Pathology in Practice

Kellye S. Joiner Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849.

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 DVM, PhD
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Ronald D. Montgomery Department of Clinical Science, College of Veterinary Medicine, Auburn University, Auburn, AL 36849.

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 DVM, MS, DACVS

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History

A 16-week-old sexually intact male Great Dane was evaluated at the Auburn University Small Animal Veterinary Teaching Hospital because it was nonambulatory and had signs of moderate to severe pain in all limbs. The dog had a history of a rapidly progressive, bilateral hind limb lameness accompanied by lethargy anorexia, and intermittent fever during the preceding week; in general, the dog had become and remained recumbent. The dog was usually fed a standard ration of commercial dog food, and dietary supplements were not provided.

Clinical and Gross Findings

At the initial evaluation, the dog was non-weight bearing in all 4 limbs and breathing was labored. Radiography of all 4 limbs was performed, and bilaterally symmetric linear radiolucent zones were evident in the distal radial and ulnar metaphyses. A CBC revealed leukopenia (5.02 × 103 cells/μL; reference range, 6.0 × 103 cells/μL to 17.0 × 103 cells/μL) attributed to neutropenia (2,058 cells/μL; reference range, 3,000 to 11,400 cells/μL) with a left shift (904 bands/μL; reference range, 0 to 300 bands/μL). Results of serum biochemical analyses were indicative of bone and muscle damage, with high activities of alkaline phosphatase (287 U/L; reference range, 3.5 to 95 U/L) and creatine kinase (1,092 U/L; reference range, 92 to 357 U/L) and high concentrations of calcium (19.6 mg/dL; reference range, 9.5 to 11.8 mg/dL) and phosphorus (10.3 mg/dL; reference range, 3.3 to 5.8 mg/dL). Within 12 hours after the initial evaluation, signs of pain in the limbs and respiratory distress intensified; rectal temperature was 40.4°C (104.8°F). The dog developed cardiopulmonary arrest, and resuscitation attempts were unsuccessful.

A complete necropsy of the dog revealed bilateral enlargement of the proximal and distal physes and metaphyses of the radii, ulnas, carpal bones, tibias, fibulas, and tarsal bones. Subjacent to the physeal cartilage, the metaphyseal architecture was obscured by 1.0- to 4.0-mm-wide bands of pale yellow, friable material admixed with fibrinous strands and bony spicula (Figure 1). These linear zones of fibrinonecrotic debris sometimes impinged on the overlying physes and were often surrounded by locally extensive regions of hemorrhage. A few of the physes were irregular or serpiginous, and thin finger-like extensions of cartilage projected slightly into the respective epiphysis and metaphysis. The radial, ulnar, and tibial metaphyses were surrounded by subperiosteal hemorrhage that slightly elevated the periosteum and extended along the outer bone cortex. These lesions were more severe in the distal physes of the affected bones.

Figure 1—
Figure 1—

Photograph of a longitudinal section of the distal portion of a tibia obtained during the necropsy of a Great Dane that was evaluated because of progressive, bilateral, non-weight-bearing lameness, lethargy, anorexia, and intermittent fever. Notice that there is extensive metaphyseal necrosis and hemorrhage with subphyseal cleft formation.

Citation: Journal of the American Veterinary Medical Association 238, 11; 10.2460/javma.238.11.1413

