Paget's disease 

Many people may dismiss these disabilities as a natural part of aging. The average age of diagnosis is 58 (although the disease actually may begin much earlier). But the disease is treatable, and with newer drugs on the market--including two approved by the Food and Drug Administration in 1991 and 1995--there is greater opportunity for patients with Paget's disease to find pain relief, limit the progression of their disease, and, in some cases, reverse bone damage.

The challenge now, experts say, is to identify patients early and, if feasible, start treatment promptly. It's estimated that 3 percent of the American population over 40 is affected. The problem is that many people with Paget's disease don't know they have it because often it develops without symptoms.

Bone Gone Awry

Paget's disease gets its name from Sir James Paget, an English doctor who served as surgeon to Queen Victoria. He first described the disease's characteristics in 1876.

Many years later, scientists realized Paget's disease is a disruption in the normal activity of bone tissue.

Bone is constantly being broken down by cells called osteoclasts and rebuilt by cells called osteoblasts. This is called bone turnover, and throughout the entire skeleton, this process is normally in precise balance.

In Paget's disease, the process goes awry. In discrete portions of bone, overly large osteoclasts dissolve bone too quickly--as much as 50 times faster than normal. Osteoblasts try to compensate for the increased pace by rapidly depositing new bone. But, in the hurried process, the newly deposited bone is loose and bulky in structure, rather than strong, compact, and neatly arranged.

Over time, pagetic bone becomes weak and soft and can easily bend, actually shortening the part of the body affected: for example, a leg or the spine. The bone may enlarge in diameter, though, and it can become painful and break easily.

Any bone can be affected, but the most common sites are the spine, skull, pelvis, and legs. Some patients may have only one affected bone, while others may have two or more. The disease usually does not spread to unaffected bones.

Common deformities include bowed legs, an enlarged head or pelvis, and a curved back. Pagetic bone can affect other parts of the body, causing added problems. For example, it can change bones around joints, causing arthritis. If in the skull and the temporal bone (the bone surrounding the inner ear), Paget's disease can affect hearing. When it affects the facial bones, it can cause dental problems.

Because of changes to the bone, pagetic bones often contain more blood vessels than normal, increasing blood flow to affected bones. Because the heart has to work harder to pump the extra blood, Paget's patients with heart disease may be at even greater risk for heart failure.

Paget's disease is rarely fatal. However, fewer than 1 percent of patients may develop osteosarcoma, a form of bone cancer, and other sarcomas. Most Paget's patients die from causes unrelated to Paget's disease.

Causes

No one knows what causes Paget's disease, although genetics may play a role. Several studies indicate that 15 to 30 percent of Paget's patients have family members with the disease. Those with a first-degree relative--parent, sibling or child--with Paget's disease are seven times more likely to develop the disease than those without an affected first-degree relative.

"It clearly runs in families," says Ethel Siris, M.D., an endocrinologist at Columbia University College of Physicians and Surgeons in New York City. She says the risk increases if the first-degree relative has more severe disease and an early age at diagnosis. Paget's disease is rarely diagnosed in people under 40, although there have been cases. Siris says she's treated patients in their late 20s and early 30s.

The family history related by several patients seems to bear out Siris' conclusions: Evelyn Nef, 83, of Washington, D.C., who was diagnosed with Paget's disease in 1962, says her brother and sister also suffer from the disease. Halstead, who was diagnosed in his 30s, says his two brothers have the disease and his mother, who is 102, was diagnosed three years ago.

The role of genetics also is supported by observations that certain ethnic groups have higher rates of Paget's disease. According to the Paget Foundation, Paget's disease is most common in Caucasian people of Anglo-Saxon and European descent, but it also occurs in African Americans. It is rare in people of Asian descent.

Research by Frederick Singer, M.D., an endocrinologist with the John Wayne Cancer Institute at Saint John's Hospital and Health Center in Santa Monica, Calif., may eventually yield proof of a genetic role. Studying an Iowa family with a history of Paget's disease, Singer and his colleagues traced a genetic abnormality to chromosome 18. The precise gene has yet to be identified, Singer says, but when it is, genetic tests may be able to predict who will get the disease. "I think that's coming pretty fast," he says.

