Hypertrophic Osteodystrophy in Dogs

Hypertrophic osteodystrophy (HOD) is a readily diagnosed, inflammatory, and osteoclastic disease process on the metaphyseal side of active physes, predominantly of large and giant breeds [1-21]. The distal radius and ulna are the most often and most severely affected sites with clinical signs. HOD was first reported in dogs in 1935 and was initially called Barlow’s disease [2,7]. HOD has had the synonyms of metaphyseal osteopathy, idiopathic osteodystrophy, osteodystrophy II, canine skeletal scurvy, Barlow’s disease, and Moeller-Barlow disease [1,2,7].1,2,7 The first two synonyms are accurate descriptors, whereas canine skeletal scurvy is not accurate based on comparison of clinical signs, pathophysiology, and etiologies [2].

Etiology

HOD has a cryptogenic etiology despite extensive investigation. Etiologies considered include excessive dietary vitamins and minerals [1-14], vitamin C deficiency [2,10], infectious agents (viral and bacterial) [10,14] immune-mediated inflammatory disease [10,11], a form of osteochondrosis [10], vascular anomalies [8,10], and genetic or familial predisposition [3,10,12]. Whether the etiology is from exogenous (e.g., infectious agents), endogenous (e.g., abnormal metabolism), or a combination of influences is unclear [1,2,10]. However, many proposed etiologies have been ruled out or determined to be unlikely as sole causes.

Dietary causes of HOD that are unlikely include excessive vitamin D, excessive mineral supplementation, excessive calories, and deficient vitamin C (only primates and guinea pigs require dietary vitamin C) [1,2]. Abnormal metabolism of vitamin C remains a possibility [1,2]. Many dogs with HOD have not had vitamin and mineral supplementation, and many dogs on high levels of vitamin and mineral supplementation do not develop HOD. High calorie diets are also much more common among young dogs than is HOD. It appears that, at most, diets that promote rapid growth and/or affect bone formation may contribute to, but not cause, HOD.

Respiratory and/or gastrointestinal disease a few weeks prior to some cases of HOD has prompted consideration of infectious agents as etiologies [2,12]. Distemper and distemper vaccination (modified-live) have been prominent etiologic considerations [2,12,18,19]. Experimentally, evidence of canine distemper virus in bone cells of the metaphyseal region of dogs has been reported [18,19]. However, Koch’s postulates have never been satisfied with regard to HOD. A comparison of multiple risk factors for HOD and canine distemper virus infection based on a Veterinary Medical Database (VMDB) survey concluded that the risk factors were not similar [3]. Although dogs less than 6 months old were identified to be at greatest risk for both diseases, distemper cases occurred over 12 times more often than HOD [3].

Nevertheless, specific vaccination protocols using killed virus, or modified-live measles instead of modified-live distemper virus, or vaccinating separately for distemper, parvovirus, and adenovirus have been proposed for Weimaraners [12,13]. Bacterial infection has also been reported in conjunction with HOD . Which came first was undeterminable, although the debilitating effects of HOD were speculated to allow an opportunistic E. coli bacteremia [14]. An autoimmune or hyper-inflammatory etiology has also been proposed, perhaps initiated by infection [11]. The relative infrequency of HOD compared with suspected infectious agents plus the predominant clinical signs being at the distal radius and ulna make an infectious agent difficult to explain, at least as a sole etiology.

