Abstract
Synopsis
Clodronate (clodronic acid, dichloromethylene bisphosphonate) is a Bisphosphonate which has demonstrated efficacy in patients with a variety of diseases of enhanced bone resorption including Pagets disease, hypercalcaemia of malignancy and osteolytic bone metastases. In addition, early reports demonstrating potential efficacy of clodronate in the treatment of osteoporosis suggest a possible role in this debilitating disease.
Short term intravenous administration (usually 300 mg/day for 5 days) or longer courses of oral clodronate (usually 1600 mg/day for 6 months) effectively reduced bone pain and/or improved mobility in most patients with Pagets disease, and these effects persisted for up to 12 months after discontinuing clodronate.
When administered intravenously (300 mg/day for up to 12 days) to patients with malignant hypercalcaemia, serum calcium levels declined significantly within 2 days of starting treatment and approximately 70 to 95% of patients became normocalcaemic. While there is less experience with oral administration, clodronate (800 to 3200 mg/day) achieved normocalcaemia in the majority of patients, usually within 1 week, and serum calcium levels remained significantly reduced from baseline for up to 6 months with continued treatment. Clodronate is clearly superior to placebo and, based on a retrospective analysis, appears to produce greater and more sustained reductions in serum calcium levels than calcitonin in patients with malignant hypercalcaemia. The few available prospective comparative trials showed that clodronate is at least as effective as etidronate, but comparisons with alendronate and Pamidronate produced results of questionable clinical relevance because of low bisphosphonate dosages used in these trials. Nevertheless, single intravenous doses of clodronate 600mg or alendronate 7.5mg (both agents repeated on day 3 if necessary) were comparable in efficacy, whereas a single intravenous dose of Pamidronate 30mg was more effective than a single intravenous dose of clodronate 600mg.
Normocalcaemic patients with osteolytic bone metastases due to advanced breast cancer experienced significant reductions in the number of episodes of hypercalcaemia and terminal hypercalcaemia, incidence of vertebral fractures and overall rate of morbid events, including the need for radiotherapy to treat bone-related pain, following treatment with clodronate 1600 mg/day for 3 years in a large placebo-controlled study. A similar large placebo-controlled trial inpatients with multiple myeloma demonstrated that clodronate 2400 mg/day orally for 2 years significantly reduced progression of osteolytic bone lesions. Follow-up data from clinical trials revealed that the effects on development of fractures and hypercalcaemia persisted for at least 12 months after the drug was discontinued.
Preliminary data on the use of clodronate in treating patients with osteoporosis are encouraging and suggest that the drug reduces bone loss and can increase lumbar bone density in these patients. However, long term (≥3 years) clinical trials, which are necessary to adequately assess the effects of bisphosphonate therapy, have yet to be completed with clodronate.
Data from clinical trials indicate that both intravenous and oral administration of clodronate are generally well tolerated, and indirect comparisons suggest better tolerability of clodronate than Pamidronate when these drugs are administered orally.
Thus, clodronate is an effective antiresorptive treatment for Pagets disease, hypercalcaemia of malignancy, osteolytic bone metastases and possibly osteoporosis. Based on available data, oral administration of clodronate seems to have a lower incidence of adverse gastrointestinal effects than Pamidronate, and unlike etidronate and Pamidronate, clodronate has not been associated with defective bone mineralisation, suggesting potential advantages ofclodronate over other bisphosphonates, particularly when longer term therapy is required.
Pharmacodynamic Properties
Clodronate, like other bisphosphonates, has a high affinity for solid-phase calcium phosphate and therefore accumulates in bone, where it inhibits the formation, aggregation and dissolution of calcium phosphate crystals. In vitro studies demonstrated that clodronate dose-dependently inhibited bone resorption induced by various stimuli including parathyroid hormone, and was more potent than etidronate. In vivo data from animals also indicated that clodronate was a more potent inhibitor of endogenous and experimentally induced bone resorption than etidronate, although on a molar basis, clodronate was less potent than Pamidronate. Tumoral bone resorption was inhibited by clodronate in vitro and in vivo, as evidenced by significant reductions in 45Ca release from mouse calvaria in tumour-conditioned media when the animals were treated with clodronate before being killed or when clodronate was added to the culture medium. Clodronate was also associated with reduced loss of bone in rats with Leydig cell tumours, on the basis of histomorphometric evaluation, and preservation of bone calcium content in rats implanted with Walker tumour cells. Clodronate has not been shown to inhibit bone mineralisation or calcification of cartilage.
