History

A 4-month-old 31.6-kg sexually intact male Mastiff with a 24-hour history of signs of severe generalized pain and progressive lethargy was referred to the Veterinary Hospital at the North Carolina State University. The other dogs in the house, including a littermate, were healthy. No prior treatments had been administered.

Clinical and Gross Findings

On physical examination, the dog was lethargic, pyrexic (39.9 °C; reference interval [RI], 38.3 to 39.2 °C), tachycardic (160 beats/min; RI, 90 to 120 beats/min), hypotensive (indirect systolic blood pressure, 79 mm Hg; RI, 90 to 140 mm Hg), and tachypneic (64 breaths/min; RI, 10 to 30 breaths/min). A CBC was performed, and results indicated mild normocytic, normochromic, nonregenerative anemia (5.25 X 10⁶ RBCs/µL [RI, 5.68 X 10⁶ to 8.8 X 10⁶ RBC/µL]; mean corpuscular volume, 66.7 fL [RI, 64.9 to 75.2 fL]; mean corpuscular hemoglobin concentration, 34.3 g/dL [RI, 32.5 to 35.3 g/dL]; and 67,000 reticulocytes/µL [RI, 8,040 to 9,3730 reticulocytes/µL]); moderate neutrophilia (27.0 X 10³ neutrophils/µL; RI, 2.8 X 10³ to 9.1 X 10³ neutrophils/µL) with a left shift (0.9 X 10³ bands/µL); mild lymphopenia (0.3 X 10³ lymphocytes/µL; RI, 0.6 X 10³ to 3.3 X 10³ lymphocytes/µL); and moderate monocytosis (2.2 X 10³ monocytes/µL; RI, 0.07 X 10³ to 0.85 X 10³ monocytes/µL). A serum biochemical profile revealed total hypercalcemia (14.0 mg/dL; RI, 9.5 to 11.1 mg/dL), hyperphosphatemia (9.2 mg/dL; RI, 2.6 to 5.3 mg/dL), hypoalbuminemia (2.6 g/dL; RI, 3.2 to 4.3 g/dL), and high alkaline phosphatase activity (267 IU/L; RI, 12 to 88 IU/L). A venous blood gas analysis revealed ionized hypercalcemia (2.04 mmol/L; RI, 0.90 to 1.32 mmol/L). The dog continued to show signs of pain, despite administration of a constant rate infusion with fentanyl (3 µg/kg/h; raised to 4 µg/kg/h), lidocaine (30 µg/kg/h; raised to 40 µg/kg/h), and ketamine (0.3 µg/kg/h). Treatment with antimicrobials (ampicillin-sulbactam, 22 mg/kg, IV, q 8 h; ceftazidime, 1.2 mg/kg, IV, bolus followed with 1.56-mg/kg/h constant rate infusion) resulted in no improvement of clinical signs.

Thoracic and appendicular joint radiographic examination revealed bilateral moderate irregularity and undulation of the femoral condyles with mild joint effusion, bilateral flattening of the humeral heads, and bilateral distal ulnar retained cartilage cores. Arthrocentesis of carpal, tarsal, femoropatellar, and medial and lateral femorotibial joints bilaterally revealed moderate suppurative cellular infiltrate without an overt etiologic infectious agent. Given the dog's worsening clinical signs despite supportive care and treatment, euthanasia was elected.

Postmortem examination revealed the proximal and distal metaphyses of the humeri, radii, ulnae, and femurs (Figure 1), and tibiae had a variably narrow transverse band of pallor directly adjacent to the physes where minimal manipulation fractured the trabeculae without disruption to the cortical bone. Bilaterally, the articular surfaces of the humeral and femoral heads were roughened. The articular cartilage of the mandibular condyloid processes was diffusely roughened, thickened, and patchy red with a roughly 1.0-cm irregularly round cartilage defect at the medial margins. Numerous teeth showed irregular grooves of reduced enamel along the lingual margins.

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Postmortem photograph of a longitudinal section of the proximal portion of the right femur from a 4-month-old 31.6-kg sexually intact male Mastiff that had been evaluated because of a 24-hour history of signs of severe generalized pain and progressive lethargy. A fracture perpendicular to the primary trabeculae is evident in a transverse band of pallor directly distal to the physis.

