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The aim of this placebo-controlled study was to determine whether once-weekly clodronate could prevent osteoporosis in patients with arthritis at the start of corticosteroid therapy. One hundred sixty-three patients, 18 to 90 years of age, with rheumatoid or psoriatic arthritis, were randomly assigned to receive either clodronate (100 mg im/week) plus calcium and vitamin D (1000 mg and 800 UI, respectively) or calcium and vitamin D alone. Patients had started therapy with prednisone or its equivalent within the previous 100 days and had bone mineral density <2.5 SD below mean young normal values at the lumbar spine or femoral neck. The primary outcome was the difference between the two treatment groups at months 12, 24, 36, and 48 in the mean percentage change from baseline in the bone mineral density of the lumbar spine, femur (neck and total), and total body. Secondary measurements included changes in the stiffness index evaluated by ultrasound measurements and the rate of new vertebral fractures. The bone density and stiffness did not change significantly in the clodronate plus calcium and vitamin D group, whereas it declined significantly in the calcium plus vitamin D group. The difference between treatment groups at 48 months in the mean change from baseline was 8.78 +/- 1.4% for the lumbar spine (P < 0.01), 7.31 +/- 1.12% for the femoral neck (P < 0.01), 7.92 +/- 1.93% for the trochanter (P < 0.01), 8.39 +/- 1.80% for total femur (P < 0.01), 6.94 +/- 1.09% for total body (P < 0.01), and 9.38 +/- 2.21% for stiffness of os calcis (P < 0.01). Depending on the skeletal regions evaluated, 85 to 98% of patients treated with clodronate had a densitometric change lower than the lowest significant densitometric difference. One hundred percent of patients treated with calcium plus vitamin D had a densitometric decrease greater than the lowest significant difference. The relative risk of vertebral fractures and multiple vertebral fractures in the clodronate group compared to the calcium plus vitamin D group was 0.63 (0.35-0.98, 95% CI) and 0.25 (0.15-0.91, 95% CI), respectively. We concluded that pulsatory administration of im clodronate once weekly is a safe therapy for preventing corticosteroid induced osteoporosis in patients with arthritis.

Several studies have shown that treatment with bisphosphonates can reduce the pain associated with different painful diseases. In a previous study we demonstrated that in mice two bisphosponates, clodronate and pamidronate, had an antinociceptive effect under acute conditions not related to bone processes, after in vein (iv) or intracerebroventricular (icv) injection. The present study tested the time-dependent antinociceptive action of clodronate and pamidronate in comparison with that of acetylsalicylic acid (ASA) and morphine after iv and icv injection using the tail-flick test in acute and chronic treatment. The effects of clodronate on other measures of animal behaviour were also evaluated. In the tail-flick test, administration of clodronate iv produced an antinociceptive effect that was greater than that of ASA and statistically significant up to 16 h; pamidronate iv showed a significant antinociceptive effect for only 6 h. Clodronate and pamidronate icv showed an increase in tail-flick latency time that was significant and lasted for 16 and 6 h, respectively, while morphine produced an antinociceptive effect for 24 h. In the test we found significant differences between male and female mice in the latency time values but not in the length of the analgesic effect. In the chronic treatment paradigm, clodronate produced a significant increase of the tail-flick latency after the first injection. The analgesic effect increased up to 50% after 5 days of treatment. Significant analgesic effects were still present after 3, 7, and 14 days from the end of treatment. Clodronate did not produce any significant behavioural effects in the Rota-rod test, pentobarbital-induced sleeping time, and locomotor activity cage. These data indicate that clodronate presents a central and peripheral prolonged antinociceptive effect, without any behavioural side effects.

Clodronate (disodium clodronate tetrahydrate) is a bisphosphonate used in the treatment of hypercalcemia and osteolysis due to malignancy. Like all bisphosphonates, clodronate has low and variable oral bioavailability. The purpose of this study was to examine the absolute bioavailability of clodronate from two different oral doses. Thirty-one healthy young volunteers participated in this open, randomized, three-period, single-dose, cross-over study. The absolute bioavailability was calculated from the area under the serum clodronate-time curve in 48 h (AUC(0-48 h)) after administration of 800 or 1600 mg (Bonefos 400 mg capsules) of oral clodronate, or 30 mg (Bonefos 60 mg/mL infusion concentrate) of intravenous clodronate. The maximum concentration of clodronate in serum (C(max)), the time to maximum concentration (t(max)), the elimination half-life (t(1/2)), and the cumulative amount of clodronate excreted into urine in 48 h (Ae(0-48 h)) were also determined. The geometric mean of the absolute bioavailability of 800 mg of clodronate was 1.9% and that of 1600 mg 2.1%. The difference in the absolute bioavailability of these two doses was statistically nonsignificant. All treatments were well tolerated, and the AE profiles were similar in the different treatment groups. There were no serious adverse events during the study., (Copyright 2002 Elsevier Science Inc.)

