Developmental and Acquired Bone Diseases.pdf

Developmental and Acquired Bone Diseases Dr. Alfred Roy, MD Assistant Professor Learning Objectives 1. Compare and contrast the genetic background, mechanisms of development, and clinicopathologic presentation of the following developmental bone diseases: achondroplasia, osteogenesis imperfecta, and...

Developmental and Acquired Bone Diseases Dr. Alfred Roy, MD Assistant Professor Learning Objectives 1. Compare and contrast the genetic background, mechanisms of development, and clinicopathologic presentation of the following developmental bone diseases: achondroplasia, osteogenesis imperfecta, and osteopetrosis. 2. Define osteoporosis and describe its causes, mechanisms, morphologic findings, investigations, and clinical importance. 3. Discuss Paget disease of the bone in terms of pathogenesis, morphology, investigations, and clinical findings. 4. Describe the avascular bone necrosis in terms of its etiology, pathogenesis, and clinicopathologic presentation. 5. Compare and contrast rickets and osteomalacia in terms of their causes, mechanisms, and clinicopathologic manifestations. Learning Objectives 6. Compare and contrast the bone changes observed in renal osteodystrophy and hyperparathyroidism in terms of their etiology, pathogenesis, and morphologic presentation. 7. Define osteomyelitis and explain its classification; compare and contrast pyogenic and tuberculous osteomyelitis in terms of their etiology, pathogenesis morphologic changes and clinical features. 8. List the types of fractures; describe process and timing of fracture healing; discuss complications of fracture healing. Developmental disorders of bone and cartilage Defects in hormones and signal transduction proteins: Achondroplasia Introduction: - autosomal dominant, common cause for dwarfism - characterized by impaired longitudinal bone growth Pathogenesis: - retarded cartilage growth - shortened proximal extremities, trunk of relatively normal length, and an enlarged head with bulging forehead (depression of root of nose), prominent brows - these skeletal abnormalities are not associated with longevity, intelligence, or reproduction Achondroplasia Pathogenesis (cont’d): - gain of function mutation of FGF receptor 3 (FGFR3) - leads to continuous receptor signaling that - inhibits cartilage synthesis at epiphysis - normal role of FGFR3: inhibits enchondral growth - age may be important Defect in extra-cellular structural proteins: Osteogenesis Imperfecta Introduction: - autosomal dominant Pathogenesis: - mutation involving COL1A1 or COL1A2 genes - this leads to reduced formation of hydrogen and sulfide bonds between type I precollagen molecules - leading to reduced synthesis of triple helix formation and reduced synthesis of normal type I collagen - bone matrix formation (osteogenesis) becomes abnormal Osteogenesis Imperfecta Clinical Features: - blue sclera: reduced collagen content - hearing loss: conduction thru’ ossicles in middle ear - dental: small, blue-yellow misshapen. Due to deficiency in dentin. - bowing of legs (saber shins) - recurrent fractures Diagnosis: - DNA analysis - ultrasound before birth Osteogenesis imperfecta 8 Defects in metabolic pathways Osteopetrosis (Marble bone disease) Incidence: - most cases are autosomal dominant, others are autosomal recessive, type I and II - dense bone, but weak (chalk-like). Pathogenesis: - defective osteoclastic activity leading to increased bone density - mutations in carbonic anhydrase type II gene (CA2) - interfere with acidification of osteoclast resorption pit, which is needed for dissolution of calcium hydroxyapatite - failure of the osteoclasts to reabsorb bone Defects in metabolic pathways Osteopetrosis (Marble bone disease) Clinical Features: Adult variant: milder (Autosomal Dominant) has good prognosis, begins in adolescence - unusually dense bones, multiple bone fractures, scoliosis - pancytopenia due to bone marrow encroachment, hepatosplenomegaly (extramedullary hematopoiesis) Infantile variant: severe (Autosomal Recessive) - dense skull bones pinch nerves in the head and face (cranial nerves), often resulting in vision loss, hearing loss, and paralysis of facial muscle, fractures, renal tubular acidosis Radiology: - broadened metaphysis on x-ray: Erlenmeyer flask Osteopetrosis Treatment: - bone marrow transplant for infantile variant Diseases associated with decrease bone mass Osteoporosis Introduction: - percent of women 65 years of age and over with osteoporosis of the femur neck or lumbar spine: 24.5% (USA). Caucasian women more vulnerable. - age of onset : 50 years to 70 years - *loss of trabecular and cortical bone - leading to porous bone and reduced bone mass - osteopenia: decreased bone strength - generalized, or localized (disuse) Osteoporosis Trabecular bone - trabecular bone has higher surface area - osteoclast and osteoblast found on the surface - examples of bones with high trabecular bone content: spine, head of femur, distal radius remember: trabecualr bone is more affected in osteoporosis Osteoporosis: age related peak bone mass Primary