P3

• Bone Remodeling Cycle


  Process by which osteoclasts eat old bone and stimulate osteoblasts to form new ones

  
• Bone Remodeling Cycle


  • Two main processes: resorption and bone formation
  • Resorption frees up ions like calcium and phosphorous, and clears out worn out pieces of the skeleton
  • Bone formation is taken care of by osteoblasts that secrete osteoids which mineralize the matrix

  
• When the remodeling cycle is characterized by more eating or resorption than replenishing or formation


  Bone mineral homeostasis is negatively affected and one may get osteoporosis
• Calcium Homeostasis


  Regulated by PTH, fibroblast growth factor 23 or FGF 23, and 1,25-Dihydroxyvitamin D or calcitriol
• Hypocalcemia


  Prompts PTH release from the parathyroid gland which has stimulatory effects on bone and kidney to increase calcium mobilization and reabsorption, thereby decreasing phosphate reabsorption and stimulating production of calcitriol

  
• Hypercalcemia


  FGF23 released from bone reduces renal phosphate reabsorption, augments calcium recovery while decreasing production of calcitriol, and suppresses PTH release by the parathyroid glands

  
• PTH and calcitriol


  Regulate bone formation and resorption, with each capable of stimulating both processes

  
• PTH and calcitriol


  • Stimulate pre osteoblast proliferation and differentiation into osteoblasts (bone forming cells)
  • Stimulate the expression of RANKL which with MCSF stimulates the differentiation and activation of osteoclasts (bone resorbing cells)

  
• Fibroblast Growth Factor 23 (FGF 23)


  • Promotes phosphate excretion and the suppression of active vitamin D production by the kidney
  • Causes decreased bone mineralization in the presence of hypophosphatemia and low calcitriol levels

  
• Calcitonin

  • Lowers serum calcium and phosphate by inhibiting osteoclastic bone resorption
  • Helps in bone formation, although both formation and resorption are reduced after some time
  • Protects during periods of calcium stress

  
• Osteoporosis


  A bone disease that occurs when the body loses too much bone, makes too little, or both; bones become weak and may easily result in a fracture

  
• Treatments for Osteoporosis


  • Bisphosphonates
  • Selective Estrogen Receptor Modulators (SERM)
  • Hormones (Teriparatide, Calcitonin)
  • RANKL Inhibitor (Denosumab)
  • Vitamin D Metabolites/Analogs
• Bisphosphonates


  • Bind to bone mineral and are taken up by osteoclasts, causing them to undergo apoptosis
  • When osteoclast number and activity decline, bone formation eventually slows down to maintain a balance of bone resorption and formation

  
• SERMs


  Interfere with osteoblast-derived factors that stimulate osteoclast, such as IGF-1, TGF-B, and TNF-alpha
• Denosumab


  Binds RANKL, preventing it from binding to its receptor RANK, thereby preventing maturation of osteoclast precursors and promoting apoptosis of mature multinucleated osteoclasts, slowing down the rate at which bone breaks down

  
• Teriparatide


  Stimulates new bone formation by increasing osteoblast activity and, to a lesser extent, inhibiting osteoclast recruitment, resulting in a substantial reduction in the incidence of fractures

  
• Bisphosphonates


  Preferential binding to bone hydroxyapatite incorporated into sites of active bone remodeling, resulting in inhibition of hydroxyapatite breakdown, thereby reducing bone resorption and induction of osteoclast apoptosis

  
• Bisphosphonates


  • Poorly absorbed from the intestine, with limited bioavailability
  • Distributed extensively into the bone and undergo negligible hepatic clearance
  • Excreted unchanged in kidneys, with renal excretion declining proportionally with kidney function
• Adverse Effects of Bisphosphonates

  Mainly related to GI system, including heartburn, esophageal irritation, esophagitis, abdominal pain, and diarrhea
• Selective Estrogen Receptor Modulators (SERMs)


  Prototype is Raloxifene, which protects against spine fractures but not hip fractures, unlike bisphosphonates, denosumab, and teriparatide

  
• Bisphosphonates


  Inhibit bone resorption and secondarily bone formation

  
• Calcitriol


  An effective form of Vitamin D, important for bone resorption, stimulates intestinal calcium absorption and renal calcium and phosphate reabsorption

  
• Alendronate


  Most studied bisphosphonate, inhibits bone resorption and secondarily bone formation, also used for bone metastases and hypercalcemia

  
• Teriparatide


  Recombinant form of PTH1-34, only anabolic agent currently available which is approved for the treatment of osteoporosis at a dose of 20μg subcutaneously daily, stimulates new bone formation

  
• Calcitonin

  Important hormone for inhibiting bone resorption, indicated for osteoporosis

  
• Teriparatide is approved only for 2 years of use
• Current trials looking into the sequential use of teriparatide followed by a bisphosphonate after 1 or 2 years are in progress and look promising
• Teriparatide is administered subcutaneously once daily in the thigh or abdominal wall
• Most common adverse effects of teriparatide

  • Injection site pain
  • Leg cramps
  • Nausea
  • Headache
  • Dizziness
• All the drugs mentioned are for inhibiting bone resorption, except for teriparatide which stimulates bone formation. All are indicated for osteoporosis.

  
• Renal excretion of bisphosphonates declines proportionately with kidney function


  As they are excreted unchanged
• Bisphosphonates should not be continued in patients with a creatinine clearance of less than 30 mL/min
• Other options in this case include denosumab or teriparatide
• Families of breast cancer and DVT exclude the use of SERMs
• Calcitriol may also be given, but it is usually not enough as monotherapy
• Treatments for Osteoporosis


  • Bisphosphonates
  • SERMs
  • Hormones
  • RANKL Inhibitor
• Bisphosphonates


  Alendronate, Ibandronate, Risedronate, Zoledronate
• Hormones


  Teriparatide, Calcitonin