Muscle, Bone, Joint, and Rheumatology

Musculoskeletal Reasoning Map

Skeletal muscle force begins at the motor neuron. An action potential opens voltage-gated calcium channels at the presynaptic terminal, calcium enters, and synaptotagmin triggers SNARE-mediated fusion of acetylcholine vesicles. Acetylcholine binds nicotinic receptors on the motor end plate, producing sodium influx greater than potassium efflux and an end-plate potential. If threshold is reached, voltage-gated sodium channels propagate depolarization along sarcolemma and down T tubules.

The skeletal muscle dihydropyridine receptor acts mainly as a voltage sensor and mechanically opens the ryanodine receptor on sarcoplasmic reticulum, releasing calcium into cytosol. Calcium binds troponin C, moves tropomyosin away from actin's myosin-binding sites, and permits cross-bridge cycling. ATP binds myosin to detach it from actin; ATP hydrolysis cocks the head; phosphate release produces the power stroke; ADP release completes the cycle. Relaxation requires SERCA to pump calcium back into sarcoplasmic reticulum and acetylcholinesterase to terminate synaptic signaling.

Step 1 neuromuscular junction questions test where the signal fails. Myasthenia gravis is a postsynaptic nicotinic acetylcholine receptor or MuSK antibody disease with fluctuating fatigable weakness, ocular symptoms, normal sensation, and improvement with acetylcholinesterase inhibition. Complement-mediated damage flattens postsynaptic folds, reducing safety factor. It is associated with thymic hyperplasia and thymoma.

Lambert-Eaton myasthenic syndrome targets presynaptic P/Q-type voltage-gated calcium channels, causing proximal weakness, reduced reflexes, autonomic symptoms such as dry mouth, and incremental improvement with repeated use because calcium accumulates in the terminal. It is classically paraneoplastic with small cell lung carcinoma. Botulinum toxin cleaves SNARE proteins, preventing acetylcholine release and causing descending flaccid paralysis with autonomic findings; tetanus toxin blocks release of GABA and glycine from inhibitory interneurons, causing spastic paralysis.

Malignant hyperthermia involves abnormal ryanodine receptor calcium release after volatile anesthetics or succinylcholine, producing rigidity, hypercarbia, hyperkalemia, acidosis, and high temperature; dantrolene blocks calcium release.

Muscle pathology is often an energy or membrane problem. Duchenne muscular dystrophy is X-linked loss of dystrophin, so repeated contraction tears the sarcolemma, calcium enters, fibers necrose, and creatine kinase rises. Becker dystrophy has reduced or abnormal dystrophin and later onset. Mitochondrial myopathies impair oxidative phosphorylation and may show ragged red fibers because abnormal mitochondria accumulate under the sarcolemma.

McArdle disease is skeletal muscle glycogen phosphorylase deficiency, causing exercise intolerance, cramps, myoglobinuria, and a second wind when blood-borne fuels become available. Carnitine palmitoyltransferase II deficiency causes recurrent rhabdomyolysis after prolonged exercise, fasting, or illness because long-chain fatty acids cannot efficiently enter mitochondria.

Bone is dynamic connective tissue. Osteoblasts arise from mesenchymal lineage cells and make osteoid, mainly type I collagen, osteocalcin, and alkaline phosphatase. Osteocytes are osteoblasts trapped in mineralized matrix and sense mechanical strain. Osteoclasts derive from monocyte-macrophage lineage and resorb bone by attaching with an actin sealing zone, acidifying the resorption lacuna through carbonic anhydrase II-dependent proton generation, and digesting matrix with cathepsin K.

Osteoblasts express RANKL and M-CSF to drive osteoclast differentiation; osteoprotegerin is a decoy receptor that binds RANKL and inhibits osteoclast activation. PTH increases osteoblast RANKL expression when continuously elevated, increasing osteoclast activity indirectly. Estrogen increases OPG and suppresses IL-1, IL-6, and TNF, so estrogen loss accelerates trabecular bone resorption.

Mineral homeostasis links gut, kidney, parathyroid gland, and bone. Low ionized calcium is sensed by calcium-sensing receptors on chief cells, increasing PTH release. PTH raises serum calcium by increasing distal tubular calcium reabsorption, decreasing proximal phosphate reabsorption, increasing renal 1-alpha hydroxylase activity, and increasing osteoclast-mediated bone resorption indirectly. Vitamin D is made in skin or ingested, 25-hydroxylated in liver, and 1-alpha hydroxylated in kidney to calcitriol, which increases intestinal absorption of calcium and phosphate.

Primary hyperparathyroidism causes high calcium, low phosphate, kidney stones, bone pain, abdominal symptoms, neuropsychiatric changes, and subperiosteal bone resorption. Secondary hyperparathyroidism in chronic kidney disease reflects phosphate retention and reduced calcitriol; tertiary hyperparathyroidism is autonomous PTH secretion after prolonged stimulation. Vitamin D deficiency causes rickets in children and osteomalacia in adults: defective mineralization of osteoid, bone pain, pseudofractures, and low or normal calcium with high PTH and alkaline phosphatase.

