Drugs Affecting Bone Mineralization Flashcards
key molecule that causes formation, activation and maintenance of osteoclasts
NF-kB ligand RANKL
The three MAJOR regulators of calcium homeostasis
PTH, vitamin D and FGF-23
PTH action in gut, kidney, and overall (on Ca and phosphorus)
PTH acts on the kidneys to increase calcium reabsorption and but it decreases phosphorous reabsorption in the kidney.
PTH works in the gut to increase BOTH calcium and phosphorous to reabsorption.
The net effect of PTH is to increase serum calcium and decrease serum phosphorous.
What is Teriparatide (Forteo)
a subunit of amino acids 1-34 of human PTH
Mechanism of action of Teriparatide (Forteo)
PTH has been shown to stimulate osteoblastic bone formation with intermittent PTH treatment. Teriparitide stimulates osteoblastic bone formation although the mechanism is not well understood. Thus Teriparatide has an anabolic effect on bone by increasing bone mass, structural integrity and strength.
Side effects of Teriparatide (Forteo)
mild hypercalcemia, and orthostatic hypotension.
What is the drug of choice for osteoporosis?
Teriparatide
Steps in Vitamin D activation
Vitamin D is hydroxylated in the liver to form 25-hydroxyvitamin D which is also called calcifediol calcidiol. Next, in kidney, 25-hydroxyvitamin D is further converted to 1,25-hydroxyvitamin D. This activated form of vitamin D is called calcitriol.
What is inactivated vitamin D and where is it stored?
vitamin D is stored in the liver as 25 -hydroxyvitamin D
What is the active form of vitamin D and what enzyme creates it
the active form of vitamin D occurs by 1-a hydroxylase in the kidney to form 1,25 -hydroxy vitamin D.
How does vitamin D lead to reabsorption in the GI system
Vitamin D metabolites increase absorption of dietary calcium and phosphorous by stimulating the synthesis of many brush border proteins that increase uptake across the GI mucosa, leading to an increase in serum calcium concentration.
Disorders where treatment is vitamin D
One of the primary treatment indications is vitamin D deficiency. It also is effective in the treatment of rickets and osteomalacia. Vitamin D is also used in the treatment of hypocalcemia. and hypoparathyroidism.
What is the main role of FGF-23
The main role of FGF-23 is to inhibit 1,25 hydroxy vitamin D formation in the kidney and phosphate reabsorption in the kidney.
What are the main functions of calcitonin
What is calcitonin used for clinically
Calcitonin is used to lower plasma calcium and phosphorous concentrations in patients with hypercalcemia due to decreased bone resorption. However, the use of calcitonin is limited for this purpose long-term due to the “calcitontin escape” occurs within a few days and likely due to downregulation of receptors. Calcitonin is also effective in disorders of increased skeletal remodeling, such as Paget’s disease and osteoporosis
What impact do glucocorticoids have one bone
Excess glucocorticoid levels decrease renal calcium reabsorption, interfere with intestinal calcium absorption, stimulate PTH secretion and stimulate osteoclastogenesis through RANKL.
Main use of estrogen
The principal therapeutic application for estrogen is in the treatment and/or prevention of postmenopausal osteoporosis.
What are SERMs and which is the most common
Selective estrogen receptor modulators, raloxifene
How does raloxifene work
SERMs work by stimulating certain estrogen receptors and inhibiting other estrogen receptors. Raloxifene stimulates bone estrogen receptors and inhibits breast and uterine estrogen receptors. Raloxifene also increases bone mineral density by inhibiting bone resorption through effects on cytokines and RANKL.
Side effects of raloxifene
raloxifene increases the risk of stroke, pulmonary emboli, and deep vein thrombosis.
Mechanism of bisphosphonates
They form a three-dimensional structure capable of chelating divalent cations such as calcium. Bisphosphonates have a strong affinity for bone and especially target bone surfaces undergoing remodeling.
The enzyme-resistant analogues of pyrophosphate inhibit osteoclast function. Bisphosphonatesincrease bone density by inhibiting bone resorption, and osteoclastic function. Bisphosphonates become incorporated into the bone matrix and ingested by osteoclasts, promoting osteoclasts apoptosis.
