Metabolic Bone Disease Approach PDF

Approach to the patient with metabolic bone disease & rheumatic disease GENERAL PATHOLOGY 3º Prof. Luis D’Marco, MD, MSc, PhD.  ROADMAP Osteomalacia and General Approach rickets Osteoarthrit...

Approach to the patient with metabolic bone disease & rheumatic disease GENERAL PATHOLOGY 3º Prof. Luis D’Marco, MD, MSc, PhD.  ROADMAP Osteomalacia and General Approach rickets Osteoarthritis 1 3 5 2 4 6 Osteoporosis Rheumatoid arthritis Spondyloarthropathies 2 Clinical examination of the musculoskeletal system  Structure of the major musculoskeletal tissues bone problem in kidney : calcium phosphate travel in blood and goes into kidney The bone remodelling cycle eat old bone new bone reparation of the bone osteoclast dead in 12 d  Example of double tetracycline labeling evaluation of the generation of new bone : double tetracycline labelling -> marked 2 times a diff time and after you see the growth by the diff btw the 2 line  Cellular and molecular regulators of bone remodelling osteoblast remaining in the bone = osteocyte deep Key regulators of bone remodelling  Investigation of musculoskeletal disease Joint aspiration Blood tests Imaging Haematology Plain X-rays Biochemistry Bone scintigraphy Immunology MRI Magnetic resonance imaging Tissue biopsy Ultrasonography Electromyography Computed tomography Dual X-ray absorptiometry MRI & Ultrasound image showing synovitis Typical biochemical abnormalities in various skeletal diseases Osteocytes = FGF23 ALKALINE PHOSPHATASE  difference = asymetrical or symetrical Patterns of joint involvement in different forms of symetricalpolyarthritis asymetrical asymetrical symetrical Rheumatoid arthritis Psoriatic arthritis Axial spondyloarthritis/ankylosing Osteoarthritis metacarpophalangeal and proximal Proximal and distal interphalangeal joints targets the spine, sacroiliac joints, entheses and large Proximal and distal interphalangeal joints interphalangeal joints of the hands and of hands, entheses and larger joints peripheral joints (asymmetrical pattern). of hands, first carpometacarpal joint at metatarsophalangeal joints of the feet (asymmetrical pattern) Sacroiliitis may the base, knees, hips, lumbar and cervical (symmetrical pattern). occur. spine.  Osteoporosis Is the most common bone disease and it has been estimated that more than 8.9 million Fx occur annually worldwide. fractures About one-third of all women and one-fifth of men aged 50 and above suffer Fx at some point in life. The burden of osteoporosis-related Fx is predicted to increase by two- to threefold 2050 worldwide (aging). mechanical stress = help the best the bone growth Fx in patients with osteoporosis can affect any bone but common sites are the forearm (Colles’ Fx), spine (vertebral Fx), humerus, and hip. fracture Dual-energy x-ray absorptiometry (DXA) take the measure of the lumber spine or neck of the femur use T and Z score = bone density information on the mineral density  Risk factors for osteoporosis oestrogen problem : no more bone mineralization plasma cell generate too much = too much space in the bone marrow Low Vit D and low Ca = increase PTH = increase bone reabsorption by osteoclast = increase in calcium phosphate into blood = normal calcium level again vit D = ingestion of Ca hyperstimulation of PT gland = hyperplasia hyper production of PTH if ou are eating  Fractures vertebral radius Colles neck femure humerus  Vertebral Fractures loss of density of the bone Castro, C; D’Marco, L; et al. J. Clin. Med. 2020.  Pathophysiology The defining feature is reduced bone density, which causes micro-architectural deterioration of bone tissue and leads to an increased risk of Fx, in response to minor Tx. This is mostly attributable to an increased risk of falling with age but is also partly due to an age-related decline in bone mass, especially in women. Bone mass increases during growth (peak 20-45 y) but falls thereafter in both genders with an accelerated phase of bone loss after menopause due to estrogen deficiency. The loss of bone with aging is caused by an imbalance in the bone remodeling cycle (new bone formed cannot keep pace with the amount that is removed) osteoclast activity is higher than osteoblast  Investigations in osteoporosis put oestrogens vit D for those that have deficiency home + exercise sun = vit D but many steps to activate the liver - kidneys final activation so if liver or kidney problem =the sun are not going to create vit D 1.25 dihydrovitamine D 23 = calcitriol (not passing into the kidney for activation) Drug treatments for osteoporosis into the osteoid = death of the osteoclast = osteoblast working to generate bone could create softer bone if too much  Osteomalacia and rickets OM and rickets are essentially the same disorders, but by definition, rickets occurs in children with open growth plates (i.e., epiphyses), and OM occurs in adults who are skeletally mature. The fundamental abnormality in these disorders is an inability to mineralize osteoid, the precursor to the mineralized bone. Although osteoid is produced, there is a defect in the mineralization process. not hard This results in the accumulation of characteristic thick osteoid leading to