Presenting signs and clinical outcome in dogs with metaphyseal osteopathy: 39 cases (2009–2018)

Objective To describe the presenting signs, concurrent conditions, treatment and outcome of dogs with metaphyseal osteopathy. Materials and Methods Multi‐centre retrospective review of medical records from January 2009 to September 2018 at four referral centres to identify dogs with a radiographic diagnosis of metaphyseal osteopathy. Results Thirty‐nine dogs were identified. The median age at onset was 14 weeks old (range, 8 to 32 weeks old). There was a higher proportion of male dogs (29 of 39 male entire, nine of 39 female entire, one of 39 female neutered and no male neutered dogs). Where information was available, median time from the most recent vaccination was 20 days (range, 2 to 144 days). The most commonly recorded clinical signs were pyrexia (34 of 39), lethargy (32 of 39), pain (30 of 39), and being non‐ambulatory (17 of 39). Thirty‐five dogs required hospitalisation for analgesia and supportive care, 19 of 39 were discharged on prednisolone (median dose 2.0 mg/kg/day; range, 0.9 to 2.6 mg/kg/day), 18 of 39 were discharged on non‐steroidal anti‐inflammatories, two of 39 did not receive NSAIDs or prednisolone at any time point. The median duration of hospitalisation for those admitted was 5 days (range, 1 to 21 days). Where follow‐up was available, relapse occurred in eight of 25 cases before reaching skeletal maturity. At the time of metaphyseal osteopathy diagnosis, five of 39 cases had concurrent conditions. Where follow‐up was available, four of 25 developed future immune‐mediated conditions. Clinical Significance Metaphyseal osteopathy should be considered in non‐ambulatory painful young dogs. Some dogs developed future immune‐mediated conditions, which may support the hypothesis that metaphyseal osteopathy is an autoinflammatory bone disorder. Further studies with a larger cohort are required to determine the clinical significance of this.


INTRODUCTION
Metaphyseal osteopathy is a rare bone disorder affecting young growing dogs between 2 and 8 months old (Grøndalen 1976, Özer et al. 2004, Safra et al. 2013. Commonly, long bones such as the radius, ulna and tibia are affected (Woodard 1982, Abeles et al. 1999. Other sites such as the humerus, ribs, scapula, femur, mandible and optic foramina have also been reported (Watson et al. 1973, Woodard 1982, Franklin et al. 2008. Large breeds are overrepresented, such as great Danes, Irish setters, Chesapeake Bay retrievers, Weimaraners and German shepherd dogs (Munjar et al. 1998, LaFond et al. 2002.
Common clinical signs include pyrexia, ostealgia and lethargy (Grøndalen 1976, Abeles et al. 1999, Safra et al. 2013. A radiolucent line in the metaphysis parallel to the epiphyseal plate is supportive of metaphyseal osteopathy (Watson et al. 1973, Grøndalen 1976, Demko & McLaughlin 2005. Histopathology of affected bones shows symmetrical, suppurative sterile osteomyelitis, periosteal proliferation and increase in osteoclast numbers (Mee et al. 1993, Joiner & Montgomery 2011. The aetiology of metaphyseal osteopathy remains unknown. Previous theories of vitamin C deficiency (Watson et al. 1973) and overnutrition (Hedhammar et al. 1974, Teare et al. 1979) have since been disproven (Grøndalen 1976, Woodard 1982. A link to vaccination and canine distemper virus has also been suggested; however, findings have failed to be reproduced (Mee et al. 1993, 1995a,b, Munjar et al. 1998. In light of this, alternate theories have been proposed. One theory is that there may be a genetic predisposition to metaphyseal osteopathy in certain breeds. Entire litters and closely related Weimaraners have been affected, supportive of heritability in this breed (Woodard 1982, Abeles et al. 1999, Harrus et al. 2002, Safra et al. 2013. This has also been reported in Australian Kelpie littermates (Greenwell et al. 2014). Recently, it has been proposed that metaphyseal osteopathy is an immune-mediated disease as affected dogs have a cytokine profile similar to that of children with autoinflammatory bone conditions (Safra et al. 2016).
Optimal treatment has not been determined. Treatment is usually supportive with analgesia including either non-steroidal antiinflammatory drugs (NSAIDs) or corticosteroids (Grøndalen 1976, Abeles et al. 1999, Demko & McLaughlin 2005. In a recent study, Weimaraners treated with prednisone had more rapid resolution of clinical signs and shorter length of hospitalisation compared with those treated with NSAIDs (Safra et al. 2013). Outcome is generally good; however, relapse episodes can be seen until growth plate closure (Safra et al. 2016).
The aim of this study was to describe the presenting signs, concurrent conditions, treatment and outcome in dogs with metaphyseal osteopathy.

