Pamidronate

Summary

Synopsis

Pamidronate [aminohydroxypropylidene diphosphonate disodium (APD), disodium pamidronate] is an orally and intravenously active amino-substituted bisphosphonate which produces potent and specific inhibition of bone resorption at doses devoid of any significant detrimental effect on bone growth and mineralisation. Clinical trials indicate that pamidronate is effective in a variety of conditions characterised by pathologically enhanced bone turnover, including Paget’s disease, hypercalcaemia of malignancy, osteolytic bone metastasis, steroid-induced osteoporosis and idiopathic osteoporosis. Pamidronate is highly effective in restoring normocalcaemia in patients with hypercalcaemia of malignancy associated with bone métastases but, in common with other bisphosphonates, is marginally less effective against humoral hypercalcaemia of malignancy. Comparative studies in this area have suggested that, at therapeutic doses, pamidronate has a more pronounced calcium-lowering action than etidronate (etidronic acid) and clodronate (clodronic acid) and provides a longer period of normocalcaemic remission. In Paget’s disease arrest and, in some patients, reversal of the progression of osteolytic lesions by pamidronate is associated with a sustained reduction in bone pain, improved mobility and a possible reduced risk of bone fracture. In patients with osteolytic bone metastasis pamidronate reduces skeletal morbidity and slows the progression of metastatic bone destruction. Long term use of low-dose pamidronate in conjunction with conventional antiosteoporotic therapy may halt bone loss in steroid-induced and idiopathic osteoporosis. Pamidronate appears to represent a valuable addition to the drugs currently available for the treatment of symptomatic Paget’s disease and cancer-associated hypercalcaemia, and shows promise in the treatment of osteolytic bone metastasis and osteoporosis.

Pharmacodynamic Properties

Adsorption onto newly synthesised bone matrix and subsequent prevention of the accession of osteoclast precursors to the calcified matrix is believed to be the predominant mechanism underlying the inhibitory action of pamidronate on bone resorption. Animal studies indicate that pamidronate is 10 and 100 times more potent than clodronate and etidronate, respectively, in inhibiting bone resorption in vivo. In addition, pamidronate produces potent inhibition of bone resorption at doses devoid of any significant detrimental effect on bone growth and mineralisation.

In patients with hypercalcaemia of malignancy, pamidronate ( 15 to 90 mg/day intravenously; 150 to 600 mg/day orally) restores normocalcaemia through inhibition of bone resorption rather than through promotion of hypercalcuria, as indicated by reductions in urinary hydroxyproline excretion (an index of osteoclastic activity) and fasting calcium excretion in the absence of changes in the renal tubular handling of calcium. Transient hypophosphataemia is believed to reflect decreased phosphate mobilisation from bone rather than enhanced urinary phosphate excretion due to secondary hyperparathyroidism. Pamidronate-induced correction of hypercalcaemia has been associated with improvement in renal function in most studies.

In patients with symptomatic Paget’s disease, pamidronate (15 to 60 mg/day intravenously; 250 to 1200 mg/day orally) produces rapid (1 to 2 weeks) normalisation of urinary hydroxyproline excretion and a more gradual (2 to 3 months) normalisation of serum alkaline phosphatase activity (an index of osteoblastic activity). Accompanying changes include slight transient hypocalcaemia and hypophosphataemia, secondary hyperparathyroidism, increased calcium balance, and longer lasting hypocalcuria which persists for 2 to 3 months after a single intravenous dose.

Pharmacokinetic Properties

Animal studies indicate that parenterally administered [¹⁴C]pamidronate is selectively accumulated in the skeleton (predominantly in metaphyseal bone and diaphyseal periosteum and endosteum), liver and spleen, and that the drug is eliminated unmetabolised, primarily via the urine. In the osteosarcoma-bearing mouse and rat, [¹⁴C]pamidronate shows a preferential accumulation in mineralised areas of the primary tumour and calcium-rich pulmonary metastases.

Pharmacokinetic data in humans are limited, essentially as a result of the absence until recently of suitable methods for the assay of pamidronate in biological fluids. As with other bisphosphonates, oral absorption of pamidronate is very low, accounting for approximately 1.0% of the administered dose. In cancer patients, pamidronate shows a biexponential pattern of elimination (urinary elimination half-lives of 1.6 and 27 hours for the α and β phases, respectively): In those with Paget’s disease steady-state plasma pamidronate concentrations were attained within 1 to 2 hours of initiating a 2-hour intravenous infusion of a 30mg dose; the mean urinary elimination half-life was 2.5 hours, while cumulative 0- to 12-hour urinary excretion was 32%.

Therapeutic Use

Noncomparative studies have demonstrated the efficacy of oral (300 to 1200 mg/day) and intravenous (15 to 90mg given as a single infusion or multiple doses) pamidronate in normalising serum calcium levels within 10 days of initiating therapy in 70 to 100% of patients with hypercalcaemia of malignancy. With an adequate dose normocalcaemia is achieved within 3 to 6 days in the majority of patients. There appears to be little difference in therapeutic efficacy (as assessed by the fall in serum calcium levels and/or the duration of normocalcaemia) between single-dose (15 to 90mg) or multiple-dose (15 to 30 mg/day for ≤ 9 days) intravenous infusion regimens of pamidronate. Restoration of normocalcaemia is associated with a general improvement in symptoms attributable to hypercalcaemia but no change in bone pain. In the absence of concomitant anticancer therapy, normocalcaemic remission lasted for 2 to 3 weeks (median) after initiation of single- or multiple-dose pamidronate administration. Responsiveness to pamidronate was apparently unrelated to primary tumour type and the prevalence of bone metastases. However,humoral hypercalcaemia of malignancy was generally less responsive to pamidronate than hypercalcaemia due to local osteolysis.

