• Information
  1. Definition and Mechanisms
  2. Markers of Bone Metabolism
  3. Hyperparathyroidism
  4. Rickets
  5. Osteomalacia
  6. Osteogenesis Imperfecta
  7. Renal Osteodystrophy
  8. Gout
  9. Pseudogout
  10. Hyperkyphosis
  11. Histiocytosis
  12. Imatinib Mesylate
  13. Primary Bone Tumors
  14. Conditions Discussed Separately

A. Definition and Mechanisms

1. Low Bone Mass = Osteopenia
2. Causes [4]
   1. Increased Bone Breakdown: osteoclast activation (PTH)
   2. Decreased Mineralization: Due to low Vitamin D (VitD) or to Vitamin D resistance
   3. Reduced Bone formation: usually due to low levels of sex hormones, mainly estrogens
   4. High leptin levels can inhibit bone formation [1]
3. Osteopenia and Osteoporosis [2]
   1. Reduced production of bone matrix
   2. Osteopenia usually refers to bone mass 1-2 standard deviations (SD) below norm
   3. Osteoporosis usually refers to bone mass >2 SD below norm or with fractures
   4. Osteopenic bone is particularly brittle and fractures easily
   5. Vertebral compression fractures most common
      [Figure] "Vertebrae"
4. Osteopetrosis - highly increased synthesis of bone matrix (abnormal histopathology)
5. Osteomalacia - reduced calcium incorporation into bone (various causes)
6. Bone metastases - common in many forms of cancer [3]
   1. Osteolytic - myeloma, breast cancer
   2. Osteoblastic - prostate cancer
   3. Mixed - many other cancers

B. Markers of Bone Metabolism [3]

1. Parathyroid Hormone (PTH)
   1. Normal levels immunoreactive PTH 1.1-6.8 pM
   2. Consider measurement of PTH-like hormone
2. Alkaline Phosphatase (Heat Labile)
   1. Primarily a marker of osteoblastic activity
   2. Frequently elevated in patients with Paget's Bone Disease
   3. Normal levels <120IU/mL (age adjustment required)
3. Osteocalcin (serum) - marker for bone formation
4. Collagen Degradation Products are markers for bone destruction
   1. Urinary Hydroxyproline - marker for bone destruction (usually fasting levels)
   2. Urinary Free Deoxypyridinoline (Pyrilinks-D Assay) - marker for bone destruction
   3. Collagen N-Terminal Fragment (Urine NTx Assay) - marker for bone destruction
5. Bone morphogenic protein 2 (BMP-2) stimulates bone growth (new bone formation)
6. BMP-7 (osteogenic protein 1, OP-1) also stimulates bone and cartilage growth
7. Other Relevant Chemstry Levels
   1. 25-hydroxyvitamin D normal levels: 22-125 nmol/L
   2. 1,25-dyhydroxyvitamin D (DHVD) normal levels: 36-144 pmol/L
   3. Serum Calcium Level 2.07-2.59 mmol/L (8.2-10.4 mg/dL)
   4. Urine calcium to urine creatinine ratio normal: <0.15

C. Hyperparathyroidism [5,6]

1. Types
   1. Primary: due to overactive parathyroid glands (adenoma, hyperplasia, carcinoma)
   2. Secondary: due to diseases outside of parathyroid gland (usually renal dysfunction)
2. PTH Effects
   1. Osteoclast activation leads to increased resorption within bone spicules
   2. Normal levels of PTH stimulate osteoblast formation and activation and bone remodeling
   3. PTH stimulates renal calcium resorption and dihydroxyvitamin D synthesis
3. Bone Histology: tunnelling resorption is pathognomonic
4. Grossly, occurs earliest usually in distal phalanges, diagnosis with radiograph
5. Skull Changes
6. Brown Cyst formation: hemosiderin with multinucleated giant cells

D. Rickets [7]

1. Vitamin D (Vit D) deficiency occurring prior to closure of epiphyseal plate
2. Low calcium at growth plate causes cartilage hyperplasia with wide epiphyseal plate
3. Usually due to nutrient deficiency, primarily vitamin D or less commonly, calcium
4. May be due to disroders of gut, pancreas, liver, kidney or metabolism (hereditary)
5. Hereditary Forms of Rickets
   1. Pseudovitamin D-deficiency (Type 1)
   2. Hypocalcemic vitamin D dependent Rickets (Type II)
   3. X-linked hypophosphatemic vitamin D dependent Rickets (Type III)
6. Iron deficiency and/or handling iron in the gut may also contribute
7. Short stature and weak, deformable bones

E. Osteomalacia [12]

1. Vitamin D deficiency after closure of epiphyseal plate
2. Means "soft bones" due to insufficient calcium incorporation into bones
3. Histology: wide osteoid seams
4. Radiograph shows weak, deformable bones
5. Causes of Osteomalacia
   1. Post-gastrectomy
   2. Pancreatic Disease
   3. Malabsorption: small bowel disease (celiac disease most common) [8]
   4. Dietary Insufficiency
   5. Decreased sun exposure may lead to vitamin D deficiency
   6. Paraneoplastic syndrome - rare, usually involves mesenchymal tumors
6. Note that vitamin D intoxication can cause high-turnover osteoporosis

