Paget’s Disease in the Elderly Patient

CASE PRESENTATION

A 67-year-old bedridden African-American female was brought to the emergency room (ER) by her husband with the acute onset of altered mental status changes and urinary incontinence. From her history it was revealed that 1 week prior to this episode she had been evaluated by the Neurology service as an outpatient for possibly having had syncopal episodes over the previous several months. An electroencephalogram (EEG) done during that visit showed cortical instability with intermittent slowing in both hemispheres, and transient sharp waves consistent with a cerebral infarction and/or an underlying structural abnormality. She had not yet been seen for follow-up of these results. The patient had also had an episode of dehydration 4 months prior, and during her work-up at that time a calcium level of 11.2 mg/dL had been found.

Investigation
The patient’s past medical history included hypertension and a cerebrovascular accident (CVA) 8 years previous, with residual left hemiparesis that left her unable to ambulate. Her medications included nifedipine, hydrochlorothiazide, aspirin, and isosorbide dinitrate. She was afebrile, and her vital signs were within normal limits, except for a blood pressure of 178/80 mm Hg. On physical examination, the patient was found to be somnolent but arousable to verbal and tactile stimuli. Her mucous membranes and oral mucosa were found to be dry, and skin turgor was reduced. The lung fields were clear and heart sounds regular without murmurs, gallops, or rubs. No carotid or abdominal bruits were auscultated. Both upper and lower extremities revealed 3+ hyperreflexia with a persistent right-sided facial droop and left-sided Babinski reflex. Her laboratory tests revealed the following: sodium 130 mEq/L; potassium 3.2 mEq/L; chloride 86 mmol/L; blood urea nitrogen and creatinine, 11 and 1.3, respectively; calcium 12.7 mg/dL; magnesium 1.3 mEq/L; and phosphate 1.8 mg/100 mL. Hemoglobin was 11.4 g/100 mL and hematocrit 34%. A finger stick was 125 mg/100 mL, and O₂ saturation was 98%. A toxicology screen was negative, and urinalysis showed only trace protein. A computed tomography (CT) scan of the head showed mild atrophy, periventricular white matter ischemic changes, and an old low-signal density around the right thalamus. A chest x-ray showed an atherosclerotic aorta and a retrocardiac opacity that could have representated atelectasis or pneumonia. An electrocardiogram (EKG) revealed normal sinus rhythm, a left anterior fasicular block, and an old septal infarct. Subsequent laboratory tests showed a low albumin level of 2.9 g/dL, thyroid-stimulating hormone (TSH) of 1.3 μIU/mL, and a mildly elevated alkaline phosphatase of 143 units per liter (U/L).

In addition to intravenous fluids, the patient was started on IV heparin and a beta blocker until the cardiac enzymes came back with negative results. A neurology evaluation in the ER had recommended a malignancy work-up for metabolic encephalopathy, and phenytoin was initiated. The patient was admitted, and a 2-dimensional echocardiogram showed an ejection fraction of 65%, mild-to-moderate mitral and tricuspid regurgitation, and an area of distal anteroseptal and apical hypokinesis.

Diagnosis
Given her elevated serum calcium and alkaline phosphatase levels, a bone scan was done, which revealed intense uptake throughout the skull with accentuation of the skull contour. There was also milder increased uptake involving the T11 and L2 vertebrae. These findings were typical and consistent with a diagnosis of Paget’s disease of bone.

