Bone Metabolism

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.

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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 in the gut
    • Stimulates bone deposition
    • Levels controlled by PTH

Purposes of bone metabolism

  • Maintain strength and 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 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 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 → 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
  • Primary functions:
    • ↓ Serum Ca2+ levels
    • Opposes the actions of PTH
  • Effects:
    • In bone: stimulates osteoblasts → promotes calcium deposition in bone/bone ossification
    • In kidneys: stimulates phosphate reabsorption → ↑ bone 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, and GI tract.

  • Bone:
    • 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.
Pathways in Calcium Homeostasis

Pathways in calcium homeostasis demonstrating how parathyroid hormone (PTH) and calcitonin work to maintain normal calcium levels

Image: “Pathways in Calcium Homeostasis” by Phil Schatz. License: CC BY 4.0

Synthesis and regulation of PTH

  • Synthesized by chief cells of the 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 of all vertebrates when exposed to sunlight.

Functions

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

  • Promotes 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 of dietary Ca2+.
    • Calbindin levels are the rate-limiting step for Ca2+ absorption.
  • Stimulates osteoblasts and enhances bone mineralization
  • Also involved in:
    • Immune function and inflammation
    • Glucose and cholesterol metabolism
    • Inhibition of angiogenesis
    • Cell signaling, growth, proliferation, differentiation, and apoptosis
Absorption of dietary calcium

Absorption of dietary calcium, which requires calbindin D9k

Image by Lecturio.

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: UV exposure causes a temperature-dependent rearrangement of 7-dehydrocholesterol → vitamin D3 (cholecalciferol)
  • In 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: 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.
Biosynthetic pathway of calcitriol

Biosynthetic pathway of calcitriol

Image by Lecturio.

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.
  • Directly stimulates (or inhibits) gene expression of target genes

Other Regulators of Bone Metabolism

Other factors that help regulate bone metabolism include:

  • Estrogens:
    • ↓ Bone 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:
    • Inhibit bone formation
    • Cause of glucocorticoid-induced osteoporosis
  • Thyroid hormones (thyroxine, triiodothyronine):
    • Increase both bone formation and bone resorption
    • ↑ Bone 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 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.
  • Osteomalacia and rickets: disorders of decreased bone mineralization. Rickets affects the cartilage of the epiphyseal growth plates in children, whereas osteomalacia affects the sites of bone turnover in children and adults. Osteomalacia and rickets are most commonly caused by vitamin D deficiency. Rickets commonly presents with skeletal deformities and growth abnormalities, whereas osteomalacia can present with bone 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, spine, pelvis, and long bones of the lower extremities. The 2 main clinical manifestations of Paget disease are bone pain and the consequences of bone deformities, such as fractures, osteoarthritis, or nerve impingement. Treatment includes bisphosphonates, calcitonin, and surgery for the management of fractures, deformities, and complications.
  • Hyperparathyroidism: a condition associated with elevated blood levels of PTH. Hyperparathyroidism may be due to an inherent disease of the parathyroid gland or abnormalities in calcium metabolism. Affected individuals classically present with “stones (nephrolithiasis), bones (↓ bone mineral density), abdominal groans (nonspecific abdominal 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: low levels of PTH due to poor function of the parathyroid glands. 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, 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), musculoskeletal (bone pain, weakness), and renal (polyuria, polydipsia) symptoms. Management depends on the severity and ranges from a low-calcium diet to IV isotonic saline, 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.

References

  1. Manolagas, S.C. (2020). Normal skeletal development and regulation of bone formation and resorption. In UpToDate. Retrieved August 4, 2021, from https://www.uptodate.com/contents/normal-skeletal-development-and-regulation-of-bone-formation-and-resorption 
  2. Goldfarb, S. (2021). Regulation of calcium and phosphate balance. In UpToDate. Retrieved August 4, 2021, from https://www.uptodate.com/contents/regulation-of-calcium-and-phosphate-balance 
  3. Khan, M. (2021) Physiology, parathyroid hormone. In StatPearls. Retrieved August 4, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/26662/

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