The disorders of the bones & musculoskeletal system

Introduction

The bones, ligaments, cartilages and muscles are important components of the musculoskeletal system. Together, they’re responsible for the shape, size of the body; motion; visceral organ protection & hematopoiesis, particularly in bones.

The layers of the bone include the periosteum & endosteum.  Within the bones are: osteoid (unmineralized organic matrix); mineral calcium hydroxyapatite; osteoprogenitor cells; osteoblasts; osteocytes & osteoclast.

Osteoid & calcium hydroxyapatite provide hardness & strength to bones. Osteoprogenitor cells produce precursors that differentiate into osteoblasts. This is mediated by the RUNX2 transcription factor & WNT/β-catenin pathway, also, the BMP (bone morphogenic protein). Osteoblasts are immature cells that line bone surfaces & produce bone matrix proteins & minerals.

Osteoblasts have receptors for parathyroid hormone; estrogen; testosterone; Vit. D; cytokines (e.g. IL-1); leptin; growth factors (e.g. BMPs); extracellular matrix proteins (e.g. fibronectin).

Osteocytes are mature cells surrounded by organic matrix, which control calcium & phosphate levels in bone. They possess canaliculi (cytoplasmic processes) that communicate with other cells, helpful in mechanotransduction.  

Osteoclasts are mature multinucleated cells that are descendants of monocyte precursors. They partake in bone resorption by releasing acids which destroy minerals, & proteases which destroy osteoid.  Important in their differentiation & maturation are Macrophage colony-stimulating factor (M-CSF), IL-1, TNF.

Signaling pathways for bone homeostasis

In order to maintain a normal bone microenvironment, different bone cells express unique ligands & receptors. Some also respond to cytokines and growth factors for their differentiation, proliferation and maturation.

Osteoclast expresses transmembrane receptor activator for NF-κB (RANK). The osteoblast & marrow stromal cells express RANKL (the ligand for RANK). Osteoblast & other cell types also produce the receptor, osteoprotegrin (OPG) which competitively inhibits binding of RANKL on RANK.

In the first signaling pathway, RANKL activates RANK which causes activation of transcription factor NF-κB. This transcription factor initiates the proliferation & survival of osteoclasts.

In the second pathway, osteoblasts produce M-CSF which activates tyrosine kinase activity on M-CSF receptor on osteoclast precursors. This then causes differentiation and maturation of osteoclast.

In the third pathway, stromal cells produce WNT proteins that activate LRP5 & LRP6 receptors on osteoblasts. Transcription factor, β-catenin is activated in the osteoblast which causes the synthesis of OPG.

We can infer that genetic mutations affecting genes including OPG, LRP5, LRP6, RANKL, RANK can disturb normal bone homeostasis.

There are other systemic factors which can affect bone formation and resorption, by affecting levels of OPG and RANKL expression. These factors include: parathyroid hormone; estrogen; testosterone; glucocorticoid; Vit. D; inflammatory cytokines (e.g. IL-1); bone morphogenic proteins (BMPs).

Osteoblasts produce type 1 collagen, adhesion proteins (fibronectin, osteopontin, thrombospondin); calcium-binding proteins (osteonectin, bone sialoprotein); mineralizing protein (osteocalcin).  These proteins form the osteoid.

Other products of osteoblast include: enzymes (collagenase, alkaline phosphatase); cytokines (IL-1, Il-6, RANKL); growth factors (IGF-1, TGF-β, PDGF).

Osteoblasts may either deposit collagen randomly to form woven bones found in fetal skeleton or base of growth plates. They may also deposit collagen in an orderly fashion to form lamellar bones, seen in adult skeletons. 

Bone modeling, remodeling, bone growth & development

The basic multicellular unit (BMU) is a functional unit of a group of cells including osteocytes, osteoclast, osteoblast. This unit is responsible for bone formation and breakdown.

Bone modeling occurs early in life, and at this stage, skeletal growth and enlargement are primary. Over time, as bone reaches maturity, bone remodeling happens in which there is bone breakdown and replacement. In early adulthood, bone reaches its peak mass. Above age 39, skeletal mass gradually begins to decrease.

How do our bones grow and develop?

