Elderly Man With Pain in His Thigh

A 77-year-old man complains of deep, aching pain of several months' duration in his left thigh that is exacerbated by both standing and walking. The pain is not relieved by lying down and frequently bothers him at night. NSAIDs and acetaminophen provide moderate but temporary relief. He denies any significant trauma to the area.

HISTORY

His health is otherwise reasonably good. He has moderate hypertension that is well controlled by an angiotensin-converting enzyme inhibitor and a diuretic. He also has mild chronic obstructive pulmonary disease that resulted from smoking (he quit 10 years ago); this is managed with a combination b₂-agonist/corticosteroid inhaler. It has been more than 5 years since he was last hospitalized. His weight is appropriate for his height and age, and his appetite is good; he reports no change in either. He has had nocturia twice nightly for several years but denies dysuria, hematuria, and other genitourinary symptoms. He is a retired mailman and does not use alcohol or illicit drugs.

PHYSICAL EXAMINATION

Blood pressure is 120/75 mm Hg; other vital signs are also normal. No enlarged lymph nodes are noted. Breath sounds are decreased, but no rales or wheezes are audible. Heart rate is 88 beats per minute and regular, without murmurs or gallops. No organomegaly or abdominal masses are detected. The left thigh is warm anteriorly over the femur, and deep palpation of the bone elicits tenderness but no evidence of a discrete mass.

LABORATORY AND IMAGING STUDIES

Results of a complete blood cell count and chemistry profile are normal. The patient's uric acid level is normal, but his alkaline phosphatase level is 492 U/L (normal, less than 125 U/L); transaminase levels are normal. Plain radiographs of the left femur reveal areas of thickened cortex and mottling (osteosclerosis and osteopenia). No discrete lytic lesions are seen, and the remainder of the skeleton shows no abnormalities. A bone scan reveals enhanced radionucleotide uptake in the left femur.

Which of the following statements about the patient's condition is true?

A. MRI and CT are required to make a definitive diagnosis.
B. Hypocalcemia is a frequent metabolic complication of the disease.
C. Neoplastic transformation is a rare but deadly complication.
D. If therapy is required, salmon calcitonin by subcutaneous injection is the pharmacological agent of choice.

CORRECT ANSWER: C

This patient has Paget disease of bone, a relatively common disease (1% of persons older than 40 years) that is seen most often in the elderly and in persons of northern European descent. Pathophysiologically, Paget disease manifests as enhanced, disordered osteoclastic bone resorption followed by abnormal and imperfect attempts at osteoblastic bone repair. Any bone can be affected, but typical targets are the skull, vertebrae, pelvis, tibia, and femur.

The disease is most commonly discovered incidentally in asymptomatic patients, either through radiographs ordered for an unrelated problem or as a result of increased alkaline phosphatase levels on routine blood testing. Symptomatic disease manifests with a deep, aching pain—which is frequently worse at night—in the affected bone, accompanied by palpable warmth in the area involved.

Diagnosis. Paget disease can usually be diagnosed using plain radiographs. Typical radiological changes include osteolytic fronts advancing in affected bones and evidence of abnormal attempts at repair, with cortical thickening, disorganized coarse trabeculae (osteosclerosis), and bone expansion. Because enhanced bone formation and blood flow show as physiological hot spots before changes can be detected on radiographs, bone scintigraphy is useful in defining the extent of disease.

Currently, CT and MRI play a very minor role in the diagnosis of Paget disease in uncomplicated cases. MRI is warranted if the disease is thought to be causing neurological sequelae (eg, Paget disease of the spine encroaching on the spinal cord or Paget disease of the skull impinging on the eighth cranial nerve), but it is not used to make the initial diagnosis. Thus, choice A is incorrect.

Complications. Complications of Paget disease (which may be the presenting findings) include pathological fracture caused by the deranged bone structure; hearing loss resulting from Paget disease of the skull, which causes bone to encroach on the neural foramen of the eighth cranial nerve; and spinal cord compression resulting from encroachment on the spinal cord by Paget bone overgrowth.

Calcium metabolism can be disordered in Paget disease, particularly when the disease is diffuse and extensive and the patient is immobilized because of a complication such as pathological fracture. However, the result is hypercalcemia rather than hypocalcemia. Thus, choice B is incorrect.

A rare but often lethal complication is degeneration of Paget-disordered osteoclasts and osteoblasts into osteogenic sarcoma. Fortunately, this complication occurs in only 1% of patients, but the incidence is far greater than in age-matched controls. In fact, most cases of osteogenic sarcoma, especially those in older patients and those that involve the axial skeleton (as opposed to the long bones, which are more typically involved in young patients) are caused by Paget disease.¹ Thus, choice C is correct.

Treatment. Therapeutics for Paget disease of bone are indicated in 4 settings:

• When symptoms such as bone pain or neurological complications are present.
• As prophylaxis when significant disease occurs in risk-laden areas, such as weight-bearing bones or areas of bone prone to neurological complications.
• When elective surgery, such as a hip replacement, is planned at an involved site.
• If hypercalcemia of immobilization has developed.²

Bisphosphonates are first-line therapy; these agents are effective and available in an oral formulation. They inhibit bone turnover and thus slow or even stop the progress of Paget disease. Reported efficacy is at least 50%; the effect is monitored by changes in alkaline phosphatase levels (normalization or reduction).^1-3 Rare adverse effects of therapy include hypocalcemia⁴ and osteonecrosis of the jaw.⁵

Salmon calcitonin is also effective in about 50% of patients. However, calcitonin requires subcutaneous injection; disease reactivation ensues promptly after lapses in therapy; and resistance develops in 25% of patients. Thus, calcitonin is now clearly a second-line therapy, and choice D is incorrect.