Where do osteoclasts and osteoblasts come from? Where do they go after the body is through with them?
The osteoclast starts as a haematopoitic stem cell => pre-osteoclast => mature osteoclast => APOPTOSIS. The osteoblast starts as a mesenchymal stem cell => pre-osteoblast => mature osteoblast => APOPTOSIS or OSTEOCYTE
What drugs do we use to build up bone via osteoclasts as a target?
Anti-resorptive drugs. They either inhibit differentiation into osteoclasts or promotes apoptosis of osteoclasts. (SERMS, bisphosphonates, denosumab and calcitonin)
What drugs do we use to build up bone via osteoblasts as a target?
Osteoanabolic drugs. Promote osteoblast differentiation or inhibit osteoblast apoptosis. Terapatide (PTH analogue) and strontium ranelate.
How does estrogen protect the skeleton?
Stimulates osteoclast apoptosis, reduces osteoblast/osteocyte apoptosis, reduces proresorptive cytokines.
What is osteoporosis defined as?
Bone mineral density more than 2.5 times below the standard deviations below the age specific reference
What osteoporosis drug is recommended for women, especially for those at risk for breast cancer?
Raloxifene. It is a selective estrogen receptor modulator (SERM). This means that it is an agonist at bone, inhibiting resorption, and an antagonist in the breast, reducing recurrence of breast cancer.
What osteoporosis drugs result in increase in bone mineral density and only need to be given a few times a year? How do they work? What classes of drugs are there?
Bisphosphonates. They work by binding to the bone matrix and inhibiting the osteoclasts when the osteoclasts come to resorb them. There are nitrogen and non-nitrogen containing bisphosphonates, all ending in "dronate"
What drug is targeted at cytokines in the osteoblast differentiation pathway?
Denosumab is a monoclonal antibody that actually binds to and inhibits free RANKL. This inhibits NF-kB activation in the osteoclast, eliminating production of M-CSF and the osteoclast does not differentiate.
How does estrogen act in the cytokine pathway of osteoclast differentiation?
It stimulates OPG production, and thus inhibition of the RANK RANKL signaling system.
What drug is recommended for use if bisphosphonates can no longer be tolerated?
Teriparatide (active PTH). It stimulates osteoblasts and increases bone mineral density. This is why it is okay for osteoclasts to go on functioning as normal.
PTH stimulates osteoclast differentiation. Why then would you use it for osteoporosis?
It also stimulates differentiation of osteoblasts and inhibits apoptosis of osteoblasts.
What drugs are used locally at sites of bone grafts?
BMPs (bone morphogenic proteins). They act to differentiate mesenchymal stem cells and pre-osteoblasts into mature osteoblasts.
What factors work to change plasma calcium levels?
Intestinal absorption/secretion , skeletal resorption/deposition, and urinary excretion. These processes are regulated by vitamin D, PTH, and calcitonin.
How does PTH affect calcium levels at high and low levels?
At high levels = stimulates osteoclasts and bone resorption. At low levels = stimulates osteoblasts and bone growth. At all levels = increased kidney resorption of Ca2+ (brings Ca2+ back into the plasma). It also stimulates 1alpha-hydroxylase in the kidney, which later activates vitamin D.
What is 1, 25 dihydroxycholecalciferol and what does it do?
Calcitriol. This is the active form of vitamin D after it has been activated by 1alpha-hydroxylase. It stimulates Ca2+ absorption in the gut and increases calcium resorption in the bone, thus increasing serum calcium levels.
What hormone decreases serum calcium?
What type of vitamin D do we make? What kind to we take into our diet?
D2 comes from plants and through our diet. D3 comes through our own metabolism in the liver and activated in the kidney.
How does the active form of vitamin D3 increase calcium absorption in the gut?
It activates transcription factors that produce Ca2+ binding transport protein that increases calcium transport out of the lumen of the gut and into the plasma.
What bone diseases result in low levels of vitamin D or sunlight?
Rickets and Osteomalacia. Less calcium is produced and does not negatively regulate PTH secretion as well. More PTH is secreted, activating osteoclasts and stimulating bone resorption to increase serum calcium levels.
How do you treat rickets or osteomalacia?
Sunlight and vitamin D2 or D3 rich foods.
How could you supplement someone who is deficient in 1alpha-hydroxylase enzyme?
Give exogenous 1,25(OH)D3
How can you promote normal restructuring of bone in Paget's disease?
Calcitonin or bisphosphonates. They inhibit osteoclasts and allow osteoblasts to repair damage done to the bone.