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Agents That Affect Bone Mineral Homeostasis. Functions of the bone: Principal structural support for the body Ca and PO4 reservoir Space for hematopoesis. Two hormones serve as principal regulators of Ca & P homeostasis: parathyroid hormone (PTH) & vitamin D (active metabolite)

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agents that affect bone mineral homeostasis

Agents That Affect Bone Mineral Homeostasis

  • Functions of the bone:
  • Principal structural support for the body
  • Ca and PO4 reservoir
  • Space for hematopoesis
slide2
Two hormones serve as principal regulators of Ca & P homeostasis: parathyroid hormone (PTH) & vitamin D (active metabolite)
  • Certain of secondary regulators— calcitonin, glucocorticoids & estrogens—are useful therapeutically
clinical pharmacology
CLINICAL PHARMACOLOGY

Conditions that alter bone mineral homeostasis:

Effects on bone can result in:

  • osteoporosis (abnormal loss of bone; remaining bone histologically normal)
  • osteomalacia (abnormal bone formation due to inadequate mineralization)
  • osteitisfibrosa (excessive bone resorption with fibrotic replacement of resorption cavities)
hypercalcemia
HYPERCALCEMIA
  • Hypercalcemiacauses CNS depression, including coma, & is potentially lethal
  • Arrhythmia cardiovascular collapse give MgSO4 (IV) to offset the dynamic effect
  • Major causes (other than thiazide therapy) are hyperparathyroidism & cancer with or without bone metastases
  • Less common causes are hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome - seldom require emergency ↓ of serum Ca (with exception of hypervitaminosis D)
  • Ca X PO4 must be < 55 mg2/dL2 in order to prevent ectopic calcification in soft vital tissues
treatment of hypercalcemia
Treatment of hypercalcemia

1. Saline Diuresis500-1000 mL/h of saline to reverse dehydration & restore urine flow + loop diuretic to ↑urine flow but also ↓Careabsorption in ascending limb of loop of Henle

2. If more prolonged treatment of hypercalcemia is required:1. BisphosphonatesEtidronate in saline IV for 3 days. Pamidronate appears to be more effective

bisphosphonates
Bisphosphonates
  • MOA: inhibit bone resorption
  • less than 10% of an oral dose of these drugs is absorbed.
  • Food reduces absorption even further  empty stomach.
  • That’s why: pamidronate is not available as an oral preparation.
  • all currently available bisphosphonates have this complication (with the possible exception of etidronate)
  • Nearly half of the absorbed drug accumulates in bone;
  • C/I: Decreased renal function, esophageal motility disorders, and peptic ulcer disease are the main
slide14
3. Calcitonin:
  • ancillary treatment.
  • effect lasts for 6-10 hours.
  • Calcimar (salmon calcitonin) is available for parenteral & nasal administration (preferred)
  • MOA: (1) inhibits osteoclastic bone resorption ((although with time both resorption and firmation of bone are reduced)

(2) In kidney: Reduces Ca and PO4 reabsorption

  • Useful for the treament of Paget’s disease, Hypercalcemia and osteoporossis
slide15
4. Gallium Nitrate (IV)
  • Acts by (-) bone resorption
  • Due to nephrotoxicity, patients should be well-hydrated & have good renal output before starting infusion
slide16
5. Plicamycin(Mithramycin):(risk of thrombocytopenia followed by hemorrhage), hepatic & renal toxicity

6. Phosphate: IV is hazardous procedure if not done properly: sudden hypocalcaemia, ectopic calcification, acute renal failure, hypotension

  • Must be given slowly (6-8 hrs) then switch to oral phosphate

Very risky

slide17
7. Glucocorticoids:
  • Glucocorticoid hormones alter bone mineral homeostasis by: 1. antagonizing vitamin D-stimulated intestinal calcium transport, 2. by stimulating renal calcium excretion, and by 3. blocking bone formation
  • no clear role in acute treatment of hypercalcemia.
  • However, chronic hypercalcemia may respond within several days to glucocorticoid therapy
  • Prednisone (30-60 mg/day)
hypocalcemia
HYPOCALCEMIA
  • Main features (neuromsucular): tetany, paresthesias, laryngospasm, muscle cramps, & convulsions
  • Major causes in adult: hypoparathyroidism, vitamin D deficiency, chronic kidney disease & malabsorption, infusions of citrated blood
  • Neonatal hypocalcemia usually resolves without therapy
  • Treatment: Ca & vitamin D (or its metabolites)
treatment of hypocalcemia
Treatment of Hypocalcemia

