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Paget Disease: Differential Diagnoses & Workup

Author: David Chow, MD, Medical Director, California Spine Center
Coauthor(s): Curtis W Slipman, MD, Director, University of Pennsylvania Spine Center; Associate Professor, Department of Physical Medicine and Rehabilitation, University of Pennsylvania Medical Center; Debra Braverman, MD, Director of Alternative and Complementary Medicine, Assistant Professor, Department of Rehabilitation Medicine, University of Pennsylvania Health System
Contributor Information and Disclosures

Updated: Dec 18, 2008

Workup

Laboratory Studies

  • Because of increased osteoblastic activity and bone formation, biochemical indices reveal elevated alkaline phosphatase levels of bone origin.
    • Analysis of alkaline phosphatase isoenzymes helps to identify the hepatic contribution to total levels of alkaline phosphatase.
    • A strong relationship exists between the extent of disease activity measured by scintigraphy and the degree of the elevation of alkaline phosphatase in persons with untreated Paget's disease.
    • In patients with monostotic disease or local disease, the total alkaline phosphatase level may be normal. Consequently, a normal alkaline phosphatase level does not exclude the disorder. In this scenario, a bone-specific alkaline phosphatase level should be ordered. In patients with abnormal liver function or other causes of elevated alkaline phosphatase activity not due to bone, bone-specific alkaline phosphatase is a reasonable means of assessing Paget's disease activity. Bone-specific alkaline phosphatase had the highest diagnostic sensitivity (84%) in a comparative study of different markers of bone turnover in patients with Paget's disease. The next most sensitive marker was total alkaline phosphatase, which had a sensitivity of 74%.8
    • Urinary hydroxyproline levels are elevated because they reflect increased osteoclastic activity and bone resorption. Hydroxyproline is a product of collagen breakdown.
    • Approximately 20-30% of total hydroxyproline levels are from bone resorption.
    • Measurement of total urinary hydroxyproline previously was the criterion standard as a marker for bone resorption, hydroxyproline levels having been demonstrated to correlate with the extent and activity of disease. Dietary sources of collagen may increase hydroxyproline excretion in 24-hour urine collections; therefore, an overnight fast often is necessary before testing.
    • Patients with skin disease also may have elevated hydroxyproline levels, since the skin is a major site of collagen synthesis. The hydroxyproline assay is difficult to perform and is not widely available.
  • More recently, measurement of the urinary excretion of bone-specific pyridinium collagen cross-links has been found to be a sensitive and specific index of bone resorption.
    • Additionally, levels of excreted bone-specific pyridinium collagen cross-links may be better indicators of bone resorption and response to treatment than the hydroxyproline assay.
    • The urinary pyridinoline collagen cross-link assay may replace assessment of hydroxyproline levels as the test of choice.
  • Urinary N-telopeptide (NTx) and alpha-C telopeptide (CTx) have emerged recently as sensitive biochemical markers for bone resorption.
    • An abnormally high alpha-CTx/beta-CTx ratio is present with active Paget's disease.
    • This ratio returns to the reference range following treatment with bisphosphonates.9
  • Sensitive plasma or serum markers for assessing bone resorption have not been developed.
    • Serum total acid phosphatase is an osteoclastic enzyme that may be elevated in active Paget's disease, but it is of little clinical value, as it also may be elevated in the presence of metastatic prostate carcinoma.
    • Serum calcium and phosphate levels should be within the reference range in patients with Paget's disease.
    • Urinary excretion of calcium also should be normal.
  • Hypercalcemia or hypercalciuria may develop with immobilization or coincident primary hyperparathyroidism.
  • Secondary hyperparathyroidism may occur in 10-15% of patients with Paget's disease. This development may be due to inadequate calcium intake in the face of increased demand from extensive bone remodeling. Increased incidence of primary hyperparathyroidism does not seem to exist among patients with Paget's disease.
  • Procollagen I N-terminal peptide (PINP) has recently emerged as a sensitive serum marker for bone formation. Serum osteocalcin, which is produced specifically by osteoblasts, does not reflect disease activity.
  • Many patients with elevated alkaline phosphatase levels have been found to have osteocalcin measurements within the reference range. Levels of osteocalcin also may increase while alkaline phosphatase levels decrease during treatment with bisphosphonates.
  • Paget's disease was found in 23% of a group of patients with gout.10
    • Elevated serum uric acid levels have been found in men with severe Paget's disease and have been associated with gouty arthritis.
    • Hyperuricemia is more common in men than in women and appears to be caused by the increased turnover of nucleic acids from high bone turnover.

