Learning Objectives

1. Describe Paget’s disease of bone and list its 5 symptoms.

2. Explain how the diagnosis of Paget’s disease is established.

3. Explain the relationship between Paget’s disease and arthritis, osteoporosis, heart disease, diabetes, kidney disorder and nervous system disorder.

4. Identify 4 complications of Paget’s disease.

5. Identify 2 classes of drugs used for treating Paget’s disease and list at least 5 specific drugs.

6. Identify 3 situations in which surgery is recommended for Paget’s disease.

What is Paget’s disease of bone?

Paget’s disease of bone is a chronic disorder which typically results in enlarged and deformed bones in one or more regions of the skeleton. Excessive bone breakdown and formation can cause the bone to weaken. As a result, bone pain, arthritis, noticeable deformities and fractures can occur.

The cause of Paget’s disease is unknown. Research findings suggest that Paget’s disease may be caused by a "slow virus" infection of bone, a condition which is present for many years before symptoms appear. There is also a hereditary factor since the disease may appear in more than one member of a family. This hereditary factor may be the reason that family members are susceptible to the suspected virus.

After the age of 40, siblings and children of someone with Paget’s disease may wish to have a standard alkaline phosphatase blood test every two or three years. If the blood test result is elevated, other tests such as the bone specific alkaline phosphatase test, bone scans or x-rays can be performed.

Paget’s disease is most common in Caucasian people of European descent, but it also occurs in African-Americans. It is rare in those of Asian descent. Paget’s disease is rarely diagnosed in people under 40 but may occur in up to 3 percent of the American population over 60. Both men and women are affected.

Bone pain, the most common symptom, may occur in any bone affected by Paget’s disease, and often localizes to areas adjacent to the joints. Headaches and hearing loss may occur when Paget’s disease affects the skull. Pressure on nerves may also occur when the skull or spine is affected. Deformities of bone such as an increase in head size, bowing of a limb, or curvature of the spine may occur in advanced cases. These deformities are due to enlargement or weakening of the affected bones. Hip pain may occur when the pelvis or thigh bone is involved. Damage to the cartilage of joints adjacent to the affected bone may lead to arthritis. Pagetic bone is susceptible to fractures with moderate stress.

No. Many patients who have Paget’s disease do not know they have it since the disease may be so mild that it is not diagnosed. Sometimes the patient’s symptoms are confused with arthritis or other disorders. In other cases, the diagnosis is made only after complications have developed.

Bones affected with Paget’s disease have a characteristic appearance on x-rays. Sometimes, the patient’s doctor is alerted to the possibility of Paget’s disease when a blood test reveals an elevated level of alkaline phosphatase. In such cases, more specific tests may be done.

Alkaline phosphatase is a chemical (enzyme) that is produced by bone cells and is over-produced by Pagetic bone. An elevated alkaline phosphatase level indicates abnormal bone cell activity which can suggest Paget’s disease. In addition to being used as a way of diagnosing Paget’s disease, the alkaline phosphatase level is also used by the physician to monitor a patient’s response to therapy. For example, if a patient had a higher than normal alkaline phosphatase level before therapy was initiated and the alkaline phosphatase level is significantly reduced after a period of therapy, then the physician can determine that the therapy is working for that patient.

Bone scans are useful in Paget’s disease in determining the extent and activity of the condition. Bone scans involve less radiation than x-rays and are also more sensitive than x-rays in detecting areas of bone affected with Paget’s disease. Bone scans use a safe and small amount of a radioactive substance which is injected and circulates through the bloodstream. This substance then localizes in areas where there is Paget’s disease. If a bone scan suggests Paget’s disease, the affected bone or bones should be x-rayed to confirm the diagnosis.

Any bone can be affected in Paget’s disease. Paget’s disease occurs most frequently in the spine, skull, pelvis and bones of the lower extremities (thighs and lower legs). Some patients will have only one affected bone, while others may have two, three or more affected bones. Usually Paget’s disease does not spread to unaffected bones.

The course of Paget’s disease varies greatly and may range from completely stable to rapid progression. In general, symptoms progress slowly in affected bones, and there is usually no spread to normal bones. The outlook is generally good, particularly if treatment is given before major changes have occurred. Treatment can control Paget’s disease and lessen symptoms but is not a cure. When untreated, Paget’s disease can cause serious complications, depending on which bones are affected.

Paget’s disease is rarely fatal. Osteogenic sarcoma, a form of bone cancer, is an extremely rare complication that occurs in less than 1 percent of all Paget’s disease patients.

Wbat is tbe relationship between artbritis and Paget’s disease? Paget’s disease can cause arthritis by changing bones around joints:

1. Long bones such as in the thigh or leg may become bowed and distort the normal alignment and pressures within the adjacent joints.

2. Pagetic bone may become enlarged, causing the joint surfaces to undergo excessive wear and tear.

Osteoarthritis is a very common cause of pain in Paget’s disease, but the disease itself also causes bone pain. Many patients with Paget’s disease have back or joint pain which is often attributed to spinal arthritis alone; however, the pain may be due to both Paget’s disease and osteoarthritis.

Osteoporosis is a condition of generalized loss of bone mass which can lead to fractures. Although Paget’s disease and osteoporosis can occur in the same patient, they are completely different disorders with different causes. Despite their marked differences, many of the treatments for Paget’s disease can also be used to treat osteoporosis.

In patients with extensive Paget’s disease, the heart has to work harder to pump extra blood to affected bones. This usually does not result in heart failure except in some people who already have heart disease such as arteriosclerosis (hardening of the arteries of the heart.)

No. The medications for each of these conditions do not interfere with the treatment of the other disorder. Insulin and calcitonin should never be mixed in the same syringe.

There is no direct relationship between Paget’s disease and kidney problems. However, kidney stones are somewhat more com-

mon in patients with Paget’s disease.

Pain is the most common symptom which brings a patient with Paget’s disease to a physician. Since most patients with painful symptoms of Paget’s disease do not have obvious deformities, they may not be aware of their correct diagnosis. Pain can take many different forms, such as headache, radicular pain (sciatica), muscular pain, osteoarthritic pain, skeletal pain, etc.

A variety of disturbances of the nervous system can be associated with Paget’s disease of the skull and spinal column as a result of pressure on the brain, spinal cord or nerves by enlarged Pagetic bones. Paget’s disease may cause reduced blood flow to the brain and spinal cord.

When Paget’s disease affects the skull and the temporal bone (the bone which surrounds the inner ear), severe and progressive loss of hearing may occur. This may involve both sides or one side predominantly. If the loss of hearing is progressive and due to Paget’s disease, treating the Paget’s disease may slow or stop the progression of the hearing loss. Hearing aids may sometimes help.

Yes. When the skull is involved, the nerves to the eye may be affected and cause some loss of vision; however, this complication is quite rare.

When Paget’s disease affects the facial bones, the teeth may be affected and become loose. Disturbance of the chewing mechanism may occur.

A. Rarely. Paget’s disease is, on rare occasions, associated with the development of a malignant tumor of bone called a sarcoma. When there is a sudden onset of severe pain or worsening of previous pain, which is not due to a fracture, sarcoma should be considered. In most cases, however, sarcoma is not the cause of increased pain.

No. There is no relationship between the diet and Paget’s disease. In general, people should receive the nutritionally proper amount of calcium (1000-1500 mg daily) and adequate sunshine or 400 units of vitamin D daily to maintain a healthy skeleton. For Paget’s disease patients with a history of kidney stones, the use of calcium and vitamin D should be discussed with your physician.

Exercise is very important in maintaining skeletal health and is recommended for patients with Paget’s disease. Exercise is also helpful in avoiding weight gain and in maintaining the mobility of the joints. Before beginning any exercise program, it is wise to discuss the program with your physician since undue stress on affected bones should be avoided.

Endocrinologists (physicians who specialize in hormonal and metabolism disorders) and rheumatologists (physicians who specialize in joint and muscle disorders) are internists who are generally knowledgeable about treating Paget’s disease. Also, orthopedic surgeons, neurologists and otolaryngologists (physicians who specialize in ear, nose and throat disorders) may be called upon to evaluate specialized symptoms in Paget’s disease.

Two classes of drugs are approved by the Food and Drug Administration (FDA) in the U.S. for the treatment of Paget’s disease. Both classes of drugs suppress the abnormal bone cell activity that is associated with Paget’s disease:

Calcitonin. Calcimar, Miacalcin,and Osteocalcin are three brands of synthetic salmon calcitonin that are taken by injection. Cibacalcin (synthetic human calcitonin) is a form of calcitonin that is only available through a physician who can request it from the manufacturer.

Bisphosphonates. Three bisphosphonates are currently approved:

Etidronate disodium (Didronel). The recommended dose is 5mg/kg/day (200-400mg per day) taken orally once a day on an empty stomach. This means no food, antacid, or other medication should be taken within two hours before or after taking the drug. Also, a course of Didronel should not exceed six months. Repeat courses can be given after rest periods, preferably of at least six months duration.

Pamidronate disodium (Aredia) . The recommended dose in patients with moderate to severe Paget’s disease of bone is three 30mg treatments given in three 4-hour infusions which can be given either on consecutive days or with longer intervals between the three infusions. Depending upon the patient’s response to initial treatment, Aredia may be readministered at various intervals. Adequate calcium intake (1000-1500 mg daily) and vitamin D (400 units) are also recommended for a period of 2 to 3 months after being treated with Aredia.

Alendronate (Fosamax). The recommended dose is a 40mg tablet taken once daily for 6 months. Alendronate should be taken with 8oz of tap water first thing in the morning. Patients should wait 30 minutes before eating any food, drinking anything other than water or taking any medication. Patients should avoid lying down for at least 30 minutes after taking Fosamax. This drug should be used with caution by patients who have disorders affecting the esophagus, the stomach or the intestines. Adequate calcium intake (1000-1500 mg daily) and vitamin D (400 units) are also recommended while taking Fosamax.

Some therapies approved for other conditions can sometimes be used for Paget’s disease. Plicamycin (mithracin) and gallium nitrate (Ganite) are intravenous drugs approved for the treatment of high blood calcium levels in cancer patients. Both have been used in research studies for Paget’s disease but are not specifically approved by the FDA for the treatment of Paget’s disease. Miacalcin (nasal spray calcitonin) is currently approved only for treatment of postmenopausal osteoporosis. Other new therapies are being developed.

There are generally three major complications of Paget’s disease for which surgery may be recommended. The first is fractures in Pagetic bone. Surgical repair of Pagetic fractures may allow the fracture to heal in better position. The second complication occurs when the patient develops severe degenerative arthritis. If medication and physical therapy are no longer helpful, and if disability is severe, surgery may be considered as an option. Total joint replacement of the hips and knees should be reserved for the most severe cases of arthritis, when other methods of treatment are no longer effective. The third situation involves bone deformity, especially of the tibia. The surgical cutting and realignment of a Pagetic bone (osteotomy) may help painful weight-bearing joints, especially the knees. Medical therapy prior to surgery helps to decrease bleeding and other complications during surgery. If you are having surgery, discuss pre-treatment with your physician.

Rarely, enlargement of the skull may cause the back of the skull to deform and injure the nervous system. This can be helped by neurosurgery. Similarly, a bone in the spine may overgrow and compress the spinal cord and spinal nerves. Often, however, even moderately severe neurologic symptoms can be treated with medication and do not require surgery.

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by bones that break easily, often from little or no apparent cause. There are at least four distinct forms of the disorder, representing extreme variation in severity from one individual to another. For example, a person may have as few as ten or as many as several hundred fractures in a lifetime.

While the number of persons affected with OI in the United States is unknown, the best estimate suggests a minimum of 20,000 and possibly as many as 50,000.

Most forms of OI are caused by imperfectly formed bone collagen, the result of a genetic defect. Collagen is the major protein of the body’s connective tissue and can be likened to the framework around which a building is constructed. In OI, a person has either less collagen or a poorer quality of collagen.

Collagen testing, which is done through a skin biopsy, is used to determine the amount of collagen present and its structure. While these studies identify the vast majority of people who have OI, approximately 15% of individuals with obvious features of OI do not demonstrate a collagen abnormality sufficient enough to be detected by the testing. Because of the complexity of the test, as well as the limited number of laboratories that are qualified to do the testing, it may take 3 to 6 months before test results are known.

The characteristic features of OI vary greatly from person to person and not all characteristics are evident in each case; however, the general features of OI, which vary in characteristics as well as severity, are:

• Most common

• Bones fracture easily

• Can usually be traced through the family

• Near normal stature or slightly shorter

• Blue sclera

• Dental problems

• Hearing loss beginning in the early twenties and thirties

• Most fractures occur before puberty; occasionally women will have fractures after menopause

• Triangular face

• Tendency toward spinal curvatures

• Newborns severely affected; frequently lethal

• Usually resulting from a new gene mutation

• Very small stature with extremely small chest and under developed lungs

• Tend to be isolated family incidents

• Very small in stature – some only three feet tall

• Fractures at birth very common

• X-ray may reveal healing of in utero fractures

• Severe early hearing loss

• Loose joints and poor muscle development in arms and legs

• Barrel-shaped rib cage

• Can frequently be traced through the family

• Bones fracture easily – most before puberty

• Normal or near normal colored sclera

• Problems with teeth – more than type 1

• Spinal curvatures

• Loose joints

OI can be dominantly or recessively inherited and can also occur as a mutation. Therefore, individuals with OI and parents of children with OI are strongly encouraged to seek genetic counseling to determine the likelihood of OI recurring in their families.

At present there is no cure for OI. Treatment is directed toward preventing or correcting the symptoms. Care of fractures, extensive surgical and dental procedures, and physical therapy are often recommended for persons with OI. Wheelchairs, braces, and other custom-made equipment are often necessary.

Individuals are encouraged to seek out medical centers where all aspects of OI, including biochemical, orthopedic, dental, and hearing problems, can be treated.

An orthopedic procedure called "rodding" is frequently considered for individuals with OI. This treatment involves inserting metal rods through the length of the long bones to strengthen them and prevent deformities.

The prognosis for an individual with OI varies greatly depending on the number of symptoms as well as the severity of the symptoms. Despite numerous fractures, restricted activity, and short stature, many adults and children with OI lead productive and happy lives.

The Osteogenesis Imperfecta Foundation, Inc. (OIF) is the only voluntary national health organization dedicated solely to helping people cope with the problems associated with OI. The mission of OIF, Inc., is to improve the quality of life for individuals affected by OI through education, awareness, mutual support, and research into the treatment and potential cure of the disorder. Contact

Osteogenesis Imperfecta Foundation

804 West Diamond Avenue Suite 210

Gaithersburg, MD 20878

Voice (301) 947-0083

Fax (301) 947-0456

Toll Free 1-800-981-BONE

TTY (202) 466-4315

Learning Objectives

1. Describe the purpose of rodding.

2. Discuss the surgery with expanding and nonexpanding rods, and aftercare of the patient.

Rodding surgery is usually restricted to children with moderate and severe forms of osteogenesis imperfecta (OI). The treatment, which is tailored to a patient’s needs, involves straightening and internal splinting (rodding) of one or more long bones.

Rodding is recommended when a child is having repeated fractures of one or more long bones. In most cases, the long bone is deformed from repeated fractures and bending of the soft bone. A curved long bone is not in itself a reason for rodding unless it worsens or becomes painful because of stress fractures.

When a child is ready to walk but is not making progress because of repeated fractures, rodding is used to help strengthen and straighten the child’s bones. Under these circumstances, straightening of the bone and internally splinting it with a rod corrects the deformities, reduces the fracture rate, and improves the child’s well being.

Babies with severe forms of OI have numerous fractures at birth and repeated fractures over the following months. The fractures are usually treated with splints or casts rather than surgery. Surgery may be needed over the following years if repeated fractures of one or more long bones occur. Children with moderately severe forms of OI also have numerous fractures at birth but few new fractures until they start to stand and walk, which is when repeated fractures of the upper thigh bone (femur) may occur; at this time, surgery may be required.

Rodding is usually undertaken as a scheduled elective procedure after the fracture has healed. However, it can also be undertaken soon after a fracture to avoid a second period in a cast.

In 1946, Dr. H. Scofield developed the commonly used method of straightening the deformed bone and internally splinting it with a stainless steel rod. This method, which used a nonexpanding rod, was refined by Drs. Miller and Williams. Drs. Bailey and Dubow developed a method that used an expanding rod, in which one half of the rod consists of a tube and the other half a spike. Flanges at the end of the rod anchor it to the ends of the bone so that the spike can slide within the tube during growth. A modified version of this rod, the Sheffeld expanding rod, was developed by Drs. Sharrard and Bell in Sheffield, U.K.

In the original Scofield procedure, the full length of the deformed long bone is exposed, divided into pieces, and threaded onto a straight, nonexpanding rod (like a shish kebab). It requires a long incision in the skin and underlying tissues, and bone healing may be slow. Alternatively, small incisions can be made at the end of each deformed bone, which is corrected with minimal disturbance of the blood supply to the bone, thus encouraging the bone cut to heal rapidly. The rod is introduced through the skin and moved through the bone under x-ray guidance.

Nonexpanding rods come in various widths and lengths and can, therefore, be used in almost any OI long bone. They are inserted to support the full length of the long bone. In some cases, the rod is advanced across the growth areas, which are near the ends of the bone, to provide better support. The smooth surface of the rod does not reduce the growth of the bone. The major disadvantage of the nonexpanding rod is that it fails to support the bone that grows beyond it. If the unsupported bone gradually bends, the end of the rod may protrude from the bone surface and the bone may fracture. Under these circumstances, the bone is straightened and a new rod inserted. In many children, however, the nonexpanding rods are inserted in early childhood, when they are needed most, and may not need to be changed later even though the x-ray may show mild bowing of the unsupported bone beyond the rod.

The expanding rods have the advantage of supporting the bone while it grows. Their use is limited to bones that are sufficiently wide to accommodate the thicker expanding rod, and the bone needs to be sufficiently strong to anchor the flanges at the ends of the rod.

Rodding procedures are most often undertaken in the thigh bone (femur) and shin bone (tibia). Occasionally, the arm bone requires rodding as well. With modern anesthesia, children can be sedated for longer periods of time, thereby enabling several bones to be rodded at one time. (e.g., the femur and tibia of one leg).

After the surgery, the limb is often supported by a lightweight cast for about four weeks. An above-the-knee cast is used following tibial surgery. The knee may be bent so that the child can sit in a wheelchair or stroller. Casting following femoral surgery is more difficult. A hip spica, which extends from the ribs down the affected leg, may be required. However, an above-the-knee half cast that does not extend above the hip may be sufficient. Bracing may be used after the removal of the cast to provide added support for standing and walking.

There are many considerations in determining whether rodding is necessary and, if so, when and how it should be done. Because OI is so variable, the treatment plan needs to be specific for each child. Overall, the rodding procedures are successful with a low frequency of complications.

This information was prepared by Dr. William G. Cole, MBBS, PhD, FRACS, FRCSC, who is Head, Division of Orthopedics, Professor of Surgery, University of Toronto, Canada. He also is a member of the OIF Medical Advisory Committee.

This information has been brought to you by:

Osteogenesis Imperfecta Foundation

804 West Diamond Avenue Suite 210

Gaithersburg, MD 20878

Tel (800) 981-BONE or (301) 947-0083

Fax (301) 947-0456

Osteoporosis and Related Bone Diseases~

National Resource Center

1150 17th Street, NW, Suite 500

Washington, DC 20036

Tel (800) 624-BONE or (202) 223-0344

Fax (202) 223-2237, TTY (202) 466-4315

Hypophosphatasia is one of several disorders that resembles osteogenesis imperfecta. It is an inherited metabolic (chemical) bone disease that results from low levels of an enzyme called alkaline phosphatase (ALP). Enzymes are proteins that break down other chemicals in the body so the body can use them. ALP is normally present in large amounts in bones and the liver. In hypophosphatasia, abnormalities in the gene that makes ALP lead to the production of inactive ALP. Subsequently, several chemicals, including phosphoethanolamine, pyridoxal 5/-phosphate (a form of vitamin B6) and inorganic pyrophosphate, accumulate in the body and are found in large amounts in the blood and urine. It appears that the accumulation of inorganic pyrophosphate is the cause of the characteristic defective calcification of bones seen in infants and children (rickets) and in adults (osteomalacia).

The severity of hypophosphatasia is remarkably variable from patient to patient. The most severely affected fail to form a skeleton in the womb and are stillborn. The mildly affected patients may show only low levels of ALP in the blood, yet never suffer bone problems.

In general, patients are categorized as having "perinatal," "infantile," "childhood," or "adult" hypophosphatasia depending on the severity of the disease and the age at which the bony manifestations are first detected. The x-ray changes are quite distinct to the trained eye, and the diagnosis is substantiated by measuring ALP in a routine blood test. It is important that the doctors use appropriate age ranges for normal ALP levels when interpreting the blood test.

Odontohypophosphatasia refers to children and adults who have only dental, not skeletal, problems. This usually involves premature loss of teeth.

It has been estimated that the severe forms of hypophosphatasia occur in approximately one per 100,000 live births. The more mild childhood and adult forms are probably somewhat more common. About one out of every 300 individuals in the United States is thought to be a carrier for hypophosphatasia.

There are reports of blue sclera (whites of the eyes) during infancy and childhood that may resemble osteogenesis imperfecta. Depending on the severity of the skeletal disease, there may be deformity of the arms, legs and chest. Frequent bouts of pneumonia can result if the chest distortion is severe. Recurrent fractures can also occur. Teeth may be lost prematurely and the teeth may have wide pulp chambers that predisposes them to cavities. These symptoms resemble some of those found in osteogenesis imperfecta.

The outcome following a diagnosis of hypophosphatasia is variable. Cases detected in the womb or with severe deformities at birth almost invariably result in death within days or weeks. When the diagnosis is made before six months of age, some infants have a downhill course while others survive and even do well. When diagnosed during childhood, underlying rickets

may or may not result in the presence of skeletal disease.

Premature loss of teeth when the child is under the age of five is the most usual manifestation. Adults may be troubled by recurring fractures in their feet and painful, partial fractures in their thigh bones.

There is no established medical therapy for hypophosphatasia.

The severe perinatal and infantile forms of hypophosphatasia are inherited as autosomal recessive conditions. The patient receives one defective gene from each parent. Some of the more mild childhood and adult cases are also inherited this way. More mild adult cases are inherited in an autosomal dominant pattern where the patient gets just one defective gene from one parent.

Individuals with hypophosphatasia and parents of children with this disorder are encouraged to seek genetic counseling to understand the likelihood and severity of hypophosphatasia in their family.

Osteoporosis and Reltated Bone Diseases~

National Resource Center

1150 17th Street, NW, Suite 500

Washington, DE 20036

Tel (800) 624-BONE or (202) 223-0344

Fax (202) 223-2237, TTY (202) 466-4315

Osteogenesis Imperfecta Foundation

804 West Diamond Avenue Suite 210

Gaithersburg, MD 20878

Tel (800) 981-BONE or (301) 947-0083

Primary hyperparathyroidism is a metabolic disorder that can result in the loss of bone. It occurs when one or more of the parathyroid glands becomes enlarged and overactive, producing too much parathyroid hormone.

The parathyroid glands are four glands located in the neck, close to the thyroid gland. They produce parathyroid hormone, which plays a critical role in maintaining the blood calcium level within the normal range.

Parathyroid hormone keeps the amount of calcium in the blood from falling too low by releasing calcium from the bones, by conserving calcium that would ordinarily be excreted by the kidneys, and by increasing absorption of calcium from food. Consequently, when too much parathyroid hormone is released, the hormone overdoes what it is supposed to do, resulting in a rise in the level of calcium in the blood.

In most cases (85%), a single parathyroid gland becomes enlarged and develops into a benign tumor, known as an adenoma. In nearly all other cases (15%), two or more glands enlarge, again in a benign fashion, a condition called hyperplasia. Parathyroid cancer is a rare cause of primary hyperparathyroidi- sm.

In the United States, 28 out of 100,000 people can be expected to develop hyperparathyroidism each year. Women outnumber men by two to one, and the frequency of the condition increases with age. In women over age 60, new cases occur in approximately two out of every 1,000 annually.

The most common symptoms of too much calcium in the bloodstream are loss of appetite, thirst, frequent urination, lethargy, fatigue, muscle weakness, joint pains, and constipation. More severe symptoms of higher levels may include nausea and vomiting, abdominal pain, memory loss, and depression.

Too much parathyroid hormone can cause bones to become weak from loss of calcium. Skeletal weakening is one of the classic effects of hyperparathyroidism. A high blood calcium level can also lead to kidney stones. In addition, normal func-

tioning of the kidneys may be impaired over a period of time.

In most cases the cause of this disorder is unknown. In certain families glandular disorders, involving other glands as well as the parathyroid glands, can be an inherited trait, but this is rare. The majority of persons with hyperparathyroidism do not have any relatives with this disorder. A small percentage of those affected inherit it from the mother or father.

Many patients do not have symptoms of hyperparathyroidism and do not develop complications such as bone loss, kidney stones, weakness, etc. These patients are discovered to have hyperparathyroidism in the course of a routine blood test.

Today, bone mass measurement using dual xray absorptiometry (DXA) is used to show a reduction in bone mass in patients with primary hyperparathyroidism. This test is essential to the complete evaluation and monitoring of patients with this disorder; it can help establish when surgery should be recommended and can be used to monitor the course of patients who are followed conservatively.

Removal of the affected gland through surgery will cure this disorder. In those few cases where all the parathyroid glands are involved, a portion of one of the glands is left in place and the rest of the glands are removed. When performed by a surgeon who is experienced in that procedure, the operation has been successful in over 95% of cases; serious surgical complications are quite uncommon. The surgery leaves a thin scar about three inches long above the collarbone.

Occasionally, as a result of surgery, a patient may become hypoparathyroid with a tendency to low blood calcium levels. In such cases, calcium supplements and vitamin D will help maintain a normal calcium level.

Not all patients with hyperparathyroidism should undergo surgery. Although surgery is considered an appropriate treatment even in patients without symptoms, patients with mild hypercalcemia (excess calcium in the blood) and without symptoms or complications are sometimes not operated on. If surgery is not to be performed, it is essential that these patients be monitored regularly by the physicians so that possible later complications can be forestalled. The decision about surgery requires careful evaluation and individual assessment by an expert in this field.

Endocrinologists (medical specialists who specialize in hormone disorders); nephrologists (medical specialists who specialize in kidney and mineral disorders); and surgeons who specialize in endocrine surgery are the physicians who specialize in treating primary hyperparathyroidism. The names of medical specialists and members of the American Association of Endocrine Surgeons can be obtained from The Paget Foundation.

For more information on primary hyperparathyroidism, contact:

200 Varick Street, Suite 1004

New York, NY 10014-1582

Tel 212-229-1582

Fax 212-229-1502

TTY 202-466-4315

Fibrous dysplasia is a chronic disorder of the skeleton that causes expansion of one or more bones due to abnormal development of fibrous tissue within the bone. The abnormality causes uneven growth, pain, brittleness, and deformity in affected bones.

Any bone can be affected by fibrous dysplasia. However, some patients have only one bone involved (monostotic), while others have numerous affected bones (polyostotic). The most common sites of disease are the femur (thigh bone), tibia (shin bone), ribs, skull, facial bones, humerus (upper arm), and pelvis. The vertebrae of the spine are less frequently involved. Although many bones can be affected at once, fibrous dysplasia is not a disease that spreads from one bone to another. Multiple affected bones are often found on one side of the body. Some individuals with fibrous dysplasia develop hormonal problems and a distinct type of skin pigmentation; this condition is referred to as McCune-Albright syndrome. Patients with fibrous dysplasia in only one bone usually do not develop this syndrome.

The exact cause of fibrous dysplasia is not known, but recent studies indicate that it may be caused by a chemical abnormality in a protein in the bone which leads to an overgrowth of the cells that produce fibrous tissue. The chemical abnormality occurs because of a mutation (change) in the structure of the gene that produces the protein. Fibrous dysplasia is thought to be a congenital disorder, meaning that individuals who have it probably had it when they were born.

Fibrous dysplasia is usually diagnosed in children and young adults. If the disease involves more than one bone, it is more likely to produce problems before the age of 10 years. The disease is found equally in males and females and does not appear to vary in incidence among the races. It is a very uncommon disorder; the exact incidence is not established.

The most common symptoms are:

Bone pain Pain may be present as a consequence of the expanding fibrous tissue in the bone. Bone that has been sufficiently weakened by this gradual expansion may signal an impending fracture by the onset of pain. A fracture may cause a sudden increase in severe pain. Less commonly, abnormal bone

could produce pain by pressing on an adjacent nerve. In patients with considerable deformity of the weight-bearing long bones (thighs and shins), arthritis can develop in the hips and knees.

Bone deformity Fibrous dysplasia bone is weaker than regular bone and is easily deformed. Because fibrous dysplasia can affect any bone, bone deformity can occur anywhere in the skeleton. However, bone deformity caused by fibrous dysplasia is most obvious when it occurs in the skull and facial bones. Fibrous dysplasia of the skull may cause loss of vision and hearing.

Fracture When a bone is affected by fibrous dysplasia, the fibrous tissue expands while the surrounding bone breaks down. As a result, although the fibrous tissue is thick, the bone becomes thin and fragile and fractures can occur, particularly in the long bones of the legs, which makes walking difficult.

The bones affected by fibrous dysplasia usually have a characteristic appearance on x-ray. When there is a doubt about the diagnosis, a doctor may obtain a small bone specimen for examination by a pathologist. In some patients, an elevation of the enzyme alkaline phosphatase is found in the blood; however, elevated alkaline phosphatase does not always mean a person has fibrous dysplasia.

There is a great variability in the clinical course of the disorder. Young patients who have fibrous dysplasia in many bones may have more problems than patients with few lesions who may have mild symptoms or no symptoms at all.

Fibrous dysplasia is not usually a fatal disease. It has seldom been thought to have been the cause of death in a patient. A very small percentage of patients with fibrous dysplasia have died from a malignant bone tumor that developed in an affected bone.

Surgical treatment: Surgery is often used to treat fibrous dysplasia. In the past, radiation therapy was also used. Because of a theoretical risk of provoking malignancy, radiation should not be used. Some of the surgical procedures commonly used

are:

- removal of affected bone followed by bone grafting in patients with persistent bone pain;

- removal of bone wedge with placement of nails or pins and bone grafts to correct a deformity;

- removal of bone wedge in tibia with fixation and/or bone grafts to correct a deformity;

- placement of a rod down the shaft of a bone to bridge the fibrous dysplasia lesion and thereby prevent the fracture of a weak bone.

Surgery is recommended for fibrous dysplasia to relieve intractable bone pain; to improve mobility that may be impaired due to skeletal deformity; to facilitate the healing of fractures; to relieve local pressure on the spinal cord, spinal nerves or brain; and to treat the unusual complication of bone sarcoma. The results of these surgical procedures may vary.

Nonsurgical treatment: Pamidronate (Aredia) is a drug previously approved by the Food and Drug Administration for control of high blood calcium levels in patients with malignancies and for Paget’s disease of bone, a disease that superficially resembles fibrous dysplasia. Preliminary studies with pamidronate suggest that some fibrous dysplasia patients may have considerable benefit from this therapy, even though it is not specifically approved for the treatment of this disease. Multiple intravenous infusions of pamidronate have been reported to relieve bone pain and improve x-rays in some patients with fibrous dysplasia. Physicians specializing in bone and mineral disorders who treat Paget’s disease are likely to have the most relevant experience with pamidronate.

Patients with fibrous dysplasia are most often evaluated and treated by orthopedic surgeons. Craniofacial or plastic surgeons are needed to correct facial deformities, and neurosurgeons are needed for treatment of brain or spinal complications.

Exercise is very important in maintaining skeletal health and appropriate exercise is recommended for patients with fibrous dysplasia. It is helpful in avoiding weight gain and in maintaining mobility of the joints. Any exercise program should be carefully supervised by a physician.

For more information on fibrous dysplasia, contact:

The Paget Foundation

200 Varick Street, Suite 1004

New York, NY 10014-1582

Tel 212-229-1582

Fax 212-229- 1502

TTY 202-466-4315

Learning Objectives

1. Explain myeloma bone disease and how it affects bones.

2. Describe clinical symptoms of myeloma bone disease and two possible treatments currently practiced.

Myeloma means, literally, a "tumor composed of cells normally found in bone marrow." The majority of patients with myeloma develop destructive bone lesions, also known as osteolytic bone lesions. These lesions occur primarily in the vertebrae, the ribs, the pelvis, and the skull. They occur in the red bone marrow, where nests of myeloma cells accumulate. Myeloma cells do not have a direct effect on the skeleton; rather, they cause bone destruction by producing signals that activate normal osteoclasts to resorb bone. Why this occurs is not clearly understood. There is currently, however, a large amount of research directed at understanding the mechanisms by which bone is destroyed by myeloma cells.

The skeletal lesions that occur in myeloma not only cause pathological fractures but sometimes deformity and occasionally nerve compression syndromes. The lesions occur most commonly in the vertebrae. The appearance of the vertebral spine may resemble osteoporosis radiologically, although the histologic abnormalities are quite different.

The incidence of myeloma is 3-4/100,000 in the U.S., which translates into approximately 13,500 new cases of myeloma in the U.S. each year. Myeloma is more common in blacks than whites, and the male/female ratio is 3:2. The incidence varies from country to country, with a higher incidence found in most Western industrialized countries. Over the past 30 years there has been a 400% increase in the incidence of the disease. This is probably due to better diagnostic techniques and the higher average age of the general population. However, more frequent myeloma in patients under age 55 may point toward environ-mental causative factors over the past three decades.

Approximately 70% of myeloma patients experience pain of varying intensity, often in the lower back. Sudden severe pain can be a sign of fracture or collapse of a vertebra. Patients also have general malaise and vague complaints. Hypercalcemia, which is present in 30% of patients, causes tiredness, thirst, and nausea, and usually occurs when a patient has impaired renal function.

It is not yet possible to cure myeloma, although it is possible to improve the clinical status and the survival in more patients through the use of chemotherapy, alpha interferon and, possibly, bone marrow transplants.

For myeloma patients with hypercalcemia, the goal is to treat the hypercalcemia and its potentially dangerous complications. In these patients, hypercalcemia is always associated with increased bone resorption and frequently with impaired renal function. The best approach is to treat the myeloma itself and to treat the hypercalcemia with drugs that inhibit bone resorption, such as bisphosphonates, and the careful use of intravenous fluids. Bisphosphonates have been very effective in the treatment of hypercalcemia of myeloma.

The more common situation is the patient with myeloma bone disease who does not have hypercalcemia. Until recently, these patients have been treated for the bone disease with symptomatic therapy, namely analgesics for pain, orthopedic treatment for fractures, or local radiation therapy for localized bone pain. However, recent information suggests that these patients may also benefit from the use of powerful inhibitors of bone resorption, such as bisphosphonates. These drugs inhibit bone resorption and markedly reduce the frequency of skeletal complications, such as fracture and hypercalcemia. They may also relieve bone pain, although this cannot be guaranteed since some patients will have significant preexisting bone disease before bisphosphonates are started. In the majority of patients, bisphosphonates will prevent the bone disease from getting worse but will not reverse the damage that has already occurred. However, the quality of life is certainly better for these patients. While bisphosphonates have not yet been approved by the FDA for this purpose, there are investigative studies currently underway both in the U.S. and in Europe.

The International Myeloma Foundation (IMF), founded in 1990, is dedicated to improving the quality of life for multiple myeloma patients and ultimately to preventing and curing myeloma. IMF focuses on patients with multiple myeloma and their family members as well as physicians and health professionals with specific clinical or research interests in myeloma. IMF holds educational conference for both patients and physicians. The IMF can be contacted at 2120 Stanley Hills Drive, Los Angeles, CA 90046, (800) 452-CURE.

The Osteoporosis and Related Bone Diseases~National Resource Center (ORBD-NRC) also has facts sheets on coping with fractures and pain as well as general information on treatment with bisphosphonates.

I. Mundy, G.R. Myeloma bone disease. Myeloma Today, September-October 1995.

2. Durie, B.G.M. "Multiple myeloma: A concise review of the disease and treatment options." Dr. Durie is the director of Research and Myeloma Programs for the Intercenter Cancer Research Group, Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA.

This information is brought to you by:

Osteoporosis and Related Bone Diseases~National Resource Center

1150 17th Street, NW, Suite 500

Washington, DC 20036-4603

Tel (800) 624-BONE or (202) 223-0344

Fax (202) 223-0344, TTY (202) 466-4315

http://www.osteo.org

ORBD~NRC is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes

of Health.

Learning Objectives

1. Understand the anatomy of the ear.

2. Explain the loss of hearing in people with osteogenesis

imperfecta and Paget’s disease of bone and its management.

For people with metabolic bone disorders such as Paget’s disease of bone or osteogenesis imperfecta, hearing loss is an often overlooked yet serious handicap. To understand the nature of hearing loss in individuals with metabolic bone disorders, it is important to first understand the basic mechanism of hearing.

The ear is divided into three sections: the external, middle, and inner ears (see Figure 1). The external ear includes the outer ear and the ear canal, at the end of which is the eardrum. Behind the eardrum is a small chamber called the middle ear. The middle ear contains three tiny bones (the malleus, the incus, and the stapes) that connect the eardrum and the inner ear; they transmit airborne sound through the middle ear to the cochlea, which is part of the inner ear. Once the sound (or vibration) reaches the cochlea, it is converted into nerve impulses and transmitted by the auditory nerve to the brain, where it is interpreted. A person with a hearing impairment might have a problem in the external ear, middle ear, inner ear, auditory nerve, brain, or in more than one of these areas.

The three primary types of hearing impairment are: conductive, sensorineural, or mixed. When hearing loss is caused by a physical problem in the external ear or in the middle ear, it is referred to as a conductive hearing loss. Sensorineural hearing loss occurs when a sound is conducted normally from the external ear through the middle ear, but the inner ear and/or auditory nerve do not transmit the sound normally to the brain. When the hearing loss involves both conductive and sensorineural components, it is referred to as a mixed hearing loss. Hearing loss is also classified according to degree of severity — mild, moderate, severe, or profound–and whether the hearing loss affects low, high, or all frequencies of sound.

As many as 50% of people with osteogenesis imperfecta (OI) experience hearing loss beginning early in adulthood. It generally appears as a conductive loss in the late teens or early twenties due to problems with the small bones in the middle ear. The bones may be fragile or malformed, or the footplate of the stapes may become fixed and no longer capable of transmitting sound effectively to the inner ear. Changes can also be observed in other areas of the middle and inner ear. A sensorineural loss may also develop. There is much variation in the severity of the hearing loss; some people may have severe to profound hearing impairment in old age, while others may be mildly or moderately hard of hearing. Some people with OI never develop hearing impairment.

It is recommended that any child with OI, and especially those who demonstrate speech problems, speech delay, or recurrent ear infections, should undergo an audiologic assessment. Young adults should have baseline assessment for later comparison, and adults who experience tinnitus (ringing or buzzing sound), often an early symptom of a fixed stapes, should undergo audiologic assessment. For either conductive, sensorineural, or mixed hearing loss, hearing aids that provide adequate amplification may help individuals of all ages.

Individuals with conductive loss that is severe and progressive may be helped with a surgical procedure known as a stapedectomy. In this procedure, the fixed foot plate of the stapes is replaced by a prosthesis that allows for the normal transmission of sound waves to the inner ear. It should be noted, however, that this operation should not be considered routine in OI because of tissue fragility. There are also many other pre- and post-operative issues that need to be assessed, discussed, and clarified before any individual with OI may be considered a "good candidate" for surgery. As a general rule, patients should seek treatment centers where the otologists (physicians who specialize in ear disorders) have considerable experience with stapes surgery.

Hearing Loss in Paget’s Disease of Bone

Although many people lose some degree of hearing as part of the aging process, individuals with Paget’s disease are more likely than other people the same age to have a hearing loss. Research studies have shown that hearing loss is associated with Paget’s disease when the temporal bone (i.e., the bone surrounding the inner ear) is involved, but that this hearing loss is usually not due to compression or other effects on the auditory nerve. Paget’s disease appears to affect the cochlea, the coiled structure of the inner ear that converts sound vibration into nerve impulses. A change in the bone density of the cochlear capsule has been observed in patients with Paget’s disease who have a hearing loss, and this change may be associated with hearing loss in Paget’s. When the temporal bone is involved, a more severe and progressive hearing loss may occur that may involve both sides or one side predominantly.

The type of hearing loss in Paget’s disease may also be conductive. Some causes of the conductive component of the hearing loss may be correctable through surgery; however, this type of surgery has been found overall to be less effective in patients with Paget’s disease than it has been in patients without this disease.

If a hearing loss is progressive and is due to Paget’s disease, treating the underlying Paget’s disease may slow the progression of the hearing loss. Any loss of hearing should be investigated as a medical condition because it may be due to serious or correctable problems such as perforation of the eardrum, infection, or even a tumor in rare cases. It is especially important to investigate the cause of hearing loss when it involves one ear more than the other because the presence of a tumor is more possible.

It is recommended that persons with Paget’s disease and hearing loss, or with Paget’s disease involving the skull, undergo an evaluation by an ear, nose, and throat specialist or an otologist and an audiologic assessment. The physician may also want to study the temporal bone with special tests to determine whether Paget’s disease is present in the ear.

Hearing loss can cause individuals to miss important conversation and communication and to withdraw from full participation in life. Even if hearing loss cannot be corrected with medication or surgery, most hearing loss can be helped with a hearing aid. Other devices may be used along with hearing aids and are available through hearing aid specialists, audiologists, and ear, nose, and throat doctors.

There are many organizations that can be contacted for information about hearing devices and available services. Some of these are:

1 Prince Street

Alexandria, VA 22314 703-836-4444

The AAO-HNS is the not-for-profit professional, educational, and research association for ear, nose, and throat specialists (otolaryngologists). They have fact sheets on hearing loss and can also provide patients with a list of otolaryngologists.

American Speech-Language-Hearing Association (ASHA) 10801 Rockville Pike

Rockville, MD 20852 (800) 638-8255

ASHA is the national professional, scientific, and credentialing association for speech-language pathologists and audiologists. Part of its mission is to ensure that individuals with hearing disorders have access to high quality services to help them communicate more effectively. A toll-free HELPLINE is available for those seeking information. ASHA can also provide a list of certified audiologists.

1 Communication Avenue

Bethesda, MD 20892-3500 (800) 241 - 1044 (800) 241-1055 (TTY)

The NIDCD Information Clearinghouse is a national resource center for information about the normal and disordered mechanisms of hearing, balance, smell, taste, voice, speech, and language. It provides an information service to respond to professional and public inquiries; develops and distributes publications such as fact sheets, bibliographies, information packets, and organization directories; and maintains a database of references to journal articles, books, audiovisual materials, brochures, facts sheets, and other educational materials.

7910 Woodmont Avenue, Suite 1200

Bethesda, MD 20814

(301) 657-2248

SHHH is a national self-help organization for people who are hard of hearing. SHHH can help with information on coping with hearing loss.

1150 17th Street, NW, Suite 500

Washington, DC 20036-4603

202-223-0344, 800-624-BONE

Fax: 202-223-2237 TTY: 202-466-4315

Internet: http://www.osteo.org