Bone pathology. László Kereskai MD

Transcription

1 Bone pathology László Kereskai MD

2 Anatomy and function Organic osteoid matrix and mineral calcium hydroxyapatite Dynamic tissue: resorption, renewal, remodeling Osteoprogenitor cells: pluripotent mesenchymal cells, vicinity of all bony surfaces, GF-s stimulationdifferentiation into osteoblasts Osteoblasts and lining cells: matrix formation and initialization of mineralization. Receptors for hormones and other factors, express factors that regulate osteoclasts. Surrounded by matrix- transformation to osteocytes. Flattened quiscent cells: lining cells

3 Anatomy and function Osteocytes: communication with each other and surface cells through canaliculi. Help to control calcium and phosphate levels in the microenvironment, and detect mechanical forces and translate them into biologic activity a process called mechanotransduction Osteoclasts: haematopoietic cell derivation (like macrophages), limited lifespan (about 2 weeks), binding to bone surfaces through integrins- formation of resorption pit (analogous to secondary lysosomes)- removal of mineral by generating acidic environment (proton pump system) and digestion of organic substances by proteases

4 Cellular elements

5 Osteocytes- AgNOR

6 Anatomy and function As osteoclasts disassemble matrix proteins deposited by osteoblasts, growth factors, cytokines, and enzymes (such as collagenase) bound to the matrix are liberated and activated, including some that stimulate osteoblasts. Thus, as bone is broken down to its elemental units, substances are released into the microenvironment that initiate its renewal The proteins of bone include type 1 collagen and many noncollagenous proteins derived mainly from osteoblasts. Osteoblasts deposit collagen either in a random weave known as woven bone or in an orderly layered manner designated lamellar bone Normally, woven bone is seen in sites of rapid bone formation such as the fetal skeleton and the base of growth plates. The presence of woven bone in the adult is always abnormal; however, it is not diagnostic of a particular disease. Lamellar bone, which gradually replaces woven bone during growth, is deposited much more slowly and is stronger than woven bone.

7 Woven and trabecular bone

8 DEFECTS IN HORMONES AND SIGNAL TRANSDUCTION MECHANISMS Achondroplasia: the most common disease of the growth plate, mutation in the FGF receptor 3 (FGFR3). Normally, FGFmediated activation of FGFR3 inhibits cartilage proliferation; in achondroplasia, the mutations cause constitutive activation of FGFR3 and thereby suppress growth. AD, but mainly with new mutations in paternal allele. Shortened proximal extremities, a trunk of relative normal length, and an enlarged head with bulging forehead and conspicuous depression of the root of the nose. No changes in longevity, intelligence, or reproductive status.

9 Achondroplasia

10 DEFECTS IN HORMONES AND SIGNAL TRANSDUCTION MECHANISMS Thanatophoric dwarfism: most common lethal form of dwarfism, caused by gain-of-function mutations in FGFR3 that differ from those in achondroplasia. 1:20000 live births. Micromelic shortening of the limbs, frontal bossing, relative macrocephaly, a small chest cavity, and a bellshaped abdomen. The underdeveloped thoracic cavity leads to respiratory insufficiency, and these individuals frequently die at birth or soon after. In the growth plate show diminished proliferation of chondrocytes and poor columnization in the zone of proliferation.

11 Thanatophoric dysplasia

12 DEFECTS IN EXTRACELLULAR STRUCTURAL PROTEINS Osteogenesis imperfecta: brittle bone disease. Various disorders caused by deficiencies in the synthesis of type 1 collagen. It principally affects bone, but also impacts other tissues rich in type 1 collagen (joints, eyes, ears, skin, and teeth). Usually AD. The genotypephenotype relationship underlying osteogenesis imperfecta is based on the location of the mutation within the protein (decreased synthesis of qualitatively normal collagen are associated with mild skeletal abnormalities, more severe or lethal phenotypes have abnormal polypeptide chains that cannot be arranged in the triple helix).

13 DEFECTS IN EXTRACELLULAR Four major subtypes STRUCTURAL PROTEINS The type II variant is at one end of the spectrum and is uniformly fatal in utero or during the perinatal period. It is characterized by extraordinary bone fragility with multiple intrauterine fractures Type I form have a normal life span but experience childhood fractures that decrease in frequency following puberty. Blue sclerae caused by decreased collagen content, making the sclera translucent and allowing partial visualization of the underlying choroid; hearing loss related to both a sensorineural deficit and impeded conduction due to abnormalities in the bones of the middle and inner ear; and dental imperfections (small, misshapen, and blue-yellow teeth) secondary to a deficiency in dentin. The basic abnormality in all forms is too little bone, thus constituting a type of osteoporosis with marked cortical thinning and attenuation of trabeculae.