When considering osteochondrosis as an etiology for HOD, details of endochondral bone formation should also be considered. Osteochondrosis affects all physes and includes microscopically visible loss of distinct chondrocyte columns and excessive thickness of the zone of chondrocyte hypertrophy. HOD affects a later step of the endochondral osteogenesis process than osteochondrosis affects and has a different pathophysiology. HOD pathology occurs in the metaphysis immediately adjacent to the physis where primary spongiosum is located and transformation to the secondary spongiosum begins. The area affected by HOD normally has rapid growth, high lysosomal enzymatic activity, and high osteoblast and osteoclast activity [5]. Although vessels do not cross the physis, the metaphyseal side of the physis has an extremely rich blood supply from the nutrient artery and peripherally from metaphyseal arteries (Fig. 94-1A) [2,8]. The normal vascularity of this region is so extreme during rapid bone growth that the distinction between normal and inflammatory is subtle, and based mainly on the lack of pathology. A multitude of small arterioles approach perpendicular to the physis, then make a “hairpin” turn away from the physis (Fig. 94-1B) [8], which affects laminar blood flow. The hairpin turns have been postulated to be “clinically important in growth deformities [8].” Capillary structure here also includes “buds” or dead end capillaries with endothelium that lacks a basement membrane and in places may be open, which allows extravasation of blood into the inter-trabecular sinuses immediately adjacent to the physis (Fig. 94-1C) [5,6]. Ironically, the area immediately adjacent to the last transverse septum of the physis is reported to have low oxygen tension and localized vascular stasis [5], despite the nearby hypervascularity.

Figure 94-1A. Microangiograms of normal immature canine radius. A. Note the extreme hypervascularity in the normal growing dog at the area where HOD occurs.

Figure 94-1B. Higher magnification shows vascular vessels make a 1800 turn at the physis, which slows laminar blood flow.

Figure 94-1C. Higher magnification demonstrates some vessels appear to be “open-ended” to sinusoidal space of relatively stagnant blood.

Rapid endochondral bone formation ostensibly plays a role in HOD, based on the disease’s location and the signalment of affected individuals. HOD occurs only in dogs with open physes Furthermore, HOD tends to coincide with peak metabolic activity of the physis, i.e., at 3 to 5 months of age, in large and giant breeds, and more often in males.

Predispositions for breed and gender were determined for this chapter by a retrieval from the Veterinary Medical DataBase including all participating institutions and from 1994-2004 inclusively (Table 94-1). Seven breeds (Great Danes, Weimaraners, Labrador retrievers, golden retrievers, German shepherd dogs, mixed breed dogs, and boxers) accounted for about two thirds (64%) of all reported cases. The 20 breeds listed in Table Table 94-1 accounted for almost 90% of all cases of HOD, the majority of which were large or giant breeds. Nineteen other breeds had 1 case of HOD each. The number of HOD cases per breed is influenced by the breed’s popularity.

Great Danes and Weimaraners appear to be greatly overrepresented, whereas mixed breed dogs appear to be under-represented, based on HOD cases/100,000 of the breed, which does adjust for breed popularity (calculated for breeds with > 1000 in the survey). For example, the VMDB survey had 2460 Great Danes, 2510 standard poodles, and 2336 border collies, yet Great Danes had 1016/100,000 whereas the latter two breeds had 80/100,000 and 171/100,000 respectively. Weimaraners had 1279/100,000, while 4 breeds with a comparable number of individuals did not exceed 186/100,000. Mixed breed dogs were ostensibly under represented with only 17/100,000. Labrador retrievers (63/100,000) accounted for 30,248 individuals in the VMDB survey (~10% of all dogs), second only to mixed breeds with 63,974 individuals (Table 94-1). Two publications based on the VMDB, but using different methods and different years surveyed, also reported Ca strong predisposition for Great Danes to have HOD, both in number of cases presented and at high risk when adjusted for breed popularity [3,4]. These articles also reported the 7 breeds listed above as having predilection for HOD between 1980-1989, and 1986-1995 [3,4].

Males are slightly more likely to develop HOD, which is irrelevant to diagnosis. However, predisposition toward males may relate to etiology, e.g., males tend to be slightly larger, hence endochondral osteogenesis is more rapid. The male:female ratio was 48:52 for the total population, and was 53:47 for cases with HOD in the VMDB 1994-2004 survey for this chapter. Most other reports indicate no gender predilection, or a slight predilection for males. A study of the VMDB study from 1980-1989 reported males were 2.3 times more likely to develop HOD than were females [3].

