Frieder Bauss

Ibandronate: A Clinical Pharmacological and Pharmacokinetic Update

Ibandronate is a potent nitrogen‐containing bisphosphonate. It has a strong affinity for bone mineral and potently inhibits osteoclast‐mediated bone resorption. Ibandronate is effective for the treatment of hypercalcemia of malignancy, metastatic bone disease, postmenopausal osteoporosis, corticosteroid‐induced osteoporosis, and Pagets disease. Oral ibandronate is rapidly absorbed (tmax < 1 hour), with a low bioavailability (0.63%) that is further reduced (by up to 90%) in the presence of food. Ibandronate has a wide therapeutic index and is not metabolized and, therefore, has a low potential for drug interactions. Given its metabolic stability, ibandronate is eliminated from the blood by partitioning into bone (40%‐50%) and through renal clearance (CLR ∼60 mL/min). The CLR of ibandronate is linearly related to creatinine clearance. The sequestration of ibandronate in bone (VD > 90 L) results in a multiphasic elimination (t1/2 range ∼10–60 hours), characterized by the slow release of ibandronate from the bone compartment. The potency of ibandronate and its sequestration into bone allow ibandronate to be developed as oral and intravenous injection formulations that can be administered with convenient extended between‐dose intervals.

Ibandronate for prevention of femoral head deformity after ischemic necrosis of the capital femoral epiphysis in immature pigs.

BACKGROUND Femoral head deformity is the most serious sequela of ischemic necrosis of the immature femoral head. The purpose of this study was to determine if a highly potent antiresorptive agent, ibandronate, can inhibit bone resorption during the repair of the infarcted femoral head and thus alter the repair process. We hypothesized that preservation of the trabecular framework by inhibiting osteoclastic bone resorption would minimize the development of deformity in a piglet model of ischemic necrosis. The effect of ibandronate on long-bone growth was also assessed. METHODS Ischemic necrosis of the right femoral head was produced in twenty-four piglets by placing a ligature tightly around the femoral neck. The animals were divided into three groups according to whether they received saline solution, prophylactic treatment, or post-ischemia treatment. The contralateral, untreated femoral heads from the animals that had received saline solution served as the normal control group. At eight weeks, the femoral heads were assessed for deformity with radiography and for trabecular bone indices with histomorphometry. Also, the length of femur from the untreated side was measured on the radiographs and compared among the groups. RESULTS Radiographic assessment showed that the epiphyseal quotient, determined by dividing the maximum height of the osseous epiphysis by the maximum diameter, was better preserved in the prophylactic (p < 0.001) and post-ischemia (p = 0.02) treatment groups than in the group treated with saline solution. Histomorphometric assessment also showed that the trabecular bone indices were better preserved in the prophylactic and the post-ischemia treatment groups than in the group treated with saline solution (p < 0.01). The mean femoral length on the untreated side of the animals treated with ibandronate was reduced compared with the length on the untreated side of the animals that had received saline solution (p </= 0.01). CONCLUSIONS Ibandronate preserves the trabecular structure of the osseous epiphysis and prevents femoral head deformity during the early phase of repair of ischemic necrosis in the piglet model.

Intermittent intravenous administration of the bisphosphonate ibandronate prevents bone loss and maintains bone strength and quality in ovariectomized cynomolgus monkeys.

Using a clinically relevant regimen, this study investigated the effects of treatment with ibandronate, a highly potent nitrogen-containing bisphosphonate, on bone loss, biochemical markers of bone turnover, densitometry, histomorphometry, biomechanical properties, and bone concentration in aged ovariectomized monkeys. Sixty-six female cynomolgus monkeys, aged 9 years and older, were ovariectomized (OVX) or sham operated. Intravenous (iv) bolus injections of ibandronate at 10, 30, or 150 microg/kg or placebo were administered at 30-day intervals (corresponding to intervals of 3 months in humans), starting at OVX, for 16 months. OVX significantly decreased bone mass at the lumbar spine, proximal femur, femoral neck, and radius and increased bone turnover in a time-dependent manner, as assessed by dual energy X-ray absorptiometry, peripheral quantitative computed tomography, or histomorphometry. Ibandronate iv bolus injections administered at 30 microg/kg every 30 days prevented osteopenia induced by estrogen depletion. OVX-induced increases in bone turnover (as determined by activation frequency, bone formation rate, and biochemical markers of bone turnover, including urinary N-telopeptide and deoxypyridinoline excretion and serum values for osteocalcin and bone-specific alkaline phosphatase) were suppressed on treatment, and bone mass, architecture, and strength were preserved at clinically relevant sites. Treatment with high-dose (150 microg/kg/dose) iv bolus injections of ibandronate further increased bone mass and improved bone strength at both the spine and femoral neck, without adversely affecting bone quality. In contrast, treatment with a 10 microg/kg/dose only partially prevented the OVX-induced effects. These data support the potential for the long-term administration of ibandronate by intermittent iv bolus injections in humans to prevent osteoporosis and improve bone quality at clinically relevant sites.

Intermittent Ibandronate Preserves Bone Quality and Bone Strength in the Lumbar Spine After 16 Months of Treatment in the Ovariectomized Cynomolgus Monkey

The dose‐dependent effect of ibandronate treatment on bone mass and architecture was assessed in a large animal study of OVX monkeys using μCT for quantitative bone morphometry and biomechanical testing for measures of bone strength. The study showed that intermittent ibandronate preserved lumbar spine bone quality and strength in these animals after 16 months of treatment.

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.

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.