Study design and inclusion criteria
A multi-centre retrospective case series of 39 dogs with a radiographic diagnosis of metaphyseal osteopathy, presenting between 2009 and 2018.

Medical record search
Medical databases were searched in October 2018 by one operator at each of the four participating four referral centres. A search was performed to identify dogs with a final diagnosis of metaphyseal osteopathy presenting between January 2009 and September 2018.

Diagnostics performed
Diagnosis was based on clinical signs and radiographic evidence of radiolucency parallel to the metaphysis on radiographs or CT images (Selman & Towle Millard 2022). For cases in which a contemporaneous imaging report was not accessible, radiographs, where available, were retrieved and reviewed by a specialist in diagnostic imaging.

Data extracted
Data describing the radiographic changes and bones affected were recorded. The following information was collected from the medical records: signalment, vaccination status, type of vaccine administered and time between last vaccination and onset of clinical signs, clinical signs, history and physical examination findings, treatment and length of hospitalisation. Pyrexia was defined as an increased body temperature (≥39.2°C). Recent vaccination was defined as dogs vaccinated within 30 days before presentation at the referral centre.
The medical records at the diagnosing hospital were reviewed for evidence of relapse and referring veterinary practices were contacted for follow-up information. Follow-up information included any relapse episodes or development of any future conditions. Relapse was defined as a recurrence of clinical signs before reaching skeletal maturity. Future conditions were defined as new conditions which developed after the dog reached skeletal maturity and were included if the information was available about how the diagnosis was reached.
Data were presented descriptively. For normally distributed variables, descriptive statistics are presented as the mean ±sd. Non-normally distributed variables were presented as the median and range.

Vaccination
History regarding vaccination status was available for 37 of 39 (94.9%) dogs; 36 of 37 (97.3%) were vaccinated. The median time from the most recent vaccination to the onset of clinical signs was 20 days (range, 2 to 144 days). Twenty-four (66.7%) vaccinated dogs had been recently vaccinated.
Of the dogs vaccinated, the type of vaccination administered was available in 27 of 37 (73.0%) dogs, protocols are described in Table S1. All dogs received live attenuated vaccines. The most common vaccination protocol was Nobivac Ⓡ DHPPi (for distemper, canine adenovirus type 2, canine parvovirus and canine parainfluenza) in combination with the Nobivac Ⓡ inactivated L2 vaccine (for Leptospirosis interrogans serogroup canicola and icterohaemorrhagiae) (11 of 27; 40.7%).
At the time of diagnosis of metaphyseal osteopathy, five (12.8%) dogs had concurrent conditions (Table 1). Three dogs (7.7%) were diagnosed with inflammatory conditions, suspected to be immune-mediated. These were juvenile cellulitis (one of three; 33.3%), vasculitis (one of three; 33.3%) and rhinitis (one of three; 33.3%). Two dogs (5.1%) had conjunctivitis at the time of diagnosis. One dog (2.6%) was diagnosed with craniomandibular osteopathy. An angular limb deformity was present in one dog (2.6%) at the time of presentation; this was assumed to have developed as a sequala of metaphyseal osteopathy. Three dogs (7.7%) had synoviocentesis performed; synovial fluid analysis revealed neutrophilic joint inflammation in all three (100%) dogs.

Length of hospitalisation
Thirty-five dogs (89.7%) were hospitalised for treatment. Median length of hospitalisation was 5 days (range, 1 to 21 days). The dogs that were not hospitalised were all prescribed NSAIDs [carprofen (two of four; 50.0%), firocoxib (one of four; 25.0%), meloxicam (one of four; 25.0%)]; the dog that was prescribed meloxicam also received methadone at the time of presentation. All dogs survived to discharge.