14 Osteogenesis imperfecta

15 DEFECTS IN METABOLIC PATHWAYS (ENZYMES, ION CHANNELS, AND TRANSPORTERS) Osteopetrosis: or marble bone disease. Bone remodeling deficiency because of the defective lysosomal function of osteoclasts The pathologic tissue consists of lamellar bone and calcified cartilage tissue. The bones easily break (brittle). The nerves are compressed (cranial nerves). The process compromises the normal haematopoeitic development (anaemia). AR (early, frequently fatal) and AD forms (later appearance, fractures, anaemia, nerve compression). Therapy: bone marrow transplantation (the first genetical disease treated with this mood), or recombinant human IFN-.

16 Osteopetrosis

17 DECREASED BONE MASS Osteoporosis: Localized (immobilized limb) and diffuse Decreased bone mass Age-related loss normally: 0,7% per year Most common forms: senile and postmenopausal Senile: decreased activity of osteoblasts and other factors: decreased bone formation; decreased physical activity Postmenopausal: decreased estrogen, increased osteoclast activity leading to resorption Main complication: bone fracture (neck of femur, per- and subtrochanter fracture) Important to rule out other causes: metastases, myeloma

18 Osteoporosis

19 OSTEOCLAST DYSFUNCTION Paget disease (osteitis deformans): 90 % of patients is over 55 ys, before 40 is rare. Localisation: lumbosacral spine, pelvic bones, skull are the most frquent locations, other involvement can happen, but the ribs are spared. Usually polyostotic with elevated ALP level. Monoostotic form: in long bones and vertebrae (ALP level can be normal). Etiology is not known: viral origin was suspected because of inclusions in osteoclast nuclei. There is some genetic predisposition (familial clustering)

20 OSTEOCLAST DYSFUNCTION Paget disease, course: lytic, osteoclastic start, secondly abnormal hyperplasia with the formation of primitive, dyscontinuous bone trabeculae, and later thick trabeculae are formed (better visualisation with reticulin stain than polarisation). The formation of lamellar bone is not well organized, there is a formation of so-called cement lines (sudden changes during the formation of trabeculae, degradation and regeneration follow each other). Cement lines are the keys of diagnosis (other diseases: irradiation defects, chronic osteomyelitis, reactive bone growth around metastasis, in polyostotic fibrous dysplasia, but in these cases they are more regular).

21 Paget disease

22 Paget disease

23 OSTEOCLAST DYSFUNCTION Paget disease, symptoms: Pain, deformities, in weight bearing places secondary osteoarthritis. Complications: fractures, secondary sarcoma formation (usually osteosarcoma, but can be chondrosc, fibrosc and giant cell tumor as well) in different locations (femur, humerus, pelvis, tibia, skull).

24 ABNORMAL MINERAL HOMEOSTASIS Rickets and osteomalacia: D-vitamine deficiency or metabolism disorder. Before the closure of epiphysis phuges: ricketts. Increase of non-mineralised matrix, decreased Caincorporation. Microscopically: nonmineralised matrix zone around bony trabeculae. Deformity, fragility.

25 Ricketts and osteomalacia

26 ABNORMAL MINERAL HOMEOSTASIS Hyperparathyroidism: mainly primary caused by adenoma. The increased PTH concentrations are detected by receptors on osteoblasts, which then release factors that stimulate osteoclast activity. The anatomic changes of severe hyperparathyroidism, known as osteitis fibrosa cystica, are now rarely encountered, because hyperparathyroidism is usually diagnosed and treated at an early asymptomatic stage detected on routine blood tests.

27 ABNORMAL MINERAL HOMEOSTASIS The increased osteoclast activity in hyperparathyroidism affects cortical bone (subperiosteal, osteonal, and endosteal surfaces) more severely than cancellous bone. Subperiosteal resorption produces thinned cortices and the loss of the lamina dura around the teeth. In cancellous bone, osteoclasts tunnel into and dissect centrally along the length of the trabeculae, creating the appearance of railroad tracks and producing what is known as dissecting osteitis. The bone loss predisposes to microfractures and secondary hemorrhages that elicit an influx of macrophages and an ingrowth of reparative fibrous tissue, creating a mass of reactive tissue, known as a brown tumor. Result: generalized osteitis fibrosa cystica (von Recklinghausen disease of bone).

