Musculoskeletal Pathophysiology

Diseases of the musculoskeletal system involve the bones, joints, muscles, and connective tissue, putting this skeletal framework in place. Most musculoskeletal can cause by degenerative, infectious, traumatic, vascular, hormonal, disuse, or endocrine processes, among other causes. This paper explains the pat physiologies of diseases that affect the musculoskeletal system or are caused by pathologic musculoskeletal processes.

Embolic Stroke and Hemorrhagic Stroke

Stroke is a neurologic condition with multisystemic outcomes on the patient. The underlying pathogenesis is a lack of adequate perfusion to a region of the brain. This can be caused by bleeding (hemorrhagic stroke) and ischemia (embolic stroke). For ischemic or embolic stroke, arterial atherosclerosis or occlusion from thromboembolism, injury, or both causes limitation in perfusion of the brain region supplied by the artery. This shifts neuronal cell metabolism to anaerobic respiration and decreases ATP production (McCance & Huether, 2022). The hypoperfusion and hypoxia of the region causes decreased glutamate reuptake by astrocytes and increased glutamate in the extracellular fluid. The reduction in ATP also leads to a reduction in Na/K ATPase pump dysfunction and increases calcium influx and ultimately, cell death.

Hemorrhagic stroke, on the other hand, is caused by various factors that include but are not limited to hypertension, amyloid angiopathy, vascular malformations, aneurysms, and certain medication. The underlying pathogenesis is the weakening of vessel walls leading to bleeding into the brain tissue and increased intracranial pressure. This bleeding form a hematoma that causes a mass effect on the brain tissue as well as a reduction in blood supply to the brain region leading to cell death as explained in embolic stroke. The affected brain region determines the symptomatic outcomes of these processes. Muscle weakness arises from the involvement motor cortex and the basal ganglia.

Focal motor weaknesses, loss of consciousness, loss of vision, poor coordination and balance, and loss of speech arise from the necrosis of neurons that are responsible for these musculoskeletal functions. Lethargy, vomiting, papilledema, and headache can result from increased intracranial pressure for inflammation ischemic stroke and bleeding in hemorrhagic stroke (McCance & Huether, 2022). Within a certain time window and the extent of neuronal damage, some symptoms can be reversed when blood flow is restored to these regions. However, permanent damage results from necrotic brain regions.

Transient Ischemic Attack

Transecting ischemic attack (TIA) is related to ischemic stroke, but the main difference is that TIA symptoms last less than 24 hours. Hypertension, diabetes mellitus, and ischemic heart disease are key risk factors for TIA. The key pathophysiologic changes are transient interruption of blood flow to certain region parts leading to transient symptoms. In most cases, the symptoms last for seconds to minutes but less than an hour (Amarenco, 2020). On brain imaging, the brain infarct cannot be identified due to revascularization and restoration of blood flow. This suggests that no significant cell death occurred, but the magnitude of the ischemia was significant enough to cause symptoms.

Multiple Sclerosis

Multiple sclerosis is neurological with musculoskeletal and sensory outcomes. This condition is an immune-mediated disease of the oligodendrocytes and the neurons. Genetics, smoking, nutritional reduction in vitamin D, and infections such as the Epstein-Barr virus are some of the risk factors for multiple sclerosis. Oligodendrocytes are brain cells that are responsible for the myelination of neurons (Chen & Kwan, 2020). This myelination serves functions such as increasing the speed of travel of impulses in the brain. The immune system, for some reason, attacks these oligodendrocytes through B and T-lymphocytes, causing demyelination and axon loss. The result of this inflammation is the formation of plaques. In the acute period, the neurons attempt to re-myelinate; thus, the symptoms become transient. The affected group of neurons determines the symptoms and outcomes of this disease process.

