JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
March 2022
M-M10

Slide A: Signalment (JPC #2506867):  An adult male Dromedary camel (Camelus dromedarius)

 

HISTORY:  This camel was one of a group of camels grazed on irrigated pastures of the Werribee Open Range Zoo (Australia).  It developed chronic progressive multiple limb lameness and stiffness that was unresponsive to treatment.  No other clinical signs were noted.

 

HISTOPATHOLOGIC DESCRIPTION:  Bone, maxilla and nasal turbinates:  Diffusely, the medullary cavity is expanded up to 5 times normal, the trabeculae are thin, decreased in number, and widely separated, and the cortices are thin or lost.  There is separation and partial to complete replacement of normal cortical and trabecular bone and hematopoietic elements by numerous loosely arranged fibroblasts and thin, haphazard collagen bundles (fibrosis) admixed with numerous, irregular, thin spicules of woven bone.  Spicules of woven bone are lined by variable numbers of osteoblasts (new bone formation) and spicules of lamellar bone are lined by decreased numbers of osteoblasts and variable numbers of osteoclasts, often within Howship's lacunae (bone resorption).  Multifocally, there are variable numbers of osteoclasts also within the medullary fibrous connective tissue.  Multifocally, in less affected turbinates are low numbers of submucosal lymphocytes and plasma cells.

 

MORPHOLOGIC DIAGNOSIS:  Bone, maxilla and nasal turbinates:  Fibrous osteodystrophy, diffuse, severe, Dromedary camel (Camelus dromedarius), camelid.

 

CAUSE:  Low dietary calcium and/or high dietary phosphorus

 

CONDITION:  Nutritional secondary hyperparathyroidism with fibrous osteodystrophy

 

SYNONYMS:  Osteodystrophia fibrosa, osteitis fibrosa, osteitis fibrosa cystica, rubber jaw, renal rickets

 

Slide B: Signalment (JPC #1947452):  An 11-week-old female Alaskan malamute dog

 

HISTORY:  Post mortem exam gross pathology findings included small, firm kidneys, multiple rib fractures, soft bones, swelling and distortion of the facial bones and mandible, enlarged parathyroid glands, and anemia.

 

Laboratory Results:

Glucose                     116 mg/dl (76-119)               RBC     2,070,000 (4.95-7.87)

Sodium                      148 mmol/l (142-152)          Hct     19.25% (35-57)

Chloride                     104 mmol/l (110-124)          Hb             5.7 gm/dl (11.9-18.9)

Calcium                     8.8 mg/dl (9.1-11.7)              MCV    92.99 fl (66-77)

Protein                       5.4 g/dl (5.4-7.5)                   MCH    27.53 pg (21.0-26.2)

Albumin                     2.6 g/dl (2.3-3.1)                   MCHC  29.61 gm/dl (32.0-36.3)

AST                            42 IU/L (13-15)                      Retic    6%

ALT                             26 IU/L (10-109)                   WBC     11,292/mm (5,0-14,100)

LDH                            70 IU/L (0-236)                      Neuts    68% (7678) (2,9-12,000)

Phosphorous                        9.3 mg/dl (2.9-5.3)                Eos     2% (226) (0-130)

Potassium                 6.2 mmol/l (3.9-5.1)              Lymph   26% (2936) (400-2,900)

BUN                           150 mg/dl (8-28)                   Mono  4% (452) (100-1,400)

Creatinine                 5.1 mg/dl (.5-1.7)

Cholesterol               296 mg/dl (135-278)

Alk Phos                    276 IU/L (1-114)

 

Clinical Pathology Summary:  Macrocytic, hypochromic anemia (with adequate regenerative response after corrected reticulocyte percentage calculation and reticulocyte index calculation) and a mild eosinophilia.  Hyperphosphatemia, azotemia, elevated alkaline phosphatase, hypocalcemia, hypercholesterolemia, and mild hyperkalemia

• Note: reticulocyte production index (RPI) controversial in dogs and cats; correlational studies not done

 