F. Osteogenesis Imperfecta [10]

1. Brittle bone disease: autosomal dominant with variable penetrance
   1. Most cases due to mutation in one of two genes that encode collagen type 1 alpha chains
   2. These genes are COL1A1 and COL1A2
   3. Type I due to mutations only in COL1A1
   4. Types II-IV due to mutations in either gene
   5. Types V-VII due to unknown mutations
2. Classification
   1. Type I: mild, blue sclerae, hearing loss, easy bruising, mild short stature (COL1A1 only)
   2. Type II: perinatal lethal, stillborn to one year
   3. Type III: severely deforming, severe bone fragility, in utero fractures, osteoporosis
   4. Type IV: moderately deforming, usually preambulatory fractures, long bone bowing
   5. Type V: moderately deforming, short sature, disolcated radial head, white sclera
   6. Type VI: moderately to severely deforming moderate short, scoliosis, osteioid in bone tissue
   7. Type VII: moderately deforming, short humeri and fermora, white sclera
3. Brittle Bone Disease
   1. Abnormal collagen production with poor crosslinking
   2. Specific gene mutations correlate with each type of disease
   3. Disordered bone remodelling and architecture
   4. Bones thin and wispy

G. Renal Osteodystrophy (Osteitis fibrosa)

1. Dysfunction of calcium and phosphate metabolism
2. 1,25 DHVD deficiency causes failed regeneration of bone and increased PTH
3. Secondary hyperparathyroidism (increased PTH) leading to osteoclast activation
4. Renal Tubular Acidosis and/or Failure: Bone destruction due to buffering action of bone on non-excreted acids
5. Treatment: Vitamin D and Calcium (such as Nephrovit®), low phosphate diet

H. Gout

1. Uric Acid crystal deposition with inflammation
   1. Usually occurs in 1st MTP joint but can occur anywhere
   2. Soft tissue infections may mimic cellulitis
2. Typically in men >40 years old
3. Soft tissue lumps, non-symmetrical ("tophus")
4. Treatment for tophi requires allopurinol or uricosuric agent

I. Pseudogout

1. Also called Calcium Pyrophosphate Deposition Disease (CPPD)
2. Crystals of CPP Dihydrate
3. More common in elderly persons and in larger joints than gout
4. Associated with chondrocalcinosis
5. Increased incidence in disorders of bone mineral metabolism

J. Hyperkyphosis [9]

1. Normal Spine
   1. Normally has 3 curves in sagittal plane
   2. Cervical lordosis (anteriorly convex): normal angles 20-40°
   3. Thoracic kyphosis (anteriorly concave)
   4. Lumbar lordosis (anteriorly convex)
2. Hyperkyphosis is usually >50° angle
3. Prevalence among older adults ~30%
4. Thought to be due to vertebral fractures, but these present in <40% of hyperkyphosis
5. May be associated with increased risk of adverse health outcomes
6. Impaired pulmonary function, reduced physical acitvity, future fractures
7. Unclear treatments

K. Histiocytosis [11]

1. Classic Forms of Histiocytosis
   1. Eosinophilic granuloma - confined to bone, usually in children
   2. Hand-Schuler-Christian Syndrome - more systemic form, usually in children
   3. Letterer-Siwe Syndrome - multiple bone lesions, fulminant reticuloendothelial invovlement
   4. Non-Langerhans' cell disease (lipogranulomatosis, Erdheim-Chester Disease)
2. Variable Clinical Syndrome
   1. Lethal leukemic disorder
   2. Multifocal local lesions
   3. Solitary lytic lesion of bone
   4. Congenital histiocytosis

L. Imatinib Mesylate (Gleevec®) [13]

1. Unusual cause of hypophosphatemia
2. Inhibits c-kit, BCR-abl, and PDGFa/b protein tyrosine kinases
3. Low or normal 1,25 VitD3 with elevated PTH levels
4. Blocks bone remodeling (likely both formation and resorption)

M. Primary Bone Tumors

1. Benign
   1. Osteoid Osteoma
   2. Osteochondroma
   3. Enchondroma
2. Malignant
   1. Osteosarcoma
   2. Chondrosarcoma
   3. Giant Cell Tumor
   4. Ewing's Sarcoma

N. Conditions Discussed Separately (see specific cards)

1. Degenerative Joint Disease
2. Infection of bone
3. Paget's Disease - high turnover bone
4. Other Hereditary Conditions
5. Myeloma

References

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2. Weinstein RS and Manolagas SC. 2000. Am J Med. 108(2):153
3. Roodman GD. 2004. NEJM. 350(16):1655
4. Seeman E and Delmas PD. 2006. NEJM. 354(21):2250
5. Mark SJ. 2000. NEJM. 343(25):1863
6. Bilezikian JP and Silverberg Shonni. 2004. NEJM. 350(17):1746
7. Wharton B and Bishop N. 2003. Lancet. 362(9393):1389
8. Basha B, Rao S, Han ZH, et al. 2000. Am J Med. 108(4):296
9. Kado DM, Prenovost K, Crandall C. 2007. Ann Intern Med. 147(5):330
10. Rauch F and Glorieux FH. 2004. Lancet. 363(9418):1377
11. Vassallo R, Ryu JH, Colby TV, et al. 2000. NEJM. 342(26):1969
12. Jan de Beur SM. 2005. JAMA. 294(10):1260
13. Berman E, Nicolaides M, Maki RG, et al. 2006. NEJM. 354(19):2006