Read-Only Case Details Reviewed: May 2010

JPC SYSTEMIC PATHOLOGY

MUSCULOSKELETAL SYSTEM

April 2025

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 osteodystrophy

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

HISTORY: Postmortem 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: Fibrous osteodystrophy, 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 a relatively common metabolic bone disease characterized by extensive bone resorption, accompanied by proliferation of fibrous tissue and poorly mineralized immature bone; considered a skeletal manifestation of primary or secondary hyperparathyroidism
1. Seen in horses, pigs, dogs, cats, ferrets, goats, reptiles, and New World primates; rare in sheep
Cats and dogs: Caused by diets consisting largely or entirely of meat or offal; these diets have a low calcium: phosphorus ratio due to low calcium (ideal is 1:1; but meat/offal can be between 1:20 to 1:1000)
Secondary hyperparathyroidism is the most common cause- nutritional or renal in origin (nutritional or renal fibrous osteodystrophy); primary hyperparathyroidism is rare (dogs, familial in Keeshonds, and isolated cases in horses and cows)
Renal osteodystrophy is now termed chronic renal failure-mineral and bone disorder
Generalized bone lesions: Earliest and most severely affected areas include bones of the skull (particularly the mandible or maxilla) especially in dogs with renal osteodystrophy; cancellous bone of the ribs and vertebrae; and the metaphyseal area of long bones
Nutritional secondary hyperparathyroidism is most often due to diets with low calcium and relatively high phosphorous in young, rapidly growing animals, except for horses
1. Horses are most susceptible to diets high in phosphorus

PATHOGENESIS:

Persistently elevated PTH causes the following:
1. Upregulation of RANKL (receptor activator for nuclear factor kappa B ligand) and downregulation of osteoprotegrin (OPG)
2. Bone marrow stromal cell differentiation into fibroblasts
Mechanism of action of PTH on bone:
1. PTH binds to osteoblast and stromal cell receptors
2. 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: Usually the result of a functional parathyroid gland adenoma; can be other functional parathyroid neoplasms (or hyperplasia) (E-N07)
1. Autonomous secretion of parathyroid hormone (PTH) > bone resorption > persistent hypercalcemia and hypophosphatemia (renal loss)
Secondary hyperparathyroidism is due to chronic renal disease or imbalance of calcium and phosphorus
1. Nutritional secondary hyperparathyroidism may be caused by simple dietary deficiency of calcium, excess dietary phosphorus (bind calcium), or in association with vitamin D deficiency > increased PTH > bone resorption by osteoclasts (resulting in rubber jaw) and, if calcium is low, replacement by fibrous connective tissue
  - Vitamin D deficiency alone results in rickets or osteomalacia
  - Vitamin D deficiency and concurrent hypocalcemia (decreased intestinal absorption) > rickets/osteomalacia and fibrous osteodystrophy
  - Excess phosphorus > binds calcium > hypocalcemia > release of PTH
  - Plasma calcium is more sensitive to dietary phosphorus than to dietary calcium
2. 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) > increases renal excretion of phosphate and suppresses 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 also inhibits sclerostin (responsible for inhibition of new bone formation) > increased bone formation but defective mineralization of new bone due to defects in regulatory proteins DMP1 and ENPP1 and decrease in 1,25(OH)₂D₃ (> decreased calcium) > disease with features of fibrous osteodystrophy and osteomalacia (aka renal osteodystrophy)
Pseudohyperparathyroidism or hypercalcemia of malignancy: Tumor production of calcitropic hormones (most commonly PTHrP) act like PTH > bone resorption by osteoclasts; commonly seen in lymphoma and apocrine gland of the anal sac adenocarcinoma
1. Others: 1,25(OH)₂D₃, prostaglandins, and cytokines (TGF-β, IL1β)
Bone lesions usually mild

TYPICAL CLINICAL FINDINGS:

Primary Hyperparathyroidism: Polydipsia/polyuria, muscular weakness, widespread mineralization of soft tissues
Nephrocalcinosis > kidney failure
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
Puppies and kittens with secondary nutritional hyperparathyroidism: Clinical signs begin a few weeks after weaning; reluctance to move, hindlimb lameness, and incoordination

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; in weight bearing bones joints may herniate into the epiphysis > irregular articular surfaces
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
Puppies and kittens with nutritional secondary hyperparathyroidism: Infractions or fractures of long bones and vertebrae leading to paralysis, callus formation and fracture site with minimal mineralization