Bone disease mechanisms are high yield because similar pain patterns have different lab signatures. Osteoporosis is reduced bone mass with normal mineralization, usually from aging, glucocorticoids, estrogen deficiency, low weight, or immobility. Paget disease is disordered remodeling with an osteolytic phase, mixed phase, and sclerotic phase; osteoclasts are initially overactive, osteoblasts respond with woven bone, and alkaline phosphatase rises with normal calcium and phosphate.

Complications include bone enlargement, hearing loss from skull involvement, high-output heart failure from vascular bone, and osteosarcoma. Osteopetrosis is defective osteoclast resorption, often due to carbonic anhydrase II or proton pump defects, causing dense brittle bones, fractures, pancytopenia from narrowed marrow space, and cranial nerve compression.

Fracture healing starts with vessel rupture and hematoma. Platelets and inflammatory cells release cytokines that recruit fibroblasts, chondroblasts, and osteoprogenitor cells. A soft callus of collagen and cartilage bridges the fracture, then endochondral ossification creates a hard woven-bone callus. Remodeling replaces woven bone with lamellar bone along lines of stress. Nonunion risk rises with poor blood supply, infection, smoking, diabetes, motion, and severe soft tissue injury.

Osteonecrosis is ischemic bone death; the femoral head, scaphoid, talus, and humeral head are vulnerable because of limited collateral blood supply. Slipped capital femoral epiphysis occurs in overweight adolescent boys and causes posterior-inferior displacement of femoral head relative to neck through the growth plate. Legg-Calve-Perthes is idiopathic avascular necrosis of the femoral head in younger children.

Osteomyelitis is infection of bone and marrow. Hematogenous spread in children favors metaphyses of long bones because slow-flow vascular loops permit bacterial seeding. In adults, vertebral osteomyelitis is common through hematogenous spread. Contiguous spread occurs after trauma, surgery, diabetic foot ulcers, or pressure ulcers. Staphylococcus aureus is the most common organism overall. Salmonella is classically associated with sickle cell disease because functional asplenia, infarcted bone, and gut translocation increase risk, although S aureus remains common.

Pseudomonas follows puncture wounds through rubber-soled shoes. Pasteurella follows animal bites. Chronic osteomyelitis can form a sequestrum of dead bone surrounded by involucrum of reactive new bone.

Arthritis pattern recognition is more important than memorizing isolated names. Osteoarthritis is degenerative cartilage loss with chondrocyte injury, subchondral sclerosis, osteophytes, pain worse with use, brief morning stiffness, and involvement of DIP, PIP, first carpometacarpal, hip, knee, and spine. Rheumatoid arthritis is a systemic autoimmune synovitis with symmetric small-joint involvement, prolonged morning stiffness, MCP and PIP disease with DIP sparing, pannus formation, cartilage destruction, marginal erosions, and extra-articular nodules, lung disease, anemia of chronic disease, and vasculitis.

Anti-CCP is more specific than rheumatoid factor. TNF, IL-1, IL-6, Th17 pathways, macrophages, fibroblast-like synoviocytes, and osteoclast activation drive joint damage. Felty syndrome is RA with splenomegaly and neutropenia.

Crystal and infectious arthritides are identified by synovial fluid. Septic arthritis is acute monoarthritis with high neutrophils and positive culture; S aureus is common, while Neisseria gonorrhoeae can cause migratory polyarthralgia, tenosynovitis, dermatitis, and monoarthritis in sexually active patients. Gout is monosodium urate deposition from hyperuricemia, often first MTP, with needle-shaped negatively birefringent crystals, NLRP3 inflammasome activation, IL-1 release, and neutrophil influx. Underexcretion is more common than overproduction.

Lesch-Nyhan, tumor lysis, and myeloproliferative disease increase production. Pseudogout is calcium pyrophosphate deposition with rhomboid, weakly positively birefringent crystals, often in knee or wrist; associations include aging, hemochromatosis, hyperparathyroidism, and hypomagnesemia.

Systemic rheumatology overlaps with vasculitis and immune complex disease. SLE is loss of tolerance to nuclear antigens with type III hypersensitivity, low complement during active disease, and anti-dsDNA association with nephritis. Anti-Smith is specific; antiphospholipid antibodies cause thrombosis and pregnancy loss with false-positive VDRL or prolonged PTT that does not mean bleeding. Drug-induced lupus classically has anti-histone antibodies and usually spares kidney and CNS. Seronegative spondyloarthropathies are RF-negative, often HLA-B27-associated, and involve entheses and axial skeleton.

Ankylosing spondylitis causes inflammatory back pain, sacroiliitis, bamboo spine, uveitis, and reduced chest expansion. Reactive arthritis follows genitourinary or gastrointestinal infection and may include conjunctivitis, urethritis, and asymmetric oligoarthritis. Psoriatic arthritis can involve DIP joints, dactylitis, nail pitting, and arthritis mutilans. Enteropathic arthritis accompanies inflammatory bowel disease.

Small and medium vessel vasculitides may present with arthralgia, purpura, renal disease, neuropathy, or pulmonary findings, so joint complaints should be interpreted with vessel size, ANCA pattern, complement level, and biopsy findings.