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(HOD)
Update 2007: Irish Setters
S. Gary Brown, D.V.M., D.
A.C.V.S.
and
Roy R. Pool, DVM, PhD
Introduction
Hypertrophic
Osteodystrophy (HOD) is a developmental disease in larger breed dogs
(commonly, the Great Dane, Alaskan Malamute, Weimaraner and Irish
Setter). This disease usually begins between the ages of 3 to 4 months
of age. Signs can vary in intensity, and several dogs from one litter
may be affected, although at different times. The heritable
predisposition of the disease has not yet been documented, and the Irish
Setter Health Committee is
supporting research into possible DNA HOD markers. The information in
this paper is based upon current published literature on HOD, treating
10 cases personally and from telephone consultations/e-mail in 104 cases
of Irish Setter HOD over a 5 to 6 year period.
Clinical
Signs of HOD
Dogs affected
with HOD generally present with lameness or reluctance to walk, and
malaise. Early in the disease, the metaphyseal regions of the long
bones, i.e. the area between the diaphysis or mid-shaft of long bones,
and the physes or growth plates will be tender to digital palpation,
slightly swollen and warm when touched by the inside of the examiner’s
wrist. The disease is usually bilateral, most prominently affecting the
distal radial/ulnar metaphysis (above the wrist joints), although the
metaphyses of all long bones
may be affected less dramatically. More adversely affected individuals
are systemically ill, depressed, febrile often reaching 104 – 105.8°F
and anorectic commonly refusing to eat. Dogs with HOD have episodic
symptoms that if not treated will generally experience progressive
clinical signs including persistent high fever, anorexia, rapid weight
loss and metaphyseal pain that accompanies progressive radiographic
signs of epiphysitis and parosteal metaphyseal cuff formation. A few of
the chronically affected individuals that survive the acute episode will
develop radius curvus, and a smaller number of dogs will die.
Pathophysiological
Changes
This is a
systemic disease in which the initial lesion occurs in the osteogenic
capillary bed of metaphyses responsible for invading and replacing the
expanding cartilage model of growth plates involved in endochondral
ossification, a developmental mechanism responsible for growth in length
of endochondral bones. Lesions of HOD are more prominent in the
osteochondral junctions of the most rapidly growing growth plates, e.g.
the distal ulna/radius and distal tibia/fibula, although histological
lesions are commonly present in metaphyseal physes of less rapidly
growing ends of long bones, metacarpal/metatarsal bones, phalanges and
growth plates in ribs and vertebral bodies. The initial lesion is
necrosis of the capillary loops that invade the cartilage model of the
metaphyseal physis. In a normal pup this is a site where the
perivascular mesenchyme comes in contact with the bare surface of empty
chondrocyte lacunae, differentiates into osteoblasts that apply an
initial thin layer of bone tissue to form trabecular systems of primary
metaphyseal spongiosa. In the earliest microscopic lesions of HOD where
the invading capillary bed and its perivascular envelop of osteogenic
precursor cells have died, the germinative layers of the unaffected
growth plate continue
to produce cartilage tissue that sends columns of chondrocytes
having terminal empty chondrocyte lacuna with mineralized walls into the
necrotic tissue at the osteochondral junction. The resulting calcified
cartilage lattice void of a bone-covered surface becomes elongated and
replaces the primary metaphyseal spongiosa. In the absence of its bony
component, the elongated calcified lattice cannot sustain loading from
weight bearing and undergoes microfracture and compaction. The band-like
zone of the necrotic capillary bed and osteogenic cells undergoes
dystrophic calcification. This band also contains a dense neutrophilic
exudate that includes macrophages and osteoclasts. The latter two cell
types attempt to remove this mineralized debris. Resolution of this
initial lesion is recognized radiographically as a zone of increased
radiodensity that gradually undergoes a loss of radio density following
gradual removal of the calcified debris by macrophages and osteoclasts.
Onset of healing of the lesion is marked by reestablishment of the
osteogenic capillary bed and production of primary spongiosa (Trostel,
Pool and McLaughlin).
While
the initial necrotic, inflammatory and early healing response is
occurring within affected bones at the metaphyseal osteochondral
junction, other important but less dramatic changes are taking place in
the soft tissues of the metaphysis in the edematous subcutis and fibrous
tissue superficial to the periosteum in the so-called parosteal (outside
of the periosteum) soft tissues. Immature spindle cells located in the
paraskeletal soft tissues are mesenchymal cells left from the period of
limb formation that are capable of chondrogenic and osteogenic cell
differentiation when properly stimulated. These primitive cells
participate along with mesenchymal cells in the osteogenic layer of the
periosteum to form the external callus in secondary fracture repair.