Citation: Journal of the American Veterinary Medical Association 259, S2; 10.2460/javma.21.07.0352

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The right kidney had 2 dark-red, wedge-shaped foci with thin, pale rims (acute to subacute infarctions). The mitral valve was mildly thickened, and corrugated with a smooth and glistening surface. There were also wide dark-red streaks throughout the myocardium of the left ventricle and interventricular septum. No other clinically meaningful findings were noted.

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Microbiologic and Histopathologic Findings

Bacterial cultures performed on samples of blood, joint fluid (carpi, tarsi, and stifle joints bilaterally), and urine yielded no growth. Histologically, the resting, proliferating, and hypertrophic zones of the physes of the proximal tibia, distal femur, and mandible were within reference limits but transitioned abruptly to a disconnected, distorted, and markedly elongated ossification zone (Figure 2). The length of the cartilage spicules at the primary spongiosa was within normal limits for a young dog; however, they were not getting thickened by osteoid deposition, and therefore were comprised of irregular, thin, pale to deeply basophilic spicules lined infrequently by scant osteoid with rare transition to fragmented trabeculae that often lacked osteocytes in lacunae; osteoblasts were nearly absent. Subjacent to the physes and within the primary spongiosa, there was a dense band of viable and degenerated neutrophils and few macrophages mixed with fibrin exudate, hemorrhage, and cellular debris. Similar cellular infiltrates aggregated occasionally around the increased number of osteoclasts within intertrabecular spaces and medullary spaces. Microfractures (infractions) were present across the primary trabeculae within these abnormal bands.

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Photomicrographs of sections of the femur from the dog described in Figure 1. A—The resting, proliferating, and hypertrophic zones of the physis are within reference limits but abruptly transition to a disconnected, distorted, and markedly elongated ossification zone. The primary spongiosa is comprised of irregular, thin, pale to deeply basophilic spicules lined infrequently by scant osteoid with rare transition to fragmented trabeculae that often lacked osteocytes in lacunae; osteoblasts are nearly absent. Microfractures (infractions; arrow) are present across the primary trabeculae. H&E stain; bar = 200 µm. B—Directly subjacent to the primary spongiosa is a dense band of viable and degenerate neutrophils, few macrophages, fibrin exudate, hemorrhage, and cellular debris that extended along the necrotic trabeculae. H&E stain; bar = 100 µm (inset, bar = 20 µm).

Citation: Journal of the American Veterinary Medical Association 259, S2; 10.2460/javma.21.07.0352

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The renal tubular epithelium was hypereosinophilic and moderately to markedly swollen, with rare karyorrhectic nuclei and sloughing (necrosis). Widespread, deeply basophilic fibrillar material extended between the tubulointerstitial spaces and within tubular lamina. The cardiomyocytes were multifocally separated, individualized, and replaced by aggregates of neutrophils with associated mineralization. Low numbers of cardiomyocytes were swollen, vacuolated, and had a loss of sarcoplasmic detail. The pulmonic and mitral valvular stroma were mildly expanded by edema and low numbers of neutrophils and plasma cells.

Morphologic Diagnosis and Case Summary

Morphologic diagnoses:

Appendicular skeleton (femurs, tibiae, humeri, radii, and ulnae) and mandible: subacute multifocal moderate to severe fibrinosuppurative metaphyseal osteomyelitis with multifocal infractions.

Teeth: multifocal enamel hypoplasia.

Kidney: peracute tubular necrosis with multifocal dystrophic mineralization.

Heart: mild, multifocal suppurative myocarditis and valvulitis (pulmonic, mitral) with multifocal degeneration and dystrophic, metastatic mineralization.

Case summary: metaphyseal osteopathy (MO) in a young dog.

Comments

The history, clinical, gross, and histologic findings of the case confirmed a diagnosis of MO, which is also referred to as hypertrophic osteodystrophy and is an inflammatory developmental disease with unknown etiology that affects young, growing, large and giant-breed dogs.¹ The typical age of onset for clinical signs is 3 to 4 months of age but can range from 8 weeks to 8 months.^1,2 Studies^3,4 suggest that the disease is an inappropriate inflammatory response of an immature immune system because affected dogs have increased proinflammatory cytokines, even after remission, and respond favorably to corticosteroid treatment. Commonly affected breeds include Great Danes, Boxers, German Shepherd Dogs, Irish Setters, and Weimaraners.² A heritable component has been suggested in Weimaraner³ and Australian Kelpie⁵ dogs.