Bone formation begins with the cartilage anlage as a model for bone construction, at around the 8^th week of gestation. The homeobox genes produce transcription factors essential in skeletal bone formation.

Two important centers of bone formation are the mid shaft & epiphysis which act as the primary & secondary centers of ossification respectively.

At the primary center of ossification (mid shaft), the cartilage anlage is cleaved by osteoclast-type cell forming the medullary canal. This cleavage progresses further along the shaft. The osteoblast on the periosteum of the mid shaft deposits the bone matrix that forms the cortex.

The secondary ossification center (epiphysis), contains areas of enchondral ossification. Below the epiphysis is the growth plate- a plate of cartilage between centers of bone deposition & ossification. Within this growth plate are chondrocytes that must proliferate, grow, mature & undergo apoptosis to contribute in the vertical growth of bones during childhood.

About the area of apoptosis of chondrocytes (metaphysis), the matrix-containing cartilage, mineralizes. This mineralized matrix is cleaved by osteoclast, leaving some remnants of cartilages on which bones are deposited forming primary spongiosa (first primary bony trabeculae).

Processes of bone formation seen on secondary ossification centers also take place at the base of articular cartilages which increase in diameter.  In bones such as the cranium & lateral part of clavicle, bone growth occurs by new bone deposition on a pre-existing bony surface by osteoblast.  

Dysostoses

These are developmental anomalies associated with problems of mesenchymal cell (osteoblast, chondrocytes) migration & formation of condensations. They are limited to certain embryological structures, & their causes include mutation of transcription factors (e.g. homeobox gene). Examples include:

1. Synpolydactyly: extra digit with fusion
2. Waardenburg syndrome: hearing loss; abnormal pigmentation; craniofacial abnormalities.
3. Oligodontia: congenital absence of teeth.
4. Nail-patella syndrome: hypoplastic nail; hypoplastic/aplastic patella; dislocated radial head; progressive nephropathy.
5. Ulnar-mammary syndrome: hypoplastic/aplastic ulna, 3^rd to 5^th fingers, breast, teeth, delayed puberty.
6. Cleidocranial dysplasia: abnormal clavicle, Wormian bones, supernumery teeth.
7. Greig syndrome: synpolydactyly; craniofacial abnormalities.
8. Holt-Oram syndrome: congenital abnormalities; fore-limb anomalies.

Dysplasias

These are defects in skeletal organogenesis arising from mutations affecting signaling molecules, or matrix components.

Examples include: achondroplasia; thanatophoric dwarfism; autosomal dominant osteopetrosis type 1 (ADO-1); Van Buchem disease; endosteal hyperostosis; autosomal dominant osteopetrosis type 2; autosomal recessive osteopetrosis; osteoporosis pseudoglioma syndrome; osteogenesis imperfecta type 1; stickler syndrome.

Achondroplasia

This is an autosomal dominant disorder that causes dwarfism, arising from FGFR-3 mutation. This mutation causes constitutive inhibition of growth plate. Life expectancy, sterility, & intelligence are unaffected.

Signs: Short proximal limbs; fairly normal trunk; macrocephaly with bulging frontal bone; depression of the root of the nose.

Thanatophoric dwarfism

A lethal form of dwarfism arising of FGFR-3 mutation. Signs include: disproportionately short limbs; bell-shaped abdomen; small thorax; large head; bulging fore-head.

Autosomal dominant osteopetrosis type 1 (ADO-1); Van Buchem disease & endosteal hyperostosis

These are a group of similar diseases, that arise from activating mutation in LRP5 gene that affects osteoclast activity. They result in high bone mass that manifest as: cortical thickening; cranial vault & mandibular enlargement; torus planus.

Autosomal dominant osteopetrosis type 2 & autosomal recessive osteopetrosis

The both are also known as Albers Schonberg disease (marble bone disease), & are unlike their other variant, ADO-1. They are caused by chloride channel gene mutation (CLCN7). This mutation prevents the functioning of H⁺ ATPase pump that pumps H⁺ into the osteoclast resorption pit, thereby affecting the normal activity of the osteoclast.

