Clodronate Group Research Articles

Long-term effects of clodronate on growing rat bone.

For evaluating the long-term effects of the bisphosphonate compound clodronate on the rat skeleton, 100 female rats were given subcutaneous injections of clodronate at doses of 0 (vehicle), 4 (low), or 12 (high) mg/kg per week, or 50 mg/kg every fourth week (cyclical). The treatment was started at 3 months of age and was continued for 6 months. The mechanical strength of bones was studied by torsion of the tibia, three-point bending of the femur, axial compression of the femoral neck, and compression of a lumbar vertebra. Quantitative histomorphometric variables were determined from distal femur and lumbar vertebra, and variables reflecting bone metabolism were measured in serum and urine. Bone mass, indicated by ash weight of the tibia, was increased with the low and high clodronate doses compared with the vehicle. The maximum load in vertebra compression was increased with the low dose of clodronate compared with the vehicle, whereas changes in other variables concerning bone strength were not significant. In bone histomorphometry, clodronate treatment induced more pronounced changes in cancellous bone volume in distal femur than in lumbar vertebra, the differences not being statistically significant between the groups at either site, however. The longitudinal growth rate of the femur, measured by double-fluorochrome labeling for 1 week at the end of the treatment period, was significantly decreased in the high-dose clodronate group compared with the other groups. Serum values for calcium, tartrate-resistant acid phosphatase, and alkaline phosphatase did not differ between the groups. However, serum osteocalcin was significantly lower in the high-dose group compared with the vehicle group. Urinary calcium, hydroxyproline, and hydroxylysylpyridinoline were decreased at all the clodronate doses administered. In conclusion, the beneficial effects of long-term clodronate treatment on bone mass and strength were observed at the lowest dose used. A high dose of clodronate decreased bone growth rate, which was, however, not reflected in the mechanical quality of bone.

51 Clodronate improves bone mineral density in early breast cancer patients. A randomized study

The aim of the study was to investigate whether clodronate will improve bone mineral density (BMD) in pre- and postmenopausal patients without skeletal metastases. <h3>Patients and Methods</h3> 268 pre- (PRE) and postmenopausal (POST) early breast cancer patients were randomized to clodronate (orally 1.6 g a day) or control groups for 3 years. PRE were treated with adjuvant chemotherapy and POST with antiestrogen for 3 years. BMD was measured on the lumbar vertebrae L1–4 and the femoral neck before treatment and after two years. <h3>Results</h3> POST: Lumbar bone mass decreased 0.4% in control group and increased 0.9% in clodronate group (<i>P</i>=0.008), in femoral neck the increase of bone mass was 0.3% in control group and 1.4% in clodronate group (<i>P</i>=0.04). PRE: Lumbar bone mass decreased in both groups 2.7% in control group and 0.8% in clodronate group (<i>P</i>=0.008). Femoral neck bone mass decreased 0.9% in control group and increased 0.4% in clodronate group (<i>P</i>=0.03). <h3>Conclusion</h3> Clodronate significantly prevents bone loss in lumbar vertebrae and femoral neck in PRE and POST early breast cancer patients. In POST clodronate with antiestrogen significantly improves BMD in lumbar vertebrae and femoral neck. In PRE the bone loss was most markedly prevented in those who developed rapid bone loss after chemotherapy.

Measurement of bone resorption by strontium excretion in prelabelled rats.

The body handles strontium (Sr) in a similar way to calcium (Ca) in that Sr is absorbed by the gut, concentrated in bone and excreted in urine and feces. In this study, rats were labelled with Sr during growth and later subjected to various treatments affecting bone resorption and Sr excretion was measured during and after treatment. Six weeks old Wistar rats were repeatedly s.c. injected with SrCl2. After a period of 2 weeks after the last Sr injection the rats were subjected to various treatments. Sr clearance was then measured weekly for 2 weeks. In the first experiment, the Sr labelled rats were sham-operated (sham) or ovariectomized (ovx) and urine collected afterwards. Sham rats were either treated with 4 daily s.c. clodronat injections at the beginning of the urine sampling, fed a low Ca diet (0.08% Ca) during the second sampling week or injected with saline. Urinary Sr excretion was decreased in the clodronate group during the first sampling week and increased in the Ca depleted group during feeding the low Ca diet. Sr excretion by ovx rats was similar to the sham control. In the second experiment, the effect of high-dose treatment with 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) or clodronate on bone resorption induced by Ca depletion was assessed by Sr output in urine and feces. Sr labelled rats were fed a low Ca diet and daily injected with 24,25(OH)2D3 or clodronate for 14 consecutive days. Clodronate significantly decreased Sr output during both sampling weeks. Treatment with 24,25(OH)2D3 resulted in an increased Sr output indicating an increase in bone resorption.

