Use of Bisphosphonates In Metabolic Bone Diseases

What Are Bisphosphonates

Bisphosphonates, analogs of a naturally occurring compound, pyrophosphate, that serves to regulate calcium, are drugs that prevent Bone Structure .

A History

Bisphosphonates have been known to chemists since the middle of the 19th century. The early uses of bisphosphonates were industrial, mainly for corrosion prevention, and largely used in the textile, fertilizer and oil industries as well as in washing powders.

The study and development of bisphosphonates as a major class of drugs for the treatment of bone diseases began only three decades ago. The first report of the biological characteristics of bisphosphonates was published in 1968. At that time, scientists discovered that bisphosphonates have a marked ability to inhibit bone resorption.

Bone Structure and Development

The two primary bone cells are the osteoclasts and the osteoblasts. The osteoclasts are the cells that resorb, or break down, bone and the osteoblasts are the cells that build up bone.

Bone is built during fetal life, youth and adolescence. Once bones are formed, their shape and structure are continually renovated and modified by two processes known as modeling and remodeling. Both modeling and remodeling result in the replacement of old bone by new bone.

Modeling and remodeling begin with bone being eroded by osteoclasts, which is then followed by osteoblasts refilling the resorption sites. It is necessary for bone resorption to occur in order to trigger bone formation.

Modeling takes place during an individual's growth and is the main process through which the skeleton increases its volume and mass. In modeling, new bone is formed at a different location than where the bone was broken down. This results in a change in the shape of the skeleton and also is the cause for the increase in bone size.

The remodeling process occurs in adults. In remodeling, the growth that increases bone shape and size is modified so that the newly formed bone replaces the broken down bone at the same site. Therefore, no change occurs in the shape of the bone.

Normally, the amount of bone formed during bone remodeling equals the amount of bone destroyed. When more bone is destroyed than formed, however, a bone loss occurs and bone diseases, such as osteoporosis, may develop. In some instances, such as Paget's disease of bone and osteopetrosis, more bone is produced than is broken down, and this bone is architecturally unsound.

How Bisphosphonates Work

Bisphosphonates are drugs that suppress or reduce bone resorption by osteoclasts. They do this both directly, by hindering the recruitment and function of osteoclasts (the bone-resorbing cells) and perhaps indirectly, by stimulating osteoblasts (the bone-forming cells) to produce an inhibitor of osteoclast formation. There is now a reasonable understanding of how these drugs work and the differences between the various types of bisphosphonates are better understood.

Though bisphosphonates suppress the abnormal bone resorption associated with Paget's disease of bone, fibrous dysplasia and metastatic cancer to bone, they do not cure the diseases. Bisphosphonates are particularly effective in relieving pain in these diseases, however. There is no evidence that bisphosphonates interfere with the healing of fractures.

Uses for Bisphosphonates

Non-malignant bone disorders:

Bisphosphonates are being used currently to treat different types of disorders. The first types are non-malignant bone diseases, the most common of which are osteoporosis and Paget's disease of bone. Other non-malignant bone disorders for which bisphosphonates are being studied include osteogenesis imperfecta, fibrous dysplasia, and primary hyperparathyroidism.

Cancer-related disorders:

Since abnormal bone resorption is present in certain cancer-related conditions, bisphosphonates also are being used or studied to prevent or treat this complication of cancer. Hypercalcemia of malignancy (HCM), in which levels of calcium in the blood are elevated, is the most common life-threatening metabolic complication of cancer. Bisphosphonates may have an important role in treating this condition. Two bisphosphonates, Aredia® (pamidronate disodium) and Zometa® (zoledronic acid for injection), are currently approved for this use in the United States.
Certain malignancies are associated with a marked tendency to spread to bone and may further complicate a patient's course with additional problems, such as pain or fractures that result from weakening of the bone. In patients with multiple myeloma or breast cancer in whom the malignancy has spread to the bone, Aredia®, which is approved for these indications, has been shown to reduce the proportion of patients experiencing such problems or to delay their onset. Zometa® was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma and patients with documented bone metastases in conjunction with standard anticancer therapy. Prostate cancer patients should have failed to benefit from continuing treatment with at least one hormonal therapy. In three large clinical trials Zometa® produced reductions in the number of patients experiencing bone complications (pathologic bone fractures, radiation therapy to bone, surgery to bone, spinal cord compression) and produced delay in the onset of such complications.

FDA-Approved Bisphosphonates:

Six bisphosphonates are currently FDA-approved in the United States. Four are in tablet form and two are in intravenous form. As a rule, bisphosphonate tablets should be taken on an empty stomach. Due to the certain properties of these medications, it is vital that patients take oral bisphosphonates in their prescribed manner or poor absorption of the drugs or severe gastrointestinal problems may occur. Patients with kidney disease may not be candidates for bisphosphonate therapy and should discuss their condition with their physician.

In addition, an adequate dietary calcium intake (1000-1500 mg daily) and vitamin D intake (400 units) are recommended during bisphosphonate use, unless there is a history of kidney stones containing calcium. Calcium should not be taken at the same time as the bisphosphonates as this will prevent the body from absorbing both.

Ongoing Studies for Bisphosphonates

Bisphosphonates are being studied in the U.S. and elsewhere for therapeutic use for non-malignant bone disorders, cancer disorders as they affect the skeleton, and hypercalcemia of malignancy.

Glossary of Terms

Bone Resorption: The normal process of breakdown of bone.

Cancer metastatic to bone: The spread of cancer cells from their original location to bone (breast and prostate cancer are the most common of these cancers). The tumor cells grow and multiply in the bone, eventually causing thinning of bone in the area where the cancer cells are deposited, bone pain and, in some cases, a fractured bone.

Glucocorticoids: Hormones produced by the adrenal gland capable of having an anti-inflammatory effect. Glucocorticoids are a type of corticosteroid. Common glucocorticoids are cortisone and prednisone.

Glucocorticoid-induced osteoporosis: Since they work rapidly to control inflammation and pain, glucocorticoids are often used to treat rheumatoid arthritis, asthma and a variety of other diseases. These steroids appear to cause premature death of bone-forming cells and slow their replacement. Therefore, osteoporosis and bone damage are severe long-term side effects of this treatment.

Hypercalcemia of malignancy: A condition in which abnormally high concentrations of calcium are found in the bloodstream of patients with some cancers. Elevations may be seen in association with some cancers, particularly those that spread to bone.

Multiple myeloma: Malignant disease of the bone marrow in which certain cells grow out of control and break down bone.

Osteogenesis imperfecta: A group of genetic diseases of the bone that result in brittle and frail bones.

Osteolysis: The dissolution, or disintegration, of bone.

Osteoporosis: A generalized loss of and thinning of bone that most frequently occurs in women after menopause and increases the risk of fractures, especially in the spine, wrist and hip. Osteoporosis is also relatively common in elderly men.

Paget's disease of bone: A chronic disorder that typically results in enlargement and deformity of certain bones. Excessive breakdown and formation can cause bone to weaken, which can result in bone pain, arthritis, deformities and fractures.

© May 2002