In both variants of osteopetrosis, the distal ends of long bones are bulbous (Erlenmeyer flask deformity) with other features including: small neural foramina which compress exiting nerves; persistent primary spongiosa which fills up medullary cavity with no room for hematopoietic marrow; woven bone architecture with fragility.

Clinical manifestations of the severe, autosomal recessive type are evident in uterus and infancy, & include:  anemia, fracture; hydrocephaly; postpartum mortality; optic atrophy; deafness; facial paralysis; recurrent infections.  

In the mild autosomal dominant variant evident among adolescents & adults, anemia, optic atrophy, deafness, & facial paralysis are mild. Treatment of both variants require bone marrow transplantation.

Osteoporosis pseudoglioma syndrome

This results from inactivating mutation in LRP5 gene. This manifests as bone osteoporosis and fractures.

Osteogenesis imperfecta type 1

This is an autosomal dominant disease, that arises from a decrease in synthesis or production of abnormal collagen type 1 fibers. It usually affects bone, but skin, eyes, ears, joint, teeth can be affected.

Signs/symptoms include: childhood fractures; fragile bone; sensorineural and conductive hearing loss; blue sclera; small, abnormal blue-yellow teeth; cortical thinning.

Stickler syndrome

This is also a connective tissue disorder, that arises from decreased synthesis, or production of abnormal type 2 collagen fibers. Signs include: myopia; flat face; retinal detachment; hearing loss; premature osteoarthritis.

Osteoporosis

This is the reduction in bone mass, resulting in the porosity of bones.

The predisposing factors include: Age, post-menopause; lack of physical activity; calcium & vit. D deficiency; increased parathyroid hormone stimulation; genetic variations of RANKL, RANK, OPG, LRP5 genes; estrogen deficiency in post-menopause (increases inflammatory cytokines which recruit osteoclasts).

In post-menopause osteoporosis, there is destruction & thinning of cancellous/spongy bone in the vertebrae. In age-related osteoporosis, there is thinning of cortex.

Signs/symptoms: pain & fracture of spine, femoral neck, pelvis; lumbar lordosis; kyphoscoliosis; weight loss; pulmonary embolism from fracture (complication).

Diagnosis: to measure bone density, dual-energy X-ray absorptiometry, quantitative computed tomography, or biopsy may be used.

Prevention/treatment: weight training exercise; calcium & vit. D intake; treatment with bisphosphonates.

Paget disease/osteitis deformans

This is an osteosclerotic bone disorder that results in increased bone mass. It usually affects people 70 years and above, with common anatomical areas including axial skeleton and femur.

Risk factors: whites; first-degree relatives of affected individuals; sequestosome-1 gene SQSTM1 mutation (enhances osteoclast activity).   

Morphological features: Mosaic pattern of lamella bone (coarsely thickened trabeculae and cortices); large bones that are soft, porous and lack stability.

Signs/Symptoms: pain; bony overgrowth, microfractures of vertebrae column; compression of spinal and cranial nerve roots; leontiasis ossea (large skull with difficulty holding head erect); platybasia (invagination of skull base & compression of posterior fossa structures).

Other clinical manifestations: anterior bowing of femur & tibia; severe secondary osteoarthritis; chalkstick-type fractures of the long bones of lower extremities; osteosarcoma (complication).

Diagnosis: X-ray; bone scintigraphy. Laboratory markers include: high serum alkaline phosphatase; high urine hydroxyproline.

Treatment: calcitonin; bisphosphonates

Rickets and osteomalacia

Rickets and osteomalacia affect children and adults respectively. These are disorders of bone matrix mineralization resulting from vit. D deficiency or disturbances in their metabolism.

In children signs include: craniotabes; frontal bossing; squared-shaped cranium; pigeon breast deformity; lumbar lordosis; bowing of legs (tibia).

In adults, sings include: weak and fragile bones of the vertebrae & femoral neck; fracture.

Fracture

fracture is a break on the surface of bone arising from traumatic or non-traumatic conditions. Several forms of fractures include:

1. complete fracture- a broken born torn apart into 2 or more pieces.
2. Incomplete fracture- a broken bone not torn apart.
3. Simple (closed) fracture- a fracture site with an intact skin surface.
4. Compound (open) fracture- a fracture site communicating with an overlying non-intact skin.
5. Comminuted fracture- a broken born torn apart into 3 or several pieces.
6. Displaced- unaligned ends of fractured bones.
7. Pathologic fracture: a break arising from a bone with an already established disease.
8. Stress fracture: a slowly developing fracture following high physical activity from repetitive load.

