Sample Thesis/Dissertation Title Page: To be used as an example only

CHAPTER 1: INTRODUCTION TO THE PROBLEM OR ISSUE

This study of hypertrophic osteodystrophy (HOD) gathers and provides the existing known theoretical causes and preventions in an effort to expand on, clarify, support and/or discredit said theories. It suggests new theories with the hope that they may be considered for future studies and that their application will help to drastically reduce the occurrences of this disorder from the canine population.

Large and giant breeds of dogs have much more accelerated growth rates in relation to other breeds of dogs in order to reach their mature sizes in the same amount of time. During normal enchondral ossification, the diameter of the bones at the growth plates increases dramatically in size in proportion to the enchondral turnover in the metaphysis. The cortices thicken as the growth rate slows and the bone diameters are reduced. Once the dog is about eleven to thirteen months of age, the growth plates close and disappear. The earlier swellings are gone and the entire bone is remodeled with a cortex extending from and through the entire length of the proximal and distal metaphyses.

The peak activity of the enchondral ossification begins at about four months of age and is most noticeable at five to six months of age. This is when the diameters of both the radius and the ulna metaphyses are their largest, up to twice what it will be when the animal is an adult. The ulna becomes about one and a half times the size of the radius. The radius growth is seventy percent at the distal end and thirty percent at the proximal end. The ulna grows at the rate of eighty-five percent on the distal end and fifteen percent on the proximal end. Since their growth plates develop at different rates, the longitudinal growth of the two bones needs to be equal or bowing and malformations will occur. Because the radius and ulna grow very rapidly and at unequal rates, they are the first bones to exhibit signs of developmental abnormalities. Excess nutrition, supplementing an otherwise normally balanced diet, feeding an abnormal diet, exercise, injuries, disorders acquired from viruses and bacteria or effects from vaccinations can all influence the bone growth and structure.

Statement of the Problem or Issue

HOD is a bilaterally symmetric, developmental skeletal abnormality involving the swelling of the metaphyseal areas of the long bones in young, rapidly growing, large and giant breed dogs. The metacarpals, mandible, maxilla, scapula, costochondral junctions of the ribs and the anterior border of the ilium can also be affected. The large bony swellings are the result of a fibrous thickening of the periosteum accompanied by periosteal new bone formation (Meier, Clark, Schnelle, & Will, 1957). Ossification can occur in the soft tissues outside the periosteum as well as calcification of the aorta, endocardium, lungs, and kidneys (Riser & Shirer, 1965). It generally occurs between two and eight months of age, the ages of the most rapid growth when the physes are open. HOD is a very painful disorder causing lameness or refusal to walk from the extremely swollen and feverish long bone metaphyses. Additional symptoms include anorexia, weight loss, fever, diarrhea, bone deformation, and depression which at present can only be treated symptomatically (Grondalen, 1976). It will occur sporadically and sometimes with multiple recurrences or relapses. Dogs have died from the disorder possibly due to the release of toxins from the dying tissues within the bones.

The etiology of this disorder is unknown, yet many theories abound such as vitamin C deficiency, excess vitamin C, excess protein, excess nutrition, excess calcium or phosphorus, genetic or familial tendency, viral infection and blood infection. Some of these theories are not only contradictory, but also controversial and veterinary treatment will vary widely depending upon what the veterinarian determines to be the cause of the illness. For almost each of the above possible causes of HOD, there is an opposing study that negates the same cause. Almost everyone agrees that HOD is probably brought on by more than one factor and most of those factors are considered to be nutritional. Coffman (2002) found “about 22% of dogs less than one year of age are affected by developmental skeletal disorders and more than 90% of these cases are influenced by nutrition” (p. 30). HOD is endemic to the large and giant breeds of dogs. Since approximately 26% of the dog population is comprised of both large and giant breeds, this represents over a quarter of the canine population and the same level to a veterinarian’s case load (Tryfonidou & Hazewinkel, 2003). It is generally accepted that such breeds have a predisposition to this malady. Owners often opt for euthanasia because of the difficulty in controlling the pain and overcoming the illness, as well as not being able to afford the expense incurred in fighting it. Freedom from HOD occurs only when the animal reaches skeletal maturity. Recurrences often occur during growth, forcing both the owners and the animals to go through the pain and the treatments over and over again.