Outcome
Follow-up information was available for 25 dogs (64.1%); median length of follow-up after diagnosis was 3.2 years (range, 10 days to 9 years). Relapse occurred in eight of 25 (32.0%) dogs; three of eight (37.5%) suffered from multiple relapse episodes. Median time from diagnosis to relapse was 50 days (range, 7 to 212 days).
Of the dogs that relapsed, management of the initial metaphyseal osteopathy episode was as follows: five of eight (62.5%) were discharged on a tapering course of prednisolone (three of five (60.0%) of these had initially failed to respond to a course of NSAIDs), the other three of eight (37.5%) were discharged on non-steroidal anti-inflammatory medication [meloxicam (two of eight; 25.0%), carprofen (one of eight; 12.5%)]. At the time of relapse, four of eight dogs (50%) were on a course of NSAIDs or prednisolone. Of the dogs that relapsed, three of eight (37.5%) went on to develop future conditions (Table 5.).   Where follow-up information was available, five dogs (20.0%) developed future conditions (Table 6). One dog acquired an angular limb deformity (ALD) 4 weeks after the diagnosis of metaphyseal osteopathy. This dog had been diagnosed with craniomandibular osteopathy at the time of metaphyseal osteopathy diagnosis; the ALD was not present during the initial investigations. The other dogs (four of 25; 16.0%) all developed a future immune-mediated disease: panniculitis (one of four; 25.0%), menigiomyelitis and myositis (one of four; 25.0%), vasculitis (one of four; 25.0%), IMPA (one of four; 25.0%) and lymphadenitis (one of four; 25.0%). IMPA was diagnosed by synovial fluid analysis and radiographic evidence of resolution of the pathology associated with previously diagnosed metaphyseal osteopathy. Of the dogs that developed future conditions, three of five (60.0%) had relapses of metaphyseal osteopathy, with two of three (66.7%) suffering two relapse episodes.

