A 68-year-old man presents to the clinic complaining of worsening hearing loss and dull headaches over the past six months. He also mentions that his favorite hat no longer fits his head comfortably. He denies any recent trauma or vision changes. On physical examination, there is noticeable bowing of the bilateral tibiae. Laboratory studies show a significantly elevated serum alkaline phosphatase (ALP) level, while serum calcium, phosphate, and parathyroid hormone (PTH) levels are all within normal limits. An X-ray of the skull shows thickened calvarial bone with a cotton-wool appearance.
Which of the following is the primary underlying pathophysiology of this patient's condition?
The correct answer is:
B) Excessive osteoclast activity followed by disordered osteoblast activity
The patient is presenting with the classic clinical triad of Paget disease of bone (osteitis deformans): an increasing hat size, hearing loss, and isolated elevation of alkaline phosphatase. The primary pathophysiology involves a localized disorder of bone remodeling that begins with a surge in disordered, hyperactive osteoclasts. This initial osteolytic phase is followed by a mixed phase where both osteoclasts and osteoblasts are active, eventually leading to a final osteosclerotic phase. During this last stage, the osteoblasts produce a large amount of structurally inferior woven bone. This disorganized mosaic pattern of bone is thicker than normal bone but much more brittle, leading to the characteristic bowing of the long bones and the "cotton-wool" appearance on skull radiography.
Answer choice A: Defective mineralization of osteoid, is incorrect. This mechanism describes osteomalacia and rickets, conditions caused by vitamin D deficiency. In those disorders, osteoblasts produce osteoid normally, but the osteoid fails to mineralize, leading to soft bones. These conditions typically present with low calcium and phosphate, not the normal calcium/phosphate with isolated ALP elevation seen in this patient.
Answer choice C: Impaired carbonic anhydrase II activity in osteoclasts, is incorrect. This defect is the hallmark of osteopetrosis, a condition in which osteoclasts cannot acidify the resorption lacuna. Without an acidic environment, bone resorption fails, producing dense, brittle “marble bone.” Patients may develop anemia, cranial nerve compression, or fractures, but they do not develop the mixed lytic–sclerotic pattern or elevated ALP typical of Paget disease.
Answer choice D: Increased secretion of parathyroid hormone, is incorrect. Primary hyperparathyroidism causes excessive bone resorption due to high PTH levels, but it produces a very different biochemical profile including hypercalcemia, hypophosphatemia, and elevated PTH. This patient’s calcium, phosphate, and PTH are all normal, making this mechanism incompatible with the presentation.
Answer choice E: Vitamin C deficiency leading to impaired collagen synthesis, is incorrect. Vitamin C deficiency causes scurvy, which impairs collagen hydroxylation and leads to poor connective tissue integrity. Classic findings include bleeding gums, petechiae, and corkscrew hairs, not bone overgrowth or deformity. Scurvy does not cause elevated ALP or the radiographic cotton-wool appearance seen in this case.
Key Learning Point
Paget disease of bone is a localized disorder of bone remodeling characterized by an initial increase in osteoclast activity followed by disorganized bone formation by osteoblasts. This results in thickened but weak bone. Diagnostically, the most important finding is an isolated elevation of alkaline phosphatase with normal calcium and phosphate levels. Clinical hallmarks include an increasing head size, hearing loss due to cranial nerve compression, and an increased risk of developing osteosarcoma.
