Dose Of Zoledronate Research Articles

F1-Adenosine Triphosphatase Displays Properties Characteristic of an Antigen Presentation Molecule for Vγ9Vδ2 T Cells

Human Vgamma9Vdelta2 T lymphocytes are activated by phosphoantigens provided exogenously or produced by tumors and infected cells. Activation requires a contact between Vgamma9Vdelta2 cells and neighboring cells. We previously reported a role for cell surface F1-adenosine triphosphatase (ATPase) in T cell activation by tumors and specific interactions between Vgamma9Vdelta2 TCRs and purified F1-ATPase. 721.221 cells do not express surface F1-ATPase and do not support phosphoantigen responses unless they are rendered apoptotic by high doses of zoledronate, a treatment that promotes F1-expression as well as endogenous phosphoantigen production. By monitoring calcium flux in single cells, we show in this study that contact of T cells with F1-ATPase on polystyrene beads can partially replace the cell-cell contact stimulus during phosphoantigen responses. Triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester, an adenylated derivative of isopentenyl pyrophosphate, can stably bind to F1-ATPase-coated beads and promotes TCR aggregation, lymphokine secretion, and activation of the cytolytic process provided that nucleotide pyrophosphatase activity is present. It also acts as an allosteric activator of F1-ATPase. In the absence of Vgamma9Vdelta2 cells, triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester immobilized on F1-ATPase is protected from nucleotide pyrophosphatase activity, as is the antigenic activity of stimulatory target cells. Our experiments support the notion that Vgamma9Vdelta2 T cells are dedicated to the recognition of phosphoantigens on cell membranes in the form of nucleotide derivatives that can bind to F1-ATPase acting as a presentation molecule.

Prolonged antiresorptive activity of zoledronate: A randomized, controlled trial

Annual intravenous administration of 5 mg of zoledronate decreases fracture risk over 3 years. The optimal dosing interval of 5 mg of zoledronate is not known. In order to determine the duration of the antiresorptive action of a single 5-mg dose of intravenous zoledronate, we conducted a 3-year double-blind, randomized, placebo-controlled trial in a volunteer sample of 50 postmenopausal women with osteopenia. The coprimary endpoints were the bone turnover markers β-C-terminal telopeptide of type I collagen (β-CTX) and serum procollagen type-I N-terminal propeptide (P1NP). Secondary endpoints were bone mineral density (BMD) at the lumbar spine, total hip, and total body. After 3 years, mean (95% confidence interval) levels of serum β-CTX and P1NP were 44% (27-60) and 40% (24%-56%) lower in the zoledronate group (p < .001 versus placebo for each marker). BMD was higher in the zoledronate group than in the placebo group by an average of 6.8% (4.6%-9.1%) at the lumbar spine, 4.0% (1.8%-6.3%) at the total hip, and 2.0% (0.9%-3.0%) at the total body (p < .001 for each skeletal site). Between-group differences in markers of bone turnover and BMD were stable from 12 to 36 months. These data demonstrate that the antiresorptive effects of a single 5-mg dose of zoledronate are sustained for 3 years; clinical trials to investigate the antifracture efficacy of dosing intervals longer than 1 year are justified.

A promising approach for treatment of tumor-induced bone diseases: Utilizing bisphosphonate derivatives of nucleoside antimetabolites