Healing mechanism: Formation of soft callus 1 week after fracture until about 2-3wks; Bony callus begins to form 3wks following fracture; Bone remodeling is enhanced also about 3wks following fracture. Healing may be affected by inadequate rest, early mobilization, & infection. 

A Soft-tissue callus is an uncalcified tissue that includes fibrocartilage, hyaline cartilage, granulation tissue, & is also surrounded by woven bone. They help stabilize fracture site. A bony callus is a calcified bone tissue, that provides stiffness to the site of fracture.  

Osteonecrosis (avascular necrosis)

This is the death of the bone and marrow tissues arising from ischemia. It occurs in the medullary cavity and subchondral region of epiphysis.

Predisposing factors: corticosteroid usage; dysbarism; radiation therapy; alcohol abuse; pregnancy; sickle cell anemia; tumors.

Signs/symptoms: chronic pain; secondary osteoarthritis especially in subchondral infarcts.

Acute osteomyelitis

This is the infection of the bone and marrow tissues by microbes. Pyogenic bacteria and mycobacteria are the most common causes.

The pyogenic bacteria include: staphylococcus aureus (predominant); E. coli, pseudomonas, klebsiella, H. influenzae & Grp. B streptococci (in neonates); salmonella (in sickle cell patients).

Predisposing factors: mucosal injury; minor skin infections; compound fractures; surgery; diabetic foot infections; genitourinary tract infection; intravenous drug abuser; sickle cell disease; immunosuppression.

Pathogenesis: In children subperiosteal abscess may lead to rupture of periosteum & skin abscesses, with eventual formation of a draining sinus. In infants, epiphyseal infections may spread to adjacent joint to cause septic or suppurative arthritis.

Signs/symptoms: fever; chills; leukocytosis; localized pulsating pain. Acute flareups or unresolved acute osteomyelitis may result in chronic osteomyelitis. Complications of chronic osteomyelitis are: endocarditis; sepsis; secondary amyloidosis; squamous cell carcinoma in a draining sinus.

In tuberculous osteomyelitis, spread to the spine is common resulting in Pott disease. Other sites include the knee & hips. Clinical manifestation may include: low-grade fevers; weight loss; sweating; localized pain.

Complications of tuberculous osteomyelitis include: pathologic fractures; scoliosis; kyphosis; neurologic defects; tuberculous arthritis; psoas abscess; amyloidosis; draining sinus. 

Diagnosis/treatment of osteomyelitis: radiography; blood culture; biopsy & bone culture (necessary). Treatment requires antibiotics & surgical drainage.

Osteoid osteoma & osteoblastoma

These are well-circumscribed, hemorrhagic, round-oval tan benign tumors, made of spongy woven bone surrounded by osteoblasts. They affect teenagers & young adults less than 25 years, & are common among males. These tumors arise more commonly in the cortex.

Osteomas are <2cm in diameter & usually arise in cortex of appendicular skeleton (femur, tibia) & posterior components of spine. This condition produces severe nocturnal pain relieved by aspirin. Treatment is by radioablation.

Osteoblastomas are lesions >2cm, and usually affects the spine. They produce dull, aching pain that are unresponsive to aspirin. Treatment proceeds by curettage or excision.   

Osteosarcoma

These are hemorrhagic, big bulky gray-white gritty tumors. They are the most common primary malignant tumor of bone, excluding hematopoietic marrow tumors. ¾ of individuals affected are younger that 20 yrs. The remainder are people above 65 with conditions like Paget disease, bone infarcts, irradiation.

The most frequent genetic causes involve mutations of the RB & p53 gene. While it may affect any bone, metaphyseal region of long bones (especially the knee) is usually affected.  They usually destroy the bone cortex and also form new bone matrix, with lace-like architecture.