The pathogenesis of the disease has not been completely elucidated. An association between vaccination with modified-live vaccines and subsequent manifestation of MO has been reported.^2,6–9 However, a study⁶ in Weimaraners assessed the correlation between a major histocompatibility complex allele (DLA-DQA1 locus) and the development of MO and found no association to any particular vaccine, which adds support to the notion that the disease pathogenesis is more likely an incidental event regardless of vaccination. Attempts to determine a specific link between canine distemper virus (CDV) and MO have been performed, with one study⁷ identifying CDV mRNA, through in situ hybridization and PCR assay, within the metaphyseal region in 3 dogs with MO that had been vaccinated with modified-live CDV. Experimental infection of Beagles with CDV identified the presence of CDV in marrow cells, osteocytes, osteoclasts, and osteoblasts, but the metaphyseal lesions were characterized by osteoclast necrosis and lacked inflammatory cell involvement on histologic evaluation.⁸ A later study⁹ looking at 131 cases of MO and 1,757 cases of CDV identified only 2 dogs that had both MO and CDV, and subsequently only identified age as a shared risk factor between the 2 conditions.⁹

Clinical manifestation of the disease can range from mild self-limiting disease to severe systemic disorders that can be life-threatening.¹ Common clinical signs are fever, malaise, anorexia, and lameness associated with the swelling and pain of the metaphyseal regions of long bones.² Other systemic signs include nasal or ocular discharge, diarrhea, vomiting, increased respiratory sounds, and vulvovaginitis.^3,4,10 Abnormal CBC and biochemical results are nonspecific and typically reflect an inflammatory process.¹⁰ For the dog in this report, there were typical inflammatory findings with an additional finding of hypercalcemia and hyperphosphatemia. Although it is reported that young, growing dogs can have high concentrations of serum calcium and phosphorus,¹¹ and that the serum total and ionized calcium concentration can be as much as 1 mg/dL and 0.1 mmol/L, respectively, and higher in younger dogs (< 12 months old), especially in giant breeds,¹² the observed hypercalcemia for the dog in this report was most likely a result from bone remodeling resulting from the disease process. The disease commonly affects the humerus, distal radius, and ulna; however, the femur, scapula, ribs, and mandible may also be involved.² Consistent with this case, bones distal to the carpus and tarsus are usually unaffected. Enamel hypoplasia can also be involved in the disease process.^2,13 Infection with CDV is also a common cause of enamel hypoplasia,^2,13 and definitive association or contribution of CDV infection to findings for the dog in this present report could not be ruled out completely.

Additional findings seen associated with the disease include mineralization in the heart, kidney, lung, liver, and spleen, as well as myocarditis and endocarditis.¹³ Chronicity of clinical signs was associated with more severe and extensive abnormalities.¹³ For the dog in this report, mineralization seen in the myocardium and kidneys was likely a consequence of either dystrophic mineralization, metastatic mineralization secondary to the systemic hypercalcemia and hyperphosphatemia, or both.

The lack of definitive radiographic findings in this case is not unusual. In some animals with MO, alternating, linear radiodense and radiolucent zones in the metaphysis parallel to the physis can be seen, which appears as a double physeal line.¹ Because the signalment and clinical history can mimic other disease processes, antemortem differential diagnoses should include panosteitis, septic physitis, and septic arthritis.² Although panosteitis is reported in similar ages and breeds of dogs, the medullary cavity rather than the metaphysis is affected, which produces different radiographic signs and rarely has accompanying inflammation. In addition, MO appears to be more painful, can cause permanent damage to the physes, and is more likely than panosteitis to be bilateral.^1,2 Septic physitis and septic arthritis were ruled out by aerobic culture.

Treatment for MO is generally targeted at controlling pyrexia and ostealgia.^1,14 Treatments with NSAIDs or corticosteroids are common, with studies^3,4 suggesting the latter being more effective. Most instances of MO will resolve within 7 to 10 days after the onset of clinical signs, with some resolving even without treatment.² Recovery is expected after the physes are closed; however, relapses of pyrexia and malaise have been reported in adults.^1,3 The most common cause of death is owner-elected euthanasia as a result of the affected animals’ signs of pain during initial manifestation or relapse.^1,2