A 70-year-old man comes to the clinic due to intermittent leg pain and difficulty walking. He describes the pain as mild-to-moderate, deep, and lasting throughout the day. The patient has a history of osteoarthritis in his hands for which he takes over-the-counter nonsteroidal anti-inflammatory drugs, but says that he never has had problems with his knees. Physical examination shows point tenderness over the right tibia. Laboratory studies show elevated serum alkaline phosphatase. Bone biopsy shows haphazardly oriented segments of lamellar bone with prominent cement lines. The initial phase of this patient's disorder involves increased activity of which of the following cell types?
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This elderly patient's bone pain, increased alkaline phosphatase, and biopsy findings are characteristic of Paget disease of bone (PDB), a condition that results in accelerated bone remodeling with eventual bony overgrowth. The disease is thought to be caused by environmental factors and gene mutations (eg, affecting RANK, osteoprotegerin) that result in excessive RANK and NF-κB activation. This leads to increased osteoclast differentiation and activity. The disease typically progresses through 3 phases:
Osteolytic (osteoclast-dominant) phase – characterized by increased numbers of osteoclasts that appear abnormally large with an excessive number of nuclei. Increased resorption activity is prominent.
Mixed (osteoclastic-osteoblastic) phase – defined by a rapid increase in osteoblastic bone formation with persistent osteoclastic activity. The newly made bone is abnormal, with interspersed areas of disorganized lamellar and woven bone.
Osteosclerotic (osteoblast-dominant) phase – characterized by continued osteoblastic bone formation and remodelling that result in a dense, hypovascular, mosaic pattern of lamellar bone with irregular, haphazardly oriented sections separated by prominent cement lines.
The end result is a thickened, deformed bone that is weaker than normal and prone to fracture.
(Choice A) Chondrocytes are not involved in the pathogenesis of PDB.
(Choices B and C) In the early stages of PDB, the adjacent marrow spaces are replaced by highly vascular stromal tissue as a result of increased endothelial cell and fibroblast proliferation due to cytokines secreted by osteoclasts. The increased vascularity causes arteriovenous shunting that can result in high-output heart failure.
(Choice D) Although this patient's bone biopsy shows findings characteristic of the osteosclerotic (osteoblast-dominant) phase of Paget disease, the question is specifically asking about the initial (osteolytic) phase of Paget disease, where osteoclast activity is predominantly increased. Increased activity and dysregulation of osteoblasts and fibroblasts increase the risk of developing sarcomas (eg, osteosarcoma) in patients with PDB.
Educational objective:
Bone pain and elevated alkaline phosphatase level in an elderly patient can occur with osteoblast metastases and Paget disease of bone (PDB). Biopsy showing a mosaic pattern of lamellar bone is diagnostic for PDB. The initial phase in PDB is characterized by an increase in osteoclastic activity.