Bone Mineral Homeostasis

Question 1

Describe the Calcium Homeostasis pathway on slide 3 of 40 for rising Ca2+ levels

Answer 1

Homeostasis: blood Ca2+ levels (about 10mg/100mL)
–stimulus: rising blood Ca2+ levels —- release of calcitonin from the parafollicular C cells of the thyroid gland —calcitonin then stimulates Ca2+ deposition in bones and reduces Ca2+ uptake in kidneys —this leads to blood Ca2+ levels declines to set point

Question 2

Describe the Calcium Homeostasis pathway on slide 3 of 40 for falling Ca2+ levels

Answer 2

Stimulus: falling blood Ca2+ levels — parathyroid chief cells in the parathyroid gland releases PTH — this stimulates Ca2+ release from bones and Stimulates Ca2+ uptake in kidneys (this activates vit D and increases Ca2+ uptake in intestines) –this all results in blood Ca2+ levels rises to set point

Question 3

What is the normal bone remolding cycle?

Answer 3

Osteoclast activity resorption of bone and osteoblasts deposit new bone to restore integrity of the tissue ( rebuilding)

Question 4

What is the effect of parathyroid hormone (PTH) on calcium and phosphate metabolism? flow chart 5 of 40

Answer 4

Decreased calcium results in increased PTH secretion from the parathyroid glands into the plasma.

• –effects on kidneys: 1. decreased phosphate reabsorption = increased urinary excretion of phosphate = decreased plasma phosphate. 2. Increased calcium reabsorption = decreased urinary excretion of calcium 3. Increased 1,25 OH2 D3 formation = increased plasma 1,25 OH2 D3 = intestine increased calcium absorption = increased plasma calcium
• –effects on bone = bone resorption increased = increased release of calcium into plasma = increased plasma calcium

Question 5

What is the effect of calcitonin (CT) on calcium and phosphate metabolism? flow chart 6 of 40

Answer 5

Increased plasma Calcium results in secretion of CT from the parafollicular cells which causes increased plasma CT

• -effects on kidneys: 1. decreased phosphate reabsorption =increased urinary excretion of phosphate = decreased plasma phosphate. 2. Decreased calcium reabsorption = increased urinary excretion of calcium = decreased plasma calcium
• -effects on bone reabsorption: decreased bone resorption = decreased calcium release = decreased plasma calcium

Question 6

What is the role of magnesium in PTH secretion?

Answer 6

A moderate decline in Mg —- enhance in PTH secretion
A severe decrease in Mg — decrease in PTH secretion
Common causes of decreased Mg — chronic diarrhea, diuretics and alcohol abuse ; Chronic PPI and aminoglycoside use

Question 7

What is the vitamin D pathway?

Answer 7

Pro hormone that gets converted to active form calcitriol (1,25 dihydroxycholecalciferol) by hydroxylation
–Sunlight to skin — 7 dehydrocholesterol — cholecalciferol (vit D3) —- LIVER via 25 hydroxylase — converted into 25 hydroxy vitamin D3– KIDNEY 1 alpha hydroxylase —- 1,25 dihydroxyvitamin D3 (maintains calcium balance in the body)

Question 8

What is the effect of 1,25-dihydroxycholecalciferol (Active form of Vit D) on calcium and phosphate metabolism?

Answer 8

Decreased calcium —- increased plasma PTH — increased renal 1 alpha hydroxylase activity — increased 1,25 OH2 D3 formation — Increased plasma 1,25 OH2 D3
–effects kidneys: increased phosphate reabsorption and increased calcium reabsorption
–effects on intestine: increased phosphate absorption and increased calcium absorption
–bone promotes PTH action: increased plasma calcium
Main result: increased plasma phosphate and calcium

Question 9

What is Fibroblast growth factor 23?

Answer 9

It is produced by osteoblasts and Osteoclasts

• -inhibits calcitriol production and phosphate reabsorption in kidney
• -therefore decreased serum phosphate; decreased calcium and phosphate absorption by intestines and increased phosphate excretion by kidneys

Question 10

Therefore what are the hormonal and non hormonal regulators of bone mineral homeostasis?