Despite palliative treatments, tumor-induced bone disease (TIBD) remains highly debilitating for many cancer patients and progression typically results in death within two years. Therefore, more effective therapies with enhanced anti-resorptive and cytotoxic characteristics are needed. We developed bisphosphonate-chemotherapeutic conjugates designed to bind bone and hydrolyze, releasing both compounds, thereby targeting both osteoclasts and tumor cells. This study examined the effects of our lead compound, MBC-11 (the anhydride formed between arabinocytidine (AraC)-5′-phosphate and etidronate), on bone tumor burden, bone volume, femur bone mineral density (BMD), and overall survival using two distinct mouse models of TIBD, the 4T1/luc breast cancer and the KAS-6/1-MIP1α multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04 μg/day; s.c.) reduced the incidence of bone metastases to 40% (4 / 10), compared to 90% (9 / 10; p = 0.057) and 100% (5 / 5; p = 0.04) of PBS- or similarly-dosed, zoledronate-treated mice, respectively. MBC-11 also significantly decreased bone tumor burden compared to PBS- or zoledronate-treated mice ( p = 0.021, p = 0.017, respectively). MBC-11 and zoledronate (0.04 μg/day) significantly increased bone volume by two- and four-fold, respectively, compared to PBS-treated mice ( p = 0.005, p < 0.001, respectively). In mice systemically injected with human multiple myeloma KAS-6/1-MIP1α cells, 0.04 and 4.0 μg/day MBC-11 improved femur BMD by 13% and 16%, respectively, compared to PBS ( p = 0.025, p = 0.017, respectively) at 10 weeks post-tumor cell injection and increased mean survival to 95 days compared to 77 days in mice treated with PBS ( p = 0.047). Similar doses of zoledronate also improved femur BMD ( p ≤ 0.01 vs PBS) and increased mean survival to 86 days, but this was not significantly different than in PBS-treated mice ( p = 0.53). These results demonstrate that MBC-11 decreases bone tumor burden, maintains bone structure, and may increase overall survival, warranting further investigation as a treatment for TIBD.

The effect of zoledronate during bone healing

BackgroundBisphosphonates have become the treatment of choice for a variety of bone diseases in which excessive osteoclastic activity is an important pathologic feature. However, inhibition of osteoclastic activity could lead to inhibition of remodeling during bone healing or repair. The objective of this study is to investigate the effect of zoledronate (the most potent bisphosphonate) in the biological process of bone healing.MethodsThirty immature male rabbits were divided into two groups (control and experimental) of 15 animals each. Both groups were submitted to fibular osteotomy. Only in the experimental group a single dose of zoledronate was administered. After 1, 2, and 4 weeks, animals of both groups were euthanized and the osteotomy site was histomorphometrically evaluated. The associated parameters analyzed were tissue volume (TV), fractional trabecular bone volume (BV/TV), fractional woven bone volume (WoV/TV), fractional periosteal fibrous volume (FbV/TV), and medullary fibrous volume (MaV/TV).ResultsThe first week of healing was characterized by small callus area (experimental group) and less periosteal fibrosis. The second week was characterized by a large quantity of woven bone and marked decrease in periosteal fibrosis in the two groups. In the control group there was also a significant increase in trabecular bone. The fourth week was characterized by increased amount of woven bone and trabecular bone in the experimental group; there was increased medullary fibrosis in the two groups, while there continued to be significantly less periosteal fibrosis in the experimental group.ConclusionsZoledronate does not prevent bone healing. However, the effect of zoledronate was characterized by accentuated stimulation of primary bone production and probably inhibition of remodeling, leading to retention of trabecular bone.

Longitudinal Cohort Study of Risk Factors in Cancer Patients of Bisphosphonate-Related Osteonecrosis of the Jaw

The reported incidence of osteonecrosis of the jaw (ONJ) ranges from 0.94% to 18.6%. This cohort study aimed to calculate the incidence of and identify the risk factors for ONJ in patients with cancer treated with intravenous zoledronate, ibandronate, and pamidronate. Data analyzed included age, sex, smoking status, underlying disease, medical and dental history, bisphosphonates (BP) type, and doses administered. Relative risks, crude and adjusted odds ratios (aORs), and cumulative hazard ratios for ONJ development were calculated. We included 1,621 patients who received 29,006 intravenous doses of BP, given monthly. Crude ONJ incidence was 8.5%, 3.1%, and 4.9% in patients with multiple myeloma, breast cancer, and prostate cancer, respectively. Patients with breast cancer demonstrated a reduced risk for ONJ development, which turned out to be nonsignificant after adjustment for other variables. Multivariate analysis demonstrated that use of dentures (aOR = 2.02; 95% CI, 1.03 to 3.96), history of dental extraction (aOR = 32.97; 95% CI, 18.02 to 60.31), having ever received zoledronate (aOR = 28.09; 95% CI, 5.74 to 137.43), and each zoledronate dose (aOR = 2.02; 95% CI, 1.15 to 3.56) were associated with increased risk for ONJ development. Smoking, periodontitis, and root canal treatment did not increase risk for ONJ in patients receiving BP. The conclusions of this study validated dental extractions and use of dentures as risk factors for ONJ development. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication; however, randomized controlled trials are needed to validate these results. Before initiation of a bisphosphonate, patients should have a comprehensive dental examination. Patients with a challenging dental situation should have dental care attended to before initiation of these drugs.

