Updated: 3/17/2018

Paget Disease of Bone

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Snapshot
  • A 65-year-old man presents with worsening left-sided hearing loss and mild headache. He reported that his symptoms began a few months prior to presentation. He denies starting any new medications but has noticed he can no longer fit the hat he has owned for many years. Physical examination is unremarkable. Laboratory testing is notable for an elevated serum alkaline phosphatase. A radiograph of the skull is shown. 
Introduction
  • Clinical definition
    • a progressive metabolic bone disorder of abnormal bone remodeling 
      • there is excessive bone resorption and formation resulting in
        • immature woven bone with collagen fibers arranged irregularly
  • Background
    • adult bone constantly undergoes bone remodeling and is accomplished by
      • osteoclasts
        • contains receptor activator for NF-κB (RANK) transmembrane receptors which
          • responds to RANK ligand (RANKL) on osteoblasts and osteocytes to differentiate and activate in order to resorb bone
      • osteocytes
        • secrete growth factors to regulate bone formation
          • bone formation is stimulated when mechanical forces are applied to bone
        • contains RANKL
      • osteoblasts
        • contain RANKL and osteoprotegerin (OPG)
          • OPG inhibits RANKL from binding to RANK on osteoclasts, thus inhibiting bone remodeling
        • functions in bone formation
    • bone matrix has two histological forms
      • woven
        • has less structural integrity
        • seen in fetal development and fracture repair
        • always considered abnormal in adults
      • lamellar
        • has more structural integrity
  • Pathogenesis
    • genetic and environmental factors may be involved
    • increased multinucleated osteoclastic and osteoblastic activity leads to a high bone remodeling rate, leading to
      • abnormal bone architecture
    • phases
      • lytic phase
        • intense osteoclastic resorption
      • mixed phase
        • resorption and compensatory bone formation
      • sclerotic phase
        • osteoblastic bone formation predominates
      • all three phases may co-exist in the same bone
  • Associated findings
    • neurologic
      • nerve root compression
      • hearing loss
      • spinal stenosis
    • orthopedic
      • pathologic fractures
      • secondary osteoarthritis
    • oncologic
      • osteosarcoma
    • cardiovascular
      • high-output heart failure
    • labs
      • normal serum phosphate, calcium, and parathyroid hormone 
      • elevated alkaline phosphatase 
    • histology
      • mosaic pattern of lamellar bone with prominent cement lines
Normal Biology and Anatomy
  • adult bone constantly undergoes bone remodeling and is accomplished by
    • osteoclasts
      • contains receptor activator for NF-κB (RANK) transmembrane receptors which
        • responds to RANK ligand (RANKL) on osteoblasts and osteocytes to differentiate and activate in order to resorb bone
    • osteocytes
      • secrete growth factors to regulate bone formation
        • bone formation is stimulated when mechanical forces are applied to bone
      • contains RANKL
    • osteoblasts
      • contain RANKL and osteoprotegerin (OPG)
        • OPG inhibits RANKL from binding to RANK on osteoclasts, thus inhibiting bone remodeling
      • functions in bone formation
  • bone matrix has two histological forms
    • woven
      • has less structural integrity
      • seen in fetal development and fracture repair
      • always considered abnormal in adults
    • lamellar
      • has more structural integrity
Laboratory Abnormalities in Select Bone Disorders
Etiology
Serum Phosphate
Serum Calcium
Serum Alkaline Phosphatase
Parathyroid Hormone
Osteomalacia/rickets 
  • Decreased
  • Decreased
  • Increased
  • Increased
Osteoporosis 
  • Normal
  • Normal
  • Normal
  • Normal
Osteopetrosis
  • Normal
  • Normal or decreased
  • Normal
  • Normal
Paget disease of bone 
  • Normal
  • Normal
  • Elevated
  • Normal
Osteitis fibrosa cystica
  • Primary
    hyperparathyroidism
    • decreased
  • Secondary
    hyperparathyroidism
    • increased
  • Primary
    hyperparathyroidism
    • increased
  • Secondary
    hyperparathyroidism
    • decreased
  • Primary and secondary hyperparathyroidism
    • increased
  • Primary and secondary hyperparathyroidism
    • increased
Hypervitaminosis D
  • Increased
  • Increased
  • Normal
  • Decreased
 
Presentation
  • Symptoms
    • usually asymptomatic
    • bone and/or joint pain
    • bone deformity
      • bowing deformity
    • hearing loss 
      • with skull involvement that lead to narrowing of the auditory foramen
  • Physical exam
    • typically unremarkable
Treatment
  • Medical
    • bisphosphonates
      • mechanism of action
        • impregnates the bone that will be acted upon by osteoclasts
          • when osteoclasts release the bisphosphonates during resorption, it impairs osteoclast activity
 

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Questions (4)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.MK.7) A 55-year-old male presents with left hip pain and stiffness. Radiographs are shown in Figures A and B. Serum alkaline phosphatase levels are elevated. A biopsy of the left femur is performed and shown in Figure C. Which of the following cells are initially responsible for this condition?

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QID: 101944
FIGURES:
1

Osteoblasts

31%

(5/16)

2

Osteoclasts

62%

(10/16)

3

Neutrophils

0%

(0/16)

4

T-Cells

0%

(0/16)

5

Fibroblasts

0%

(0/16)

M1

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