Infection causes osteomyelitis. Bacterial pyogens are the most common agents, but the disease may also result from fungi or viruses. The most common pyogenic organism in osteomyelitis is Staphylococcus aureus; others include Streptococcus pyogenes, Pseudomonas aeruginosa, Escherichia coli, and Proteus vulgaris.

Typically, these organisms find a culture site in a recent hematoma or a weakened area such as a site of local infection (as in furunculosis). From there, they spread directly to bone. As the organisms grow and produce pus within the bone, pressure builds within the rigid medullary cavity and forces the pus through the haversian canals. A subperiosteal abscess forms, depriving the bone of its blood supply and eventually causing necrosis.

In turn, necrosis stimulates the periosteum to create new bone (involucrum). The old, dead bone (sequestrum) detaches and works its way out through an abscess or the sinuses. By the time the body processes sequestrum, osteomyelitis is chronic.

Osteomyelitis may lead to chronic infection, skeletal deformities, joint deformities, disturbed bone growth (in children), differing leg lengths, and impaired mobility.

Usually, chronic and acute osteomyelitis have similar clinical features. (See Detecting osteomyelitis.) However, chronic infection can persist intermittently for years, flaring up spontaneously after minor trauma. Sometimes, the only sign of chronic infection is persistent pus drainage from an old pocket in a sinus tract.