The symptom includes pain. On a radiogram, Codman triangle (triangular shadow btw cortex and raised end of periosteum) is characteristic. Metastasis to lungs, bones, brain, & other parts occur.

Osteochondroma (exostosis)

This is a benign, 1-20cm cartilage-capped tumor, attached with the underlying host bone by a bony stalk. It is the most common benign bone tumor. It arises from germline inactivating mutation of EXT1, EXT2 (exostosin glycosyltransferase-1) gene, resulting in defective endochondral ossification.

Normally, these genes encode proteins useful in heparin sulfate synthesis. These lesions usually occur in the metaphysis of long bones (especially around the knee). Other regions include: ribs, pelvis, scapula. They are painful, & may impinge on nearby nerves.  

Ewing sarcoma

This is the second most common primary malignancy of bone in children and young adults <20 yrs, with boys highly affected. Ewing sarcomas are undifferentiated.

It is an enlarging soft, tan-white tumor, with areas of necrosis and hemorrhage & is composed of sheets of small, round cells. It arises in the diaphysis of long bones (especially the femur), & pelvis, where it begins in the medullary cavity, invades cortex, periosteum & soft tissues.

Cause: involves chromosomal translocation btw EWS gene on Ch 22, & FLI1 transcription factor gene on Ch 11. Together, they produce a fusion protein-a transcription factor that drives cell proliferation & survival.

Signs/symptoms: pain, swelling, warmth, tenderness around sites of involvement; anemia; leukocytosis; fever; high sedimentation rate. On a radiograph, the characteristic appearance shows the periosteum with layers of reactive bone deposition in an onion-skin fashion.

ABOUT THE JOINT

The function of the joint is to enable motion, & provide mechanical stability to bones. The types of joints include: fibrous synarthroses; cartilaginous synarthroses; & synovial joints.

The fibrous synarthroses include the cranial sutures, & attachment btw the teeth & jaw bones. The cartilaginous synarthroses include the xiphisternal joint, pubis symphysis, & intervertebral disc. The synovial joint includes the hip joint, elbow joint; atlantooccipital joint etc.

The synovial joint is made of hyaline cartilage & the joint space. The boundary of the joint space is made of synovial membrane lined by synoviocytes. The synoviocytes produce hyaluronic acid for joint lubrication.

The hyaline cartilage is made of water, collagen type 2, proteoglycan, chondrocytes. The chondrocytes produce the matrix & produce degradative enzymes in their inactive forms, together with their inhibitor. IL-1 & TNF trigger the degradative processes of joints.

Osteoarthritis

A degenerative joint disease in which cartilage breakdown results from biochemical and metabolic alterations in susceptible individuals. It affects hips in males, with hands and knees in females.

Predisposing factors: >50 yrs of age; obesity; diabetes; hemochromatosis; ochronosis; genes involved in prostaglandin metabolism & WNT signaling.

Pathogenesis: chondrocyte injury & death; matrix degradation; subchondral bone plate exposure with sclerosis, osteophytes & subchondral cysts.

Signs/symptoms: pain that worsens with use; morning stiffness; crepitus; limitation of range of movement; cervical and lumbar nerve root compression by osteophytes; radiculopathy; muscle spasm; neurologic deficits.

The effects regions of hand include: proximal, distal interphalangeal joint; first carpometacarpal joint; first tarsometatarsal joint. In women Heberden nodes (prominent osteophytes at distal interphalangeal joints) are common.   

Rheumatoid arthritis

This is a nonsuppurative proliferative & inflammatory synovitis of joints, that causes cartilage destruction and joint ankylosis. It may also affect skin, blood vessels, heart, lung muscles. Predominant among female & people btw 40 & 70 yrs.

Pathogenesis: pannus formation on articular cartilage results in juxta-articular erosion, osteoporosis, cartilage destruction, subchondral fibrous ankylosis, & bony ankylosis. The pannus consists of a mass of synovium, inflammatory cells, and granulation tissue.

RA causes rheumatoid nodules & rheumatoid vasculitis. Rheumatoid nodules are firm, non-tender round-oval lesions. RA nodules are found in subcutaneous tissues around the elbow, ulnar aspect of forearm, occiput & lumbosacral area.