The Effect of Soaking Allograft in Bisphosphonate: A Pilot Dose-response Study

Long-term survival of uncemented total joint replacements relies on osseointegration. With reduced bone stock impacted morselized allograft enhances early implant fixation but is subject to resorption. We therefore asked whether soaking morselized allograft in different concentrations of bisphosphonate before impaction would enhance fixation. In each of 10 dogs, we implanted four unloaded titanium implants surrounded by a 2.5-mm gap into the proximal humerus, two implants in each humerus. The gap was filled with impacted morselized allograft soaked in saline or a low-, middle-, or high-dose bisphosphonate solution (0.005, 0.05, or 0.5 mg zoledronate/mL). At 4 weeks, the implants were evaluated by histomorphometric analysis and mechanical pushout test. The low dose of zoledronate increased new bone formation in the allograft but the high dose decreased new bone formation. The high dose of zoledronate resulted in the greatest inhibition of allograft resorption, whereas the low dose of zoledronate resulted in the lowest inhibition of allograft resorption. Implants surrounded allograft soaked in the low dose of zoledronate or saline had better fixation for all three mechanical parameters compared with implants surrounded by allograft soaked in the middle or high dose of zoledronate. These data suggest bisphosphonate may enhance osseointegration of allografted implants and emphasize the need for preclinical testing of antiresorptive therapies.

The Antiresorptive Effects of a Single Dose of Zoledronate Persist for Two Years: A Randomized, Placebo-Controlled Trial in Osteopenic Postmenopausal Women

In a previous study, 12 months after a single annual intravenous dose of 5-mg zoledronate, mean levels of bone resorption markers were 50% to 60% less than the placebo. In another trial, a placebo-controlled randomized study of osteopenic HIV-infected men, bone turnover markers stably decreased for up to 24 months after the second of two annual intravenous doses of 4 mg zoledronate. The duration of action of the currently recommended dose of 5 mg is not known. This double-blind, randomized, placebo-controlled trial, evaluated the duration of the antiresorptive action of a single dose of 5 mg intravenous zoledronate in a volunteer sample of 50 postmenopausal women with osteopenia over a period of 2-year at an academic research center. The participants were randomly assigned to receive a single intravenous infusion of either 5 mg zoledronate (n = 25) or placebo (n = 25). Biochemical markers of bone turnover measured included β-C-terminal telopeptide of type I collagen, N-telopeptide of type 1 collagen, procollagen type-I N-terminal propeptide and serum osteocalcin. Bone mineral density (BMD) of the lumbar spine, proximal femur, and total body was also measured. Compared to the placebo, at 12, 18, and 24 months after administration of the drug, the mean level of each of the 4 bone markers was decreased by at least 38% (range: 38%-64%) (P < 0.0001 for each marker). At 24 months, bone mineral density was higher in the zoledronate group by an average of 5.7% (95% confidence interval [CI], 4.0-7.4) at the lumbar spine; 3.9% (95% CI, 2.2-5.7) at the proximal femur; and 1.7% (95% CI, 0.8-2.5 at the total body (P < 0.0001 for each site). For all markers of bone turnover and BMD measured, between groups, differences were similar at 12 and 24 months. Treatment with zoledronate induced a mild secondary hyperparathyroidism throughout the study. These findings show that the antiresorptive actions of a 5-mg dose of zoledronate persist for 24 months and may be associated with anti-fracture efficacy. There was no evidence that the treatment effect changed over time.