Because of the low and variable bioavailability of bisphosphonates and the huge effect of food on their gastrointestinal absorption, it is of utmost importance to know the optimal timing of drug intake in relation to food intake. We investigated the effect of time on the bioavailability of clodronate when the drug was administered 2, 1, or 0.5 h before breakfast, with breakfast, or 2 h after breakfast (in the middle of a 4-h fast). The study was conducted as a single-center, open, balanced, randomized, crossover pharmacokinetic study in 31 healthy subjects aged 21 to 34 years. The volunteers participated in five different sessions with 800 mg of oral clodronate, and these sessions were separated by washout phases, each for at least 1 week. The primary pharmacokinetic variables were the area under the serum concentration time curve in 24 h (AUC(0-24)) for clodronate and the maximal concentration of clodronate in serum (C(max)). Clodronate was absorbed rather similarly when taken in the morning on an empty stomach 2, 1, or 0.5 h before breakfast, but because the best absorption occurred (as expected) when the drug was taken 2 h before breakfast, this scheme served as the reference treatment. As evaluated by area under the serum concentration time curves, the dose-breakfast interval of 1 h scarcely reduced absorption from the reference treatment level (relative absorption 91%, p = 1.0). Compared with the reference treatment, clodronate was absorbed with 69% efficacy (p = 0.65) when breakfast followed only 0.5 h later. The dose-breakfast intervals of 0.5 and 1 h did not differ significantly from each other (p = 0.85). Absorption was, however, only 34% (p < 0.0001) of the optimum when the drug was taken 2 h after breakfast, and only 10% of optimal when clodronate was taken with breakfast (p < 0.0001). In conclusion, it can be recommended to take Bonefos capsules in the morning on an empty stomach at least 0.5 h before breakfast.

The aim of the study was to compare the effects on bone mass and turnover of continuous vs. intermittent clodronate administration on 120 postmenopausal women (average age 61 years) with low bone mass (femoral neck bone mineral density [BMD] of at least -1 SD or more, T-score), with another 30 women as a control group. Participants were given 1800 mg of clodronate every 6 months over 2 years using different treatment patterns: a) two continuous regimens, consisting of a daily oral dose of 400 mg or 100 mg every 10 days by intramuscular injection, the latter being considered continuous because the interval between injections is shorter than the time employed by each bone remodelling unit to complete the resorption phase of a remodelling cycle; and b) two intermittent regimens, consisting of 1800 mg every 6 months administered either as a single 18-h intravenous infusion or by separate infusions of 300 mg over 6 consecutive days. All women, including those in the control group, received calcium and vitamin D supplementation. After 2 years, continuous clodronate regimens caused an increase in BMD both at lumbar spine and proximal femur (L(1-4) BMD = 3.07% and 2.69%; femoral neck = 2.12% and 2.09%, respectively, with intramuscular and oral regimens). Intermittent clodronate administration was associated with a small increase or a stabilization in bone mass (L(1-4) BMD = 0.53% and 1.22%; femoral neck = 0.30% and 0.77%, respectively, with 1- and 6-day intravenous infusion regimens). From the 12th month, changes in spine and femoral neck BMD after continuous regimens were statistically different compared with that obtained with intermittent ones. Twenty-five of the 150 women (16.7%) discontinued the study before the end of the 2-year follow-up, but of these, only 7 dropped out because of adverse events related to the treatment itself. To summarize, intermittent clodronate administration could be a suitable option for the prevention of osteoporosis.

