AGENTS THAT AFFECT BONE MINERAL HOMEOSTASIS Flashcards
Describe the actions of Fibroblast Growth Factor 23
FGF3 is a phosphatonin released from bone in
response to hyperphosphatemia or hypervitaminosis D
FGF 23 inhibits PTH secretion
and renal activation of Vitamin D. It also acts on the kidney to decrease phosphate
reabsorption.
Excess FGF23 leads to decreased bone mineralization and osteomalacia
Estrogen action on bone?
net bone protective effects
Estrogen reduces the osteoclastic response to PTH and increases circulating 1,25(OH)2
levels by increasing hepatic production of Vitamin D binding protein.
Glucocorticoids effect on bone?
net catabolic effect on bone
antagonize vitamin D
stimulated intestinal calcium absorption, antagonize osteoblast secretion of osteoid and
stimulate renal calcium excretion
Clincal use: hypercalcemia associated with sarcoidosis, lymphoma
and Vitamin D intoxication.
treatment for acute hypercalcemia?
Forced diuresis with liters of intravenous saline and a loop diuretic is the treatment of choice for acute hypercalcemia
Hypocalcemia causes, manifestations, and preferred therapy?
Iatrogenic in nature following inadvertent parathyroidectomy with thyroidectomy.
Clinical manifestations include tetany, carpopedal spasm and Chvostek’s sign. Emergent infusion of intravenous calcium
gluconate is preferred as calcium chloride salts are more sclerosing to veins.
List risk factor for osteoporosis
- Loss of gonadal function as in menopause
- Long-term use of glucocorticoids
- Thyrotoxicosis
- Hyperparathyroidism
- Malabsorption syndrome
- Alcohol abuse
- Cigarette smoking
Preventative measures to reduce fracture risk?
- Regular weight-bearing and muscle-strengthening exercise.
- Adequate childhood dietary calcium and vitamin D to achieve peak bone mass.
- Supplementation of Vit. D and calcium in those at risk of D deficiency e.g. elderly
- Smoking and excessive alcohol use should be avoided.
How is formal diagnosis conducted and optimal treatment performed? What are the cut off point defining osteopenia and osteroporosis?
Formal diagnosis is made via bone mineral density testing (BMP) with dual-energy x-ray
absorptiometry (DEXA scan)
Optimal treatment requires an integrated approach using the following pharmacotherapeutics and repeating a DEXA scan every 1 to 2 years until findings are
stable
Osteoporosis is present if the T-score is equal or less than
- 2.5. Osteopenia, or lower BMD than normal, is a precursor of osteoporosis and is defined
as a T-score between -1 and -2.5
List 5 bisphosphonates?
Etidronate Alendronate Pamidronate Risedronate Zoledronat
Bisphosphonates actions, structure, and where do they target?
Bisphosphonates are potent inhibitors of bone resorption. They increase bone density
and reduce the risk of fractures in the hip, spine, and other locations.
Bisphosphonates are analogs of pyrophosphate that contain two phosphonate groups
attached to a central carbon. Because they chelate Ca2+, they have a strong affinity for bone, targeting surfaces undergoing remodeling.
Bisphosphonates two MOA?
The antiresorptive activity involves two primary mechanisms: osteoclast apoptosis and
inhibition of components of the cholesterol biosynthetic pathway
First generation bisphosphonates use what mechanism?
Osteoclast apoptosis accounts for the antiresorptive effect of first-generation
bisphosphonates
Later generations of bisphosphonates MOA?
The later generation nitrogen containing bisphosphonates, such as alendronate, directly
inhibit multiple steps in the synthetic pathway from mevalonate to cholesterol and isoprenoid lipids. Geranylgeranyl diphosphate is one such lipid that is required for the
prenylation of proteins that are important for osteoclast function e.g. formation of cell membrane ruffle border for bone resorption
Describe 1st generation bisphosphonate?
Etidronate - least potent and in some instances cause bone demineralization thus are not preferred for osteoporosis management.
List 2 and describe Second generation bisphosphonate?
Alendronate, pamidronate - 10-100 times more potent than first-generation compounds.
List 2 third generation bisphosphonates and describe?
Risedronate, zoledronate - up to 10,000 times more potent than first-generation agents.
Describe oral availability concerns with alendronate and risedronate and risk reduced side effects of this admin?
Oral bioavailability can be less than 10%. Food
reduces absorption even further, necessitating administration on an empty stomach with
a full glass of water following an overnight fast and at least 30 minutes before breakfast.
This reduces risk of bisphosphonate induced
heartburn, esophageal irritation, or erosive esophagitis. Other GI side effects include abdominal pain and diarrhea.
PK of bisphosphonates?
Calcium supplements, antacids, food or medications containing divalent cations, such as
iron, may reduce intestinal absorption of bisphosphonates
IV allows larger doses, reduces frequency of administration.
Bisphosphonates are not metabolized
in the human body. Nearly half of the absorbed drug accumulates in bone; the remainder is excreted unchanged in the urine. Drug in bone often is retained for months to years.