A double-blinded, randomized controlled trial of zoledronate therapy for HIV-associated osteopenia and osteoporosis

To evaluate the efficacy of a single dose of intravenous zoledronate for the treatment of HIV-associated osteopenia and osteoporosis. A double-blinded, randomized, placebo-controlled, 12-month trial of 5 mg intravenous zoledronate dose to treat 30 HIV-infected men and women with osteopenia and osteoporosis. Following zoledronate or placebo infusions, participants were followed for 12 months on daily calcium and vitamin D supplements. Lumbar spine and hip bone density was assessed at baseline, 6 and 12 months. Biomarkers of bone metabolism were measured at baseline, 2 weeks, 3, 6, 9, and 12 months. Student's t-test and repeated measure analyses were used to evaluate bone density and bone marker changes over time. In the 30 HIV-infected individuals [men (27) and women (3)] in the trial, median T-scores at entry were -1.7 for the lumbar spine and -1.4 for the hip. Median CD4 cell count was 461 cells/microl, 93% had HIV-RNA viral loads less than 400 copies/ml, and 97% were taking antiretroviral medications. Bone density measured either absolutely or as sex-adjusted T-scores significantly improved in zoledronate recipients as compared with minimal changes in those receiving placebo. Bone resorption markers significantly decreased over the study period in the zoledronate recipients as compared with placebo controls. No acute infusion reactions were detected, but one patient developed uveitis, a recognized complication of zoledronate, which responded to therapy. In this small study, annual zoledronate appears to be a well tolerated and effective therapy for HIV-associated bone loss.

Bone structure and remodelling in stroke patients: Early effects of zoledronate

IntroductionWe have reported that after an acute stroke, intravenous zoledronate prevented bone loss in the hemiplegic hip. Participants from the trial also volunteered for trans-iliac bone biopsy, to assess the early effects of stroke and zoledronate on iliac bone remodelling. MethodsPatients with acute stroke were randomly assigned to a single intravenous dose of zoledronate 4 mg or placebo within 5 weeks of stroke. Biopsies from 14 patients (3 female, 11 male, mean age 71±11) were suitable for analysis. These were taken at mean 10 weeks (±2) post-stroke, and included 5 patients who had received zoledronate. Histomorphometry was performed on undecalcified sections using light and fluorescence microscopy. Static and dynamic indices of remodelling were compared to a local reference range from healthy controls. Osteoclasts and their precursors were identified on frozen sections using tartrate resistant acid phosphatase (TRAP) staining. Dual-energy x-ray absorptiometry (DXA) of the proximal femora was performed at baseline and 6 months later. ResultsThe eroded surface in cancellous bone (ES/BS) was significantly higher in stroke patients than controls (5.7% vs. ref 1.6%, p<0.0001). Although ES/BS did not differ between zoledronate and placebo-treated groups, there were significantly fewer osteoclasts and their precursors in zoledronate-treated individuals (p=0.023). Bone formation indices (osteoid surface, OS/BS and mineralising surface, MS/BS) were significantly lower in stroke patients than controls and although OS/BS was higher in the zoledronate group than the placebo group (p=0.033), MS/BS was not different (p=0.924). There were no differences between hemiplegic and unaffected sides for any histomorphometric parameter despite asymmetric reductions in hip bone mineral density (p=0.013). ConclusionStroke patients had higher resorption indices and lower bone forming surfaces than controls, consistent with uncoupling of bone remodelling. These findings are preliminary and a larger study is required to evaluate the contributions of gender, age and hemiplegic status to the remodelling imbalance. Zoledronate therapy was associated with a reduction in osteoclastic cell numbers consistent with its known mode of action in bone.

