1. Agents That Affect Bone Mineral HomeostasisBY
S. Bohlooli, PhD
School of Medicine, Ardabil University of Medical Sciences

2. Hormonal regulators of bone mineral homestasis
PTH
Vitamin D
Calicitonin
Estrogens
Glucocorticoids

3. Bone mineral homeostasis
Figure Some mechanisms contributing to bone mineral homeostasis. Direct actions are shown and feedback may alter the net effect. Calcium and phosphorus concentrations in the serum are controlled principally by two hormones, 1,25(OH)2D3 (D) and parathyroid hormone (PTH), through their action on absorption from the gut and from bone and on excretion in the urine. Both hormones increase input of calcium and phosphorus from bone into the serum; both hormones also stimulate bone formation; vitamin D also increases absorption from the gut. Vitamin D decreases urinary excretion of both calcium and phosphorus, whereas PTH reduces calcium but increases phosphorus excretion. Calcitonin (CT) is a less critical hormone for calcium homeostasis, but in pharmacologic concentrations CT can reduce serum calcium and phosphorus by inhibiting bone resorption and stimulating their renal excretion. FGF23 is a recently discovered hormone that stimulates renal excretion of phosphate. Feedback may alter the effects shown; for example, vitamin D usually increases urinary calcium excretion because of effects on calcium absorption from the gut and effects on PTH.

4. The hormonal interactions controlling bone mineral homeostasis
Figure The hormonal interactions controlling bone mineral homeostasis. 1,25(OH)2D is produced by the kidney under the control of PTH, which stimulates its production, and FGF23, which inhibits its production. 1,25(OH)2D in turn inhibits the production of PTH by the parathyroid glands. 1,25(OH)2D is the principal regulator of intestinal calcium and phosphate absorption. Both PTH and 1,25(OH)2D regulate bone formation and resorption, each capable of stimulating both processes. This is accomplished by their stimulation of preosteoblast proliferation and differentiation into osteoblasts, the bone forming cell. PTH and 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which, with MCSF, stimulates the differentiation and subsequent activation of osteoclasts, the bone resorbing cell. FGF23, fibroblast growth factor; MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANK, receptor for activation of nuclear factor-kB.

5. The hormonal interactions controlling bone mineral homeostasis

6. Vitamin D and its major metabolites and analogs
Chemical and Generic Names
Abbreviation
Vitamin D3; cholecalciferol D3
Vitamin D2; ergocalciferol D2
25-Hydroxyvitamin D3; calcifediol
25(OH)D3
1,25-Dihydroxyvitamin D3; calcitriol
1,25(OH)2D3
24,25-Dihydroxyvitamin D3; secalcifediol
24,25(OH)2D3
Dihydrotachysterol
DHT
Calcipotriene (calcipotriol)
None
1a-Hydroxyvitamin D2; doxercalciferol
1a(OH)D2
19-nor-1,25-Dihydroxyvitamin D2; paricalcitol
19-nor-

7. Conversion of 7-dehydrocholesterol to vitamin D3 and metabolism
Figure Conversion of 7-dehydrocholesterol to vitamin D3 and metabolism of D3 to 1,25(OH)2D3 and 24,25(OH)2D3. Control of the latter step is exerted primarily at the level of the kidney, where low serum phosphorus, low serum calcium, and high parathyroid hormone favor the production of 1,25(OH)2D3. The inset shows the side chain for ergosterol. Ergosterol undergoes similar transformation to vitamin D2 (ergocalciferol), which, in turn, is metabolized to 25(OH)D2, 1,25(OH)2D2, and 24,25(OH)2D2. In humans, corresponding D2 and D3 derivatives have equivalent effects and potency. They are therefore referred to in the text without a subscript.

8. Actions of Parathyroid Hormone (PTH), Vitamin D, and FGF23 on Gut, Bone, and Kidney
PTH 
Vitamin D 
FGF23 
Intestine
Increased calcium and phosphate absorption (by increased 1,25[OH]2D production)  
Increased calcium and phosphate absorption by 1,25 (OH)2D  
Decreased calcium and phosphate absorption by decreased 1,25(OH)2 production  
Kidney
Decreased calcium excretion, increased phosphate excretion
Calcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH)2D1  
Increased phosphate excretion
Bone
Calcium and phosphate resorption increased by high doses. Low doses may increase bone formation.
Increased calcium and phosphate resorption by 1,25(OH)2D; bone formation may be increased by 1,25(OH)2D and 24,25(OH)2D  
Decreased mineralization due to hypophosphatemia
Net effect on serum levels
Serum calcium increased, serum phosphate decreased
Serum calcium and phosphate both increased
Decreased serum phosphate

9. Secondary Hormonal Regulators of Bone Mineral Homeostasis
Calcitonin
Glucocorticoids
Estrogens

10. Nonhormonal agents Bisphosphonates Calcimimetics Thiazides Fluoride
Other drugs
Gallium nitrate
Plicamycin
Strontium Ranelate

11. The structure of pyrophosphate
Figure The structure of pyrophosphate and of the first three bisphosphonates¾etidronate, pamidronate, and alendronate¾that were approved for use in the USA.

12. Typical changes in bone mineral density with time after the onset of menopause
Typical changes in bone mineral density with time after the onset of menopause, with and without treatment. In the untreated condition, bone is lost during aging in both men and women. Fluoride, strontium (Sr2+), and parathyroid hormone (PTH) promote new bone formation and can increase bone mineral density in subjects who respond to it throughout the period of treatment, although PTH also activates bone resorption. In contrast, estrogen, calcitonin, and bisphosphonates block bone resorption. This leads to a transient increase in bone mineral density because bone formation is not initially decreased. However, with time, both bone formation and bone resorption are decreased with these pure antiresorptive agents, and bone mineral density reaches a new plateau.