2. Agents That Affect Bone Mineral Homeostasis
Dr. S. A. Ziai

3. Ca & P
98% of the 1-2 kg of calcium and 85% of the 1 kg of phosphorus in the human adult are found in bone
Dynamic, with constant remodeling
Tetany, coma, muscle weakness, osteoporosis with fractures, loss of hematopoietic capacity
From mg of calcium of diet per day ~ mg is absorbed
Absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum)

4. Ca & P
In diet P= Ca
The efficiency of absorption (principally in the jejunum) is greater, (70% to 90%)
Renal excretion of calcium and phosphate balances intestinal absorption
Over 98% of filtered calcium and 85% of filtered phosphate is reabsorbed by the kidney
The movement of Ca & P across the intestinal and renal epithelia is closely regulated
nontropical sprue, or CRF disrupts bone mineral homeostasis

5. Players Major Players Minor Players (secondary regulators)
Vitamin D (1,25(OH)2D)
PTH (parathyroid hormone)
Fibroblast growth factor 23 (FGF23)
Minor Players (secondary regulators)
Calcitonin (CT)
Prolactin
Growth hormone
Insulin
Thyroid hormone
Glucocorticoids
Sex steroids

9. PARATHYROID HORMONE Calcium-sensitive protease
Synthetic 1-34 PTH is fully active.
Loss of the first two amino terminal amino acids eliminates most biologic activity

10. PARATHYROID HORMONE
Increases serum calcium and decreases serum phosphate
Increases bone turnover or bone remodeling (RANKL)
The net effect of excess PTH is to increase bone resorption
In low and intermittent doses recombinant PTH (teriparatide) for the treatment of osteoporosis (indirect by IGF-1)

11. PARATHYROID HORMONE
In the kidney, PTH ↑the ability of the nephron to reabsorb calcium and magnesium but ↓ its ability to reabsorb phosphate, amino acids, bicarbonate, sodium, chloride, and sulfate.

12. PARATHYROID HORMONE
Another important action of PTH on the kidney is its stimulation of 1,25- dihydroxyvitamin D (1,25[OH]2D) production.
Teriparatide must be given daily by subcutaneous injection

14. Chemical and Generic Names
VITAMIN D
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-1,25(OH)D2

15. VITAMIN D
Only vitamin D and 1,25(OH)2D (as calcitriol) are available for clinical use (natural basis)
Calcipotriene (calcipotriol), is being used to treat psoriasis
Doxercalciferol and paricalcitol have recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease

16. VITAMIN D The vitamin D-binding protein
This a-globulin binds 25(OH)D and 24,25(OH)2D with comparable high affinity and vitamin D and 1,25(OH)2D with lower affinity
Vitamin D rapidly cleared by liver
Excess vitamin D is stored in adipose tissue
The clinical utility of 1,25(OH)2D analogs is likely to expand:
insulin secretion from the pancreas, cytokine production by macrophages and T cells, and proliferation and differentiation of a large number of cells, including cancer cells

17. INTERACTION OF PTH & VITAMIN D
Actions of parathyroid hormone (PTH) and vitamin D on gut, bone, and kidney.
PTH
Vitamin D
Intestine
Increased calcium and phosphate absorption (by increased 1,25[OH]2D production)
Increased calcium and phosphate absorption by 1,25 (OH)2D
Kidney
Decreased calcium excretion, increased phosphate excretion
Calcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH)2D1
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
Net effect on serum levels
Serum calcium increased, serum phosphate decreased
Serum calcium and phosphate both increased
1Direct effect. Vitamin D often increases urine calcium owing to increased calcium absorption from the intestine and resulting decreased PTH.

18. calcium sensing receptor

19. CALCITONIN
Heterogen
Human calcitonin monomer has a half- life of about 10 minutes
Salmon calcitonin has a longer half-life
Lowers serum calcium and phosphate by actions on bone and kidney
Calcitonin inhibits osteoclastic bone resorption

20. CALCITONIN
No readily demonstrable problem develops in cases of calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid)
The ability of calcitonin to block bone resorption and lower serum calcium makes it a useful drug for the treatment of Paget's disease, hypercalcemia, and osteoporosis

21. GLUCOCORTICOIDS
Antagonizing vitamin D-stimulated intestinal calcium transport
Stimulating renal calcium excretion
Blocking bone formation
useful in:
Hypercalcemia (lymphomas and granulomatous diseases such as sarcoidosis (in which production of 1,25[OH]2D is increased)
Vitamin D intoxication