stress or pseudofractures, fractures, bowing of the long bones, and other skeletal deformities. Mineralization disorders are due to disturbances in VD, Ca, P or inhibitors of mineralization. tetracyclin = huge separation without mineralization between Causes of osteomalacia and rickets no details too much treatment  Osteomalacia and rickets (A) A typical example of rickets, with bowing of the femurs and tibias, wrist enlargement due to metaphyseal flaring and rachitic rosary, and enlargement of the costochondral junctions of the ribs. (B) The weight-bearing bones of the lower extremities are bowed, and the epiphyses are open, mottled, and overgrown. (C) Looser’s zones or pseudofractures (arrows) are characteristic of osteomalacia or rickets. The closed epiphyses indicate the patient is an adult. (This radiograph is diagnostic of osteomalacia.) microfractures  Osteomalacia huge limitation of the movements A X-ray of the pelvis showing pseudofractures affecting the inferior and superior pubic rami on the left side (arrows). Healing pseudofractures with callus formation are also visible at the inferior and superior pubic rami on the right side (arrows). B Bone biopsy from an osteomalacic patient showing thick osteoid seams (stained light blue, arrows) that cover almost all of the bone surface. Calcified bone is stained dark blue.  Paget’s disease Is characterized by focal areas of increased and disorganized bone remodeling involving one or more skeletal sites. The disease is common in the UK (1% of those aged above 55) and in other European countries. PD is characterized by an increase in bone resorption by abnormal osteoclasts, followed by rapid formation of poorly organized, structurally weak “woven” bone. The markedly increased osteoblast activity accounts for the typical sclerotic lesions observed on plain radiographs, the increased uptake of radionuclide on bone scan, and the concomitant increase in serum levels of alkaline phosphatase, the latter of which is a protein byproduct of maker of bone activity bone formation and the biochemical hallmark of PD.  Clinical features The axial skeleton is predominantly affected, and common sites of involvement are the pelvis, femur, tibia, lumbar spine, skull, and scapula. The most common presentation is bone pain and pathological fractures may also be presenting features. Many patients are asymptomatic (Dx is made on the basis of an X-ray or blood test made for another reason). Clinical signs include bone deformity and expansion, and increased warmth over an affected bone. Neurological problems, such as deafness, cranial nerve defects, nerve root pain, spinal cord compression and spinal stenosis, may occur. Osteosarcoma (unusual) is serious complication that presents with increasing pain and swelling of an affected site.  Paget’s disease microfractures A 99mTc-labelled bisphosphonate scintigraphy, illustrating the intense tracer uptake and deformity of the affected femur. B The typical radiographic features with expansion of the femur, alternating areas of osteosclerosis and radiolucency of the trochanter, and pseudofractures breaching the bone cortex (arrows). intense activity  Treatment Involves a combination of nonpharmacologic (i.e., physical therapy) and pharmacologic therapy, including antiresorptive agents and analgesics. Bisphosphonates, the mainstay of treatment, decrease bone resorption at pagetic sites by inhibiting osteoclasts. IV zoledronic acid is the first-line treatment and leads to more rapid and sustained normalization of alkaline phosphatase than oral bisphosphonates. Surgery may be needed for an impending or complete Fx through pagetic bone, realignment of arthritic joints, and total joint arthroplasty (hips or knees).  Rheumatoid arthritis Is a common form of inflammatory arthritis, occurring throughout the world and in all ethnic groups. The prevalence of RA is approximately 0.8–1.0% in Europe and the Indian subcontinent, with a female-to-male ratio of 3:1. Is lower in Asia (0.4%). It is a chronic disease characterized by a clinical course of exacerbations and remissions.  Pathophysiology of rheumatoid arthritis ADAMTS5 = aggrecanase; IL = interleukin; M-CSF = macrophage colony-stimulating factor; MMP = matrix metalloproteinase; RANKL = receptor activator of nuclear factor kappa B ligand; TNF = tumour necrosis factor envi trigger = modify protein = sense dentritic cell = LT c = Plasma c = Ab = immune complex = vasculitits and inflamatory synovial fibrosis : bone erotion = stimulation of osteoclast generate infla mediator and bone destruction Criteria for diagnosis of rheumatoid arthritis rheumatoid factors nodules and deviation of the hands = swan neck problem ulnar deviation to the  CLINICAL PRESENTATION Clinical Characteristics Extra-articular Features acccumulation in the back of the knee Rheumatoid nodules and olecranon bursitis swelling oedema  Investigations and monitoring for Rheumatoid Arthritis most of the drug to treat = kidney problem Calculation of the Disease Activity Score & Algorithm for the management HCQ = hydroxychloroquine; MTX = methotrexate; SSZ = sulfasalazine  Osteoarthritis Is by far the most common form of arthritis and is a major cause of pain and disability in older people. It is characterized by focal loss of articular cartilage, subchondral osteosclerosis, osteophyte formation at the joint margin, and remodeling of joint contour with enlargement of affected joints. The prevalence rises progressively with age (45% of all people develop knee OA and 25% hip OA). Although some are asymptomatic, the lifetime risk of having a total hip or knee replacement for OA in someone aged 50 is about 11% for women and 8% for men. There are major ethnic differences in susceptibility: The prevalence of hip OA is lower in Africa, China, Japan and the Indian subcontinent than in European countries, and that of knee OA is higher.  