DISCUSSION
This study describes the presenting signs, concurrent conditions, treatment and outcome in dogs with metaphyseal osteopathy. There were a high proportion of males in our population. Previous studies containing various breeds found males were 2.3 times more likely to develop metaphyseal osteopathy compared with females (Munjar et al. 1998(Munjar et al. , Özer et al. 2004); this finding was not identified in Weimaraners (Crumlish et al. 2006, Safra et al. 2013. Treatment for dogs with metaphyseal osteopathy in this cohort of dogs included analgesia and anti-inflammatory medication with either NSAIDs or prednisolone. In our group, treatment protocols were based upon clinician preference and subjective assessment of response to treatment. Supportive treatment typically consists of intravenous fluid therapy, analgesia, nutritional support, gastrointestinal protectants and nursing care (Selman & Towle Millard 2022). Many dogs received NSAIDs as first-line therapy. Several different NSAIDs were used with a failed response subjectively evaluated by the attending clinician. It is therefore difficult to assess if dogs may have responded to NSAIDs had a different class been given or a standard protocol been followed. In dogs perceived to have failed NSAID treatment the NSAID was discontinued and prednisolone was prescribed. Prednisolone was administered to most dogs at an immunosuppressive dose (median 2.0 mg/kg/day; range, 0.9 to 2.6 mg/kg/day). In a case series of Weimaraners with metaphyseal osteopathy, there was a quicker resolution of clinical signs when treated with prednisone compared with those treated with NSAIDs (Safra et al. 2013). Prednisone dosage (0.75 to 1.5 mg/kg twice daily) was similar to that of prednisolone used in our population (0.9 to 2.6 mg/kg/ day), however, optimal dosage remains unknown.
It has been hypothesised that metaphyseal osteopathy is induced by vaccination (Mee et al. 1993(Mee et al. , 1995a. Within our study recent vaccination was defined as within 30 days before presentation, as reported previously (Duval & Giger 1996, Safra et al. 2013. Using this definition, 24 of 36 (66.7%) of dogs had been recently vaccinated. Previous authors have suggested that development of metaphyseal osteopathy is triggered by recent vaccination and that an alternative vaccination protocol, with a killed vaccine, should be considered for Weimaraners. This was proposed due to the suspicion of immunodeficiency in this breed (Day et al. 1997, Abeles et al. 1999, Harrus et al. 2002. However, the hypothesis that metaphyseal osteopathy is linked to vaccination is not supported by other study findings (Munjar et al. 1998, Crumlish et al. 2006.
It has been suggested that vaccination can act as a trigger for the development of immune-mediated conditions in people, such as immune-mediated thrombocytopaenia (ITP) (Black et al. 2003). Currently, it is unclear whether vaccination in dogs can act as a trigger for autoimmune diseases such as ITP (Huang et al. 2012) and immune-mediated haemolytic anaemia (Garden et al. 2019). As metaphyseal osteopathy is a juvenile disease and a primary course of vaccination is commonly administered to young dogs (Day et al. 2016, The People's Dispensary for Sick Animals 2018), it is likely that dogs with metaphyseal osteopathy have been recently vaccinated. It is therefore not possible to prove causation between recent vaccination and the development of metaphyseal osteopathy.  Clinical signs most commonly reported within our population were pyrexia (34 of 39; 87.2%), lethargy (32 of 39; 82.0%) and pain (30 of 39; 76.9%); this is in line with the presentation of dogs in prior studies. Our dogs and those in previous study populations also commonly suffered from gastrointestinal signs (Abeles et al. 1999, Safra et al. 2013. Affected dogs can also show concurrent jaw pain and nasal discharge (Safra et al. 2013). Dermatological changes, such as juvenile cellulitis, were present within our study and in previous groups of puppies (Wentzell 2011, Safra et al. 2013.
Radiographic lesion distribution and changes were described within our study. Most dogs had metaphyseal osteopathy diagnosed on radiographs, the others were diagnosed on CT scan. Due to the retrospective nature of the study, it was not possible to determine the clinician's reason for choosing a different imaging modality for these dogs. One dog had lymphadenopathy detected; the remainder had musculoskeletal changes which would be detected on radiographs. In this population of dogs, there appeared to be limited benefit of CT scan compared with radiography for diagnosing metaphyseal osteopathy and concurrent conditions. Lesions commonly were found in long bones and less frequently in other areas (rib, vertebra, mandible, metacarpals, metatarsals); this was in keeping with previous reports (Abeles et al. 1999, Franklin et al. 2008, Joiner & Montgomery 2011, Greenwell et al. 2014. The lesions associated with metaphyseal osteopathy are thought to represent a spectrum of disease, with dogs initially developing soft tissue swelling and a radiolucent line parallel to the metaphysis. This progresses to areas of sclerosis, metaphyseal widening (also known as "flare") and new bone formation (Grøndalen 1976, Demko & McLaughlin 2005. These radiographic changes were all seen within our population. At the time of diagnosis, three dogs (7.7%) had neutrophilic joint inflammation on synovial fluid analysis. From the literature, synoviocentesis does not appear to be routinely performed on dogs with metaphyseal osteopathy. There are two cases where this has been reported previously. A British Shorthair with metaphyseal osteopathy was reported to have neutrophilic joint fluid (Adagra et al. 2014). The other case was a dog that had nor-41 British Small Animal Veterinary Association mal synovial fluid with no evidence of inflammation (Greenwell et al. 2014). From the few previous reports and few cases in our population, it is not possible to determine whether the neutrophilic effusion was a reaction to the metaphyseal osteopathy diagnosed, or if there was concurrent immune-mediated polyarthritis present.