Pathology

Inflammation is the overwhelming characteristic seen in HOD. HOD affects a transverse zone of the metaphysis immediately adjacent to the physis, which corresponds to the radiolucent line referred to as a pseudophyseal line (Fig. 94-2A-B). This diseased area consists of massive infiltration of neutrophils and mononuclear cells, hemorrhage, osteoclastic resorption of trabeculae, fibrosis, and necrotic trabeculae (Fig. 94-2C) [2]. Osteoid, which should be developing on the calcified cartilage spicules, is absent [2]. In a few cases, the physis may be of irregular width or abnormally wide, owing to increased length of the zone of hypertrophy [2]. In more severe cases, subperiosteal hemorrhage beginning near the affected metaphysis can occur.

Figure 94-2. A. Pseudophyseal line (solid arrow) just proximal to the physis (hollow arrow) is pathognomonic for HOD.

Figure 94-2. B. Gross sagittal section showing area of bone lysis (solid arrow) on the metaphyseal side of the physis (hollow arrow) which corresponds to the radiolucency of the pseudophyseal line.

Figure 94-2. C. Microscopic section (low magnification/H & E stain) of the same area showing necrosis of mineralized primary spicules and massive inflammation (solid arrow) adjacent to the normal physis (hollow arrow).

New bone formation can occur subsequent to subperiosteal hemorrhage, which elevates the periosteum (Fig. 94-3). The new bone may persist as permanent deformity (abnormally enlarged metaphyseal region, valgus deformity) (Fig. 94-4). The extent of subperiosteal hemorrhage and periosteal new bone formation can be extensive, but this is rare. All bones that develop primarily via endochondral ossification (i.e., long bones, metacarpi) can potentially be affected by HOD [2]. Bone remodeling after HOD results in normal bones in the vast majority of cases. Necropsies performed on fatal cases have reported HOD lesions at the ends of other long bones, ribs, and vertebrae plus diffuse mineralization of pleura, pericardium, aorta, and lungs [10]. Hypertrophic bone lesions concurrent with classic HOD have also been reported in the axial skeleton (calvarium, maxilla, mandible, scapula, vertebrae, costochondral junction of ribs, and ilial wing) [2,10,15,20,21].

Figure 94-3. Severe case of HOD which, in addition to pseudophyseal line, has subperiosteal hemorrhage and subsequent osseous metaplasia.

Figure 94-4. Mature Great Dane with deformity owing to severe HOD as a juvenile, which included extensive periosteal hemorrhage and subsequent new bone formation.

Clinical Diagnosis

Signalment

HOD typically occurs in 3- to 5-month-old (range 2 to 8 months old), large-breed dogs of either gender [1]. The age at clinical presentation for HOD is typically younger than for other juvenile bone and joint diseases of large-breed dogs, although there is overlap.1,2 Great Danes have a greater incidence of HOD than any other breed, and along with Weimaraners are at greatest risk when adjusted for breed popularity (1016 HODs/100,000 Great Danes and 1279 HODs/ 100,000 Weimaraners). Great Danes, Weimaraners, Labrador retrievers, golden retrievers, German shepherd dogs, mixed breed dogs, and boxers account for the majority of HOD cases. Mixed breed dogs ostensibly have a lower risk, with only 17 HOD cases/100,000 mixed breed dogs (Table 94-1).

Patient History

Dogs with HOD typically present with either acute or peracute onset of signs, often of a day or less duration. Mild HOD cases occur, with less severe clinical signs and longer duration prior to presentation; however, mild HOD cases are uncommon in the author’s experience. History typically includes malaise, pain (vocalization), reluctance or inability to stand, and anorexia. HOD is most often a single event in a dog’s life, but can be episodic until skeletal maturity. Because clinical signs of HOD are obvious to owners, a diagnosis of HOD as a juvenile would be expected in the history of the rare adult dog with musculoskeletal deformity due to HOD (Fig. 94-4).