The Antiresorptive Effects of a Single Dose of Zoledronate Persist for Two Years: A Randomized, Placebo-Controlled Trial in Osteopenic Postmenopausal Women

Annual iv administration of 5 mg zoledronate decreases fracture risk. The optimal dosing interval of 5 mg zoledronate is not known. Our objective was to determine the duration of antiresorptive action of a single 5-mg dose of iv zoledronate. We conducted a double-blind, randomized, placebo-controlled trial over 2 yr at an academic research center, in a volunteer sample of 50 postmenopausal women with osteopenia. Intervention included 5 mg zoledronate. Biochemical markers of bone turnover and bone mineral density of the lumbar spine, proximal femur, and total body. Compared with placebo, zoledronate treatment decreased mean levels of each of four markers of bone turnover by at least 38% (range 38-45%) for the duration of the study (P < 0.0001 for each marker). After 2 yr, bone mineral density was higher in the zoledronate group than the placebo group by an average of 5.7% (95% confidence interval = 4.0-7.4) at the lumbar spine, 3.9% (2.2-5.7) at the proximal femur, and 1.7% (0.8-2.5) at the total body (P < 0.0001 for each skeletal site). Between-groups differences in markers of bone turnover and bone mineral density were similar at 12 and 24 months. Mild secondary hyperparathyroidism was present throughout the study in the zoledronate group. The antiresorptive effects of a single 5-mg dose of zoledronate are sustained for at least 2 yr. The magnitudes of the effects on markers of bone turnover and bone mineral density are comparable at 12 and 24 months. Administration of zoledronate at intervals of up to 2 yr may be associated with antifracture efficacy; clinical trials to investigate this possibility are justified.

Effects of Intravenous Zoledronate on Bone Turnover and BMD Persist for at Least 24 Months

The duration of the antiresorptive effects of the intravenous bisphosphonate, zoledronate, is not known. Recently, we reported that two annual 4-mg doses of zoledronate suppressed bone turnover and increased BMD in HIV-infected men over 24 mo. We set out to determine the persistence of these effects after two doses of zoledronate. Thirty-three HIV-infected men who completed a randomized trial of 4 mg annual zoledronate (n = 17) or placebo (n = 16) were studied for a further 12 mo, during which time no skeletal therapy was administered. Participants received calcium (400 mg/d) and vitamin D supplements (50,000 IU/mo) for the first 24 mo of the study only. Biochemical markers of bone turnover and BMD were measured every 6 mo. Bone turnover markers were stably suppressed at 24 and 36 mo (12 and 24 mo after the second annual dose of zoledronate, respectively). There were no significant within-group changes in urine N-telopeptide, serum C-telopeptide, and osteocalcin between 24 and 36 mo (p > 0.07), and at each time point, each of the turnover markers was significantly lower in the zoledronate group. There were also no significant between-group differences in the changes in BMD at each site between 24 and 36 mo (p > 0.5), and at each time point, BMD at each site was significantly higher in the zoledronate group. These results suggest that the antiresorptive effects of zoledronate last >12 mo and raise the possibility that zoledronate could be administered less frequently than annually. Randomized trials that address this issue should be performed.

Pharmacokinetics and pharmacodynamics of a single dose of zoledronate in healthy dogs

Pharmacokinetics and pharmacodynamics of a single dose of zoledronate in healthy dogs

Acute Renal Effects of Intravenous Bisphosphonates in the Rat

Bisphosphonates are potent osteoclast inhibitors that have been associated with renal toxicity following rapid intravenous administration of high doses, which was hypothesised to be due to precipitation of bisphosphonate aggregates or complexes in the kidney. Five studies were conducted in rats investigating the characteristics of bisphosphonate-related acute renal effects. These studies included single intravenous injections of the nitrogen-containing bisphosphonates (1) ibandronate (1-20 mg/kg), or (2) zoledronate (1-10 mg/kg); (3) a single nephrotoxic dose of the non-nitrogen-containing bisphosphonate, clodronate (2 x 200 mg/kg intraperitoneal injection); (4) a single low dose of ibandronate (1 mg/kg); (5) a single high dose of zoledronate (10 mg/kg). Clinical biochemistry and kidney histopathology were performed 1 and/or 4 days after bisphosphonate dosing. The proximal convoluted tubules were the primary target for renal injury. Tubular degeneration and single cell necrosis of the these tubules were observed with all three bisphosphonates on the fourth, but not the first day after dosing. Differences between the bisphosphonates in the type and/or localisation of the lesions were apparent. Granular deposits in the lumen of distal tubules were apparent with the highest dose of zoledronate (10 mg/kg). However, intraluminal debris was proteinaceous with no evidence of any precipitation of bisphosphonate, or formation of aggregates or complexes in the kidney. Generally, biochemical parameters of renal safety and urinary enzymes did not differ significantly from controls. In summary, bisphosphonate-related renal changes did not appear to be due to the precipitation, aggregation or complexation of bisphosphonate, and biochemical parameters of renal safety did not reliably detect this renal injury.

