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August 2003 Volume 5, Issue 7:
Ask the Expert:
The Pathogenesis and Treatment of Multiple Myeloma Bone Disease
By Robert A. Vescio, M.D.
One of the most common symptoms that lead patients with multiple myeloma to first seek medical attention is bone pain. This pain is caused by the destruction of bone material induced by myeloma cells within the center of the bone.

One of the most common symptoms that lead patients with multiple myeloma to first seek medical attention is bone pain. This pain is caused by the destruction of bone material induced by myeloma cells within the center of the bone. The bones can then become weak and eventually result in small or more substantial fractures most commonly within the spine or ribs. Fortunately, there are now medications that can limit this process. In addition, other treatments such as radiation therapy or new surgical procedures such as kyphoplasty can alleviate or even correct some of these complications.

One might think that there would be evolutionary pressure to produce bones as strong as possible. This is not the case nor is it in your body's best interest. While it is important to have bones strong enough to not break during normal activities, it is not in one's interest to have bones so heavy that limbs become inefficient to move. To accomplish this balance, the body somehow senses the shocks and stresses transmitted throughout the bones and lays down new bone matrix material in areas that are structurally stressed, and dissolves away material in areas which are not needed. This is why it is very important for patients with multiple myeloma to keep active. The stresses incurred by even seemingly non-strenuous activities such as walking, can keep the bones of the legs and spine strong. As an example, astronauts returning from the space station have been found to lose significant bone mass due to prolonged weightlessness. The first astronaut to Mars will likely be taking a bisphosphonate on the way! One can see that prolonged bed rest could also induce similar reductions in bone mass.

If one looks inside the femur, the largest bone in your leg, you can see a strong outer shell with a scaffolding matrix in the middle. The outer portion of the bone is called the bone cortex, while the center of the bone is called cancellous bone. It is in the center of the large bones of the body where blood cells are produced. This area is called the bone marrow. This is where normal plasma cells reside and, consequently, where the malignant version (myeloma cells) also prefers to grow. The smaller bones of the hands and feet do not have bone marrow; hence patients with multiple myeloma typically do not develop fractures or bone lesions in these areas.

The cells within the bone marrow that are responsible for bone remodeling are called osteoblasts (the cells that produce bone material) and osteoclasts (the cells which dissolve bone). In patients with multiple myeloma, the osteoclasts are overactive. The myeloma cells secrete hormones that can stimulate the osteoclasts to break down bone inappropriately. One of these hormones produced by myeloma cells is called RANK Ligand. It attaches to a receptor called RANK on the surface of the osteoclast and stimulates its activation. In addition, other hormones (also called cytokines) are overproduced in the multiple myeloma environment such as IL-6 and TNF. These cytokines may also indirectly stimulate osteoclast overactivity. This is why areas of increased bone breakdown (lesions or lucencies on X-rays) often occur in the regions where myeloma cell proliferation is particularly prominent. When osteoclastic activity is severe, the bone in that area can become weak and calcium (present within the bone matrix) comes out of the bone and into the bloodstream. That is why multiple myeloma patients can have hypercalcemia (high calcium blood levels) when their disease is not well controlled. The pattern of bone involvement differs from patient to patient. Some patients have multiple myeloma diffusely spread throughout their bone marrow. These patients may not have individually identifiable lesions on X-ray but are instead noted to have diffuse osteoporosis (thinning of the bone). Other patients will have discrete collections of tumor cells in their bones that result in what looks like holes on X-ray. One of the problems with multiple myeloma is that the bones do not readily repair these holes even when the multiple myeloma is controlled. This is because the osteoblasts don't rush in to repair these areas of weakness for unknown reasons. It should be remembered that a lesion on X-ray does not mean that there is multiple myeloma still present in this spot. The myeloma cells could have been destroyed by treatment such as radiation but the bone just hasn't filled in the weakened area.

Fortunately, there are now new treatments for multiple myeloma bone disease which have made skeletal related complications such as fractures less common. Treatment of the myeloma itself is one of the most effective ways of controlling further bone breakdown. Often patients at diagnosis will be discovered to have hypercalcemia. With successful treatment, the calcium levels often fall, indicative of less calcium release from resorbed bone. As this occurs, the patient's pain often improves as well. It is likely that much of the pain experienced by multiple myeloma patients comes from some of the cytokines and inflammation that exists around these nests of tumor cells within the bone marrow.

Another important treatment for multiple myeloma directly attacks the overacting osteoclasts. Bisphosphonates are a class of drug known to suppress osteoclastic activity. The initial studies completed in multiple myeloma used relatively weak agents such as etidronate and clodronate. In the Canadian study involving etidronate, 166 patients were randomized to etidronate (5 mg/kg) or placebo in addition to primary chemotherapy with melphalan and prednisone. No significant difference in clinically meaningful events such as new fractures, hypercalcemic episodes and bone pain were noted between the two arms. Clodronate is an oral agent, available in Canada and Europe, which has shown some beneficial effects in multiple myeloma. Treated patients developed less hypercalcemia and non-vertebral fractures. However, back pain and poor performance status were not significantly different between the two groups except at one time point (24 months) and the proportion of patients requiring radiotherapy was similar between the two arms. Similar studies suggest that oral clodronate has a mild to modest beneficial effect on bone pain and fracture development in multiple myeloma. It should be noted that Fosamax (alendronate) and Actonel (risedronate) oral bisphosphonates useful in the treatment of osteoporosis, have not been studied in multiple myeloma. The doses of drug needed to impede bone breakdown in multiple myeloma is significantly higher than that needed for osteoporosis treatment. This is demonstrated by the fact that a recent study showed a single 5mg dose of Zometa per year may be sufficient treatment for osteoporosis.

