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.
Who should oral bisphosphonates not be used for?
Oral bisphosphonates have not been used widely in children or adolescents because of uncertainty of long-term effects of bisphosphonates on the growing skeleton.
Zoledronate pk? AE?
Zoledronate is administered IV once per year. This convenient dosing schedule
increases compliance.
Adjusted doses for patients with diminished renal function have not been determined
AE:
Zoledronate can cause severe hypocalcemia. It has been associated with renal toxicity.
Pamidronate pk and AE?
Pamidronate may be given intravenously and can cause skin flushing, flu-like symptoms, muscle and joint aches and pains, nausea and vomiting, abdominal discomfort and diarrhea (or constipation) but mainly when given in higher concentrations or at faster rates than those recommended
AE and other indication for bisphosphonates use?
Osteonecrosis of the jaw (ONJ) has received considerable attention as a potential
adverse effect but is rare in patients receiving therapeutic doses of bisphosphonates.
Long term use of any bisphosphonate, more than 5 years, may over-suppress bone
turnover increasing risk of subtrochanteric femur fractures (atypical fracture).
OTHER INDICATIONS FOR USE of bisphosphonates?
OTHER INDICATIONS FOR USE
Bisphosphonates are approved for use in the management of malignancy-associated
hypercalcemia.
AE of Denosumab?
Transient hypocalcemia has been noted , especially in patients with marked bone loss (such as bone hunger following parathyroidectomy) or compromised calcium regulatory mechanisms, including chronic kidney disease and Vitamin D deficiency.
As many leukocytes also express RANKL, there is a theoretical increased risk of infection. Slightly increased rates of cystitis and community acquired pneumonia have been noted.
The risk of osteonecrosis of the jaw and sub-trochanteric fractures is slightly increased.
Denosumab moa and clinical indication? PK?
This monoclonal antibody RANKL inhibitor is approved for treatment of postmenopausal osteoporosis. It is given subcutaneously every 6 months.
By antagonizing RANKL function, denosumab inhibits osteoclast formation and activity to suppress bone resorption.
Denosumab is given subcutaneously and reduces the risk of both vertebral and nonvertebral fractures with comparable effectiveness to the most potent
bisphosphonates.
Teriparatide analog, clincal use?
PTH ANALOG
recombinant form of PTH 1-34, is the only anabolic (bone building) agent approved for treatment of osteoporosis in both men and postmenopausal women at high risk for fractures
Teriparatide AE?
The most common adverse effects associated with teriparatide include injection-site pain
following subcutaneous injection, nausea, headaches, leg cramps, and dizziness.
Teriparatide guidelines for use?
First line in highest risk patients, e.g. long term steroid use. Second line in lower risk patients who have failed to tolerate or respond to bisphosphonates or SERMs.
Recommended duration of use 18- 24 months. Can be used beyond two years for highest
risk patients.
Paget disease bisphosphonate therapy guidelines?
Bisphosphonates are the first-line agents. Calcitonin may be used if a patient is unable to tolerate bisphosphonate therapy.
Treatment failures may respond to plicamycin.
Etridronate contraindication?
As a result, etidronate is contraindicated in patients with lytic lesions in weightbearing bones and is generally used only in patients with an intolerance to the nitrogen-containing bisphosphonates.
The newer nitrogen-containing bisphosphonates such as risedronate and alendronate do not share this adverse effect.
Downsides of etidronate
Etidronate is a relatively weak bisphosphonate that normalizes the serum alkaline phosphatase in less than 20 percent of patients. In addition, etidronate worsens bone pain in many patients and can impair bone mineralization, resulting in osteomalacia and fractures
Bisphosphonate guideline with dental work and paget disease? Treatment duration?
Because of a small but undetermined level of risk for ONJ in association with
bisphosphonate use in Paget disease, planned invasive dental work, such as extractions or implants, should be performed at least three to six months prior to institution of bisphosphonate therapy whenever possible.
Treatment should not exceed 6 months per course but can be repeated after 6 months if
necessary.
Discuss calcitonin use, pk, ae?
Salmon derived calcitonin is a polypeptide which is administered subcutaneously, intramuscularly or intranasally to patients who cannot tolerate bisphosphonate therapy.
Improvement in bone pain and reduction in serum alkaline phosphatase and urine hydroxyproline levels indicate therapeutic response. Often patients who respond well initially, lose that response to calcitonin. This refractoriness may be correlated with the
development of antibodies.
Nausea, vomiting, or flushing are commonly reported. These adverse effects can be avoided by giving the drug at bedtime and slowly increasing the dose
Plicamycin overview and moa?