HISTOPATHOLOGIC DESCRIPTION:  Bone, maxilla with tooth and nasal turbinates:  Diffusely there is expansion, separation, and partial to complete replacement of the compact and trabecular bone and hematopoietic elements by variably dense fibrous connective tissue with many large fibroblasts (fibrosis) and randomly arranged thin trabeculae of woven bone that are frequently scalloped, thin, and lined by numerous osteoblasts (new bone formation), while trabeculae of remaining lamellar bone are lined by variable numbers of osteoclasts within Howship’s lacunae (resorption), which are also free within the fibrous stroma.  There are occasional microfractures of woven bone spicules surrounded by hemorrhage, fibrin, and edema with few hemosiderin-laden macrophages.  Multifocally the nasal respiratory mucosa is infiltrated by low to moderate numbers of neutrophils, and within the nasal passage lumen there is a focal accumulation of abundant degenerate neutrophils admixed with eosinophilic cellular debris.   

 

MORPHOLOGIC DIAGNOSIS:  1. Bone, maxilla and nasal turbinates:  Osteodystrophy, fibrous, diffuse, severe, Alaskan malamute, canine.

2. Nasal turbinate mucosa: Rhinitis, suppurative, acute, multifocal, moderate.

 

CAUSE:  Hyperparathyroidism secondary to renal failure

 

CONDITION:  Renal secondary hyperparathyroidism with fibrous osteodystrophy

 

GENERAL DISCUSSION:

• Fibrous osteodystrophy (FOD) is the result of osteoclastic resorption of bone and replacement by fibrous connective tissue associated with elevations in PTH
• Secondary hyperparathyroidism is the most common cause- nutritional or renal in origin (nutritional or renal fibrous osteodystrophy)
  • Renal osteodystrophy is now termed chronic renal failure-mineral and bone disorder
  • Bones of the skull are most affected in dogs with renal osteodystrohy
  • Most often due to low calcium and relatively high phosphorous-containing diets in young, rapidly growing animals, except for horses
• Generalized bone lesions: Earliest and most severely affected areas include bones of the skull (particularly the mandible or maxilla); cancellous bone of the ribs and vertebrae; and the metaphyseal area of long bones

 

PATHOGENESIS:

• PTH causes the following:
  • Upregulation of RANKL (receptor activator for nuclear factor kappa B ligand) and downregulation of osteoprotegrin (OPG)
  • Bone marrow stromal cell differentiation into fibroblasts
  • Mechanism of action of PTH on bone:
    • PTH binds to osteoblast and stromal cell receptors
    • Up-regulates RANKL and blunts expression of OPG > RANKL binds RANK-receptor on osteoclast precursors> osteoclast differentiation
    • Osteoclasts secrete collagenase and proteases which result in the degradation of the osteoid
  • Primary hyperparathyroidism: Functional parathyroid neoplasm (or hyperplasia) (E-N07) produces parathyroid hormone (PTH) > bone resorption by osteoclasts and persistent hypercalcemia
  • Secondary hyperparathyroidism:
  • Nutritional secondary hyperparathyroidism: Decreased calcium or excess phosphorus intake (binds Ca) or vitamin D deficiency > increased PTH > bone resorption by osteoclasts (resulting in rubber jaw) and replacement by fibrous connective tissue
    • Vitamin D deficiency alone results in rickets or osteomalacia, and when there is concurrent hypocalcemia due to decreased intestinal absorption > rickets/osteomalacia and fibrous osteodystrophy
  • Renal secondary hyperparathyroidism: Reduction in functional nephrons> decreased GFR > phosphorus retention and decreased calcium (due to inverse Ca – P relationship) > increased serum fibroblast growth factor 23 (FGF23) > depresses renal 1-α-hydroxylase (decreased synthesis of calcitriol [active vitamin D] > decreased circulating levels of calcitriol results in chief cell hyperplasia and hypocalcemia > increased secretion of PTH > increased bone resorption by osteoclasts and replacement with fibrous connective tissue
    • PTH inhibits sclerostin > increased bone formation but defective mineralization of new bone due to hypocalcemia > fibrous osteodystrophy and osteomalacia (aka renal osteodystrophy)
  • Paraneoplastic syndrome: PTHrP (or other factors such as vitamin D analogs and cytokines) acts like PTH > bone resorption by osteoclasts
    • Bone lesions usually mild

