Bone Physiology and Skeletal System

• Covers physiology of bone
• Outlines roles of osteoclasts, osteoblasts, and osteocytes in osteogenesis

Bone Types

• Long bones, irregular bones, flat bones

Bone Summary

• Structure and composition of bone described
• Bone cells and their function outlined: Osteoblasts, Osteoclasts, Osteocytes
• Ossification process detailed
• Bone marrow functions including haematopoiesis highlighted

What bones do

• Bones are strong, like iron, but as light as wood
• They adapt to functional requirements and repair themselves

Skeletal Functions

• Structural support for heart, lungs, and marrow
• Protection for brain, uterus, and other internal organs
• Attachment sites for muscles allow limb movement
• Mineral reservoir for calcium and phosphorus
• Defense against acidosis

Bone architecture structure

• Cortical bone (compact bone): outermost layer that is strong, dense, and has regular structure
• Trabecular bone (cancellous, spongy bone): lightweight, with irregular lattice, porous
• Marrow cavity: within the bone

Bone Anatomy (Gross)

• Initially woven bone is deposited and replaced by lamellar bone
• Cortical and trabecular bone are types of bone
• Lamellar bone forms Haversian systems

Bone Composition Percentages

• 30% organic, Osteoblasts, Osteoclasts and Osteocytes
• 98% matrix, with collagen
• 70% mineral, with Hydroxyapatite

Osteoblasts

• Form bone
• Derived from mesenchym stem cell line and are similar to fibroblast, chondroblast
• Found on surface of bone and marrow cavity
• Secrete proteinous organic matrix with high mitochondria and Golgi content
• Involved in mineralisation of matrix
• Have hormone receptors for vitamin D, estrogen, and parathyroid hormone

Osteoblast function

• Secrete factors to activate osteoclasts (RANK-ligand) and other cells
• Become osteocytes when trapped by new bone
• Those remaining on the surface of new bone differentiate into lining cells
• Remaining osteoblasts undergo apoptosis

Osteoclasts

• Breakdown bone
• Derived from blood cell line and similar to macophage, monocyte
• Formed on fusion of precurser cells to make large, multinucleated syncytium
• Stimulated by RANK receptors on precursers

Osteoclast Process

• Clearance occurs with bone resorption, involving breaking bones and releasing the material

Osteoclast Requirement:

• Required for radial growth, bone remodeling, maintaining vascularity, and liberating ions

Osteogenesis

• Calcium phosphate crystals precipitate attach to a collagenous lattice support
• Bone always arises by the replacement of some pre-existing tissue
• Cartilage in long bones undergoes endochondral ossification
• Embryonic mesenchyme undergoes intramembranous ossification in flat bones
• The process and cells involved are the same
• Requires matrix formation and mineralisation

Ossification Process

• Red indicates hardened bone, blue indicates cartilage model
• Ossification starts at primary zone in middle of long bones and extends as a wave

Endochondral Ossification

• Cartilage model laid down by chondrocytes
• Cartilage calcified provides a scaffold for osteoblasts
• Osteoblasts form matrix by secreting osteoid (unmineralised pre-bone - type 1 collagen)
• Osteoblasts secrete alkaline phosphatase to calcify the matrix
• Successive waves of osteoclasts and blasts remove calcified cartilage and woven bone to replace it with lacunar bone.

Bone Growth

• Bone growth length occurs by proliferation of chondrocytes at the epiphyseal plates and at the primary ossification front
• Bone growth in diameter occurs by deposition of new bone under periosteal collar, while osteoclastic resorption maintains bone shape.

Bone Marrow

• Large organ around 3.5 kg that fills hollow centre of bones
• Responsible for haematopoiesis
• The formation, development, and specialisation of cellular elements and in immune cell production.

Bone Marrow components

• Can be either red or yellow
• Yellow can revert to red in times of blood loss or reduced haematopoietic activity
• It contains different populations of stem cells that are either haematopoietic or Mesenchymal

Bone Marrow Characteristics

• Extensive capillary network around a central vein
• Haematopoiesis occurs in the extravascular spaces between the sinuses
• Narrow sieve-like openings in epithelial cells lining the sinus permit passage of mature blood cells into the circulation

Lecture content

• Role of bone in mineral (calcium and phosphate) homeostasis
• Symptoms and pathophysiology of diseases affecting bone composition
• Osteoporosis, osteomalacia/rickets and Pagets disease
• Pharmacological treatment available for metabolic bone disorders

Mineral Requirements

• Calcium is required for muscle contraction, neurotransmitter release, contributing to resting membrane potential, signal transduction, blood coagulation, and bone
• Phosphorus is required for signal transduction, energy transaction, and bone