Site‐specific human breast cancer (MDA‐MB‐231) metastases in nude rats: Model characterisation and in vivo effects of ibandronate on tumour growth

Animal models are important tools to study the development of bone metastases and to evaluate strategies for their prevention and treatment. We here describe a new model in which tumour inoculation is achieved by injection of cancer cells into the femoral artery. This approach results in the development of multiple osteolytic lesions in the distal femora and proximal tibiae within 18 days after inoculation, with a success rate of 95–100% and no additional comorbidity. In untreated animals, osteolyses expanded continuously at a growth rate of 4.7–8.2 mm2/4 days, causing extensive destruction of resident bone structures by the tumour, significant loss of tibial bone density and a transient rise in urinary bone resorption markers. Continuous daily treatment with ibandronate (10 μg/kg) inhibited further growth of fully established metastases and reduced the mean osteolytic growth rate to 0.03 mm2/4 days. In lesions <6 mm bisphosphonate treatment resulted in a negative growth rate (−0.33 to −0.81 mm2/4 days). When ibandronate was started 3 days prior to tumour cell inoculation, the development of osteolytic lesions was substantially reduced (take rate only 17%) and bone density and structure were mostly preserved. We conclude that the intra‐arterial approach used in this new model of metastatic bone disease results in site‐specific osteolytic lesions with high take rates, steady tumour growth and no additional morbidity. While serial bone marker assessments did not prove useful to monitor osteolytic growth, our studies provide in vivo evidence that ibandronate treatment induces tumour remission by reversal of tumour growth.

Effect of daily and intermittent use of Ibandronate on bone mass and bone turnover in postmenopausal osteoporosis: A review of three Phase II studies

BACKGROUND Oral bisphosphonates are well established for the treatment and prevention of postmenopausal osteoporosis; however, they are poorly absorbed from the gastrointestinal (GI) tract and have been associated with GI adverse events. Thus, current dosing guidelines recommend that the patient not eat or lie down for at least 30 minutes after taking oral bisphosphonates, a requirement that is inconvenient and may be associated with reduced compliance. The drawbacks of these dosing requirements may be overcome either by reducing dosing frequency or by using alternative routes of administration. OBJECTIVE Ibandronate is a potent nitrogen-containing bisphosphonate that can be given orally or IV, daily or intermittently, with a between-dose interval of up to 3 months. This article presents the results of published Phase II trials of the efficacy and safety profile of oral and IV ibandronate administered daily or intermittently to postmenopausal women with low bone mass. METHODS MEDLINE was searched through January 2002 to identify all published Phase II clinical studies of oral and IV ibandronate in the treatment of post-menopausal osteoporosis. RESULTS In the 3 Phase II studies identified, marked reductions in biochemical markers of bone resorption (50%-70%) and bone formation (40%-50%) were seen to a similar and statistically significant extent with oral ibandronate 2.5 mg/d (P<0.001), oral ibandronate 20 mg QOD given for 12 doses at the start of each 3-monthly period (P<0.001), and injections of ibandronate 2 mg IV given every 3 months (P<0.01). All treatment regimens produced comparable significant increases in bone mineral density at the lumbar spine (P<0.01) and hip (P<0.05). Ibandronate was well tolerated when administered both orally and as an IV injection. CONCLUSIONS In these Phase II studies, oral or IV ibandronate, administered continuously or intermittently, reduced markers of bone turnover, significantly increased bone mineral density, and was well tolerated in the treatment of osteoporosis in postmenopausal women. The data from these studies provided the rationale for further investigation of ibandronate in larger longer-term Phase III studies evaluating its potential as an efficacious and flexible alternative to existing bisphosphonate regimens.

Retention, distribution, and effects of intraosseously administered ibandronate in the infarcted femoral head.

The local distribution, retention, and effects of intraosseous administration of ibandronate in the infarcted femoral heads were studied. Intraosseous administration effectively delivered and distributed ibandronate in the infarcted femoral heads and decreased the femoral head deformity in a large animal model of Legg‐Calve‐Perthes disease.

Preclinical evidence for nitrogen-containing bisphosphonate inhibition of farnesyl diphosphate (FPP) synthase in the kidney : Implications for renal safety

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and play an important role in the treatment of osteoporosis, metastatic bone disease, and Paget disease. However, nephrotoxicity has been reported with some bisphosphonates. Nitrogen-containing bisphosphonates directly inhibit farnesyl diphosphate (FPP) synthase activity (mevalonate pathway) and reduce protein prenylation leading to osteoclast cell death. The aim here was to elucidate if this inhibition also occurs in kidney cells and may directly account for nephrotoxicity. In an exploratory study in rats receiving zoledronate or ibandronate an approximate 2-fold increase in FPP synthase mRNA levels was observed in the kidney. The involvement of the mevalonate pathway was confirmed in subsequent in vitro studies with zoledronate, ibandronate, and pamidronate, using the non-nitrogen containing bisphosphonate clodronate as a comparator. In vitro changes in FPP synthase mRNA expression, enzyme activity, and levels of prenylated proteins were assessed. Using two cell lines (a rat normal kidney cell line, NRK-52E, and a human kidney proximal tubule cell line, HK-2), ibandronate and zoledronate were identified as most cytotoxic (EC50: 23/>1000 microM and 16/82 microM, respectively) and as the most potent inhibitors of FPP synthase (IC50; 1.6/7.4 microM and 0.5/0.7 microM, respectively). In both cell lines, inhibition of FPP synthase activity occurred prior to a decrease in levels of prenylated proteins followed by cytotoxicity. This further supports that the mechanism responsible for osteoclast inhibition (therapeutic effect) might also underlie the mechanism of nephrotoxicity.