The Use of Bone Markers in a 6-Week Study to Assess the Efficacy of Oral Clodronate in Patients with Metastatic Bone Disease

Biochemical markers of bone metabolism are strongly associated with skeletal complications in metastatic bone disease. The bisphosphonate clodronate reduces skeletal morbidity by inhibiting bone resorption. This study investigated the use of bone markers to assess the efficacy of oral clodronate across a range of clinically relevant doses. There were 125 patients with metastatic bone disease randomized to daily oral clodronate (800, 1,600, 2,400 and 3,200 mg) or placebo in a double-blind, multicenter study. Urinary N-terminal telopeptide of type I collagen (U-NTX), serum C-terminal telopeptide of type I collagen (S-CTX), urinary calcium (U-Ca), and bone alkaline phosphatase were measured weekly for a 6-week treatment period. Doses of ≥1,600 mg clodronate produced mean reductions of >40% in U-NTX, S-CTX and U-Ca, all significantly different from placebo (P = 0.0015, 0.001, 0.0036, respectively), after 6 weeks. Evaluation of least significant changes in markers suggested that the commonly used 1,600 mg dose was most appropriate for breast cancer patients. However, this dose was suboptimal for other (mainly prostate cancer) patients, who showed better response to 2,400 mg. The number of adverse events in the treatment arms was not significantly different from that in placebo, but a higher number of patients had diarrhea in the 3,200 mg arm and withdrew from the study. This trial is the first to explore the dose-response relationship of clodronate in oncology using specific markers of bone turnover. It has confirmed that the 1,600 mg dose is safe and effective for breast cancer patients but may be suboptimal for the other tumors studied.     

Effects of 4-year treatment with once-weekly clodronate on prevention of corticosteroid-induced bone loss and fractures in patients with arthritis: evaluation with dual-energy X-ray absorptiometry and quantitative ultrasound

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.     

Clodronate increases mineralization of callus after Colles' fracture: a randomized, double-blind, placebo-controlled, prospective trial in 32 patients

In a randomized study of 32 postmenopausal women with a Colles' fracture, we studied whether 8 weeks of treatment with clodronate, a bisphosphonate, could prevent posttraumatic osteopenia. The patients were treated with a plaster splint for 4 weeks. The bone mineral density (BMD) of the forearm bones was measured at 2 levels with dual-energy x-ray absorptiometry (DEXA) 2, 6 and 12 months after the fracture. At 2 months, in the clodronate group, there was a median 53% higher BMD in the fracture region of the radius than in the uninjured radius. In the placebo group, we found a 33% higher BMD in the fractured radius at that level than in the uninjured radius. This increase in BMD of the fractured radius, caused by clodronate, was statistically significant. At 12 months, the BMD of the fracture side had been reduced by 17% and 12%, respectively, at that time it was still significantly increased in the clodronate group alone. In the ulna at the same level, we found no significant changes in BMD in either group on either side at any time. At 2 months, at the level between the distal and middle thirds, in the fractured radius, the median BMD was 7% lower in the clodronate group and 6% lower in the placebo group than in the uninjured radius. Although the reduction in BMD at that level was significant, there was no difference between the two treatment groups. At this level, the ulna on the fractured side showed a similar pattern, with a 5% lower BMD in the clodronate group and a 4% lower BMD in the placebo group. This osteopenia showed a small but significant progression on the fractured side after 6 and 12 months.     

Clodronate increases mineralization of callus after Colles' fracture: A randomized,double-blind,placebo-controlled,prospective trial in 32 patients