When the spinal neurons are affected, abnormal motor, sensory, and autonomic symptoms such as numbness, pain, paresthesia, incontinence, retention, and weakness can result. Plaques in the cerebral cortex can cause cognitive and psychological abnormalities such as anxiety, depression, emotional changes, and memory loss. The involvement of the medial, lateral fasciculus and optic nerve causes visual abnormalities such as diplopia, changes in gaze, nystagmus, vision loss, and eye pain. Coordination problems result from the involvement of the cerebellum.

Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder with mixed etiologies. In most cases, the trigger of autoimmunity is unknown. However, thymoma and thymic hyperplasia have been implicated in about a third of the cases. The thymus produces autoantibodies against the acetylcholine receptors (AChR) on the postsynaptic receptors in the skeletal muscles. These autoantibodies bind to AChR, leading to blockage of binding of actual acetylcholine and reduction and AChR function. This leads to a reduction of musculoskeletal response to actual acetylcholine signaling and thus, muscular contractions become weaker. This constant weakness is painless and symptoms depend on the affected muscle. Generally, patients have fatigue and muscle strength that improves with rest. The involvement of muscle respiration causes a myasthenia crisis that presents with signs of respiratory insufficiency (McCance & Huether, 2022). Upper limb involvement signs are more common than in the lower limb. Nevertheless, movements worsen muscle strength. When ocular and extraocular muscles are involved, the patient can present with diplopia and ptosis. The involvement of bulbar muscles leads to dysarthria and dysphagia.


Headache is the neurological presentation of various underlying pathophysiologic processes. Headache is a type of pain that results from diseases affecting the brain tissue, the meninges, nerves, blood vessels, head, neck and facial muscles, and spinal nerves. This pain perception results when these structures undergo stretching, constriction, swelling, dilatation, or other stimuli that lead to nociception in these strictures. Intracranial inflammatory processes and an increase in intracranial pressures are some of the common processes that cause headaches. For example, migraines are a type of headache that results from the activation of the trigeminovascular system and the release of inflammatory markers in the headache phase (Khan et al., 2021). Inflammation of the meninges in meningitis leads to a headache. Inflammation of the brain tissue in encephalitis causes the aforementioned changes in ICP and cellular response that cause headaches. An increase in ICP in head trauma and intracranial hemorrhage lead to a headache. Therefore, headache is multifactorial and can represent more than one process within and outside the cranium.

Seizure Disorders

The brain and the entire central and peripheral nervous system are connected by circuits where electric impulses in the form of action potential flow in a controlled and well-triggered manner. This communication is enabled by a neuronal circuitry that fires impulses to enable musculoskeletal and autonomic coordination. Changes in intracellular electrolyte levels and neurotransmitter levels, external processes such as cytokine rise as seen in inflammation, demyelination processes, and membrane channel disturbances cause a group of neurons to fire in burst activity. This abnormal firing leads to an uncontrolled muscular contraction in the affected regions of the body and the limbs. When these misfiring situations are recurrent, the resultant condition is called seizures and can result in the transformation of the neuronal network that has loss of voluntary control, loss of muscular reflex, and loss of consciousness (McCance & Huether, 2022). The outcomes are injuries, accidents, and falls among seizure patients. In some cases, the airway reflexes can be involved and aspiration can occur.

Head Injury

Head injury result from accidental and non-accidental trauma to the head with neurological changes. Violence, car accidents, child abuse, and industrial accident are some of the risks of head injury. Blunt force trauma penetrating head trauma, or traumatic shaking of the head and rolling of the whole body, cause various injuries to the brain tissue and the head. These traumatic forces can cause injuries to the cerebral parenchyma and the skull bones, cause coup injuries, or counter-coup injuries. During acceleration-deceleration forces, diffuse axonal injuries can occur that lead to neurological deficits. These traumatic injuries lead to damage in the vascular networks in the cranial cavity leading to bleeding and hematoma. These injuries can occur together during head injuries. Neurological deficits can manifest as seizures, loss of consciousness, apnea, irritability, or even coma. Therefore, the head injury requires emergency evaluation and intervention to prevent severe outcomes and mortality.