When is bisphosphanate indicated
Current guidelines recommend oral bisphosphonates first line for primary and secondary prevention of fractures. Additionally, bisphosphonates are indicated for osteoporosis and postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, paget’s disease, and bone metastases and cancer-induced hypercalcemia
Bisphosphonates side effects
Bisphosphonates cause gastric and esophageal irritation. A very rare, but quite serious, side effect of bisphosphonates is osteonecrosis of the jaw.
Contraindications for bisphosphonates
Contraindications to the administration and use of bisphosphonates include decreased renal function, esophageal motility disorder and peptic ulcers.
Mechanism of denosumab
Denosumab (Prolia or XGEVA) is a monoclonal antibody. Its primary mechanism of action is that it binds to and prevents the action of RANKL. If you need to review the action of RANKL, go back to PAGE 2 of this learning activity. Remember since RANK ligand stimulates bone resorption, inhibition of RANK ligand would favor overall bone building as osteoclast activity would be less than osteoblast activity.
Indications for denosumab
dications for the use of denosumab include the treatment of postmenopausal women or men with osteoporosis at high risk for fracture. Treatment is also indicated to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer or in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.
Contraindications for denosumab
Contraindications to denosumab includes hypocalcemia.
Side effects of denosumab
Hypocalcemia can occur with treatment. Like bisphosphonates, osteonecrosis of the jaw has been reported with denosumab (Prolia).
Mechanism of gallium nitrate
Gallium nitrate acts by inhibiting resorption through the inhibition of osteoclast activity. By preventing the activity of osteoclasts, gallium nitrate can successfully decrease serum levels of calcium. Gallium nitrate is given as an IV infusion.
Clinical indications for gallium nitrate
Gallium nitrate is currently FDA approved for the management of hypercalcemia of malignancy.
Side effect of gallium nitrate
nephrotoxicity
Contraindication for gallium nitrate
severe kidney disease.
Mechanism of calcimetics - Cinacalcet (Sensipar)
Cinacalcet activates the Calcium-sensing receptor (CaSR) in the parathyroid gland. Recall that the calcium sensing receptor is expressed on parathyroid cells, bone and kidneys and senses the fluctuations of calcium. Activation of the CaSR increases intracellular calcium resulting in inhibition of PTH secretion via negative feedback.
Ultimately inhibits PTH
Indications for cinacalcet
Cinacalcet is approved for the treatment of secondary hyperparathyroidism in chronic kidney disease. It is also indicated for the treatment of parathyroid carcinoma and primary hyperparathyroidism in patients who are unable to undergo surgical resection of the parathyroid.
Contraindications for cinalcalcet
patients with hypocalemia
Side effects of cinalcalcet
dizziness, myalgia, nausea, vomiting, and hypoparathyroidism.
Mechanism for calcylitics
Calcilytics are a calcium sensing receptor (CaSR) antagonist. By inhibiting the action of the CaSR, PTH secretion is stimulated
Indication for calcylitics
have potential use for the short term stimulation of PTH secretion to have increase in bone formation, similar to the intermittent use of Teriparatide.
Mechanism for Furosemide (Lasix)
Furosemide inhibits sodium reabsorption in the ascending limb of the loop of henle. Calcium reabsorption is coupled to sodium reabsorption in the loop. Sodium infusion leads to increase sodium loss and increase calcium loss. The net effect of furosemide is to decrease serum calcium levels by excreting calcium in the urine.
Indications for furosemide
Hypercalcemia
Example of thiazide diuretic
Hydrochorothiazide (Diurel)
Mechanism of hydrochlorothiazide
Primary function is reducing renal calcium excretion. Calcium reabsorption occurs at the distal tubule in the kidney. Thiazides diuretics may increase the effectiveness of PTH in stimulating reabsorption of calcium by the renal tubules. They may also act on calcium reabsorption secondarily by increasing sodium reabsorption in the proximal tubule. The net effect is a decrease in calcium excretion in the urine. This could cause an increase in serum calcium levels since urine calcium excretion is reduced.
Indications for hydrochlorothiazide
Hydrochlorothiazide is indicated for idiopathic hypercalciuria since they effectively reduce the hypercalciuria and incidence of stone formation.
Contraindications for hydroxycholorthiazide
Since thiazide diuretics decrease urine calcium excretion, they are contraindicated in the treatment of hypercalcemia.
