2022 Bone Remodeling, Developmental Abnormalities, and Fracture Healing PDF

Bone remodeling, development and developmental abnormalities and fracture healing Dr. Hüseyin Keml Türköz What is bone?... The bone-forming cells- osteoblasts and osteocytes (derived from pluripotent mesenchymal cells) Bone-digesting cells: Osteoclast (derived from marrow monocyte/macrophage precurs...

Bone remodeling, development and developmental abnormalities and fracture healing Dr. Hüseyin Keml Türköz What is bone?... The bone-forming cells- osteoblasts and osteocytes (derived from pluripotent mesenchymal cells) Bone-digesting cells: Osteoclast (derived from marrow monocyte/macrophage precursors) Organic matrix (35%) cells of bone and the proteinaceous osteoid. Inorganic elements (65%) mainly calcium hydroxyapatite. 99% of the body’s calcium. 85% of the body’s phosphorus. 65% of the body’s sodium and magnesium. The only thing that is constant is the change Ἡράκλειτος, Herakleitos of Ephesus 535 BC – 475 BC unity of opposites, "the path up and down are one and the same", all existing entities being characterized by pairs of contrary properties The only thing which is constant in the bone is Change... Remodelling:. Never ending, ongoin process. Constant breakdown and renewal Balance : The relative activities of osteoblasts and osteoclasts RANK (receptor activator for nuclear factor-κB) + RANK ligand (RANKL) => NF-κB. NF-κB is necessary for osteoclast formation, fusion, differentiation, function, and survival. Osteoprotegerin (OPG): “decoy” receptor produced by a number of tissues including bone, hematopoietic marrow, and immune cells. Osteoblastic and stromal cells control over osteoclast development and activity A mechanism for biologic mediators (hormones, cytokines, growth factors) to influence the homeostasis of bone tissue and bone mass. Fractures Complete or incomplete, Closed (simple) or compound, Comminuted, Displaced, Pathologic fracture... Stages of fracture healing Continuous process... 1. Inflammatory Phase 2. Reperative Phase 3. Remodelling Phase Inflammatory Phase imp 1. Haematoma: Blood and fibrin clot (1-2 days after fracture) Necrosis – empty lacune 2. Local inflammation: fibrin, polymorphs and macrophages. 3. Ingrowth of granulation tissue begins with neovascularisation and proliferation of mesenchymal cells from periosteum and endosteum. A soft callus is thus formed which joins the ends of fractured bone without much strength. 4. Callus composed of immature (woven) bone and cartilage starts within the first few days. The cells of inner layer of the periosteum lay down collagen as well as osteoid matrix in the granulation tissue. The osteoid undergoes calcification and is called woven (immature) bone => procallus. The woven bone callus (procallus) bridges the gap between the ends of fractured bone. * Earliest bone formatin: 7th day (Invariably woven bone) Reperative phase Lasts for months Acute inflammation dissipates The procallus acts as scaffolding on which osseous callus composed of lamellar bone is formed. Calcified and lamellar bone is formed Haversian system concentrically built around the blood vessels Remodeling phase Osteoblasts build new bone and osteoclasts remove malformed bone segments => remodelling of the united bone ends After sometime,fractured area is indistinguishable from normal bone. But biological process of remodelling may last for years Factors delaying fracture healing:. Displaced and comminuted fractures. Inadequate immobilization. Infection!!! Developmental abnormalities in Bone  Dysostoses: Developmental anomalies resulting from localized problems in the migration of the mesenchymal cells and the formation of the condensations. (Aplasia, extra bones, abnormal fusion)  Dysplasias: mutations in the regulators of skeletal organogenesis (signaling molecules, matrix components). Affect cartilage and bone tissues globally. Osteodysplasia/ chondrodysplasia Developmental abnormalities in Bone 1. Defects in the nuclear proteins and transcription factors 2. Defects in hormones and signal transduction 3. Defects in extracellular structural proteins 4. Defects in the folding / degradation of macromolecules 5. Defects in methabolic pathways 6. Diseases associated with decreased bone mass 7. Diseases associated with osteoclast dysfunction 8. Diseases associated with Abnormal mineral homeostasis * Congenital * Acquired 1. Defects in nuclear proteins and transcription factors  Defective mesenchymal condensation- cartilage anlage Mutation in Homeobox gene Extra digits, syndactily 2. Hormones/ Signal Transducers - Achondroplasia (the most common form of dwarfism). Constitutive FGFR3 (fibroblast growth factor) activation. FGFR3 => inhibition in proliferation and function of growth plate chondrocytes => abnormal endochondral ossification, periosteal ossification is not affected. AD or spontaneous.. Shortened proximal extremities, normal trunk length, enlarged head - Thanatophoric dwarfism (the most common lethal form of dwarfism). FGFR3 activation. spontaneous mutations. Shortened limbs, small chest cavity, and a bell-shaped abdomen. Death at birth or soon after Achondroplasia Thanatophoric