In a randomized study of 32 postmenopausal women with a Colles' fracture, we studied whether 8 weeks of treatment with clodronate, a bisphosphonate, could prevent posttraumatic osteopenia. The patients were treated with a plaster splint for 4 weeks. The bone mineral density (BMD) of the forearm bones was measured at 2 levels with dual-energy x-ray absorptiometry (DEXA) 2, 6 and 12 months after the fracture. At 2 months, in the clodronate group, there was a median 53% higher BMD in the fracture region of the radius than in the uninjured radius. In the placebo group, we found a 33% higher BMD in the fractured radius at that level than in the uninjured radius. This increase in BMD of the fractured radius, caused by clodronate, was statistically significant. At 12 months, the BMD of the fracture side had been reduced by 17% and 12%, respectively, at that time it was still significantly increased in the clodronate group alone. In the ulna at the same level, we found no significant changes in BMD in either group on either side at any time. At 2 months, at the level between the distal and middle thirds, in the fractured radius, the median BMD was 7% lower in the clodronate group and 6% lower in the placebo group than in the uninjured radius. Although the reduction in BMD at that level was significant, there was no difference between the two treatment groups. At this level, the ulna on the fractured side showed a similar pattern, with a 5% lower BMD in the clodronate group and a 4% lower BMD in the placebo group. This osteopenia showed a small but significant progression on the fractured side after 6 and 12 months.     

The effect of hemodialysis, vitamin D metabolites and renal transplantation on the skeletal demineralization associated with renal osteodystrophy: a computerized histomorphometric analysis

Twenty-three patients with end-stage renal failure treated by hemodialysis or transplantation were followed for up to 10 years. Sequential full thickness iliac crest bone biopsies were obtained to assess the effects on bone disease of hemodialysis, treatment with 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] and 24,25-dihydroxycholecalciferol [24,25-(OH)2D3] and renal transplantation. The biopsies were analyzed by a computerized histomorphometric technique which allowed accurate measurements of calcified bone and osteoid areas. Serum aluminum and parathyroid hormone concentrations were also monitored. Hemodialysis was associated with a loss of calcified bone and an increase in osteoid areas. The progressive bone loss was arrested but not reversed following treatment with either 1,25-(OH)2D3 or 24,25-(OH)2D3. Osteoid area was unchanged or reduced following treatment with 1,25-(OH)2D3 in all but three patients who had serum aluminum concentrations in excess of 5 mumol/l. 24,25-(OH)2D3 was not effective in reducing osteoid area, and combined treatment with 1,25 and 24,25-(OH)2D3 had no effect beyond that expected with 1,25-(OH)2D3 alone. Bone biopsies showed loss of calcified bone and an increase in osteoid areas one year and more after successful renal transplantation in five patients. Nineteen of the 23 patients developed serum aluminum concentrations greater than 3 mumol/l, probably because of the use of oral aluminum hydroxide as a phosphate binding agent. In these patients serum parathyroid hormone concentrations greater than 600 pg/ml appeared to prevent the development of osteopenia.     

Effects of Short-Term Treatment with Clodronate on Parameters of Bone Metabolism and Their Diurnal Variation

The goal of the present study was to answer the question whether the diurnal variation of markers of bone turnover is abolished by inhibition of osteoclasts by bisphosphonates and to assess the effects of short-term treatment with clodronate on parameters of calcium and bone metabolism. Nine healthy, postmenopausal women, all aged 68 years, were studied before and after oral administration of clodronate, first 800 mg daily for 2 weeks and then 1600 mg daily for 2 weeks. During the two-study sessions of 24 hours, the subjects received exactly similar meals and were recumbent from 10:00 p.m. to 6:00 a.m. Blood was sampled every 2 hours and urine was collected in 4-hour aliquots. On each study occasion, three markers of bone resorption (ICTP, serum type-I collagen carboxyterminal telopeptide; F-Pyr, urinary-free pyridinoline; and NT_x, crosslinked N-telopeptide of type I collagen) and one marker of bone formation (PICP, serum type I procollagen carboxyterminal propeptide) showed a diurnal variation; only that of NT_x was lessened by treatment with clodronate. Mean area under curve (AUC) values for the 24-hour study periods decreased by 41% (P= 0.0002) and 4.7% (P= 0.016) for urinary NT_x and F-Pyr, but remained unchanged for serum ICTP (P= 0.41) and PICP (P= 0.99). Treatment with clodronate decreased mean AUC for the serum concentration of total calcium by 1.4% (P= 0.030) and that for the urinary excretion of calcium by 33% (P= 0.021). Mean AUC for serum-intact PTH increased by 19% (P= 0.004). We conclude that short-term treatment with clodronate lowers serum and urine calcium levels and causes compensatory hyperparathyroidism. Treatment also clearly decreases the urinary excretion of NT_x and lessens its diurnal variation. As assessed by sensitive markers such as NT_x, the nocturnal rise in bone resorption is greatly blunted by inhibition of osteoclasts with bisphosphonates. Received: 13 October 1995 / Accepted: 3 May 1996     

