A complicated case of Paget’s disease of the bone

Issue: April 2009

ByStephanie L. Lee, MD, PhD, ECNU

ByDaniel J. Rubin, MD

An inpatient endocrinology consult was requested for a 67-year-old man admitted with three weeks of progressive lower back pain and left leg weakness. The patient was diagnosed 25 years prior to presentation with asymptomatic Paget’s disease of bone by spinal X-rays performed for a minor back injury. He had never received anti-Pagetic therapy. The patient had no family history of Paget’s disease or cancer.

Daniel J. Rubin

Stephanie L. Lee

This alert white man had no skeletal deformities, no spinal tenderness and no muscular atrophy. Cranial nerves and sensation were intact, however strength of the left leg muscles was diminished and reflexes were equivocal. Complete blood count, chemistry panel and liver function tests, serum protein electrophoresis and prostate specific antigen were normal. Serum alkaline phosphatase was markedly elevated at 1287 U/L (reference range 25-100) with normal levels of calcium 9.1 mg/dL and 25-hydroxyvitamin D 37 ng/mL.

Cross-sectional imaging by CT scan and MRI scan revealed osteolytic and sclerotic bone lesions typical of Paget’s disease in the spine and pelvis (see figures 1 and 2A) with a 6x5x7 cm bony mass arising from the L3-L5 vertebrae causing neuroforaminal narrowing, spinal canal stenosis and spinal cord compression. Nuclear Medicine bone scan with a technetium-99m-methylene diphosphonate with planar and single photon emission computed tomography (SPECT) views showed increased radiotracer uptake at multiple boney sites including the T3, T6, T11, and T12 , L3-L5 vertebrae, sacrum, left hemipelvis, sternum, and tip of the left scapula consistent with Paget’s disease but also concerning for metastatic carcinoma (see figure 3). SPECT imaging of the L3-L5 mass demonstrated that it took up the radiotracer relatively poorly which is not typical of Paget’s disease (see figure 4). CT-guided biopsy of the mass revealed increased osteoclastic activity and irregular bone trabeculae consistent with Paget’s disease. Pamidronate 60 mg IV and 2 weeks of high dose corticosteroids provided only minimal symptomatic relief. A lumbar laminectomy resulted in modest improvement in his pain and weakness.

After three monthly doses of pamidronate 60 mg IV, his alkaline phosphatase decreased to 416 U/L, but his symptoms worsened. After a second laminectomy, he was given two monthly doses of zoledronic acid 4 mg IV for persistent elevation of alkaline phosphatase levels >1,000 U/L with continued pain and weakness. Because of severe symptoms, he had a third laminectomy with removal of tissue that contained a small focus of high grade osteoblastic osteosarcoma. Erythrocyte sedimentation rate (ESR) was 18 mm/hr (normal 0-20). Post-operative CT scans showed new local invasion of the lumbar mass into the psoas muscle as well as new pulmonary metastases (see figures 2B and 5).

After six cycles of chemotherapy with cisplatin and doxorubicin, the alkaline phosphatase level remained 150-200 U/L for several months and the patient’s pain was controlled. Unfortunately, 14 months after initial presentation, the patient developed complications including a malignant pleural effusion requiring pleurodesis.

Despite a third dose of zoledronic acid 4mg IV, the alkaline phosphatase climbed to 1818 U/L. He was discharged with hospice care and died two months later.

There are different types of the sarcomas seen in Paget’s disease including osteosarcoma, fibrosarcoma, chondrosarcoma, and anaplastic sarcoma. Several types of histology may be present in a single tumor but the most common form seen in Paget’s is osteosarcoma. The annual incidence of sarcoma complicating Paget’s disease of the bone is estimated at <1% with a 30-fold greater than the risk of osteosarcoma than in the general population older than 40 years of age. Although the association of sarcoma with Paget’s disease is undisputed, the etiology remains unknown.