Mineral Regulation

• Calcium (Ca) and phosphorus (P) levels are controlled by parathyroid hormone (PTH) and vitamin D
• Primary phosphorus regulation occurs in kidney
• Parathyroid hormone (PTH) enhances urinary phosphate excretion
• Vitamin D inhibits PTH production

Calcium Regulation

• Body contains 1-2kg of calcium
• 98% in the skeleton and 0.1% ECF

Plasma regulation

• Primary HyperPTH - (hypercalcaemia)
• Osteomalacia/rickets, ROD - (hypocalcaemia)
• Skeletal source of calcium
• ECF only contains 0.9g, a dynamic balance exists between skeletal calcium and ECF
• Turnover is approx 0.25-0.5 g/day with no net gain/loss
• Hypocalcaemia prompts rapid mobilisation of calcium form skeletal stores

ECF Importance

• Maintenance of appropriate levels of ECF calcium take precedence of skeletal strength

Calcium Regulation

• PTH and vitamin D control plasma levels
• PTH is a fast control and vitamin D is slow
• PTH's control: increasing bone resorption, distal tubing Ca reabsorption, induces synthesis
• Vitamin D control: bone resorption and increased Ca absorption inhibits PTH transcription

Low Serum Explanation

• With low serum, calcium comes from kidney/intestine/bone, with decreased levels of Phosphorus
• PTH levels increase with high vitamin D, increase blood serum levels, and phosphorus is lost

Parathyroid Hormone Mechanism

• Binds and activates PTH receptor, but osteoclasts do not express PTH receptors
• Prolonged PTH receptor activation leads to bone resorption, while intermittent activation promotes bone formation

Vitamin D Synthesis

• Synthesis increased by PTH
• Activity of Vitamin D is stimulated by oestrogen, prolactin, and growth hormone
• This is increased by hypocalcaemia, vitamin D reduces activity

Bone density actions

• Increases absorption of Ca++
• Efficiency of intestinal Ca++ absorption increases from 10% to 70% in presence of vitamin D)
• Stimulates protein transcription and opens Ca++ channels

Vitamin D Impact

• Indirectly stimulates osteoclast activity and inhibits PTH synthesis

Bone Disease

• Osteomalacia / Rickets are an Adult or Children's disease.
• Osteomalacia is when minerals are low or absent
• Rickets is when there's defective mineralisation in epiphyseal cartilage
• Several subtypes exisit

Risk Factors

• Osteomalacia mineralisation is defective bone matrix or osteoid remodeling
• Rickets defective mineralisation of the epiphyseal cartilage in growing
• Subtypes exists are calciopenic such as Ca++, VD deficiency

Osteomalacia/Rickets Summary

• Largely eradicated but Vitimin D deficiency impacts population
• Common with Asian/Afro Caribbean, Elderly, Vegan and limited sun exposure
• Consider supplements recommended

Metabolic Bone Disease

• Disorders of bone mineralisation which causes composition imbalances (hydroxyapatite and collagen ratio altered)
• Primary hyperPTH - (hypercalcaemia)
• Osteomalacia/rickets,
• disorders of bone density causes (hydroxyapatite and collagen ratio unchanged) such as Osteoporosis, Paget's

Hyperparathyroidism

• Conditions include Parathyroid adenoma, Hyperplasia and routinely the condition is treated with surgery
• Characterised by symptom of hypercalcaemia Stones in Kidney (20%), Bones that are Brown tumors (10%), the patient Moans: Psychiatric depression and Groans: GI tract irregularities

Hyperparathyroidism explained

• It is increased PTH secretion in response to (hypocalaemia)
• Leads to Renat osteodystrophy (ROD) and Chronic renal failure
• Decreased filtration of phosphate, Hyperphosphataemia with Decreased activation vit. D and Decreased Ca absorption
• The patient presents with Hypocalcaemia,No VD mediated inhibitory feedback on PTH which leads to Secondary hyperparathyroidism

Osteoporosis Summary

• Weak bone
• Roughly 3 million postmenopausal women in UK
• 180000 osteoporosis-related fractures in UK
• wrist, hip Common Sites for pain
• Spine fractures associated with significant morbidity, spinal fracture

Osteoporosis Risk

• Prevalence increases as aged
• WHO classification Normal
• BMD not < 1 SD below YAM
• Osteopenia is a low bone mineral
• Precursor BMD mineral content reduced as a Osteoporosis- BM > 2.5 SD below YAM

Ultrasonics

• U/S use measure bone density using
• More bone = more Sound absorption and bone is dense

Osteoporosis Causes

• Causes of this type of mineral reduction are usually Primary (Progressive bone loss associated with aging caused by Multimodal deficiencies
• postmenopausal deficiency with age related deterioration
• Other impacts causes of these deficits Smoking, Alcohol , less Exercise or Poor bone Diet