Bone Metabolic Effects of Single-Dose Zoledronate in Healthy Dogs

Zoledronate, an aminobisphosphonate with potent antiresorptive activity in bone, has the potential for treatment of malignant osteolysis and hypercalcemia in dogs. The purpose of this study was to evaluate the bone metabolic effects of a single dose of zoledronate in healthy dogs. Four skeletally mature, male, intact dogs received a 15-minute IV infusion of zoledronate at a dosage of 0.25 mg/kg. Urine N-telopeptide of type I collagen (NTx) excretion decreased significantly from baseline by 76, 63, 77, and 73% on days 7, 14, 21, and 28, respectively (P <. 0125). Serum bone-specific alkaline phosphatase (bALP) decreased significantly from baseline by 36 and 42% on days 21 and 28, respectively (P <. 0125). No changes were detected in indices of calcium homeostasis (ionized calcium, intact PTH, or urine calcium excretion). Single-dose IV zoledronate at 0.25 mg/kg appears to inhibit homeostatic osteolytic activity in healthy, skeletally mature dogs. Prospective studies should assess repeated-dose safety and activity in healthy and diseased animals of various age groups.

Bone Metabolic Effects of Single-Dose Zoledronate in Healthy Dogs

Zoledronate, an aminobisphosphonate with potent antiresorptive activity in bone, has the potential for treatment of malignant osteolysis and hypercalcemia in dogs. The purpose of this study was to evaluate the bone metabolic effects of a single dose of zoledronate in healthy dogs. Four skeletally mature, male, intact dogs received a 15-minute i.v. infusion of zoledronate at a dosage of 0.25 mg/kg. Urine N-telopeptide of type I collagen (NTx) excretion decreased significantly from baseline by 76, 63, 77, and 73% on days 7, 14, 21, and 28, respectively (P < .0125). Serum bone-specific alkaline phosphatase (bALP) decreased significantly from baseline by 36 and 42% on days 21 and 28, respectively (P < .0125). No changes were detected in indices of calcium homeostasis (ionized calcium, intact PTH, or urine calcium excretion). Single-dose i.v. zoledronate at 0.25 mg/kg appears to inhibit homeostatic osteolytic activity in healthy, skeletally mature dogs. Prospective studies should assess repeated-dose safety and activity in healthy and diseased animals of various age groups.

Zoledronate Inhibits Leukemia Growth in Bone Marrow and Synergizes with Imatinib Mesylate Against Ph+ Primary Leukemic Cells.

Imatinib mesylate has drastically changed Philadelphia chromosome positive (Ph+) leukemia treatment. However, remissions induced in advanced phase Ph+ leukemias tend to be short-lived even treated with imatinib. Combined therapy of imatinib with an agent which inhibits downstream signaling of BCR/ABL such as Ras is intriguing. Phase I studies of farnesyl transferase inhibitors (FTIs), which targeted farnesylation of Ras, with imatinib against Ph+ leukemias demonstrated limited combination effects. We previously reported that the third-generation bisphosphonates (BPs) zoledronate (ZOL) synergized with imatinib mesylate to inhibit Ph+ leukemia. BPs which inhibit both farnesylation and geranylgeranylation of Ras proteins may be more potent than FTIs. However, three important questions have remained unanswered to promote this attractive combination to a clinical trial. Concentrations of 20-30 μM ZOL are required in vitro to induce apoptosis in leukemic cell lines. However, peak serum concentrations after infusion of 4 mg ZOL were 1–2 μM. Therefore, it is important to investigate how ZOL achieves effective concentrations in vivo. The second is whether ZOL augments the effects of imatinib against not only cell lines but also primary cells from Ph+ leukemia patients. In addition, the safety of this combination therapy must be established, because the dose of ZOL used in our previous study was high compared with clinical doses administered for inhibition of bone lesions. To answer these questions, we herein investigated about the combination therapy of ZOL plus imatinib using NOD/SCID mice engrafted with primary Ph+ leukemic cells with or without mutations in the ATP binding site. ZOL inhibited the geranylgeranylation of Ras proteins of leukemic cells in bone marrow but not in peripheral blood, indicating that sufficient concentration of ZOL could be achieved in bone marrow. ZOL synergized with imatinib to enhance survival of mice engrafted with primary Ph+ leukemic cells without mutations and this combination was well-tolerated without any severe adverse effects. These findings suggest that ZOL inhibits leukemia growth in bone marrow and the combination of ZOL plus imatinib is a potential therapy for Ph+ leukemia patients.

