R.F SHEET 019 + SLIDES Lecture 1

بسم هللا BONE FUNCTION

1- Mechanical support 2- Forces transmission 3- Protection 4- Mineral homeostasis 5-Hematopoiesis

ايه مش عجبك ؟ عاوز اكتر BONE STRUCTURE

– Matrix→ (osteoid 35% +minerals 65%) Osteoid → organic type I collagen and glycosaminoglycans & other proteins Inorganic hydroxyapetite [Ca10(PO4)6(OH)2)

What are the major cells of bone ? 1- Osteoblasts → forms 2– Osteoclas → resorbs 3- – Osteocytes → mature WOVEN BONE

1- More cellular and disorganized. 2- The trabeculae are wider )عشوائي ( The arrangement between cells And type 1 collagen is haphazard 3- 4- In early young born in children and in certain diseases

الصور مهمين والزم نعرف الفرق Lamellar bone

1- The cells are more linear and organized +Less cells 2-main structure of mature long bones ( adult ) 3- More collagen OSTEOBLASTS

– Smaller Cells – The nuclear cytoplasmic ratio a little bit high – Mono nuclear cells – osteoid has been formed OSTEOCLASTS

– Big cells – They eat up mature bone [forming white pets] – Multi nucleated cells The development of the bone

– two major ways→ Endochondral ossification – →- Intra-membranous ossification Endochondral ossification

– formation of bone from young mature cartilage – main process where long bone is formed – starts with cartilage → endochondral ossification starts in the center → replaced by mature bone **only a remnant of articular cartilage at both ends.** Intra-membranous ossification

– Formation of flat bones – doesn’t require Cartilage Homeostasis & remodeling

– Continuous and dynamic complex process – Resorption > bone formation on 4th decade

Parathyroid hormone – RANK ligand→ stimulate stem cell → differentiated into osteoclast precursor→mature osteoclast →bone resorption **the cytoplasm will increase and the size of nucleus will decrease.** RANK-RANK ligand receptor interaction (osteoprotegerin)→ inhibits the maturity of osteoclast Lecture 2

Keep going CONGENITAL DISORDERS

: abnormal condensation and migration of mesenchyme →Genetic abnormalities of homeobox genes, cytokines and its receptors – Example: 1-Aplasia→ lack of synthesis of certain group of bone 2-Supernumerary digit→ additional finger or toe 3- Syndactyly & craniosynostosis Syndactyly & craniosynostosis

– Syndactyly → Fusion of the fingers

– Craniosynostosis→ abnormality In formation of the skull CONGENITAL DISORDERS

Disorganized bone & cartilage →Gene mutations that control development and remodeling **Dysplasia here: not premalignant** Example: 1- Achondroplasia (dwarfism) 2-THANATOPHORIC DYSPLASIA 3-OSTEOGENESIS IMPERFECTA 4-OSTEOPETROSIS Achondroplasia → common

– Mutations in FGFR3

– No impact on – longevity, intelligence or reproductive status THANATOPHORIC DYSPLASIA → lethal

– FGFR3 mutations (different from Achondroplasia) – Lethal → small chest leading to respiratory insufficiency **Die at birth or shortly after** OSTEOGENESIS IMPERFECTA ((brittle bone disease))

– disorders of connective tissue (deficiency of type I collagen synthesis) مرض وراثي → (autosomal dominant(AD – - Type 2 (lethal) and type I (relatively normal life)

– Symptoms : Too little bone curved spine Fragility Blue sclera hearing loss teeth abnormalities OSTEOPETROSIS

- stone bone = hard bone Cause : – reduced bone resorption ( osteoclast ) leading to diffuse sclerosis - Mutation in CA2 AND TCIRG1 gene - Diagnosis→ X-ray - Symptoms :→ Fractures and leukopenia in severe forms Metabolic disorder:

– Osteopenia → decreased bone mass (1-2.5 SD below the mean). - Osteoporosis →severe osteopenia; > than 2.5 SD below the mean→increase risk for fractures Classification of osteoporosis Osteoporosis is a multi-factorial disease; the factors could be:

People with good activity → less osteoporosis

estrogen decreases osteoclasts

OSTEOPOROSIS CLINICALLY

– Vertebral fractures – Femur and pelvic fractures → immobility +pulmonary embolism PE +pneumonia special imaging – Diagnosis: technique – bone mineral density (BMD scan) – Dual energy X-ray absorptiometry (DXA or DEXA scan) – bone densitometry PREVENTION

– Exercise – Calcium & vitamin D TREATMENT

– Bisphosphonates → reduce osteoclast activity and induce its apoptosis

– Denosumab → anti-RANKL; blocking osteoclast activation – Hormones (estrogen): risking DVT and strok Lecture 3

Go go goo !!! In children, Rickets in adults it is called Osteomalacia. – Rickets and Osteomalacia Due to vitamin D deficiency or abnormal metabolism of vitamin D. – low levels of vitamin D →decreases the concentration of calcium in matrix→decreased mineralization of bone→unmineralized matrix.