Inhibition of bone resorption was not correlated with the physicochemical effects of clodronate or other bisphosphonates, and these agents appear to exert their activity predominantly through an effect on osteoclast (bone removal) activity. Clodronate altered the morphology of osteoclasts in vitro and in vivo in studies showing an inhibitory effect on bone resorption. However, discrepancies between the relative potencies of various bisphosphonates in vivo and their effects on osteoclasts in vitro imply that other mechanisms may also be involved, such as an indirect effect on osteoclasts via inhibition of osteoblasts.
Pharmacokinetic Properties
Following single dose intravenous administration of clodronate over a wide range of doses to healthy volunteers or patients with Paget’s disease or cancer, pharmacokinetics were linear with respect to dosage. Area under the plasma concentration-time curve increased proportionally with dosage, while volume of distribution was approximately 0.25 L/kg, plasma elimination half-life was about 2 hours and total body clearance was about 7 L/h. Some studies also indicated a short distribution phase (t½α of approximately 0.25 hours) and a slow disposition phase (t½γ of at least 12 hours in studies which collected serum samples for up to 12 hours), the latter suggesting that a proportion of the dose remains in the bones and is eliminated very slowly (over several months or possibly years based on animal data). Approximately 60 to 80% of an intravenous dose of clodronate is eliminated unchanged in the urine and 5% is eliminated in the faeces. Plasma protein binding is low, with a free fraction in plasma of 64%. Oral bioavailability of clodronate is very low, at about 1 to 2%, and is reduced when the drug is administered with food or calcium.
Therapeutic Efficacy
Clodronate has demonstrated efficacy in the treatment of various resorptive bone diseases including Paget’s disease, hypercalcaemia of malignancy and osteolytic bone metastases, and preliminary studies suggest therapeutic potential in osteoporosis. The majority of patients with Paget’s disease receiving a short course of intravenous clodronate (usually 300 mg/day for 5 days) or a longer course of oral clodronate (usually 1600 mg/day for 6 months) exhibited normalisation of biochemical markers of increased bone turnover. Thus, clodronate reduced urinary hydroxyproline excretion (an indicator of osteoclastic activity) and serum alkaline phosphatase activity (an indicator of osteoblastic activity) to normal or near normal levels, which were frequently maintained for 4 to 12 months after discontinuation of therapy. Clinically, biochemical improvement was usually associated with reduced bone pain and/or improved mobility, and these effects also persisted for 12 months after discontinuation of clodronate in one study. Histomorphometric evaluation of Pagetic and non-Pagetic bone biopsies from patients with Pag-et’s disease confirmed that clodronate reduced bone turnover, was associated with resumption of normal lamellar bone formation and, unlike etidronate, did not interfere with bone mineralisation.
Intravenous administration of clodronate 300 mg/day for up to 12 days achieved normocalcaemia in approximately 70 to 95% of patients with hypercalcaemia due to a variety of malignancies. In most studies, significant reductions in serum calcium levels were noted after 2 days of intravenous clodronate treatment. Normocalcaemia was attained within 4 to 5 days and serum calcium levels began to rise towards pretreatment levels approximately 5 to 7 days after clodronate was discontinued. Although fewer data are available with oral administration, the majority of patients with hypercalcaemia of malignancy receiving oral clodronate 800 to 3200 mg/day became normocalcaemic, usually within 7 days of treatment. In patients with hypercalcaemia of malignancy who became normocalcaemic following intravenous administration, oral clodronate 400 to 3200 mg/day for up to 6 months maintained serum calcium levels significantly below pretreatment levels.
The few available prospective comparative studies demonstrated that intravenous administration of clodronate had equivalent or superior activity compared with etidronate over a wide range of dosages (100 to 1000 mg/day for 2 days to 1 month), but comparisons with other bisphos-phonates used 1 or 2 intravenous doses of clodronate 600mg, alendronate 7.5mg and Pamidronate 30mg — regimens which may have been subtherapeutic, thereby providing results of questionable clinical significance. A retrospective comparison revealed that treatment with intravenous (usually 300 to 400 mg/day) and/or oral (usually 1600 to 3200 mg/day) clodronate produced more marked and sustained reductions in serum calcium levels, and achieved normocalcaemia in a greater proportion of patients than calcitonin (dosage not specified).
In normocalcaemic patients with osteolytic bone metastases associated with breast cancer, oral administration of clodronate 1600 mg/day for 3 years significantly reduced the incidence of episodes of hypercalcaemia and terminal hypercalcaemia, vertebral fractures, and overall morbid events, including the need for palliative radiotherapy, in a large placebo-controlled trial. The effects of clodronate on decreasing development of hypercalcaemia and bone fractures appeared to persist for at least 1 year after discontinuing clodronate, but reductions in osteolytic bone lesions did not persist after discontinuation of clodronate therapy in clinical trials. In a large placebo-controlled study of 336 patients with multiple myeloma, progression of radiographically assessed osteolytic bone lesions occurred in 12% of those receiving clodronate 2400 mg/day orally for 2 years compared with 24% of placebo recipients, and this difference was statistically significant.
