Sodium Clodronate
Adverse Effects, Treatment, and Precautions
As for the bisphosphonates in general. Gastrointestinal symptoms with oral clodronate may be reduced by giving it in divided doses rather than as a single daily dose. Reversible increases in liver enzyme values and serum parathyroid hormone have occurred; transient moderate leucopenia has been reported. Monitoring of hepatic and renal function, white cell counts, and serum calcium and phosphate is advised. Clodronate has precipitated bronchospasm, even in patients with no history of asthma. Transient proteinuria has been reported immediately after intravenous infusion.
Effects on the eyes.
For reports of ocular effects associated with the bisphosphonates, including clodronate, see under Bisphosphonates.
Effects on the kidneys.
For mention of renal failure developing in a patient with slightly raised serum-creatinine concentrations who subsequently received an intravenous infusion of clodronate, see under Bisphosphonates.
Effects on the respiratory system.
For a report of bronchospasm in an aspirin-sensitive asthmatic, induced by an infusion of clodronate.
Hypersensitivity.
Allergic reactions to bisphosphonates are rare. For published reports of cutaneous reactions associated with clodronate.
Interactions
As for the bisphosphonates in general.
Aminoglycosides.
Severe hypocalcaemia has been reported after treatment with amikacin, or netilmicin in patients who had previously received clodronate. In both cases, signs of aminoglycoside toxicity were evident; clodronate had been withdrawn in one patient upon starting the aminoglycoside, and in the other several weeks before. Bisphosphonates and aminoglycosides can induce hypocalcaemia by different mechanisms and the effects of both drugs may persist for several weeks; care should be taken when giving them together.
Pharmacokinetics
Like other bisphosphonates, clodronate is poorly absorbed after oral doses. Absorption is decreased by food, especially by products containing calcium or other polyvalent cations. Bioavailability is only 1 to 4%, and may differ appreciably between different oral formulations. On absorption or intravenous dosage it is cleared rapidly from the blood with a reported plasma half-life of only about 2 hours, but has a high affinity for bone. Binding to serum plasma proteins is low. Clodronate is not metabolised. Over 70% of an intravenous dose is excreted unchanged in the urine within 24 hours, the remainder being sequestered to bone tissue.
Bioavailability.
Enhanced bioavailability tablets of clodronate disodium are available in some countries, the licensed dose of which is 35% less than the dose of the standard capsule formulation. However, an open, randomised, crossover study in 88 subjects found that a 1040-mg dose of the tablet formulation provided only 52% of the bioavailable dose of 1600 mg of the standard capsule formulation.
Uses and Administration
Clodronate is a bisphosphonate with general properties similar to those of the other bisphosphonates. It inhibits bone resorption, but appears to have less effect on bone mineralisation than etidronate at comparable doses. Clodronate is used, generally as the disodium salt, as an adjunct in the treatment of severe hypercalcaemia associated with malignancy. In addition, it is used in the management of osteolytic lesions and bone pain associated with skeletal metastases. Doses are expressed in terms of anhydrous clodronate disodium; 125 mg of clodronate disodium tetrahydrate is equivalent to about 100 mg of anhydrous substance.
Clodronate is given by slow intravenous infusion, diluted in sodium chloride 0.9% or glucose 5%, or by mouth, as a single daily dose or in 2 divided doses; food should be avoided for at least 1 hour before or 1 hour after an oral dose. Clodronate disodium is available in capsules of 400 mg and standard tablets of 800 mg. Tablets of clodronate disodium 520 mg are also available in some countries, and have a greater bioavailability than the capsules or standard tablets; one such tablet of clodronate disodium 520 mg is equivalent to about two capsules each containing clodronate disodium 400 mg or one 800-mg standard tablet.
In the management of osteolytic lesions, hypercalcaemia, and bone pain associated with skeletal metastases in patients with breast cancer or multiple myeloma, clodronate disodium 1.6 g daily (4 capsules or 2 standard tablets) is given by mouth, and may be increased if necessary to a maximum of 3.2 g daily. Alternatively a dose of 1.04 g (2 tablets) daily, increased if necessary up to 2.08 g daily, may be given as enhanced bioavailability tablets.
In hypercalcaemia of malignancy clodronate disodium is given by intravenous infusion over not less than 2 hours in a dose of 300 mg in 500 mL of infusion solution daily on successive days until normocalcaemia is achieved (usually within 5 days); duration of treatment should not exceed 10 days. Alternatively, it may be given as a single intravenous infusion of 1.5 g in 500 mL of infusion solution over a period of 4 hours. Once serum-calcium concentrations have been reduced to an acceptable level, maintenance therapy may be given by mouth in similar doses to those used for initial oral treatment of metastases. If hypercalcaemia recurs, the intravenous dose may be repeated.
Administration.