Clodronate treatment of established bone loss in cardiac recipients: a randomized study

BACKGROUND: Bone loss has been reported as a complication after heart transplantation (HTx), and the increase in bone fractures is an effective problem. Treatment of osteoporosis has obtained mixed results. In this study we evaluate the effect of treatment with an oral bisphosphonate. METHODS: Sixty-four patients with low mineral density 6 months after HTx were randomized as follows: Group A received oral clodronate (1600 mg/day in two divided doses), and Group B received placebo. Every patient was also treated with 2000 mg/day of oral calcium carbonate. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry at the lumbar spine, 1/3 and 1/10 of the distal nondominant forearm before and after 12 months of treatment. Laboratory tests were performed at 3, 6, and 12 months of treatment. RESULTS: All patients demonstrated manifest bone loss 6 months after HTx compared with normal non-HTx controls (P=0.0001). After 1 year of clodronate therapy, BMD at the lumbar spine increased from 0.77+/-1.4 g/cm(2) to 0.86 g/cm(2) (P=0.02). Laboratory tests did not show any significant variation, except for the bone isoenzyme of alkaline phosphatase, which showed a significant decrease after 1 year of treatment. The incidence of new fractures was 9.3% in the placebo group and 0% in the clodronate group. Therapy was well tolerated without impact on graft function. CONCLUSIONS: One year of clodronate therapy induced a significant increase in BMD at the lumbar spine in our HTx patients. Treatment was well tolerated without onset of new bone fractures.     

Decreased Periprosthetic Bone Loss in Patients Treated with Clodronate: A 1-Year Randomized Controlled Study

The efficacy of clodronate to reduce bone loss around uncemented stems after total hip arthroplasty (THA) was evaluated. Ninety-one patients operated with uncemented THA were randomized to receive either intramuscular clodronate at a dose of 100 mg weekly for 12 months or no treatment. Periprosthetic and contralateral bone mineral density (BMD) scans were performed and biochemical markers of bone turnover measured at baseline and at 3, 6, and 12 months. At month 12, with the exception of Gruen zones 4 and 5, patients treated with clodronate showed less bone loss at all zones, reaching statistical significance (P < 0.05) in Gruen zones 2 and 6 (difference of 6.6 and 5.9%, respectively). Analysis of data according to gender revealed sex-related differences in bone loss and efficacy of treatment. After 12 months, the difference in bone loss between treated and untreated women in five out of seven Gruen zones ranged from 6.2 to 13.3% (SS at zones 2 and 6), whereas comparison between treated and untreated men showed no BMD differences in all zones (P > 0.05). Median percent changes in serum levels of markers of bone metabolism by gender were consistent with BMD changes. A 1-year treatment with intramuscular clodronate determined a significant reduction of bone loss after THA. This was mainly attributed to its greater efficacy in the female population, which is at higher risk for bone loss. This observation suggests the need for the characterization of high-risk subjects as potential candidates for prevention strategies.     

Effect of clodronate on fracture healing in denervated rats

The effect of clodronate on healing of the fracture of osteopenic bone was studied in rats. A total of 165 female rats (14 ± 1 weeks, 216 ± 2 g) were divided into five fracture groups (n = 30), and a neurectomized group (n = 15). Osteopenia (op) was induced by right sciatic neurectomy 4 weeks before the fracture. Nonosteopenic (nop) rats were not operated. A closed prepinned diaphyseal fracture of the right femur was done by three-point bending method both to op and nop rats, and the left femur served as an unoperated control. All the fracture groups were divided into treatment (clodronate 10 mg/kg/day sc) and control (saline sc) groups, and the administration was continued throughout the study. The op rats were killed 2, 4, 8, and 12 weeks and nop rats 8 weeks after the fracture. Fracture healing was examined by x-ray and bone-bending strength. Neurectomy reduced bone strength (p < 0.01) at 4 weeks. Clodronate did not affect the bending strength of healing callus of op rats at 2, 4, 8, or 12 weeks after fracture, but reduced the strength of healing callus in nop rats (p < 0.05) at 8 weeks. Radiologic callus width increased in clodronate-treated groups both in op (8 and 12 weeks, p < 0.001) and nop rats (8 weeks, p < 0.05) when compared with saline-treated groups. Clodronate did not affect normal bone strength.