GENERAL ASPECTS OF PAGET’S DISEASE

Paget’s disease (also known as osteitis deformans) is a chronic skeletal disorder that is commonly seen in the elderly, and is the second most common bone disease in the United States after osteoporosis. It involves a dysfunction of osteoclasts that causes rapid bone remodeling, resulting in disorganization, enlargement, and deformation of the architectural structure of bone. There is also an increase in osteoblastic activity. It is usually diagnosed incidentally when x-rays are taken for other reasons, or as part of a work-up such as that for elevated alkaline phosphatase. Paget’s disease is often asymptomatic (80-90% of cases), but when symptoms do occur, localized pain is most common. Arthritis, bony deformities, and fractures can also complicate this condition. Areas of the body commonly affected include the femur (Figure 1), pelvis (Figure 2), spine, and skull (Figure 3). Bony involvement may be monostotic (involving only one bone) or polyostotic (involving multiple bones).¹ With increasing age there is an increase in prevalence. Two to five percent of people age 50 years and older and 10% of those age 80 years and older are affected. The average age of diagnosis is age 58 years. There is a slight predominance of Paget’s disease in men. Epidemiological studies show that Paget’s disease occurs in 1-3% of white Americans age 50 years and over.² It is rare in African Americans and in people of Asian descent.

ETIOLOGY

The etiology is unknown but is thought to be related to viral pathology.³ This is based on various observations having detected particles and viral inclusion bodies of measles, respiratory syncytial virus (RSV), and adenovirus in osteoblasts and osteoclasts of diseased bone.^4-6 Some studies have examined a possible relationship between Paget’s disease and hyperparathyroidism, given that both involve calcium metabolism.⁷ Twenty to 30% of patients have a family history of the disease, and increased frequencies of human leukocyte antigen (HLA)-DQW1 have been found in patients with Paget’s disease. Researchers are investigating a possible genetic role of an abnormality on chromosome 18.⁸ Patients with a first-degree relative with the disease are seven times more likely to develop the condition than the general population. Some researchers suggest that individuals with such a family history have their alkaline phosphatase levels measured after the age of 40 years at a frequency of every 5-10 years.

STAGES

Three stages have been designated, including an osteolytic, an osteogenic, and a late osteosclerotic phase. In the osteolytic phase (occurs early in the disease process), there is heavy osteoclastic activity with breakdown of bone, accelerated bone turnover, and remodeling. The bone marrow is replaced by a richly vascularized fibrous network of tissue that causes the formation of giant, hyperactive osteoclasts.^2,9 Some of these cells contain up to 100 nuclei. The osteogenic (mixed) stage includes both osteoblastic (leading to osteogenesis) and osteolytic activity that is erratic and uncoordinated. A “mosaic pattern” of bone matrix is formed—pathognomonic of Paget’s disease—along with fibrosis of intertrabecular spaces. Cortical thickening occurs that may affect the skull, causing enlargement of the calvarium (Figure 3); however, all affected bones are structurally weak. The late phase of Paget’s disease involves an inactive, “burned-out” osteosclerotic stage where the mosaic pattern persists. The affected bones lack structural strength, are brittle, and are at extreme risk for pathologic and compression fractures.

SIGNS, SYMPTOMS, AND COMPLICATIONS

Paget’s disease can develop insidiously, and no symptoms may be appreciated until the disease has made significant progression. In fact, between 70% and 95% of patients have no symptoms at the time they are diagnosed following an incidental test, such as an x-ray or high alkaline phosphatase level. Signs and symptoms of Paget’s disease include bowing of the femur and tibial bones (due to bone remodeling and stress at those areas), coarsening of facial features, skull enlargement, kyphosis, headache, facial and bone pain, palpable warmth of the skin over an affected bony area, neurologic deficits from spinal cord and nerve root compression, angioid streaks in the retina, and visual disturbances from cranial nerve impingement. Complications involve a heightened risk of deformity and pathologic fractures, usually of the long bones of the lower extremities and axial skeleton (Table I). Arthritis may be present, and there may be increased warmth and erythema overlying pagetic bone, simulating a cellulitic process. Hip fractures typically occur at the femoral neck. Rarely, high-output congestive heart failure can occur from the formation of multiple arteriovenous shunts that return overloading amounts of venous blood to the heart. Osteogenic sarcoma occurs in about 1% of cases.^1,10 Over time, skull and temporal bone deformity compressing the 8th cranial nerve may result in hearing loss, due to involvement of the bones of the middle ear (the ossicles) or narrowing of the auditory foramen.¹⁰ When the facial bones are impacted, dental complications can occur. Unusual presentations such as chest pain and shoulder immobility have also been reported.¹¹ Paget’s disease is also associated with primary hyperparathyroidism, hyperuricemia and gout, as well as certain bone tumors (ie, osteogenic sarcoma, chondrosarcoma, fibrosarcoma, and, rarely, benign giant cell tumors).