Spinal Cord Injury

Spinal cord injury can be broadly categorized into two types: acute impact and compression (Chronic injury) (Anjum et al., 2020). Acute impact injury, also known as a concussion of the spinal cord, leads to a cascade of events primarily affecting the gray matter, resulting in hemorrhagic necrosis. This cascade is triggered by a lack of blood flow to the gray matter and is exacerbated by increases in intracellular calcium and reperfusion injury. The extent of necrosis is dependent on the initial force of trauma, as well as factors such as compression, blood flow, and pharmacological agents. On the other hand, spinal cord compression occurs when a mass places pressure on the spinal cord, leading to tissue damage such as gliosis, demyelination, and axonal loss, primarily in the white matter. Rapid or severe compression can cause a collapse of the microvasculature, resulting in vasogenic edema, further exacerbating the pressure on the spinal cord and leading to rapid deterioration of function. Thus, compression treatment should focus on removing the mass causing the pressure.

Inflammatory Diseases of the Musculoskeletal System

Inflammatory diseases of the musculoskeletal system can be caused by infective and non-infective etiologies. This inflammation can be acute or chronic, deepening on the duration of the presence of the offending agent in the musculoskeletal system. Many musculoskeletal diseases, including osteoporosis, osteoarthritis, and sarcopenia, are caused by chronic inflammation (McCance & Huether, 2022). The chronic inflammation associated with osteoarthritis and intervertebral disc degeneration would also result from excessive inflammation in degenerative musculoskeletal diseases. However, inflammation also plays a critical role in the healing process of all musculoskeletal tissues (Deng et al., 2022). Therefore, we can understand the pathogenesis of musculoskeletal diseases after understanding the spatiotemporal sequence regulation of inflammation after injury.


Osteoporosis is a degenerative musculoskeletal disease that specifically affects the bones and leads to reduced bone density due to an imbalance in bone-forming and bone resorption processes. Primary osteoporosis is caused by normal aging and physiological changes such as the postmenopausal period and genetic susceptibility. On the other hand, secondary osteoporosis is accelerated by factors such as smoking, medications, thyroid disease, chronic kidney disease, malnutrition, alcohol use, malignancies, and parathyroid disease. These conditions lead to a reduction in bone formation and an increase in bone resorption. Postmenopausal women have lower estrogen leading to a reduction in the stimulation of osteoblasts in the bone (McCance & Huether, 2022). Malnutrition and kidney disease lead to reduced calcium absorption in the gut, thus reducing the deposition of calcium in the bone. Instead, the bones are mobilized to provide ionized serum calcium leading to osteoporosis. Smoking and steroid use lead to increased osteoclast activity that increases bone resorption. The outcomes of osteoporosis are an increased risk of bone fracture injuries and reduced bone mass.


Osteopenia results from the reduction in bone mineral density. However, this reduction is not severe enough to meet the diagnosis of osteoporosis. Similar processes in osteoporosis come into play in the pathophysiology of osteopenia. The criteria for osteopenia include a reduction in bone mineral density not below -2.5 standard deviations of normal BMD for a certain population. Women and men after age 30 start to experience osteopenia because the peak bone mass has been achieved. Therefore, the balance between bone formation and bone resorption is required to prevent osteopenia (McCance & Huether, 2022). Fractures from abnormally slight forces on the bone are a feature of osteopenia. Therefore, BMD measurement is required to distinguish osteoporosis and osteopenia in a patient.


Bursae are usually located near tendons around large joints. They serve to cushion the joint’s surrounding soft tissues from forces of tear and wear during movement and are, therefore, fluid-filled. Bursitis is the inflammation of these synovial sacs. This can result from overuse, infection, trauma, and other non-infective inflammatory disorders (McCance & Huether, 2022). Septic bursitis occurs when microbes, whether directly inoculated or hematogenous, spread from other sites and cause an inflammatory reaction and increase in fluid content and swelling (Nchinda & Wolf, 2021). Bursitis presents with swelling and pain around the affected joints. In non-infective bursitis, self-resolution can be achieved without pharmacological management.


