Sclerosis in bisphosphonate-related osteonecrosis of the jaws and its correlation with the clinical stages: study of 43 cases.

We analysed the degree of sclerosis in the different stages of bisphosphonate-related osteonecrosis of the jaws (BRONJ) and studied the relation between the grade of sclerosis, the clinical symptoms, and the depth of lucency. We compared 43 patients with mandibular BRONJ with a control group of 40 cases with no bony lesions. The presence of sclerotic bone, cortical irregularities, radiolucency, fragmentation or sequestration, periostitis, and narrowing of the mandibular canal were studied from computed tomographic (CT) scans using the program ImageJ 1.47v (National Institute of Health, Bethesda, USA) to measure the radiolucency, width of the cortices, and degree of sclerosis. Patients with BRONJ had more severe sclerosis than controls (p<0.01). There was also a significant difference among the different stages of BRONJ, with the highest values found in stage III (p=0.02). The degree of sclerosis differed according to sex, type of bisphosphonate, and the clinical characteristics such as pain, or suppuration, but not significantly so (p>0.05). We conclude that the degree of sclerosis increases with the clinical stage of BRONJ, and is correlated with the depth of lucency.

Bisphosphonate-related osteonecrosis of the jaw: what we have learned.

Bisphosphonate related osteonecrosis of the jaws (BRONJ) is an entity that has become prevalent upon the dental and medical community for more than 10 years. This entity is unfortunate because both oral and intravenous nitrogen containing bisphosphonates have beneficial effects for patients for certain conditions. The exact pathology of BRONJ has yet to be determined, although many hypotheses have been put forth. Since its prevalence, a clinical staging system has been developed and radiological findings have been described. BRONJ can be prevented if oral healthcare is undertaken before the start of bisphosphonate therapy or after a short time from the start of their use. However, after BRONJ has developed in patients, a myriad of treatments have been proposed that may help these patients.

Adverse events across generations of bone-modifying agents in patients with solid tumor cancers reported in Phase III randomized trials.

AIMS: The objective of this study is to compare adverse events experienced among different bone-modifying agents. METHODS: A literature search was conducted to identify Phase III bisphosphonate and bone-modifying agent trials reporting adverse effects. Thirty-seven adverse events of interest were identified for six different treatment options. Weighted linear regression modeling was performed on the adverse event proportions with treatment groups, normalized through applying natural log transformations. RESULTS: There were significant differences in adverse events of vomiting (p = 0.045) and osteonecrosis of the jaw (p = 0.017), and combined item events of nausea/vomiting (p = 0.048), hematological and lymphatic system toxicities (p = 0.020), and any respiratory system problem (p = 0.023) between bone-modifying agent and placebo trials. The significant toxicities were observed even after adjusting for the two confounding factors of age and primary cancer site. CONCLUSION: While adverse effects are consistently experienced more frequently in patients receiving bone-modifying agents when compared with placebos, we find that the majority of individual side effects are not significantly more frequent in patients receiving bone-modifying agents compared with placebo.

Prediction of bioavailability of selected bisphosphonates using in silico methods towards categorization into a biopharmaceutical classification system.

The physicochemical properties relevant to biological activity of selected bisphosphonates such as clodronate disodium salt, etidronate disodium salt, pamidronate disodium salt, alendronate sodium salt, ibandronate sodium salt, risedronate sodium salt and zoledronate disodium salt were determined using in silico methods. The main aim of our research was to investigate and propose molecular determinants thataffect bioavailability of above mentioned compounds. These determinants are: stabilization energy (deltaE), free energy of solvation (deltaG(solv)), electrostatic potential, dipole moment, as well as partition and distribution coefficients estimated by the log P and log D values. Presented values indicate that selected bisphosphonates a recharacterized by high solubility and low permeability. The calculated parameters describing both solubility and permeability through biological membranes seem to be a good bioavailability indicators of bisphosphonates examined and can be a useful tool to include into Biopharmaceutical Classification System (BCS) development.

Surgical treatment of bisphosphonate-associated osteonecrosis of the jaw: technical report and follow up of 21 patients.

INTRODUCTION: Bisphosphonates are used to reduce skeletal related events in patients with bone consuming diseases such as osteoporosis and bone metastases. However recently there has been an increased awareness of bisphosphonate-associated necrosis of the jaws (BP-ONJ). Many authors propose conservative management in these cases but invariably the problem is not treated successfully allowing the bone defect to worsen. Recently there has been a move to treat this problem surgically. The aim of this retrospective study was to provide a surgical solution for patients suffering from BP-ONJ. MATERIALS AND METHODS: All patients presenting with BP-ONJ were treated with bone debridement of the affected area and multilayer wound closure. The considered variables were: gender, age, underlying diagnosis, type of bisphosphonate (BP) used, duration of bisphosphonate use, route of administration, location of the osteonecrosis, clinical symptoms, association with dental treatment and surgical outcome. RESULTS: Nineteen cases of a total of 21 demonstrated no recurrence of osteonecrosis during follow up (Mean 16 months - Range 12-24 months). One patient with a bilateral defect showed a dehiscence on one side and a small fistula on the contralateral side 6 weeks post-operatively and required revision surgery. Another patient developed a fistula after 4 weeks that was treated successfully with antibiotics and curettage. No patients had evidence of exposed bone, bland mucosa nor pain at the surgical site. CONCLUSION: The technique described can be recommended for patients with BP-ONJ if a conservative treatment fails.

Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism.

PURPOSE: Osteonecrosis of the jaw has been reported in patients receiving high doses of intravenous nitrogen-containing bisphosphonates (N-BPs) because of malignant disease. The exact pathomechanisms have been elusive and questions of paramount importance remain unanswered. Recent studies have indicated toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Multipotent stem cells play an important role in the processes of wound healing and bone regeneration, which seem to be especially impaired in the jaws of patients receiving high doses of N-BPs. Therefore, the aim of the present study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH levels on the mesenchymal stem cells in vitro. MATERIALS AND METHODS: The effect of 2 N-BPs (zoledronate and ibandronate) and 1 non-N-BP (clodronate) on immortalized mesenchymal stem cells was tested at different concentrations, reflecting 1, 3, and 6 months and 1, 3, 5, and 10 years of exposure to standard oncology doses of the 2 N-BPs and equimolar concentrations of clodronate at different pH values (7.4, 7.0, 6.7, and 6.3). Cell viability and activity were analyzed using a WST assay. Cell motility was investigated using scratch wound assays and visualized using time-lapse microscopy. RESULTS: Both types of bisphosphonates revealed remarkable differences. Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and an acidic milieu led to a significant decrease in cell viability and activity (P < .01), with more pronounced effects for zoledronate. Equimolar concentrations of clodronate did not affect the cell survival or activity significantly, apart from the effect of pH reduction itself, which was also detectable in the patients in the control group who did not receive bisphosphonates. CONCLUSIONS: Our results have shown that high concentrations of N-BPs and a local acidic milieu, which is commonly present in infections of the jaw, might play a key role in the pathogenesis of osteonecrosis of the jaw in patients receiving high doses of N-BPs for malignant diseases. Also the potency of N-BPs might be different, suggesting a greater risk of osteonecrosis of the jaw with zoledronate.

[Use of bisphosphonates in chronic kidney disease]. / Uso de bifosfonatos en la enfermedad renal crónica.

Bisphosphonates are synthetic compounds similar to organic pyrophosphates. The bioavailability of intravenous preparations is 100%, whereas the availability of oral therapy ranges from 1 to 5%. About 50% to 80% of free bisphosphonates are incorporated into bone. Because of their urinary elimination, bisphosphonates must be carefully administered in chronic kidney disease (CKD) patients. In spite of this, bisphosphonates can safely be used in all CKD stages, including dialysis and kidney transplant. The renal toxicity seems different among these compounds, and it is due basically to their protein binding and the average lifespan in renal tissues. In practice, renal toxicity have been associate to the infusion velocity and excessive dosage In patients with CKD, it is very relevant to maintain the time of infusion and in haemodialysis patients we recommend the administration during the haemodialysis session. When bisphosphonates are given to 4-5 CKD patients it seems reasonable to reduce the dose to 50%. No renal pathology has been associated to oral administration. The indications of bisphosphonates in CKD include: hypercalcemia episodes, prevention of bone loss after renal transplantation, treatment of low bone mineral density in all CKD stage including transplantation. They are too a promising therapy of calciphylaxis and to prevent vascular calcifications. When suppressed bone turnover is suspected, bone biopsy is mandatory before bisphosphonates therapy.

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.

Labeling, characterization, and in vivo localization of a new 90Y-based phosphonate chelate 2,3-dicarboxypropane-1,1-diphosphonic acid for the treatment of bone metastases: Comparison with 99mTc-DPD complex.

The goal of this investigation was to examine the possibilities for yttrium-90-labeling of the 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD), which is currently labeled with technetium-99m and as a (99m)Tc-DPD clinically used as bone imaging agent. Analysis of the complex enclosed the radiochemical quality control methods, biodistribution studies, as well as the determination of pharmacokinetic parameters. The biological behavior of complexes (90)Y-DPD, (99m)Tc-DPD and (90)Y-labeled DPD-kit formulation [(90)Y-(Sn)-DPD] in animal model was compared. The labeling conditions were standardized to give the maximum yield, which ranged between 93% and 98%. The examined (90)Y complex could be easily prepared, with an outstanding yield and was also found to be very stable for at least 10h after (90)Y-labeling. Protein binding value was 4.6+/-0.7% for (90)Y-DPD complex and the complex possess a hydrophilic character. The satisfactory results of (90)Y-DPD biodistribution in healthy test animals were obtained; the uptake in the bone was 11-13%ID/g after 24h depending on the pH value during the preparation. With high skeletal uptake, a minimum uptake in soft tissues and rapid blood clearance the (90)Y-DPD complex proved to be an excellent candidate for targeting tumor therapy.