In conclusion, clodronate did not affect the bending strength of op fracture nor the strength of the control bones. The remodeling of the fracture was delayed with clodronate.     

The 'oral 1,25-dihydroxyvitamin D3 pulse therapy' in hemodialysis patients with severe secondary hyperparathyroidism

Many hemodialysis patients are still suffering from secondary hyperparathyroidism although 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been used to treat renal osteodystrophy for the last two decades. The main reason for its failure to correct the secondary hyperparathyroidism is that in patients, hypercalcemia occurs before adequate parathyroid hormone (PTH) suppression is obtained when a large daily dose of 1,25(OH)2D3 is started. In this study, the oral dose of 1,25(OH)2D3 (4.0 micrograms) was administered only twice a week at the end of hemodialysis ('oral 1,25(OH)2D3 pulse therapy'), in 19 patients with severe secondary hyperparathyroidism. Serum immunoreactive PTH started to decrease after 6 weeks of therapy, and the original level of 41.2 +/- 7.24 was reduced to 24.4 +/- 6.12 ng/ml by the end of the 6-month therapy (p less than 0.001). Serum alkaline phosphatase also was reduced by 64.4%. Three out of 19 patients suffered from hypercalcemia during the 4th month of therapy. Calcium supplement given to 6 other patients with severe secondary hyperparathyroidism did not lower serum PTH levels significantly after 6 weeks of therapy, although serum calcium levels increased and were sustained above 10 mg/dl for the last 5 weeks. These findings strongly suggest that the suppressive effect of the oral 1,25(OH)2D3 pulse therapy was attained by a direct action of 1,25(OH)2D3 on the parathyroid gland rather than by its ability to elevate serum calcium levels. In conclusion, the oral 1,25(OH)2D3 pulse therapy effectively lowered PTH levels in hemodialysis patients who cannot tolerate large daily doses of 1,25(OH)2D3.     

Risedronate and Pamidronate Treatment in the Clinical Management of Patients with Severe Paget’s Disease of Bone and Acquired Resistance to Bisphosphonates

The aim of this study was to evaluate the efficacy and safety of risedronate and pamidronate in 30 patients (mean age = 57.86 ± 8.90 years) with severe Pagets disease of bone (PDB), showing acquired resistance to intravenous (IV) clodronate treatment. Fifteen patients were treated with oral risedronate (30 mg/day for 8 weeks). Treatment was repeated in patients without evidence of PDB remission [total alkaline phosphatase (tALP) serum levels in the normal range] at day 120. Fifteen patients were treated with IV pamidronate (30 mg/day for 3 days). Pamidronate treatment (60 mg/day for 3 days) was repeated in patients without evidence of PDB remission at day 120. At day 60, a significant decrease in tALP serum levels was obtained in all pagetic patients. At day 360, 13 (86.6%) patients treated with risedronate achieved PDB remission, 9 patients during the initial treatment and 4 after retreatment. Two patients showed a significant decrease in tALP serum levels without clinical remission after two risedronate treatments. At the same time, 12 (80%) patients treated with pamidronate achieved PDB remission, 6 patients during the first treatment and 6 after retreatment. Three patients showed a significant decrease in tALP serum levels but no clinical remission after two pamidronate courses. Two of these patients showed a relapse during the study. The incidence of minor side effects and transient hyperparathyroidism related to bisphosphonate treatment was significantly lower after risedronate therapy. In patients with resistant PDB, oral risedronate therapy has comparable efficacy to IV pamidronate with a lower incidence of treatment-related side effects.     

