The use of osteoclast inhibitors in patients with multiple myeloma
- James R Berenson, MD
James R Berenson, MD
- Medical and Scientific Director
- Institute for Myeloma and Bone Cancer Research
- Section Editors
- Robert A Kyle, MD
Robert A Kyle, MD
- Section Editor — Plasma Cell Disorders
- Professor of Medicine
- Mayo Medical School
- Reed E Drews, MD
Reed E Drews, MD
- Section Editor — Complications of Cancer
- Associate Professor of Medicine
- Harvard Medical School
Bisphosphonates are synthetic analogues to inorganic pyrophosphates found within the bone matrix that, unlike natural pyrophosphates, are resistant to hydrolysis by phosphatases found in the blood. Bisphosphonates inhibit bone resorption by suppressing osteoclast activity. They are widely used in the management of lytic bone lesions in patients with multiple myeloma (MM), in the treatment and prevention of osteoporosis, in the treatment of moderate to severe hypercalcemia, and in the therapy of certain other bone diseases.
Lytic skeletal lesions are present at the time of diagnosis in approximately 60 percent of patients with MM and almost all patients with MM will have lytic bone lesions at some point in their disease course. In addition, up to 20 percent of patients with MM will have osteopenia and 10 to 15 percent will have hypercalcemia. (See "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma", section on 'Clinical presentation'.)
The use of bisphosphonate therapy and other osteoclast inhibitors in patients with MM will be presented here. The role of bisphosphonate therapy in the management of other disorders is presented separately, as are the specific side effects associated with each agent. (See "The use of bisphosphonates in postmenopausal women with osteoporosis" and "Treatment of hypercalcemia" and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)
MECHANISM OF ACTION
While the exact mechanism is unknown, bisphosphonates appear to inhibit bone resorption by suppressing osteoclast activity. Clinically, this translates into fewer lytic bone lesions and fewer skeletal events (eg, pathologic fracture) in patients with MM. Bisphosphonates are attracted to calcium and calcium containing molecules, such as hydroxyapatite, which is the major calcium-containing mineral in bone . Bone resorption by osteoclasts results in the exposure of molecules of hydroxyapatite within the lytic lesions. Bisphosphonates are attracted to the hydroxyapatite and accumulate in this space, thereby creating a high local concentration of drug and inhibiting further osteoclast activity [1-3]. Although the exact half-life is unknown, bisphosphonates that are incorporated into bone are thought to remain for at least 10 years .
There are two main classes of bisphosphonates, each with a different proposed mechanism of action . Etidronate and clodronate are non-nitrogen containing bisphosphonates. Non-nitrogen containing bisphosphonates are metabolized to cytotoxic ATP analogues, incorporated into the osteoclast, and induce osteoclast apoptosis. In contrast, nitrogen containing bisphosphonates are proposed to suppress osteoclast activity by binding to and inhibiting the enzyme farnesyl diphosphate synthase in the HMG-CoA reductase pathway. Pamidronate, zoledronic acid, ibandronate, and risedronate are examples of nitrogen-containing bisphosphonates.
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- MECHANISM OF ACTION
- BENEFITS OF BISPHOSPHONATES IN MYELOMA
- Use in symptomatic MM
- Use in smoldering MM, MGUS, or solitary plasmacytoma
- RISKS OF BISPHOSPHONATE THERAPY
- PRETREATMENT EVALUATION
- Laboratory evaluation
- Imaging studies
- Dental exam
- CHOICE OF AGENT
- Intravenous pamidronate
- Intravenous zoledronic acid
- Intravenous ibandronate
- ORAL BISPHOSPHONATES
- MONITORING DURING THERAPY
- DURATION OF THERAPY
- SOCIETY GUIDELINES
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS