Paget’s disease: A therapy update

You’ve probably heard of Paget’s disease, but you may not realize it’s the second most common metabolic bone disease, after osteoporosis. In this chronic and progressive bone-remodeling condition, large and abnormal osteoclasts increase bone resorption (breakdown) at single or multiple bone sites.
At first, bone resorption exceeds bone formation. Eventually, normal bone-forming cells (osteoblasts) are stimulated to form new bone rapidly in a disorganized, dysfunctional way. Bones affected by Paget’s disease are larger and weaker than normal, with increased metabolism and blood supply, which in turn can lead to bone pain, arthritis, skeletal deformities, and fractures. Although the disease can affect any bone, the most common sites are the spine, skull, pelvis, and weight-bearing leg bones. Long-term observation indicates that the disease doesn’t spread from one bone to another.
The earlier a correct diagnosis is made, the sooner effective treatment can begin. Complications (which may include stress fractures, painful joints, and bowed limbs) can lead to disabilities that affect independence and mobility, contribute to depression, and reduce quality of life. If the disease affects the skull, headaches and hearing loss may occur.
Appropriate therapy may suppress disease activity and prevent further complications. That’s why it’s important for you to understand this disease, be able to recognize symptoms, and teach patients about management.

Incidence
Paget’s disease affects about 1% to 3% of the U.S. adult population older than age 60. Prevalence increases with age and is slightly higher in men than women. Its cause is unknown, although studies point to both genetic and environmental factors. First-degree relatives of Paget’s disease sufferers are more likely to have the disease than individuals in the general population.

Assessment and diagnosis
Paget’s disease sometimes doesn’t cause symptoms. When it does, the most common primary symptom is bone pain. If long bones are affected, they may become bowed, and skin over the pagetic lesion commonly feels warm from increased blood flow to the site.
A healthcare provider may first suspect the disease when laboratory tests show an elevated level of serum alkaline phosphatase (ALP)—a biochemical marker of bone turnover—with no apparent cause (such as hepatic disease). However, the serum ALP level may be normal if the disease site is small.
In some cases, Paget’s disease is first diagnosed from X-rays taken after a bone fracture or for some other reason. At diagnosis, experts commonly recommend a radionuclide bone scan to document disease extent throughout the body.

Obtaining the patient history
Find out if and when the patient was previously diagnosed with Paget’s disease, the dates of pharmacologic therapy, previous and current primary and secondary symptoms, and family history of the disease. Also document current and previous medical conditions, fractures, surgeries, medications, height (maximum and current), and weight. To help individualize therapy, assess the patient’s mobility, balance, hearing, ability to perform activities of daily living, and psychosocial status.

Drug therapy
The physician may prescribe drugs if the patient:
•    has signs or symptoms of the disease
•    will undergo surgery at an affected bone site (to decrease the risk of excessive bleeding)
•    has hypercalcemia, as from immobilization.
Drug therapy also can help prevent the disease from progressing and reduce future complications.
Currently available drugs for Paget’s disease, known as antiresorptive agents, act by inhibiting osteoclast function, which leads to reduced bone turnover, normal new bone deposition, and slowed disease progression. These drugs also may reduce complications, such as pathologic fractures. Bisphosphonates, a category of antiresorptives, are the drugs of choice.

Oral bisphosphonates
Oral bisphosphonates include risedronate (Actonel), alendronate (Fosamax), tiludronate (Skelid), and etidronate (Didronel). They are taken daily in courses that typically last several months. Because these drugs are poorly absorbed from the GI tract and may bind with calcium in the stomach, patients must follow specific dosing instructions carefully to ensure adequate drug absorption and avoid esophagitis and other GI adverse effects.
A normal or reduced serum ALP level several months after therapy mean bisphosphonate treatment has succeeded. Periodic serial ALP measurements are done to determine if or when the patient needs additional treatments.
If the patient relapses after successful therapy, a treatment course with the same bisphosphonate might be repeated. On the other hand, if a specific bisphosphonate is unsuccessful or poorly tolerated, the physician may prescribe a different bisphosphonate. Unfortunately, some patients acquire bisphosphonate resistance—a progressive decrease in drug efficacy with repeated courses of the same agent.


I.V. bisphosphonates
Two I.V. bisphosphonates are available:
•    Pamidronate (Aredia) requires a 2- to 3-hour I.V. infusion. Dosage and number of infusions vary with disease severity and remission rates.
•    Zoledronic acid (Reclast) is given once as a 5-mg, 15-minute I.V. infusion. After a single infusion, many patients experience extended disease remission.