This study provides insight into the disease progression, relapse episodes and other conditions that affect dogs with metaphyseal osteopathy. Relapse in our population was defined as a recurrence of clinical signs associated with metaphyseal osteopathy before the dog reaching skeletal maturity. This was based on the definition of relapse used by previous authors (Franklin et al. 2008, Safra et al. 2013. Relapse rate was 32.0% (eight of 25); this was similar to other studies findings (15.2 to 50.0%) which also suggest that relapse episodes can occur until dogs reach skeletal maturity (Abeles et al. 1999, Safra et al. 2013). Length of time from diagnosis to relapse episode(s) has not been reported previously. In our population, the median time from diagnosis to relapse was 50 days (range, 7 to 212 days). A limitation to the diagnosis of relapse was that further investigations had not been performed for any of our cases during suspected relapse episodes. Ideally, radiography (and other investigations if warranted) would be carried out to confirm that metaphyseal osteopathy is present and to exclude any other disease processes with similar clinical signs (e.g. immune-mediated polyarthritis). It is, therefore, possible that the relapse rate reported here, and in previous literature, may be in excess of the true relapse rate within the population.
Long-term follow-up in dogs with metaphyseal osteopathy has been described in this study. Interestingly, a proportion of our population suffered from concurrent, or future, suspected immune-mediated conditions. Future conditions in our population were defined as those which occurred after dogs reached skeletal maturity. This is in keeping with previous reports that relapse episodes of metaphyseal osteopathy can occur up to the point that dogs are skeletally mature (Abeles et al. 1999, Safra et al. 2013. In this study, there were four of 25 (16.0%) dogs that developed future immune-mediated diseases. Aside from a case report of concomitant juvenile cellulitis in an Australian shepherd puppy (Wentzell 2011), the incidence of immune-mediated conditions in dogs with metaphyseal osteopathy has not been reported. To the authors' knowledge there is no current literature reporting the incidence of immune-mediated diseases in the general population of dogs. An epidemiologic study of insured Nova Scotia duck tolling retrievers (NSDTR) revealed 0.44% suffered from an immunological disease (Bremner et al. 2015). Unfortunately, as they are a small select group of dogs, it is not possible to compare this group of NSDTR to either the general population of dogs or our study population. However, it may be suggestive that the rate of immunologic diseases in the general population of dogs is low. It remains unknown if the development of future immune-mediated conditions is more common in dogs with metaphyseal osteopathy than the general population. However, given the large proportion of these conditions in our dogs, development of immune-mediated disease should be taken into consideration.
Relapse rate was higher in the population of dogs that developed future conditions (60.0%) than the study population as a whole (32.0%). This may suggest that dogs that have relapse(s) of metaphyseal osteopathy could be more likely to develop a future immune-mediated condition.
It has been proposed that metaphyseal osteopathy is immunemediated. Cytokine profiles in dogs show altered cytokine production during active disease and remission (Safra et al. 2013(Safra et al. , 2016. This is suggestive that metaphyseal osteopathy may be an autoinflammatory bone condition similar to chronic recurrent osteomyelitis (CRMO) in children. This disorder is thought to develop due to an imbalance of pro-inflammatory and antiinflammatory cytokines leading to an increase in osteoclast activation (Sharma & Ferguson 2013, Moghaddas & Masters 2015, Hoffman et al. 2017.
A large proportion of people with CRMO suffer from concurrent inflammatory conditions; 19% have skin manifestations (Girschick et al. 2018) and 10% have inflammatory bowel disease (Hoffman et al. 2017). Interestingly, people with an immunemediated disease have been found to be at greater risk of suffering another concurrent, or future, immune-mediated condition (Robinson et al. 2006, El-Gabalawy et al. 2010.
Chronic recurrent multi-focal osteomyelitis (CRMO) is thought to be heritable, with several forms of the disease found to have a genetic molecular basis (Safra et al. 2016, Hoffman et al. 2017. Entire litters and closely related Weimaraners and Australian kelpie dogs have been affected by metaphyseal osteopathy, suggesting that it may be heritable (Woodard 1982, Abeles et al. 1999, Harrus et al. 2002, Safra et al. 2013, Greenwell et al. 2014. Within our study Border collies, Weimaraners and Labrador retrievers were common. It is difficult to comment on the significance of this in the absence of a control group of dogs without metaphyseal osteopathy during the same time period.
Limitations of our study include its retrospective nature, small sample size and lack of follow-up in all cases. Treatment protocols were not standardised, and length of treatment was not recorded in many dogs. The follow-up period varied between dogs which may have led to inaccuracies in reported outcome. It was also not possible to evaluate how all of the other conditions were diagnosed; therefore, the prevalence of immune-mediated diseases may have been under-or overestimated. Given the retrospective nature of our study, it is difficult to draw conclusions about optimal treatment regime. Ideally, a prospective randomised controlled trial would be performed to evaluate the efficacy of NSAIDs versus prednisolone.
In summary, although short-term outcome for metaphyseal osteopathy is excellent, with all dogs within the current study surviving to discharge from hospital, relapse of clinical signs appears common. Optimal treatment and the underlying aetiology remain unknown. The findings of this study suggest a large proportion of dogs diagnosed with metaphyseal osteopathy may go on to develop future immune-mediated diseases, which should be considered in the long term.