Serum tartrate-resistant acid phosphatase 5b in monitoring bisphosphonate treatment with clodronate: a comparison with urinary N-terminal telopeptide of type I collagen and serum type I procollagen amino-terminal propeptide

Osteoclastic tartrate-resistant acid phosphatase activity in serum (S-TRACP 5b) was measured in postmenopausal women ( n =59, mean age 56.1 years) with vertebral osteopenia before and during 2-year treatment with an 800-mg daily dose of clodronate, with a non-amino bisphosphonate. Changes in TRACP 5b were compared with those in urinary excretion of type I collagen amino-terminal telopeptide (U-NTX), corrected for creatinine excretion, a well-established marker of bone resorption, and to serum type I procollagen amino-terminal propeptide (S-PINP), a marker of bone formation. Marker changes 1 year after start of treatment were correlated with changes in bone mineral density (BMD). The least significant change (LSC) for each marker and BMD was calculated from values for subjects receiving placebo. Responders to treatment were those exhibiting a change larger than LSC. In response to clodronate treatment S-TRACP 5b (mean change up to -18%) decreased less than did U-NTX (up to -51%) or S-PINP (up to -46%). Marker changes correlated with changes in lumbar spine and trochanter BMD. The most efficient marker for finding responders to treatment was S-PINP, which changed more than the LSC (32%) in 72% of the subjects at the 1-year time point and in 79% at the 2-year time point. S-TRACP 5b change exceeded the LSC (27%) in 40% and 34% of the subjects at each time point, while U-NTX change exceeded the LSC (55%) in 55% and 40%, respectively. We conclude that, in terms of the proportion of subjects exhibiting any change exceeding the LSC, S-TRACP 5b did not appear to be superior to U-NTX and S-PINP in the follow-up of clodronate treatment. The reason may lie in the mechanism of action of clodronate, which rather than reducing the number of TRACP 5b-secreting osteoclasts, reduces the activity of bone proteolytic enzymes and thus the rate of bone organic matrix degradation. This is seen in decreased amounts of type I collagen breakdown products (U-NTX), and through coupling of bone resorption with bone formation, in a decrease in circulating levels of the marker that reflects new collagen formation (S-PINP).     

Intermittent versus continuous clodronate administration in postmenopausal women with low bone mass

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.     

Timing of food intake has a marked effect on the bioavailability of clodronate

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.     

Pharmacokinetics of clodronate in haemodialysis patients.

BACKGROUND: Clodronate is a bisphosphonate used in the treatment of hypercalcaemia of various aetiologies. The major route of elimination of clodronate is renal excretion. The aim of the study was to derive data for the adjustment of dosage in haemodialysis patients. METHODS: The pharmacokinetic parameters describing the fate of an intravenous infusion of 300 mg clodronate disodium were studied in 10 haemodialysis patients. Clodronate disodium in serum, urine and dialysate samples was analysed by capillary gas chromatography with mass-selective detection. RESULTS: Of the 300 mg clodronate infused, 159 mg (53%) was excreted into dialysate within 4 h. Clearance by haemodialysis (CLD) was 87.8+/-16.2 ml/min, accounting for 84% of total serum clearance (CLtot). Non-renal, non-dialysis clearance (CL(NRD)) represents the removal of the drug via other routes than dialysis or kidneys. The greatest CL(NRD) was observed in patients with most severe hyperparathyroidism. There was a positive correlation between CL(NRD) and plasma intact PTH concentration. CONCLUSIONS: According to the present findings, standard haemodialysis removes clodronate effectively from the circulation, and total clearance in haemodialysis patients on a dialysis day is not very different from that in healthy subjects. The regimen of dosing intravenous clodronate in hypercalcaemia can also be used in haemodialysis patients. The portion of clodronate eliminated by routes other than via dialysate or kidneys, i.e. predominantly via skeletal deposition, was related to the severity of hyperparathyroidism.     