22. ESTROGENS Reduce the bone-resorbing action of PTH
increases 1,25(OH)2D level in blood (no direct effect)
It has direct effects on bone remodeling
It has effects in men
HRT (side effects on breast, uterus, and the cardiovascular system)

23. Raloxifene Selective estrogen receptor modulators (SERMs)
It may actually reduce the risk of breast cancer
Raloxifene has been shown to reduce vertebral fractures
In all cases, adequate intake of calcium and vitamin D needs to be maintained

24. NONHORMONAL AGENTS AFFECTING BONE MINERAL HOMEOSTASIS
BISPHOSPHONATES
CALCIMIMETICS (Cinacalcet)
PLICAMYCIN (MITHRAMYCIN)
THIAZIDES
FLUORIDE

25. BISPHOSPHONATES Etidronate pamidronate alendronate risedronate
tiludronate
ibandronate
zoledronate

26. BISPHOSPHONATES
Retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system
Their greatest effects on osteoclasts
less than 10% of an oral dose of these drugs is absorbed
Food reduces absorption
Nearly half of the absorbed drug accumulates in bone
Decreased renal function, esophageal motility disorders, and peptic ulcer disease are the main contraindications to the use of these drugs

27. BISPHOSPHONATES
Useful for the treatment of hypercalcemia associated with
malignancy
Paget's disease
osteoporosis
Alendronate appears to increase bone mineral density well beyond the 2-year period
The bisphosphonates exert a variety of other cellular effects
inhibition of 1,25(OH)2D production
inhibition of intestinal calcium transport
metabolic changes in bone cells (inhibition of glycolysis)
inhibition of cell growth
changes in acid and alkaline phosphatase

28. BISPHOSPHONATES
Amino bisphosphonates such as alendronate have recently been found to block farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway that appears to be critical for osteoclast survival (Statins role)
These drugs have proved to be remarkably free of adverse effects when used at the doses recommended for the treatment of osteoporosis.

29. BISPHOSPHONATES
Induction of a mineralization defect by higher than approved doses of etidronate
Gastric and esophageal irritation by pamidronate and by high doses of alendronate,
Higher doses used in the treatment of hypercalcemia have been associated with renal deterioration and osteonecrosis of the jaw.
Esophageal irritation can be minimized by taking the drug with a full glass of water and remaining upright for 30 minutes

30. CALCIMIMETICS Cinacalcet Activates the calcium sensing receptor (CaR)
Cinacalcet blocks PTH secretion is approved for the treatment of:
Secondary hyperparathyroidism in chronic kidney disease
Treatment of parathyroid carcinoma.

31. PLICAMYCIN (MITHRAMYCIN)
A cytotoxic antibiotic that has been used clinically for two disorders of bone mineral metabolism: (1/10 cytotoxic doses)
Paget's disease and
Hypercalcemia
Interruption of DNA-directed RNA synthesis

32. THIAZIDES Reduces renal calcium excretion Idiopathic hypercalciuria
Increasing the calcium- sodium exchange in distal tubules
May increase the effectiveness of parathyroid hormone
Idiopathic hypercalciuria
Reducing stone formation
decrease urine oxalate excretion
increase urine magnesium and zinc levels

33. FLUORIDE Prophylaxis of dental caries
Under investigation for the treatment of osteoporosis
In naturally fluoridated water (1-2 ppm) there are less dental caries and fewer vertebral compression fractures
It may stabilize the hydroxyapatite crystal
Useful before permanent teeth are fully formed
> 1 ppm  Fluorosis
At present, fluoride is not approved by the FDA for use in osteoporosis

35. HYPERCALCEMIA CNS depression (coma) It is potentially lethal
major causes
Hyperparathyroidism
cancer
thiazide therapy
Less common causes
Hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency, and immobilization

36. HYPERCALCEMIA MANAGEMENT
Saline Diuresis
prerenal azotemia
mL/h of saline + furosemide
Beware of heart failure and pulmonary edema
Bisphosphonates
Pamidronate, mg, infused over 2-4 hours, and zoledronate, 4 mg, infused over at least 15 minutes
replaced the less effective etidronate
hypercalcemia of malignancy
7-day interval
self-limited flu-like syndrome,
Repeated doses  renal deterioration and osteonecrosis of the jaw
Calcitonin
ancillary treatment
refractoriness frequently develops
Calcimar (salmon calcitonin)
An effect on serum calcium is observed within 4-6 hours and lasts for hours

