Various bone cells

ii. Osteoblasts:
- synthesize, transport and arrange matrix proteins
- initiate mineralization process
- express cytokine, hormone binding receptors.
- Under the control of calcitonin to take blood calcium and put it into the bone.
iii. Osteocytes:
- Osteoblasts surrounded by matrix after end of their life span
- Osteocytes : Osteoblasts ratio=10:1

b. Bone resorbing cells (Osteoclasts):
- Macrophage lineage cells
- IL-1, IL-3, IL-6, IL-11, TNF, GM-CSF and M-CSF for osteoclast differentiation and maturation
- Osteoclastogenesis: Differentiation of preosteoclasts into osteoclasts by RANK-RANKL contact
- Osteoprotegrin (OPG) inhibits osteoclastogenesis by binding to RANKL
- Scalloped resorption pits osteoclasts produce and reside in are known as “Howship lacunae”
- Under control of PTH to chew up the calcium of bone and put it into blood

c. Bone Proteins:
- Type I collagen (90%)
- Cell adhesion proteins
- Clacium binding proteins
- Mineralization proteins (Osteocalcin)
- Enzymes (collagenase, alkaline phosphatase)
- Cytokines (Prostaglandins, IL-1, IL-6, RANKL)
- Growth factors (GF-1, TGF-β, PDGF)
Osteoblasts and osteoclasts act in coordination and are considered to be functional unit of bone known as the Basic Multicellular Unit (BMU).

ANATOMY OF A LONG BONE:
The bone is enclosed in a tough, fibrous, connective tissue covering called the periosteum, which is continuous with the ligaments and tendons that anchor bones. The periosteum contains blood vessels that enter the bone and service its cells. At both ends of a long bone is an expanded portion called an epiphysis; the portion between the epiphyses is called the diaphysis. The diaphysis is not solid but has a medullary cavity containing yellow marrow. The medullary cavity is bounded at the sides by compact bone. The epiphyses contain spongy bone. Beyond the spongy bone is a thin shell of compact bone and, finally, a layer of hyaline cartilage called the articular cartilage. The medullary cavity and the spaces of spongy bone are lined with endosteum, a thin, fibrous membrane.

i. Cortical (80%):
ii. Spongy/Trabecular/Cancellous (20%):

SPONGIOSA:
i. Primary spongiosa : the mineralized cartilage in the developing metaphysis.
ii. Secondary spongiosa : second stage in the mineralization of bony trabeculae; comprises the enlarged, mineralized bony trabeculae of the primary spongiosa.

DEVELOPMENTAL & ACQUIRED ABNORMALITIES IN BONE CELLS, MATRIX AND STRUCTURE:
Dysostoses: Developmental anomalies resulting from localized problems in the migration of mesenchymal cells and their formation of condensation.
Dysplasias: Mutations in the regulators of organogenesis (growth factors, receptors, matrix components) affecting cartilage and bone tissues globally.

A. Defect in nuclear proteins and transcription factors: usually due to mutation in homeobox genes
i. Congenital absence of phalanx, rib or clavicle

ii. Polydactyly

iii. Syndactyly

iv. Craniorachischis

B. Defects in hormones and signal transducing mechanisms:
i. Achondroplasia :
- Mutation in the FGFR3 coding genes causing constant activation of FGF3 leading to growth suppression cartilage proliferation
- Autosomal dominant disorder
- Non-lethal dwarfism
ii. Thanatophoric dwarfism: lethal

Some common features in both:
a. Shortening of limbs
b. Frontal bossing

C. Defects in extracellular structural proteins:
i. Osteogenesis Imerfecta:
- Deficiencies in the synthesis of type I collagen
- Mutations in the gene that code for a1 and a2 chains of type I collagen
- 4 variants: type I, type II, type III, type IV
- Type II: Fatal in utero or perinatal period
- Other types are compatible with survival
- Features:
a. Blue sclera
b. Hearing loss
c. Dental imperfections
d. Skeletal fragility
ii. Achondrogenesis II, Hypochondrogenesis, Sickler syndrome: collagen II
iii. Multiple epiphyseal dysplasia: collagen IX
iv. Schmid metaphyseal chondrodysplasia: collagen X

D. Defects in misfolding and degradation of macromolecules:
i. Mucopolysaccharidoses:
- A lysosomal storage disease
- Deficiency in enzymes that degrade dermatan, heparain and keratain sulfate
- Cartilage disorders: Short stature, chest wall abnormalities, malformed bones

E. Defect in metabolic pathways (Enzymes, Ion Channels, and Transporters):
i. Osteopetrosis:
- Reduced osteoclast bone resorption
- Known as marble bone disease: brittle and bones fracture like chalk
- 4 variants: infantile malignant, type II carbonic anhydrase deficiency and autosomal dominant type I and II
- Osteoclasts cannot acidify the resorption pits preventing digestion of bone
- Ends of the long bone are bulbous (Erlenmeyer flask deformity)
- Primary spongiosa persists and fills the medullary cavity
- Brittle bone, fracture, hepatosplenomegaly and anemia, nerve compressions

F. Diseases associated with decreased bone mass:
i. Osteoporosis:
- Accelerated bone loss causing increased porosity of skeleton
- Peak bone mass achieved during early adulthood
- Factors leading to osteoporosis:
a. Age related (Senile) : Decreased replicative activity of osteoprogenitor cells, Decreased synthetic activity of osteoblasts, Decreased biologic activity of matrix-bound growth factors, Reduced physical activity (Wolff’s law – a bone is only big and strong as it has to be)
b. Post-menopausal: Decreased serum estrogen  Increased IL-1, IL-6, TNF levels  Increased expression of RANK and RANKL  Increased osteoclastic activity
c. Genetic: Polymorphism in vitamin D and PTH receptor molecules
d. Nutrition: Calcium intake in diet
e. Secondary factors: hyperparathyroidism, multiple myeloma, malnutrition, vitamin C and D deficiencies, corticosteroid administration, anemia, osteogenesis imperfect, immobilization, etc.