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page

Histopathologic Findings

Sections of long bones were fixed by immersion in neutral-buffered 10% formalin, then decalcified for 48 hours in decalcifying solution.a Decalcified sections were routinely processed, embedded in paraffin, sectioned at 4 to 6 μm, and stained with H&E stain for microscopic examination. Histologically, the affected bones contained abrupt linear zones of trabecular necrosis that dissected between the primary and secondary spongiosa and replaced most of the normal metaphyseal architecture. These regions of necrosis were accompanied by massive accumulations of hemorrhage and an inflammatory cell influx that was predominantly comprised of degenerate neutrophils. Greater than typical numbers of osteoclasts were scattered along the distal margin of the hemorrhage and necrosis, in close apposition with the secondary spongiosa (Figure 2). The remaining primary and secondary spongiosa trabeculae were disorganized and variably spiculated, often arranged parallel to the physis, which was consistent with previous microfracture. There was extensive metaphyseal osteonecrosis. Ossified trabeculae were frequently hypereosinophilic and refractile with low numbers of lacunae that were empty or contained karyolytic osteocytic debris (Figure 3). In addition, masses of neutrophils dissected between these remaining trabeculae and filled the marrow cavity. Aggregates of fibrinous to osteolytic debris and poorly organized areas of fibrous connective tissue were present throughout the metaphysis. Lesions rarely extended into the distal physis (including the zones of cartilage degeneration and ossification) or proximal diaphysis. Some of the examined sections contained focal subperiosteal hemorrhage and fibrosis.

Figure 2—
Figure 2—

Photomicrograph of the left distal radial metaphysis of the dog in Figure 1. The predominantly neutrophilic inflammation and cellular debris (asterisk), osteoclastic activity (arrow), and remaining spongiosa (arrowhead) with scalloped resorption lines are indicative of bone remodeling. H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 238, 11; 10.2460/javma.238.11.1413

Figure 3—
Figure 3—

Photomicrograph of the left distal radial metaphysis of the dog in Figure 1. Notice the extensive osteonecrosis. Hypereosinophilic fragments of degenerate bone contain few lacunae that are often empty or contain karyolytic osteoclastic debris (arrow). The intertrabecular areas are filled with degenerate neutrophils, fibrinous to osteolytic debris (arrowhead), and irregular areas of fibrosis with proliferative fibroblasts (asterisk). H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 238, 11; 10.2460/javma.238.11.1413

Morphologic Diagnosis

Severe, bilaterally symmetric, suppurative osteomyelitis of multiple long bones with metaphyseal microfractures and periosteal proliferation.

Comments

For the dog of this report, a final diagnosis of hypertrophic osteodystrophy (HOD) was supported by the radiographic, gross, and histologic findings. Hypertrophic osteodystrophy is an uncommon, but well recognized orthopedic developmental disorder of young, rapidly growing, large- and giant-breed dogs. Hypertrophic osteodystrophy is predominantly characterized by extensive suppurative inflammation and necrosis in the metaphyseal regions of long bones. Variable degrees of periosteal proliferation, fibrosis, ossification, and subperiosteal hemorrhage frequently accompany metaphyseal necrosis. However, the pathogenesis is unknown and the complexity of the disease, including variations in the severity of the associated clinical and pathological changes, suggest a multifactorial process.

Hypertrophic osteodystrophy has been identified in 40 breeds of dog.1 Although most breeds are represented sporadically with regard to HOD in the veterinary medical literature, the Great Dane appears to be the most frequently affected breed. The disease has affected entire litters of Weimaraner puppies.2 Typically, clinical signs develop at 3 to 4 months of age but may be observed as early as 2 months of age and as late as the time of physeal closure.1–3 Clinical gait deficits directly correlate with the extent of skeletal involvement, and the range of clinical signs can vary from mild limping in minimally affected animals to reluctance to move and an inability to stand in severely affected animals.4

