The Role of Bisphosphonates in Multiple Myeloma

• Multiple myeloma
• Diphosphonates
• Osteopenia
• Bone resorption
• Fractures, spontaneous

Multiple myeloma is characterized by bone destruction that often leads to some of the most debilitating manifestations of this disease: pain, hypercalcemia, osteopenia, pathologic fractures, and spinal cord compression. These clinical manifestations are due not only to myeloma deposits in the bone, which lead to focal bone destruction, but also to increased osteoporotic activity, resulting in bone resorption. Chemotherapy, even when successful, does not produce skeletal healing, and the dual risks of osteopenia and pathologic fracture persist. Fortunately, this often grim situation has at last begun to yield to pharmacologic intervention since the administration of bisphosphonates has been found to reduce the bone destruction caused by multiple myeloma.

Chemically, the bisphosphonates consist of a phosphorus-carbon-phosphorus backbone and two additional chains (R₁ and R₂) of variable structure (Figure). This structure confers some highly desirable characteristics on these compounds. For instance, the substitution of a carbon atom for oxygen makes the pyrophosphates resistant to hydrolysis and preserves their inhibition of bone resorption. In addition, if the R₁ position is occupied by a hydroxyl group, the molecule has a high affinity for calcium crystals and bone mineral, accounting for its binding to hydroxyapatite crystals in the mineralized bone matrix (1). This results in interference with osteoclastic activity, probably by preventing the attachment of osteoclast precursors to bone. Different chemical groups at the R₂ site account for variability in antiresorptive potency (2).

In general, bisphosphonates are poorly absorbed when administered orally. In addition, many foods, beverages, and medications can reduce drug absorption. Significant gastrointestinal toxicity, manifested by esophagitis, is an additional potential problem with oral administration (3).

Etidronate, a weak bisphosphonate, has not been found to be beneficial in the treatment of myeloma bone disease (4). However, clodronate, which is 10 times more potent than etidronate, …