Physiology of Bone

Functions of Bone Tissue

Mechanical Functions

• Give shape to the body
• Load transmission
• Mediate movement
• Support & protect soft tissue

Mineral Reservoir

• Largest reservoir of ${\text{Ca}}^{++}$
• Regulation of ${\text{Ca}}^{++}$

Bone Components

A: Matrix

• Organic (40% of dry weight):
  • Collagen fibers
• Inorganic (Minerals) (60%):
  • Ca⁺⁺ hydroxyapatite, Ca⁺⁺ phosphate

B: Cells

• Osteoblasts: bone-forming cells (hyperactivation produces tumors)
• Osteoclasts: bone-resorbing cells (hyperactivation produces osteoporosis)
• Osteocytes: normal mature bone cells

Bone is Active

• Continuous activity & flow
• Structure & composition changing all the time
• Regulation by cellular activity:
  • Osteoclasts & Osteoblasts

Diagram: Regulation of Bone Activity

The diagram shows a cyclical relationship between:

• Cellular Activity
• Modulation of Bone Structure & Composition
• Changes in mineral ion concentrations
• Hormones & Local Factors

Bone Growth & Remodeling

Growth Processes

• Epiphyseal growth: Endochondral ossification
• Surface growth: Appositional ossification

Adult Remodeling

• Continuous remodeling of existing bone (no growth)
• “Old bone” continuously replaced by “new bone”
• Annual turnover rates:
  • 4% of cortical bone
  • 25% of cancellous bone
• Age-related changes:
  • Initially: formation slightly exceeds resorption
  • Later: resorption exceeds formation → Bone mass steadily declines

Age-Related Bone Changes

Childhood – Adolescence

• Growth phase (↑ size & change shape)

Adolescence – 35 years

• Bones get heavier and stronger
• Annual bone mass gain: 3%

35 – 50 years

• Slow loss of bone mass annually:
  • Men: 0.3% annually
  • Women:
    • 0.5% annually to menopause
    • Then 3% annually for 10 years (due to ↑ osteoclastic activity from ↓ estrogen hormones)

65 years – onwards

• Loss of mass slows gradually to 0.5% (↓ osteoblastic activity)

Body Calcium

• Most calcium in the body is present in bone
• Calcium release from bone is a slow process
• Serum calcium is essential for:
  • Cell function
  • Nerve conduction
  • Muscle contraction
• Normal level: 8.8-10.4 mg/dl (2.2-2.6 mmol/L)
• Serum calcium levels must be controlled continuously and promptly through:
  • Renal reabsorption
  • Bone resorption
  • Intestinal absorption

Causes of ↓ Calcium Absorption

• ↑ intake of phosphates (as in soft drinks)
• ↑ intake of oxalates (as in tea and coffee)
• Drugs: corticosteroids
• Intestinal mal-absorption syndromes

Players in Calcium Regulation

Primary Regulators

• Vitamin D: The general crude regulator
  • Target organs:
    • Small intestines (↑ absorption of Ca, Mg, ${\text{PO}}_4$)
    • Bones (↑ mineralization)
• PTH (Parathyroid Hormone): The sensitive fine regulator
  • Target organs:
    • Kidneys (quick): ↑ reabsorption of Ca, ↓ reabsorption of ${\text{PO}}_4$, converts Vit D2 to D3
    • Bones (slow): through Vitamin D
    • Small intestine: indirectly through Vitamin D
• Calcitonin: From C cells of Thyroid
  • Opposite to PTH on bone and kidneys
  • Protective effect: ↓ osteoclast activity, ↓ kidney reabsorption of Ca, ↓ serum Ca

Secondary Modulators

• Estrogen:
  • Protects bone from PTH effects
  • In Menopause: osteoclasts become more active
• Corticosteroids (Bad to bone): from supra-renal gland
  • ↓ osteoblastic activity, ↑ osteoclastic activity
  • ↓ calcium absorption from intestine
  • ↑ renal excretion of calcium
• Local factors – BMP (Bone Morphogenic Proteins)
• Mechanical stress:
  • Strengthens bone

Normal Calcium & Phosphate Metabolism

Organ Systems Involved

• Intestine
• Kidney
• Bone

Metabolic Pathway

Intestine

• Absorbs ${\text{Ca}}^{2+}$ and ${\text{PO}}_4$ from food and Vitamin ${\text{D}}_2$
• Vitamin ${\text{D}}_2$ is converted to Vitamin ${\text{D}}_3$ in the Liver

Skin

• Synthesizes Vitamin ${\text{D}}_3$ from Vitamin ${\text{D}}_2$ using Sunlight (Ultraviolet light)

Liver

• Converts Vitamin ${\text{D}}_3$ to $25{\text{-D}}_3$ using $\text{Vit. D25-hydroxylases}$

Kidney

• Converts $25{\text{-D}}_3$ to $1,25{\text{-D}}_3$ using $1\text{-}\alpha \text{-hydroxylase}$
• $1,25{\text{-D}}_3$ promotes absorption of ${\text{Ca}}^{2+}$ and ${\text{PO}}_4$ from the intestine

Bone

• $1,25{\text{-D}}_3$ is necessary for normal mineralization of bone

Parathyroid Glands

• Secrete Parathyroid hormone (PTH)

Regulation Mechanisms

Regulation of Serum Calcium and Phosphate

• Central feedback loop regulates serum and extracellular fluid levels of ${\text{Ca}}^{2+}$ and ${\text{PO}}_4$

PTH Actions

• Increases production of $1,25{\text{-D}}_3$
• Promotes ${\text{Ca}}^{2+}$ reabsorption
• Inhibits ${\text{PO}}_4$ reabsorption in the kidney
• Promotes osteoclastic resorption of bone, releasing ${\text{Ca}}^{2+}$, ${\text{PO}}_4$, and matrix

1,25-D Actions

• Stimulates the Parathyroid glands (increasing PTH secretion)
• Inhibits the Parathyroid glands (decreasing PTH secretion)
• Kidney: stimulates $1\text{-}\alpha \text{-hydroxylase}$ (increasing $1,25{\text{-D}}_3$ production) and inhibits $1\text{-}\alpha \text{-hydroxylase}$ (decreasing $1,25{\text{-D}}_3$ production)
• Intestine: stimulates absorption of ${\text{Ca}}^{2+}$ and ${\text{PO}}_4$
• Bone: stimulates bone mineralization

Calcium Metabolism

Calcium Metabolism Diagram