Long-term daily administration of oral bisphosphonates has been effective in the treatment of postmenopausal osteoporosis, but the duration, mode and cost of the therapy may sometimes affect patient compliance. In Italy, the bisphosphonate clodronate is also available via the intramuscular (i.m.) route of administration, and the present study was performed to test its efficacy in postmenopausal osteoporosis. Ninety osteoporotic postmenopausal women were enrolled in a randomized, controlled 3 year study. The diet of all patients was adjusted to provide 1200-1300 mg of calcium daily, eventually by administration of supplements. Patients were randomly assigned to no therapy (30 patients) or to receive clodronate 100 mg i.m. either every 2 weeks (30 patients) or 1 week (30 patients). The i.m. injection caused substantial pain at the site of injection, which led to treatment withdrawal in almost 50% of the patients receiving weekly dosing. In control patients, a progressive, slow decline in spine and femoral bone mineral density (BMD), which became statistically significant at the end of the second year of observation, was observed. In the patients given weekly i.m. clodronate, spinal BMD rose by 3.8% (+/-7.3 SD) within 6 months. A slight, nonsignificant increase was observed thereafter, such that, at the completion of 3 years of observation, the mean gain was 4.5% (+/-6.3). In the patients treated with injections of 100 mg of clodronate every two weeks the increase in BMD was somewhat lower and slower, becoming significant only at month 24 (2.9+/-4.6%). In none of the two active groups was the femoral neck BMD changed significantly during the 3 years of the study. A significant increase in trochanter and Ward's triangle BMD was observed at month 12 only in the patients on the highest dose of clodronate. In both groups treated, the hip BMD changes were significantly different from those observed in control patients. The biochemical markers of bone turnover were suppressed in both clodronate groups. These results indicate that intermittent i.m. clodronate administration can provide clinically relevant benefits to skeletal bone density in osteoporotic postmenopausal women, but the in situ pain may limit its extensive use.

Recent in vitro findings suggest that bisphosphonates, potent inhibitors of osteoclastic bone resorption, may also have a direct action on osteoblasts. The purpose of this study was to search for potential effects of etidronate and alendronate on the formation of early and late osteoblastic cell precursors by measuring the number of colony-forming units for fibroblasts (CFU-F) and colony-forming units for osteoblasts (CFU-OB) in murine and human bone marrow cultures. In murine marrow cultures, etidronate (10(-5) to 10(-9) mol/L) significantly stimulated the formation of CFU-F with a maximal effect at 10(-5) mol/L (mean increase over control values+/-SD: 106+/-17%;p < 0.001), whereas alendronate had a biphasic effect, being stimulatory at concentrations below 10(-7) mol/L (78+/-5%; p < 0.001), and inhibitory at higher doses. The formation of CFU-OB was also inhibited by both bisphosphonates at the highest concentrations (10(-5) mol/L and 10(-6) mol/L), but it was significantly stimulated at lower concentrations (from 10(-7) to 10(-9) mol/L for etidronate and 10(-7) to 10(-10) mol/I, for alendronate; p < 0.001). In human bone marrow cultures, alendronate (10(-8) to 10-(12) mol/L) increased CFU-F formation with a maximal effect at 10(-10) mol/L (161+/-12 %; p < 0.01). CFU-OB formation, observed only in the presence of dexamethasone (10(-8) mol/L), was markedly stimulated by alendronate at the above concentrations with a maximal increase at 10(-10) mol/L (133+/-34%; p < 0.001). The in vivo short-term effects of bisphosphonates on the formation of early osteoblast precursors were also studied in bone marrow cultures from young female mice treated with weekly subcutaneous injections of etidronate (0.3, 3, and 30 mg/kg) or alendronate (0.3, 3, and 30 microg/kg) and from aging female mice treated with the two lowest doses of both drugs. After 1 month of treatment, etidronate (0.3 and 3 mg/kg) and alendronate (0.3 and 3 microg/kg) significantly increased the number of CFU-F colonies in the bone marrow from young and old animals, whereas the highest dose of both drugs had no effect in young mice. Our results, together with previously reported observations of bone-forming effects in osteoporosis, suggest that bisphosphonates may have, in vivo, a potentially relevant influence on cells of the osteoblastic lineage, distinct from their inhibitory action on osteoclasts.

