Musculoskeletal, Skin, and Connective Tissue—Physiology

Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Calcium levels are regulated and affected by factors such as dietary intake and pH, and the levels of parathyroid hormone (PTH), vitamin D, and albumin. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Generally, neuropsychiatric (confusion, altered mental status), GI (vomiting, abdominal pain), musculoskeletal (bone pain, weakness), and renal (polyuria, polydipsia) manifestations are seen. Confirmation of hypercalcemia is required. Correction of the value is based on the albumin levels or after determining the ionized calcium levels (the metabolically active form), which is followed by determining PTH levels. Subsequent laboratory tests and imaging studies are ordered based on history and presentation. Correction of hypercalcemia depends on its severity. Calcium levels > 14 mg/dL are treated using IV isotonic saline hydration, calcitonin, and bisphosphonates. Hemodialysis is considered in rare cases. Treatment of the underlying cause is recommended.

Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Patients can exhibit symptoms from neuromuscular irritability (tetany, Chvostek sign, Trousseau sign) to cardiovascular dysfunction (arrhythmia). Confirmation of hypocalcemia is required with correction of the value depending on albumin level or ionized calcium (the metabolically active form), followed by PTH level, and determination of the underlying cause. Correction of calcium is dictated by the degree of severity of hypocalcemia. In severe cases, IV calcium administration is required. Treatment of the underlying cause is recommended.

Smooth muscle is primarily found in the walls of hollow structures and some visceral organs, including the walls of the vasculature, GI, respiratory, and genitourinary tracts. Smooth muscle contracts more slowly and is regulated differently than skeletal muscle. Smooth muscle can be stimulated by nerve impulses, hormones, metabolic factors (like pH, CO2 or O2 levels), its own intrinsic pacemaker ability, or even mechanical stretch. Whatever the stimulus is, it results in an increase in sarcoplasmic Ca levels. This Ca results in a phosphorylation of myosin, which activates it, allowing the myosin to interact with the actin. In smooth muscle, the actin is attached to cytoskeletal proteins located throughout the sarcoplasm and cell membrane known as dense bodies. Therefore, when the myosin pulls on the actin, the actin pulls on the dense bodies, causing the entire cell to “scrunch” up and contract.

Skeletal muscle is striated muscle containing organized contractile structures known as sarcomeres that are made up of overlapping myofilaments: actin and myosin. When a nerve impulse arrives from a motor neuron, the signal triggers an action potential (AP) in the sarcolemma (muscle cell membrane), resulting in the release of Ca ions from the sarcoplasmic reticulum (SR) within the muscle cell. The Ca causes a conformational change in regulator proteins (troponin and tropomyosin), exposing myosin-binding sites on the actin filaments. Using ATP energy, the myosin heads pull the myosin along the actin, shortening the sarcomere and resulting in muscle contraction. The ATP can be produced via anaerobic and aerobic mechanisms, and the primary source of ATP energy in a muscle fiber determines its functional characteristics.

Bone, while seemingly inert, is an active, growing, and changing part of the human body, in addition to being the body's primary calcium reservoir. In the correct homeostatic conditions, bone can remodel in response to damage, stress, or hormonal signaling (parathyroid hormone and calcitonin). Osteocytes located deep in the bone sense damage and signal bone-lining cells that will begin the process of remodeling. This process is vital not only for damage repair but also to adapt to a new environment and conditions.

Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Calcium levels are regulated and affected by factors such as dietary intake and pH, and the levels of parathyroid hormone (PTH), vitamin D, and albumin. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Generally, neuropsychiatric (confusion, altered mental status), GI (vomiting, abdominal pain), musculoskeletal (bone pain, weakness), and renal (polyuria, polydipsia) manifestations are seen. Confirmation of hypercalcemia is required. Correction of the value is based on the albumin levels or after determining the ionized calcium levels (the metabolically active form), which is followed by determining PTH levels. Subsequent laboratory tests and imaging studies are ordered based on history and presentation. Correction of hypercalcemia depends on its severity. Calcium levels > 14 mg/dL are treated using IV isotonic saline hydration, calcitonin, and bisphosphonates. Hemodialysis is considered in rare cases. Treatment of the underlying cause is recommended.

Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Human marrow composition changes with age. In the young, the entire bone marrow is red, as there is increased blood cell production. As age increases, there is gradual change to the yellow marrow variety. The yellow marrow can revert to red marrow when hematopoiesis is needed (e.g., anemia). The red marrow, by hematopoiesis, produces about 6 billion cells per kilogram per day. The process relies on hematopoietic cells (stem cells and progenitors) producing mature effector cells (lymphocytes, platelets, granulocytes, erythrocytes) with the aid of nonhematopoietic elements. Production is regulated by cytokines released in the bone marrow environment and feedback from target tissues. The marrow structure allows hematopoiesis to take place in the extravascular area, and after staged differentiation, blood cells are released into circulation.

Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Because the matrix is mineralized (rather than aqueous), nutrients and waste cannot diffuse through the matrix. Bone has developed a unique structure to allow the functions to occur. The structure of bone allows the bone to be hard, but not too brittle, and gives bone the strength to resist compressive and bending forces. As a result, bone is ideally suited for the functions of support, protection of vital organs, and movement. In addition, bone produces blood cells in the marrow and is the body's primary storage site for calcium.

Bone is the primary storage site of calcium in the body; thus, bone metabolism plays a critical role in maintaining normal calcium levels. Bone metabolism (and thus calcium levels) are primarily regulated by 3 hormones, namely, calcitonin, parathyroid hormone (PTH), and vitamin D. Calcitonin stimulates bone deposition, decreasing serum calcium, whereas PTH works to stimulate bone resorption, increasing serum calcium. Vitamin D levels are regulated by PTH. Vitamin D increases calcium absorption from the gut and stimulates bone deposition. Abnormalities in bone metabolism can lead to clinical conditions such as osteoporosis, osteomalacia, Paget disease of bone, and hypo- or hypercalcemia.

The process of bone formation is called ossification. The 2 types of ossification are intramembranous ossification, in which bone is developed directly from mesenchyme cells, and endochondral ossification, in which a hyaline cartilage model is created 1st and then later replaced with bone. Bone continues to grow into early adulthood at the epiphyseal plates, where chondrocytes continue to divide, die, and be replaced with mineralized bone. Bone mineralization occurs because the osteoblasts allow high levels of calcium and phosphate to accumulate above critical threshold levels within bone.

Muscle tissue is one of the basic tissue types. Histologically, the muscles of the body can be classified into 3 types: skeletal, smooth, and cardiac. The 3 types of muscle tissue are based on the morphologic and functional properties of the cells. One of the defining characteristics of muscle tissue is its contractility, which generates forces that move the musculoskeletal system as well as cause movement in the vasculature and multiple organ systems. This contractility is due to specialized proteins known as myofilaments, which create organized structures that have the ability to lengthen and contract.

Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Patients can exhibit symptoms from neuromuscular irritability (tetany, Chvostek sign, Trousseau sign) to cardiovascular dysfunction (arrhythmia). Confirmation of hypocalcemia is required with correction of the value depending on albumin level or ionized calcium (the metabolically active form), followed by PTH level, and determination of the underlying cause. Correction of calcium is dictated by the degree of severity of hypocalcemia. In severe cases, IV calcium administration is required. Treatment of the underlying cause is recommended.