The Natural HO Osteoporosis Bisphosphonate, Raloxifene, Calcitonin, Denosumab

3.2 – “The Natural h/o Osteoporosis”: Bisphosphonate, raloxifene, calcitonin, denosumab • All of the rx here are useful in the treatment of osteoporosis by preventing or decreasing bone resorption. Will cause a moderate increase in bone mineral density & decreased fracture risk (TA is drawing out a fresh piece of chalk to replace the fractured boneshaped piece). • Mostly directed against osteoclasts (destructive kids in class) rather than osteoblasts (don’t disturb the builders) • PTH (PhD) stimulates osteoblasts to express RANKL (Receptor activator of nuclear factor κ-Β ligand) → osteoclast activation (RANKL = crank-drill; builder giving to kid, & kids drilling out bone). • Bisphosphonates o Alendronate, pamidronate, zoledronate, others (“Donate” box for -dronate) o Actions: ▪ Have a chemical strucutre similar to pyrophosphate (2 Ⓟ coins in the box). Attach to hydroxyapatite in bone (T-rex appetite). Osteoclasts that try to latch onto bone bind instead to the bisphosphonate & are unable to adhere to bone (kid is stuck in box so cannot destroy things). ▪ decrease development & recruitment of osteoclast precursors (lady with 2 Ⓟ coins blocking next class from entering. ▪ Induce osteoclast apoptosis (popping Apatosaurus balloon). ▪ Net result: decreased bone lost and stable or increased bone mineral density. o Indications: ▪ First line treatment for osteoporosis ▪ Alendronate, zoledronate used for hypercalcemia d/t ↓bone resorption (elevated ice cream). • Especially important in hypercalcemia of malignancy, a common cause of severe hypercalcemia requiring acute treatment (fossil with lots of crabs) ▪ Paget’s disease • uncontrolled osteoclast resorption with secondary disorganized bone formation (disorganized human skeleton • Helps prevent high bone turnover, preventing pain & progressive deformity o Adverse effects ▪ Upper GI effects (e.g. acid reflux, esophagitis, esophageal ulcers). Can be avoided by drinking lots of water & staying upright after taking (corrosion of dinosaur neck) • May administer IV (much less frequent administration) with severe intolerance. ▪ Rare: osteonecrosis of the jaw (crumbling jawbone). More likely with IV administration ▪ Can cause hypocalcemia d/t inability to resorb bone (fallen ice cream cup) • Selective Estrogen Receptor Modulators (SERMs) o Estrogen receptors are found throughout bone. Activation inhibits osteoclast differentiation. Estrogen therapy can prevent & treat postmenopausal osteoporosis (); however, not recommended d/t increased risk of breast cancer and other adverse effects. o Instead, use SERMs, such as Raloxifene (relax sign). o SERMs have estrogen agonist activity in bone (inhibiting osteoclast differentiation [slowing down the classmates] → net resorption is decreased, slowing postmenopausal osteoporosis), CV system, & blood lipoproteins. Estrogen antagonists activity in uterus & breast (↓risk of breast cancer) • Denosumab (dino-suit) o Monoclonal antibody against RANKL (antibody shaped spines) o As effective as bisphosphonates o Used in treatment of postmenopausal osteoporosis • Calcitonin – “tones down calcium” (curator) o Peptide hormone released by thyroid parafollicular cells → ↓serum calcium & phosphate by actions in bone & kidney (curator pointing down) Not as effective as bisphosphonates, so not first line. o Inhibits osteoclasts, and thereby decreases bone resorption (curator grabbing destructive kid). o Promotes Ca excretion by the kidney by inhibiting resorption (pouring ice cream down leg). o Used in hypercalcemia of malignancy (crabs on fossil) o Useful in Paget disease (misaligned skeleton) o Adverse effects: ▪ Hypocalcemia (fallen ice cream)