Overview

Principal regulators of bone metabolism

The 3 primary regulators of bone metabolism are:

• Calcitonin:
  • Primary goal: ↓ serum calcium 
  • Stimulates bone deposition
  • Opposes the action of parathyroid hormone (PTH)
• PTH: 
  • Primary goal: ↑ serum calcium
  • Stimulates bone resorption
  • Opposes the action of calcitonin
• Vitamin D:
  • Stimulates Ca²⁺ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption in the gut
  • Stimulates bone deposition
  • Levels controlled by PTH

Purposes of bone metabolism

• Maintain strength and structure of bones Structure of bones 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. Structure of Bones
• Storage and regulation of serum calcium (and phosphate)

Review of bone

• Structure:
  • Collagen matrix
  • Calcium and phosphate → hydroxyapatite crystals (Ca₁₀[PO₄]₆[OH]₂)
  • Hydroxyapatite crystals deposit on the collagen matrix and form bone.
• Bone Bone 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. Structure of Bones cells:
  • Osteoblasts: build new bone
  • Osteoclasts: remove/breakdown bone (known as resorption)

Review of calcium homeostasis

Calcium has many important functions in the body and its levels must be tightly regulated to stay around 10 mg/dL. Calcium is the most abundant mineral in the body.

• Absorption:
  • Cannot be synthesized by the body
  • Must be obtained through the diet
  • Absorption requires a protein called calbindin (its synthesis is stimulated by Vitamin D)
• Calcium functions:
  • Bone Bone 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. Structure of Bones mineralization
  • Tooth health
  • Muscle contraction
  • Regulation of heart rate
  • Assists in coagulation
  • Regulation of nerve impulse conduction
  • Vision/detection of light
  • Cell signaling
• Calcium transport:
  • Present in both free, ionized form as well as bound to proteins
  • When protein bound, calcium is primarily bound by albumin → serum Ca²⁺ levels are affected by albumin levels
    • ↑ Serum albumin → ↑ serum calcium (though free ionized levels may be normal)
    • ↓ Serum albumin → ↓ serum calcium (though free ionized levels may be normal)
• Calcium within cells:
  • Taken up by cells through calcium pumps
  • Ca²⁺ is toxic to DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure → not allowed to “roam freely” within cells; instead, it is:
    • Sequestered within the ER/sarcoplasmic reticulum
    • Bound to intracellular binding proteins (e.g., calmodulin)

Calcitonin

• Synthesis: produced by C cells in the thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland
• Primary functions:
  • ↓ Serum Ca²⁺ levels
  • Opposes the actions of PTH
• Effects:
  • In bone: stimulates osteoblasts → promotes calcium deposition in bone/ bone ossification Bone ossification 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 Development and Ossification
  • In kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: stimulates phosphate reabsorption → ↑ bone ossification Bone ossification 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 Development and Ossification

Parathyroid Hormone

Parathyroid hormone is the most important regulator of calcium homeostasis.

Function of PTH

The primary function of PTH is to ↑ serum Ca²⁺ levels. The primary effects of PTH are on the bones, kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys, and GI tract.

• Bone Bone 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. Structure of Bones:
  • PTH stimulates osteoclasts → ↑ bone resorption
  • Results in ↑ serum Ca²⁺ and phosphate
• Kidneys:
  • ↑ Renal Ca²⁺ reabsorption
  • ↑ Renal phosphate excretion (so it does not combine with Ca²⁺ to form bone)
  • ↑ Hydroxylation of calcidiol → calcitriol (activated vitamin D)
• GI tract: Calcitriol promotes intestinal Ca²⁺ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption.

Synthesis and regulation of PTH

• Synthesized by chief cells of the parathyroid glands Parathyroid glands The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Parathyroid Glands
• Primarily regulated by calcium levels:
  • ↓ Ca²⁺ → stimulates PTH secretion
  • ↑ Ca²⁺ → inhibits PTH secretion
• Mechanism: Parathyroid gland has plasma membrane calcium receptors.
  • Binding of calcium to its receptors in the parathyroid gland → inhibition of PTH secretion
  • When receptors are free → PTH is secreted

Vitamin D

Although a vitamin, vitamin D acts more like a hormone than a true vitamin. Vitamin D₃ is synthesized in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin of all vertebrates when exposed to sunlight.

