View source for 66. Hereditary, inflammatory and metabolic bone diseases

== Introduction ==
Bone is comprised of an organic osteoid matrix which is mineralized by a calcium phosphate salt called hydroxyapatite. It’s a dynamic tissue that is constantly remodelled by being resorbed and put down but osteoclasts and osteoblasts, respectively.

Bone is comprised of proteins like type I collagen and many noncollagenous proteins produced by osteoblasts. Osteoblasts produce either woven bone or lamellar bone. Woven bone is the result of rapid bone formation. It is randomly ordered and weak and is characteristic for bone growth during child growth. Lamellar bone is more orderly layered and therefore stronger. It also takes much longer to form. The presence of woven bone in adults is always pathological and is evidence of too rapid bone formation.

X-rays are important in diagnosing bone abnormalities, so some terms should be described first. Tissues that are easily penetrated by x-rays are visible on the x-ray as black or dark and is described as ''radiolucent'', which comes from the word “translucent”, which is similar to transparent. Soft tissues like muscle and skin are radiolucent.

The opposite is ''radiopaque'' tissues, which comes from the word “opaque”, the opposite of transparent. These tissues are not easily penetrated by x-rays and are visible as white or light grey parts on an x-ray. Bone is radiopaque.

A ''pathological fracture'' is a fracture which occurs after a force that would not fracture a healthy bone. Common examples include getting fractures while lifting something, bending over or even just sneezing.

== Congenital disorders of bone ==
Achondroplasia is a disorder of cartilage proliferation in the epiphyseal growth plate. It’s due to a gain-of-function mutation in fibroblasts growth factor receptor 3 (FGFR3). Most of these mutations occur sporadically, but they are autosomal dominantly inherited. The mutation impairs endochondral ossification but not intramembranous ossification and therefore affects growth of long bones but not flat bones.

The result is that the patient will have short extremities with normal-size head and chest. Mental function, lifespan or fertility are not affected.

''Peter Dinklage (Tyrion Lannister) and Wee Man have achondroplasia.''

Thanatophoric dwarfism is a more severe form of achondroplasia. It’s also due to a gain-of-function mutation in FGFR3, but a different mutation than in achondroplasia. Affected babies develop such a small chest cavity that they die soon after birth due to respiratory insufficiency.

Osteogenesis imperfecta is a congenital defect of bone formation resulting in weak bone. It’s most frequently due to an autosomal dominant defect in the synthesis of type I collagen.

Clinical features include multiple fractures, blue sclera and hearing loss. Type I collagen is also found in the sclera. In osteogenesis imperfecta the collagen component of the sclera will be reduced, which exposes the veins below, giving a blueish colour of the sclera. Hearing loss develops due to fracture of the bones of the inner ear.

Osteopetrosis (petra means rock in Greek) is a congenital defect in the resorption function of osteoclasts. It results in abnormally thick and heavy bones, with a bone marrow that is replaced by bone. The bones are brittle and fracture easily despite their thickness. The bone, including the bone marrow, is completely radiopaque. There are multiple genetical causes of osteopetrosis. It’s often due to a defect in the enzyme ''carbonic anhydrase''.

The carbonic anhydrase defect also gives renal tubular acidosis. Myelophthisis occurs due to ossification of the bone marrow, which causes anaemia, thrombocytopaenia and leukopaenia. Extramedullary haematopoiesis occurs. Cranial nerves are compressed, causing vision and hearing impairment. It’s treated by bone marrow transplant.

== Acquired disorders of bone ==
Osteoporosis occurs when the bone mass is decreased, resulting in a porous bone with increased risk for fracture. It often develops in elderly and postmenopausal women. The bone mass peaks at around 30 years. Approximately 1% of bone is lost per year after the peak. The rate of bone loss depends on diet, exercise and oestrogen levels. Oestrogen decreases the rate of bone loss.

Fractures often occur at the neck of the femur. Compression of the vertebrae causes kyphosis and loss of height. Treatment is exercise, vitamin D and calcium.

Paget disease of bone is the result of an imbalance between osteoclast and osteoblast function. It’s usually seen in late adulthood (> 55 years). The etiology is unknown but may be viral. It affects one or more bones but not the whole skeleton, causing bones to be thickened but weak and fragile. The spine, pelvic bones and skull are most commonly affected.

It has three phases:

# Lytic phase: Osteoclasts go crazy and resorb too much bone
# Mixed lytic and blastic phase: Osteoblasts start to produce bone to compensate for the excessive bone resorption. Osteoclasts and osteoblasts rapidly remodel the bone.
# Sclerotic phase: Osteoclasts and osteoblasts calm down and stop remodelling the bone

The resulting bone is the result of rapid remodelling and is therefore abnormal and weak. The bone has a characteristic mosaic pattern on histology.

Clinical features:

* Bone pain – due to microfractures
* Bone deformities
* Increased hat size – a characteristic symptom that occurs as the skull is thickened
* Hearing loss – compression of cranial nerve

Complications involve high-output heart failure and osteosarcoma. High-output cardiac failure develops due to AV shunts forming in the remodelled bone. Osteosarcoma, a malignant tumor of osteoblasts is a potential risk as the osteoblasts in Paget disease are highly active and proliferative.

Rickets and osteomalacia is due to vitamin D hypovitaminosis. The lack of vitamin D impairs the mineralization of osteoid. In children it causes rickets, as their growth plate hasn’t closed yet. They have pigeon breast deformity and bowing of the legs.

Osteomalacia occurs in adults as their growth plates are closed. The bones become weak and the risk for fracture increases.

Generalized osteitis fibrosa cystica, also called ''von Recklinghausen disease of bone'' is a complication of hyperparathyroidism, often due to a parathyroid adenoma. PTH increases the osteoclast activity and bone resorption, causing loss of bone mass. Brown cystic masses form in the bones, hence the name of the disease. They can be mistaken for primary bone tumors.

Osteomyelitis is the infection of the bone marrow and bone. It most frequently affects children. The infection often spreads haematogenously into the bone marrow, but it can also occur after fracture. The most common pathogen is Staph. aureus. Tuberculosis can also cause osteomyelitis. Symptoms include bone pain, fever and leukocytosis.

Avascular necrosis (or osteonecrosis) is ischaemic necrosis of bone and bone marrow. They often occur due to trauma or fracture.
[[Category:Pathology 2 - Theoretical exam topics]]