JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
March 2022
M-M16

 

Signalment (JPC# 2314364):  Dog

 

HISTORY:  This dog had hyperadrenocorticism.

 

HISTOPATHOLOGIC DESCRIPTION:  Bone, rib:  Diffusely both cortical and trabecular bone are markedly reduced in density and thinned (osteopenia), and remaining trabeculae are frequently irregular, scalloped, fragmented (microfractures), and lined by few osteoblasts.  Focally, there is medullary hemorrhage, fibrin, and edema surrounding trabecular microfractures.  At the level of the costochondral junction and within the chondrous rib there are multiple, small, well-demarcated foci with loss of differential staining and normal cartilage architecture or loss with replacement by hypereosinophilic, vacuolated matrix (cartilage degeneration and necrosis).

 

MORPHOLOGIC DIAGNOSIS:  Bone, rib:  Osteopenia, cortical and medullary, diffuse, marked, with trabecular microfractures and rare multifocal chondronecrosis, breed not specified, canine.

 

ETIOLOGY:  Glucocorticoid-induced osteoporosis

 

CONDITION:  Osteoporosis

 

GENERAL DISCUSSION:

• Osteopenia: reduction in bone mass (volume and external dimensions may be unchanged) with increased porosity, but normal mineralization; often associated with increased radiolucency, but does not necessarily suggest changes in bone quality
  • It includes osteoporosis (decreased bone quantity with normal quality) as well as osteomalacia, fibrous osteodystrophy, and osteogenesis imperfecta (concurrent decreased bone quality and quantity)
• Osteoporosis describes a state of bone, not a specific disease
• Osteoporosis occurs in already mineralized bone (mature animals)
• Rickets and osteomalacia represent a defect in bone mineralization with subsequent endochondral ossification
• Considered a part of the normal aging process, however many disease states can accelerate bone loss/increase resorption

 

PATHOGENESIS:

Causes of osteoporosis:

• Endocrine disturbances:
  • Hyperadrenocorticism: Most common cause of generalized osteopenia in dogs; glucocorticoids inhibit collagen synthesis and osteoblastic differentiation, while prolonging osteoclast lifespan and stimulating osteoclastic bone resorption; inhibit intestinal calcium absorption via antagonistic effects on vitamin D, and they increase urinary calcium excretion (serum calcium normal)
    • Glucocorticoids à ↑ expression of caspase 3 à increases osteoblast and osteocyte apoptosis à disruption of bone mechanosensory functionality à decreased bone strength
    • Glucocorticoids à diversion of osteoprogenitor cells to the adipocyte line à decrease in formation of mature osteoblasts
  • Hyperthyroidism: Bone changes may be secondary to negative metabolic balance; excess thyroxine reported to stimulate bone resorption
  • Sex hormone deficiency: Estrogen and androgens stimulate osteoblastic activity and formation of bone on endosteal surfaces of cortical bone, but indirectly inhibit production of IL-1 (promotes osteoclast bone resorption); sex hormone deficiency (e.g. during menopause) results in increased osteoclast activity by increasing IL-1 à increases IL-6 (potent stimulator of osteoclast activity) and RANKL, diminishes expression of the soluble decoy receptor osteoprotegerin (OPG) à eventual decreased bone mass
  • Receptor-activator of NF-κB, its ligand RANKL, and OPG are the key regulators of osteoclast differentiation and bone remodeling
• Disuse: Due to Wolff’s law; e.g. fracture plating, paralysis, prolonged immobilization, confinement; affects load-bearing bones
• Nutritional Disturbances:
  • Hypoproteinemia: Protein deficiency, starvation, parasitism, malabsorption; bone formation is decreased due to decreased IGF-1 and estrogen and increased PPARγ (causes osteoprogenitor cells to convert to adipocytes instead of to osteoblasts); marrow adipocytes are eventually lost and replaced with hyaluronic acid-rich fluid (i.e. serous atrophy of fat)
    • Lambs with Trichostrongylus columbriformis and Ostertagia circumcincta have developed osteoporosis
  • Vitamin C deficiency (M-M07): Humans, non-human primates, guinea pigs, some birds and fish; impaired production of matrix (collagen and intercellular substance)
  • Copper deficiency: Occurs in lambs and calves, often with molybdenum toxicosis; reduced osteoblastic activity with decreased osteoid formation (lysyl oxidase which cross-links collagen and elastic fibers requires copper)
  • Calcium deficiency: Caused by increased bone resorption; most common cause of osteoporosis in sheep and cattle; secondary to excess dietary oxalates (oxalates chelate calcium in rumen, and mineral cannot be absorbed); uncomplicated calcium deficiency rarely if ever occurs with normal dietary phosphorus and vitamin D levels
  • Low calcium, high phosphorus diets: Lead to osteoporosis or fibrous osteodystrophy
  • Phosphorous deficiency: Classically produces osteomalacia in adults, and

rickets in growing animals; may cause osteoporosis

• Hypervitaminosis A: Osteoporosis in pigs, cattle, rats; premature closure of epiphyseal plate (retarded growth)
• Can be a normal part of aging process (i.e. senile) but seldom results in clinical signs in animals
• Inflammatory states may promote bone loss: Production of TNF-α, IL-1, and IL-6
  • Inhibit osteoblastic maturation via inhibition of Runx2, the Wnt-frizzled pathway, and BMPs
  • Stimulate osteoclastogenesis via activation of the NF-kB, MAPK, and JAK-STAT pathways (in addition to IL-17 elaboration which stimulates RANKL)