Vitamin D Receptor Gene Polymorphisms Predict Acquired Resistance to Clodronate Treatment in Patients with Paget’s Disease of Bone

Bisphosphonates are first-choice drugs for treatment of Paget’s disease of bone (PDB); nevertheless, acquired resistance to bisphosphonate therapy has been described in PDB patients. The 1,25(OH)₂D₃/vitamin D receptor (VDR) system influences the effectiveness of antiresorptive treatments in metabolic bone disorders. This study evaluated the relationship between acquired resistance to clodronate treatment and BsmI, TaqI, and FokI VDR polymorphisms in Caucasian patients with polyostotic PDB (n = 84). We also evaluated the influence of mutations in exons 7 and 8 of the sequestosome 1 (SQSTM1) gene on the occurrence of this phenomenon. All patients were treated from diagnosis for several cycles with intravenous clodronate infusion (1500 mg/cycle). Acquired resistance to clodronate treatment was defined as the failure of total alkaline phosphatase serum levels to be suppressed to at least 50% of the patient’s previous highest levels during a subsequent treatment course with the same compound, which produced a >50% response after the first exposure. During an observation period of 10.6 ± 2.7 years, 31 PDB patients (36.9%) showed acquired resistance to clodronate. It was observed that the bb and TT VDR genotypes as well as a lower persistence of the biochemical response to the first treatment course were significantly and independently associated with the risk of developing resistance to clodronate treatment. SQSTM1 gene mutations, considered altogether, did not influence the occurrence of this phenomenon. Our results indicate that 3′VDR allelic variants and duration of biochemical response to the first treatment course are independent predictors of acquired resistance to clodronate treatment in patients with polyostotic PDB.     

Beneficial effect of intermittent cyclical etidronate therapy in hemiplegic patients following an acute stroke.

Significant decreases in bone mineral density (BMD) occur on the hemiplegic side in chronic stroke patients, which correlate with the degree of paralysis and hypovitaminosis D. In this double-blind, randomized, and prospective study of 98 patients with hemiplegia involving both an upper and lower extremity (55 males and 53 females; mean age, 71.4 +/- 0.6 years) after an acute stroke, 49 were given etidronate for 56 weeks and 49 received a placebo. The BMD was measured by computed X-ray densitometry (CXD) of the second metacarpal bone bilaterally. Forty age-matched control subjects were followed for 56 weeks. At baseline, both groups had 25-hydroxyvitamin D [25(OH)D] insufficiency, increased serum ionized calcium and pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), and low serum concentrations of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D], suggesting immobilization-induced hypercalcemia and inhibition of renal synthesis of 1,25(OH)2D. The BMD on the hemiplegic side decreased by 2.3% and 4.8% in the etidronate and placebo groups, respectively (p = 0.0003). After treatment, the serum 1,25(OH)2D concentration increased by 62.2% in the etidronate group and decreased by 12.4% in the placebo group. The etidronate group had significant decreases in the serum ionized calcium and ICTP and increases in PTH and bone Gla protein (BGP), whereas the placebo group had higher serum calcium and ICTP concentrations but stable PTH. These results suggest that etidronate can prevent decreases in the BMD in hemiplegic stroke patients because it decreases the serum calcium through inhibition of bone resorption and causes a subsequent increase in the serum 1,25(OH)2D concentration.     

Effects of clodronate on vertebral fracture risk in osteoporosis: a 1-year interim analysis

The aim of this study was to determine whether clodronate reduced the incidence of vertebral fractures in patients with osteoporosis. We report here the interim analysis after 1 year of a 3-year double-blind placebo-controlled study. The objectives of the interim analysis were to determine whether there was a trend in fracture frequency and to examine the effects of clodronate on bone mineral density (BMD). Patients with densitometrically proven osteoporosis (T-score <-2.5 and <-3 for women and men, respectively) or with at least one prevalent vertebral fracture were recruited to a 3-year double-blind, controlled study. Patients were randomized to three strata, namely women with postmenopausal osteoporosis (stratum I, n = 483), women with secondary osteoporosis (II, n = 110), and men with osteoporosis of any causation (III, n = 84). They received either clodronate 800 mg daily by mouth or an identical placebo, and all patients received a calcium supplement of 500 mg daily. BMD was measured at six monthly intervals, and lateral spine radiographs for vertebral morphometry were obtained at baseline and 1 year. Treatment with clodronate was associated with a significant increase in BMD at the spine of 3.2 +/- 0.3% (p < 0.0001 vs. baseline) compared with a nonsignificant change of 0.5 +/- 0.3% in the placebo group (p < 0.0001 between treatments). At the hip, clodronate was associated with a significant increase in total hip BMD of 1.3 +/- 0.3% (p = 0.018 vs. baseline) compared with a small decrease of 0.4 +/- 0.3% in the placebo group (p = 0.027 for the difference between treatment groups). The mean changes at the spine and hip were similar in all three strata. Incident vertebral fractures were observed in 27 patients at 1 year in the placebo group (9.0%) and in 14 patients receiving clodronate (4.9%) (relative risk 0.54; 95% CI 0.29-1.02; p = 0.07). A trend was observed in all treatment strata. Treatment was well tolerated, with no significant adverse events attributable to clodronate treatment. We conclude that clodronate 800 mg daily is effective in preventing bone loss, and at 1 year, there is a trend consistent with antifracture efficacy in patients with established osteoporosis regardless of causation.     

