Musculoskeletal Disorders PDF

Musculoskeletal Disorders SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE Lea...

Musculoskeletal Disorders SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE Learning Objectives 1. Identify bone types and provide examples of each 2. Describe bone structure 3. Identify the role of osteoblasts, osteoclasts, RANKL, OPG, estrogen, and cytokines and other mediators on bone 4. Correlate various condition and medications with their effect on RANKLE and OPG 5. Differentiate between clinical signs and symptoms of a disease state or condition 6. Describe the pathophysiologic processes for a given disease state or condition 7. Differentiate the pathophysiology of osteomalacia, osteoporosis, and Paget’s disease 8. Describe the basic bone deformities expected in osteomalacia, osteoporosis, and Paget’s disease 9. Differentiate the pathophysiology of rheumatoid arthritis, osteoarthritis, and gout 10. Identify common clinical manifestations that may result secondary to the primary disease (i.e nephropathy from gout) 11. Categorize diseases presented based autoimmune system involvement, common areas or distribution of tissue involvement Outline Anatomy & Physiology ○ Bone Structure ○ Bone Tissue and Regulation  Hormonal control (review) ○ Cartilage Disorders ○ Bone disorders  Osteomalacia  Paget’s disease  Osteoporosis ○ Joint Disorders  Gout  Rheumatoid arthritis (autoimmune disorder)  Osteoarthritis ○ Tissue/Connective Tissue Disorders  Systemic Lupus Erythematosis (autoimmune disorder)  Types of Bones Long ○ Upper and lower extremities Short ○ Wrist, ankles Flat ○ Ribs, skull, scapula Irregular ○ Vertebrae, jaw bones Bone Structure Bone structure types ○ Compact (Cortical)  Outer layer  Rigid, calcified matrix ○ Cancellous (spongy)  Inner layer  Lattice-like pattern  Contain osteogenic cells and interfaces with bone marrow  Most metabolically active Bone Structure Bone Marrow ○ Present in long bones, vertebrae, ribs, sternum, pelvis ○ Marrow types  Red – hematopoiesis ○ As age, replaced with yellow marrow in long bones  Yellow – adipose tissue Blood Supply  ○ Mostly present in compact bone  Regulation of Bone Structure Bone formation ○ Ossification  Forms structural matrix (including collagen) ○ Calcification  Depostion of calcium into structural matrix ○ Metabolically active cells  Osteoprogenitor cells ○ Differentiates into osteoclasts, osteoblasts, fibroblasts, chondrocytes, myocytes, adipocytes  OsteoBlasts – bone formation; B – builds bone ○ Produce bone matrix, collagen, growth factors, and alkaline phosphatase (involved Calcium bone deposition)  OsteoClasts – bone resorption; C = chews bone ○ Phagocytic cells (macrophage/monocyte lineage) ○ Secrete acid which releases Ca from bone ○ Stimulated by PTH ○ Reduced activity by calcitonin and estrogen Key points: Bone maintenance/repair involves 1. Bone resorption via osteoclasts 2. Bone formation via osteoblasts 3. Imbalance of these processes is basis for bone and joint disease Bone remodeling cycle. (A) Overview of remodeling process, Step 1 = initiation, Step 2 and 3 = resorption, Step 4 = reversal, Step 5 = formation, and Step 6 = quiescence Citation: Osteoporosis and Osteomalacia, DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e; 2017. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146068952 Accessed: November 24, 2018 Copyright © 2018 McGraw-Hill Education. All rights reserved Control of Bone Metabolism and Remodeling Pathway linking bone formation and resorption is RANK(L) + OPG Receptor activator of nuclear factor κB ligand (RANKL), it receptor RANK OPG – osteoprotegerin Osteoblasts produce RANKL binds to RANK (receptor) –stimulating osteoclast activity OPG inhibits RANKL-RANK binding – inhibits osteoclast activity  Osteoclast/osteoblast balance influenced by numerous mediators Bone Protective Estrogens ↑OPG, ↓RANKL stimulate osteoclast apoptosis (↑ TGF), ↓ TNF, IL-1, IL-6 (osteoclast stimulators) Calcitonin (↓RANKL) Bone Degradation Inflammatory mediators (TNF, IL-1, IL-6, PGE2)- (↑ RANKL) Glucocorticoids (↑ RANKL, ↓ OPG) Hormones (↑ RANKL) Parathyroid hormone (PTH) Vitamin D (calcitriol) Hormonal Regulation Hormonal Regulation Target Organ PTH Action PTH Effect Bone ↑ bone resorption ↑ Ca Kidney ↑ Ca renal reabsorption ↑ Ca (↓urinary elimination) ↓ PO4 renal reabsorption ↓PO4 (↑urinary elimination) ↑ Calcitriol formation ↑ Ca, PO4 intestinal absorption Target Organ Calcitriol Action Calcitriol Effect Bone ↑ bone resorption (high ↑ Ca concentrations) Kidney Inhibits own synthesis ↓ calcitriol ↑PO4 renal elimination Intestine ↑ intestinal absorption ↑ Ca, ↑PO4  Cartilage Consists of ○ 80% water ○ 20% collagen and proteoglycans ○ Produced from chondrocytes  + growth factors  - cytokines (TNF, Il-1) Avascular ○ Nutrients, gases, waste diffuses in/out  Movement/load promotes diffusion  Calcification impedes diffusion  cartilage dies Found in ○ Ligaments and tendons ○ Appendages (nose, ears) – contains elastin for flexibility ○ Articular joints (hyaline cartilage)  Facilitate bone movement (“frictionless”)  Facilitates load bearing (compressible) Musculoskeletal Disorders Bone disorders ○ Osteomalacia ○ Paget’s disease ○ Osteoporosis Joint Disorders ○ Gout ○ Rheumatoid arthritis (autoimmune disorder) ○ Osteoarthritis Tissue/Connective Tissue Disorders ○ Systemic Lupus Erythematosis (autoimmune disorder) Bone Disorders Osteopenia – general term for bone disease with loss of bone mass ○ Osteomalacia ○ Paget’s disease ○ Osteoporosis  Osteomalacia Characterized by inadequate mineralization of bone ○ Osteomalacia = adult form of disease ○ Rickets = children form of disease = “soft bones” as osteoblast continues with insufficient mineralization Causes ○ Vitamin D deficiency  Insufficient Calcium  Biologically active forms of vitamin D ○ 25-OH vitamin D (cholecalciferol) ○ 1,25 –(OH)2 vitamin D (calcitriol) ○ Phosphate deficiency (less common) Osteomalacia Calcium/Vitamin D Vitamin D ○ Impaired GI absorption  Fat soluble vitamin – requires bile acids for absorption ○ Inadequate intake (600-800 IU/day)  Less common overall; may occur in vegan diet ○ Inadequate endogenous synthesis  Inadequate sunlight exposure – limits cholesterol conversion to Vit D3 (cholecalciferol)  Kidney failure – limits formation of calcitriol (1,25 hydroxycholecalciferol) ○ Deficiency  impaired Ca absorption  ↑PTH  normalizes Ca + promote Phosphate renal excretion Phosphate Renal loss ○ Impaired bone mineralization Osteomalacia/Rickets Clinical Manifestations Osteomalacia ○ Bone pain ○ Tenderness ○ Fractures  Proximal femur  Distal radius ○ Labs: hypophosphatemia, ↑PTH, low Vit D ○ Skeletal muscle weakness Rickets ○ Stunted skeletal growth ○ Deformed bones  Osteomalacia/Rickets Treatment Vitamin D replacement and supplementation Phosphate replacement and supplementation Calcium supplementation Paget’s Disease Characterized by ↑ number and activity of osteoclasts  compensatory osteoblastic activity ○ High bone turnover Newly formed bone is abnormal and disorganized resulting in thickened (less compact), deformed, painful bone ○ Pelvis, spine, skull, femoral commonly affected, long axial bones ○ Bone is more vascularized Typically presents in fourth decade of life ○ Commonly asymptomatic ○ Only 5% symptomatic (bone pain) Paget’s Disease Clinical Manifestations Poor bone formation quality  fractures and bowing Waddling gait due to softening of pelvis and reduced femoral neck angle Skull remodeling  headaches, tinnitus, vertigo, hearing loss Vertebral fx  kyphosis CV disease – aortic stenosis  Paget’s Disease Treatment Pain: Non-steroidal anti-inflammatory agents ↓Osteoclastic activity ○ Bisphosphonates  Alendronate ○ Calcitonin Optimize bone formation ○ Calcium and vitamin D supplementation Osteoporosis Loss of mineralized bone mass Age related changes in bone mineralization such that: bone resorption( ↑osteoclast activity) >>bone formation(osteoblast activity) Primary disorder ○ Influenced by dietary deficiencies and/or impaired intestinal absorption in calcium, vitamin D  ↓ GI Calcium absorption and ↑ renal excretion ○ Hormone deficiencies  Post-menopausal estrogen loss ○ ↑ osteoclastic activity via RANKL, Il-1, IL-6, TNF ○ Loss of inhibition of osteoclast activity via ↓ estrogen stimulated OPG production  Androgenendogenous estrogen decrease in males Osteoporosis Secondary disorder ○ Hyperthyroidism  ↑ bone turnover ○ Malignances (i.e. multiple myeloma) secrete osteoclast activating factor ○ Alcohol inhibits osteoblast activity ○ Cushing syndrome & long-term corticosteroid use  (↑ RANKL, ↓ OPG) ○ Female athletes  ↓ estrogen  Osteoporosis Clinical Manifestations Bone changes occur at ends of long bones Loss of trabeculae from cancellous (spongy) bone and thinning of bone cortex ○ Minimal stress causes fractures Normal femoral head Osteoporosis Osteoporosis Clinical Manifestations Postmenopausal woman ○ Up to 2% bone mass loss per year ○ 2.5% bone strength loss per year ○ Greatest affect on cancellous bone of vertebral spine  collapse Senile osteoporosis ○ Lose 0.5-1.5% bone mass per year (after age 30) ○ Bone cortex thinning ○ Hip fractures most common presentation Osteoporosis Diagnosis & Treatment Fractures (with minimal stress) may be first indication Bone Mineral Density (BMD) scan ○ Dual energy x-ray absorptiometry (DEXA) scan of hip, L1-L4 lumbar spine, femoral neck ○ BMD > 2.5 standard deviations compared to normal Prevention ○ Exercise (weight bearing) Treatment ○ Calcium/vitamin D supplementation ○ ↓ osteoclast activity  Bisphosphonates  Calcitonin  Reloxifine (via estrogen receptor; postmenopausal)  Joint Disorders Gout Rheumatoid Arthritis Osteoarthritis Gout Gout disorders are caused by the crystallization of urate deposits secondary to increase uric acid concentrations Disorders include ○ Acute gouty arthritis ○ Chronic tophaceous gout ○ Nephropathy ○ Kidney stones Gout Uric acid serum concentrations > 6.8 mg/dL = hyperuricemia (without symptoms) = gout disorder (with symptoms) Solubility of uric acid limited ○ Less soluble in synovial fluid (vs blood)  Exists as monosodium urate  As concentrations increase, urate come out of solution (crystallizes)  Crystallization more frequent at lower temperatures (distal phalanges – great toe)  Pathogenesis Uric acid (urate) is end product of purine (adenine and guanine) metabolism PRPP=phosphoribosyl pyrophosphate HGPRTase = hyopxanthine guanine phosphoribosyl tranferase Citation: Gout and Hyperuricemia, DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e; 2017. Available at: https:// accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146069254 Accessed: November 23, 2018 Copyright © 2018 McGraw-Hill Education. All rights reserved Pathogenesis: Urate Concentrations ↑ Urate ↓ Urate Production Excretion (10% of cases) (90% of cases 1/3 Gut: Urate  CO2 + NH3 2/3 Kidney – see urate accumulation at CrCl < 20ml/ min  Urate Kidney Excretion Glomerular filtration 100% Proximal tubule reabsorption 100% Tubular secretion 50% Distal tubule reabsorption 40% 10% net excretion Risk Factors Hyperuricemia ○ Only 15% develop gout Obesity Males 3X >> females Diet ○ Red meat ○ Sugary beverages Alcohol ○ ↑purine synthesis ○ Lactate formed during acute ingestions, ↓ urate excretion Medications ○ Thiazide and loop diuretics, aspirin, niacin Pathogenesis Crystaline deposits in synovial fluid, joint cartilage Attract polymorphonuclear leukocytes phagocytosis of crystals  PMN cell death  release of lysosomal enzymes  inflammation and destruction of cartilage and subchondrial bone Prolonged disease (~ 10 years) causes tophi (large, hard nodules)  Clinical Presentation of Gout Abrupt onset of pain with swelling/redness of affected joint ○ Pain is severe; light touch unbearable ○ Fever, leukocytosis Typically monoarticular Most common sites ○ First metatarsophalangeal joint (big toe) ○ Ankles, heels, knees, wrists, fingers, elbow also affected Frequently occurs at night Attack may last days to weeks with (potentially) long periods of remission between attacks Non-articular Manifestations Nephrolithiasis ○ Uric acid kidney stones  Precipitates in acidic urine < pH 5.5  Occurs in about 15% of patients with gout Gouty Nephropathy ○ Acute  Commonly precipitation