 

TYPICAL CLINICAL FINDINGS:

• Fractures without excessive trauma or pain
• Decreased radiographic density (must lose 30-50% of density to be detected radiographically)

 

TYPICAL GROSS FINDINGS:

• Primarily affects portions of bones with large component of cancellous tissue,

e.g. vertebral bodies, flat bones (scapula, ilium), and the metaphyses of long bones

• Bones are light and brittle with a thin cortex and large medullary cavity (decreased amount & increased porosity of cancellous bone)
• Epiphyseal compression, articular collapse, distortion and fracture of growth

plates

• Formation of transverse reinforcement lines or bone bars (thick trabeculae extending horizontally across the medullary cavity visible grossly) within metaphysis or diaphysis
• Growth arrest lines arise secondarily from episodes of malnutrition or starvation, which differ from reinforcement lines and are radiographically apparent
• Depending on cause, gelatinous serous atrophy of fat may be evident

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Trabeculae are reduced in number and/or size (often thin, fractured and

discontinuous); the medullary cavity is enlarged

• Depending on cause there may be increased osteoclastic and decreased osteoblastic activity
• Cortical bone is resorbed most rapidly from the endosteal surface and along vascular channels (cutting cones); the cortex is often thin and porous
• In young severely osteoporotic young animals the hypertrophic zone of the growth plate may be narrowed or absent and when growth ceases, the physis is sealed by a plate of bone

 

DIFFERENTIAL DIAGNOSIS:

• Osteomalacia: Defective mineralization causing excess unmineralized osteoid on

trabecular surfaces of adult bones; deficient phosphorus or vitamin D; thin cortex; thin, not brittle bone

• Rickets (M-M08): Inadequate mineralization of developing cartilaginous and osseous matrix; thickened, irregular epiphyseal plates; results in osteomalacia of growing skeleton; involves bone and cartilage; soft, not brittle, bones
• Fibrous osteodystrophy (M-M10): Extensive osteoclastic resorption of bone, with

replacement by fibrous connective tissue

 

COMPARATIVE PATHOLOGY:

• Sheep: infections with Trichostrongylus colubriformis and Teladorsagia circumcincta have been shown to produce osteoporosis
• Animal models:
  • Resorption dominant model: Ovariectomized sheep        
  • Formation deficit models: Senile rats, senescence accelerated mice (SAM), glucocorticoid administration
• Pigs: Lactational osteoporosis in gilts fed diets marginally deficient in calcium with normal or high phosphorous over extended periods during gestation/lactation
• Racehorses: Transient periods of focal osteoporosis can result from excessive repetitive, high impact training and racing that exceed bone repair capabilities; can precede catastrophic fractures
• Laying hens (cage layer fatigue): In addition to brittle bones, the sternum is often infolded at the costochondral junctions; caused by a dietary vitamin D, calcium, or phosphorous deficiency, or an imbalance in the Ca:P
• Nonhuman primates: Cortical bone loss more prominent (as opposed to predominantly axial trabecular bone involvement in humans); osteoporosis in aged NHPs attributed to subclinical vitamin D deficiency (inducing secondary hyperparathyroidism), and decreased bone storage of insulin-like growth factor-1 (IGF-1) and transforming growth factor-β (TGF- β) (uncouples bone resorption and formation processes)
• Wildlife:
  • Mountain sheep: Described in skulls; suggested etiologies include Cu or Mg deficiency and increased Ca demand secondary to pregnancy/lactation
  • Asian yak, water buffalo: Osteoporotic lesions most prominent in mandible, scapulae, sacrum, ilium, and ribs; associated with low dietary phosphorus in Asian yak and known colloquially as “Stiffness of the extremities disease”
  • Bottlenose dolphins: Osteoporotic lesions in the ribs associated with elevated liver cadmium levels

 

REFERENCES:

1. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie G, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016: 30, 63-67.
2. Crespo R, Franca MS, Fenton H, et al. Galliformes and Columbiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London: Elsevier/Academic Press; 2018:748.
3. El Khassawna T, Merboth F, Malhan D, et al. Osteocyte regulation of receptor activator of NF-kappa B ligand/osteoprotegerin in a sheep model of osteoporosis. Am J Pathol. 2017:187(8);1686-1699.
4. Jones MEB, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London: Elsevier/Academic Press; 2018:119.
5. Olson EJ, Carlson, CS. Bones, joints, tendons and ligaments. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. Louis: MO Elsevier; 2017: 980-981.
6. Pritzker KPH, Kessler MJ. Arthritis, muscle, adipose tissue, and bone diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. 2nd ed. Waltham, MA: Elsevier; 2012: 667-670.
7. Schmidt RE, Reavill DR, Phalen DN. Musculoskeletal system. In: Schmidt RE, Reavill DR, Phalen DN, ed. Pathology of Pet and Aviary Birds. 2^nd Ames, IA: Wiley Blackwell; 2015:208.
8. Shrivaprasad HL. Miscellaneous diseases.  In: Boulianne M., ed. Avian Disease Manual. 8th ed. Jacksonville, FL: American Association of Avian Pathologists; 2019:170-1.
9. Leger J, Raverty S, Mena A. Cetacea. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London: Elsevier/Academic Press; 2018:540.
10. Stover SM. Nomenclature, classification, and documentation of catastrophic fractures and associated preexisting injuries in racehorses. J Vet Diagn Invest. 2017;29(4):396-404.
11. Weitzmann MN. Bone and Immune System. Tox Pathol. 2017; 45(7):911-925.

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