Severe Osteomyelitis of the Jaws in Long Term Survivorsmultiple Myeloma Patients Treated with Biphosphonates.A New Clinical Entity.

Multiple Myeloma is a frequent and usually fatal lymphoproliferative disorder with a median survival of around 30 months.Supportive therapy includes monthly intravenous injections of biphosphonates as prevention, or therapy,of lytic bone disease.We report three cases of Multiple Myeloma patients who developed severe osteomyelitis of the jaws while receiving prolonged biphosphonate therapy.All three patients are very long survivors of Myeloma,being alive 6 to 12 years after diagnosis.They have been treated with biphosphonates for more than 4 years, receiving large doses of Pamidronate(3420 to 4680 mg) and lesser doses of Zoledronate(16 to 72 mg).Jaw infection was unprovoked in wo parients and was cused by dental extraction in the third.Diagnosis of osteomyelitis was confirmed by histology in all three patients, while in two we could demonstrate the presence of Actinomyces.Therapy with hyperbaric oxygen of osteomyelitis refractory to prolonged antibiotherapy, was curative in one patient. To the best of our knowledge, these are the first cases of osteomyelitis of the jaw reported in the literature in Myeloma patients treated with chronic administration of intravenous biphosphonates.Recent reports have alerted physicians of a '' growing epidemics'' of Pamidronate and Zoledronate induced avascular necrosis of the jaw, most of them provoked by teeth removal.Both of these biphosphonates have strong antiosteoclastic activity, and Zoledronate is antiangeogenic, all properties which contribute to the development of bone necrosis.Since the jaws are the only bones in the skeleton exposed to the external environment, the association of bone necrosis with secondary chronic infections may lead to osteomyelitis.Even though it is not possible to prove beyond doubt an etiological link between biphosphonate therapy and the occurrence of osteomyelitis of the jaws, the association of Myeloma with severe immunosupression, the very prolonged biphosphonate therapy in our three patients, and the localization to the jaw, are in favor of a clear relationship between therapy with Zolandronate, Pamidronate and osteomyelitis of the jaws. With the expected life prolongation of Myeloma patients due to recent therapeutic breakthroughs and the increasing use of antiangeogenic agents, it is crucial to be aware of the possibility of a rise in the number of osteomyelitis of the jaws in Myeloma patients.

The renal effects of minimally nephrotoxic doses of ibandronate and zoledronate following single and intermittent intravenous administration in rats.

Rapid, intravenous (i.v.) administration of high doses of bisphosphonates has been associated with acute renal toxicity. This controlled, preclinical study over 25 weeks investigated the potential for subclinical renal damage to accumulate to clinically relevant levels when minimally nephrotoxic doses of ibandronate (1 mg/kg) or zoledronate (1 or 3 mg/kg) were given intermittently, with a between-dose interval of 3 weeks, or as a single dose by i.v. injection. In rats, a single dose and intermittent dosing of ibandronate resulted in a similar incidence (one of six and two of six rats, respectively) and severity score (1.0 for both) of proximal tubular degeneration and single cell necrosis. No accumulation of histopathological renal damage occurred. However, intermittent dosing of zoledronate induced a higher incidence (six of six rats) and severity score (3.0) of renal damage compared with single dosing (four of six rats and 1.3, respectively). Accumulation of renal damage was also observed for a lower intermittent dose of zoledronate (1 mg/kg) that had not exhibited histopathological renal damage when given as a single 1 mg/kg dose. Biochemical parameters confirmed these histopathological findings. In summary, the results from this study indicate that administering ibandronate intermittently provides sufficient time for regeneration of potential subclinical renal damage.