dwarfism 3. Extracellular structural proteins Type I collagen diseases (the most common inherited disorder of connective tissue) Osteogenesis Imperfecta Brittle (Glass) Bone Disease Deficiencies in the synthesis of type 1 collagen The fundamental abnormality: too little bone, extreme skeletal fragility Four types... Type II: Fatal in utero or perinatal, Type I: Normal life span Also effects joints, eyes (blue sclera), ears (hearing loss), skin, and teeth 4. Defects in holding and degradation of macromolecules Mucopolysacchariodeses Lysosomal storage diseases. Problem in degradation of mucopolysaccarides Mucopolysaccharides accumulate within chondrocytes (chondrocytes degrade extracellular matrix mucopolysaccharides)and induce apoptosis. Abnormalities in the cartilage anlage, growth plates, costal cartilages, and articular surfaces. Affected individuals are frequently of short stature and have chest wall abnormalities and malformed bones. 5. Methabolic pathways Enzymes, ion channels, transporters... Osteopetrosis (Marble bone disease) Osteopetrosis is an umbrella term for a number of genetic diseases causing reduced bone resorption due to dysfunction of osteoclasts. Most of the mutations interfere with acidification of resorption pit of osteoclasts- defects in dissolution of calcium hydroxyapatite (Example: Albers-Schönberg disease -> mutation in genes encoding carbonic anhydrase or vacuolar ATPase=> an acidic pH can not be obtained in osteoclasts=> bone resorbtion is reduced) Deficiency in osteoclast activity: No medullary canal, small neural foramina => compression in exiting nerves=> pain and function lost in innervated area. No remodeling in bone => rise in woven bone/ reduction in lamellary bone => fracture ***Bone marrow transplantation Narrowed bone marrow area->leukopenia, anemia etc… 6. Decreased Bone Mass Osteoporosis porous bones... reduced bone mass... Localized / Systemic Osteopenia ->decreased bone mass Osteoporosis-> osteopenia that is severe enough to significantly increase the risk of fracture - Age related - Hormonal influences - Reduced physical activity - Genetic factors * Hormonal influences First postmenopausal decade: 2% of cortical bone and 9% of cancellous bone lost per year Decreased estrogen => inflammatory cytokines =>RANKL/OPG => Osteoclast recruitment and activity trabecular bone loss is prominent, compression fractures -> collapse of vertebral bodies High turnover variant * Age-related changes Osteoblasts of elderly – reduced proliferative and biosynthetic potential Cortical bone loss is prominent=> fractures in weight-bearing bones Low turnover variant Trabecular plates become thinned, lose their interconnections -> microfractures and vertebral collapse - Deformities, loss of height, fractures, emboly 7. Osteoclast dysfunction Paget Disease (Osteitis Deformans) Etiology... uncertain. Environmental and genetic factors... - SQSTM1 gene mutation- NFkB activation (RANK)-> Osteoclast activation - Unknown mutations inactivating OPG - Viruses and other unknown enviromental factors alteration in VitD sensitivity – IL6 secretionAll cause increase in Osteoclast activity Increased bone metabolism and turnover. Starting event is increased osteoclastic activity Three phases: (1) an initial osteolytic stage (2) a mixed osteoclastic-osteoblastic stage, which ends with a predominance of osteoblastic activity (3) a burnt-out quiescent osteosclerotic stage The net effect is a gain in disordered / weak / misshapen bone mass - Begins in late adulthood (average age at diagnosis, 70 years) Morphology remarkable histologic variation over time and from site to site The hallmark is the mosaic pattern of lamellar bone initial lytic phase: waves of osteoclastic activity and numerous resorption pits. Large Osteoclasts mixed phase: osteoclasts+osteoblasts Osteosclerotic phase: Bone is larger than normal. Trabeculae are coarsely thickened lamels are in mosaic pattern. Cortices are soft and lack structural stability Clinical Course Most cases are mild and are discovered as an incidental The axial skeleton or proximal femur is involved in up to 80% of cases. Microfractures or bone overgrowth that compresses nerve roots (Pain), bowing of long bones. Benign tumors: giant-cell tumor, giant-cell reparative granuloma… Malignant lesions: 0.5% - 1% of all individuals with Paget disease, and in 5% to 10% of those with polyostotic disease. Osteosarcoma or fibrosarcoma Microscopy: Abnormal lamellar bone with a pathognomonic mosaic pattern (likened to a jigsaw puzzle) due to prominent haphazardly arranged cement lines 8. Abnormal homeostasis Rickets/ osteomalacia Vitamin D deficiency -> calcium deficiency Impairment of mineralization => accumulation of unmineralized matrix. Adulthood- Osteomalacia Childhood- Rickets (growth plates and long bones are more severly effected) Osteitis dissecans in hyperparathyroidism Hyperparathyroidism PTH => RANK => osteoclast activity=> Bone Resorption=> generalized osteoporosis Repeating fractures and healing with fibrosis -> Brown tumors Generalized skeletal changes in hyperthyroidism is callled generalized osteitis fibrosa cystica (von Recklinghausen disease of bone)