28 Hyperparathyreosis

29 ABNORMAL MINERAL HOMEOSTASIS Renal osteodystrophy: (1) increased osteoclastic bone resorption mimicking osteitis fibrosa cystica, (2) delayed matrix mineralization (osteomalacia), (3) osteosclerosis, (4) growth retardation, and (5) osteoporosis. High-turnover osteodystrophy is characterized by increased bone resorption and bone formation, with the former predominating. In contrast, low-turnover or aplastic disease is manifested by adynamic bone (little osteoclastic and osteoblastic activity) and, less commonly, osteomalacia. Many affected individuals have the third type, which is a mixed pattern of disease.

30 Renal osteodystrophy

31 ABNORMAL MINERAL HOMEOSTASIS Chronic renal failure results in phosphate retention and hyperphosphatemia. Hyperphosphatemia induces secondary hyperparathyroidism Hypocalcemia develops as the levels of vitamin D (1,25- dihydroxyvitamin D 3 ; 1,25-(OH) 2 D 3 ) fall because of decreased conversion from the vitamin D metabolite 25- (OH)D 3 by damaged kidneys Secondary hyperparathyroidism produces increased osteoclast activity Metabolic acidosis associated with renal failure stimulates bone resorption and the release of calcium hydroxyapatite from the matrix.

32 OSTEONECROSIS Most frequent cause: corticosterois administration (head of femur), otherwise it is usually idiopathic (others: trauma, infection, radiation therapy, connective tissue disorders, pregnancy, Gaucher disease, sickle cell and other anemias, alcohol abuse, chronic pancreatitis, tumors, epiphyseal disorders) Medullary infarcts: geographical areas. Wedge-shaped subcondral infarcts. Cortical bone and cartilage are spared. Subchondral infarcts cause chronic pain, secondary osteoarthritis, medullary infarcts are usually silent.

33 Osteonecrosis

34 INFECTIONS- OSTEOMYELITIS Pyogenic osteomyelitis: Usually bacterial, % caused by coagulase-positive staphylococcus. Other bacteria: Klebsiella, Aerobacter, Proteus, Pseudomonas, Streptococcus, Pneumococcus, Gonococcus, Meningococcus, Brucella and Salmonella (abnormal hgbsickle-cell anaemia). Cause: fracture (usually mpx), or hematogenous (mainly before 20 ys, in 75% involvement of lower extremities). Acute, subacute and chronic forms, the latter can mimic tumors clinically and radiologically (destructive and regenerative bone changes). Sometimes extensive regeneration can happen: Garré-type or sclerotising osteomyelitis, with other name periostitis ossificans.

35 INFECTIONS- OSTEOMYELITIS Morfology depends: localisation, causative agent, age. Before 1 year: epiphyseal damage and joint infection, metaphysis és diaphysis is involved only in the minority of cases, over 1 year the opposite: extensive corticali metaphyseal involvement, continuous cartilage and joint injury is rare. In case of metaphyseal start cortical spread through Volkmann channels, and progression in the medulla as well, through the periosteum it can break into the neighbourhood. Sequester is fomed with a bony cavity from the periosteum. Around necrotic bone granulation tissue forms, in the necrotic bone mottled appearance.

36 Acute osteomyelitis

37 INFECTIONS- OSTEOMYELITIS Solution: surgical, removal of sequester. In aduts: joint involvement can happen when there is an extensive bone process. Microscopically: mixed inflammation, fibrosis, bone necrosis, new bone formation. Variants: plasma cell-rich, xanthogranulomatous. In chronic processes widespread periosteal bone formation. In soft tissues fistulas covered by epithel, epidermal inclusión cysts.

38 Chronic osteomyelitis

39 Osteomyelitis sclerotisans (Garré)

40 INFECTIONS- OSTEOMYELITIS Tuberculous osteomyelitis: Hematogenous, young adults and children. Most frequently involved bones: vertebrae, pelvic bones, around knees, wrists. In childhood mainly metaphyseal, in adults rather epiphysealis. Joint involvement: synovia and cartilage destruction. Cutaneous sinuses: secundary bact. infection. Healing: joint fusion with total denudation of cartilage ( kissing sequestra ). Here the sequester isn t cortical, like in bacterial infection, but present in cancellous bone.

41 Tuberculous osteomyelitis