Plicamycin is a potentially lethal antineoplastic antibiotic produced by Streptomyces plicatus. It is an RNA synthesis inhibitor which is thought to lower calcium serum levels by inhibiting the effect of parathyroid hormone upon osteoclasts. The inhibition of DNA dependent RNA synthesis appears to render osteoclasts unable to fully respond to parathyroid hormone stimulation of osteolysis. Reduction in plasma Ca2+ concentrations occurs within 24-48 hours
When is plicamycin employed?
It is only employed when bisphosphonates and calcitonin therapy have failed and symptoms are debilitating. For Paget’s disease, much lower doses are employed compared to use in cancer chemotherapy.
AE of plicamycin?
Toxicities include thrombocytopenia, severe hemorrhage and death. Use of this drug must be accompanied by careful monitoring of platelet counts, liver and kidney function, and serum calcium levels.
Treatment for high bone turnover?
Dietary phosphate restriction in combination with a phosphate binder is utilized to counteract the hyperphosphatemia stimulated PTH excess.
Treatment for low bone turnover?
Treatment with an active vitamin D preparation is indicated if serum 25-OHD
levels are <30 ng/mL and serum calcium is <9.5 mg/dL (2.37 mM). However, if 25-OHD and serum calcium levels are elevated, Vitamin D supplementation should
be discontinued.
Phosphate binder overview?
Sevelamer is a nonabsorbable phosphate-binding polymer, indicted for use in hemodialysis patients. It consists of cross-linked poly[allylamine hydrochloride] that is
resistant to digestive degradation. The partially protonated amines chelate phosphate ions, trapping phosphate in the gut without affecting calcium absorption. Sevelamer is modestly water soluble and only trace amounts are absorbed from the GI tract. Serum phosphate levels are reduced within two weeks
AE of sevelmar?
Adverse effects of include vomiting, nausea, diarrhea, and dyspepsia.
Sevelamer hydrochloride is associated with a high rate of metabolic acidosis while sevelamer carbonate is not.
List 2 vitamin D analogs?
Doxercalciferol
Paricalcitol
Superior to suppressing calcitriol for secondary hyperparathyroidism, less likely to cause hypercalcemia for any given reduction in PTH
Hypercalcemia in CKD patients has been associated with vascular calcification further exacerbating hypertension and increasing risk of end organ damage.
Cinaclet monitoring and ae?
Serum Ca2+, PO4
3- and PTH levels must be checked periodically. A major
adverse effect
cinacalcet is hypocalcemia. Thus, the drug should not be used if the initial serum Ca2+ is borderline or frankly low. Seizure threshold is lowered by hypocalcemia, placing patients with a history of seizure disorders at particular risk. Adynamic bone disease may develop
if the PTH level is over suppressed, and the drug should be discontinued in such cases.
List a Calcium receptor agonist, moa, clinical uses?
Cinacalcet is a calcimimetic which enhances the sensitivity of the parathyroid calcium sensing receptor (CaSR) to extracellular Ca2+
. This resets the threshold for stimulation of PTH secretion and lowers the serum concentration of Ca2+ at which PTH secretion is suppressed.
Cinacalcet may be considered in CKD patients on dialysis with secondary hyperparathyroidism that is refractory to phosphate binders and Vitamin D
supplementation
Gallium nitrate action and AE?
Gallium nitrate is approved by the FDA for the management of hypercalcemia of
malignancy. This drug inhibits bone resorption. Clinical trials have demonstrated
superiority of gallium nitrate to calcitonin in reducing serum calcium in cancer patients.
The principal potential adverse effect is nephrotoxicity which can be prevented by
hydration before starting the infusion.
Fluoride overview, moa
Fluoride enhances osteoblast activity and increases bone volume. Macroscopically this
effect increases bone density but reduces bone microstructure quality. With chronic exposure fluoride accumulates in peripheral bone and increases the risk of fractures. Sustained consumption of water with a fluoride content of 4 mg/L (4 ppm) is associated
with deficits in cortical bone mass and increased rates of bone loss over time
Calcipotriol structure, moa, pk, and ae?
Calcipotriol is a synthetic vitamin D3 analog which regulates keratinocyte development.
Via intracellular vitamin D receptors it inhibits keratinocyte proliferation and enhances
keratinocyte differentiation in patients with psoriasis.
Calcipotriol is applied topically as a cream, ointment or foam to psoriatic plaques.
Adverse effects are usually localized to application site and include burning of the skin with occasional dermatitis.