Hypertrophic osteodystrophy generally affects the radii, ulnas, and tibias; however, lesions may develop in rapidly growing long bones throughout the appendicular skeleton and occasionally in the axial skeleton (including the maxilla, mandible, costochondral junctions of the ribs, scapulas, and ilia).1,4–6 The acute onset of bilateral and symmetric lameness is associated with progressive metaphyseal enlargement, which correlates with periosteal proliferation, fibrosis, and ossification.3 Other clinical signs include anorexia, weight loss, fever, and signs of depression and severe metaphyseal pain. These signs may be episodic, paralleling changes in body temperature.3 Most affected dogs have severe clinical signs that necessitate treatment. Corticosteroid treatment is typically very effective.7 Spontaneous remission generally occurs subsequent to physeal closure, and in most dogs, relapses are rare.4,5,8 Multiple recurrences are rare and are typically progressive, leading to the development of severe pain, hyperthermia, and prolonged recumbency.4,8 Radiographic lesions, including irregular medullary radiolucencies, bone sclerosis, and periosteal proliferation, are consistently observed in the affected metaphyses,9,10 often confirming the clinical diagnosis. Dogs that recover from multiple or uncontrolled episodes may have residual skeletal deformities, including radiocarpal valgus, as a result of growth rate discrepancies within or between affected metaphyses. In addition, radiographic changes in bone shape and texture as well as the presence of osteophytes are occasionally detected in adults. Hematologic alterations, including neutrophilia, monocytosis, and lymphocytopenia, may be observed during the acute phase of the disease and are concomitant with variable degrees of stress and inflammation.2,8,11 Serum alkaline phosphatase activity and calcium and phosphorous concentrations are often abnormal, depending on the degree of osteonecrosis.11

Various mechanisms, including dietary requirements and infectious processes, have been implicated as contributing factors for the development of HOD. Rapid growth is a consistent feature of clinical HOD cases, as evidenced by the fact that affected dogs are typically of large breeds, are receiving a high plane of nutrition, and are in their most rapid growth period (most commonly 3 to 5 months of age). It has been proposed that in combination, the requirement of the physis for a good blood supply to maintain its high metabolic rate and the vascular stasis that occurs where vessels must make a U-shaped turn because they do not cross the physis contribute to the development of HOD.7 Vitamin C deficiency or derangements in vitamin C metabolism, storage, and utilization as a cause of HOD have been a primary research emphasis.12 Overnutrition with excess diet supplementation with minerals, vitamin D, and calcium has also been implicated in HOD development.13 Other evidence lends support to the role of infectious causes such as Escherichia coli and canine distemper virus infection or the use of modified-live canine distemper virus vaccines.8,11,13,14 Antibody response following vaccine administration may also have a role in the development of HOD. Differences in the development and patterns of recurrent episodes of HOD in a litter of Weimaraner puppies that each received 1 of 2 vaccination protocols involving modified-live canine parvovirus and canine distemper virus vaccines have been described.14 Another study15 to investigate the role of immune-response genes in the canine major histocompatibility complex DQA1 failed to reveal an association between DQA1 alleles and HOD. However, because many major histocompatibility complex alleles can influence antibody response to a vaccine, it is plausible that other immune-response genes may have a role in disease development. A risk assessment of the development of orthopedic diseases in dogs has revealed an exceedingly high odds ratio (186.7) for the development of HOD among Great Danes, which is strongly suggestive of a genetic predisposition.16 However, a primary cause has yet to be identified, which may suggest that multiple environmental and genetic factors have roles in the development of HOD.

For the dog of this report, no additional risk factors other than a potential breed predisposition were identified. This dog was receiving a standard ration of commercial dog food, and dietary supplements were not provided. Although most affected dogs generally respond well to supportive treatments, the dog of this report refused to eat and remained in moribund recumbency, eventually, the dog developed cardiopulmonary arrest, and resuscitation attempts were unsuccessful. However, the severity of disease in this case was not typical and spontaneous remission is common. Pain may be alleviated with administration of NSAIDs or corticosteroids. Relapses do not occur following cessation of long bone growth.

a.

Decalcifier II, Surgipath, Leica Microsystem, Richmond, Ill.

References

  • 1.

    Munjar TAAustin DDBreur GJ. Comparison of risk factors for hypertrophic osteodystrophy, craniomandibular osteopathy and canine distemper virus infection. Vet Comp Orthop Traumatol 1998; 11: 3743.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Abeles VHarrus SAngles JM, et al. Hypertrophic osteodystrophy in six Weimaraner puppies associated with systemic signs. Vet Rec 1999; 145: 130134.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Bellah JR. Hypertrophic osteopathy. In: Bojrab MJ, ed. Disease mechanisms in small animal surgery. 2nd ed. Philadelphia: Lea & Febiger, 1993; 858864.