Apparently, active hyperemia associated with the osteochondral lesions
in HOD is responsible for creating edema of the parosteal soft tissues
overlying the surface of the metaphyses. Sustained edema and likely
inflammatory mediators produced by intra-osseous lesions of HOD
stimulate the parosteal mesenchyme to form coalescing islands of
cartilage and bone that begin to form an annular extra-periosteal
metaphyseal cuff here referred to as a parosteal cuff of mineralized
matrix that first becomes apparent in radiographic images from the
initial stages of HOD when the transverse HOD line is observed. As this
parosteal cuff becomes more radiodense, it progressively obscures the
radiographically diagnostic transverse HOD line. With the passage of
time, the parosteal bony cuff begins to make initial “spot-well”
like attachments through the fibrous periosteum to the cortical bone
surface.
In the healing phase of the HOD lesion there is re-establishment of the
osteogenic capillary bed at the osteochondral junction, invasion and
replacement of the expanding cartilage model of the growth plate by
primary spongiosa and resumption of growth in length of the affected
bones. Two phenomena occur regarding the parosteal bony cuff at this
time. Sequential radiographs demonstrate that the parosteal cuff
“appears” to migrate toward the diaphysis; however, in reality, the
bony cuff has increased its sites of attachment to the underlying
cortical surface, is static and cannot move. But resumption of
longitudinal growth by the physis moves the ends of the bone away from
parosteal cuff. In the absence of effective treatment, the growth plate
disruption may result in reduced bone length or long bone curvature of
paired bones, especially at the wrist, e.g., radius curvus. In my
experience, this is more common in the Great Dane than the Irish Setter.
This less common phenomenon is caused after the parosteal bony cuff has
established “spot-welds” connecting the parosteal cuff to the
cortical surfaces of the epiphysis and metaphysis and has formed a
bridge overlapping the borders of the metaphyseal physis. This bony
bridge acts like a staple that sets the physeal border under
sustained compression when physeal growth is re-established and
the epiphysis attempts to move away from the parosteal bony cuff.
In
fatal cases (Pool, personal communication) in addition to the
aforementioned bone lesions finds not only interstitial pneumonia but a
diffuse pattern of metastatic calcification of the interstitium and
pleural surfaces of the lungs and both epicardial and endocardial
surfaces of the heart and rarely a diffuse periosteal new bony response
involving the surfaces of both rami of the mandible.
Causes
and Predispositions
The cause of HOD
remains unknown; however, there are many speculations. In Weimaraners, a
hyper immune response to some trigger has been noted (Abels, Harrus,
Angles; and Harrus, Waner, Aizenberg). The disease in Weimaraners
closely mimics the disease pattern in the Irish Setters. This is the
rationale for anti-inflammatory prednisone. Stress may precipitate the
disease, including a rapid dietary change over 1 to 4 days. Viral causes
and vaccinations have been implicated, although they too just might be
one more kind of stress, e.g., 3 to 5 days after the third “combo”
vaccine (modified live virus); a second DA2PPV;
or after administration of Rabies vaccines in four- month old puppies
(two cases); or after a fourth (often unnecessary) vaccine at 16 to 18
weeks. 70 to 75% of the HOD cases have followed distemper vaccine 3 or 4
days prior. The causal effect of recombinant (rCDV) vaccine (Recombitek®)
on the initiation of HOD is not yet known. Vitamin C deficiency also has
been speculated as a possible cause; however, there is neither
documentation nor a scientific reason for this in the dog, and Vitamin C
therapy has not met with scientific success. An
infectious origin has been proposed, and there are reports of
hematogenous (blood borne) bacteria producing florid radiographic
changes in the metaphyses similar to those of HOD. An experienced
radiologist may be necessary to distinguish between possible
hematogenous infection, osteomyelitis (bone infection) and HOD
radiographic changes. The authors are unaware of any published
literature correlating blood culture results with HOD.
Diagnosis
Diagnosis is
usually clinical and is supported by radiographic confirmation. Blood
panels are always done. In the early stages there is point tenderness in
the metaphyses. Radiographic changes including HOD lines and beginning
parosteal cuffs may be present as early as one week later. There almost
always is an HOD line to aid one in the diagnosis of HOD! Metaphyseal
regions may remain mildly affected throughout the course of the disease
if well treated, or if poorly treated, may show early irregular widening
with abnormal endochondral ossification and growth plate alterations.
Severe alterations to the growth plate (most often occurring in the
distal ulna), may produce lateral bowing deformities of the front legs
(radius-curvus). CBC will show neutrophilia, with bands of 3% or less.
One should pay attention to the finding of increased numbers band
neutrophils, since that is an indicator of acute sepsis and not a
feature of HOD. The normal acceptable range of neutrophil bands is up to
3% or 300 bands, whichever is lower. Values higher than this indicate
possible sepsis. One treated HOD case was coughing and had slight
pulmonary changes on the radiographs. Pasturella sp. bacteria grew from
a trans-tracheal aspirate. This dog was treated for 8 days with
antibiotics and NSAIDs; then, the dog was changed to the HOD protocol
(with excellent results). We definitely use antibiotics for the first
four weeks.