The first bisphosphonate demonstrated to reduce the bony complications in multiple myeloma patients was pamidronate (Aredia). A randomized trial was performed in which 377 patients with Durie-Salmon Stage III multiple myeloma received either Aredia or placebo (salt water infusion). The proportion of myeloma patients having a skeletal complication (fracture, need for radiation, hypercalcemia, spinal cord compression) was 41% in patients receiving placebo but only 24% in pamidronate-treated patients (p<0.001). In addition, the number of skeletal events/yr was cut approximately in half in those patients treated with pamidronate (p<0.001). The patients randomized to receive pamidronate also had significant decreases in bone pain, and, in contrast to patients receiving the placebo, showed no deterioration in performance status and quality of life at the end of nine months. These benefits continued for the remaining twelve months of the study. In fact, although overall survival was not significantly different between the two treatment groups, the median survival time for the patients with more advanced disease was 21 months if they received pamidronate vs. 14 months for those on the placebo arm (p=0.47).

After this study was completed most patients with bony lesions and multiple myeloma began treatment with Aredia. Recently, a newer more potent agent, zoledronic acid (Zometa) has become available. This drug was noted in animal models to be 100-800 times as potent on a mg per mg basis. This led to a trial comparing Aredia to Zometa in the treatment of hypercalcemia. Zometa was approved for use because a dose of 4 or 8 mg corrected hypercalcemia ~90% of the time vs. only 70% of the time with 90 mg of Aredia. Subsequently, a large randomized trial was performed comparing Zometa to Aredia in patients with multiple myeloma and breast cancer. This was done to see if Zometa was at least as effective as Aredia at preventing the bony complications that these patients develop. The final results demonstrated that the zoledronic acid was at least as effective at preventing bony complications as Aredia in multiple myeloma and slightly more effective than Aredia for patients with breast cancer.

The bisphosphonates are relatively safe drugs. They can cause a flu-like illness and even exacerbate bone pain the first couple of times they are received. All bisphosphonates can cause kidney problems (usually reversible) if given too quickly intravenously. In the above trial, Zometa was given at two different doses (8 mg and 4 mg) each over 5 minutes (compared to the 120 minute infusion time for Aredia). It was then discovered that at this rapid infusion time, some patients receiving Zometa developed kidney damage particularly when the higher dose was used. Because of this, all patients randomized to receive Zometa, received the lower 4mg dose and over a longer period of time (15 minutes). After this modification, the incidence of kidney problems with Zometa matched that seen for patients receiving Aredia. At the present time, either of these drugs (Aredia or Zometa) can be used to prevent bone problems. Zometa is more convenient since it takes only 15 minutes to give versus 120 minutes for Aredia. Since it is likely that these drugs prevent bone disease from getting worse (by impeding osteoclasts), but do not necessarily reverse damage already done, these drugs work best as a preventative treatment. Although never definitively proven in a long-term study, most patients with multiple myeloma and bone disease should receive these medications indefinitely with careful monitoring of kidney function. In addition, it has never been proven that patients with earlier stages of multiple myeloma require treatment with a bisphosphonate. My practice, however, is to treat most patients with these drugs since they work best as preventative treatment, and because there is also laboratory evidence that these drugs can kill myeloma cells in the culture dish. Furthermore, reducing osteoclast numbers and activity by bisphosphonate administration may indirectly slow myeloma cell growth since the osteoclast is the greatest producer of IL-6 in the body and IL-6 is the primary growth factor for the myeloma cell.

Several new agents are under development, the most promising being a synthetic homologue to the naturally occurring osteoclast inhibitor (OPG). This drug AMG-162 has been given to patients with multiple myeloma and appears to be safe and inhibit bone resorption at least comparable to that achieved with pamidronate. Comparative phase III trials are being formulated right now and should start shortly.

Finally, a new procedure has been developed which can help patients who have already developed fractures within the spine causing chronic pain. Unlike fractures elsewhere in the body, once a vertebrae collapses it will never regain its normal height and shape. Many times, this is not a major problem. Patients will lose some height and may lean forward (due to kyphosis of the spine) but eventually, the pain will resolve. Unfortunately, some patients will develop chronic pain due to the non-healing vertebral fracture. If the offending vertebrae can be identified and the collapse is not too severe, a balloon can be inflated into the vertebrae and filled with cement. This procedure is called a kyphoplasty and is being done by more and more orthopaedists. Although not always successful, the procedure itself is relatively safe requiring only an overnight stay in the hospital and can often achieve instant pain relief in suffering patients with vertebral compression fractures of the lower spine.

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