JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
March 2022
M-M09 (NP)

Signalment (JPC #1171672):  11-month-old female black spider monkey (Ateles fusciceps robustus)

 

HISTORY:  This monkey had a misshapen skull and long bones.

 

SLIDE A: HISTOPATHOLOGIC DESCRIPTION: Tooth with alveolar bone, mandible (per contributor):  Cortical bone is thinned or absent and there is diffuse paucity of alveolar and mandibular medullary bony trabeculae (osteopenia).  Remaining trabeculae are thin, irregular, predominantly composed of woven bone, and are lined by rare osteoblasts and increased numbers of osteoclasts within Howship’s lacunae (active resorption) with distinct basophilic resting and reversal lines. Osteoclasts are also free within the medullary fibrous stroma. Trabeculae are surrounded and widely separated by haphazardly arranged spindle cells (fibroblasts) admixed with dense, well-vascularized fibrous connective tissue that replaces normal hematopoietic elements and adipose tissue and extends to the adjacent periosteal surface. 

 

SLIDE B: HISTOPATHOLOGIC DESCRIPTION:  Long bone:  Diffusely, cortical bone and metaphyseal and diaphyseal medullary cancellous bone are thin to absent and are widely separated by increased amounts of loose fibrous connective tissue and fibroblasts that multifocally replace medullary adipocytes and hematopoietic cells.  Multifocally, there are variably sized clusters of osteoclasts within Howship's lacunae (bone resorption). Focally, the physis is expanded up to twice normal by a thickened zone of hypertrophy.  Small blood vessels in this area form irregular channels into the cartilaginous matrix. There are retained fragmented cores of cartilage in the primary spongiosa, which are often surrounded by variable amounts of homogeneous eosinophilic matrix (osteoid).  There is an overall decrease in the number of osteoblasts. Within the epiphyseal growth plate, there are additional areas of retained unmineralized cartilage.  There is a focal 1 x 1.5 mm diameter subchondral cyst in the epiphysis. 

 

MORPHOLOGIC DIAGNOSIS:  Bones, alveolar and mandibular, and long bone: Fibrous osteodystrophy, diffuse, marked, with focal physeal osteochondrodysplasia (rachitic), black spider monkey (Ateles fusciceps robustus), nonhuman primate.

 

ETIOLOGIC DIAGNOSIS:  Nutritional secondary hyperparathyroidism

 

CAUSE:  Dietary vitamin D3 deficiency and/or dietary calcium/phosphorus imbalance

 

SYNONYMS:  Simian bone disease; cage paralysis

 

GENERAL DISCUSSION:

• Simian bone disease is a historic disease from laboratory and zoo settings, and remains an infrequent problem in pet monkeys
• Fibrous osteodystrophy (FOD) in non-human primates is a form of nutritional hyperparathyroidism; in New World primates it has historically been associated with commercial diets containing vitamin D2 as the sole source of vitamin D (i.e. deficient in vitamin D3); also reported in apes and young Old World primates housed indoors in absence of full spectrum sunlight
• FOD in general is characterized by extensive bone resorption, fibrous tissue proliferation, and poorly mineralized immature bone; most often occurs in response to primary or secondary hyperparathryroidism (see also M-M10)
• FOD also occurs more often in horses, pigs, dogs and cats, ferrets, and reptiles; rarely occurs in goats; there is unsubstantiated evidence of the disease occurring in sheep and cattle
• Rickets (M-M08) is a disease of young growing animals in which there is inadequate mineralization of the developing cartilaginous and osseous matrix; the disease is caused by deficiencies of vitamin D or phosphorous; fibrous osteodystrophy results in animals affected with Rickets when there is concurrent low calcium levels (due to decreased absorption)
• Secondary hyperparathyroidism associated with marmoset wasting syndrome (malabsorption due to inflammatory gastrointestinal disease) has been reported in a group of common marmosets with bone lesions (FOD, rickets, and osteopenia)

 

PATHOGENESIS:

• FOD in general: The common denominator is the stimulation of excess parathyroid hormone (PTH) production caused by low plasma ionized calcium levels, due to several different potential dietary imbalances: 1) low calcium diet; 2) excessive phosphorous with normal or low calcium; or 3) inadequate amounts of vitamin D3
  • Elevated plasma phosphorus levels depress calcium levels and may also stimulate the release of PTH
• In the classic disease of New World primates, dietary vitamin D3 is required to prevent hypocalcemia; a dietary deficiency in vitamin D3, even in the presence of a normal amount of vitamin D2, will result in inadequate levels of 1,25
• hydroxycholecalciferol (calcitriol), the active form of vitamin D
• The apparent vitamin D2-resistance and absolute requirement of vitamin D3 in New World primates, particularly marmosets (not Old World primates), may be associated with differences in binding characteristics of transport proteins or to a high degree of stereospecificity of receptors in target cells for cholecalciferol
• Deficiency in active metabolites of vitamin D → decreased intestinal calcium and phosphorus absorption (with subsequent decreased serum levels) and decreased bone matrix synthesis and mineralization → hypocalcemia → stimulates parathyroid glands to secrete PTH → increased mobilization of calcium and phosphorus from bone AND decreased renal tubular resorption of phosphate and increased resorption of calcium (with normal renal function) → restores normal blood calcium levels
• Concurrent gastrointestinal disease may play a role in development of bone disease through decreased absorption of vitamin D and/or calcium
• In response to elevated PTH, bone marrow stromal cells differentiate into fibroblasts

 

TYPICAL CLINICAL FINDINGS:

• Affected monkeys reluctant to move and are inactive, and have thin, dull hair coats; normal resistance to handling is diminished
• There is difficulty with mastication; distortion of limbs and facial bones may be present (often maxilla and mandible)
• May show non-weight bearing lameness of one or more extremities; pathologic fractures are common
• Maintain a stiff, hunchback posture as a result of lordosis, scoliosis, and kyphosis of the spine
• Radiographically, generalized skeletal demineralization (decreased radiodensity) and bowing deformities of long bones are evident
• Serum levels of calcium and phosphorous are often in the low normal ranges
• Elevated alkaline phosphatase level is probably the most reliable indicator in animals with overt bone disease

 

TYPICAL GROSS FINDINGS:

• Skeletal system:
  • Distortion or bowing of the distal aspects of long bones
  • On sectioning, cortical bone is thin with prominent trabeculae and a widened marrow cavity
  • Fractures and healed fractures with abundant fibrous callus
  • Predilection for cancellous bones of the skull
  • Large, fibrous jaw bones (both maxilla and mandible) with separation and loss of teeth and marked thickening of the maxilla and calvarium
• Parathyroid glands are diffusely enlarged

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Adult animals: Widespread increased osteoclastic resorption and replacement by fibrous connective tissue
  • Increased osteoid seams with marked resorption of existing spongy or cortical bone and high numbers of osteoclasts within Howship's lacunae; osteoclastic
  • resorption begins on the endocortical bone surface, but any vascular spaces within the bone can undergo marked enlargement by osteoclastic resorption and replacement by fibrous tissue
  • Invasion of Haversian spaces and the marrow canal by fibrous tissue
  • Formation of cysts within the fibrous marrow, most often in mandible, maxilla or long bones; also known as “brown tumors” due to blood and hemosiderin within lesion, and arise from expansion of cortical bone secondary to endocortical bone resorption and the increased intraosseous pressure from vascular congestion
  • No lesions are expected in the growth plate or articular-epiphyseal cartilage complex in adult animals
• Young animals: Persistence of irregular, distorted cartilage masses; osteoid is deposited more abundantly in young animals, and osteoid is resistant to osteoclastic resorption, therefore osteoclast activity may be less pronounced in fibrous osteodystrophy associated with rickets (M-M08)

 

DIFFERENTIAL DIAGNOSIS:

• Neoplasia: Fibrosarcoma, giant cell sarcoma

 

COMPARATIVE PATHOLOGY: 