- Features: Fractures, pain, lumbar lordosis, kyphoscoliosis

- Treatment and prevention: Exercise, Calcium & vit.D intake, estrogen replacement, etc.

G. Disease caused by Osteoclast dysfunction:

i. Paget Disease (Osteitis Deformans):
- Collage of matrix madness (osteoclast gone wild); osteoclasts are hyperresponsive to RANKL and vitamin D
- Caused due to a slow virus infection by a paramyxovirus which induces production of IL-6, M-CSF and other cytokines which stimulate osteoclastic activity
- 3 stages:
a. Osteolytic stage: increased resorption pits and osteoclastic activity
b. Mixed osteoclastic-osteoblastic stage: osteoclastic activity persists but osteoblastic activity dominates leading to formation of woven or lamellar bone
c. Osteosclerotic stage: burn out quiescent stage; soft and thickened trabeculae and cortices

- Histologic hallmark: Mosaic pattern, Jigsaw like lamellar bone
- Clinical findings:
a. Elevated alkaline phosphate and urine hydroxyproline
b. Monostotic (15%) and Polyostotic (85%)
c. Pain due to microfactures (chalk like fractures) and nerve compression
d. Leontiasis osseas and platybasia
e. Kyphosis
f. Heart diseases
g. Progression to osteoporosis and sarcomas like osteosarcoma and chondrosarcoma

H. Diseases associated with abnormal mineral homeostasis:
a. Rickets and Osteomalacia:
- Lack of vitamin D or defect in its metabolism
- Rickets (osteopenia usually not seen) in children and osteomalacia in adults (characterized by osteopenia)

b. Hyperparathyroidism:

- Primary hyperparathyroidism due to adenoma of parathyroid gland
- Secondary hyperparathyroidism due to hypocalcemia is not as severe as primary one
- Entire skeleton is affected ; fractures
- Osteitis fibrosa cystica (von Recklinghausen’s disease of bone) in severe cases
- Brown tumor due to increased vascularity, hemorrhage and hemosiderin deposition
- Dissecting osteitis, osteopenia, thinning of cortices

c. Renal osteodystrophy:
- Skeletal changes of chronic renal disease like osteitis fibrous cystica, osteomalacia, osteosclerosis, osteoporosis, growth retardation, etc.
- Pathogenesis:
a. Phosphate retention and hyperphosphatemia
b. Hypocalcemia (vitamin D : 1,25(OH)2D3 deficiency
c. Increased PTH
d. Metabolic acidosis  Release of hydroxyapatites from matrix
e. Iron accumulation of bone and aluminium deposition at site of mineralization
- Complication: Amyloidosis

Osteoporosis is a condition in which the bones are weakened due to a decrease in the bone mass that makes up the skeleton.Throughout life, bones are continuously remodeled. While a child is growing, the rate of bone formation is greater than the rate of bone breakdown. The skeletal mass continues to increase until ages 20 to 30. After that, the rates of formation and breakdown of bone mass are equal until ages 40 to 50. Then, reabsorption begins to exceed formation, and the total bone mass slowly decreases.

Over time, men are apt to lose 25% and women 35% of their bone mass. But we have to consider that men tend to have denser bones than women anyway, and their testosterone (male sex hormone) level generally does not begin to decline significantly until after age 65. In contrast, the estrogen (female sex hormone) level in women begins to decline at about age 45. Because sex hormones play an important role in maintaining bone strength, this difference means that women are more likely than men to suffer fractures, involving especially the hip, vertebrae, long bones, and pelvis. Although osteoporosis may at times be the result of various disease processes, it is essentially a disease of aging. Everyone can take measures to avoid having osteoporosis when they get older. Adequate dietary calcium throughout life is an important protection against osteoporosis. Males and females require 1,000 mg per day until age 65 and 1,500 mg per day after age 65, because the intestinal tract has fewer vitamin D receptors in the elderly. A small daily amount of vitamin D is also necessary to absorb calcium from the digestive tract. Exposure to sunlight is required to allow skin to synthesize vitamin D. Therefore, you should avail yourself of the vitamin D in fortified foods such as low-fat milk and cereal. Postmenopausal women should have an evaluation of their bone density. Presently, bone density is measured by a method called dual energy X-ray absorptiometry (DEXA). This test measures bone density based on the absorption of photons generated by an X-ray tube. Soon, a blood and urine test may be able to detect the biochemical markers of bone loss, making it possible for physicians to screen all older women and at-risk men for osteoporosis.

If the bones are thin, it is worthwhile to take measures to gain bone density because even a slight increase can significantly reduce fracture risk. Regular, moderate, weight-bearing exercise such as walking or jogging is a good way to maintain bone strength . A combination of exercise and drug treatment, as recommended by a physician, may yield the best results. A wide variety of prescribed drugs that have different modes of action are available. Hormone therapy includes black cohosh, which is a phytoestrogen (estrogen made by a plant as opposed to an animal). Calcitonin is a naturally occurring hormone whose main site of action is the skeleton where it inhibits the action of
osteoclasts, the cells that break down bone. Promising new drugs include slow-release fluoride therapy and certain growth hormones. These medications stimulate the formation of new bone.