Postmenopausal Senile Secondary (Endocrine) Hyperparathyroidism Addison disease Gastrointestinal Hepatic insufficiency Malabsorption Malnutrition Drugs Alcohol Anticoagulants Miscellaneous Anemia Immobilization Osteoporosis: Causes Osteoporosis Pathogenesis: - the most common cause is postmenopausal, following menopause, there is acceleration of bone loss - may lose as much as 35% of their cortical bone and 50% of their cancellous bone by 30 to 40 years after menopause - Normal: estrogen stimulates osteoblasts and inhibits osteoclasts Post menopause: decreased estrogen is related to increase secretion of inflammatory cytokines (IL-1, TNF, IL-6) - these cytokines promote osteoclast recruitment, proliferation and prolong osteoclast survival - increased levels of RANKL, reduced OPG Remember: Calcium, PTH, & Alkaline phosphatase are all normal Postmenopausal Osteoporosis Osteoporosis: Secondary Causes Drugs 1) Corticosteroids: long term administration especially in Autoimmune Diseases 2) Anti-convulsants 3) L-thyroxine (always test for TSH when treating) 4) Anticoagulants 5) Proton pump inhibitors 6) Aromatase inhibitors (Anastrozole, Letrozole) Risk Factors for Osteoporosis: - cigarette smoking - malabsorption (also includes vegan diet in some cases) - excessive alcohol intake - immobilization Osteoporosis Morphology: - histologically, the bone appears normal, but reduced in quantity - in postmenopausal osteoporosis the increase in osteoclast activity affects mainly bones or portions of bones that have increased surface area, - Example: cancellous compartment of vertebral bodies - this produces microfractures and eventual vertebral collapse Osteoporosis Clinical Features: - mostly asymptomatic - increased fragility of bones leads to “Pathological Fractures” - common sites: vertebral, femoral neck, distal radius (Colles fracture) - vertebral: microfractures cause significant loss of height and various deformities, including lumbar lordosis and kyphoscoliosis - cannot be reliably detected in plain radiographs until 30% to 40% of the bone mass is lost Osteoporosis Diagnosis: DXA - dual energy x-ray absorptiometry - recommended for women who are over 65 years - resuts: T score -2.5 SD or less means osteoporosis - T score between -1 to -2.5 means osteopenia Diseases caused by osteoclast dysfunction Paget Disease - also referred to as Osteitis Deformans Incidence: - affect 1 to 3 million people in the United States - increases with age, more in males, with the highest prevalence in persons older than 65 years Pathogenesis: - three sequential phases 1) initial osteolytic stage 2) mixed osteoclastic-osteoblastic stage, which ends with a predominance of osteoblastic activity 3) final burned-out quiescent osteosclerotic stage Paget disease of the Bone Paget Disease Pathogenesis (cont’d): what causes these changes? - unknown mechanism - possible: Genetic and Environment Genetic - in some cases, mutations in SQSTM1 gene noted - SQSTM1 mutation stimulate NF-kB by RANK signaling - also, possible mutation involving RANK Paget Disease Pathogenesis (cont’d): 1) initial osteolytic stage - there are waves of osteoclastic activity and numerous resorption pits - these osteoclasts are abnormally large and have increased number of nuclei, sometimes up to 110 (normal: 10 to 12 nuclei) 2) mixed osteoclastic-osteoblastic stage - osteoclasts are seen in the mixed phase, but now many of the bone surfaces are lined by prominent osteoblasts - newly formed bone may be woven or lamellar, but eventually all of it is remodeled into lamellar bone. Mosaic pattern is noted 3) final burned-out quiescent osteosclerotic stage - final: the bone is composed of coarsely thickened trabeculae and cortices that are soft and porous and lack structural stability Paget Disease Morphology: - the most important finding: mosaic pattern of lamellar bone, seen in the sclerotic phase - this appears as jigsaw puzzle-like appearance is produced by unusually prominent cement lines, which join haphazardly oriented units of lamellar bone Paget Disease Clinical Course: - the disease is monostotic in about 15% of cases and, the rest are polyostotic - axial skeleton or proximal femur is involved in up to 80% of cases - leontiasis ossea (lion face): craniofacial involvement - platybasia: invagination of the skull base and compression of the posterior fossa - hearing loss, bone pain, severe secondary osteoarthritis Paget Disease: Radiology Paget Disease Clinical Course: - elevated alkaline phosphatase, and urinary hydroxyproline - high-output heart failure: hypervascularity of Pagetic bone may create blood flow like an arterio-venous shunt - warm skin - increased risk for osteosarcoma Diagnosis: - bone scans show “hot spots” (radionucleotide uptake) Avascular Necrosis Introduction: - death of bone tissue due to interruption of blood supply Etiology: - trauma - cellular toxicity: drugs (corticosteroids), smoking, alcohol, radiation Subtypes: 1) Osgood Schlatter: tibial tuberosity, 9 to 14 years of age 2) Panner disease: capitulum of humerus, 5 to 10 years of age 3) Kienbock disease: lunate