Mutations in tumor suppressor genes such as p53 and RB1 have been implicated. Paget’s sarcoma tends to occur more often in older men with polyostotic disease, especially, in the pelvis, femur, humerus, vertebrae and skull. Clinically, most patients present with pain associated with a soft tissue mass, a lytic lesion, and variable elevations of alkaline phosphatase and ESR. Rapid progression of neurologic symptoms over weeks should prompt suspicion of Paget’s sarcoma. It is difficult to detect an early stage of a sarcoma with imaging studies because of the abnormal pagetic bone. Typically, a radiolucent focus with speckled regions of calcification will be observed to disrupt the cortex of the bone.

A bone scan will show an area of poor radioisotope accumulation at the site of the sarcoma. Imaging by CT or MRI and histological examination of tissue are critical for making the diagnosis of Paget’s sarcoma, staging the disease, and directing therapy. It has been reported that 29% of patients will have pulmonary metastases at the time of the diagnosis of the sarcoma and, in fact, up to 50% of patients will have distant metastases at diagnosis. Treatment options include surgery and/or chemotherapy usually with palliative intent in older adults. There have been no reports that bisphosphonate therapy improves the clinical course of osteosarcoma in Paget’s disease despite many promising published results in animal models. Prognosis is poor, with a five-year survival rate of 7.5% to 10%. Paget’s sarcoma must be suspected in refractory cases of symptomatic Paget’s disease, especially with evidence of new pain, bone destruction and soft tissue mass.

Figure 1: CT and MRI scans of spine
Figure 1. CT and MRI scans of the spine. Sagittal image shows a large, heterogeneous lumbar mass with lytic and sclerotic bone changes (red arrow) causing vertebral body destruction, spinal canal stenosis and compression of the spinal cord (blue arrow). Typical sclerotic changes of Paget’s are shown in T11-T12 with osteophytes and narrowed disc spaces (green arrows).

All images courtesy of Stephanie L. Lee

Figure 2: CT of lumbar spine
Figure 2 A & B. Non-contrast CT of the lumbar spine on presentation (A) and 7 months later (B). The transverse image through the L5 vertebral body shows the typical lytic and sclerotic changes seen in Pagetic bone (A). An ossified soft-tissue mass extended into the psoas muscle (red arrow) was seen in a subsequent image obtained seven months later (B). The posterior aspect of the L5 vertebral body is surgically absent (yellow arrowhead).

Figure 3: Anterior and posterior planar images
Figure 3 A & B. Technetium-99m-methylene diphosphonate bone scan. Anterior (A) and posterior (B) planar images show multiple areas of intense isotope uptake especially T3, T6, T11, and T12 , L3-L5 (red arrow) vertebra, the sacrum and the left hemipelvis consistent with polyostotic Paget’s disease of the bone.

Figure 4: Bone scan SPECT images
Figure 4. Bone scan SPECT images through the L3-5 mass. Coronal, sagittal and axial tomographic images shows the relative paucity of radiotracer uptake in the sacomatous mass (green arrows) despite apparent intense uptake on planar images (Figure 3).

Figure 5: Non-contrast CT of the chest
Figure 5. Non-contrast CT of the chest showing multiple, subcentimeter, calcified pulmonary nodules consistent with metastatic Paget’s sarcoma (red arrows). The patient also had a malignant pleural effusion (blue arrows) with a cytology positive for metastatic sarcoma.

Daniel J. Rubin, MD, is a Fellow in Endocrinology in the Section of Endocrinology, Diabetes and Nutrition at Boston Medical Center.

Stephanie L. Lee, MD, PhD, is an Associate Chief in the Section of Endocrinology, Diabetes and Nutrition, and an Associate Professor of Medicine at Boston Medical Center.

For more information:

Deyrup AT. Arch Pathol Lab Med. 2007;131:942-946.

Hansen MF. J Bone Miner Res. 2006;21(Suppl 2):P58-63.

Rubin D. Endocrine Practice. 2009;In press.

Smith J. Radiology. 1984:152:583-590.

Vuillemin-Bodaghi V. Skeletal Radiol. 2000;29:349-53.