DIAGNOSTIC EVALUATION

Common laboratory derangements include an elevated alkaline phosphatase due to bony turnover. The normal range is 20 to 140 U/L, and patients with severe disease may have levels up to 6-10 times that. However, serum and urine calcium and phosphorus are typically within the normal ranges. Since alkaline phosphatase is made in other areas of the body besides the bone, such as the liver, some cases may require a bone-specific alkaline phosphatase assay to assist in confirming an active disease process. Osteocalcin (the major calcium-binding protein of bone matrix) is typically high, as is urinary hydroxyproline excretion, which is a measure of bone breakdown and indicates the degradation of collagen. Urinary excretion of 3-hydroxypyridinium residues and serum procollagen-1 extension peptide are new markers of bony turnover that may be more sensitive indicators of the chronic disease process.¹² Imaging studies utilized in the work-up of Paget’s disease include a radionuclide bone scan, which, with increased uptake of technetium in areas such as the skull and mandible, indicates the extent and activity of the disease (Figure 4). However, an x-ray of the locally affected area showing typical changes, such as osteolysis, is more specific and often diagnostic. A bone biopsy is rarely needed, and should in fact be avoided in weight-bearing bones. However, it should be considered if a radiographically localized bony lesion remains of an unclear etiology, even after an x-ray is done (Table II). Other specialized tests being evaluated to assist in the diagnosis of Paget’s disease include ultrasound, dual energy x-ray absorptiometry (DEXA), and scintigraphy.^13,14

TREATMENT

Depending on the stage of disease progression, the overall prognosis for a patient suffering from Paget’s disease is good; however, there is no cure. No treatment is required if there are no symptoms or evidence of active disease. Traditionally, physicians have only treated patients with Paget’s disease if they manifested symptoms. With newer medications, the goal has shifted from symptom relief to prevention of pathologic sequelae. The location of active disease and its likelihood of progression are key determinants when deciding whether to treat an asymptomatic patient. Areas of concern that may necessitate the initiation of therapy sooner rather than later include disease in the spine, skull, legs, or near joints. General treatments for Paget’s disease include exercise and physical therapy to maintain a normal weight, and the use of nonsteroidal anti-inflammatory drugs and salicylates for mild-to-moderate localized bone pain management. More specific regimens include the administration of bisphosphonates.

Bisphosphonates—which are also often used in the treatment of osteoporosis, as well as fibrous dysplasia, osteogenesis imperfecta, primary hyperparathyroidism, and metastatic bone cancer (ie, multiple myeloma, breast cancer)—have various mechanisms of action. They are first-line drug treatments for Paget’s disease and are analogs of the naturally occurring compound pyrophosphate, which is involved in the regulation of calcium in the body. As antiresorptive agents, they inhibit the function of osteoclasts, thereby suppressing the hyperactive bone turnover that osteoclasts cause, and promoting apoptosis of them. They also reduce the expression of adhesion molecules involved in the disease process, and decrease production of certain cytokines that stimulate osteoclasts (eg, interleukin-6 [IL-6], vascular endothelial growth factor [VEGF]).^8,15-17 Their overall effect is to inhibit bone resorption and relieve pain (Table III). Regimens often include oral alendronate or risedronate,¹⁸ and newer intravenous formulations are being investigated for their efficacy¹⁹ (Table IV). Side effects include gastrointestinal upset and pruritis. Patients should take tablet formulations on an empty stomach and with water to maximize their absorption.

