Osteoporosis & Paget Disease of Bone

Bone homeostasis is maintained by a well-regulated balance of bone formation & bone resorption. This is orchestrated through specialized cellular mechanisms involving cells like osteoblasts, osteoclasts, and osteocytes. Osteoblasts are involved in bone formation and regulation of mineralization. In contrast, osteoclasts produce enzymes that resorb bone. Osteocytes translate mechanical forces into biochemical signals and reside within canaliculi in the bone matrix.

Key molecules such as RANK and RANK-L are integral in this balance. RANK (receptor activator of nuclear factor K) is a receptor found on osteoclasts that is activated upon binding with RANK-L, resulting in bone resorption by the osteoclast. RANK-L is expressed by osteoblasts and acts as the activating ligand for RANK, thereby stimulating osteoclasts. Osteoprotegerin is also produced by osteoblasts and acts as a decoy receptor for RANK-L that inhibits its binding, thus inhibiting osteoclast activation.

Osteoporosis is a metabolic bone disorder characterized by reduced bone mass but with normal mineralization and calcium/phosphate levels. Multiple factors contribute to its onset, including age, as bone resorption tends to exceed bone formation in older individuals due to osteoblasts losing functional activity. The decline in weight-bearing activities with age also contributes. Estrogen decline or discontinuation also contributes to osteoporosis, as a decrease in estrogen ultimately results in increased recruitment and activity of osteoclasts.

Endocrine disorders such as Cushing syndrome, hyperparathyroidism, and hyperthyroidism are also associated with osteoporosis. In Cushing syndrome, excessive cortisol stimulates osteoclast formation by increasing the expression of RANK-L and decreasing the expression of osteoprotegerin. Hyperparathyroidism and hyperthyroidism are can also cause osteoporosis, as excessive PTH and T4 hormones stimulate osteoclasts and increase bone resorption.

Lifestyle factors like lack of load-bearing activities, calcium, and vitamin D intake also influence bone health. Secondary osteoporosis can result from drugs like exogenous corticosteroids and substances like alcohol & tobacco, which inhibit osteoblast activity and promote osteoclast activity.

Clinically, osteoporosis manifests as decreased bone mineral density (BMD), cortical thinning & widened Haversian canals, as well as thinner trabecular bone with fewer connections between trabeculae, leading to a ‘hollow’ appearance. This often manifests as compression fractures of the vertebral column that can progress to excessive kyphosis, resulting in a stooped posture known as 'Dowager’s Hump.' Specific fractures like distal radial fracture from falling on an outstretched hand can also occur, which displays as ‘dinner fork’ appearance on x-ray. Fracture of the surgical neck of the femur can occur following mild trauma in severe osteoporosis.

Dual-energy X-ray absorptiometry (DEXA) scanning serves as a diagnostic tool for both osteoporosis and osteomalacia, and it employs a T-score to compare a patient's bone density to that of a young adult reference. A T-score of -2.5 or less is indicative of osteoporosis, while a score between -1 and -2.5 suggests osteopenia. Notably, even in cases where the T-score is greater than -2.5, fragility fractures can still diagnose osteoporosis. The Z-score is used for age-matched comparisons, with a score of -2 being the cutoff.

Treatment for osteoporosis primarily involves bisphosphonates, such as alendronate or zoledronate, which increase osteoclast apoptosis and inhibit bone resorption. Calcitonin also inhibits osteoclast activity and is approved for postmenopausal osteoporosis.

Paget’s disease, also known as osteitis deformans, is characterized by an increase in bone resorption that leads to a decrease in bone mass and lytic structures. Paget’s disease progresses in multiple phases, beginning with the osteolytic phase, which features extensive osteoclastic activity leading to bone resorption. This is followed by a mixed phase where both osteoblasts and osteoclasts are active, causing rapid but disorganized bone turnover. The subsequent osteosclerotic phase involves the formation of bulky, fragile bone. The final phase is the quiescent phase, knows as the ‘burned-out phase,’ where malignant degeneration is seen.

Clinical manifestations of Paget's disease include skull enlargement, often causing patients to report that their hats no longer fit. Hearing loss can occur due to cochlear involvement. Physical deformities such as bowing & asymmetry of the lower extremities, as well as osteoarthritis are also observed. The affected bone in Paget’s disease is weak and susceptible to ‘chalk-stick’ fractures that cause bone pain.

Metabolic demand in early Paget’s disease causes extensive hypervascularity, which can result in arteriovenous shunts that can lead to high-output heart failure. Long-standing Paget’s disease is a risk factor for osteosarcoma, though it is rare (< 1%).

Diagnostic imaging such as X-rays can show ‘shaggy’ dark areas of radiolucency in early disease and abnormally thick bone in the late stages. Furthermore, elevated levels of alkaline phosphatase are often present due to increased osteoblast activity, serving as a biochemical marker for Paget’s disease.