bone of hand, 20 to 30 years of age 4) Legg-Calve-Perthes: femoral head, 4 to 10 years of age Avascular necrosis Bones vulnerable to ischemia: - there are certain bones which are more vulnerable to ischemia due their peculiar blood supply - example: head of femur, body of talus, and scaphoid - these bones a very large portion of their total surface is covered with articular cartilage through which vessels do not penetrate - blood supply for these bones enters through very restricted spaces, and there is limited collateral circulation Femoral head: - subcapsular fracture disrupts the blood supply (retinacular arteries from medial circumflex femoral artery); therefore, aseptic necrosis occurs Avascular necrosis Rickets Introduction: - both are disoders of bone mineralization - Rickets: new bone formation is defective (growing children) - Osteomalacia: remodeling of pre-existing bone is defective Pathogenesis: Rickets - deficient mineralization affecting growth plate, does not occur once growth plate is closed. Only osteiod laid down leading to thichening of growth plates Osteomalcia - normal bone remodeling is affected leading to excess of persistent osteoid - bone becomes weak and increases risk for gross fractures or microfractures (pseudofractures or Looser zone) - myopathy, spasms, cramps, symptoms of hypocalcemia Rickets Osteomalacia: Pseudofracture/Looser zones Renal osteodystrophy Introduction: - bone changes seen in renal failure Pathogenesis: mechanisms 1. dereased renal excretion of phosphate leads to hyperphosphatemia - calcium phophate precipitation in tissues producing fall in calcium levels 2. reduced hydroxylation of vitamin D to 1,25 dihydroxyvitamin D leads to poor absorption of calcium from intestines leading reduced calcium Hyperparathyroidism: Osteitis fibrosa cystica Introduction: - seen mostly with advanced Primary hyperparathyroidism, rare condition - replacement of calcified bone by fibrous tissue Pathogenesis: Primary Hyperparathyroidism - activation of osteoclasts leading to bone resorption and calcium mobilization - increasing calcium resorption by renal tubules - increasing urinary phosphate excretion - increasing synthesis of active Vitamin D and increasing the intestinal absorption of calcium - increased PTH leads to increased serum calcium Hyperparathyroidism: Osteitis fibrosa cystica Morphology: - increased bone resorption by osteoclasts driven by increased PTH levels - bone marrow replacement by vascularized tissue - stress forces acting on bone leads to cyst formation (weakening) - bone loss leads to micro fractures, secondary h’age, macrophage recruitment, and ingrowth of fibrous tissue as repair mechanism - also called as ‘brown tumor’ Clinical: Bone pain and fractures Osteitis Cystica Fibrosa - also called as ‘brown tumor’ - note: hemorrhage, cystic spaces, reparative fibrosis, osteoclasts (multinucleated) Osteitis Cystica Fibrosa - x-ray shows ‘black spaces’ Osteomyelitis Introduction: - inflammation of bone and marrow, mostly secondary to infection - may be a complication of any systemic infection but frequently manifests as a primary solitary focus of disease Types: 1) Pyogenic osteomyelitis 2) Mycobacterial osteomyelitis 3) Skeletal syphilis Osteomyelitis Pyogenic Osteomyelitis - caused by bacterial infections - organisms may reach the bone by 1. hematogenous spread 2. extension from a contiguous site 3. direct implantation Pediatric age group, most osteomyelitis is hematogenous in origin and develops in the long bones - initiating bacteremia may stem from seemingly trivial mucosal injuries Adults, osteomyelitis more often occurs as a complication of open fractures, surgical procedures, and diabetic infections of the feet Osteomyelitis Pyogenic Osteomyelitis Organisms commonly seen: - Staphylococcus aureus is responsible for 80% to 90% - Escherichia coli, Pseudomonas, and Klebsiella: with genitourinary tract infections or intravenous drug abusers - Salmonella infection: sickle cell disease Sites in bone: - in neonate the metaphyseal vessels penetrate the growth plate, resulting in frequent infection of the metaphysis, epiphysis, or both - in children, is typically seen in the metaphysis - in adults, after growth plate closure, the metaphyseal vessels reunite with their epiphyseal counterparts and provide a route for the bacteria to seed the epiphyses and subchondral regions Vascular supply of bone: Changes with age Osteomyelitis Osteomyelitis Osteomyelitis Pyogenic Osteomyelitis Morphology: - in acute phase, bacteria proliferate and produce neutrophilic inflammatory reaction - following this there is necrosis of bone, and marrow cells (first 48 hours) - then bacteria and inflammation spread longitudinally to reach the periosteum - in children periosteum is loosely attached to the cortex, this allows subperiosteal abscesses that can dissect for long distances along the bone surface - lifting of the periosteum impairs the blood supply leading to necrosis. Dead bone is known as a sequestrum Osteomyelitis Pyogenic Osteomyelitis Morphology: - periosteum may rupture leads to formation of soft tissue