Imaging Studies

  • Radiographs
    • Typical expanding lytic lesions, transverse lucent areas or osteoporosis circumscripta, thickened cortices, sclerotic changes, and bone expansion with coarse, disorganized trabecular patterns are seen on plain radiographs.
    • Lytic lesions may be the only finding early in the disease.
    • Plain radiographs are less sensitive than bone scan scintigraphy in the diagnosis of Paget's disease. An entire skeletal survey with plain radiographs to assess the extent of skeletal involvement is not recommended when bone scanning would be more sensitive and involve less radiation exposure.
    • Radiographic features are diagnostic with an initial osteolytic phase, commonly in the skull and tubular bones, followed by an osteosclerotic phase that is most notable in the axial skeleton and pelvis. An enlarged bone with increased radiodensity and trabeculations is characteristic.
    • Osteolysis of the cranial vault is most frequent in the frontal or occipital regions. Osteolysis of the tubular bones usually occurs subchondrally in the epiphysis with extension into the metaphysis and diaphysis. Advancing osteolysis may appear as a V- or wedge-shaped radiolucent area that may resemble a blade of grass or flame. The remaining trabeculae may be obliterated and a hazy ground glass or washed-out pattern observed. Focal radiodensities have a cotton-wool appearance. Areas of lysis and radiodensities may be separate or superimposed.
    • Later in the disease, evidence of lysis may be absent because only sclerotic thickened bones may remain.
    • Radiographic evidence of remineralization may occur after initiation of appropriate treatment, such as with the bisphosphonates.
    • Paget's disease typically affects the vertebral bodies and posterior elements.
    • The enlarged coarse trabeculae combined with the prominent radiodense peripheral contour of the vertebral body gives the appearance of a picture frame that is diagnostic of Paget's disease.
    • A homogeneous increase in osseous density in the vertebral body gives the manifestation of an ivory vertebra. Skeletal metastasis and lymphoma also may produce ivory vertebrae.
    • Furthermore, altered vertebral body shape is common as a result of structurally weak pagetic bone. Biconcave-shaped vertebral bodies, also called fish vertebrae, may be seen in osteomalacia, hyperparathyroidism, and osteoporosis. The biconcave shape is caused by intervertebral disc compression of the weakened vertebrae.
    • Intervertebral disc space narrowing may occur from secondary degenerative disc and joint disease. Vertebral body ankylosis may be seen. Loss of vertebral height is observed commonly as a result of bone remodeling and compression fractures. Posterior element involvement may manifest as increased pedicular radiodensities that also are seen in osteoblastic metastasis.
  • Computed tomography (CT) scanning and magnetic resonance imaging (MRI)
    • CT scanning and MRI are not needed for the diagnosis of Paget's disease of bone. Both are useful in the evaluation of complications of Paget's disease, such as neoplastic degeneration, articular abnormalities, and spinal involvement with neurologic compromise.
    • Articular abnormalities require CT scanning or MRI to delineate the extent of involvement.
      • CT scanning and MRI are useful to diagnose and evaluate neurologic complications, such as basilar invagination, spinal cord compression, or hydrocephalus.
      • Spinal stenosis and vertebral involvement are assessed best with CT scanning or MRI.
      • CT scanning provides better visualization of bone and the posterior fossa, while MRI gives superior detailing of the brain, spinal cord, cauda equina, and soft tissue. Thus, neoplastic entities, such as pagetic sarcomas, and their extent of involvement are evaluated better with MRI.

Other Tests

  • Bone scan
    • Bone scanning is the most sensitive test for evaluating the extent of lesions in the whole skeleton affected by Paget's disease. Bone scintigraphic abnormalities are observed earlier than radiographic changes during the active stage of Paget's disease. However, bone scanning is less specific than plain radiography, and changes detected by scintigraphy may need to be confirmed by a plain radiograph of at least one site.
    • Plain radiographs and bone scanning should be performed upon initial diagnosis.
      • With bone scanning, the percentage of isotope retention after 24 hours may provide an index of total pagetic nuclear imaging.
      • The concentration of scintigraphic uptake in a pagetic lesion may correlate with the grade of radiologic deformation and the frequency of pain.
      • Total skeletal uptake may correlate with levels of serum alkaline phosphatase and urinary hydroxyproline; however, bone scans are sensitive but not specific.
    • During the aggressive osteoclastic resorptive phase, bone scanning may underestimate disease activity, as in multiple myeloma.
    • In the quiescent osteosclerotic stage, pagetic lesions may be detected radiographically but not scintigraphically.
      • Quantitative bone scintigraphy is useful for assessing a monostotic lesion with a normal alkaline phosphatase.
      • Serial bone scans may provide objective evidence of the effect of therapeutic agents.

