Bone Pathology: Composition & Cells

• Bone pathology focuses on non-neoplastic conditions.

Bones

• Provide mechanical support for the body
• Play a role in mineral homeostasis
• Facilitate hematopoiesis
• Protect internal organs
• Determine body shape and size
• An adult human skeleton consists of 206 bones

Bone Composition

• Inorganic elements constitute 65% of bone composition
• Calcium hydroxyapatite is the main inorganic component that provides bone strength
• Calcium, phosphorus, sodium, and magnesium are key inorganic elements found in bone
• Organic elements comprise 35% of bone composition
• Organic elements include osteoprogenitor cells, osteocytes, osteoblasts, and osteoclasts

Cells of Bone

• Osteoprogenitor cells are pluripotent mesenchymal cells
• Growth factors stimulate osteoprogenitor cell division and differentiation into osteoblasts
• Osteoblasts synthesize, transport, and arrange the protein matrix of bone (osteoid)
• Osteoblasts initiate mineralization
• Osteoblasts express receptors for hormones
• Osteocytes are encased by bone and release chemical mediators
• Osteoclasts are related to monocytes and macrophages, and are responsible for bone resorption
• Cytokines and growth factors regulate osteoclast differentiation and maturation

Bone Matrix

• Osteoblast-derived proteins are found in the bone matrix
• Type I collagen is a key component of the bone matrix
• Woven bone has a random deposition pattern
• Lamellar bone has an orderly deposition pattern

Bone Matrix Proteins

• Cell adhesion proteins include osteopontin, fibronectin, and thrombospondin
• Calcium-binding proteins include osteonectin and sialoprotein
• Osteocalcin contributes to mineralization and is unique to bone
• Enzymes such as collagenase and alkaline phosphatase are present
• Growth factors like IGF-1, TGF-β, and PDGF are present
• Cytokines include PGs, IL-1, IL-6, and RANKL

Diseases and Abnormalities

• Diseases can stem from defects in hormones and structural proteins
• Achondroplasia and thanatophoric dwarfism are examples of such diseases
• Achondroplasia is the most common disease of the growth plate
• Defects in hormone and signal transduction pathways occurs with achondroplasia
• Achondroplasia is related to autosomnal dominant, with 80% spontaneous mutations
• There is reduced chondrocyte proliferation in with achondroplasia
• Mutation of FGF receptor 3 is a point mutation that causes achondroplasia
• Individuals with achondroplasia will have a normal torso and head size, short extremities, as well as a prominent forehead
• Radiographs of achondroplasia patients will show short, slightly bowed long bones without osteopenia
• Thanatophoric dwarfism is the most common lethal form of dwarfism
• Characterized by gain-of-function mutation in FGFR3
• Characteristics of thanatophoric dwarfism include micromelic shortening of the limbs, frontal bossing, macrocephaly, small chest cavity, and a bell-shaped abdomen
• Infants with thanatophoric dwarfism frequently die at birth due to respiratory insufficiency

Type 1 Collagen Diseases

• Type 1 collagen diseases include Osteogenesis imperfecta and are caused by mutations in collagen genes
• Osteogenesis imperfecta is a brittle bone disease
• Osteogenesis imperfecta is the most common inherited connective tissue disorder
• Prominent skeletal manifestations include joint, eye, skin, and teeth issues (dentin deficiency)
• It is caused by mutation in a-1 and a-2 chains of collagen (COL1A1, COL1A2)
• An autosomnal dominant inheritance (>800 mutations) leads to scant bone formation
• There are four subtypes of Osteogenesis imperfecta, which is a Type I collagen disease
• Osteopetrosis features reduced resorption
• It is associated with a defect in the metabolic pathway
• Mutations of carbonic anhydrase II interferes with the process of acidification of the osteoclast resorption pit
• Associated with Mutation chloride channel gene is an autosomal recessive inheritance
• Symmetric sclerosis leads to stonelike bones with reduced fragility
• The mild autosomnal dominant form might not be discovered until adolescence or adulthood
• Multiple fractures may appear in a patient's history due to the osteopetrosis
• Osteopetrosis was the 1st genetic disease treated with bone marrow transplantation
• Fetus with osteopetrosis exhibit a cortical area without osteogenesis, & a medullary cavity without bone marrow