abscess - which can tunnel and reach the skin surface as a draining sinus - sometimes the fragments of sequestrum pass through the sinus tract - following first week, chronic inflammatory cells release cytokines that stimulates osteoclastic bone resorption - ingrowth of fibrous tissue, and the deposition of reactive bone at the periphery - newly deposited bone is now called as involucrum, is seen around the segment of devitalized infected bone Osteomyelitis Pyogenic Osteomyelitis Morphology: Brodie abscess: - small intraosseous abscess that frequently involves the cortex and is walled off by reactive bone Sclerosing osteomyelitis of Garré: - characteristically seen in the jaw and is associated with extensive new bone formation that obscures much of the underlying osseous structure Osteomyelitis Pyogenic Osteomyelitis Clinical Course: - acute: less than 2 weeks - sub-acute: between 2 weeks to 6 weeks - fever, chills, weakness, throbbing pain over the affected region Lab Findings: Complete Blood Counts: leukocytosis Blood culture (before starting antibiotics). Bone biopsy for culture ESR, C-Reactive Protein (CRP) Radio imaging: X-rays not helpful in early stages. New bone formation takes 5 to 7 days in children, and 10 to 14 days in adults. MRI with or without gadolinium is best. Complications: secondary amyloidosis, squamous cell carcinoma of skin due to irritation from discharging sinus Osteomyelitis Pott disease, also known as tuberculous spondylitis - usually secondary to an extra-spinal source of infection - anterior aspect of the vertebral body adjacent to the subchondral plate is usually affected - Tuberculosis may spread from that area to adjacent intervertebral disks - progressive bone destruction leads to vertebral collapse and kyphosis - kyphotic deformity is caused by collapse in the anterior spine - lesions in the thoracic spine are more likely to lead to kyphosis than those in the lumbar spine - cold abscess can occur if the infection extends to adjacent ligaments and soft tissues - abscesses in the lumbar region may descend the sheath of the psoas to the femoral trigone region and eventually erode into the skin Tuberculous Osteomyelitis Fracture Healing Fractures Classification Stable fracture: broken ends of the bone line up and are barely out of place Open, compound fracture: skin may be pierced by the bone or by a blow that breaks the skin at the time of the fracture. The bone may or may not be visible in the wound Transverse fracture: this type of fracture has a horizontal fracture line Oblique fracture: this type of fracture has an angled pattern Comminuted fracture: in this type of fracture, the bone shatters into three or more pieces Fractures Healing of fracture: Immediately after fracture: - rupture of blood vessels results in a hematoma, which fills the fracture gap - the clotted blood provides a fibrin mesh, sealing off the fracture site and at the same time creates a framework for the influx of inflammatory cells and ingrowth of fibroblasts and new capillaries - platelets and migrating inflammatory cells release PDGF, TGF-β, FGF - these activate osteoprogenitor cells in the periosteum, medullary cavity, and surrounding soft tissues and stimulate osteoclastic and osteoblastic activity Fractures Healing of fracture: By end of the first week: - organization of the hematoma, matrix production in adjacent tissues, and - remodeling of the fractured ends of the bone - this fusiform and predominantly uncalcified tissue- called soft tissue callus or procallus - provides some anchorage between the ends of the fractured bones but not structural rigidity for weight bearing By two weeks: - the soft tissue callus is transformed into a bony callus - there is deposition of woven bone - bony callus reaches its maximal girth at the end of the second or third week and helps to stabilize the fracture site Fractures Healing of fracture: By three to four weeks: - newly formed cartilage along the fracture line undergoes enchondral ossification, - forming a contiguous network of bone with newly deposited bone trabeculae in the medulla and beneath the periosteum - in this fashion, the fractured ends are bridged, and as it mineralizes, the stiffness and strength of the callus increases to the point that controlled weight bearing is tolerated - the callus is reduced in size and the shape and outline of the fractured bone are re-established as lamellar bone - healing process is complete with restoration of the medullary cavity Fractures Complications: Early Complications Volkman’s ischemic contracture - this is a compartment syndrome, mostly associated with fractures of supracondyle of humerus - the underlying cause is that the artery is severed completely, kinked, or compressed, contused - clinically can cause the 5P’s: pale, pulseless, paresthesia, pain, paralysis Late Complications Delayed union: smoking, inadequate blood supply, infection Non-union: bone stops healing, usually following delayed union Malunion: bone heals, but poorly aligned. Pseudoarthrosis: healing process is disturbed by motion of the fracture ends Thank you