 

TYPICAL CLINICAL FINDINGS:

• Persistently elevated PTH
• Lameness from bone pain; multiple fractures
• Pliable jaw (“rubber jaw”) with protruding tongue
• Maxillary/facial swelling
• Anorexia, malaise, nervousness
• Horses may demonstrate dyspnea when the palate is involved due to a reduction in the nasal passage; also may observe a wet face due to occlusion of the lacrimal canal

 

TYPICAL GROSS FINDINGS:

• Entire skeleton may be involved; usually the bones of the calvarium, maxilla, and mandible are most severely affected; bones are enlarged, pliable, and fracture easily
• Diffuse bilateral parathyroid gland enlargement
• Loose teeth
• Bilateral swelling of the bones of the skull including both mandible and maxilla
• Skull bones: Moth eaten appearance
• Detachment of ligaments and tendons in the lower limbs
• Nephrocalcinosis may be present prior to skeletal lesions

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Three key features of FOD across species / etiology are osteoclastic bone resorption, fibrosis, and osteoblastic deposition of new woven bone; however, lesions may vary with state of disease and specific bones involved:

Lesions (early):

• Increased numbers of plump, active osteoclasts, often within Howship’s lacunae along the surface of the bone
• Prominent osteoblastic activity along with bone resorption
• Wide osteoid seams at sites of rapid bone formation
• Resorption cavities lined by osteoclasts in cortical bone and within trabeculae
• Lightly fibrillar connective tissue surrounding / within trabeculae undergoing resorption

Chronic Lesions (with disease progression)

• Replacement of mature cortical and trabecular bone with loose fibrous connective tissue
• Irregular trabeculae of poorly mineralized or unmineralized woven bone which may encroach on the medullary cavity and expand peripherally to elevate the periosteum
• Compact bone resorbed from endosteal and periosteal surfaces
• Porous remnants of the original cortex remain (advanced lesion)
• Osteoclasts may be absent or remain in isolated “pockets” where bone is still being resorbed (advanced lesion)
• Spicules lined by 2-3 cell layers of osteoclasts and/or osteoblasts
• Fibrous tissue may undergo cystic degeneration and there may be areas of hemorrhage w/ hemosiderin
• Growth plates are unaffected
• Primary spongiosa may be resorbed in young, growing animals

 

ADDITIONAL DIAGNOSTIC TESTS:

• Radiographs: Thinned cortices; fractures; normal growth plates
• Clinical pathology:
  • Primary hyperparathyroidism: Hypercalcemia, decreased serum phosphate
  • Renal secondary hyperthyroidism: Hyperphosphatemia, low normal calcium, serum biochemistry consistent with renal failure; in cats, increased concentrations of FGF23 and PTH predicted development of azotemia
  • Nutritional secondary hyperparathyroidism: Variable phosphorus, low normal calcium, hyperphosphaturia
• Horses: Serum PTH and Urinary Fractional Clearance of Phosphorus (UFCP):
  • UFCP is higher in horses affected with nutritional secondary hyperparathyroidism than control horses

 

DIFFERENTIAL DIAGNOSIS:

• Other metabolic bone diseases may overlap (rickets, osteomalacia, osteoporosis)
  • Rickets (M-M08): generally a disease of young animals
    • Gross: prominent at sites of rapid growth; especially metaphyseal and epiphyseal regions of long bones and costochondral junctions
    • Histology: persistence of hypertrophic chondrocytes at area of endochondral ossification at physes and below articular cartilage
  • Osteomalacia: occurs only in adults
    • No lesion associated with cartilage growth
    • Defective mineralization
  • Osteoporosis: most common metabolic bone disease
    • Reduction in the quantity of bone, quality of bone is normal
    • May be age related, normal process; due to starvation; or lactational
      • Lactational osteoporosis: often in gilts fed marginally deficient calcium in rations; minimal evidence of fibrous osteodystrophy
      • Bone resorbed and reduced
    • Histology: variable, but may provide clue to pathogenesis
      • Increase resorption à decreased numbers trabeculae
      • Decreased formation à normal numbers of thin trabeculae
      • Starvation à growth arrest lines with decrease in number and size of trabeculae
    • Osteogenesis imperfect (M-M04)
    • Repairing fractures are associated with hyperostosis
    • Neoplasia: fibroma; giant cell sarcoma

 

COMPARATIVE PATHOLOGY:

Nutritional secondary hyperparathyroidism in other species:

• Occurs in horses, goats, pigs, cattle, dogs, cats, and rarely sheep; common in pet reptiles; reported in birds and rodents
• Equine: “Big head”, “bran disease”; most characteristic gross feature is bilateral enlargement of the mandible and maxilla
  • 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
• Dogs/Cats: Caused by diets consisting primarily or entirely of meat or offal;
  • Kittens fed exclusively beef hearts will develop signs within 4 weeks
• Non-human primates:
  • Simian bone disease (M-M09): “cage paralysis”; inadequate vitamin D or excess phosphorous from unusual diets; new world monkeys have an absolute requirement for vitamin D3 (can’t synthesize)
  • Common marmosets: Secondary hyperparathyroidism from malabsorption due to inflammatory gastrointestinal disease
• Goats: Often a result of high concentrate rations; may be severe with enlargement of the mandible and maxilla which is characteristic, causing respiratory distress
• Reptile: High phosphorus or low calcium diets; typically manifests as thickening / softening of the bones of the skull and limbs; a reduction in radiographic bone density
• Swine: most common in young growing pigs fed a diet of unsupplemented grain; accompanied by rickets with vitamin D deficiency
• Dromedary camel: Singe case report with bilaterally enlarged parathyroid glands and a history of eating an unbalanced diet of cookies and treats (Hines, J Vet Diagn Invest. 2021)

Renal secondary hyperparathyroidism in other species:

• F344 rats: Fibrous osteodystrophy may develop secondary to age-related spontaneous chronic progressive nephropathy
• Dogs: May develop renal secondary hyperparathyroidism: Develop “rubber jaw” and resorption of alveolar bone around teeth; head and costochondral junctions may appear enlarged; may have concurrent rickets due to impaired vitamin D synthesis
• Horses: Renal secondary hyperparathyroidism is not reported in the horse, as renal failure typically results in hypercalcemia in horses instead of hypocalcemia

 

REFERENCES:

1. 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. St. Louis, MO: Elsevier; 2016: 74-80.
2. Ferguson DC, Hoenig M. Endocrine system. In: Latimer KS, Mahaffey EA, Prasse KW, eds. Duncan & Prasse's Veterinary Laboratory Medicine, Clinical Pathology. 5th ed. Ames, IA: Wiley-Blackwell; 2011: 295-297.
3. Hines ES, Stevenson VB, Patton ME, et. al. Fibrous osteodystrophy in a dromedary camel. J Vet Diagn Invest. 2021;33(1):144-148.
4. 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; 2017:981-983.
5. Olson EJ, Shaw GC, Hutchinson EK, et al. Bone disease in the common marmoset: radiographic and histologic findings. Vet Pathol. 2015; 52(5)883-93.
6. Rosol, TJ, Gröne A. Endocrine glands. In: Maxie, MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6^th St. Louis, MO. Elsevier, 2016:292-301.
7. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology, 2nd Ed. Ames, IA: Blackwell Publishing. 2008.
8. Taylor MB, Geiger DA, Saker KE, Larson MM. Diffuse osteopenia and myelopathy in a puppy fed a diet composed of an organic premix and raw ground beef. J Am Vet Med Assoc. 2009; 234(8):1041-1048.

 

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