Metabolic Bone Disease

Metabolic Bone DiseaseMetabolic Bone Disease

Douglas Stahura DO

19 March 2002

OverviewOverview

Normal bone undergoes constant remodeling:– Production of organic matrix (osteoblasts)– Matrix maturation– Mineralization of mature matrix– Osteoclastic resorption of mineralized bone

OverviewOverview

Metabolic bone disease refers to :– Diffuse decrease in bone density

(osteopenia) and strength– Due to:

– Increased bone resorption– Decreased bone formation

OverviewOverviewExamples

– 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 OsteodystrophyRenal Osteodystrophy

Spectrum of disorders that include:– Osteitis fibrosa – increased bone turnover– Adynamic bone disease – low turnover– Osteomalacia – defective mineralization

All related to disorders of:– Mineral ions Ca++, PO4

--, Mg++

– Parathyroid hormone (PTH)– Vitamin D metabolism

Sherrard,Hercz Kid Int 1993;43:436-42

EpidemiologyEpidemiology

Clinical FeaturesClinical 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 FeaturesClinical Features

Pruritus – common in hemodialysisMetastatic calcification

– Extraskeletal – aggravated by persistently elevated Ca x P product

Most commonly found in the arteries

CalciphylaxisCalciphylaxisSyndrome 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

CalciphylaxisCalciphylaxis

Calciphylaxis Calciphylaxis HistologyHistology

Pathogenesis of Renal Pathogenesis of Renal OsteodystrophyOsteodystrophy

Role of Phosphorous retentionRole of Calcitriol replacementRole of parathyroidectomy

Phosphorous and CalciumPhosphorous and Calcium

Phosphate – found as a mineral and as a ester

Widely found in milk products, meat, eggs and cereal


Na+/Phosphate co-transport major route of absorption

Calcitriol stimulates Na+/Phosphate function

Hyperphosphatemia directly suppresses calcitriol production


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 MetabolismVitamin D Metabolism


Ionized Ca++ level is regulated closely

Regulators are:– PTH– Calcitriol ( 1,25-

dihydroxycholecalciferol)


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


Slatopolsky, Bricker Kid Int 1973;4:14


Martinez, Llach Neprol Dial Transplant 1996,11:22-28

Recent InvestigationRecent Investigation

Recent InvestigationRecent Investigation

Calcitriol ReplacementCalcitriol Replacement

Calcitriol therapy for advanced and end-stage 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 BindersPhosphate Binders

Target Ca++ level 7.5-9.5, Phos 3.0-5.0minimize hyperphosphatemia by use of phosphate binders

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


– 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).


Vitamin D Analogs– Hectorol (doxercalciferol) PO or IV– Zemplar (paracalcitol) PO or IV– Paracalcitol produces less hypercalcemia

or hyperphosphatemia, much more effective than Calcitriol.

CalcimimeticsCalcimimetics

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)

ParathyroidectomyParathyroidectomy

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.

TreatmentTreatment

ReferencesReferences

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.

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Metabolic Bone Disease