Transcript Metabolic Bone Disease 2009

Metabolic Bone Disease
Douglas Stahura DO
19 March 2002
Overview

Normal bone undergoes constant
remodeling:
– Production of organic matrix (osteoblasts)
– Matrix maturation
– Mineralization of mature matrix
– Osteoclastic resorption of mineralized bone
Overview

Metabolic bone disease refers to :
– Diffuse decrease in bone density
(osteopenia) and strength
– Due to:
– Increased bone resorption
– Decreased bone formation
Overview
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Examples
– Osteoporosis - decreased bone mass in
combination with disruption of normal
architecture
– Osteomalacia – disorder of mineralization
of newly formed matrix
– Hyperparathyroidism – chronic excess of
PTH leads to marrow fibrosis, woven
osteoid, expansion of osteoid surface,
increased collection of osteoclasts
Renal Osteodystrophy
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Spectrum of disorders that include:
– Osteitis fibrosa – increased bone turnover
– Adynamic bone disease – low turnover
– Osteomalacia – defective mineralization
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All related to disorders of:
– Mineral ions Ca++, PO4--, Mg++
– Parathyroid hormone (PTH)
– Vitamin D metabolism
Epidemiology
Sherrard,Hercz Kid Int 1993;43:43642
Clinical Features

Musculoskeletal
– Bone Pain - in advanced renal/severe bone
 Low back, hips, legs aggravated by weight
bearing
 Acute localized pain
 Periarthritis with deposition of calcium
phosphate crystals
 Gradual onset muscle weakness
 Axial bone fractures – small increase in
axial/hip fractures
Clinical Features
Pruritus – common in hemodialysis
 Metastatic calcification

– Extraskeletal – aggravated by persistently
elevated Ca x P product

Most commonly found in the arteries
Calciphylaxis
Syndrome characterized by skin necrosis that
is attributed to medial calcification of small
and medium sized arteries
Possible depression of Protein C activity
causes vessel thrombosis
Manifests as painful violaceous lesions with
peu d’orange changes, often symmetrical
with involvement of the trunk and extremities
Commonly progress to superficial ulceration,
necrosis, and infection
Calciphylaxis
Calciphylaxis
Histology
Pathogenesis of Renal
Osteodystrophy
Role of Phosphorous retention
 Role of Calcitriol replacement
 Role of parathyroidectomy

Phosphorous and Calcium
Phosphate – found
as a mineral and as
a ester
 Widely found in milk
products, meat,
eggs and cereal

Phosphorous and Calcium

Na+/Phosphate cotransport major
route of absorption
 Calcitriol stimulates
Na+/Phosphate
function
 Hyperphosphatemia
directly suppresses
calcitriol production
Phosphorous and Calcium

Kidney eliminates phosphate in amount equal
to GI absorption
 5-20% of filtered load is excreted
 In renal failure (loss of nephron mass),
ultrafiltered load goes up, Tubular
reabsorption goes down, and fractional
excretion of phosphate can reach 60-90%
until GFR falls to <25 ml/min
 Phos excretion in kidney is stimulated by
PTH, but limited by total GFR.
Vitamin D Metabolism
Phosphorous and Calcium
Ionized Ca++ level is
regulated closely
 Regulators are:

– PTH
– Calcitriol ( 1,25-
dihydroxycholecalcif
erol)
Phosphorous and Calcium

Calcitriol binds to VDR
and increases the
activity of calbindin D9k
and CA++ ATPase
 Paracellular transport is
greatly increased in the
presence of CITRATE
 Paracellular transport
not affected by
ACETATE.

In renal failure

Hyperphosphatemia due to reduced nephron
mass
– Reduces Ca concentration
– Suppresses calcitriol production directly
– Reduces the sensitivity of parathyroid to inhibition by
calcitriol

Hypocalcemia stimulates PTH
– Maintenance of Ca level with exogenous Ca does
not prevent hyperparathyroidism

Decreased responsiveness to Calcitriol
– Normal levels of calcitriol cannot suppress PTH
possibly due to downregulation of VDR receptors
– Monoclonal expansion of parathyroid cells/nodular
adenoma = tertiary hyperparathyroidism


Skeletal resistance to PTH
Chronic metabolic acidosis
Phosphorous and Calcium
Phosphorous and Calcium
Slatopolsky, Bricker Kid Int
1973;4:14
Recent Investigation
Martinez, Llach Neprol Dial
Transplant 1996,11:22-28
Recent Investigation
Calcitriol Replacement

Calcitriol therapy for advanced and endstage renal disease and iPTH> 200
pg/ml
– Calcitriol superior to Ca alone in
suppressing PTH
– Prevention of hyperparathyroidism is key to
minimizing metabolic bone disease
– Calcijex(IV), Rocaltrol(po)
Phosphate Binders

Target Ca++ level 7.5-9.5, Phos 3.0-5.0
minimize hyperphosphatemia by use of
phosphate binders
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
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CaCO3 – Tums
CaAcetate – Phoslo
Sevelemar – Renagel, Renvela
Lanthanum Carbonate - Fosrenol
Aluminum hydroxide - alternagel only for severe cases
for short term control only!
Magnesium Oxide - Magox (watch Mag level!)
– Up to 2.5 gms elemental Ca/day tolerated
Calcitriol Replacement
– Must control serum phosphate levels <6 mg/dl to
prevent metastatic calcification
– Therapeutic endpoint is iPTH between 130-195
pg/ml
– Adverse side effects are hypercalcemia,
hyperphosphatemia, possibly metastatic
calcification
– PTH <100 could set pt up for adynamic bone
disease which can also cause hypercalcemia (not
a typo- hypercalcemia).
Calcitriol Replacement

Vitamin D Analogs
– Hectorol (doxercalciferol) PO or IV
– Zemplar (paracalcitol) PO or IV
– Paracalcitol produces less hypercalcemia
or hyperphosphatemia, much more
effective than Calcitriol.
Calcimimetics

New treatment for secondary
hyperparathyroidism:
– Sensipar (30-60-90 mg pills)
– Binds to receptors for calcium in the
parathyroid cytoplasm.
– Potent suppression of PTH
– Rare hypercalcemia (but it still happens)
Parathyroidectomy

Severe Hyperparathyroidism
–
–
–
–

Tertiary (iPTH > 700)
Or refractory hypercalcemia…
Or refractory hyperphosphatemia…
Despite adequate therapy
Secondary Hyperparathyroid
– With refractory symptoms (pruritis), or
– In transplant candidate

PTX is Rare since the introduction of Zemplar
and Sensipar.
Treatment
References
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Comprehensive Clinical Nephrology, Johson 2000.
Atlas of Physiology, Despopoulos 1991.
Llach et al, Secondary Hyperparathyroidism in
Chronic Renal Failure: Pathogenic and Clinical
Aspects, AJKD;38;5,Suppl 5, s20-s33.
Clinical Physiology of Acid-Base and Electrolyte
Disorders, Rose, 2001
Harrison’s Priniples of Internal Medicine, 14th Ed
Martin et al, Vitamin D Analogs for the Management
of Secondary Hyperparathyroidism, AJKD;38:5,
Suppl 5, s34-s40.