Responses to treatment are assessed over a 1 to 3-month interval. If the first round of therapy is found to have been inadequate, a second course may be given. An adequate response is regarded as one in which there is a fall in alkaline phosphatase of less than 50% when the initial value taken was at least twice the upper limit of normal. Adequate calcium and vitamin D intake is also recommended (1000-1500 mg and 400 IU, respectively). During treatment, the patient’s serum proteins of bone-specific alkaline phosphatase and osteocalcin (both markers of bone formation) should be monitored. The urinary N-telopeptide—a marker of bone resorption—can also be followed.

Other treatments that have been used have included calcitonin (both human and salmon formulations) and plicamycin, both of which act by decreasing osteoclastic activity. Calcitonin (intranasal or subcutaneous) may also provide an analgesic effect, although only injectable calcitonin is approved for treatment. Calcitonin should be given to patients in whom bisphos-phonates are contraindicated or not tolerated; it is not used simultaneously with bisphosphonates. Plicamycin has been used for patients with severe disease who have been found to be refractory to other treatment regimens. Newer diphosphonates (ie, aminohydroxypropylidene diphosphonate [APD])¹¹ may replace some of the traditional treatments. Orthopedic surgery may become necessary in order to repair or replace a severely damaged or deformed joint, such as the hip or knee, or in cases of severe arthritis or fractures. Surgical intervention may also be necessary if the patient is to undergo a needle biopsy, arthroplasty, or spinal stenosis repair with a laminectomy. Braces, splints, and other assistive orthotic devices such as canes and walkers may be utilized as well. The overall goal with the use of these techniques is to improve movement and function by strengthening muscles and reducing pain. Hearing aids may also be useful in patients with hearing loss.

DIFFERENTIAL DIAGNOSIS

A differential diagnosis of Paget’s disease would include other diseases of the bone that cause changes in the levels of measured serum proteins and ions (Table V). These would require the consideration of osteoporosis, multiple myeloma, osteomalacia, and von Recklinghausen’s disease (osteitis fibrosa cystica). Osteoporosis affects two million Americans and is marked by a decrease in bone mass with normal bone mineralization. In terms of bone disease, its prevalence is higher than that of Paget’s disease, and it affects bones throughout the body as opposed to being localized. It is most common in Caucasians and persons of Asian descent, and has the lowest occurrence in African Americans and Hispanic Americans. Risk factors include age and a family history of hip fractures. It is a diagnosis of exclusion. The mechanism of action involves reduced bony formation, as well as elevated resorption of bone matrix. These processes favor normal bony formation until about age 30 years, when peak bone mass is achieved. Between the ages of 30 and 40 years there is a balance; thereafter, resorption dominates with loss of cortical and trabecular bone, and both men and women lose about 0.3-0.5% of bone mass annually.²⁰ Complications involve pathologic fractures (often at the distal end of the radius and the femoral neck) due to bone strength being inadequate for weight bearing. In addition, compression fractures of the vertebrae occur, typically causing kyphosis and shortening of stature, features common in Paget’s disease as well. X-rays show diffuse radiolucency and osteopenia (poorly mineralized bone).

Laboratory tests often show normal levels of calcium, phosphorus, and alkaline phosphatase. X-rays are not sufficient to detect the bone loss; half of the matrix must be resorbed before its absence is detectable by radiographs. Single-photon energy x-ray absorptiometry and DEXA, which provides a bone mineral density (BMD), are much more sensitive in the evaluation of bone density than x-rays, and help to differentiate osteoporosis from other disease entities such as osteomalacia and von Recklinghausen’s disease. Bisphosphonates approved for treatment of osteoporosis are alendronate and risedronate. Multiple myeloma is regarded as a clonal B-lymphocyte malignancy of the elderly, which is diagnosed in about 15,000 people in the United States every year. Last year it was expected that multiple myeloma would be found in 15,270 Americans, and just over 11,000 of them would die from it, according to the American Cancer Society.²¹ It represents 1% of all cancers and 2% of all deaths related to cancer. This pathologic entity is characterized by a triad of: (1) multifocal lytic bone lesions; (2) bone marrow plasmacytosis (to wit, the bone marrow is occupied by plasma cell conglomerates, called plasmacytomas or solid tumors, in concentrations greater than 10% of the total number of cells present, but can be as high as 90%); and (3) a monoclonal gammopathy that can affect the urine, serum, or both.