Diseases Associated with Decreased Bone Mass

• Osteoporosis is associated with decreased bone mass
• Osteoporosis is characterized by decreased bone mass (osteopenia) of normally mineralized bone which causes the bone to become porous
• Osteoporosis can be diffuse or localized
• It is diagnosed by iliac crest bone biopsy and dual-photon absorptiometry (DEXA scan)
• Senile or post-menopausal is the most common form
• Secondary osteoporosis may be caused by endocrine disorders, drugs, neoplasia, or GI issues like malnutrition
• Related to hormonal influences such as estrogen deficiency as well as a high-turnover form

Osteoporosis Pathogenesis

• Age-related changes reduce osteoblast proliferative and biosynthetic potential
• Reduced physical activity increases bone loss
• Increase includes the rate of bone loss, jogging, and endurance activity
• Genetic factors like RANKL, OPG, RANK, and the MCH locus contribute
• Calcium nutritional state is related to osteoporosis
• Complications of osteoporosis include fractures of the femoral neck, pelvis, and spine, as well as pulmonary embolism and pneumonia
• Prevention includes exercise, appropriate calcium and vitamin D intake, and pharmacologic agents like bisphosphonates

Diseases Caused by Osteoclast Dysfunction

• Paget Disease is caused by osteoclast dysfunction
• It is also known as Osteitis Deformans and occurs in late adulthood, around 70 years
• Osteolytic, osteoclastic-osteoblastic, and osteosclerotic are the stages of Paget Disease
• There is an elevated serum alkaline phosphatase (ALP) as well as the presence of urine hydroxyproline
• Osteosarcoma occurs in 0.7-0.9% of Paget disease cases
• Paramyxovirus infection and mutations in the SQSTM gene are possible mechanisms of pathogenesis
• Axial skeleton and proximal femur are commonly affected
• Common clinical manifestations are axial skeleton and proximal femur, chalk stick -type fractures, enlargement of craniofacial skeleton, and severe 2° osteoarthritis
• Giant cell tumors, giant cell reparative granulomas, and extra-osseous masses of hematopoiesis are also present

Paget Disease Characteristics

• Enlargement of the skull, lower-back pain, and hearing loss, arthritis, stress fractures, and increased bone turnover can occur
• Elevated serum alkaline phosphatase and urinary hydroxyproline are elevated
• Bone scans are preferred for detection, but the treatment option is calcitonin or bisphosphonates
• Bone mosaic occurs with a prominent cement lines, and large osteoclasts
• Paget disease has 3 distinctive phases: osteolytic, mixed, and osteosclerotic

Diseases Associated with Abnormal Mineral Homeostasis

• Rickets, osteomalacia, hyperparathyroidism, and renal osteodystrophy are diseases associated with abnormal mineral homeostasis
• Defect in bone matrix mineralization and associated with lack of vitamin D are signs of Rickets/Osteomalacia
• Rickets typically occurs in children whereas osteomalacia is found in adults
• Primary Hyperparathyroidism is the result of parathyroid hyperplasia or tumor
• Secondary Hyperparathyroidism: Prolonged hypocalcemia with compensatory PTH secretion
• Osteitis fibrosa cystica: Severe form, rare due to early detection
• Hyperparathyroidism has an X-ray of sub-periosteal resorption of radial aspect of middle phalanx of index and middle fingers
• Brown tumor: mass of reactive tissue

Avascular Necrosis

• Avascular Necrosis/osteonecrosis is an infarction of bone and marrow
• Possible root causes may include fracture, corticosteroids, thrombosis, vessel injury, and venous hypertension
• It can lead to Geographic necrosis
• Can include subchondral wedge-shaped of the bone