Answer 10

Hormonal: PTH, Vit D, Calcitonin, Estrogen and Glucocorticoids
Non-Hormonal: Bisphosphonates, Fluoride, Calcimimetics

Question 11

Explain the effects of PTH on bone homeostasis

Answer 11

PTH increase both osteoclasts and osteoblasts activity in the bone via ligand RANKL (a TNF cytokine)
PTH couples Gs receptors to increase cAMP in bone and renal tubular cells
High levels of PTH present continuously causes sub-periosteal bone resorption
Low dose given intermittently increases new bone formation

Question 12

The first drug to discuss is Teriparatide which is a recombinant PTH analog. What are some features of this drug?

Answer 12

Teriparatide:
–pulsatile doses stimulate bone formation (intermittent SQ injections)
–tx: osteoporosis, provides significant intervention for restoring normal bone loss. use for less than 2 years due to increased risk for osteosarcoma
AE: transient hypercalcemia and hypercalciuria

Question 13

The second drug to discuss is Denosumab which is a monoclonal antibody. What are some features?

Answer 13

Denosumab
--is a RANKL inhibitor 
---monoclonal antibody ; binds with RANKL and prevents it from stimulating osteoclast differentiation and function 
--Inhibits bone resorption 
--Tx: osteoporosis 
AE: increased risk of infections

Question 14

Vitamin D acts by activating steroidal nuclear receptor. Deficiency of Vit D causes what?

Answer 14

Rickets in kids:
–type 1: defective 1 alpha hydroxylase enzyme – decreased calcitriol — decreased calcium and phosphate
–type 2: defective receptor for vit D
Osteomalacia in Adults

Question 15

Treatment with Calcitriol (Active Vit D) is approved for what?

Answer 15

Tx: secondary hyperparathyroidism in patients with chronic renal disease and liver disease ; psoriasis (topical)

Question 16

Vitamin D supplements are used for what?

Answer 16

Osteoporosis, chronic renal failure, nutritional rickets due to inadequate dietary intake, chronic liver disease

Question 17

What is the result of too much supplemental Vit D?

Answer 17

Chronic over dose leads to hypercalcemia and hyperphosphatemia

Question 18

What is the serum calcium and PTH levels in primary and secondary hyperparathyroidism?

Answer 18

Primary Hyperparathyroidism: High PTH and High Calcium

Secondary Hyperparathyroidism: High PTH and Low/Normal Calcium ( due to vit D deficiency or chronic renal failure)

Question 19

Name the various vitamin D and their metabolites and analogs

Answer 19

Vitamin D3: Cholecalciferol (commonly added to Ca supplements)
Vitamin D2: Ergocalciferol (commonly added to Ca supplements)
1,25 Dihydroxyvitamin D3: Calcitriol
1 alpha Hydroxyvitamin D2: Doxercalciferol
19 nor- 1,25 - Dihydroxyvitamin D2: Paricalcirol
Calcipotriene: Calcipotriol

Question 20

Explain the use of the drug Sevelamer

Answer 20

Phosphate binding drug used to prevent hyperphosphatemia in patients with chronic renal failure
–binds to dietary phosphate and prevents its absorption in GI

Question 21

What are the oral and IV calcium preparations?

Answer 21

Oral: Ca carbonate , Ca citrate , and Ca lactate
IV: Calcium gluconate for the treatment of hypocalcemic tetany
–it is used to counteract overdose of Magnesium sulfate used in eclampsia
AE: IM injection may causes necrosis and abscess formation IV can result in thrombophlebitis

Question 22

Calcitonin is a peptide hormone and is used to treat what?

Answer 22

Tx: osteoporosis and has been shown to increased bone mass and reduce spine fractures

• -salmon calcitonin has a longer half life and greater potency
• -give as injection and nasal spray

Question 23

What are estrogens used for in terms of bone homeostasis?