Clodronate is a novel drug used for inhibiting osteoclastic activity. The aim of the present double-blind study was to evaluate the efficacy and tolerability of clodronate (Leiras, Finland) in corticosteroid-induced bone loss among asthmatic patients. Seventy-four adult patients (41 women and 33 men, mean age 57.3 years) having a long history (mean 8.1 years) of oral and inhaled corticosteroid therapy were randomized to four parallel treatment groups: clodronate 800, 1600, or 2400 mg/day, or an identical placebo. The bone mineral density (BMD) of the lumbar spine (L2-4), femoral neck, and trochanter were assessed using dual-energy X-ray absortiometry at entry, 6 months, and 12 months. The baseline BMDs did not differ significantly between the study groups. In the lumbar spine, the mean BMD increased significantly between the baseline and 12-month visit in the clodronate groups of 1600 and 2400 mg/day, 2.6% (0.02 g/cm2, p < 0.02) and 3.0% (0.03 g/cm2, p < 0.01), respectively, but not in the placebo and clodronate 800 mg/day groups. The test for a linear trend (BMD percent change for L2-4) at 12 months was significant (p < 0.02), indicating a dose response to clodronate. The mean BMD values of the femoral neck increased significantly in the 2400 mg/day group, 4.3% (0.03 g/cm2, p < 0.0001), as well as in the trochanter region 2.8% (0.02 g/cm2, p < 0.02). Gastric irritation was the most common adverse effect noted on a clodronate dose of 2400 mg/day. We conclude that oral clodronate is effective in preventing bone loss or increasing bone mass in asthmatic patients having a long history of continuous peroral and inhaled corticosteroid administration.

The high prevalence of bone metastases in breast cancer and the risk that spinal and femoral osteoporosis may add further morbidity provide a rationale for bisphosphonate therapy in patients with skeletal metastases from mammary carcinoma. We investigated the effects of oral clodronate given during 9 months, with a 24-month follow-up, on bone mineral density (BMD), on biochemical markers of bone remodeling, and on osseous complications in 67 women with documented relapsing breast cancer, aged 58.7 +/- 1.5 years (x +/- SEM). Patients with active cancer disease were randomly allocated to two groups, with or without clodronate treatment (1600 mg/day, orally). Twenty-six women considered in complete remission (52.4 +/- 2.4 years) were also studied. Expressed in deviation from gender- and age-matched normals (z score), base-line BMD at the levels of lumbar spine (LS), femoral neck (FN), and midfemoral shaft (FS) was +0.10 +/- 0.22 vs. -0.12 +/- 0.25, +0.03 +/- 0.19 vs. -0.54 +/- 0.24, and +0.08 +/- 0.14 vs. -0.02 +/- 0.22, in patients with active breast cancer and in subjects in remission, respectively. After 9 months of treatment, fasting urinary calcium to creatinine ratio was lower (0.26 +/- 0.04 vs. 0.40 +/- 0.04 mmol/mmol creatinine, p < 0.02) and serum osteocalcin was stabilized (-2.1 +/- 1.1 vs. +7.0 +/- 3.3 micrograms/L, as compared with pretreatment values, p < 0.02), in the clodronate-treated group. The rate of osseous complications (pathological fracture, hypercalcemic episode, scintigraphic or radiological evidence of metastasis development, chemo- or radiotherapy for bone disease progression) was 28.8 events per 100 patient-year in the clodronate-treated group vs. 39.0 in controls, and 31.5 vs. 40.5, after 9 and 15 months of follow-up, respectively. In 15 women without evident LS bone metastasis (7 clodronate-treated and 8 controls), LS BMD increased in the clodronate-treated group by +5.2 +/- 2.5% vs. -0.3 +/- 1.4%, and +8.1 +/- 4.7 vs. -0.9 +/- 1.7, after 10.3 +/- 0.4 and 17.3 +/- 1.2 months, respectively (p < 0.01), as compared with pretreatment values. These results indicate that clodronate treatment decreased bone turnover and attenuated cancer-related bone morbidity. In addition, clodronate increased LS BMD in apparently unaffected bone of women with relapsing breast cancer.

We studied 60 women with postmenopausal bone loss randomly allocated to the following treatments: Group 1 (20 patients), no treatment; Group 2 (20 patients), clodronate 400 mg daily by mouth for 30 consecutive days, followed by 60 days of no treatment; Group 3 (20 patients) oral calcitriol 2 mcg by mouth for 5 days and oral clodronate 400 mg daily for additional 25 days, followed by 60 days of no treatment. The therapeutic cycles were repeated four times in the 12-month study period. In the 36 treated patients of Groups 2 and 3 who completed the study period we observed a progressive and significant increase in lumbar bone density both at 6 and 12 months of therapy, without significant differences between the two treatment protocols (+3.88 +/- 0.65%, P < 0.001 and +3.21 +/- 0.89%, P < 0.005 in Groups 2 and 3, respectively, at the end of the study). In contrast, there was a progressive and significant decline of bone mineral density in untreated patients (-2.34 +/- 0.49%, P < 0.001). After 12 months serum calcium values in treated subjects were higher than in untreated patients (P < 0.05). Serum phosphate was raised only in Group 2, mean values being higher after 12 months than before treatment (P < 0.05); parathyroid hormone (PTH) declined in all treated patients, the fall being significant in Group 2 (P < 0.02). No important side effects were observed with treatment and no patient withdrew because of these. We conclude that cyclical low dose clodronate therapy induced a gain in lumbar spine bone mass in patients with postmenopausal osteoporosis.