1. Calcium:

  • IV: gluceptate, gluconate, chloride. Gluconate is the preferred form (less irritating to veins)
  • Rapid infusion can lead to cardiac arrhythmias
  • Oral: carbonate, lactate, phosphate, citrate

Carbonate is preparation of choice: high % of Ca, ready availability, low cost, & antacid properties

  • Treatment:
      • Severe symptomatic hypocalcemia: slow infusion of 5-20 mL of 10% Cagluconate. Avoid rapid infusion (cardiac arrhythmias)
      • Less severe cases: oral Ca (carbonate to provide 400-1200mg of elemental Ca
slide20
2. Vitamin D

1,25(OH)2D3 (calcitriol), is the metabolite of choice for rapid action (↑serum Ca within 24-48 hrs). Also ↑ serum P but usually not observed early in treatment

  • Combined effects of calcitriol on both Ca & P make careful monitoring of serum Ca × P product important to avoid ectopic calcification
hyperphosphatemia
HYPERPHOSPHATEMIA
  • Causes: renal failure, hypoparathyroidism & vitamin D intoxication
  • Emergency treatment: by dialysis or glucose & insulin infusions
  • Chronic treatment:

1.↓ dietary phosphate

2. Ca supplements

3. Al(OH)3-containing antacids (potential to induce Al-associated bone disease)

4. Phosphate-binding gels (Sevelamer)

diet management of hyperphosphatemia
Diet Management of hyperphosphatemia
  • Minimize (but not avoid: cheese (no more than 1 oz per day, milk (250 mL per day), egg (no more than 1 per day- maximum 3-4 per week), heart, liver, kidney (no more than once per fortnight
  • Avoid: Pilchards, Sardines, Kippers, Herrings, Whitebait, Sprats, Fish Roe, Prawns or Crab, All Bran., Cocoa powder, Horlicks and Ovaltine, Evaporated milk, Chocolate (especially milk) and Fudge, Chocolate spread, Peanut butter, Nuts, popcorn.
hypophosphatemia
Hypophosphatemia
  • Causes: e.g. hyperparathyroidism, vitamin D deficiency, idiopathic hypercalciuria, vitamin D-resistant rickets, various other forms of renal phosphate wasting
  • Leads to:
  • reduction in the intracellular levels of ATP,
  • interfere with normal hemoglobin-to-tissue oxygen transfer, and
  • Rhabdomyolysis
  • Treatment: Depending on the clinical situation, replacement options include dietary phosphate, oral phosphate preparations, and IV phosphate
nutritional vitamin d defficiency
NUTRITIONAL VITAMIN D DEFFICIENCY
  • Vitamin D deficiency in pediatric & geriatric populations on vegetarian diets & with ↓sunlight exposure
  • Prevention: 800-1200 units/d of vitamin D
  • Treatment: higher dosages (4000 units/d)
  •  25(OH)D No other metabolite is indicated
  • Diet should also contain adequate amounts of Ca & P
chronic renal failure
CHRONIC RENAL FAILURE
  • Major problems: loss of 1,25(OH)2D & 24,25(OH)2D production, retention of P →↓ionized Ca levels → 2ry hyperparathyroidism
  • With loss of 1,25(OH)2D production, < Ca is absorbed from intestine & < bone is resorbed under influence of PTH → hypocalcemia→ exacerbation of hyperparathyroidism
  • Bones show mixture of osteomalacia & osteitisfibrosa
  • Less commonly hypercalcemia (adynamic bone disease)
use of vitamin d preparations
Use of Vitamin D Preparations
  • Vitamin D in patients with substantial degree of renal failure cannot be converted to its active metabolites
  • Two analogs of calcitriol, doxercalciferol & paricalcitol, are approved for the treatment of 2ry hyperparathyroidism of chronic renal failure. They are less likely to induce hypercalcemia
use of vitamin d preparations1
Use of Vitamin D Preparations
  • 1,25(OH)2D3 (calcitriol) rapidly corrects hypocalcemia & at least partially reverses 2ry hyperparathyroidism & osteitisfibrosa. ↑ serum Ca in 1-2 days
  • Dihydrotachysterol, analog of 1,25(OH)2D, is equally effective. ↑Ca in 1-2 weeks
  • Neither calcitriol, nor dihydrotachysterol correct osteomalacia, & neither should be used in patients with hypercalcemia
  • Calcifediol (25[OH]D3) is < effective than calcitriol in stimulating intestinal calcium transport → < hypercalcemia
