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Cancer Resources > Cancer News > OncoLink News Flash > May, 2004

Bone metastasis and the bisphosphonates

Julia Draznin Maltzman, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 10, 2004

Introduction

Bone metastases are an extraordinarily common complication of advanced cancer. They are especially prevalent (up to 70%) in breast and prostate cancer. Bone metastases are also a frequent cause of morbidity and mortality. They can cause severe pain, bone fractures, life-threatening electrolyte imbalances, and nerve compression syndromes. Taking care of patients with bony lesions can be very frustrating as the pain and neurologic dysfunction may be difficult to treat and significantly compromises the patients' quality of life. Furthermore, bony metastases, usually signify advanced, often incurable disease.

Osteolytic vs. osteoblastic

Bony metastases are characterized as being either osteolytic or osteoblastic. Osteolytic means that the tumor caused bone break down or dissolution. This usually results in loss of calcium from bone. On X-rays these are seen as "holes" within the bone. Osteolytic lesions are most characteristic of a blood cancer called Multiple Myeloma. Osteoblastic bony lesions, by contrast, imply that there are areas of bone with increased bone production. The tumor somehow signals to the bone to overproduce bone cells and result in rigid, inflexible bone formation. The prototypical cancer that causes osteoblastic bony lesions is prostate cancer. Most cancers result in either osteolytic or osteoblastic bony changes, but some malignancies can lead to both. Breast cancer patients usually develop osteolytic lesions, although at least 15-20 percent can have osteoblastic pathology.

Why the bone?

The bone is not an uncommon site of metastasis for many solid tissue cancers including prostate, breast, lung, kidney, stomach, bladder, uterus, thyroid, colon and rectum. Researches speculate that this may be due to the high blood flow to the bone and bone marrow. Once cancer cells gain access to the blood vessels, they can travel all over the body and usually go where there is the highest flow of blood. Furthermore, tumor cells themselves secrete adhesive molecules that can bind to the bone marrow and bone matrix. This molecular interaction can cause the tumor to signal for increased bone destruction and enhance tumor growth within the bone. A recent scientific discovery showed that the bone is actually a rich source of growth factors. These growth factors signal cells to divide, grow, and mature. As the cancer attacks the bone, these growth factors are released and serve to further stimulate the tumor cells to grow. This results in a self-generating growth loop.

What are the symptoms of bone metastasis?

It must be recognized that the symptoms of bone metastasis can mimic many other disease conditions. Most people with the following problems have other causes for their symptoms and not bone metastasis. That being noted, the most common symptom of a metastasis to the bone is pain. Another common presentation is a bone fracture without any history of trauma. Some people with more advanced disease may come to medical attention because of numbness and tingling sensation in their feet and legs. They may have bowel and bladder dysfunction – either losing continence to urine and/or stool, or severe constipation and urinary retention. Others may complain of leg weakness and difficulty moving their legs against gravity. This advanced presentation would imply that there is tumor impinging on the spinal cord and compromising the nerves. This is considered an emergency and requires immediate medical attention. Another less common presentation of metastatic disease to the bone is high levels of calcium in the body. High calcium makes patients constipated, results in abdominal pain, and can lead to confusion and mental status changes.

Diagnosis of bone metastasis

Once a patient experiences any of the symptoms of bone metastasis, various tests can be done to find the true cause. In some cases bone metastasis can be detected before the symptoms arise. Doctors use x-rays, bone scans, and MRIs to diagnose this complication of cancer. X-rays are especially helpful in finding osteolytic lesions. These often appear as "holes" or dark spots in the bone on the x-ray film. Unfortunately, bone metastases often do not show up on plain x-rays until a quite advanced stage and the cancer has destroyed most of the bony tissue. By contrast, a bone scan can detect very early bone metastases. This test is done by injecting the patient with a small amount of radio-tracing material in the vein. Special x-rays are taken sometime after the injection. The radiotracer will preferentially go to the site of disease and will appear as a darker, denser, area on the film. Because this technique is so sensitive, sometimes infections, arthritis, and old fractures can appear as dark spots on the bone scan and may be difficult to differentiate from a true cancer. Bone scans are also used to follow patients with known bone metastasis. Sometimes CT scan images can show if a cancer has spread to the bone. An MRI is most useful when examining nerve roots suspected of being compressed by tumor or bone fragments due to tumor destruction. It is used most often in the setting of spinal cord compromise.

There are no real blood tests that are currently used to diagnose a bone metastasis. There are, however, a number of blood tests that a physician can obtain that may suggest the presence of bone lesions, but the diagnosis rests with the combination of radiographic evidence, clinical picture, and natural history of the malignancy. For example, elevated levels of calcium or an enzyme called alkaline phosphatase can be related to bone metastasis but these data alone are insufficient to prove their presence.

Treatment

The best treatment for bony metastasis is the treatment of the primary cancer. Therapies may include chemotherapy, hormone therapy, radiation therapy, immunotherapy, or treatment with monoclonal antibodies. Pain specifically is often treated with narcotics and other pain medications such as non-steroidal anti-inflammatory agents. Physical therapy may become important and surgery has an important role to play if the cancer resulted in a fracture of the bone or impingement of a nerve or a nerve root. More recently a new class of medications have become available that treat the pain associated with bony metastasis and serve to restore bone health and integrity.

Along came the bisphosphonates?

The group of drugs that decrease pain from bone metastasis and may improve overall bone health are called the bisphosphonates. Bisphosphonates are analogs of a naturally occurring compound called pyrophosphate that prevents bone breakdown. They are a class of medications widely used in the treatment and prevention of osteoporosis and certain other bone diseases (such as Pagets) as well as in the treatment of elevated calcium. These drugs suppress bone breakdown by cells called osteoclasts, and, can indirectly stimulate the bone forming cells called osteoblasts. It is for this reason and for the fact that bisphosphonates are very effective in relieving bone pain associated with metastatic disease, that they have transitioned to the oncology arena. Unfortunately, bisphosphonates still do not offer a cure. There is increasing evidence that bisphosphonates can prevent bony complications in metastatic malignant diseases and may even improve survival in patients with Multiple Myeloma with lytic bone lesions. Most researchers agree that these drugs are more helpful in osteolytic lesions and less so in osteoblastic metastasis in terms of bone restoration and health, but the bisphosphonates are able to alleviate pain associated with both types of lesions.

Bisphosphonates can be given either orally or intravenously. The latter is the preferred route of administration for many oncologists as it is given monthly as a short infusion and does not have the same thorny side effect profile as the oral bisphosphonates. There are currently two approved and commonly used IV bisphosphonates –Pamidronate disodium (Aredia, Novartis) and zolendronic acid (Zometa, Novartis). Their side effect profile is fairly mild, however patients with renal impairment may not be candidates for this therapy. Research is currently on going on finding new and improved bisphosphonates that may offer more bone protection as well as pain relief. In fact, at last year's San Antonio Breast Cancer Symposium a number of abstracts were presented that looked into novel bisphosphonates and their effect on breast cancer metastasis to the bone. Ibandronate (Bondronet, Hoffman La-Roche) has shown some promise when compared to placebo and Clodronate (etidronate) was shown to actually reduce the number of skeletal metastasis in preliminary clinical trials.

The future

Skeletal metastases remain one of the more debilitating problems for cancer patients. Research is ongoing to identify the molecular mechanisms that result in both osteolytic and osteoblastic bone lesions. Perhaps the use of proteomics and gene array data may permit us to identify some factors specific to the tumor or to the bony lesion itself that could be used as therapeutic targets to teat or even prevent this complication.