37. HYPERCALCEMIA MANAGEMENT
Gallium Nitrate
Inhibit bone resorption
hypercalcemia of malignancy
potential nephrotoxicity
Plicamycin (Mithramycin)
is not the drug of first choice
sudden thrombocytopenia followed by hemorrhage
Hepatic and renal toxicity can also occur
Hypocalcemia, nausea, and vomiting may limit therapy
Phosphate
should be used only after other methods of treatment
sudden hypocalcemia, ectopic calcification, acute renal failure, and hypotension
Glucocorticoids
no clear role in the acute treatment
the chronic hypercalcemia of sarcoidosis, vitamin D intoxication, and certain cancers may respond within several days to glucocorticoid therapy
The malignancies responding best to glucocorticoids

38. Phosphate, Potassium
INJECTION
PARENTERAL
(KH2PO4 225mg+ K2HPO4 236mg) / ml
Phosphate, Potassium Monobasic *
UNKNOWN
UNASSIGNED
**(KH2po4)**
Phosphate, Potassium Monobasic* 500 mg
TABLET
ORAL -
Phosphate, Sodium Dibasic *
**(Na2hpo4)**
Phosphate, Sodium monobasic *
**(Nah2po4)**
Phosphate, Sodium*
TABLET, EFFERVESCENT
NaH2PO mg+ NaHCO3 350 mg+KHCO3 315 mg

39. HYPOCALCEMIA
Neuromuscular-tetany, paresthesias, laryngospasm, muscle cramps, and convulsions
The major causes in the adult are:
hypoparathyroidism
vitamin D deficiency
chronic kidney disease
Malabsorption
Neonatal hypocalcemia is a common disorder that usually resolves without therapy.

40. HYPOCALCEMIA MANAGEMENT
Calcium
intravenous, intramuscular, and oral
I.v.: Calcium gluceptate (0.9 mEq calcium/mL), calcium gluconate (0.45 mEq calcium/mL), and calcium chloride ( mEq calcium/mL)
Oral: calcium carbonate (40% calcium), calcium lactate (13% calcium), calcium phosphate (25% calcium), and calcium citrate (21% calcium)
slow infusion of 5-20 mL of 10% calcium gluconate
Vitamin D
Rapid action: 1,25(OH)2D3 (calcitriol), mcg daily (raising serum calcium within hours)
Calcitriol also raises serum phosphate

41. HYPERPHOSPHATEMIA common complication of renal failure
also found in all types of hypoparathyroidism (idiopathic, surgical, and pseudo-), vitamin D intoxication, and the rare syndrome of tumoral calcinosis
Seldom emergency treatment
dialysis or glucose and insulin infusions
Restriction of dietary phosphate plus the use of phosphate-binding gels such as sevelamer and of calcium supplements
Aluminum antacids  aluminum-associated bone disease

42. HYPOPHOSPHATEMIA
clinically significant acute effects of hypophosphatemia are seldom seen
primary hyperparathyroidism
vitamin D deficiency
idiopathic hypercalciuria
vitamin D-resistant rickets
various other forms of renal phosphate wasting (eg, Fanconi's syndrome)
overzealous use of phosphate binders
parenteral nutrition with inadequate phosphate content.

43. SPECIFIC DISORDERS PRIMARY HYPERPARATHYROIDISM HYPOPARATHYROIDISM
NUTRITIONAL VITAMIN D DEFICIENCY OR INSUFFICIENCY
CHRONIC KIDNEY DISEASE
INTESTINAL OSTEODYSTROPHY
OSTEOPOROSIS
X-LINKED & AUTOSOMAL DOMINANT HYPOPHOSPHATEMIA
VITAMIN D-DEPENDENT RICKETS TYPES I & II
NEPHROTIC SYNDROME
IDIOPATHIC HYPERCALCIURIA
PAGET'S DISEASE OF BONE
ENTERIC OXALURIA
Osteitis fibrosa cystica, also known as Von Recklinghausen's disease of bone, is characterized by increased osteoclastic resorption of calcified bone with replacement by fibrous tissue. It may be caused by primary hyperparathyroidism or other causes of the rapid mobilization of mineral salts.
Osteomalacia the general term for the softening of the bones due to defective bone mineralization. Osteomalacia in children is known as rickets, and because of this, osteomalacia is often restricted to the milder, adult form of the disease. It may show signs as diffuse body pains, muscle weakness, and fragility of the bones. A common cause of the disease is a deficiency in Vitamin D, which is normally obtained from the diet and/or sunlight exposure.