Bisphosphonates: mode of action and pharmacology.

The profound effects of the bisphosphonates on calcium metabolism were discovered over 30 years ago, and they are now well established as the major drugs used for the treatment of bone diseases associated with excessive resorption. Their principal uses are for Paget disease of bone, myeloma, bone metastases, and osteoporosis in adults, but there has been increasing and successful application in pediatric bone diseases, notably osteogenesis imperfecta. Bisphosphonates are structural analogues of inorganic pyrophosphate but are resistant to enzymatic and chemical breakdown. Bisphosphonates inhibit bone resorption by selective adsorption to mineral surfaces and subsequent internalization by bone-resorbing osteoclasts where they interfere with various biochemical processes. The simpler, non-nitrogen-containing bisphosphonates (eg, clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes. In contrast, the more potent, nitrogen-containing bisphosphonates (eg, pamidronate, alendronate, risedronate, ibandronate, and zoledronate) inhibit a key enzyme, farnesyl pyrophosphate synthase, in the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small guanosine triphosphate (GTP)-binding proteins (which are also GTPases) such as Rab, Rho, and Rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity. The recently elucidated crystal structure of farnesyl diphosphate reveals how bisphosphonates bind to and inhibit at the active site via their critical nitrogen atoms. Although bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, there is new knowledge about how they work and the subtle but potentially important differences that exist between individual bisphosphonates. Understanding these may help to explain differences in potency, onset and duration of action, and clinical effectiveness.

Skeletal bone diseases impact the periodontium: a review of bisphosphonate therapy.

Healthcare professionals should be aware that systemic bone conditions impact the periodontium. Bisphosphonate drugs used for systemic bone loss affect the maxilla and mandible. Alveolar bone loss in periodontitis and skeletal bone loss share common mechanisms. At present, bisphosphonates are in wide use for prevention and treatment of osteoporosis, Paget's disease and metastatic bone conditions. This therapy is linked to a negative side effect called osteonecrosis of the jaws. At the same time, bisphosphonate therapy is also reported to be beneficial to the periodontium. In fact, periodontal therapy using bisphosphonates to modulate host response to bacterial insult may develop into a potential strategy in populations in which periodontal therapy is not convenient. Unlocking the full potential of bisphosphonates involves understanding the mechanisms of action of different classes of bisphosphonates, limiting unwanted side effects and expanding its indications. Developing bisphosphonates to slow the progression of periodontal disease depends on identifying an effective dosage regimen and delivery system that would reach the target site in the periodontium, while limiting unwanted side effects.

The role of bisphosphonates in early breast cancer.

Clinical trials are investigating the use of bisphosphonates in patients with early (nonmetastatic) breast cancer. Results from trials of clodronate are generally encouraging but somewhat contradictory. Of the three trials published to date, two reported that clodronate had beneficial effects on both bone metastases and survival. In contrast, the third trial reported that clodronate had no effect on metastases and a negative effect on survival. Small studies of adjuvant pamidronate and zoledronic acid also produced promising data, but these need to be reproduced in a large-scale, randomized trial setting before clinically meaningful conclusions can be drawn. A number of adjuvant trials are in progress to further evaluate the role of oral clodronate and i.v. zoledronic acid and to examine the effects of the newer bisphosphonate, ibandronate (oral formulation), in this setting. One of these trials is the joint Southwest Oncology Group/Intergroup/National Surgical Adjuvant Breast and Bowel Project trial, which is designed to compare the efficacy and safety of all three of these bisphosphonates in approximately 6,000 women with early breast cancer. Patient preference for oral or i.v. therapy will also be assessed.

Association of osteonecrosis of the jaws and bisphosphonate pharmacotherapy: dental implications.

Bisphosphonates are drugs of choice in the management of a variety of bone disorders including osteoporosis, Paget's disease and bone cancer. Recently there have been increasing reports of a possible relationship between bisphosphonate therapy and osteonecrosis of the jaws. Osteonecrosis may occur following extractions or dental surgery and, in some cases, may appear spontaneously. Because of the potentially serious nature of these complications and the failure of exposed bone to heal, dentists must be aware of recommended precautions for the management of patients taking bisphosphonate medication.

[Bisphosphonates in the treatment of multiple myeloma]. / Bifosfoniany w leczeniu szpiczaka mnogiego.

Bisphosphonates are the most potent class of antiresorpitve drugs used in the treatment of bone diseases with enhanced resorption, like malignant osteolysis, osteoporosis and Paget's disease. Multiple myeloma is commonly associated with skeletal morbidity, including osteolysis, bone fractures, pain and hypercalcemia. These clinical complications result from increased osteoclast number and function which is due to release of osteoclast-stimulating factors by myeloma cells and the tumoral environment. By inhibition of osteoclast activity and inducing cell apoptosis, bisphosphonates can prevent development of bone destruction in myeloma patients. This article reviews efficacy of bisphosphonates in reducing skeletal events in patients with multiple myeloma and several in vitro studies which have shown that aminobisphosphonates may act as antimyeloma agents.