Functions

The most important impacts of vitamin D are related to calcium and phosphate regulation.

• Promotes absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of calcium and phosphate from the intestines:
  • Mechanism: upregulating the expression of the intracellular calcium-binding protein, calbindin D9k
  • Calbindin D9k is required for the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of dietary Ca²⁺.
  • Calbindin levels are the rate-limiting step for Ca²⁺ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption.
• Stimulates osteoblasts and enhances bone mineralization
• Also involved in:
  • Immune function and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Glucose and cholesterol metabolism Cholesterol Metabolism Cholesterol is an important lipid molecule that is used for many biologic functions. Cholesterol can either be synthesized from endogenous acetyl-CoA or absorbed from food in the GI tract. Because cholesterol is lipophilic, it must be transported through the bloodstream via lipoproteins, where it can be picked up by hepatocytes or peripheral tissues. Cholesterol Metabolism
  • Inhibition of angiogenesis
  • Cell signaling, growth, proliferation, differentiation, and apoptosis

Synthesis of vitamin D

Vitamin D is synthesized from cholesterol upon stimulation by exposure to UV light. Vitamin D must undergo 2 hydroxylation reactions to become active.

Vitamin D₃: 1,25-dihydroxy-vitamin D₃:

• In skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin: UV exposure causes a temperature-dependent rearrangement of 7-dehydrocholesterol → vitamin D₃ (cholecalciferol)
• In liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Vitamin D₃ is hydroxylated to 25-hydroxy-vitamin D₃.
  • Abbreviated as 25(OH)D₃, and also known as calcidiol, calcifediol, and 25-hydroxy-cholecalciferol
  • 25(OH)D₃ is the primary circulating form of vitamin D in the body.
  • Half-life is 2–3 weeks.
• In the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: 25(OH)D₃ undergoes 2nd hydroxylation and forms the physiologically active 1,25-dihydroxy-vitamin D₃.
  • Abbreviated as 1,25(OH)D₃ and also known as calcitriol
  • Most active form
  • Half-life is 4–6 hours.

Vitamin D receptors

• Vitamin D binds to cell-surface receptors → transported into the cell
• Binds to an intracellular receptor inside the cell
• The vitamin D-receptor complex binds to the hormone-response elements in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure.
• Directly stimulates (or inhibits) gene expression of target genes

Other Regulators of Bone Metabolism

Other factors that help regulate bone metabolism include:

• Estrogens:
  • ↓ Bone Bone 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. Structure of Bones turnover in both sexes
  • Act on both osteoblasts and osteoclasts
  • Necessary for closure of the epiphyseal plates
• Growth hormone:
  • Stimulates cartilaginous endplates
  • Stimulates endochondral bone formation
• Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids:
  • Inhibit bone formation
  • Cause of glucocorticoid-induced osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
• Thyroid hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones (thyroxine, triiodothyronine):
  • Increase both bone formation and bone resorption
  • ↑ Bone Bone 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. Structure of Bones turnover