44. PRIMARY HYPERPARATHYROIDISM
Asymptomatic patients may be left untreated
Cinacalcet approved for secondary hyperparathyroidism
It is in clinical trials for the treatment of primary hyperparathyroidism
Secondary hyperparathyroidism refers to the excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels) and associated hypertrophy of the glands. This disorder is especially seen in patients with chronic renal failure. It is often--although not consistently--abbreviated as SHPT in medical literature

45. HYPOPARATHYROIDISM
Absence of PTH (idiopathic or surgical hypoparathyroidism)
Abnormal target tissue response to PTH (pseudohypoparathyroidism)
calcium falls and serum phosphate rises
lack of stimulation by PTH of 1,25(OH)2D production

46. HYPOPARATHYROIDISM pseudohypoparathyroidism
Normal or high PTH levels
Have bone response (have osteitis fibrosa), but not renal response (diminished excretion of cAMP or phosphate)
Restore normocalcemia and normophosphatemia
Vitamin D (25, ,000 units three times per week) and dietary calcium supplements
Disadvantage: Episodes of hypercalcemia
Calcitriol  more rapid action
Advantage: In patients tend to have hypercalcemia crises
Osteitis fibrosa is a complication of hyperparathyroidism (too much parathyroid hormone) in which the bones turn soft and become deformed

47. NUTRITIONAL VITAMIN D DEFICIENCY
Vitamin D deficiency  25(OH)D levels < 10 ng/mL
In the pediatric and geriatric populations on vegetarian diets and with reduced sunlight exposure
Vitamin D insufficiency  25(OH)D levels between 10 ng/mL and 32 ng/mL (common)
Decreased bone mineral density and predisposition to falls and fractures in the elderly
Avoided by daily intake of units of vitamin D
Treated by higher dosages (4000 units per day or 50,000 units per week for several weeks)
The diet should also contain adequate amounts of calcium and phosphate

48. CHRONIC KIDNEY DISEASE
The major problems:
Loss of 1,25(OH)2D production (less calcium absorbed)
Retention of phosphate
Reduces ionized calcium
Secondary hyperparathyroidism
The bones show a mixture of osteomalacia and osteitis fibrosa (low vitamin D and high PTH)
Some patients may become hypercalcemic:
overzealous treatment with calcium
severe secondary (tertiary) hyperparathyroidism with high ALP  parathyroidectomy
Adynamic bone disease: decrease in bone cell activity with sensitivity to vitaminD and normal PTH & ALP (high aluminum in bones)  Defroxamine

49. CHRONIC KIDNEY DISEASE
Vitamin D preparation
Choice depends on the type and extent of bone disease and hyperparathyroidism
25(OH)D levels restored to normal (above 32 ng/mL) with vitamin D
1,25(OH)2D3 (calcitriol)  rapid action  correct hyperparathyroidism and osteitis fibrosa
Doxercalciferol & paricalcitol
they are less likely than calcitriol to induce hypercalcemia for any given reduction in PTH
A calcium x phosphate product (in mg/dL units) less than 55 is desired with both calcium and phosphate in the normal range
Calcium adjustments in the diet and dialysis bath
Phosphate restriction (dietary and with oral ingestion of phosphate binders) should be used along with vitamin D metabolites

50. INTESTINAL OSTEODYSTROPHY
Some GI & hepatic disease
malabsorption of calcium & malabsorption of vitamin D
Reduction in reabsorption of endogenous vitamin D metabolites as well as limit absorption of dietary vitamin D (distal jejunum and ileum)
Disordered calcium & phosphate homeostasis  osteoporosis & osteomalacia
Treatment:
vitamin D (25,000-50,000 units three times per week)
Dietary calcium supplementation and monitoring of serum calcium and phosphate levels

51. OSTEOPOROSIS Abnormal loss of bone $13.8 billion in 1996
Postmenopausal
Long term glucocorticoids
Thyrotoxicosis
Hyperparathyroidism
Malabsorption syndrome
Alcohol abuse
Cigarette smoking
Idiopathic

52. OSTEOPOROSIS Postmenopausal osteoporosis Estrogen deficiency
lower 1,25(OH)2D levels
reduced intestinal calcium transport
Estrogen deficiency
HRT
Side effects:
increases the risk of breast cancer and fails to reduce the development of heart disease
Selective estrogen receptor modulators (SERMs) Raloxifene
reduce the risk of breast and uterine cancer
protects against spine fractures but not hip fractures
does not prevent hot flushes
same increased risk of thrombophlebitis