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Key microscopic features are similar in all species and are characterized by increased osteoclastic bone resorption, marked fibroplasia, and increased osteoblastic activity with formation of immature woven bone
Lesions of FOD vary between different bones, depending on their rate of turnover, and with stage of the disease process
Young, growing animals: Premature resorption of the primary spongiosa
Lesions (early):
1. Increased numbers of plump, active osteoclasts, often within resorption bays (Howship’s lacunae) along the surface of the bone
2. Prominent osteoblastic activity along with bone resorption
3. Wide osteoid seams at sites of rapid bone formation
4. Resorption cavities lined by osteoclasts in cortical bone and within trabeculae
5. Lightly fibrillar connective tissue surrounding / within trabeculae undergoing resorption
Chronic Lesions (with disease progression)
1. Mature trabecular and cortical bone are extensively replaced by a combination of loose fibrous connective tissue and irregular trabeculae of poorly mineralized or unmineralized woven bone
2. Compact bone resorbed from endosteal and periosteal surfaces
3. Porous remnants of the original cortex remain (advanced lesion)
4. Osteoclasts may be absent or remain in isolated “pockets” where bone is still being resorbed (advanced lesion)
5. Spicules lined by 2-3 cell layers of osteoclasts and/or osteoblasts
6. Fibrous tissue may undergo cystic degeneration and there may be areas of hemorrhage w/ hemosiderin
7. Growth plates are unaffected
8. 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
1. Gross: Prominent at sites of rapid growth; especially metaphyseal and epiphyseal regions of long bones and costochondral junctions
2. Histology: Persistence of hypertrophic chondrocytes at area of endochondral ossification at physes and below articular cartilage
Osteomalacia: Occurs only in adults
1. No lesion associated with cartilage growth
2. Defective mineralization
Osteoporosis: Most common metabolic bone disease
1. Reduction in the quantity of bone, quality of bone is normal
2. May be age related, normal process; due to starvation; or lactational
3. Lactational osteoporosis: often in gilts fed marginally deficient calcium in rations; minimal evidence of fibrous osteodystrophy
4. Bone resorbed and reduced
5. Histology: variable, but may provide clue to pathogenesis
6. Increase resorption à decreased numbers trabeculae
7. Decreased formation à normal numbers of thin trabeculae
8. 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; common in pet reptiles; reported in birds and rodents; no convincing cases in sheep or cattle
Equine: “Big head”, “bran disease”; most characteristic gross feature is bilateral enlargement of the mandible and maxilla
1. Horses are extremely sensitive to high phosphorus diets; do not develop renal secondary hyperparathyroidism as renal failure usually results in hypercalcemia in horses
2. Gross: Curved vertebral column, reduces rib arch, avulsion of ligaments, fractures; bones may be macerated and crumbly with reduced weight
3. Clin path: Serum concentrations of PTH is the most diagnostically relevant; fractional urine clearance of phosphorus may be helpful
4. Occurs in horses fed diets with excessive phosphorus from grain, corn, and grain by‑products (bran) or in horses on lush pasture with up to 7.8% oxalate d/w
5. Adequate diet consists of ~1:1 calcium to phosphorous ratio
6. Ratio of 1:3 is likely to result in fibrous osteodystrophy
7. Also occurs in horses grazing certain grasses (Setaria sphacelata, Cenchrus ciliars, Pancium spp., Brachiaria mutica, Digitaria decumbens, Pennisteum clandestinum) high in oxalates, which bind dietary calcium
Dogs/Cats: Caused by diets consisting primarily or entirely of meat or offal;
1. Kittens fed exclusively beef hearts will develop signs within 4 weeks
Non-human primates:
1. 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)
2. 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: Almost always due to nutritional imbalances and/or renal hyperparathyroidism; dietary deficiencies include inappropriate calcium to phosphorus ratio or low calcium and/or vitamin D; inappropriate exposure to ultraviolet B (UVB) light; renal disease resulting in abnormal and progressive loss of calcium can be a predisposing condition
1. Pathogenesis: Limited availability of calcium > production of parathyroid hormone > progressive resorption of calcium from bones
  - Preclinical: Bone resorption is occurring, but there are no clinical signs
  - Early clinical: Anorexia, difficulty moving, lethargy, twitching/tremors, neuro signs, and calcium drops under physiologic levels
  - Late clinical: characteristic severe thickening and swelling of limbs
  - Progressive reduction in cortical bone; movement > exuberant deposition of cartilage and fibrous tissue along periosteal surfaces > pressure atrophy of surrounding muscles
2. Typically manifests as thickening/softening of the bones of the skull and limbs; a reduction in radiographic bone density; “rubber jaw”; pathologic fractures; kyphosis, lordosis, and scoliosis in animals affected at a young age
3. Less common in chelonians as in other reptile species
4. Reported in crocodilia, but detailed gross/histo descriptions not available
5. Chameleons have bowing of limbs
Swine: Most common in young growing pigs fed a diet of unsupplemented grain; accompanied by rickets with vitamin D deficiency
1. Clinical signs: Stiffness, reluctance to rise, lameness; +/- skull lesions similar to horses; mobile teeth
2. Gross: Ribs can be broken; pathologic fractures; growth plates normal unless accompanied by 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
1. Nutritional secondary hyperparathyroidism described in wild, juvenile red foxes (enlargement of distal epiphyses of long bones and costochondral junction of ribs); suspected in African wild dogs
Horses: Renal secondary hyperparathyroidism is not reported in the horse, as renal failure typically results in hypercalcemia in horses instead of hypocalcemia
Birds:
1. Develop both primary and secondary hyperparathyroidism
2. Nutritional secondary hyperparathyroidism: Adult birds; diet deficient in calcium or contains excess phosphorus; all seed diets
  - Soft bones; pathologic fractures; bone deformities
  - Extremely common in all captive species of birds; commercial diets are usually adequate, but homemade breeder diets are prone to errors; carnivorous birds in rehab facilities may not receive proper mineral balances if they are fed an all-meat diet that is not balanced with supplemental calcium
3. Rental secondary hyperparathyroidism has not been conclusively documented in pet birds
4. Fibrous osteodystrophy is usually seen in birds with hyperparathyroidism
5. Free-ranging royal northern albatross chicks receiving supplemental hand-feeding
Four-toed hedgehog (Atelerix albiventris): Case report of bilateral cystic renal dysplasia leading to fibrous osteodystrophy (Makishima, J Comp Pathol, 2024)

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