Many experts, Singer included, also suspect that a slow virus may play a role. The theory is that the virus infects a person early in life, without causing symptoms for many years. This theory is based on studies identifying viral-like particles in osteoclasts from pagetic bone. According to Sakamuri Reddy, Ph.D., assistant professor at the University of Texas Health Science Center at San Antonio, these particles react with antibodies that detect a group of viruses which includes the measles and canine distemper viruses. Reddy and his group also have shown that osteoclasts from patients with Paget's disease contain the measles virus messenger RNA. Osteoclasts of people without Paget's disease do not contain this RNA.

This isn't to say that measles is the cause, though, says Leo Lutwak, M.D., Ph.D., an endocrinologist and medical reviewer in FDA's division of metabolism and endocrine drug products. "The agent may be related to the measles virus," he says.

How do the viral theory and genetics' role fit together? Experts in Paget's disease surmise that heredity may put people at risk for the suspected Paget's virus.

"It may be that some people inherit the tendency to have this virus affect their osteoclasts, while other people are, due to their own genetic makeup, more resistant," Siris writes in the Paget Foundation publication A Patient's Guide to Paget's Disease of Bone.

Accidental Diagnoses

Many patients, especially those with mild cases, first learn they have Paget's disease when a routine blood test reveals an abnormally high blood level of total alkaline phosphatase, an enzyme produced by osteoblasts, as well as cells of the intestine and liver.

When osteoblasts are more numerous or are especially active, the amount of alkaline phosphatase throughout the skeleton is increased. The increased bone alkaline phosphatase spills over into the blood, increasing the serum alkaline phosphatase.

A normal serum alkaline phosphatase ranges from 20 to 141 units per liter (U/L). Patients with severe Paget's disease may have six to 10 times that range. Halstead recalls that at one point his serum alkaline phosphatase rose to nearly 2,000 U/L. Jan Brown of Rockville recalls her alkaline phosphatase was more than 1,000 U/L when she was first diagnosed. "The doctor said he had never seen such a high alkaline phosphatase in as young a person," recalls Brown, who was 52 when diagnosed with Paget's disease.

Sometimes, Paget's patients first learn about their diagnosis when an x-ray taken for other reasons reveals pagetic bone.

Usually, bone pain is the first complaint of patients with symptoms. Bone deformities, arthritic pain, and hearing loss are other complaints that may lead patients to seek medical attention.

Laboratory tests, such as the serum alkaline phosphatase and urinary hydroxyproline (a measure of bone breakdown), may offer evidence of Paget's disease, but x-rays give the definitive diagnosis. Bone scans also may be taken to determine the extent and activity of Paget's disease. Bone scans involve less radiation and are more sensitive than x-rays in detecting areas of pagetic bone.

Treatments

Safe drugs for treating Paget's disease of bone became available only in the last 25 years. FDA approved the first two, calcitonin and Didronel (etidronate disodium), in the mid-1970s.

Salmon calcitonin (Calcimar and Miacalcin) and human calcitonin (Cibacalcin) are synthetic substances similar to the human hormone calcitonin. Synthetic calcitonin preparations help inhibit bone breakdown by decreasing the activity of osteoclasts. Only injectable calcitonin is approved for patients with Paget's disease, although nasal-spray calcitonin, which is approved for other uses, is under study for Paget's disease also, according to the Paget Foundation.

Didronel is taken orally in the middle of a four-hour fast. It is a bisphosphonate, a class of drugs that slows bone turnover.

Two newer bisphosphonates, Aredia (pamidronate disodium for injection) and Fosamax (alendronate sodium tablets), appear to achieve more effective results--as measured by laboratory tests--according to studies, and usually in smaller doses because they are more potent. Aredia, approved by FDA in October 1991, is given intravenously over four hours daily for three consecutive days.

Fosamax, approved by FDA in October 1995, is taken orally. Because this medicine is poorly absorbed, patients should take Fosamax with a glass of water first thing in the morning, then wait at least 30 minutes before taking other medications, eating, or drinking anything other than water. Also, to help prevent esophageal irritation and to ease delivery of the medicine to the stomach, patients should drink a glass of water and not lie down for at least 30 minutes after taking Fosamax.