    • Search Google Scholar
    • Export Citation
  • 4.

    Lenehan TMFetter AW. Hypertrophic osteodystrophy. In: Newton CDNunamaker DM, eds. Textbook of small animal orthopedics. Philadelphia: Lippincott, 1983; 597601.

    • Search Google Scholar
    • Export Citation
  • 5.

    Alexander JW. Selected skeletal dysplasias: craniomandibular osteopathy, multiple cartilaginous exostoses and hypertrophic osteodystrophy. Vet Clin North Am Small Anim Pract 1983; 13: 5570.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Schulz KSPayne JTAronson E. Escherichia coli bacteremia associated with hypertrophic osteodystrophy in a dog. J Am Vet Med Assoc 1991; 199: 11701173.

    • Search Google Scholar
    • Export Citation
  • 7.

    Montgomery RD. Hypertrophic osteodystrophy in dogs. In: Bojrab MJMonnet E, eds. Mechanisms of disease in small animal surgery. 3rd ed. Jackson, Wyo: Teton New Media, 2010; 564569.

    • Search Google Scholar
    • Export Citation
  • 8.

    Muir PDubielzig RRJohnson KA, et al. Hypertrophic osteodystrophy and calvarial hyperostosis. Compend Contin Educ Pract Vet 1996; 18: 143151.

    • Search Google Scholar
    • Export Citation
  • 9.

    Konde LJ. Diseases of the immature skeleton: hypertrophic osteodystrophy. In: Thrall DE, ed. Textbook of veterinary diagnostic radiology. 2nd ed. Philadelphia: WB Saunders Co, 1994; 98101.

    • Search Google Scholar
    • Export Citation
  • 10.

    Franklin MARochat MCBroaddus KD. Hypertrophic osteodystrophy of the proximal humerus in two dogs. J. Am Anim Hosp Assoc 2008; 44: 342346.

  • 11.

    Grondalen J. Metaphyseal osteopathy (hypertrophic osteodystrophy) in growing dogs. A clinical study. J Small Anim Pract 1976; 17: 721735.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Woodard JC. Canine hypertrophic osteodystrophy, a study of spontaneous disease in littermates. Vet Pathol 1982; 19: 337354.

  • 13.

    Collett P. La maladie de Barlow spontanee chez le chien (scorbut infantile). Revue Vet Goulorese 1935; 87: 497.

  • 14.

    Harrus SWaner TAizenberg, et al. Development of hypertrophic osteodystrophy and antibody response in a litter of vaccinated Weimaraner puppies. J Small Anim Pract 2002; 43: 2731.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Crumlish PTSweeney TJones B, et al. Hypertrophic osteodystrophy in the Weimaraner dog: lack of association between DQA1 alleles of the canine MHC and hypertrophic osteodystrophy. Vet J 2006; 171: 308313.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    LaFond EBreur GJAustin CC. Breed susceptibility for developmental orthopedic diseases in dogs. J Am Anim Hosp Assoc 2002; 38: 467477.

  • Figure 1—

    Photograph of a longitudinal section of the distal portion of a tibia obtained during the necropsy of a Great Dane that was evaluated because of progressive, bilateral, non-weight-bearing lameness, lethargy, anorexia, and intermittent fever. Notice that there is extensive metaphyseal necrosis and hemorrhage with subphyseal cleft formation.

  • Figure 2—

    Photomicrograph of the left distal radial metaphysis of the dog in Figure 1. The predominantly neutrophilic inflammation and cellular debris (asterisk), osteoclastic activity (arrow), and remaining spongiosa (arrowhead) with scalloped resorption lines are indicative of bone remodeling. H&E stain; bar = 100 μm.