Rheumatoid vasculitis is a complication of RA & frequently affects small arteries resulting in peripheral neuropathy, cutaneous ulcers, & gangrene.

Predisposing factors: HLA-DRB1 alleles; citrullinated proteins; Epstein-Bar virus; retroviruses; parvoviruses; mycobacteria; Borrelia; Proteus mirabilis; Mycoplasma; CD4+ effector T cells & memory T cells.

Signs/Symptoms: Initially: malaise, fatigue, generalized musculoskeletal pain. several wks.-months:  Symmetrically warm, painful, swollen joints, with stiffness following inactivity. Radial deviation of wrist; ulnar deviation of fingers; swan neck deformity (PIP hyperextension + DIP flexion); boutonniere deformity (PIP flexion + DIP hyperextension)

In a descending order of event, the joints affected are: metacarpophalangeal joint; proximal interphalangeal joint; feet; wrists; ankles; elbows; knees.

Diagnosis: On a radiograph there is joint effusion; juxta-articular erosion & osteopenia; narrowing of joint space with loss of articular cartilage. Laboratory markers are the rheumatoid factors (IgM, IgG) & anti-CCP antibody (more specific)  

Treatment: corticosteroids; methotrexate or TNF antagonists.

Ankylosing spondyloarthritis/Marie-Strumpell disease

This is a chronic joint inflammation that causes articular cartilage destruction and bony ankylosis (stiffness), with resultant spinal immobility. It is common among young men 20-30 yrs of age.   

It usually affects the facet joint of spine; costotransverse joints; sacroiliac joint. Patients present with low back pain & complications including uveitis, aortitis, amyloidosis.

Predisposing factors: HLA-B27 allele.

Reiter syndrome

This is a reactive arthritis with symptoms including arthritis, nongonococcal urethritis/cervicitis, & conjunctivitis. Patients are usually HLA-B27 positive and are also men between 20 & 30 years old.

Predisposing factors: Salmonella; Yersinia Campylobacter; Shigella; Chlamydia; HIV.

Symptoms appear within several wks. of diarrhea or urethritis & include joint stiffness and lower back pain. Ankle, feet, & knee are usually affected in an asymmetric pattern with occasional involvement of the spine.

Gout and Gouty Arthritis

Gout is an acute, transient inflammation of the joint, triggered by urate crystallization into monosodium urate. Gouty arthritis is a continuous attack of gout arising from repetitive crystallization of urate crystals, eventually resulting in tophi.

Tophi is an aggregate of urate crystals surrounded by macrophages, lymphocytes, & large foreign body giant cells. Urate is a byproduct of purine metabolism-the genesis of these conditions.

Predisposing factors: urate overproduction (from diets, high cell turnover; chemotherapy-induced tumor lysis; Hyperuricemia (>6.8mg/dl); Age (>30 yrs old); deficiency of hypoxanthine guanine phosphoribosyl transferase HGPRT in Lesch Nayan syndrome.

Other predisposing factors include: temperatures at 20^oC; heavy alcohol consumption; obesity; thiazides; lead toxicity; chronic kidney disease.

Pathogenesis: Macrophages phagocytize crystals, which then release CXCL8-a chemokine that attracts neutrophil to the site of inflammation. Neutrophils release free radicals, lysosomal enzymes & leukotriene B4, leading to acute arthritis.

Signs/symptoms: acute attack: excruciating join pain & tenderness, mild fever, localized hyperemia & warmth. 12 yrs. after the acute attack, then appears tophus. Complications include cardiovascular disease and renal failure.

Regions affected include 1^st metatarsophalangeal joint; insteps; ankles; heels; knees; wrists; fingers & elbows.

Lipoma

Lipoma is a benign encapsulated tumor of mature adipocytes of variable sizes that usually arises in the hypodermis of proximal extremities & trunk. It is a soft-tissue tumor of middle adult-hood.

Signs: Lipomas are soft, mobile & painless & can be cured by excision.

Leiomyomas

This is a benign smooth muscle tumor that often arises in the uterus. Other regions may include the skin’s arrector pili muscle, nipples, scrotum, labia. Their sizes vary & are composed of fascicles of spindle cells, with few atypia & mitoses.