The survival rate of persons with multiple myeloma after diagnosis is 3-5 years, and less than 1 year without treatment. Vitamin D deficiency causes defective mineralization and calcification of bone matrix (osteoid), leading to osteomalacia in adults.¹⁰ This can occur due to various causes: a lack of the vitamin in the diet (rare); gastrointestinal pathology (such as hepatic or biliary disease and status post-gastrectomy); or abnormalities of vitamin D metabolism (ie, renal disease). Symptoms involve diffuse skeletal pain and proximal muscle weakness. The patient can display a waddling gait and a tendency to suffer repeated fractures. Laboratory evaluations usually show a high alkaline phosphatase, and reduced serum calcium and/or phosphorus. Treatment requires vitamin D replacement with tablets, drops, or combination calcium supplements. von Recklinghausen’s disease of bone results from either primary or secondary hyperparathyroidism. Due to heightened osteoclastic activity, osteolytic lesions occur and are widespread. Cystic spaces referred to as “brown tumors” may form, lined by multinucleated osteoclasts and filled with vascular fibrous stroma.¹ X-rays may show diffuse radiolucency similar to osteoporosis. Laboratory work-up would show a high serum alkaline phosphatase and calcium, and low serum phosphorus. Other considerations in the differential could include osteoarthritis (which may occur concomitantly with Paget’s disease), and malignancy of bone (either primary or metastatic), as occurs with breast and prostate cancers, and lymphoma.

OUTCOME OF THE CASE PATIENT

The patient received adequate hydration with resolution of her urinary incontinence and dehydration. Her mental status returned to baseline, as did her electrolyte derangements, and phenytoin was discontinued. No episodes of syncope or near-syncope occurred during hospitalization, and the family began serious consideration of long-term care placement. The patient was started on a course of alendronate 40 mg by mouth per day. She was to be on this regimen for a total of 6 months. Because bisphos-phonates can cause erosive esophagitis, she and the family were instructed that she should take the medication 30 minutes before meals with 6-8 ounces of water. Her alkaline phosphatase levels were to be monitored during the course of treatment. The patient’s overall presentation was atypical for a case of Paget’s disease. Her serum alkaline phosphatase was only slightly above the normal range. Her serum calcium was elevated, contributing not only to an altered sensorium and hyperreflexia but also—by blocking the effect of antidiuretic hormone (ADH) on the renal tubules—led to water loss and dehydration. The hypercalcemia was likely due to a combination of high bone turnover and the fact that one of her home medications was hydrochlorothiazide, which can increase the reabsorption of calcium in the kidney and lead to a reduction of other serum electrolytes. In addition, her status at home of being bed-bound and immobilized likely facilitated the release of significant amounts of calcium from its stores in the bone. Her elevated blood pressure and history of a CVA suggested a cardiovascular etiology that could have had a cerebral impact. However, by focusing on her various symptoms and performing routine laboratory assessments, the findings were sufficient enough to allow our team to form a differential that led us to her ongoing pathology. Had the alkaline phosphatase level been tested earlier by Neurology, she may have been diagnosed sooner. However, such a laboratory test is not routinely checked at an initial outpatient specialty visit. If a calcium level had been checked instead, its result could have thrown off an accurate diagnosis of the true etiology, given that most persons with Paget’s disease do not have hypercalcemia. As in so many medical conditions, one size does not fit all; a set of signs, symptoms, and laboratory findings do not always correlate with every patient with a given disease process. It is the clinical team’s responsibility to fit seemingly disparate points of data together in order to formulate a reasonable differential diagnosis. Acknowledgment This article is dedicated to the memory of my friend, “The Brown Lion,” whose loyalty and dedicated spirit has been a steadfast source of strength to me and my family for ten years, and will continue to be far into the future. You shall be missed.

The author reports no relevant financial relationships.