Bone and Muscle Physiology Overview

• The session will cover bone physiology, altered bone physiology, conditions affecting the articular system like osteoarthritis, rheumatoid arthritis, and gout, altered muscle physiology, focusing on sarcopenia, and lower back pain.
• Textbook figures on osteomyelitis and bone tumors provide essential context, although they wont be directly addressed.

Skeletal System Overview

• The skeletal system is the body's structural framework.
• Supports tissues and enables movement via muscle attachment points.
• Functions as a site for blood cell formation.
• Stores essential minerals, including calcium and phosphorus.
• The neuromuscular system enables controlled movement and strength required for daily activities.
• Musculoskeletal disorders impact movement and function, and are linked to pain mechanisms.
• These disorders are a frequent reason for primary healthcare visits.

Constituents of Bone Tissue

Osteoblasts

• Osteoblasts are bone-forming cells derived from mesenchymal stem cells.
• Synthesize the bone matrix (osteoid) and regulate mineralization.
• Alkaline phosphatase, secreted by osteoblasts, is essential for mineral deposition.
• Serum alkaline phosphatase levels are a clinical marker used to assess bone formation.
• Osteoblasts influence osteoclast activity by secreting cytokines.
  • Macrophage Colony-Stimulating Factor (M-CSF) promotes osteoclast precursor differentiation.
  • RANK Ligand (RANKL) binds to RANK receptors on osteoclast precursors, promoting their activation and survival.
  • Osteoprotegerin (OPG) acts as a decoy receptor for RANKL, preventing osteoclast activation and inhibiting bone resorption.

Osteocytes

• Osteocytes are mature bone cells.
• Terminally differentiated osteoblasts become embedded in the bone matrix.
• Serve as mechanosensors and coordinators of bone remodeling.
• Detect microdamage and initiate targeted remodeling by signaling to osteoclasts and osteoblasts.
• Produce fibroblast growth factor (FGF).
• FGF helps regulate phosphate homeostasis.

Osteoclasts

• Osteoclasts are large multinucleated cells, responsible for bone resorption.
• Secrete hydrogen ions to dissolve bone mineral content.
• Release proteolytic enzymes, such as cathepsin K, to degrade the collagen matrix.
• Activation relies on RANKL binding to RANK.
• OPG inhibits osteoclast activation by binding to RANKL, preventing its interaction with RANK.

Bone Remodeling

• Bone remodeling is a continuous process of bone resorption by osteoclasts followed by bone formation by osteoblasts.
• This cycle maintains bone strength and mineral homeostasis.
• Phases:
  • Activation: Recruitment of osteoclast precursors and differentiation into active osteoclasts.
  • Resorption: Osteoclasts dissolve bone mineral and degrade organic matrix.
  • Reversal: Transition phase where bone resorption ceases and osteoblasts are recruited.
  • Formation: Osteoblasts lay down new osteoid, which is subsequently mineralized.
  • Resting: Newly formed bone enters a quiescent state until the next remodeling cycle.

RANK/RANKL/OPG Pathway

• RANK, found on osteoclast precursors and mature osteoclasts, is central in bone remodeling.
• RANKL, produced by osteoblasts, binds to RANK, promoting osteoclast differentiation and activation.
• OPG is a decoy receptor that binds to RANKL, which prevents its interaction with RANK, thereby inhibiting osteoclastogenesis.
• An imbalance in the RANKL/OPG ratio, such as excess RANKL or insufficient OPG, leads to increased bone resorption and conditions like osteoporosis.
• Denosumab, a monoclonal antibody that inhibits RANKL, is a therapeutic strategy.

Factors Influencing Bone Health

Hormonal Regulation

• Estrogen: Inhibits bone resorption by reducing IL-6 production and blocking PTH effects, leading to reduced osteoclast activity by suppressing RANKL.
  • Post-menopausal women experience a drop in estrogen levels, leading to an imbalance in bone remodeling and a higher osteoporosis risk.
• Parathyroid Hormone (PTH): Increases calcium reabsorption in the kidneys and promotes the production of active vitamin D, enhancing intestinal calcium absorption.
  • High PTH levels lead to increased bone resorption through direct effects on osteoclasts and by enhancing RANKL expression.
• Vitamin D: Acts as a hormone to regulate calcium absorption in the gut and promotes bone mineralization.
• Calcium is essential for bone structure.
  • Calcium deficiency can lead to increased bone resorption.

Cytokines and Inflammation

• Pro-inflammatory Cytokines: TNF-α and IL-1 promote bone resorption by enhancing RANKL expression and osteoclast activity.
• Inflammation and Bone Loss: Chronic inflammation in rheumatoid arthritis and periodontitis is linked to increased osteoclastogenesis and bone erosion.

Nutritional Factors

• Calcium and Vitamin D: Essential for bone mineralization.
• Proteins and Vitamins (K, B12, Folate): Support osteoblast function and collagen synthesis.

Pathophysiology of Bone Disorders

Osteoporosis

• Osteoporosis is a metabolic bone disorder with reduced bone mineral density and microarchitectural deterioration, increasing fracture risk.
• Causes: Hormonal (post-menopausal estrogen deficiency), nutritional (low calcium/vitamin D), and inflammatory (high cytokine levels).
  • DEXA scan with a T-score ≤ -2.5 is the diagnostic criteria.
  • Women are three times more likely to develop osteoporosis than men.
  • Fractures from osteoporosis are more common than heart attacks, strokes, and breast cancer combined.

Osteoarthritis

• Osteoarthritis involves degeneration of articular cartilage and hypertrophic changes in subchondral bone.
• Key features include cartilage breakdown, inflammation of the synovium, and osteophyte formation.
• Pain mechanisms involve nociceptive, neuropathic, and central sensitization components.

Rheumatoid Arthritis

• Rheumatoid arthritis is an autoimmune disease causing systemic inflammation, primarily affecting synovial joints.
• Key features include synovitis with immune cell infiltration, pannus formation leading to cartilage and bone erosion, and systemic symptoms due to circulating immune complexes.

Gout

• Gout is caused by hyperuricemia leading to uric acid crystal deposition in joints.
• Uric acid crystals activate the inflammasome pathway which triggers intense inflammation.
• Management involves lifestyle modifications (diet, alcohol reduction) and pharmacotherapy (allopurinol, NSAIDs).

Bone Remodeling Across the Lifespan

• Childhood and Adolescence: Peak bone mass development occurs through adequate nutrition and physical activity.
• Adulthood: Bone mass is maintained through balanced bone resorption and formation.
• Post-Menopause: Accelerated bone loss occurs due to decreased estrogen levels, emphasizing the need for preventive strategies.

Conclusion and Recommendations

• Health Promotion: Emphasis on lifestyle modifications, adequate intake of calcium and vitamin D, regular weight-bearing exercise, and minimizing pro-inflammatory factors.
• Early Detection: Routine screening for bone density in at-risk populations to prevent osteoporosis-related fractures.
• Integrated Approach: Collaborative care involving dieticians, physiotherapists, and primary care providers to optimize bone health and manage musculoskeletal disorders effectively.
• Future Directions: Focused research on inflammation's role in bone disorders and the development of targeted therapies.