  • requires several weeks to restore normocalcemia
intestinal osteodystrophy
INTESTINAL OSTEODYSTROPHY
  • Malabsorption of Ca & vitamin D →combination of osteoporosis & osteomalacia
  • Liver disease may:
  • ↓production of 25(OH)D from vitamin D
  • Impaired secretion into bile of vitamin D metabolites & conjugates → deplete body of endogenous vitamin D & metabolites
  • In mild forms of malabsorption, vitamin D can be used. In severe disease: calcitriol & calcifediol
intestinal osteodystrophy1
INTESTINAL OSTEODYSTROPHY
  • Malabsorption of Ca & vitamin D →combination of osteoporosis & osteomalacia
  • Liver disease may:
  • ↓production of 25(OH)D from vitamin D
  • Impaired secretion into bile of vitamin D metabolites & conjugates → deplete body of endogenous vitamin D & metabolites
  • In mild forms of malabsorption, vitamin D can be used. In severe disease: calcitriol & calcifediol
osteoporosis
OSTEOPOROSIS
  • Osteoporosis is abnormal loss of bone predisposing to fractures.
  • Occurs in:
  • postmenopausal women
  • older men
  • Chronic/long term glucocorticoids therapy
  • hyperparathyroidism
  • malabsorption syndrome
postmenopausal osteoporosis
Postmenopausal osteoporosis
  • may be accompanied by ↓1,25(OH)2D levels & ↓intestinal Ca transport
  • Estrogen deficiency → best treated with cyclic doses of estrogen
  • The most rapid loss of bone occurs within the first 5 years after menopause → administration of estrogens after this time may be < effective.
  • If estrogens are discontinued, accelerated bone loss may occur → treatment with estrogens should be started shortly after onset of menopause & may need to be continued for life
slide34
Risk of endometrial carcinoma is minimized by addition of a progestin
  • Estrogen therapy may be reserved for women with ↓bone mineral content at the time of menopause or those who lose bone rapidly in the first year after it
  • Treatment may reinitiate menstrual bleeding.
  • Other complications: hypertension & thrombophlebitis
  • Small ↑risk (if it exists at all) of breast cancer is outweighed by ↓ risk of osteoporosis
slide35
Vitamin D is often employed + dietary Ca supplementation
  • In several large studies, vitamin D supplementation (400-800 IU/d) has been shown to be useful
  • Calcitriol& its analog 1α(OH)D3↑bone mass & ↓ fractures
  • Use of these agents for osteoporosis is not FDA-approved, though they are used in other countries
slide36
Fluoride: the only agent that can directly (+) bone formation →↑ bone density
  • Calcitonin is approved for use in treatment of postmenopausal osteoporosis. Reduces bone resorption
  • Bisphosphonates: Alendronate & most recently, risedronate, are approved for treatment of osteoporosis
  • Raloxifene, SERM, without adverse effects on breast or uterus, has been approved for prevention (not treatment) of osteoporosis Like estrogen, ↑bone density & ↓fractures in spine. However, ↑risk of thrombophlebitis
paget s disease of bone
PAGET\'S DISEASE OF BONE
  • This is a disease of bone that initially results in the excessiveresorption of bone (by osteoclasts) followed by the replacement of normalbone marrow with vascular and fibrous tissue.
  • Manypatients are asymptomatic and diagnosed by routine X-rays.
  • The goal of treatment: ↓ bone pain & prevent progressive deformity, hearing loss, high-output cardiac failure, & immobilization hypercalcemia
  • Calcitonin & bisphosphonates are DOC
  • Treatment failures may respond to plicamycin (highly toxic)
slide39
Calcitonin is administered intranasally, SC or IM
  • Sodium etidronate, alendronate, risedronate, & tiludronate are bisphosphonates currently approved for this condition in the USA
  • Pamidronate is used in other countries
  • Etidronate, but not pamidronate & alendronate can cause osteomalacia & ↑incidence of fractures
  • Alendronate & newer bisphosphonates cause gastric irritation when used at high doses
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