• Secondary nutritional hyperparathyroidism (see also E-N07): Horses, goats, pigs, cattle, dogs, cats, and rarely sheep; common in pet reptiles; reported in birds and rodents
• Dromedary camel: Fibrous osteodystrophy due to nutritional secondary hyperparathyroidism was diagnosed with bilateral enlarged parathyroid glands (Hines et al., J Vet Diagn Invest. 2021)
• Horses: “big head”, “bran disease”; most characteristic gross feature is bilateral enlargement of the mandible and maxilla (see also M-M10)
  • Horses are extremely sensitive to high phosphorus diets
  • Occurs in horses fed diets with excessive phosphorus from grain, corn, and grain by‑products (bran)
    • Adequate diet consists of ~1:1 calcium to phosphorous ratio
    • Ratio of 1:3 is likely to result in fibrous osteodystrophy
  • Also occurs in horses grazing tropical grasses (Setaria sphacelata, Cenchrus ciliars, Pancium maximum var. trichoglume) high in oxalates, which bind dietary calcium
• Swine: Most common in young growing pigs fed a diet of unsupplemented grain
  • Accompanied by rickets with vitamin D deficiency
• Dogs/Cats: Caused by diets consisting primarily of meat or offal
  • Dogs with renal failure may develop renal secondary hyperparathyroidism: Develop rubber jaw and resorption of alveolar bone around teeth; head and costochondral junctions may appear enlarged and may have concurrent rickets due to impaired synthesis of vitamin D
• Goats: Often a result of high concentrate rations
  • May be severe with enlargement of the mandible and maxilla, is characteristic, causing respiratory distress
• Reptiles: FOD is one of the most frequent forms of metabolic bone disease
  • Typically due to chronic dietary calcium insufficiency (may be due to high dietary phosphorus) à secondary hyperparathyroidism à FOD
  • Typically manifests as thickening / softening of the bones of the skull and limbs; a reduction in radiographic bone density
  • Kyphosis, lordosis, and scoliosis are common findings in young lizards that develop nutritional or renal secondary hyperparathyroidism early in life
• F344 rats: Fibrous osteodystrophy may develop secondary to age-related spontaneous chronic progressive nephropathy
• Mice: Fibro-osseous lesions in sternebrae, femurs, vertebrae, and other bones; most frequently in females and age-related; B6C3F1 mice particularly prone; estrogen presumed to play a role in development; partial to complete replacement of bone marrow by fibroblast-like cells in eosinophilic matrix, occasionally extending to periosteal region
• Rabbits: Nutritional hypocalcemia with secondary hyperthyroidism reported in rabbits fed calcium-deficient diet; may also have dental abnormalities
• Red foxes: Nutritional secondary hyperparathyroidism suspected in juvenile red foxes; microscopic lesions consistent with fibrous osteodystrophy
• Birds: Nutritional secondary hyperparathyroidism can result from diets low in calcium, high in phosphorous, or low in vitamin D3 (ie, all seed diets, peanuts, and corn); renal secondary hyperparathyroidism has not been documented in pet birds
• Humans: Osteitis fibrosa cystica

 

REFERENCES: 

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016:105.
2. Benirschke K, Garner FM, Jones TC. Pathology of Laboratory Animals. Vol 1. New York, NY: Springer-Verlag, Inc; 1978: 473-482, 727-734.
3. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016: 60-84.
4. Hines ES, Stevenson VB, Patton ME, Leventhal HR. Fibrous osteodystrophy in a dromedary camel. J Vet Diagn Invest. 2021;33(1):144-148.
5. Keel MK, Terio KA, McAloose D. Canidae, Ursidae, and Ailuridae. In: Terio KA, McAloose D, Judy St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA: Academic Press; 2018:230-231.
6. Kumar V, Abbas AK, Aster JC, eds. Environmental and nutritional diseases.In: Robbins and Cotran’s Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Saunders Elsevier; 2015: 438-441.
7. Mätz-Rensing K, Lowenstine LJ. New World and Old World Monkeys. In: Terio KA, McAloose D, Judy St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA: Academic Press; 2018:345.
8. Olson EJ, Carlson CS. Bones, joints, tendons and ligaments. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 980-983.
9. Olson EJ, Shaw GC, Hutchinson EK, Schultz-Darken N, et al. Bone disease in the common marmoset: radiographic and histologic findings. Vet Pathol. 2015; 52(5)883-93.
10. Origgi FC. Lacertilia. In: Terio KA, McAloose D, Judy St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA: Academic Press; 2018:875, 878, 879.
11. 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. Vol 2. San Diego, CA: Academic Press; 2012: 658-659.
12. Reavill DR, Dorrestein G. Psittacines, Coliiformes, Musophagiformes, In: Terio KA, McAloose D, Judy St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA: Academic Press; 2018:795.e12.
13. Schmidt RE, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2^nd Ames, IA:John Wiley & Sons, Inc; 2015: 209-210.

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