Tendinitis is the inflammation of tendons. Tendinitis can be multifactorial and some people are more predisposed than others. Risk factors such as repeated overuse, gout, rheumatoid arthritis, statin use, and aging are associated with a higher risk of tendinitis (McCance & Huether, 2022). Joint injuries cause strain on the tendons leading to injury. The reactive inflammatory process leads to tendinitis (Roberts, 2019). Tendinitis thus presents with pain that worsens with movement, joint swelling, and heat. Joint movement worsens the impingements on these tendons leading to more pain.


Gout can be acute or chronic and results from an increased amount of uric acid (hyperuricemia) in the blood. The conditions leading to increased cell turnover, such as psoriasis and hemolysis, also lead to hyperuricemia. Other risks, such as alcohol intake, lead to the production of ketones and lactic acid that compete with uric acid for excretion in the kidney and thus increase uric acid buildup in the blood. The uric acid crystalizes in blood and deposits in the peripheral joints, especially the leg and hand joints, because they are cooler. Deposition of uric acid crystals called monosodium urate (MSU) crystals deposited in the synovium of the peripheral joint initiate a cascade of inflammation that recruits neutrophils to take up the crystals for degradation. However, this process fails when these crystals are needle-shaped and pierce the neutrophil releasing degradative enzymes into the joint, worsening the inflammation and thus the severe pain, redness, and swelling. The continuous process leads to tophaceous gout, seen in chronic gout when the hyperuricemia is not resolved.

Lyme Disease

Lyme disease is an infective disease caused by a bacterial called Borrelia burgdorferi. This bacterium is transmitted by a vector tick called Ixodes pacificus, Ixodes ricinus, and Ixodes scapularis, which are common in Canada, Europe, and the United States, respectively. Tick bites last more hours (36 hours), increasing the risk of transmission of this bacterium to human hosts whose plasminogen bind and transports the bacteria to other tissues. Late spring and summer seasons increase the risk of this transmission in the United States. At the site of the bite, the body responds through acute inflammation with macrophages and T-cells producing cytokines to recruit eosinophils in the first 30 days. This slowly enlarges the patch at the bite site leading to erythema migrans (Hammer & McPhee, 2019). In the meantime, the systemic response occurs against the disseminated bacteria and flu-like symptoms such as chills, fever, headache, muscle aches, fatigue, and lymphadenopathy. In the next three months without treatment, this infection can complicate to carditis, meningitis, cranial nerve palsies, and many erythema migrans on the skin. After the next three months without treatment, the joint becomes more involved with vascular proliferation, synovial hypertrophy, and an increase in mononuclear cell infiltrates as key pathophysiologic processes.


Spondylosis is an age-related degeneration of the vertebral discs leading to a decrease in disc height and vertebral support. This causes facet joint osteoarthritis with osteophyte formation, joint hypertrophy, hypertrophy of ligaments, and ligament laxity. This can lead to disc herniation in some cases. These changes can compress the vertebral canal in severe cases and impinge nerve roots and arteries supplying the vertebral canal contents. Myelopathies and radiculopathy are some of the main complications of advanced spondyloses.


Fractures of the bones result from diminished bone strength and integrity following an external or internal force. Many factors can cause bone integrity reduction, some of which are related to bone mineral density, such as osteoporosis and osteopenia (Hammer & McPhee, 2019). In healthy bone, the pathophysiology of fractures can be explained by the mechanism of falling, magnitude of the external force, frequency of falling, and presence of other injuries. Healthy bones have a limit within which they can withstand external force or pressure. Above these limits, these bones lose their continuity and break to cause fractures. Just like other tissues, bones are live tissues and respond to fractures by inflammation that will initiate a cascade of events leading to healing.