– Symptoms : – Fragile – pain in their bone – dental issues , – poor development and growth & skeletal abnormalities HYPERPARATHYROIDISM HPT

– Thyroid gland regulates→ calcium via parathyroid hormone (PTH) secretion→increasing calcium absorption in GI tract →raises blood calcium → conversion of inactive vitamin D to active form →( increase resorption of the bone

stabilize calcium level in the blood. PRIMARY HPT

– PATHOLOGY → - HYPERFUNCTION OF PARATHYROID CELLS WHY ? * HYPERPLASIA OR * ADENOMA OR * CARCINOMA ASSOCIATIONS → WITH MULTIPLE ENDOCRINE NEOPLASIA SERUM CALCIUM -→ HIGH SERUM PHOSPHATE → LOW / NORMAL MANAGEMENT → SURGERY IF SYMPTOMATIC CINACACALCET WITH THOSE NOT FIT FOR SURGERY * High calcium concentration in blood→low calcium concentration in bone→ weaken bone SECONDARY HPT

– PATHOLOGY → Physiology stimulation of parathyroid in response to hypocalcaemia – ASSOCIATIONS →chronic renal failure or other causes of VITAMIN D deficiency – SERUM CALCIUM →low / normal – SERUM PHOSPHATE →high – MANAGEMENT → treatment of underlying cause TERTIARY HPT

– PATHOLOGY → FOLLOWING long term physiological stimulation leading ro hyperplasis – ASSOCIATIONS →chronic renal failure – SERUM CALCIUM→ high – SERUM PHOSPHATE → high

– MANAGEMENT → CINACACALCET OR Surgery if not respond HPT Clinically

– depend on the conc. of calcium & phosphate in serum because many labs can not measure PTH level in the blood

– Brown tumor 1- mass of collection of blood ( blood hematoma ) 2- fractures of bone that suffer from osteoporosis OSTEITIS FIBROSA CYSTICA (OFC)

– HPT ( not treated ) → OFC تخربطوش بينو وبين – von Recklinghausen's disease neurofibromatosis type I

- inflammatory response → resorption of the bone (weak bone)→fibrosis and cyst formation

*The bones appear less white in color under X-ray Paget disease (Osteitis Deformans)

*Some times the 3 phases happened in the same bone so if you see that , make sure that it’s a paget disease case

– Bone is deformed & there is a little inflammatory response. – divided into 3 phases: 1- Osteolytic phase :

2- Mixed phase :

3- osteosclerotic phase Paget disease (Osteitis Deformans)

– Etiology ( cause) → unknown BUT some scientists blame viruses such as measles and RNA viruses -There are Factors: 1- Environmental and acquired factors → RNA viruses 2-Genetic factor → 50% of familial Paget + 10% SQSTM1 gene mutations → increase in RANK expression → decrease in OPG (osteoprotegerin) expression → increase the osteoclastic activity

SQSTM1 → OSTEOCLASTIC Paget Clinically

– 85% Paget is polystotic →generalized – 15% Monostotic →(one bone is affected only) – (vertebral body, pelvic bone, shoulder bone ) is more affected than femur & tibia) – Most are mild and asymptomatic and Pain is caused by micro fractures & repair during physical activity or nerve compression – Leontiasis ossea : (lion face (: platybasia: severe Paget disease – secondary osteoarthritis &fractures – osteosarcoma (primary bone sarcoma) (1%) – Increase risk of cancer Leontiasis ossea

- DX: pain fractures , x-ray , ,increase in serum Alkaline Phosphatase, Normal Ca and PO4 → differentiate between hyperparathyroidism’s patients and Paget’s patients by the amount of alkaline phosphatase (increased in Paget’s patients) Lecture 4

You can do it doctor !! Keep going Fractures

– Classification of bone fractures: – Simple : Closed , Skin is intact , Swelling. easy to treat and heal quickly العظم المكسور طالع من الجلد , Compound :Opened , Skin is ruptured – harder to treat and take longer time to heal. – Displaced: fractured bone are not at the same axial line – Non-displaced :two ends are at the same axial line Classification of bone fractures

