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Pamidronate

A Review of its Use in the Management of Osteolytic Bone Metastases, Tumour-Induced Hypercalcaemia and Paget’s Disease of Bone

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Abstract

Synopsis

Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour- induced hypercalcaemia or Paget’s disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix- boundpamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone.

In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality- of- life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy.

Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer. In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin).

In most patients with Paget’s disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged.

Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis).

Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first- line use in the management of patients with tumour- induced hypercalcaemia. It is an effective treatment for Paget’s disease and is the treatment of choice where oral bisphosphonates are not an option.

Pharmacology

Pamidronate (APD) is an inhibitor of bone resorption that, unlike etidronate, does not appear to impair bone mineralisation at therapeutic dosages in patients with Paget’s disease. Pamidronate inhibits osteoclast activity primarily by binding with hydroxyapatite crystals in the bone matrix, preventing the attachment of osteoclast precursor cells. Other mechanisms of action of matrix-bound pamidronate may include direct inhibition of mature osteoclast function, promotion of osteoclast apoptosis and interference with osteoblast-mediated osteoclast activation.

The initial plasma half-life of the drug is <1 hour (for a 1- to 24-hour infusion). 31 to 41% of an intravenous dose of 60mg is recovered in the urine within 24 hours of administration. Most of the remaining drug is taken up by bone, from where it is eliminated very slowly. The terminal half-life is many months. Body retention after an intravenous dose correlated with the number of metastases in patients with cancer. The area under the plasma concentration-time curve was increased in patients with severe renal dysfunction.

Therapeutic Use

Osteolytic bone metastases. Administered in conjunction with systemic antitumour therapy in patients with breast cancer or Durie-Salmon stage III multiple myeloma and at least 1 bone lesion, Pamidronate reduced the overall incidence and delayed the onset of skeletal complications (pathological fracture, hypercalcaemia, or radiation treatment or surgery to bone). Pamidronate also prolonged the time to progressive disease in bone in patients with breast cancer. In patients with breast cancer and in those with myeloma, pamidronate recipients had better pain control than patients who did not receive the drug. Quality-of-life and performance status scores of pamidronate recipients were the same as, or better than, those in patients who did not receive the drug. Pamidronate did not affect overall survival in these 2 year studies.

Tumour-induced hypercalcaemia. 70 to 100% of patients with hypercalcaemia of malignancy achieve normocalcaemia after pamidronate therapy. Elevated calcium levels begin to fall within 24 to 48 hours after administration of the drug and normocalcaemia is typically achieved after 3 to 5 days. The duration of normocalcaemia is variable, but many patients achieve remissions of ≥3 weeks. Pamidronate appears to be more effective than other available osteoclast inhibitors in patients with hypercalcaemia. More patients achieved normocalcaemia, and the duration of this response was longer, after treatment with pamidronate than after treatment with etidronate, clodronate or plicamycin (mithramycin).

Paget’s disease of bone. Pamidronate reduces bone pain, serum alkaline phosphatase (ALP) levels and urinary hydroxyproline to creatinine ratios in most patients. Duration of biochemical response did not appear to correlate with the administered dose, but did correlate with both pretreatment biochemical disease severity and the percentage decrease in ALP levels 6 weeks after treatment. Response durations may be long.

Tolerability

Pamidronate is very well tolerated. Within 5 days of their first infusion, 60 to 75% of patients experience a transient febrile response (v0.5°C elevation in body temperature) that lasts ≤24 hours. This acute-phase reaction, which may be accompanied by myalgias and lymphopenia, is normally responsive to paracetamol (acetaminophen). Nonfebrile patients may also develop transient lymphopenia.

Mild thrombophlebitis at the injection site and transient, asymptomatic hypocalcaemia and transient neutropenia have also been reported after pamidronate. A small proportion of patients (≤ 1%) experience reversible ocular complications, principally uveitis and scleritis reactions.

Dosage and Administration

Pamidronate is administered by intravenous infusion. Patients with stage III multiple myeloma or breast cancer and at least 1 osteolytic bone lesion should receive pamidronate 90mg monthly together with systemic antitumour treatment. The optimum duration of pamidronate therapy is not yet defined. However, in large, randomised trials, patients with breast cancer or multiple myeloma, respectively, received 24 and 21 monthly cycles of pamidronate.

For patients with moderate tumour-induced hypercalcaemia [adjusted serum calcium 2.99 to 3.37 mmol/L (12.0 to 13.5 mg/dl)], the recommended dose of pamidronate is a single 60 to 90mg infusion. In severe hypercalcaemia [>3.37 mmol/L (13.5 mg/dl)], pamidronate 90mg should be administered.

In patients with Paget’s disease, the optimum pamidronate dosage is not known. Recommended regimens include pamidronate 30mg daily for 3 days (US) and 180 to 210mg administered in divided doses over 6 weeks (UK). Dosage regimens based on initial biochemical disease severity may also be appropriate.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Allan J. Coukell & Anthony Markham

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  1. Allan J. Coukell
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Correspondence to Allan J. Coukell.

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Coukell, A.J., Markham, A. Pamidronate. Drugs & Aging 12, 149–168 (1998). https://doi.org/10.2165/00002512-199812020-00007

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