Parkinson’s Disease

Parkinson’s disease (PD) is among the top neurodegenerative disease with musculoskeletal outcomes among older adults. According to MacMahon Copas et al. (2021), inflammation of the nervous system, degradation of dopamine-producing cells in a particular region of the brain, and the accumulation of aberrant proteins termed alpha-synuclein in the form of Lewy bodies are some of the clinical features of Parkinson’s disease. Through a process known as gliosis, microglia and astrocytes are crucial in maintaining the stability of the central nervous system and safeguarding it. However, when these cells are not functioning properly, it can result in a protracted inflammatory state that worsens a variety of illnesses in the central nervous system. The resultant outcomes are the motor weakness of the limb and diminished muscular function. Recent studies have demonstrated that immune cells from the peripheral nerve system, particularly T-lymphocytes, are involved in PD development. These cells penetrate the brain and cluster in one location, where they produce substances that promote inflammation, stimulate other immune cells, and kill cells that make dopamine. Therefore, newer insights keep on coming up on the pathophysiology of Parkinson’s disease.

Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease of the central nervous system whose hallmark is progressive dementia and cognitive loss. One of the hypotheses put forward to explain the pathophysiology of AD suggests that amyloid deposition in neurons and extracellular compartments leads to disruption of calcium homeostasis and cell death through inflammation, free radical production, and toxicity of the neurons (Cacabelos, 2019). The cholinergic hypothesis, on the other hand, suggests that AD arises from a reduction in acetylcholinesterase, leading to impairments in nerve potential conduction. The neuronal dysfunction and death lead to cognitive and memory loss that is also associated with other psychological outcomes such as anxiety and depression. Regulation of motor neurons becomes a problem for these patients and tremors can occur due to this dysregulation and poor verve potential conduction.

The Basics of Bone Formations:

Osteogenesis or ossification is the process by which bones form from mesenchymal tissue in embryonic periods. Bone forms through stages of proliferation, matrix maturation, and mineralization. During bone formation, the cellular components osteoblasts, osteocytes, and osteoclasts play a significant role. The osteogenic cell, the bone stem cell, differentiates into osteoblasts which are responsible for bone mineralization. Therefore, osteoblasts form the bone matrix. When osteoblasts get trapped in this bone matrix, they become osteocytes that maintain the bone tissue. However, there is a group of cells called osteoclasts that work to counter the effects of osteoblasts. Osteoclasts participate in bone matrix breakdown by initiating phagocytosis. These cells are located in the areas of injured bone and bone surface. Therefore, in a healthy bone, there exists an equilibrium between osteoclast and osteoblast activity. This balance ensures that the bone tissue is not overproduced or over-degraded. This balance is maintained by hormones such as estrogen, testosterone, and parathyroid hormone, electrolytes such as serum calcium and phosphate level, and micronutrients such as vitamin D.


The musculoskeletal system is not just about bones and muscles but as joints, tendons, ligaments, bursas, and blood vessels supplying these structures. The musculoskeletal system works closely with the central nervous system, endocrine system, cardiovascular system, and electrolyte balance. This paper demonstrates this association through the pathophysiology of CNS, endocrine, and metabolic disorders such as stroke, parathyroid disease, hypercalcemia, and hyperuricemia. Even though musculoskeletal pain, swelling, weakness, and dysfunction can suggest musculoskeletal disease, other system disorders, especially the nervous system, need to be ruled out and evaluated before making conclusions. Most chronic disorders primarily arising from the musculoskeletal system tend to have an impact on mobility. Still, they become urgent when an external stimulus, such as trauma or acute electrolyte changes, worsens their states. An example from this paper is osteoporosis, osteopenia, and gout. Therefore, patient evaluation assessing the musculoskeletal system must focus on the complications and related organ systems.


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