– Stress : repetitive slowly progressive bone fracture →happens in osteoporosis , chronic abnormal bone and weak bone – Greenstick :soft bone fracture in children or young when – the bone is not completely ossified (mineralized) + it doesn’t appear under the X-ray scan , neither the hematoma has appeared yet. – Pathologic: fracture that happens in an abnormal bone weakened by an underlying disease process, or a tumor. = pathologic fractures → TUMOR or disease – Transverse: Simple +Non-displaced – Linear : Simple + Non-displaced +Longitudinal →Happens due to a direct hit on the bone – Spiral: Non-displaced + Simple +oblique fracture →t happens when torque (a rotating force) is applied along the axis of a long bone. – Comminuted: Break of the bone into more than two fragments.(( sever → compound + displaced + indicating sever traumas such s road traffic accidents )) Bone Healing

1- After 1-day →organizing hematoma which fills the fracture gap and surrounds the area of bone injury. 2- Induction of multiple mediators of inflammation including: A- Platelet Derived Growth Factor (PDGF) B- TGF-β C- Fibroblast Growth Factor (FGF) D- Platelets E- Inflammatory cells F- osteoclastic and osteoblastic activity are stimulated. Bone Healing * During the healing process , woven bone appears.

3- Chondrocytes will be stimulated → cartilage healing 4- late phases of the healing process→lamellar bone appears 5- Complete repair of the bone after 3-4 weeks FACTORS IMPACTING PROPER HEALING:

– Displaced and comminuted fractures :: hard to treat , require more time to heal – Inadequate immobilization : leads to delayed union or nonunion. – Pseudoarthrosis : : happens in severe cases→ nonunion persists→the luminal surface may become lined by synovial-like cells →creating a false joint – Infection in open fractures →lead to osteomyelitis post fracture – Malnutrition →protein, calcium and vitamin D is required to speed up the healing process. – Steroids & anti-inflammatory drugs (AIDrugs) OSTEONECROSIS (AVASCULAR NECROSIS)

– Death of the bony tissue → due to ischemia → common in femoral head – Associated conditions: *Vascular injury → Trauma + fractures + Vasculitis (→ ischemia) التفاصيل بالشيت او الساليد بس اخذنا الفكره بمحاضره Drugs →Steroids → ischemia → avascular necrosis 1 * * Systemic diseases→ Sickle cell disease ((at higher risk)) *Radiation →Repeated radiation therapy→damages vascular components → ischemia معلومه بربع نيره ^_^ – one of the complications of pelvic fractures following a trauma is Avascular Necrosis of the head of the femur. Mechanisms →due to vascular occlusion

– Mechanical disruption (Trauma leading to cut of blood supply by force ) – Thrombotic occlusion (Sickle cell , Drugs-steroids-, Radiation ) – Extra vascular compression ( Trauma / Hematoma / Tumors / Fracture leading to compression on blood supply) Osteomyelitis→it is the inflammation of bone marrow due to an infection

-Causes of Osteomyelitis : ❖ part of a systemic infection ❖ Primary solitary focus→only one bone is infected → (ex :from surgical procedure at a certain site). ❖ Pyogenic Osteomyelitis→ pus forming inflammation of the bone caused by an infecting organism , mainly bacteria

Staph. aureus ( gram +ve cocci ) →cause of acute pyogenic osteomyelitis → most common Escherichia-coli (gram –ve bacilli) , Pseudomonas & Klebsiella → common in patients with history of recurrent UTI or patients who are intravenous drug abusers معلومه ب 35

Any organism can cause osteomyelitis , but bacterial osteomyelitis is the most common one Mechanism of spread Osteomyelitis

– Hematogenous spread→ mainly in children – Extension from a contiguous site→mainly in adults – Direct implantation after compound fractures and orthopedic surgeries

** (patient that was partially treated) or (previous improper administration of antibiotic) → (False Negative result)** → that doesn’t mean that there is no bacteria

** The most common cause of pyogenic osteomyelitis for patients with sickle cell disease is (( Staph. aureus )) but we should think about Salmonella .** معلومه بــ

– Long bones get infected more often . • in adults : Metaphysis & epiphysis • in children : Metaphysis Or epiphysis (not both ) Stages of osteomyelitis

Sequestrum ( plural = sequestra ) is a piece of dead bone that has become separated during the process of necrosis from normal or sround bone One of the major causes of chronic osteomyelitis is undiagnosed or improperly treated acute osteomyelitis. – Sequestrum→ necrotic (dead ) bone – Involucrum →(the area of the active bone that surrounds the dead bone) – Cloaca→opening in the involucrum through which Pus & sequestra make their way out . Osteomyelitis clinically هو الموضوع ده مش حيخلص وال ايه !!؟