Long term studies (i.e. ≥ 3 years) of clodronate in the treatment of osteoporosis, which are necessary to adequately assess the effects of bisphosphonates in patients with established osteoporosis, have not yet been conducted. However, intermittent oral treatment with clodronate 400 mg/day over 1 year significantly increased lumbar bone density while bone density decreased in women with postmenopausal bone loss not receiving clodronate. Clodronate also inhibited bone loss due to immobilisation in paraplegic patients and, based on biochemical and histomorphometric parameters in a few patients, appeared to have comparable activity to calcitonin.
Tolerability
Clodronate is well tolerated and few serious adverse events have been associated with its use. Tolerability data from clinical studies in a total of 1930 patients with resorptive bone disease showed that approximately 3% of patients receiving clodronate orally, intravenously or intramuscularly exhibited modest, transient hypocalcaemia which was rarely of clinical significance; 0.6% demonstrated a transient elevation in serum creatinine levels which seldom required discontinuation of the drug. Rapid intravenous administration of clodronate can produce acute renal failure; therefore, slow intravenous infusion over 2 to 3 hours is recommended. Although this analysis indicated that 1.8% of patients develop gastrointestinal problems such as nausea, vomiting, diarrhoea and epigastric pain, additional pooled tolerability data indicated that 2 to 10% of patients receiving oral clodronate develop these dose-related gastrointestinal adverse effects. Based on available data, clodronate, unlike etidronate and Pamidronate, does not appear to be associated with defective bone mineralisation.
Dosage and Administration
In the treatment of resorptive bone disease, the recommended intravenous dosage of clodronate is 300 mg/day for up to 10 days (usually 3 to 5 days). The drug should be diluted in 500ml of normal saline solution and infused over at least 2 hours. A single intravenous dose of 1500mg diluted in 500ml of normal saline solution and infused over 4 hours has also been used successfully in the management of malignant hypercalcaemia. The recommended oral dosage of clodronate is 1600 mg/day, with a maximum dosage of 3200 mg/day. Oral clodronate should not be administered with food or milk, and may be taken in divided doses to reduce adverse gastrointestinal effects.
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Various sections of the manuscript reviewed by: S. Adami, Università Degli Studi di Verona, Verona, Italy; R.S. Bockman, Hospital for Special Surgery, New York, New York, USA; J.J. Body, Endocrinology and Bone Metabolism Unit, Centre des Tumeurs de l’Université Libre de Bruxelles, Brussels, Belgium; N. Conte, Ospedale Regionale, Treviso, Italy; I. Elomaa, Department of Radiotherapy and Oncology, University Central Hospital of Helsinki, Helsinki, Finland; D.S. Ernst, Department of Medicine, Tom Baker Cancer Center, Calgary, Alberta, Canada; H. Fleisch, Department of Pathophysiology, University of Berne, Berne, Switzerland; R. Gucalp, Albeit Einstein Cancer Center, Montefiore Medical Center, Bronx, New York, USA; H. Gurney, Department of Medical Oncology and Palliative Care, Westmead Hospital, Westmead, New South Wales, Australia; H.K. Ibbertson, Department of Endocrinology, Auckland Hospital, Auckland, New Zealand; J.A. Kanis, Sheffield Metabolic Bone Unit, University of Sheffield, Sheffield, England; D. Levenson, Hospital for Special Surgery, New York, New York, USA; A.A. Licata, Cleveland Clinic Foundation, Cleveland, Ohio, USA; G.R. Mundy, Division of Endocrinology and Metabolism, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; S.H. Ralston, Department of Medicine and Therapeutics, Aberdeen University Medical School, Foresterhill Hospital, Aberdeen, Scotland; N. van Rooijen, Department of Cell Biology, Division of Histology, Vrije Universiteit, Amsterdam, The Netherlands; C.S. Wink, Department of Anatomy, Louisiana State University Medical Center, New Orleans, Louisiana, USA; R. Ziegler, Medizinische Klinik, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany.
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Plosker, G.L., Goa, K.L. Clodronate. Drugs 47, 945–982 (1994). https://doi.org/10.2165/00003495-199447060-00007
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DOI: https://doi.org/10.2165/00003495-199447060-00007