Metabolic Bone Disease

Introduction

Skeletal Turnover – 10% of your skeleton remodels every day

Metabolic turnover – spongy bone 3x> compact bone

Regional variations of cortical and trabecular bone: trabecullar (Heel, hip); cortical (Lumbar spine, midshaft of long bones)

Clinical measurements used in bone pathology:

Serum Calcium (Ca) Þ involved in bone mineralization, more than 99% stored in skeleton (normal – 8.5-10.5 mg/dl)

Phosphorus (P) Þ also involved in bone mineralization (normal – 3.0-4.5 mg/dl)

Mg Þ measured when Ca levels are unexplainably high

Parathormone (PTH) Þ induces mobilization of Ca and P from bone (specifically acts on osteoBLAST receptors), activates renal a ₁ – hydroxylase increasing the amount of active Vitamin D and Ca absorption, Ý excretion of P (therefore serum levels will be ß with PTH excretion)

1,25 (OH) Vitamin DÞ the most potent form of the steroid hormone Vitamin D, stimulates intestinal absorption of Ca and P, works in conjunction with PTH in maintaining normal serum Ca and P levels

Alkaline Phosphatase Þ enzyme cleaves PO₄^- available for mineralization, indicative of abnormally high bone formation

Osteocalcin Þ Non-collagenous protein in bone matrix (osteoblast specific therefore a measure of bone formation)

Bone Intoxications:

Tetracycline Þ detrimental to developing fetus

Aluminum Þ seen in dialysis patients, interferes with osteoblastic mineralization (osteomalacia). Also in antacids Al(OH)₃ which can bind to phosphorus causing malabsorption.

Corticosteroid Þ ß bone formation, Ý bone absorption

Chemotherapy Þ osteoblastic interference (seen in transplant patients)

Fourides Þ causes flourosis (Ý osteoblastic activity Þ can cause thickened spinal vertebrae Þ compression of nerve)

Vitamin A Þ hypercalcemia

Vitamin D Þ hypoparathyroidism (causes low Ca, Ý P) Þ hypercalcemia can result

Radionucleotides

Osteitis Fibrosa Cystica (Hyperparathyroidism) – excessive Parathormone (PTH) production

Primary Hyperparathyroidism

Etiology: The parathyroid gland itself is overproducing PTH (usually because of solitary adenoma of hyperplasia of all 4 glands)

Pathology: increased osteoclastic absorption of calcified bone (Ý osteoclasts) with replacement by fibrous tissue (Ý fibroblasts).

a spectrum ranging from osteomalacia (demineralization with excess osteoid) to severe osteitis fibrosa cystica (large cysts)
"Brown tumors" – the most severe end of the spectrum – represents an area of complete absorption, fibrovascular proliferation with hemorrhaging resulting in hemosiderin pigments. Osteoclast WINS!!

Clinical Manifestations: kidney stones, bone pain and fractures. Abdominal pain, constipation, etc.

X-ray: sub-periosteal erosion and resorbtion, cysts (osteoclastomas), demineralization, "salt and pepper" lysis of skull

Serum Chemistry: Ca-Ý , P-ß (due to actions of PTH), Alk Phos-Ý (indicative of high bone turnover)

Treatment: Surgical removal of tissue (parathyroidectomy)

Secondary hyperparathyroidism

Etiology: chronic parathyoid actvity resulting from an underlying pathological state which causes hypocalcemia. Pathological states include:

Intestinal malabsorption of Ca or Vitamin D

Resistance of bone to resorptive action of PTH

Renal loss of Ca

Excess Phosphate retention in renal failure (Ý P activates parathyroid gland directly)

Resistance to and decrease in formation of Vitamin D

Last three causes are due to renal failure which is the most common cause of secondary hyperparathyroidism

Pathology: predominant osteomalacia but can have a mixture of fibroma cystica along with osteomalacia

Serum Chemistry: Ca-ß , P-Ý (Ca loss and P retention due to renal failure-GFR<25ml/min) Alk Phos-Ý

Treatment: Vitamin D (only when Ca x P product is <65; use of Vit D in osteitis when Ca x P >65 results in hypercalcemia and metastatic calcification because Vit D resistance. refer to figure 1), reduce serum Phosphorus, parathyroidectomy.

Tertiary hyperparthyroidism

Etiology: Severe irreversible secondary hyperparathyroidism. A state of overcompensation by the parathyroid gland following a long period of secondary hyperparathyroidism. Seen in malabsorption states or end stage renal failure (GFR<20, Ca x P>65) figure 1

Pathology: Chief cell hyperplasia of all four glands, can have metastatic calcification of soft tissue due to elevated Ca

Serum Chemistry: Ca-Ý (elevated in response to PTH), P-Ý (elevated due to renal failure), Alk Phos-Ý Ý

(note:serum levels are for renal failure only, in malabsorption states the P would be decreased)

Treatment: Parathyroidectomy prior to renal homotransplantation

Osteomalacia and Rickets – deficient mineralization

Osteomalacia

Etiology: Failure of normal calcification of formed osteoid due to:

