AGENTS THAT AFFECT BONE MINERAL HOMEOSTASIS

Question 1

Describe the actions of Fibroblast Growth Factor 23

Answer 1

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

Question 2

Estrogen action on bone?

Answer 2

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.

Question 3

Glucocorticoids effect on bone?

Answer 3

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.

Question 4

treatment for acute hypercalcemia?

Answer 4

Forced diuresis with liters of intravenous saline and a loop diuretic is the treatment of choice for acute hypercalcemia

Question 5

Hypocalcemia causes, manifestations, and preferred therapy?

Answer 5

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.

Question 6

List risk factor for osteoporosis

Answer 6

• Loss of gonadal function as in menopause
• Long-term use of glucocorticoids
• Thyrotoxicosis
• Hyperparathyroidism
• Malabsorption syndrome
• Alcohol abuse
• Cigarette smoking

Question 7

Preventative measures to reduce fracture risk?

Answer 7

• 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.

Question 8

How is formal diagnosis conducted and optimal treatment performed? What are the cut off point defining osteopenia and osteroporosis?

Answer 8

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

Question 9

List 5 bisphosphonates?

Answer 9

Etidronate
Alendronate
Pamidronate
Risedronate
Zoledronat

Question 10

Bisphosphonates actions, structure, and where do they target?

Answer 10

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.

Question 11

Bisphosphonates two MOA?

Answer 11

The antiresorptive activity involves two primary mechanisms: osteoclast apoptosis and
inhibition of components of the cholesterol biosynthetic pathway

Question 12

First generation bisphosphonates use what mechanism?

Answer 12

Osteoclast apoptosis accounts for the antiresorptive effect of first-generation
bisphosphonates

Question 13

Later generations of bisphosphonates MOA?

Answer 13

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

Question 14

Describe 1st generation bisphosphonate?

Answer 14

Etidronate - least potent and in some instances cause bone demineralization thus are not preferred for osteoporosis management.

Question 15

List 2 and describe Second generation bisphosphonate?

Answer 15

Alendronate, pamidronate - 10-100 times more potent than first-generation compounds.

Question 16

List 2 third generation bisphosphonates and describe?

Answer 16

Risedronate, zoledronate - up to 10,000 times more potent than first-generation agents.

Question 17

Describe oral availability concerns with alendronate and risedronate and risk reduced side effects of this admin?

Answer 17

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.

Question 18

PK of bisphosphonates?

Answer 18

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.

Question 19

Who should oral bisphosphonates not be used for?

Answer 19

Oral bisphosphonates have not been used widely in children or adolescents because of uncertainty of long-term effects of bisphosphonates on the growing skeleton.

Question 20

Zoledronate pk? AE?

Answer 20

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.

Question 21

Pamidronate pk and AE?

Answer 21

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

Question 22

AE and other indication for bisphosphonates use?

Answer 22

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).

Question 23

OTHER INDICATIONS FOR USE of bisphosphonates?

Answer 23

OTHER INDICATIONS FOR USE
Bisphosphonates are approved for use in the management of malignancy-associated
hypercalcemia.

Question 24

AE of Denosumab?

Answer 24

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.

Question 25

Denosumab moa and clinical indication? PK?

Answer 25

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.

Question 26

Teriparatide analog, clincal use?

Answer 26

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

Question 27

Teriparatide AE?

Answer 27

The most common adverse effects associated with teriparatide include injection-site pain following subcutaneous injection, nausea, headaches, leg cramps, and dizziness.

Question 28

Teriparatide guidelines for use?

Answer 28

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.

Question 29

Paget disease bisphosphonate therapy guidelines?

Answer 29

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.

Question 30

Etridronate contraindication?

Answer 30

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.

Question 31

Downsides of etidronate

Answer 31

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

Question 32

Bisphosphonate guideline with dental work and paget disease? Treatment duration?

Answer 32

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.

Question 33

Discuss calcitonin use, pk, ae?

Answer 33

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

Question 34

Plicamycin overview and moa?

Answer 34

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

Question 35

When is plicamycin employed?

Answer 35

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.

Question 36

AE of plicamycin?

Answer 36

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.

Question 37

Treatment for high bone turnover?

Answer 37

Dietary phosphate restriction in combination with a phosphate binder is utilized to counteract the hyperphosphatemia stimulated PTH excess.

Question 38

Treatment for low bone turnover?

Answer 38

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.

Question 39

Phosphate binder overview?

Answer 39

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

Question 40

AE of sevelmar?

Answer 40

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.

Question 41

List 2 vitamin D analogs?

Answer 41

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.

Question 42

Cinaclet monitoring and ae?

Answer 42

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.

Question 43

List a Calcium receptor agonist, moa, clinical uses?

Answer 43

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

Question 44

Gallium nitrate action and AE?

Answer 44

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.

Question 45

Fluoride overview, moa

Answer 45

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

Question 46

Calcipotriol structure, moa, pk, and ae?

Answer 46

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.