatment of plasmocytoma, bone metastasis of malignant disease, tumor-associated hypercalcaemia and in the treatment of osteoporosis. Due to the importance of this side effect of bisphosphonates, we report six cases. Six patients (two women and four men) with a median age of 69 years (range 55-37) were diagnosed with osteonecrosis of the maxilla and/or mandible. These osteonecroses did not react adequately to local treatment and systemic therapy with antibiotics. Four patients suffered from plasmocytoma and two patients had a history of metastasising breast cancer. Besides cytostatic chemotherapies, all patients received bisphosphonates over an extended period. Bisphosphonates are considered an important standard in the treatment of plasmocytoma and bone metastasis due to malignancies. Since 2003, several reports have been published describing patients in whom therapy resistant osteonecrosis of jaw bones occurred either after dental extractions or spontaneously. Until then, unknown side effects of bisphosphonate therapy had been suspected. Since patients with malignant diseases receive cytostatic therapy and a range of other drugs, including bisphosphonates, enhancement of the side effects may be presumed. The probable association of the therapeutic use of bisphosphonates and the occurence of jaw bone necrosis has to be studied in further investigations. Patients receiving bisphosphonates should be followed-up regularly to avoid the occurrence of extended osteonecrotic lesions, which should be diagnosed early and treated adequately.