Agents that affect bone mineral homeostasis
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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

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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


Agents that affect bone mineral homeostasis

  • 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


Agents that affect bone mineral homeostasis

Some mechanisms contributing to bone mineral homeostasis.


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)


Osteomalacia osteitis fibrosa cystica

OsteomalaciaOsteitisfibrosacystica


Abnormal serum ca p levels

ABNORMAL SERUM Ca & P LEVELS


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


Agents that affect bone mineral homeostasis

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


Agents that affect bone mineral homeostasis

4. Gallium Nitrate (IV)

  • Acts by (-) bone resorption

  • Due to nephrotoxicity, patients should be well-hydrated & have good renal output before starting infusion


Agents that affect bone mineral homeostasis

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


Agents that affect bone mineral homeostasis

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


Agents that affect bone mineral homeostasis

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


Specific disorders involving the bone mineral regulating hormones

SPECIFIC DISORDERS INVOLVING THE BONE MINERAL-REGULATING HORMONES


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


Agents that affect bone mineral homeostasis

  • 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


Agents that affect bone mineral homeostasis

  • 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


Agents that affect bone mineral homeostasis

  • 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)


Paget s disease of bone1

Paget’s disease of bone


Agents that affect bone mineral homeostasis

  • 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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