Dosing regimens and main adverse events of bisphosphonates

The bisphosphonates pamidronate and clodronate are most often used in oncology. Newer, more potent compounds under study are ibandronate and zoledronate. The main route of administration is by intravenous infusion (1–2 hours for pamidronate) but oral formulations are or soon will be available for some bisphosphonates (clodronate, ibandronate) and shorter infusion times are being studied (zoledronate, ibandronate). After oral administration of aminobisphos-phonates, the main adverse event can be epigastric pain and esophagitis for which the current recommendations include swallowing 180 to 240 mL of water and remaining upright for 30 minutes after tablet ingestion. After intravenous administration, the main adverse events are injection site reaction and flu-like syndrome. Injection site reactions are seen in up to 6% of patients given pamidronate, and this figure is likely to be lower with ibandronate and zoledronate. Flu-like syndrome is seen in up to one third of patients given pamidronate, less with ibandronate, and no figure is yet available for zoledronate. Adverse effects on kidney function were only seen when using a high dose of zoledronate (8 mg over 5–15 minutes) and the current recommended dose is 4 mg given as a 15-minute infusion. Disadvantages of the oral route are poor absorption (<5%) and occasional digestive side effects. With protracted use the size and number of tablets required can reduce compliance. The advantage of oral administration is use on an outpatient basis and it may thus be the preferred route for patients on hormonal therapy and in the adjuvant setting. The main route of administration, however, is currently a 1- to 2-hour intravenous pamidronate infusion, often preferred for patients receiving chemotherapy. The disadvantage of the latter is the need for an appropriate hospital environment. Shorter infusion times are being studied with newer compounds. Intravenous administration is the preferred route for patients receiving chemotherapy. Equivalent intravenous doses to achieve similar success rates in normalizing serum calcium levels are approximately 90 mg, 4 mg, and 2 mg for pamidronate, ibandronate, and zoledronate, respectively. The expectation from the new, more potent compounds is for more convenient therapeutic schemes leading to increased patient compliance and improvements in the reduction of the skeletal morbidity rate and hopefully increase in survival rate.

Current and future directions in medical therapy: hypercalcemia.

Tumor-induced hypercalcemia (TIH) is essentially due to a marked stimulation of osteoclast-mediated bone resorption. An inhibition of bone formation and an enhanced tubular reabsorption of calcium play an important contributory role. These factors explain why serum calcium often rises rapidly in cancer patients and why high doses of bisphosphonates are needed to normalize bone resorption and to overcome the contributory role of the kidney. The author provides a short review of clinical trials in hypercalcemic cancer patients, with an emphasis on the most recent trials. Rehydration and bisphosphonates now constitute the standard treatment of TIH. A single-day 1500-mg infusion of clodronate achieves normocalcemia in approximately 80% of the cases. Clodronate also can be given by subcutaneous infusion that can be particularly useful in the palliative setting. A dose of 90 mg of pamidronate achieves normocalcemia in more than 90% of the patients and has a longer-lasting effect than clodronate. Newer more potent bisphosphonates, such as ibandronate and zoledronate, may improve these results, and they certainly will simplify the therapeutic schemes. Ibandronate at the dose of 6 mg normalizes serum calcium in more than 75% of the patients with moderate or severe hypercalcemia. Of note, the same doses of pamidronate and ibandronate, repeated monthly for 1-2 years, have been shown to substantially reduce the skeletal morbidity rate in normocalcemic patients with tumor bone disease. Even lower doses of zoledronate, the most potent bisphosphonate tested so far, are able to correct TIH when administered as a 30-minute infusion. Bisphosphonates have become the standard treatment for cancer hypercalcemia. Success is achieved in more than 90% of the cases. Other classes of compounds are being tested for their antiosteoclastic activity, and animal studies suggest that osteoprotegerin could be as efficient and act faster than bisphosphonates.