The most visible aspect of myeloma disease is its effect on bones throughout the body. In the majority of patients with multiple myeloma, soft spots develop where the bone structure has been damaged. These can extend from the inner bone marrow to the outside surface of the bone. Soft spots appear as "holes" on a standard bone x-ray and are referred to as osteolytic lesions (see figure). These lesions weaken the bone, causing pain and increasing the risk of fractures.
Although it affects the bone, myeloma is considered a hematologic cancer (or blood cancer), because it develops in the blood's B cells. Treatment of myeloma differs from that of bone cancers (known as sarcomas of the bone).
Bone destruction by osteolytic lesions is caused by two separate events. Rapid growth of myeloma cells inhibits normal bone-forming cells, damaging bone. In addition, production of substances that activate the cells that resorb bone called osteoclasts is increased. Osteoclasts normally break down old or worn out bone and work with bone-forming cells to repair bone. Increased activity of osteoclasts, however, causes bone loss with concomitant loss of bone repair and growth from the suppression of bone formation.
Normally, osteoclasts function with bone-forming cells called osteoblasts to rebuild areas of bone that are wearing out (fatigued). This process is called bone remodeling and healthy bone is continually being remodeled.
During the normal process of bone remodeling, the following steps occur:
Normally, the activity of the osteoclasts and osteoblasts is well balanced–the osteoclasts clear out the fatigued bone and the osteoblasts begin the rebuilding of new bone. In patients with multiple myeloma, bone resorption by the osteoclasts is increased and exceeds bone reformation. Calcium lost from the bones appears in increasing amounts in the patient's serum and urine. This increase in bone resorption may result in pain, bone fractures, spinal cord compression, and hypercalcemia.
In myeloma there is an increase in osteoclast activity that is caused by factors called osteoclastic activating factors or OAFs. These osteoclastic activating factors are known to be released by tumor cells and include a variety of soluble factors known as cytokines. Some of these cytokines are described in the next section.
The bone marrow microenvironment is the area within the bone (the marrow) where stem cells develop into blood cells and the cells of the immune system. In multiple myeloma, the bone marrow microenvironment is the area where the malignant plasma cells develop and grow. An important and promising area of myeloma research is the investigation of ways to make the bone marrow microenvironment less hospitable to myeloma cells.
The bone marrow microenvironment plays an important role in the increased bone resorption that occurs in myeloma. The following steps outline what happens:
A clearer understanding of these mechanisms may make it possible to develop more effective treatments to interrupt, slow down, or halt the series of steps that lead to bone disease and contribute to tumor cell growth and survival in myeloma.
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