Transcript Bone - BMC Dentists 2011

Agents That Affect
Bone Mineral
Homeostasis
Functions of the bone:
1.
Principal structural support for the body
2.
Ca and PO4 reservoir
3.
Space for hematopoesis
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Two hormones serve as principal
regulators of Ca & P homeostasis:
parathyroid hormone (PTH) & vitamin D
(active metabolite)
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Certain of secondary regulators—
calcitonin, glucocorticoids & estrogens—are
useful therapeutically
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Some mechanisms contributing to bone mineral
homeostasis.
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Actions of PTH & vitamin D on gut, bone, & kidney.
PTH
Vitamin D
Intestine
↑ Ca & P absorption (by ↑ ↑ Ca & P absorption by
1,25 [OH]2D
1,25(OH)2D
production)
Kidney
↓ Ca excretion, ↑ P
excretion
Ca & P excretion may be ↓ by
25(OH)D & 1,25(OH)2D
Bone
Ca & P resorption ↑ by
high doses. Low doses
may ↑ bone formation
↑ Ca & P resorption by
1,25(OH)2D; bone
formation may be ↑ by
24,25(OH)2D
Net effect
Serum Ca↑, serum P ↓
on serum
levels
Serum Ca & P both ↑
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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)
 osteitis fibrosa (excessive bone resorption with
fibrotic replacement of resorption cavities)
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Osteomalacia
Osteitis fibrosa cystica
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ABNORMAL SERUM Ca & P
LEVELS
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HYPERCALCEMIA
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Hypercalcemia causes 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)
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Ca X PO4 must be < 55 mg2/dL2 in order to prevent
ectopic calcification in soft vital tissues
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Treatment of hypercalcemia
1. Saline Diuresis
500-1000 mL/h of saline to reverse dehydration &
restore urine flow + loop diuretic to ↑urine flow but
also ↓Ca reabsorption in ascending limb of loop of
Henle
2. If more prolonged treatment of hypercalcemia is
required:
1. Bisphosphonates
Etidronate in saline IV for 3 days. Pamidronate
appears to be more effective
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Bisphosphonates
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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
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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)
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(2) In kidney: Reduces Ca and PO4 reabsorption
Useful for the treament of Paget’s disease,
Hypercalcemia and osteoporossis
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4. Gallium Nitrate (IV)
 Acts by (-) bone resorption
 Due to nephrotoxicity, patients should be wellhydrated & have good renal output before
starting infusion
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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
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7. Glucocorticoids:
 Glucocorticoid hormones alter bone mineral
homeostasis by: 1. antagonizing vitamin Dstimulated intestinal calcium transport, 2. by
stimulating renal calcium excretion, and by 3.
blocking bone formation
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no clear role in acute treatment of hypercalcemia.
However, chronic hypercalcemia may respond within
several days to glucocorticoid therapy
Prednisone (30-60 mg/day)
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HYPOCALCEMIA
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Main features (neuromsucular): tetany, paresthesias,
laryngospasm, muscle cramps, & convulsions
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Major causes in adult: hypoparathyroidism, vitamin
D deficiency, chronic kidney disease & malabsorption,
infusions of citrated blood
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Neonatal hypocalcemia usually resolves without
therapy
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Treatment: Ca & vitamin D (or its metabolites)
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Treatment of Hypocalcemia
1. Calcium:
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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:
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Severe symptomatic hypocalcemia: slow infusion of 5-20 mL of 10% Ca
gluconate. Avoid rapid infusion (cardiac arrhythmias)
Less severe cases: oral Ca (carbonate to provide 400-1200mg of elemental
Ca
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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
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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)
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Diet Management of
hyperphosphatemia
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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
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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.
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Hypophosphatemia
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Causes: e.g. hyperparathyroidism, vitamin D deficiency,
idiopathic hypercalciuria, vitamin D-resistant rickets, various
other forms of renal phosphate wasting
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Leads to:
reduction in the intracellular levels of ATP,
interfere with normal hemoglobin-to-tissue oxygen transfer,
and
Rhabdomyolysis
1.
2.
3.
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Treatment: Depending on the clinical situation, replacement
options include dietary phosphate, oral phosphate
preparations, and IV phosphate
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SPECIFIC DISORDERS
INVOLVING THE BONE
MINERAL-REGULATING
HORMONES
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NUTRITIONAL VITAMIN D
DEFFICIENCY
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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
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CHRONIC RENAL FAILURE
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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 & osteitis fibrosa
Less commonly hypercalcemia (adynamic bone
disease)
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Use of Vitamin D Preparations
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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
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Use of Vitamin D Preparations
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1,25(OH)2D3 (calcitriol) rapidly corrects hypocalcemia
& at least partially reverses 2ry hyperparathyroidism &
osteitis fibrosa. ↑ 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
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INTESTINAL
OSTEODYSTROPHY
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1.
2.
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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
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INTESTINAL
OSTEODYSTROPHY
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1.
2.
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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
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OSTEOPOROSIS
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Osteoporosis is abnormal loss of bone
predisposing to fractures.
Occurs in:
postmenopausal women
older men
Chronic/long term glucocorticoids therapy
hyperparathyroidism
malabsorption syndrome
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Postmenopausal osteoporosis
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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
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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
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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
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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
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PAGET'S DISEASE OF BONE
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This is a disease of bone that initially results in the
excessive resorption of bone (by osteoclasts) followed by
the replacement of normal bone marrow with vascular
and fibrous tissue.
Many patients 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)
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Paget’s disease of bone
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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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