Histologic Findings

The initial osteolytic phase is marked by disordered areas of resorption by an increased number of overly large osteoclasts. These abnormal osteoclasts may contain as many as 100 nuclei. The subsequent osteoblastic phase follows, with haphazard laying of new bone matrix and formation of woven bone. Repeated episodes of bone removal and formation result in the appearance of many small, irregularly shaped bone fragments that appear to be joined in a jigsaw or mosaic pattern. This pattern is the histologic hallmark of Paget's disease.11

As the disease progresses, the osteoblastic phase predominates, and excessive abnormal bone formation occurs, resulting in more compact and dense bone. The pagetic bone is coarse and fibrous, with avidity for calcium and phosphorus. Marrow spaces fill with loose, highly vascularized connective tissue. The hypervascular bone, combined with cutaneous vasodilation, causes an increase in the regional blood flow and accounts for the rise in skin temperature seen clinically. The hypervascularity consists of an increased number of patent capillaries and dilated arterioles, as well as of larger venous sinuses.

The normal trabecular appearance is distorted, with a mosaic pattern of irregular cement lines joining areas of lamellar bone. Pagetic bone shows no tendency to form haversian systems or to center on blood vessels; the bones are very hard and dense. Eventually, the osteoblastic activity diminishes, and an osteosclerotic or burned-out phase predominates. The new bone is disordered, is poorly mineralized, and lacks structural integrity.

More on Paget Disease

Overview: Paget Disease
Differential Diagnoses & Workup: Paget Disease
Treatment & Medication: Paget Disease
Follow-up: Paget Disease
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

Paget disease, Paget's disease, bone pain, bone disease, Paget's disease of bone, Paget's bone disease, osteoblast, osteoclast, osteoblasts, osteoclasts, osteoblastic, Paget disease of bone, osteitis deformans, osteoclastic, bone deformity

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Contributor Information and Disclosures

Author

David Chow, MD, Medical Director, California Spine Center
David Chow, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Society of Interventional Pain Physicians, North American Spine Society, and Physiatric Association of Spine, Sports and Occupational Rehabilitation
Disclosure: Nothing to disclose.

Coauthor(s)

Curtis W Slipman, MD, Director, University of Pennsylvania Spine Center; Associate Professor, Department of Physical Medicine and Rehabilitation, University of Pennsylvania Medical Center
Curtis W Slipman, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, Association of Academic Physiatrists, International Association for the Study of Pain, and North American Spine Society
Disclosure: Nothing to disclose.

Debra Braverman, MD, Director of Alternative and Complementary Medicine, Assistant Professor, Department of Rehabilitation Medicine, University of Pennsylvania Health System
Debra Braverman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, and Association of Academic Physiatrists
Disclosure: Nothing to disclose.

Medical Editor

Patrick J Potter, BSc, MD, FRCP(C), Associate Professor, Physical Medicine and Rehabilitation, The University of Western Ontario; Consulting Staff, Department of Physical Medicine and Rehabilitation, St Joseph's Health Care Centre
Patrick J Potter, BSc, MD, FRCP(C) is a member of the following medical societies: American Paraplegia Society, Canadian Association of Physical Medicine and Rehabilitation, Canadian Medical Association, College of Physicians and Surgeons of Ontario, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada
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Kat Kolaski, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine and American Academy of Physical Medicine and Rehabilitation
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CME Editor

Kelly L Allen, MD, Regional Medical Director, IMX-Medical Management Services
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Chief Editor

Denise I Campagnolo, MD, MS, Director of Multiple Sclerosis Clinical Research and Staff Physiatrist, Barrow Neurology Clinics, St Joseph's Hospital and Medical Center; Investigator for Barrow Neurology Clinics; Director, NARCOMS Project for Consortium of MS Centers
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