The bisphosphonate clodronate has been widely used in the treatment of hypercalcaemia and osteolytic bone metastases. It can normalize plasma calcium in most hypercalcaemic, rehydrated cancer patients when increased bone resorption is the prevailing disturbance of calcium metabolism. When given intravenously either as a single infusion or as repeated daily administrations, serum calcium levels fall to normal 3-5 days after the onset of therapy. Long-term maintenance treatment must be adjusted individually since relapse appears to depend upon the tumour type, the degree of malignancy and any anticancer therapy. In patients in whom increased tubular calcium reabsorption is the prevailing disturbance of calcium metabolism, the effect of clodronate on plasma calcium is incomplete, despite the normalization of bone resorption. This type of therapeutic response can be reproduced experimentally in bisphosphonate-treated animals receiving a constant infusion of parathyroid hormone-related peptide, a peptide isolated from various tumour types including lung, kidney, breast and neuroendocrine tumour of the pancreas. In patients having a good response to clodronate, the fall in plasma calcium is accompanied by an increase in the calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3. This homeostatic response probably explains why hypocalcaemia occurs rarely in clodronate-treated patients. No serious side-effects of treatment have been reported. Clodronate appears to be a safe and effective treatment for the hypercalcaemia of malignancy, where increased bone resorption is the major mechanism disturbing the homeostasis of extracellular calcium.

Complications of breast cancer involving the skeleton include hypercalcaemia, bone pain and fracture. These complications arise because of progressive osteolysis which is in turn dependent on the activation of osteoclasts by tumour and host tissues. Clodronate is a powerful inhibitor of osteoclastic bone resorption which led us to evaluate its potential in metastatic breast cancer. When given intravenously it lowers serum calcium in the majority of hypercalcaemic patients. A convenient regimen is 600 mg iv as a single dose infused over several hours. We have additionally shown in a double-blind cross-over study that this regimen also has a significant effect on bone pain. This had led us to assess the longer term effects of clodronate by mouth in a prospective double-blind study of patients with established skeletal metastases. These studies are not yet complete but the agent appears to prevent hypercalcaemia and trends are emerging which indicate that the incidence of bone pain and fractures may also decrease.

We have studied the administration of both oral and intravenous dichloromethylene diphosphonate (Cl2MDP) in patients with hypercalcemia and/or hypercalciuria due to increased bone resorption in the setting of multiple myeloma (N = 16) or chronic lymphocytic leukemia (N = 1). The effectiveness of 1600 mg of oral Cl2MDP twice daily was studied in 14 subjects with refractory multiple myeloma, active osteolytic disease and either persistent hypercalciuria (urinary Ca greater than 200 mg per g creatine on a low Ca intake) or hypercalcemia (serum Ca greater than 11.0 mg/dl), in a double-blind, placebo-controlled, 16 week-long trial. Of the 12 patients who received Cl2MDP (2 died in the placebo phase), 11 had marked reductions in urinary calcium (P less than 0.001), which fell into the normal range in 9. Urinary hydroxyproline decreased significantly in 8. Eight of the 11 responders also appeared to have decreases in bone pain associated with Cl2MDP therapy. Similar results were found when this protocol was used in a study of 10 women with breast cancer metastatic to bone. In addition, intravenous Cl2MDP was studied in 12 patients with hypercalcemia of malignancy, of whom 2 had multiple myeloma and 1 had chronic lymphocytic leukemia (CLL) associated with extensive osteolytic bone destruction. We gave 2.5 mg/kg on the first treatment day and 5 mg/kg daily thereafter for up to six more days. Serum calcium fell to normal after a mean of four days in the three patients with hematologic malignancies as well as in eight of the nine with solid tumors. Both urinary Ca and OHP also declined significantly.(ABSTRACT TRUNCATED AT 250 WORDS)