• Outer layer
• Compact, high density
• Turnover (remodeling) is slow

• Inner (core) bone
• Low density
• Turnover (remodeling) is fast

• Has greater diameter of trabecular bone
• At ends of bones

• Strongest part of bone
• Made of more compact cortical bone compared to the epiphysis

• Anabolic cells
• Rebuilds bone
• Secrete matrix and eventually become surrounded by mineralized bone --> becomes an osteocyte

• Catabolic cell
• Breakdown bone
• Dissolve hydroxyapatite by secreting organic acids and form a resorption lacuna

• Factors such as PTH, shear stress, and TGF-beta cause osteoblast precursors to express RANKL
• RANKL binds to RANK, a receptor expressed on osteoclast precursors
• The RANKL-RANK binding interaction, together with other factors (macrophage colony stimulating factor), cause osteoclast precursors to differentiate into mature osteoclasts
• As mature osteoclasts resorb bone, matrix bound factors such as TGF-beta, IGF-1, and other factors are released
• The liberated factor stimulate osteoblast precursors to develop into mature osteoblasts, which begin to refill the resorption cavities excavated by the osteoclasts

• Endogenous continuous secretion of PTH stimulates bone resorption and stimulates tubular reabsorption of calcium in the nephron --> Both effects of PTH raise plasma Ca2+
• In contrast, exogenous once-daily injection of PTH stimulates new bone formation
• PTH enhances phosphate excretion from the kidneys

• Exogenous and endogenous calcitonin inhibits bone resorption

• Increased PTH secretion from parathyroid glands
• PTH promotes bone resorption, which liberates Ca2+ and phosphate
• In the kidneys, phosphate reabsorption is decreased and Ca2+ reabsorption is increased
• Also in the kidneys, PTH increases the hydroxylation of 25 (OH) vitamin D to 1,25 (OH)₂ vitamin D --> this results in increased mucosal Ca2+ uptake and transport proteins in the intestines
• In a tightly controlled negative feedback loop, increased plasma [Ca2+] inhibits further PTH secretion by the parathyroid glands

• Increased production of cytokines --> activation of osteoclasts
• Longer lifespan of osteoclasts (decreased apoptosis)
• Shorter lifespan of osteoblasts (increased apoptosis)
• Shorter lifespan of osteocytes (increased apoptosis) --> decreased mechanosensing --> microdamage in bone

• Hormone Replacement Therapy
• SERMs
• Bisphosphonates
• Calcitonin
• Vitamin D

Note: these inhibitors of bone resorption only result in a transient increase in bone mineral density --> with time, bone formation is decreased which counteracts the drug's effect (bone mineral density reaches a plateau)

MOA

• Has estrogen agonist activity on some tissues (bone) and estrogen antagonist activity on other tissues (breast, endometrium)
• Only activates certain genes (such as the ones in bone) and does not activate other genes (such as the ones in breast and endometrial tissues)

ADR

• Cardiovascular (VTE)
• Hotflashes, edema

MOA

• Binds Ca2+ causing concentration in mineralized bone --> hydroxyapatite with incorporated bisphosphonate is more resistant to dissolution by organic acids secreted by osteoclasts thus slowing bone resorption
• Block the mevalonate pathway (HMG-CoA reductase pathway) inside osteoclasts --> this pathway is important for protein prenylation in osteoclasts --> inhibition of prenylation results in osteoclast apoptosis

ADR

• GI irritation
• Nausea, abdominal pain, dyspepsia

MOA

• Binds to receptors on osteoclasts and reduces bone resorption

ADR

• Hypersensitivity
• Tachyphylaxis -- due to receptor downregulation

MOA

• PTH is 84 amino acids, but nearly all the activity on calcium metabolism is retained in the first 34 amino acids -- this is teriparatide
• It has selective stimulation on osteoblasts

ADR

• Osteosarcoma in animal studies

MOA

• Blocks RANKL-RANK binding
• Decreases osteoclast activity

ADR

• Hypocalcemia
• Skin infections