Preliminary comparative data indicate that intravenous single-dose pamidronate 30mg is more effective than single-dose clodronate 600mg or multiple-dose etidronate 7.5 μg/kg/day for 3 days in controlling hypercalcaemia of malignancy, and provides a significantly longer period of normocalcaemic remission, although the symptomatic improvements with pamidronate and clodronate acid are similar. Intravenous pamidronate 15 mg/day for 6 days had a more pronounced antihypercalcaemic effect than intravenous plicamycin (mithramycin) 25 μg/kg/day or oral prednisolone 40 mg/day + subcutaneous calcitonin 1200 U/day.

Noncomparative studies in patients with Paget’s disease have indicated that pamidronate (60mg single dose or 2 to 30 mg/day intravenously; 300 to 1200mg orally) effectively reduces bone pain, thereby improving mobility and weight-bearing capacity, and that this effect is sustained for up to 6 months following short term (≤ 5 days) therapy. Radiographic findings suggestive of arrest of bone resorption in pagetic lesions (remineralisation of decalcified bone and filling of radiolucencies) are seen in approximately 50% of patients after 6 months of treatment, with improvement most frequently occurring in osteolytic lesions in the pelvis and long bones. These changes are associated with an apparent reduction in the risk of fracture. Bone densitometry indicates that pamidronate reverses the normal physiological decline in bone mineral content in middleaged and elderly patients. Biochemical remission (normalisation of indices of bone turnover) occurs within 6 months of initiating short or long term pamidronate therapy in the majority (80 to 90%) of patients with mild to moderate Paget’s disease and is sustained for up to 3 years. Resistance to pamidronate does not appear to occur with prolonged exposure.

The limited comparative data available suggest that oral pamidronate (4.5 mg/kg/day) and etidronate (20 mg/kg/day) are of comparable efficacy in alleviating bone pain in Paget’s disease, while pamidronate is more effective than etidronate (both 10 mg/kg/day) in repairing the osteolytic bone lesions of Paget’s disease.

Intravenous (15 to 30 mg/day) and oral (300 to 600 mg/day) pamidronate reduced skeletal morbidity (bone pain, fracture, development of hypercalcaemia) when used alone or in combination with standard chemotherapy in preliminary studies in patients with osteolytic bone metastasis; previously progressive metastatic bone destruction was arrested in 25 to 45% of patients during a 4- to 6-month (median) treatment period.

Addition of low-dose ( 150 mg/day) pamidronate to conventional antiosteoporotic therapy may halt the loss of bone mass characteristic of steroid-induced and idiopathic osteoporosis.

Adverse Effects

Pamidronate is generally well tolerated at intravenous and oral doses of up to 90 mg/day and 600 mg/day, respectively. The most common adverse effect of pamidronate is a transient, self-limiting and generally asymptomatic pyrexia, typically occurring during the first 3 days of administration in approximately 10% to 20% of patients. Pamidronate-induced pyrexia is frequently paralleled by a transient leucopenia and lymphopenia. This acute phase response of pyrexia, leucopenia and lymphopenia, which is also exhibited by other amino-substituted bisphosphonates, is independent of the route of drug administration and is apparently observed only on initial exposure to pamidronate.

Adverse responses to intravenous pamidronate (15 to 45mg; 15 to 20 mg/day) include acute exacerbation of bone pain in Paget’s disease, mild thrombophlebitis at the infusion site, and transient muscle rigor on initiation of therapy.

While pamidronate is well tolerated at oral doses of up to 300 mg/day, the higher dose of 600 mg/day is associated with gastric irritation in 40 to 50% of patients. Clinically significant hypocalcaemia associated with pamidronate use appears to be rare; however, episodes of mild hypocalcaemia may be of importance in lowering seizure threshold in patients with malignant disease and brain metastasis.

Long term (≤ 6 years) administration of low-dose oral pamidronate (150 mg/day) to patients with osteoporosis has not been associated with any adverse effect on bone mineralisation.

Dosage and Administrations

The recommended intravenous dose of pamidronate in the treatment of hypercalcaemia of malignancy is 15 to 90mg, depending on the initial serum calcium level. The infusion rate should not exceed 7.5 to 15 mg/h. Optimal pamidronate dosage regimens have yet to be established for the treatment of Paget’s disease and osteolytic bone metastasis associated with normocalcaemia. Clinical experience indicates that initial intravenous therapy with a single 60mg dose or multiple doses of 20 mg/day for 10 days followed, where necessary, by oral maintenance therapy with doses of 250 to 600 mg/day, provides a rapid and sustained clinical response in Paget’s disease. Similarly, an initial oral pamidronate dose of 120 mg/month, given in aliquots of 30 to 60mg, followed by 60 to 90 mg/month is effective in normocalcaemic patients with progressive osteolytic bone metastasis.

The use of oral pamidronate 150 mg/day in conjunction with conventional antiosteoporotic therapy is effective and well tolerated in the long term treatment of idiopathic osteoporosis.