Pathophysiology Degeneration of articular cartilage is the defining feature of OA. Under normal circumstances, chondrocytes are terminally differentiated cells but in OA they start dividing to produce nests of metabolically active cells. Initially, matrix components are produced by these cells at an increased rate, but in OA there is accelerated degradation of the major structural components of cartilage matrix, including aggrecan and type II collagen. Eventually, the concentration of aggrecan in the cartilage matrix falls and makes the cartilage vulnerable to load-bearing injury. Pathologic features of osteoarthritic joint tissues increase thickness subcondral bone and desorganaize cartilage infiltration leucocyte or neutrophil = inflammation infiltration inside join destruction of cartilage and pain degeneration of osteophyte (prolongation of subchondral bone) -> X ray  Risk factors & Pathological changes in osteoarthritis nest of bad cartilage cells generating inflammation A Abnormal nests of proliferating chondrocytes interspersed with matrix devoid of normal chondrocytes. B Fibrillation of cartilage. C X-ray of knee joint affected, showing osteophytes at joint margin osteophyte (white arrows), subchondral sclerosis (black arrows) and a subchondral cyst (open arrow). Symptoms and signs of osteoarthritis osteophyte  Investigations Plain X-ray of the affected joint should be performed and often this will show one or more of the typical features of OA. In addition to providing diagnostic information, X-rays are of value in assessing the severity of structural change, which is helpful if joint replacement surgery is being considered. If nerve root compression or spinal stenosis is suspected, MRI should be performed. Routine biochemistry, haematology and autoantibody tests are usually normal, though OA is associated with a moderate acute phase response. vision of osteophyte = osteoarthritis Synovial fluid aspirated from an affected joint is viscous with a low cell count.  X-ray appearances in knee osteoarthritis A. Advanced osteoarthritis showing almost complete loss of joint space affecting both compartments and sclerosis of subchondral bone. B. Skyline view of the patella femoral joint in a patient with severe patello-femoral osteoarthritis. There is almost complete loss of joint space and lateral displacement of the patella. bone to bone pain Typical varus knee deformity resulting from marked medial tibio-femoral osteoarthritis  Spondyloarthropathies SpAs comprise a group of related inflammatory musculoskeletal diseases that show overlap in their clinical features and have a shared immunogenetic association with HLA-B27. They include: Axial spondyloarthritis Ankylosing spondylitis Reactive arthritis Psoriatic arthritis Arthritis with inflammatory bowel disease (enteropathic spondyloarthritis)  Spondyloarthropathies In axial and ankylosing spondylitis, the axial skeleton (i.e. the central core skeleton) is predominantly affected. In contrast to RA, in the SpAs there are frequent and notable non-synovial musculoskeletal lesions (mainly inflammatory in nature) of ligaments, tendons, periosteum and other bone lesions. A hallmark lesion of all SpAs is enthesitis, which is inflammation at the site of a ligament or tendon insertion into bone. Dactylitis, inflammation of a whole finger or toe, may also occur. Pathophysiology of axial spondyloarthropathy Comparison of the Spondyloarthritis  Radiographic changes in spondyloarthritis diff calcification of the ligament not growth pof the bone A Fine symmetrical marginal syndesmophytes typical of ankylosing spondylitis (arrow). B Coarse, asymmetrical non-marginal syndesmophytes typical of psoriatic spondylitis (arrow). * Note the symmetrical marginal syndesmophytes (arrows), sacroiliac joint fusion and generalized osteopenia.  Reactive arthritis (A) Keratoderma blennorrhagicum. Red to brown papules, vesicles, and pustules with central erosion show characteristic crusting and peripheral scaling on the dorsolateral and plantar foot. (B) Balanitis circinata. Moist, well-demarcated erosions with a slightly raised micropustular circinate border on the glans penis. (C) Bilateral conjunctivitis associated with anterior uveitis.  Psoriatic arthropathy A Dactylitis. B Distal interphalangeal joint pattern with accompanying nail dystrophy (pitting and onycholysis). Mechanism of action of non-steroidal anti-inflammatory drugs Disease-modifying antirheumatic drugs Targets for biologic therapies in inflammatory rheumatic diseases