in renal collecting ducts/ureters  Usually due to tumor lysis syndrome/proliferative disorders (↑nucleic acid turnover) ○ Chronic  Precipitation in renal parenchyma  Loss of tubular function (urine concentrating ability) and proteinuria Treatment of Gout Pain: Non-steroidal Anti-inflammatory Agents (NSAIDS) ○ Not Aspirin (block secretion) Xanthine oxidase inhibitor ○ Allopurinol ○ Febuxostat Antimitosis / leukocyte migration inhibition ○ Colchicine Uricosuric agents ○ Probenecid ○ Lesinurad (reabsorption inhibitor) Pegloticase ○ Uricase ; converts uric acid to allantoin  Rheumatoid Arthritis Prevalence = 1% ○ Any age but 30-50 years is highest incidence Females 3x>>males Etiology ○ Autoimmune disease  70-80% have serologic presence of Rheumatoid Factor (RF, Ig RF) which reacts with Ig G to form immune complexes  Anti-Citrullinated Protein Antibody (ACPA) present in most patients ○ Family history (1st degree family) strong risk factor = genetic basis  Monozygotic twins only 15% concordance of disease ○ Genetic risk/etiology shaped by environmental factors  Cigarette smoking  Environmental stress Rheumatoid Arthritis ○ Systemic disease  Extra-articular manifestations  Inflammatory dz = increase CV death ○ Synovial joint inflammation  joint destruction NEJM 388:6:2023 RA Pathophysiology Immune complexes attract neutrophils, macrophages, lymphocytes These phagocytize the complexes  release lysozymes Lysozymes promote joint destruction Angiogenesis and pannus development Pannus (proliferation/ inflammatory synovial fluid) irreversible destruction of cartilage and bone  RANKL RANKL, proinflammatory cytokines (IL-6, TNF, IL-17), fibroblasts stimulate osteoclasts Citation: Rheumatoid Arthritis, DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e; 2017. Available at: https:// accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=133893255 Accessed: November 26, 2018 Copyright © 2018 McGraw-Hill Education. All rights reserved RA Joint Manifestations Symmetric, polyarticular Fingers, hands, wrists, knees, feet, C-spine Proximal (not distal) phalanges involved Pain,stiffness resolves in 30 min to hours Limited motion due to pain (initially), fibrosis (late) Synovial inflammation  tendon, joint instability  deformations RA Treatment Pain relief: NSAIDS, corticosteroids Disease Modifying AntiRheumatic Drugs (DMARDS) ○ Non-biologics: methotrexate, sulfasalazine, hydroxychloroquine, leflunomide ○ Biologics  Anti-TNF ○ Adalimumab, certilizumab, golimumab, infliximab, etanercept  IL-6 receptor antagonist ○ Tocilizumab  IL-1 receptor antagonist ○ Anikinra  B-cell depletion ○ Rituximab  T-cell activator inhibitor ○ Abatacept  Osteoarthritis ~ Degenerative joint disease Characterized by slow progressive destruction of articular (joint) cartilage and inflammation ○ Collagen is key component of cartilage Cartilage formed from chondrocytes ○ Growth factors  Morphogenic protein 2, transforming growth factor, insulin-like growth factor-1 ○ Catabolism  TNF, IL-1, matrix metalloproteinases Cartilage is avascular; nutrient from synovial fluid Osteoarthritis Weight bearing joints and fingers/toes Normal Joint Break down Osteoarthritis Pathophysiology ↓ collagen synthesis & ↑ breakdown of existing collagen Superficial cartilage layer weakens and cracks Cartilage worn away and replaced by weaker fibrocartilage plug + neovascularization Subchondrial bony plate exposed and thickens New bone/cysts form on margins (osteophytes/spurs) Characteristics of osteoarthritis in the diarthrodial joint. (Courtesy of Dr. D. Gotlieb.) Citation: Osteoarthritis, DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e; 2017. Available at: https:// accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=133893029 Accessed: November 26, 2018 Copyright © 2018 McGraw-Hill Education. All rights reserved Osteoarthritis Clinical Manifestations Achy diffuse joint pain initially ○ Mono/oligo-articular ○ Asymmetric ○ Pain duration usually < 30 minutes  Due to  nociception; expansion of synovial capsule, inflammatory mediators May be associated with crepitus and/or grinding