A closer look at zoledronic acid
The most recently approved bisphosphonate for treating Paget’s disease, zoledronic acid, has a high affinity for hydroxyapatite crystals (bone mineral), which accounts partly for its increased potency. This affinity allows the drug to be recycled at the bone site during normal bone turnover, maintaining therapeutic effect longer than other bisphosphonates. Given only once, it offers the advantages of convenience and assurance of compliance. (Important: Patients should not take Reclast if they are receiving zoledronic acid as cancer therapy.)
Drug efficacy. Pooled results from two double-blind, randomized clinical studies found that a single I.V. infusion of 5 mg zoledronic acid produced a therapeutic response at 6 months (defined as either normal serum ALP or at least a 75% reduction from baseline in total ALP excess) in 96% of patients. In contrast, only 74% of patients who received risedronate (Actonel) 30 mg P.O. daily for 60 days achieved this result. Most patients taking zoledronic acid obtained a therapeutic response by day 63 of the study. At 6 months, ALP levels were normal in 89% of the zoledronic acid patients, compared with 58% of risedronate patients.
In a long-term follow-up study, 98% of patients who’d received zoledronic acid maintained a therapeutic response and tolerated the drug well after 2 years. About half had previously received other bisphosphonates and relapsed.
Adverse effects. Zoledronic acid may cause adverse effects within 3 days of administration—primarily flulike symptoms, such as fever and chills, nausea, fatigue, headache, and pain in muscles, bones, or joints. Most symptoms were of mild to moderate severity and resolved within 4 days.
A small percentage of patients with Paget’s disease develop osteonecrosis of the jaw (ONJ) during bisphosphonate therapy. This rare condition is marked by dissolution of the gums, which leaves the underlying bone exposed. The bone may heal after antibiotic therapy, but in some patients it must be removed. About 95% of ONJ cases occur in patients with advanced cancer (particularly breast cancer and multiple myeloma) who receive high doses of I.V. bisphosphonates for more than 1 year to help prevent complications of cancer metastasis to the skeleton. The estimated risk is less than 1 in 100,000 patient-years in noncancer (Paget’s and osteoporosis) patients.
Administering zoledronic acid. Because I.V. infusion of the 5-mg formulation in 100-ml solution takes only 15 minutes, it can be given in an outpatient setting with appropriate I.V. equipment. Although no specific follow-up or retreatment guidelines exist, retreatment might be considered in patients who relapse and have an increased ALP level, or if the ALP level fails to normalize after initial therapy.

Caring for patients with Paget’s disease
Nurses can help patients and their families understand Paget’s disease and its treatment. Increasing concerns about skeletal health, complications, and safety of drug therapy can cause stress and anxiety. Education and counseling help allay these concerns.
Keep in mind that while bisphosphonates can relieve bone pain, they don’t ease pain caused by such complications as arthritis or nerve compression. Be sure to assess the source of your patient’s pain to help identify appropriate therapies. Besides analgesics, pain management might include physical therapy, hydrotherapy, acupuncture, or orthotics (such as canes or shoe lifts). Some patients also may need surgical repair of fractures or surgical joint realignment or replacement.

Patient teaching
Inform patients that bisphosphonates don’t cure the disease, but they can control it. Tell them complete biochemical remission is less likely in patients with the greatest disease severity. Encourage patients to follow their individualized treatment plan to help minimize symptoms, improve physical functioning, slow disease progress, and limit disability. An excellent resource for patient and family education is available online from The Paget Foundation (www.paget.org).

Selected references
Hosking D, Lyles K, Brown JP. Long-term control of bone turnover in Paget’s disease with zoledronic acid and risedronate. J Bone Miner Res. 2007;22:142-148.
Siris ES, Lyles KW, Singer FR, Meunier PJ. Medical management of Paget’s disease of bone: indications for treatment and review of current therapies. J Bone Miner Res. 2006;21(suppl 2):P94-P98.
The Paget Foundation for Paget’s Disease of Bone and Related Disorders. A nurse’s guide to the management of Paget’s disease of bone. 2007. www.paget.org/pdf/nurse-guide2007.pdf. Accessed April 7, 2008.
Visit www.AmericanNurseToday.com/journal for a complete list of selected references

Betsy McClung is Associate Director of the Oregon Osteoporosis Center in Portland and a member of the Paget Foundation Board of Directors. Jacques P. Brown is Clinical Professor and Head of the Division of Rheumatology at the Centre Hospital of the University of Quebec in Quebec City, Canada and a Member of the Paget Foundation Advisory Medical Panel.  The authors wish to thank BioScience Communications of New York for editorial assistance in development of this manuscript.

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