53. OSTEOPOROSIS
vitamin D therapy is often used in addition to dietary calcium supplementation
calcitriol and its analog 1a(OH)D3 increase bone mass and reduce fractures (not FDA approved)
Fluoride remains controversial
Teriparatide 20 mcg subcutaneously daily stimulates new bone formation
Calcitonin increases bone mass and reduce fractures only in the spine
Bisphosphonates potent inhibitors of bone resorption. They increase bone density and reduce the risk of fractures in the hip, spine, and other locations
alendronate 10 mg/d, risedronate 5 mg/d, ibandronate 2.5 mg/d
alendronate 70 mg/wk, risedronate 35 mg/wk
ibandronate 150 mg/mo
These drugs are effective in men as well as women and for various causes of osteoporosis
Reclast zoledronic acid once in year

54. 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 and PTH promote new bone formation and can increase bone mineral density in subjects who respond to it throughout the period of treatment. 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 and bone mineral density reaches a new plateau.

55. X-LINKED & AUTOSOMAL DOMINANT HYPOPHOSPHATEMIA
Appearance of rickets (phosphate is critical to normal bone mineralization )and hypophosphatemia in children, although they may first present in adults
By mutations in PHEX (endopeptidase)
By mutations in FGF23
FGF23 blocks the renal uptake of phosphate and blocks 1,25(OH)2D3 production
Oral phosphate (1-3 g daily) and calcitriol ( mcg daily)

56. VITAMIN D-DEPENDENT RICKETS TYPES I & II
These diseases are rare
Type I vitamin D-dependent rickets
deficiency of 1,25(OH)2D production
mutations in 25(OH)D-1a-hydroxylase
treated with vitamin D (4000 units daily) or calcitriol ( mcg daily)
Type II vitamin D-dependent rickets
mutations in the gene for the vitamin D receptor
The serum levels of 1,25(OH)2D are very high
large doses of calcitriol has been claimed to be effective
One recent report indicates a reversal of resistance to calcitriol when 24,25(OH)2D was given

57. NEPHROTIC SYNDROME loss of the vitamin D-binding protein
lose vitamin D metabolites in the urine (25(OH)D)
Some of them develop bone disease
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein (at least 3 grams per day) from the blood into the urine

58. IDIOPATHIC HYPERCALCIURIA
Hypercalciuria and nephrolithiasis with normal serum calcium and PTH levels
(1) hyperabsorbers, high-normal serum calcium, low- normal PTH
(2) renal calcium leakers, low-normal serum calcium and high-normal serum PTH
(3) renal phosphate leakers, leading to stimulation of 1,25(OH)2D
Hydrochlorothiazide, up to 50 mg twice daily
Allopurinol (altrnative)
hyperuricosuria is associated with idiopathic hypercalcemia
a small nidus of urate crystals could lead to the calcium oxalate stone formation

59. PAGET'S DISEASE OF BONE A localized bone disease
Uncontrolled osteoclastic bone resorption with secondary increases in bone formation
This new bone is poorly organized
Elevation of ALP & urinary hydroxyproline (diagnostic & treatment response aids)
Treatment:
To reduce bone pain, progressive deformity, hearing loss, high-output cardiac failure, and immobilization hypercalcemia
Calcitonin and bisphosphonates are the first-line agents
Plicamycin

60. PAGET'S DISEASE OF BONE
Sodium etidronate, alendronate, risedronate, pamidronate, and tiludronate are the bisphosphonates currently used
Etidronate, 5 mg/kg/d; alendronate, 40 mg/d; risedronate, 30 mg/d; and tiludronate, 400 mg/d
Long-term (months to years) remission may be expected in patients who respond to these agents
Treatment should not exceed 6 months per course but can be repeated after 6 months if necessary
The principal toxicity of etidronate is the development of osteomalacia (bone pain) and an increased incidence of fractures when the dosage is raised substantially above 5 mg/kg/d
The principal side effect of alendronate and the newer bisphosphonates is gastric irritation

61. ENTERIC OXALURIA
Short bowel syndromes  fat malabsorption  oxaluria calcium oxalate stones
in the intestinal lumen, calcium (which is now bound to fat) fails to bind oxalate and no longer prevents its absorption
enteric flora, acting on the increased supply of nutrients reaching the colon, produce larger amounts of oxalate
One to 2 g of calcium carbonate can be given daily in divided doses