In Italy, clodronate is also used intramuscularly. The usual dose for maintenance therapy of hypercalcaemia is 100 mg daily for 2 to 3 weeks; in the prevention and treatment of postmenopausal osteoporosis, 100 mg is given every 7 to 14 days. However, injection into the gluteal muscle caused local hardening; severe pain at the injection site may limit prolonged use of this route. In Canada, clodronate has been given subcutaneously in doses of 1500 mg in 50 to 250 mL of infusion solution over 2 to 3 hours, to treat hypercalcaemia associated with malignancy. The chest and abdomen were the sites most frequently used; pain was the most common adverse effect.
Administration in renal impairment.
A pharmacokinetic study found that renal clearance of intravenous clodronate was highly dependent on renal function. While recommending caution in interpreting these results for patients with malignancy or severe bone disease, the authors recommended the following dose adjustments based on creatinine clearance (CC):
CC 50 to 80 mL/minute: up to 25% reduction in dose
CC 12 to 49 mL/minute: 25 to 50% dose reduction
CC less than 12 mL/minute: 50% dose reduction
However, some manufacturers recommend that intravenous infusion of clodronate should be avoided in patients with moderate to severe renal impairment (serum creatinine greater than 440 micromoles/litre). Others recommend, where multiple infusions are given, adjustment according to creatinine clearance (CC) as follows:
mild renal impairment (CC 50 to 80 mL/minute): 25% reduction in dose
moderate renal impairment (CC 10 to 50 mL/minute): 25 to 50% dose reduction
severe impairment (CC below 10 mL/minute): contra-indicated
For the oral route the following adjustments may be made:
CC between 10 and 30 mL/minute: 50% dose reduction
CC below 10 mL/minute (or serum creatinine greater than 440 micromoles/litre): contra-indicated
Complex regional pain syndrome.
Osteoporosis is one of the features of complex regional pain syndrome. Bisphosphonates may be of benefit in controlling associated pain in some patients. In a small study, intravenous clodronate 300 mg daily for 10 days significantly improved pain, tenderness, swelling, and motion compared with placebo.
Hypercalcaemia.
Bisphosphonates are the preferred drugs for treating hypercalcaemia of malignancy once the patient has been adequately rehydrated. Clodronate has been shown to be effective in the treatment of malignant hypercalcaemia. A small dose-response study found low-dose clodronate for mild cases to be as effective as high-dose clodronate for moderate to severe cases of tumour-induced hypercalcaemia.
Malignant neoplasms of the bone.
Bisphosphonates are of benefit in some patients with metastatic bone disease not only to manage bone pain and hypercalcaemia, but to reduce skeletal complications such as fractures. Clodronate is licensed for such use in many countries. Studies in breast cancer patients with bone metastases found that clodronate reduced the incidence of fractures, and delayed the time to onset of new bone events. Whether bisphosphonates can prevent the development of new skeletal metastases is unclear. Results of studies using clodronate to reduce skeletal metastases in women with breast cancer have been conflicting, and one study in women with node-positive disease actually suggested an increase in concomitant visceral metastases. Overall, the studies appeared limited by duration, and further data are needed. In a trial of patients with multiple myeloma, oral clodronate was found to slow the progression of skeletal disease, especially in those patients with less overt disease at diagnosis; the authors suggested starting clodronate early in the course of the disease.
Osteogenesis imperfecta.
Clodronate has been reported to be of benefit in a boy with osteogenesis imperfecta type I. Starting at 131/2 years old he was given oral clodronate 400 mg daily for 5 years, and sustained no new low-trauma fractures during this time. Treatment was stopped for 8 months, but bone mineral density remained below normal limits. Clodronate was restarted at 800 mg daily and given with no untoward effects, until the patient was 22 years old, 8 years after initial referral.
Osteoporosis.
Bisphosphonates are used for the prevention and treatment of osteoporosis. Clodronate is licensed for this use in some countries. Studies of its use in daily oral doses, or intermittent intravenous infusions, or intramuscular injections (at 7-, 10- or 14-day intervals) found increases in bone mineral density at various sites in postmenopausal women with osteoporosis or low bone mass. A large study in postmenopausal women with vertebral osteopenia found that oral clodronate 800 mg daily prevented bone loss in the lumbar spine and femoral trochanter, but not the femoral neck; this dose has been shown to reduce vertebral fracture risk in women with postmenopausal or secondary osteoporosis. The risk of vertebral fractures was also reduced in patients with arthritis receiving corticosteroids, who were given intramuscular clodronate once weekly. Oral clodronate may be of benefit in reducing bone loss after heart transplantation, but the benefits of intravenous clodronate in a small prospective study in patients receiving parenteral nutrition (who are at high risk of osteoporosis) were uncertain.
Paget's disease of bone.
Bisphosphonates may be indicated for patients with Paget's disease of bone if bone pain is persistent, or to prevent further progression of the disease. A review of clodronate stated that oral doses of 800 to 1600 mg daily were effective in reducing bone turnover in patients with Paget's disease, and that remission after stopping was longer with the higher dose. Duration of therapy also appears to affect response; longer treatment was associated with a longer time to relapse. Short-term intravenous clodronate (300 mg daily for 5 to 10 days) has also been found to reduce biochemical markers of bone turnover, and sustain remission for up to 1 year.