Clinical Relevance

• Osteoporosis: a decrease in bone mass and density leading to an increased number of fractures. Osteoporosis is most commonly caused by a loss of protective estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries and/or testosterone later in life, or as a result of immobilization, underlying medical disorders, or the long-term use of certain medications. Osteoporosis most often presents clinically with frequent fractures and a loss of vertebral height. Diagnosis is established by measuring bone mineral density. Management includes lifestyle modifications, maintaining adequate calcium and vitamin D levels, and the use of bisphosphonates Bisphosphonates Bisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix "-dronate" or "-dronic acid" (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption. Bisphosphonates.
• Osteomalacia and rickets: disorders of decreased bone mineralization. Rickets Rickets Rickets and osteomalacia are disorders of decreased bone mineralization. Rickets affects the cartilage of the epiphyseal growth plates in children. Although most cases of rickets are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Rickets commonly presents with skeletal deformities and growth abnormalities. Osteomalacia and Rickets affects the cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage of the epiphyseal growth plates in children, whereas osteomalacia Osteomalacia Rickets and osteomalacia are disorders of decreased bone mineralization. Osteomalacia affects the sites of bone turnover in children and adults. Although most cases are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Osteomalacia can present with bone pain, difficulty with ambulation and pathologic fractures. Osteomalacia and Rickets affects the sites of bone turnover in children and adults. Osteomalacia and rickets are most commonly caused by vitamin D deficiency. Rickets Rickets Rickets and osteomalacia are disorders of decreased bone mineralization. Rickets affects the cartilage of the epiphyseal growth plates in children. Although most cases of rickets are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Rickets commonly presents with skeletal deformities and growth abnormalities. Osteomalacia and Rickets commonly presents with skeletal deformities and growth abnormalities, whereas osteomalacia Osteomalacia Rickets and osteomalacia are disorders of decreased bone mineralization. Osteomalacia affects the sites of bone turnover in children and adults. Although most cases are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Osteomalacia can present with bone pain, difficulty with ambulation and pathologic fractures. Osteomalacia and Rickets can present with bone pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, difficulty with ambulation, and pathologic fractures. Treatment includes supplementation with vitamin D, calcium, and phosphorus.
• Paget disease of bone: a focal disorder of bone metabolism that commonly affects the skull Skull The skull (cranium) is the skeletal structure of the head supporting the face and forming a protective cavity for the brain. The skull consists of 22 bones divided into the viscerocranium (facial skeleton) and the neurocranium. Skull, spine, pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis, and long bones of the lower extremities. The 2 main clinical manifestations of Paget disease are bone pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and the consequences of bone deformities, such as fractures, osteoarthritis Osteoarthritis Osteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis, or nerve impingement. Treatment includes bisphosphonates Bisphosphonates Bisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix "-dronate" or "-dronic acid" (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption. Bisphosphonates, calcitonin, and surgery for the management of fractures, deformities, and complications.
• Hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism: a condition associated with elevated blood levels of PTH. Hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism may be due to an inherent disease of the parathyroid gland or abnormalities in calcium metabolism. Affected individuals classically present with “stones ( nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis), bones (↓ bone mineral density), abdominal groans (nonspecific abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain), and psychiatric overtones (neuropsychiatric symptoms).” Diagnosis is based on laboratory assessment of serum PTH, calcium, and phosphate, and urinary calcium levels. Management is typically surgical to treat any underlying conditions.
• Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism: low levels of PTH due to poor function of the parathyroid glands Parathyroid glands The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Parathyroid Glands. Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism is most commonly iatrogenic following neck surgery but can also be associated with genetic, infiltrative, or autoimmune disorders, causing the destruction of normal parathyroid tissue. Deficiency of PTH results in hypocalcemia Hypocalcemia 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). Hypocalcemia, which leads to increased neuromuscular excitability (e.g., tetany), osteosclerosis, and cardiac and neuropsychiatric manifestations. Management involves calcium and vitamin D supplementation, and potentially recombinant human PTH in chronic cases.
• Hypercalcemia: a condition typically characterized by serum calcium levels > 10.5 mg/dL. Hypercalcemia can result from several conditions, most commonly hyperparathyroidism and malignancy. Clinical presentations include neuropsychiatric (confusion, altered mentation), GI (vomiting, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain), musculoskeletal (bone pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, weakness), and renal (polyuria, polydipsia) symptoms. Management depends on the severity and ranges from a low-calcium diet to IV isotonic saline, bisphosphonates Bisphosphonates Bisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix "-dronate" or "-dronic acid" (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption. Bisphosphonates, calcitonin, and hemodialysis.
• Hypocalcemia: a condition typically characterized by serum calcium levels < 8.5 mg/dL. Hypocalcemia can result from various factors including hypoparathyroidism, disorders leading to vitamin D deficiency, and medications. The presentation can range from asymptomatic with mild deficiency to life-threatening with acute and significant calcium decline. Treatment is with calcium supplementation while correcting any underlying conditions.