Symptoms 1- Fever 2-malaise 3-chills 4- leukocytosis ( increased WBC count ) 5-Throbbing pain locally→presence of pus اعراض مخفيه 6-In infants the presentation is subtle , with only unexpected fever Diagnosis -Dependence on symptoms) high index of suspicion) - X-ray→ normal in early phases → changes in the X-ray scan→ patient is in a late phase of the disease. -Biopsy and bone cultures Treatment of Osteomyelitis

– Admission IV antibiotics and surgical drainage of pus.→ unless the patient suffers from UTIs or is a drug abuser→more broad spectrum antibiotics. Chronic osteomyelitis

– TB→can start as chronic infections without the acute phase - Causes of Chronic Osteomyelitis: 1- One of the major causes of chronic osteomyelitis is undiagnosed or improperly treated acute osteomyelitis. 2-Extensive necrosis→ very hard to clear with antibiotics 3-Weakened Host Immunity→patient is taking immunosuppressive drugs or steroids COMPLICATIONS OF CHRONIC OSTEOMYELITIS

– Pathologic fractures – Secondary amyloidosis – Endocarditis→ rare → inflammation of the heart lining→ lethal – Sepsis – Squamous cell carcinoma of draining sinus → rare – Sarcoma of the bone Mycobacterial Osteomyelitis (chronic inflammation)

– Caused → mycobacterium tuberculosis. – Hematogenous or direct spread – Pathology: necrotizing (caseating) granulomas TB SPNDYLITIS (POTT DISEASE) مهم عليه سؤال باالمتحان

– caused →TB infecting → vertebral body – referred to → chronic osteomyelitis of the vertebral body – taking a biopsy →necrotizing granuloma. – Treatment →anti TB drugs →Difficult to treat – COMPLICATIONS →pathologic fractures (compression fractures)+ neurologic deficit, scoliosis, kyphosis Lecture 5

LLLLLLAST ONE ☺ Bone tumors and tumor like conditions:

– Primary bone tumors are rare BUT f it’s occur more common to be Benign than malignant - Treatment : aims to maintaining function - Age & location help narrow differential diagnosis - Mostly asymptomatic BUT if the lesions is big and involves an area which is very active, sometimes there will be a fracture due to this tumor which is called pathological fracture. Common bone tumors table: BONE-FORMING TUMORS -General features for: OSTEOSARCOMA

– Malignant – Mre common in males – Location: Metaphysis →(distal femur & proximal tibia) – Symptoms: Progressive pain or pathologic fracture elevate the periosteum forming Codman triangle Genetic abnormalities→mutations in RB gene, TP53 gene, CDKN2A (p16 & p14), MDM2 & CDK2 :OSTEOSARCOMA FEATURES افهم وامشي بسرعه to the soft tissue tumor arises at the metaphysis and extends angle between actual bone and the periosteum is called Codman’s triangle.

malignant osteoid haphazard abnormal mitosis,

tumor area. OSTEOSARCOMA (MDTeam TREATMENT

– Neoadjuvant chemotherapy – Surgery→ remove the tumor – Chemotherapy and radiation → Chemotherapy= prevent any metastatic possibility →Radiation = control the local diseases – COMPLICATIONS →Hematogenous spread to lungs – 5 year survival reaches 60-70%: probably, it’s improving now 75-80% ** Presence of metastasis at diagnosis is a bad prognostic factor:** less than 5 year THERE IS NO CARTILAGE-FORMING Codman’s triangle. TUMORS:

– Osteochondroma: :benign cartilaginous tumor – Cause : 1- solitary (85% OR 2- part of multiple hereditary exostoses MHE characterized by EXT1, EXT2 gene mutations Rare transformation to chondrosarcoma (malignant ) → when they are MHE

** They cause pain and pathological fractures ** SOMETIMES there’s CHONDROSARCOMA: Codman triangle

– Malignant tumors producing malignant cartilage – 40-50 years of age – Characterized with large masses around the shoulder, the pelvis, the ribs – Genes: EXT, IDH1, IDH2, COL2A1, CDKN2A – Px→ depends on grade – Treatment : surgical +/- chemotherapy CHONDROMA (ENCHONDROMA)

– Benign hyaline cartilage tumors – Solitary – occurring in the metaphyseal lesions,→ most common location: the hands and the feet → AGE 20-50 years – Multiple enchondromas: Ollier disease – Maffucci syndrome → multiple enchondromas + skin hemangiomatosis – Cause : IDH1 & IDH2 gene mutations WELL DONE