Answer 23

Effective in preventing the bone loss
Preventive treatment of osteoporosis in post menopausal women
Given as a hormonal replacement therapy
AE: thromboembolism, migraine, increased risk of breast and endometrial cancer

Question 24

What are the two SERMs (selective estrogen receptor modulators)?

Answer 24

1. Tamoxifen: estrogen antagonist action in the breast, while agonist in the bone and uterus (therefore beneficial effects on bone but not uterus increased risk of endometrial cancer)
2. Raloxifene: estrogen antagonist action on breast and agonist at bone. Has no estrogenic effect on endometrium. Use for tx of osteoporosis in post menopausal women.
   - -both these drugs can cause thromboembolism and hot flushes

Question 25

Moving on to Bisphosphonates, what is the MOA?

Answer 25

Inhibit osteoclastic activity via decreased farnesyl pyrophosphate synthesis by disrupting mevalonate pathway (decreased osteoclast H ATPase)
—bisphosphonates bind with hydroxyapatite in the bone and reduce resorption
4 Bisphosphonates: Etidronate, Alendronate, Pamidronate and Risedronate

Question 26

Chronic use of Etidronate and Pamidronate, results in what?

Answer 26

Bone Malformation and Decreased Osteoblastic Activity

Question 27

What are Bisphosphonates used for?

Answer 27

Tx of osteoporosis, malignancy associated with hypercalcemia, Pagets disease of bone
Alendronate: is drug of choice for glucocorticoid induced osteoporosis and in post menopausal along with HRT causes increase in bone mineral density
Pagets disease of bone characterized by increased turnover with extreme bone resorption and excessive bone formation (suspected to be due to latent viral infection and associated with genetic causes chr 5 and 6)

Question 28

What are the adverse effects of Bisphosphonates?

Answer 28

1. Erosive Esophagitis: due to direct irritation to esophageal lining (prevented by: upright position after taking medicine and increased fluid intake)
2. Etidronate: associated with osteomalacia and osteonecrosis of jaw and fractures

Question 29

Next drug is Cinacalcet, what is the MOA and used and AE?

Answer 29

MOA: activates calcium sensing receptors in parathyroid cells, leading to decrease in PTH synthesis and release
Use: Secondary hyperparathyroidism in chronic renal disease and hyperparathyroidism in patients with parathyroid carcinoma
AE: nausea and hypocalcemia

Question 30

What do the drugs Fluoride and Gallium Nitrate and Plicamycin (mithracin) have on calcium homeostasis?

Answer 30

Fluoride: chronic exposure can lead to new bone synthesis which is denser but brittle
Gallium Nitrate: inhibits bone resorption, useful in cancer related hypercalcemia and nephrotxoic
Plicamycin (Mithracin): cytotoxic anticancer drug, useful in cancer related hypercalcemia. ADR: thrombocytopenia, hepatic and renal toxicity

Question 31

What drugs cause osteoporosis and osteomalacia?

Answer 31

Osteoporosis: corticosteriods, heparin, lithium, anastrozole, and alcohol
Osteomalacia: phenytoin, etidronate (more than 12 months use)

Question 32

What drugs prevent calcium excretion?

Answer 32

Thiazide diuretics decreases the excretion of calcium by increasing reabsorption
Useful in prevention of renal stone formation
Treatment of hypertension in osteoporosis patients

Question 33

What are the treatment options for hypercalcemia?

Answer 33

Most cases are asymptomatic or may be mild
–severe cases present with stones (nephrolithiasis); bones (bone pain and myalgias); groans (abd pain) ; thrones ( sites on throne for polyuria) ; psychiatric overtones (fatigue and depression)
Tx: Flurosemide, Bisphosphonates, Calcitonin, and Parathyoridectomy

Question 34

What are the treatment for osteoporosis?

Answer 34

Affects thin built, postmenopausal women; Caucasians and Asians
–low bone mineral density and bone mass
–hip, vertebral compression fractures and history of steroid use or smoking
Tx: stop smoking, drinking and steroids ; HRT ; Calcium and vit D supplimentation ; Bisphosphates ; SERMS ; Teriparatide.