with joint motion Limited motion of joint as disease progresses Joints commonly affected hips, knees, lumbar/cervical vertebrae, proximal & distal joints of hands, distal joints of feet Osteoarthritis Diagnosis & Treatment Clinical presentation + joint x-rays ○ Pain ○ Joint narrowing (xray) ○ Osteophyte formation (xray) Treatment ○ Pain relieve  Acetaminophen  NSAIDs  Intra-articular corticosteroid injection ○ May accelerate joint destruction  Immunologic Tissue/Connective Tissue Disorders Systemic Lupus Erythematosis Systemic Lupus Erythematosis Autoimmune disease that can affect nearly all tissues 10:1 female, 30:1 during childbearing years ○ Systemic lupus erythematosis (70% of patients) ○ Discoid (10%)  Primarily dermatologic manifestation ○ Drug-induced (10%)  Reversible  Procainamide, hydralazine, minocycline ○ Combine SLE with other rheumatoid disorders (10%) SLE Pathophysiology ↑ B cell hyperreactivity ○ Self antigens (autoimmune antibodies)  Nuclear and cytoplasma cell components ○ Antinuclear antibodies (ANA) ○ Anti-deoxyribonucleic antibodies ○ Antiphospholipid antibodies ○ Anti-Smith antibodies ○ Non-self antigens Formation of immune complexes  Pathogenesis of systemic lupus erythematosus (SLE). Genes confirmed in more than one genome-wide association analysis in northern European whites (several confirmed in Asians as well) as increasing susceptibility to SLE or lupus nephritis are listed (reviewed in SG Guerra et al. Arthritis Res Ther 2012;14:211). Gene-environment interactions (reviewed in KH Costenbader et al. Autoimmune Rev 2012;11:604) result in abnormal immune responses that generate pathogenic autoantibodies and immune complexes that deposit in tissue, activate complement, cause inflammation, and over time lead to irreversible organ damage (reviewed in GC Tsokos. N Engl J Med 2011;365:2110 and BH Hahn, in DJ Wallace, BH Hahn, eds. Dubois’ Lupus Erythematosus and Related Syndromes, 8th ed. New York, Elsevier, 2013). Ag, antigen; C1q, complement system; C3, complement component; CNS, central nervous system; DC, dendritic cell; EBV, Epstein-Barr virus; HLA, human leukocyte antigen; FcR, immunoglobulin Fc-binding receptor; IL, interleukin; MCP, monocyte chemotactic protein; PTPN, phosphotyrosine phosphatase; UV, ultraviolet. (Reproduced with permission from Hahn BH. Systemic lupus erythematosus. Citation: In: Kasper DL, Systemic Lupus Erythematosus, Fauci DiPiro AS, Hauser JT, Talbert SL, Matzke RL, Yee GC, et al., eds. Harrison’s GR, Wells Principles BG, Posey of Internal L. Pharmacotherapy: Medicine. 19th A Pathophysiologic ed. 2015.) Approach, 10e; 2017. Available at: https://accesspharmacy.mhmedical.com/content.aspx?sectionid=146068129&bookid=1861&Resultclick=2 Accessed: November 26, 2018 Copyright © 2018 McGraw-Hill Education. All rights reserved SLE Clinical Manifestations Arthralgias/arthritis (90%) ○ Symmetrical ○ Ligament, tendon, joint capsule may be involved  Flexion contractures, hyperextension of interphalangeal joints, subluxation of phalangeal joints, rupture of intrapatellar and Achilles tendons, avascular necrosis of femoral head SLE Clinical Manifestations Dermatologic ○ Sun sensitivity ○ Mucous membrane ulceration ○ Hair loss ○ Malar (“butterfly”) rash ○ Discoid lesion  Discoid Lesion Malar rash SLE Clinical Manifestations Renal disease (50%) ○ Glomerularnephritis ○ Interstitial nephritis Pulmonary ○ Pleuritis ○ Pulmonary effusions Cardiovascular ○ Pericarditis ○ Myocarditis SLE Clinical Manifestations Hematologic ○ Hemolytic anemia ○ Leukopenia, lymphopenia ○ Thrombocytopenia ○ Thrombosis – Ab to protein C inducing TF Lymphadenopathy Central Nervous System ○ Acute vasculitis & Ab development  Stroke, hemorrhage ○ Seizures (esp with renal involvement) ○ Depression, impaired cognition, confusion  SLE Treatment NSAIDS for inflammation Hydroxychloroquine for dermatologic and arthritis Corticosteroids for CNS Immunosuppresants ○ Cyclophosphamide, methotrexate, azathioprine, mycophenolate ○ Belimumab-IgG monoclonal Ab binds to B lymphocyte stimulator preventing binding to B cellsapoptosis