Skeletal deposition of clodronate is related to parathyroid function and bone turnover in dialysis patients

AIMS: Bisphosphonates inhibit osteoclastic bone resorption, and in the future, they may also have a role in the therapy of renal osteodystrophy. Our aim was to study whether the severity of hyperparathyroidism has an effect on the clearance of clodronate via routes other than dialysis or kidneys (nonrenal, non-dialysis clearance, CL(NRD)), which most likely represents the deposition of the drug in the skeleton. METHODS: We studied 31 dialysis patients (9 female/22 male, aged 28 - 79, median 58 years), 18 on hemodialyis (HD) and 13 on peritoneal dialysis (PD). HD patients were studied on a non-dialysis day. An intravenous infusion of 300 mg clodronate was given during 60 min at 8:00 a.m. Blood, urine and PD fluid samples were collected for 1 + 24 h, and pharmacokinetic parameters were calculated. RESULTS: In PD patients, 7% of the infused drug was excreted into PD fluid within 24 h, and in those HD or PD patients with residual diuresis 11% was excreted via the kidneys. The highest CL(NRD) was seen in patients with the most severe hyperparathyroidism. There was a positive correlation between CL(NRD) and plasma intact PTH (r = 0.79, p < 0.001). CL(NRD) was also related to the serum levels of bone markers PINP (procollagen type I N-terminal propeptide, r = 0.81, p < 0.001), osteocalcin (r = 0.65, p < 0.001) and ICTP (type I collagen cross-linked telopeptide, r = 0.68, p < 0.001). However, even in the patients with normal PTH, more than one-third of the infused drug was taken up by bone. CONCLUSION: In dialysis patients, the skeletal deposition of clodronate is related to bone turnover being highest in severe hyperparathyroidism. However, even in the case of low turnover, the uptake of the drug in bone takes place in amounts that might be clinically significant.     

Intravenous intermittent neridronate in the treatment of postmenopausal osteoporosis

Bisphosphonates have been used with success in the treatment of osteoporosis, but oral therapy often lacks compliance. Here we report the results of clinical trial with aminobisphosphonate neridronate administered intravenously (i.v.). The study included 78 postmenopausal women with spine bone mineral density (BMD) at least -2.5 SD below peak. Patients were randomized to receive for 2 years either 50 mg i.v. neridronate bimonthly and 500 mg calcium plus 400 U vitamin D supplements daily (n=39) or calcium-vitamin D supplements alone (control group, n=39). Treatment was continued over 2 years with an additional 1 year follow-up of calcium-vitamin D supplements alone. Neridronate was well tolerated with the appearance of typical clinical signs of an acute phase reaction in only 3 of the patients after the first infusion. In the control group no significant changes in BMD or bone markers were observed. In the neridronate group BMD rose progressively at the spine rose up to 7.4% +/- 6.1% (SD) and at the femoral neck up to 5.8% +/- 8.2% (SD) at the end of the second year. In the succeeding follow-up these gains were maintained at both skeletal sites. Serum bone alkaline phosphatase (bone ALP) and serum type I collagen C-telopeptide (s-CTX) significantly decreased within 2 months. The bone ALP values reached a -35% plateau after 6 months, while s-CTX attained the lowest mean value (-47%) only by the end of the treatment with neridronate. Both bone markers returned almost to baseline values 1 year after treatment discontinuation. Treatment of postmenopausal osteoporosis with 50 mg i.v. neridronate bimonthly results in clinically relevant increases in BMD, among the largest so far observed with any other bisphosphonate.