  • Figure 3—

    Photomicrograph of the left distal radial metaphysis of the dog in Figure 1. Notice the extensive osteonecrosis. Hypereosinophilic fragments of degenerate bone contain few lacunae that are often empty or contain karyolytic osteoclastic debris (arrow). The intertrabecular areas are filled with degenerate neutrophils, fibrinous to osteolytic debris (arrowhead), and irregular areas of fibrosis with proliferative fibroblasts (asterisk). H&E stain; bar = 100 μm.

  • 1.

    Munjar TAAustin DDBreur GJ. Comparison of risk factors for hypertrophic osteodystrophy, craniomandibular osteopathy and canine distemper virus infection. Vet Comp Orthop Traumatol 1998; 11: 3743.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Abeles VHarrus SAngles JM, et al. Hypertrophic osteodystrophy in six Weimaraner puppies associated with systemic signs. Vet Rec 1999; 145: 130134.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Bellah JR. Hypertrophic osteopathy. In: Bojrab MJ, ed. Disease mechanisms in small animal surgery. 2nd ed. Philadelphia: Lea & Febiger, 1993; 858864.

    • Search Google Scholar
    • Export Citation
  • 4.

    Lenehan TMFetter AW. Hypertrophic osteodystrophy. In: Newton CDNunamaker DM, eds. Textbook of small animal orthopedics. Philadelphia: Lippincott, 1983; 597601.

    • Search Google Scholar
    • Export Citation
  • 5.

    Alexander JW. Selected skeletal dysplasias: craniomandibular osteopathy, multiple cartilaginous exostoses and hypertrophic osteodystrophy. Vet Clin North Am Small Anim Pract 1983; 13: 5570.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Schulz KSPayne JTAronson E. Escherichia coli bacteremia associated with hypertrophic osteodystrophy in a dog. J Am Vet Med Assoc 1991; 199: 11701173.

    • Search Google Scholar
    • Export Citation
  • 7.

    Montgomery RD. Hypertrophic osteodystrophy in dogs. In: Bojrab MJMonnet E, eds. Mechanisms of disease in small animal surgery. 3rd ed. Jackson, Wyo: Teton New Media, 2010; 564569.

    • Search Google Scholar
    • Export Citation
  • 8.

    Muir PDubielzig RRJohnson KA, et al. Hypertrophic osteodystrophy and calvarial hyperostosis. Compend Contin Educ Pract Vet 1996; 18: 143151.

    • Search Google Scholar
    • Export Citation
  • 9.

    Konde LJ. Diseases of the immature skeleton: hypertrophic osteodystrophy. In: Thrall DE, ed. Textbook of veterinary diagnostic radiology. 2nd ed. Philadelphia: WB Saunders Co, 1994; 98101.

    • Search Google Scholar
    • Export Citation
  • 10.

    Franklin MARochat MCBroaddus KD. Hypertrophic osteodystrophy of the proximal humerus in two dogs. J. Am Anim Hosp Assoc 2008; 44: 342346.

  • 11.

    Grondalen J. Metaphyseal osteopathy (hypertrophic osteodystrophy) in growing dogs. A clinical study. J Small Anim Pract 1976; 17: 721735.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Woodard JC. Canine hypertrophic osteodystrophy, a study of spontaneous disease in littermates. Vet Pathol 1982; 19: 337354.

  • 13.

    Collett P. La maladie de Barlow spontanee chez le chien (scorbut infantile). Revue Vet Goulorese 1935; 87: 497.

  • 14.

    Harrus SWaner TAizenberg, et al. Development of hypertrophic osteodystrophy and antibody response in a litter of vaccinated Weimaraner puppies. J Small Anim Pract 2002; 43: 2731.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Crumlish PTSweeney TJones B, et al. Hypertrophic osteodystrophy in the Weimaraner dog: lack of association between DQA1 alleles of the canine MHC and hypertrophic osteodystrophy. Vet J 2006; 171: 308313.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    LaFond EBreur GJAustin CC. Breed susceptibility for developmental orthopedic diseases in dogs. J Am Anim Hosp Assoc 2002; 38: 467477.

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