ABSTRACT: Bisphosphonates have an established role in treating tumor-induced hypercalcemia and decreasing the incidence of skeletal-related events. Recent data suggest that these agents may also prevent skeletal metastases. This review explains how cancer metastasizes to bone and how bisphosphonates may block this process, with a summary of clinical trials supporting the use of bisphosphonates to treat and prevent bone metastases. For skeletal metastases in patients with breast cancer, multiple myeloma, or other solid tumors, bisphosphonates are important adjuncts to systemic therapy. Despite promising results in metastatic prostate cancer, additional trials are needed before bisphosphonates become part of standard treatment in this setting. Ongoing trials are evaluating the preventive role of the third-generation bisphosphonates in breast cancer patients. Until the results of these trials are presented, bisphosphonates should only become a component of adjuvant treatment in the context of a clinical trial. Bone loss, a common consequence of cancer treatment, should be treated with the usual measures indicated for the management of osteoporosis, including bisphosphonates.
The skeleton is a frequent site of metastases in human cancer, and as such is associated with morbid skeletal-related events such as pain, pathologic fractures, hypercalcemia, and cord compression. Bisphosphonates, specific inhibitors of osteoclasts, have an established role in the treatment of tumor-induced hypercalcemia and in decreasing the frequency of skeletal-related events. More recently, evidence is emerging that these agents may prevent skeletal metastases. This review summarizes what happens when cancer metastasizes to bone, how bisphosphonates work, and the clinical trials that support the use of bisphosphonates in the treatment and prevention of bone metastases.
Pathophysiology of Skeletal Metastases
Normal bone is maintained by a dynamic balance between the cells that breakdown or resorb bone (osteoclasts) and the cells that form new bone (osteoblasts). Bone breakdown and new bone formation is constantly ongoing in discrete areas called remodeling units. The regulation of the remodeling unit occurs at several levels. First, the force of gravity puts mechanical stress on bone. Without gravity, as in space, humans lose bone-a major problem for astronauts in prolonged spaceflight. Second, circulating hormones (including parathyroid hormones, calcitonin, insulin, thyroid hormones, vitamin D, sex steroid hormones, and growth hormones) stimulate bone breakdown or new bone formation. Third, the autocrine and paracrine factors are derived from osteoclasts, osteoblasts, and stromal cells in the bone microenvironmment. Gravity, circulating hormones, and most importantly, factors within the remodeling unit orchestrate the activity of osteoclasts and osteoblasts to maintain the balance between breakdown and new bone formation.
The autocrine and paracrine factors that maintain the balance between resorption and new bone formation include transforming growth factors (TGFs), insulin-like growth factors (IGFs), platelet-derived growth factors (PDGFs), tumor necrosis factors (TNFs), interleukins (ILs), and the more recently identified receptor activator of nuclear factor-kappa B ligand (RANK-L), RANK receptor, and osteoprotegerin.[2,3] These factors not only maintain the normal balance, but some (ie, IGFs, PDGFs, TGFs, TNFs) are growth factors for tumors. The bone microenvironment is rich in the relevant factors that support tumor growth, and this may explain why, for example, breast cancer, prostate cancer, and multiple myeloma have a high frequency of skeletal metastases.
RANK-L and osteoprotegerin play central roles in regulating bone resorption. RANK-L drives resorption, osteoprotegerin blocks resorption, and the ratio between them governs normal remodeling, benign metabolic bone disease, and tumor-related osteoclast activation. When tumors metastasize to bone, they produce parathyroid hormone-related protein that stimulates the osteoblasts to produce RANK-L.[4,5] The RANK receptor on the osteoclast precursors is activated by ligand binding and causes immature precursor cells to grow and differentiate into mature osteoclasts (Figure 1). With increased resorption, more tumor growth factors are released, causing a "vicious cycle" of osteoclast activation.[5,6] The increased resorption leads to the clinical sequelae of pain, hypercalcemia, and pathologic fracture, as well as the appearance of a lytic lesion on the skeletal radiograph. Osteoprotegerin is a soluble receptor produced by osteoblasts and stromal cells in the bone marrow. Osteoprotegerin binds to RANK-L and inactivates it, limiting RANK receptor activation and, in turn, resportion.
Increased osteoblastic activity is found in skeletal metastases from prostate cancer. This manifests as new bone formation or sclerosis on the skeletal radiograph. Prostate cancer cells produce the fibroblast growth factor (FGF), bone morphogenetic protein, PDGF, endothelin-1, TGFbeta, and IGF that increase osteoblast activity. Likewise, they produce proteases such as urokinase-type plasminogen activator and prostatespecific antigen, which activate latent TGF-beta and IGF from the bone microenvironment. These support the further growth of prostate cancer cells-hence, another vicious cycle.[10,11]
Action of Bisphosphonates
Bisphosphonates are synthetic analogs of inorganic pyrophosphate (Figure 2). Substituting the central oxygen atom for carbon renders the bisphosphonate structure more stable and resistant to thermal, chemical, and enzymatic degradation. The side-chain substitutions (R1 and R2) of the carbon atom with halogen, sulfur, nitrogen, hydroxyl, or other groups, result in a wide range of structures with varying antiresorptive potencies (Table 1).
Bisphosphonates are specific inhibitors of osteoclasts and act via several mechanisms. These include inhibition of cancer cells binding to the bone matrix[12,13]; inactivation of the adenosine triphosphate-dependent proton pump, which inhibits the secretion of protons required to dissolve the bone mineral matrix; disruption of the osteoclast cytoskeleton; induction of apoptosis of osteoclasts[ 16,17]; inhibition of the recruitment and differentiation of osteoclast precursors; inhibition of matrix metalloproteinases[19,20]; and direct antiproliferative and proapoptotic effects on tumor cells, both in vitro and in vivo.[21-25]
Pamidronate, a second-generation bisphosphonate, and zoledronate (zoledronic acid, Zometa), a third-generation bisphosphonate, have been approved by the Food and Drug Administration for the treatment of hypercalcemia of malignancy and lytic skeletal metastases from breast cancer and multiple myeloma; zoledronate is also indicated for patients with other solid tumors. Clodronate is not approved in the United States but is available in Europe.
Bisphosphonates are not metabolized. When administered intravenously (IV), clearance from the plasma is rapid, but the majority of the drug is taken up by the skeleton, where it remains for a prolonged period. About 20% to 40% of these drugs is excreted unchanged in the urine 24 hours after administration. When administered as an oral formulation, bisphosphonates are poorly absorbed from the gastrointestinal tract with limited bioavailability.
Pamidronate and zoledronate are relatively well tolerated with few side effects.[26,27] Fever, myalgia, arthralgia, headache, diarrhea, asymptomatic hypocalcemia, and nausea are some of the common side effects following intravenous infusion. Severe toxic reactions, acute renal failure, aseptic peritonitis, and a variety of eye lesions have also been reported rarely.
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