Cyclical clodronate is effective in preventing postmenopausal bone loss: A comparative study with transcutaneous hormone replacement therapy

An investigative study was carried out for 2 years involving 124 randomly selected early postmenopausal women with spine bone mineral density (BMD) below the mean value of a normal premenopausal subject. After random division into three groups, the first 42 patients were treated with transcutaneous 17-beta-estradiol (50 micrograms daily), the second 42 were treated with cyclical intravenous clodronate (200 mg/month iv infusion), and the third group of 40 (controls) was left untreated. After 2 years, the total drop in BMD within the control group was more than 7% as opposed to the values of -0.14% +/- 0.93 in the estradiol group and 0.67% +/- 0.84 in the clodronate group. A change in BMD of < 1% was considered satisfactory, and this result was obtained in 32% of the controls, in 79% of the estradiol group where the percentage change in BMD moderately correlated with serum estradiol levels (r = 0.399), and in 90% of the clodronate-treated patients, in whom the percentage change in BMD inversely correlated with basal values of markers of bone turnover. Both estrogen and clodronate prevent postmenopausal bone loss. The response to transcutaneous hormone replacement therapy may be influenced by transcutaneous absorption and by a lower sensitivity to estrogen. Response to cyclical clodronate seems to be influenced by the rate of bone turnover. An interdosage interval ranging from 2-4 weeks appears suitable for most patients.

Oral continuous clodronate in the prevention of early postmenopausal bone loss

The aim of this study was to investigate the effects of 12 months of continuous oral clodronate therapy on bone metabolism in healthy early postmenopausal women. A total of 137 evaluable healthy early postmenopausal women were given 400 mg/d oral clodronate continuously for 12 months. Thirty age-matched healthy early postmenopausal women were included as controls. Measures of lumbar L 2–L 4 and ultradistal radius bone mineral density (LBD and URBD, respectively) and bone turnover biochemical analyses were performed at baseline and after 6 and 12 months of therapy. After 12 months, statistically significant increases in LBD (+1.78 ± 0.87%) and in URBD (+4.23 ± 0.91%) were shown in the clodronate group versus the control group (−4.6 ± 0.96% and −2.80 ± 0.51%, respectively; P < 0.01). At the same time, significant decreases in serum osteocalcin (−4.2 ± 1.5%), free calcium (−2.5 ± 0.7%), and urinary hydroxyproline (−9.7 ± 3.8%) levels were observed in the treated group ( P < 0.01 vs baseline). Within the clodronate group, patients were divided into two subgroups on the basis of biochemical indexes indicating a normal (subgroup N) or high (subgroup H) bone turnover. Statistically significant differences between subgroups N and H were observed after 6 and 12 months in the percent change in ultradistal forearm mineral density, serum alkaline phosphatase, and urinary hydroxyproline excretion. Thus 12 months of oral clodronate treatment was shown to be effective in preventing bone loss in early postmenopausal women, and the drug was particularly effective in high bone turnover conditions.

Prospective Randomized Trial of Dichloromethylene Bisphosphonate (Clodronate) in Patients with Multiple Myeloma Requiring Treatment. A Multicenter Study

<i>Background</i>: Characteristic features of multiple myeloma are bone resorption, osteoporosis and osteolytic lesions. Bisphosphonates can inhibit osteoclast activity and bone resorption. In this controlled randomized multicenter trial the effect of the bisphosphonate clodronate on the progression of bone involvement in multiple myeloma was evaluated. <i>Patients and Methods</i>: 170 patients with multiple myeloma requiring treatment and with bone involvement were recruited and randomized. All patients received 15 mg/m² i.v. melphalan on day 1 and 60 mg/m2 p.o. predisone on days 1-4 every 4 weeks. Patients randomized to the bisphosphonate arm received 1,600 mg clodronate p.o./day for 1 year. Bone response was evaluated on the basis of X-ray controls of the skeleton at baseline, 6, and 12 months staging. In addition chemotherapy response, blood chemistry, cytology, pain, and analgesic drug consumption were documented. <i>Results</i>: After one year of treatment there was a higher bone response in the clodronate group (13%) when compared to the control group (6%, n.s.). The difference was mainly due to the change of the osteolytic lesions. Hypercalcemia was observed more often in the control group. The number of progressive sites was lower in the clodronate group (mean 0.49 vs. 0.66, result after one year, p = 0.09). The bone resorption index was significantly reduced in the clodronate group, but not in the control group. A reduction of pain and analgesic consumption was observed under clodronate treatment.

Subgroup and cost‐benefit analysis of the Finnish multicentre trial of clodronate in multiple myeloma

Osteolytic lesions and pathological fractures are the major problems in the clinical management of multiple myeloma. We previously reported the main results of a randomized, controlled multicentre trial in 350 Finnish patients with multiple myeloma. All patients received standard melphalan-prednisolone treatment and were randomized to receive either clodronate 2.4 g daily or a placebo for 24 months. The proportion of patients with progression of osteolytic bone lesions was twice as high in the placebo group as in the clodronate group (24.0% v 12.0%, P = 0.026). The purpose of the present study was to investigate factors associated with the progression of osteolytic lesions and to identify subgroups of patients who would benefit most from clodronate treatment. In univariate logistic regression analysis, including treatment (placebo, clodronate), sex, age, pain index, serum calcium and creatinine, myeloma stage, number of osteolytic lesions at baseline, and number of vertebral fractures at baseline as independent variables and the progression of osteolytic lesions as a dependent variable, only the treatment with a placebo was associated with the progression of osteolytic bone lesions. Separate analyses with respect to the progression of osteolytic bone lesions were carried out in the following subgroups: male v female, < or = 64 v > 64 years, stage I v stage II-III myeloma, no osteolytic lesions at baseline versus osteolytic lesions at baseline, no vertebral fractures at baseline versus vertebral fractures at baseline. and a 50% treatment response to cytotoxic drugs versus no treatment response to cytotoxic drugs. The treatment with clodronate delayed the progression of osteolytic lesions similarly in these subgroups, with the exception of a subgroup of patients who did not have a 50% treatment response to cytotoxic drugs. The treatment with clodronate did not significantly increase treatment costs. We conclude that the treatment effect of clodronate seems to be independent of sex and age of the patients, the stage of myeloma, and the severity of bone lesions at diagnosis, but not of treatment response to cytotoxic drugs.

Clodronate increases the calcium content in fracture callus. An experimental study in rats.

Eighty-eight rats underwent intramedullary pin fixation and fracture of both tibiae. Half of the animals were given clodronate 50 mg/kg s.c. weekly. Clodronate treatment did not affect the growth of fibrocartilage or the endochondral and membranous new bone formation. The regaining of tensile load capacity of fractured bone remained unaffected by the drug. Calluses were remodeled to lamellar bone in both groups. However, although the total area invaded by mineralized tissue in callus remained unaffected by the drug, the areas of hematopoietic bone marrow tissue within mineralized callus were observed to be markedly smaller in clodronate-treated animals than in controls. The calluses in the clodronate group were significantly heavier and contained more calcium at 2 months after fracture than those in the controls.

Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma

Osteolytic lesions and pathological fractures are common in multiple myeloma. Because clodronate inhibits osteoclastic resorption, we did a randomised, controlled trial in 350 patients from 23 hospitals. All patients received standard melphalan-prednisolone, and were randomised to receive clodronate 2·4 g daily or placebo for 24 months. The proportion of patients with progression of osteolytic bone lesions was twice as high in the placebo group (n = 168 at baseline) than in the clodronate group (n = 168 at baseline) in an intention-to-treat analysis (24 vs 12%, p=0·026). Progression of vertebral fractures was lower in the clodronate group, but the difference was not significant (30 vs 40%). Serum calcium and urinary calcium excretion decreased significantly in both groups, but the changes were greater in the clodronate group. The percentage of patients feeling no pain increased more in the clodronate group (from 24 to 54%, p<0·001) than in the placebo group (from 29 to 44%, p<0·01). Side-effects were similar in both groups. We conclude that clodronate is an effective and safe adjunct in the management of multiple myeloma. The drug delays osteolytic bone lesions, reduces the degree of hypercalcaemia and hypercalciuria, and decreases pain.

Use of Dichloromethylene Diphosphonate in Metastatic Bone Disease

Dichloromethylene diphosphonate (clodronate), a new compound, has powerful activity against osteoclasts and has been used successfully to treat hypercalcemia associated with cancer. We studied its effects on calcium balance in patients with malignant osteolytic lesions. Ten normocalcemic patients with advanced metastatic bone disease or myeloma were evaluated in a baseline 20-day balance and calcium kinetic study. They were then randomized to a clodronate or placebo regimen, treated intravenously for two weeks and orally for a month, and finally reevaluated in another 20-day balance and kinetic study, conducted while they were still receiving treatment. The results show that both calcium balance and calcium absorption increased from base line in the clodronate group and that these changes were significantly different from those in the placebo group (mean change [+/- S.D.] in calcium balance [clodronate vs. placebo], 203.8 +/- 140.1 vs. -65.2 +/- 98.8 mg [5.1 +/- 3.5 vs. -1.6 +/- 2.5 mmol] of calcium per day, P less than 0.01; change in calcium absorption, 158.8 +/- 158 vs. -38.2 +/- 96.0 mg [4.0 +/- 4.0 vs. -1.0 +/- 2.4 mmol] per day, P less than 0.05). There was a marginal decrease in bone resorption in the clodronate group and no change in bone accretion. Our results suggest that clodronate may be a useful adjuvant in managing metastatic bone disease.