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Diseases of the bone include non-neoplastic disorders such as genetic defects (e.g., achondroplasia), osteoporosis, infections of the bone (i.e., osteomyelitis), and Paget disease. The age of the patient and the location of the tumor are very important considerations in the diagnosis of bone tumors. For example, most chondrosarcomas occur in older adults and almost never occur in the bones of the hands, whereas most Ewing sarcomas occur in the diaphysis of long bones of children.

Diseases of the joints include inflammatory and noninflammatory arthritides. The two major types of arthritis are osteoarthritis and rheumatoid arthritis. Wear and tear is one of the major etiologic agents for the development of osteoarthritis, whereas rheumatoid arthritis is considered to be an autoimmune condition. An important molecular topic regarding bone pathology is the receptor for nuclear factor-κβ (RANK), which is expressed on macrophages, monocytes, and preosteoclasts. The binding of RANK ligand (RANKL) to RANK stimulates osteoclastogenesis. RANKL is produced by osteoblasts and marrow stromal cells. Osteoprotegerin binds to RANK and blocks the binding of RANKL; therefore, it is inhibitory.

This chapter will discuss non-neoplastic bone diseases (including those caused by genetic defects, osteoporosis, osteonecrosis, osteomyelitis, Paget disease, renal osteodystrophy, and fractures), bone neoplasms, and joint disorders, primarily osteoarthritis, rheumatoid arthritis, and gout.

Overview: There are many inherited conditions that result in abnormalities of bone structure. Three of the more common types, achondroplasia, osteogenesis imperfecta, and osteopetrosis, will be discussed below.


Inheritance pattern: Autosomal dominant; 80% of new cases are the result of spontaneous mutations.

Mutation: Gene for FGF receptor 3 (FGFR3) on the p arm of chromosome 4.

Effect of mutation: FGF receptor 3 (FGFR3) is an inhibitor of cartilage proliferation. The mutation places the receptor in a constant state of activation.

Manifestations of achondroplasia

  • Gross: Disproportionate dwarfism with normal trunk length and short extremities, varus and valgus deformities of legs, short fingers and toes, and large head with prominent forehead.
  • Microscopic: Narrow and disorganized zones of proliferation and hypertrophy.

Important points: Achondroplasia accounts for 70% of cases of dwarfism. Less commonly, dwarfism may be due to pituitary dysfunction or secondary to a mutation in the growth hormone receptor (Laron dwarfism).

Osteogenesis Imperfecta

Overview: There are several different types of osteogenesis imperfecta, each one caused by one of several different mutations. Some of the mutations have an autosomal dominant inheritance pattern. Only type I and type II osteogenesis imperfecta, two of the more common forms of the disease, will be discussed in detail here.

Mutations: Gene for α1 and α2 chains of type I collagen.

Effect of mutation: Varies, depending upon mutation. The results vary from phenotypically normal collagen produced in decreased amounts to absence of collagen production.


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