Vitamin D deficiency, resistance, or abnormal metabolism resulting in Ca deficiency (deficient diet, lack of sunlight, malabsorption deficient receptor for Vit D absorption, dilantin and phenobarbital (epileptic drugs), renal and liver disease, etc.)
Hypophosphatemia (diet, malabsorption due to antacids Al(OH)₃, Familial Hypophosphatemic Rickets (x-linked Phos transport deficency)
Acidosis (acetazolamide (CA inhibitor), renal acidosis,etc.)
Inhibition of Mineralization (diphosphonates, flouride, uremia, Al)

Pathology: Mineralization of cartilage serves as a guideline for vascular invasion, protects ingrowing capillaries and acts as a scaffold for bone deposition. With no mineralizatoin, no resorption, Chondrocytes DON’T DIE. Ý in uncalcified osteoid (nonmineralized matrix) on surfaces of bony trabeculae Þ large growth plates. Bone can’t form. ß mineral:matrix ratio Þ "soft bone".

Clinical Manifestation: Pain of weight bearing bones

X-ray: pseudofractures (Looser’s line), increased or decreased density

Serum Chemistry: Ca-ß , P-ß , Alk Phos-Ý

Treatment: Vitamin D, Oral P, eliminate cause

Rickets

Etiology: Same as osteomalacia

Pathology: failure of both cartilage and osteoid mineralization

Clinical Manifestations: Rachitic Rosary (beading of costochondral joints because of uncontrolled intramembranous bone formation), Harrison’s groove (depression along rib-diaphragm attachment), chicken breast appearance, curvature of long bones.

X-ray, Treatment: same as above

Osteoporosis – Reduced bone formation

Etiology: -reduced bone formation (deficient protein, vitamin D, insulin, Ca, Ý corticosteroids, mechanical stress)

accelerated bone resorption (deficiency of androgens, estrogens (closes epiphysis), Ý corticosteroids, Ý PTH, heparin, acid diet, ß mechanical stress)

Post-menopausal, Senile, idiopathic osteoporosis Þ unknown etiology

Pathology: reduction of cortical and trabecular bone mass making the bone very fragile, Normal mineral:matrix ratio, less bone per unit volume, NO osteoblast or osteoclast activity

Clinical Manifestations: Fractures of vertebrae, wrists, ribs, hips, pelvis, humeri (brittle bones)

X-ray: generalized demineralization – appearing first in trabecular and later in cortical bone

Serum Chemistry: Ca, P, Alk Phos Þ normal

Treatment: Prevention: exercise, diet (Ca+intake, Vitamin D),

Estrogen Replacement therapy, testosterone replacement therapy, Testosterone cypionate (Depo-Testosterone), Calcitonin, Bisphophonates (structural analog to naturally occurring pyrophosphates (P-O-P) which normally inhibit calcification unless hydrolyzed by alkaline phosphatase) Þ inhibits either bone resorption or both mineralization and resorption.

alendron (Fosamax) Þ helps with trabecullar bone NOT cortical

Flourides – increase in trabecular bone spine mass

Glucocorticoid Osteoporosis

Etiology: Doctor induced from physician prescription of corticosteroids (typically prednisone>30 mg/day for rheumatic disease)

Pathology: Major loss in trabecular bone

Treatment: Ca, Vit D, estrogen and testosterone replacement, Bisphosphoatse (alendronate), Calcitonin

Paget’s disease (Osteitis deformans) – rapid resorption replaced with dense disorganized bone

Etiology: Unknown. BUT probably a slow virus infection (RNA paramyxovirus Þ measles, parainfluenza (3), Simian virus (5). Therefore NOT a metabolic bone disease

Pathology: Spectrum of soft, porotic bone to ivory hard, dense bone. Initial active osteoclastic activity and vascular fibrosis filling marrow spaces Þ mixed osteolytic-osteoblastic stage: osteoclastic activity with appositional growth (Rapid bone turnover like hyperparathyroidism except end-stage is different) Þ Quiscent ostesclerotic phase: Ý bone formation, thick brittle bone with marrow spaces filled with highly vascularized connective tissue

So: Ý osteoclasts; Ý osteoblasts; Ý fibroblasts; Ý vascularity

Clinical Manifestations: mosaic pattern: enlarged head, deafness (due to nerve compression by overgrown spine), heat over involved bones (due to vascularity). Pain and deformityin legs, lower back, hips, knees. Complications: Fractures, arthritis, heart failure (due toarteriovenous shunts), sarcoma.

X-ray: thickening of cortical bone, disorganized trabecular patter giving fluffy appearance, osteoporosis, circuscripta of skull or lytic areas early in the disease process

Serum Chemistry: Ca-Norm, P-Norm, Alk Phos-Ý Ý (degree of elevation correlates with activity of disease (osteoblastic)

Treatment: Necessary in <30% of patients

Bisphosphonates (EHDP, alendronate, etc.) Þ interferes with bone healing

Calcitonin Þ does NOT interfere with the healing of fractures in Pagetic bone