Background Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. Methods Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration >12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly. Results Among 392 treated patients, th...

https://www.nejm.org/doi/pdf/10.1056/NEJM199602223340802

Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma

Bisphosphonates: The first 40 years

PURPOSE: To assess whether pamidronate can reduce the frequency of skeletal morbidity in women with lytic bone metastases from breast cancer treated with hormone therapy. PATIENTS AND METHODS: Three hundred seventy-two women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy were randomized to receive 90 mg of pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 weeks for 24 cycles. Patients were evaluated for skeletal complications: pathologic fractures, spinal cord compression, irradiation of or surgery on bone, or hypercalcemia. The skeletal morbidity rate (the ratio of the number of skeletal complications to the time on trial) was the primary efficacy variable. Bone pain, use of analgesics, quality of life, performance status, bone tumor response, and biochemical parameters were also evaluated. RESULTS: One hundred eighty-two patients who received pamidronate and 189 who received placebo were assessable. The skelet...

Pamidronate Reduces Skeletal Morbidity in Women With Advanced Breast Cancer and Lytic Bone Lesions: A Randomized, Placebo-Controlled Trial

The geminal bisphosphonates are a new class of drugs characterised by a P-C-P bond. Consequently, they are analogues of pyrophosphate, but are resistant to chemical and enzymatic hydrolysis. The bisphosphonates bind strongly to hydroxyapatite crystals and inhibit their formation and dissolution. This physicochemical effect leads in vivo to the prevention of soft tissue calcification and, in some instances, inhibition of normal calcification. The main effect is to inhibit bone resorption, but in contrast to the effect on mineralisation, the mechanism involved is cellular. These various effects vary greatly according to the structure of the individual bisphosphonate. The half-life of circulating bisphosphonates is very brief, in the order of minutes to hours. 20% to 50% of a given dose is taken up by the skeleton, the rest being excreted in the urine. The half-life in bone is far longer and depends upon the turnover rate of the skeleton itself. Bisphosphonates are very well tolerated; the relatively few adverse events that have been associated with their use are specific for each compound. Bisphosphonates have been used to treat various clinical conditions, namely ectopic calcification, ectopic bone formation, Paget's disease, osteoporosis and increased osteolysis of malignant origin. The three compounds commercially available for use in tumour-induced bone disease are in order of increasing potency, etidronate, clodronate and pamidronate. Most data have been obtained with the latter two agents. By inhibiting bone resorption, they correct hypercalcaemia and hypercalciuria, reduce pain, the occurrence of fractures, as well as the development of new osteolytic lesions, and in consequence improve the quality of life. In view of these actions, of their excellent tolerability and of the fact that they are active for relatively long periods, these compounds are, after rehydration, the drugs of choice in tumour-induced bone disease and an excellent auxiliary to the drugs used in oncology.

Bisphosphonates. Pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease.

Three new bisphosphonates of various chain length, namely, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP), 5-amino-1-hydroxypentylidene-1,1-bisphosphonate (AHPeBP), and 6-amino-1-hydroxyhexylidene-1,1-bisphosphonate (AHHexBP) were compared with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (AHPrBP), and dichloromethylene bisphosphonate as to their effect on metaphyseal bone remodeling in the rat. The parameters assessed were growth in length, mineralization, metaphyseal density, mean trabecular diameter, and number of trabeculae. Both metaphyseal density, an index of metaphyseal Ca balance, and number of trabeculae, an index of bone resorption, showed the following sequence of potency: AHBuBP greater than AHPrBP = AHPeBP = AHHexBP greater than Cl2MBP. All compounds decreased trabecular diameter somewhat, an index of bone formation, with AHBuBP decreasing the least. AHBuBP and possibly AHHexBP appear to be interesting new bisphosphonates for future clinical use.

F.J.M. van Breukelen

Papers

Inhibition of osteolytic bone lesions by (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate (A.P.D.).

Vindesine, cisplatin, and bleomycin combination chemotherapy in non-small cell lung cancer: survival and quality of life.