In clinical studies, patients receiving Fosamax had a 20 to 25 percent greater drop in serum alkaline phosphatase levels than those receiving Didronel. The drop was up to 65 percent greater compared with placebo, which had little effect on alkaline phosphatase levels. Bone tissue studies indicated that normal bone was produced during treatment with Fosamax, even where preexisting bone had the abnormally disorganized pattern characteristic of Paget's disease.

Fosamax and Didronel usually are taken for no longer than six months at a time. If symptoms worsen or laboratory tests indicate a worsening of the disease, the drugs may be restarted after at least a six-month break from the medications.

Additional Therapies

According to the Paget Foundation, several more bisphosphonate drugs are undergoing clinical tests. These drugs may offer greater ease of use, says Charlene Waldman, executive director of the Paget Foundation.

Because new bone formation occurs as part of the process of repair in pagetic bone, it is important that along with calcitonin and the bisphosphonates to inhibit abnormal bone breakdown, patients eat a diet that provides 1,000 to 1,500 milligrams of calcium and 400 International Units of vitamin D daily. These nutrients are needed for proper bone formation.

Calcium can be obtained by eating a well-balanced diet that includes foods that are good sources of calcium--for example, milk and milk products, dark-green leafy vegetables (such as mustard greens and kale), and canned fish with soft bones (such as sardines and salmon). Dietary supplements of calcium may be another source.

Some Paget's patients, especially those with severe bowing of legs, fractures, and degenerative arthritis, may need splints, braces, and other devices such as canes and walkers. Patients also may receive physical therapy.

Although uncommon, surgery may be required, especially in cases of fractured bones, severe arthritis, and progressive deformity of leg bones.

Exercise is important for patients with Paget's disease, just as it is for everyone. Because patients with Paget's disease are prone to bone fractures, they should consult their doctors or physical therapists before starting an exercise program.

Various laboratory tests monitor the progression of Paget's disease. The most common is the total alkaline phosphatase. FDA has cleared two tests--Hybritech Ostase in 1994 and Metra Alkphase-B in 1995--that measure only the alkaline phosphatase from bone, since the enzyme in the blood can come from other organs, too.

A possible future test, which is still under research, would measure osteocalcin, a byproduct of osteoblasts, to determine bone turnover rates.

Deciding When to Treat

For many years, doctors generally treated patients with Paget's disease only if they had symptoms. In recent years, with the availability of a wider range of drugs, doctors have begun treating patients without symptoms, as well, hoping that the drugs may prevent the effects of Paget's disease. Factors to consider in deciding whether to treat patients without symptoms, according to Siris, are the location of the disease and the likelihood of its progression. Diseased bone near joints, in the spine or skull, or in the leg bones are particularly "bad spots," she says, and may indicate the need for drug therapy.

Patients who are told they have Paget's disease may want to seek a medical specialist in that condition. The Paget Foundation recommends endocrinologists (doctors who specialize in hormonal and metabolic disorders) or rheumatologists (doctors who specialize in joint and muscle disorders). Orthopedic doctors (who specialize in bone problems), neurologists (doctors who specialize in nerve disorders), and otolaryngologists (eye, ear, nose, and throat specialists) also may be called on to evaluate specific symptoms.

Siris and Michael McClung, M.D., an endocrinologist and director of the Oregon Osteoporosis Center in the Oregon Health Sciences University in Portland, say that too often doctors who aren't specialists in the disease fail to follow up on laboratory tests or x-rays that indicate Paget's disease. "They might tell patients: 'Forget about it. You'll just end up in a wheelchair,'" Siris says. She believes that many doctors aren't aware of current treatments because effective drugs for Paget's disease weren't available when they were trained.

Since Paget's disease often runs in families, medical experts recommend that people with a family history of Paget's disease have their serum alkaline phosphatase measured after age 40, since the disease rarely shows up in people under 40. The laboratory test can be done as part of the routine medical exam.

With prompt medical attention and treatment, when needed, people with Paget's disease may be able to avoid some of the disease's serious, often painful effects.

Maryland resident Brown hopes that will be true for her. "[The disease] is foremost in my mind," she says. "I wonder: 'Am I going to suffer any deformities from this?' I don't know. But I must be treated or so many things could happen."

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