Treatment
In all cases of
HOD, treatment is begun by immunosuppresive doses of Prednisone, covered
by antibiotics. The dosing regimen is as follows: (1) place the dog
initially on a 1.5 mg/kg/day dose of Prednisone for 4 to 5 days
if symptoms show regression, and up to but not more than 7 days if signs
are persisting, with half given in the a.m. and the other half in the
p.m.; (2) gradually wean down for 6 weeks, cutting the total daily dose
by approximately one-half each week; and (3) administer 5 mg of
Prednisone every other day for an additional 1 to 2 weeks. Supportive
care should be provided as needed. We add oral antibiotics: usually
Clavamox, Simplicef or Keflex for 4 weeks. Also, administer antacids (Pepcid
b.i.d.) to counter acid secretions stimulated by the Prednisone. With
Prednisone treatment, pain medications can be stopped sooner, thereby
avoiding possible appetite suppression often associated with pain
medications. HOD dogs should not be exposed to possible contagious
disease, and owners should be advised not to take their dogs to dog
shows, dogs parks, etc. Revaccination for distemper and Parvovirus is
usually not necessary as the immune system hyperreacts to these. If in
doubt, do distemper and parvo titres indicating possible protective
levels. Don’t invite relapse with a vaccine before 11 -12 months of
age. The prognosis for most cases is good if this protocol is instituted
early. Even in severe cases this protocol has been effective. In our
experience, mild cases are not difficult to treat, whereas the more
severely affected animals require more aggressive care. Those animals
that are not treated early may require IV fluids and electrolytes,
nutritional support, and tremendous nursing care to arrive at a
successful result. Nursing care is paramount in the successful
management of the more severe cases. Mild cases which have been treated
solely with non-steroidal anti-inflammatory may respond incompletely,
and usually have a subsequent relapse. One pup experiencing a severe
relapse had multiple small subcutaneous abcesses. This dog was only on
Amoxicillin for a short period of time – possibly a wider spectrum
antibiotic (Simplicef) could be used for a longer period of time in such
relapse cases. In two
cases of Great Dane HOD, mild puppy strangles (juvenile cellulitis/Staphylococcus
plus toxins) were apparent. The use of Prednisone concomitant with
antibiotics in cases of puppy strangles was critically important.
Conclusion
Early recognition
and appropriate treatment of HOD will hopefully prevent your dog from
reaching a critical state. We hope that some of this information will
assist in making the early diagnosis of HOD, and welcome your feed back.
Thanks to everyone who has shared information with us about Hypertrophic
Osteodystrophy (HOD) cases. This is very informative and important
information.
As a result, a few comments are in order:
1. Be sure sepsis or other infection has been ruled out before
initiating glucocorticoid therapy (Prednisone, Prednisolone). Do a
complete workup, including a full blood panel and chest radiographs. In
the initial stage of the disease there should be a radiographic HOD line
parallel to the osteochondral junction of the metaphysis often affecting
the distal ends of paired long bones for a diagnosis of HOD! However,
remember that the parosteal cuff in time will progressively obscure the
intial radiographic finding should you be presented with the dog in the
later stage of HOD.
2. The dosing regimen is as follows: (1) place the dog initially on a
1.5 mg/kg/day dose of Prednisone for 4 to 5 days if symptoms show
regression, and up to but not
more than 7 days if signs are persisting, with half given in the
a.m. and the other half in the p.m., (2) gradually wean down for 6
weeks, cutting the total daily dose by approximately one-half each week,
and (3) administer 5 mg of Prednisone every other day for an additional
1 to 2 weeks.
3. Cover with Clavamox, Simplicef or Keflex for at least four weeks.
4. Administer antacids (Pepcid twice daily) to counter acid secretions
stimulated by the Prednisone.
5. Two HOD cases also evidenced sore mandibles before breaking with
overt HOD. These
cases showed more tenderness than that normally associated with normal
puppy teeth eruptions.
6. Relapses occur in 20 to 25% of cases, and are treated as the initial
protocol suggests (with the use of antibiotics again too). One third of
these cases can not come off low doses of Prednisone for about 9 – 10
months.
S. Gary Brown
Roy R. Pool
Thank
you to Drs. Brown and Pool for this important information about HOD.
________________________________________________________________________
Trostel, C.T.;
Pool, R.R.; McLaughlin, R.M.:
Canine Lameness Caused by Developmental orthopedic Diseases, in Compendium
volume 25(4). Pp282-293; April 2003.
Abeles,V.; Harrus, S.; Angles, J.M., et al: Hypertrophic
Osteodystrophy in six Weimaraner puppies with Systemic Signs, in Vet
Rec 145:130-134; 1999.
Harrus, S.; Waner, T.: Aizenberg, I.; et al: Development of
Hypertrophic Osteodystrophy and Antibody Response in a Litter of
Vaccinated Weimaraner puppies.Journal of Small Animal Practice 43:
27-31, 2002 |