Examination Findings

Bilaterally symmetrical swelling of the distal radius/ulna area is obvious via palpation and often readily visible (Fig. 94-5A). Swelling of the distal tibia/fibula area may also be present but is typically less severe (Fig. 94-5B). Other locations (see Pathology) are uncommon or unnoticed owing to less clinically detectable signs. Gentle palpation of the swollen areas results in a painful to extremely painful response, and excessive warmth of the area is often appreciated. Core body temperature in excess of 104°F is a consistent finding. Dehydration is often present as a consequence of malaise and reluctance or inability to stand. Arthrocentesis of the carpi will yield inflammatory synovial fluid indicative of and owing to the extreme inflammation of the adjacent area; the adjacent joints (carpi and perhaps tarsii) are otherwise not involved in the pathophysiology. Arthrocentesis is not indicated but, if HOD is not recognized, may be performed owing to suspicion of infectious arthritis (infectious arthritis typically occurs in older dogs, affects one joint, and has less pronounced swelling, which is centered over the joint).

Figure 94-5A. A 4-month-old Labrador retriever with HOD. Note the bilateral enlargement just proximal to the carpi.

Figure 94-5B.A 6-month-old golden retriever with atypical clinical presentation of HOD affecting the distal tibia more prominently than the radius/ulna.  

Radiographic Findings

A pseudophyseal line is pathognomonic for HOD (Fig. 94-2A-C) and is located adjacent to and on the diaphyseal side of the physis of the distal radius and ulna (and distal tibia if affected). The radiolucency is due to the attending osteoclasia and osteonecrosis plus the increased fluid density of inflammation characteristic of HOD’s pathophysiology. Subperiosteal hemorrhage and/or calcification may be observed in the metaphyseal area adjacent to the pseudophyseal line (Fig. 94-3). Pseudophyseal lines can potentially be identified on the metaphyseal side of any physis. Osteopathy at other locations (see Pathology) when classic HOD lesions are present may be identified radiographically.

Treatment

Treatments ranging from nothing to corticosteroids have been reported, depending on the severity of clinical signs [2,21]. Treatments limited to correcting diet, symptomatic supportive care, and/or nonsteroidal anti-inflammatory drugs tend to be unacceptably slow or completely ineffective. The author prefers intravenous prednisolone sodium succinate (Solu-Delta-Cortef; Pharmacia & Upjohn Company, Kalamazoo, Michigan 49001 USA) because of its speed and reliability in reversing clinical signs. Other injectable corticosteroids are acceptable, including long-acting corticosteroids. However, it is often unnecessary to repeat even the short-acting prednisolone sodium succinate. Such short-term use of corticosteroids makes side effects unlikely. Nonsteroidal anti-inflammatory drugs may be adequate for mild cases, but are not preferred over corticosteroids.

Supportive care is indicated for severe or refractory cases until clinical signs abate, including administering intravenous fluids, providing a well padded area to lie on, and alternating sides of recumbency at 2-3-hour intervals. Refractory cases may dictate forced feeding. Stress and anorexia may potentiate opportunistic bacterial infections, so blood cultures and/or antibiotics may be warranted [14]. Stopping excessive dietary supplements is probably appropriate. Dietary supplementation with vitamin C and vitamin D may be contraindicated for HOD because of the possibility of promoting dystrophic calcification [2,9,10].

Prognosis

HOD is a single-episode, completely reversible disease in the vast majority of cases. Relapses are infrequent and are treated in the same manner as described above. HOD only occurs while physes are present, primarily in rapidly growing dogs (a function of age and the breed’s size). Cases that develop after 8 months of age are unknown in the author’s experience. Death in treated cases is exceedingly rare. Euthanasia, although uncommon and usually unjustified, is the most common cause of death. Deformity owing to HOD is rare (Figure 94-4), but when present is accompanied by lameness. Lameness is caused by mechanical dysfunction, valgus deformity, and perhaps degenerative arthritis caused by the malformations (ostensibly not directly owing to HOD affecting the joint). The acute pain and other signs associated with HOD are not present in adult dogs with deformity caused by HOD.