Background and History

HOD was first reported in 1935 in Europe by Collett and Morell (as cited in Meier et al., 1957). The disorder has had many names and has been referred to as skeletal scurvy, infantile scurvy, Moeller Barlow’s disease, osteodystrophy type I, osteodystrophy type II, hypo or avitaminosis C, metaphyseal osteopathy and metaphyseal dysplasia (Özer, Altunatmaz, & Gülçubuk, 2004). Grondalen (1976) thought the name of the disorder should be metaphyseal osteopathy (MO) “since the aetiology is still unknown, because hypertrophy does not always develop (the present study) and since the metaphyses are affected” (p. 721). Even though HOD usually affects dogs of large and giant breeds, even medium sized breeds have been affected. It occurs during the growth period, when the long bones are actively lengthening. Giant breeds have to grow much faster than any other breed during the same period of time to reach their adult size. For this reason they are the number one affected breed group. Another factor that influences this group is that many owners obtain giant breeds for the status enjoyed by owning a very large dog. They want a “super specimen” (p. 50) and they try to create the biggest animal that they can raise (Riser & Shirer, 1965). In their efforts to have such a large animal, they not only look for puppies from the biggest breeding stock, but they also over-feed the puppies and give supplements to them in the hopes of increasing their size, which is actually genetically determined. So it turns out that even with all of that pushing by the owners to grow bigger animals with the resulting damage caused to the puppies, the animals would never get any larger than their genetic potential would allow.

HOD is not only debilitating to the animal, causing deformation of their bones and extreme pain, high fever, anorexia, diarrhea, and depression, but it can also cause death either directly from the disorder, mishandling of the malady through inappropriate treatments, or indirectly through the owners’ decision to euthanize the animal. Since no one has isolated a single cause for HOD, prevention of the disorder is difficult to accomplish. Veterinarians are presently left with only being able to treat the symptoms and then hope for the best. They can try to educate their clients about HOD, but until a true cause that initiates it is found, they can only tell their clients about what they believe to be the factors that may bring on the illness.

Research Questions

What are the true causes of hypertrophic osteodystrophy?

What can be done to prevent HOD?

Does excess nutrition cause HOD?

Does excess calcium or vitamin D cause HOD?

Does vaccinosis cause HOD?

Does vaccinosis cause poor immune systems?

Does a poor immune system cause vaccinosis?

Does the thymus gland failure cause a poor immune system?

Significance of the Study

Presently HOD is a disorder of young, rapidly growing puppies involving the metaphyseal areas of the long bones. It is unknown why calcium is not properly absorbed causing inflammation, intense pain, fever, anorexia, depression, enlargement and deformation of the affected bones and sometimes death. The cause has yet to be discovered, yet at least 26% of the canine population has the potential to become affected. Presently, animals and their owners are at the mercy of their veterinarian’s knowledge regarding treatments. Since no one factor has ever been determined to be the main cause of the disorder, veterinarians have to guess as to the reasons for it to surface for that particular dog. If one true single cause can be identified, prevention of the disorder can be universally applied. The illness can then be addressed and overcome without having to do lengthy symptomatic treatments that do not always help and sometimes even hinder both the health and the recovery of the animal.

Of the many possible factors that may cause HOD, the most prominent one seems to be that of excess nutrition which encompasses calcium, phosphorus, vitamin D, and calories (energy). Excess nutrition is followed by the lesser causes of genetic and breed tendencies, vaccinosis, a poorly functioning immune system, bacterial and blood infections.

Definition of Terms

ACTH - (Adrenocorticotropin), a hormone of the pituitary gland that stimulates the

adrenal cortex.

Aetiology - The origin or cause of a disorder that is determined by medical

diagnosis.

Analgesic – Medication which is capable of reducing or eliminating pain

without causing a loss of consciousness.

Anorexia - Loss of appetite for food especially as a result of illness.

Antebrachium - The part of the arm or forelimb between the elbow and the wrist.

Articular – Relating to a joint or joints.

Brachium - The upper segment of the arm or forelimb which extends from the shoulder

to the elbow.

Cachexia - Weight loss, wasting of muscle, loss of appetite, and general debility that can

occur during a chronic disorder.

Calcific – Relating to the forming or depositing of calcium salts.

Calcitonin - A peptide hormone produced by the thyroid gland that

lowers plasma calcium and phosphate levels.

Carpals - Any of the bones of the wrist joint that join with the radius, ulna or

metacarpal bones.

Cartilaginous –Having to do with cartilage or the texture of cartilage.

Chondrolysis - The disappearance of joint cartilage as the result of the

breakdown of the cartilage matrix and cells.

Chronicity - A slow and progressively serious illness of indefinite duration.

Corticosteroids - Any of the steroid hormones (including synthetics).

Costochondral – Relating to the ribs and their cartilage joints.

Diaphysis – The shaft of any long bone.

Distal - Anatomically located far from a point of reference, such as a point of

attachment.

Dysplasia – Abnormal development or growth of tissues, organs, or cells.

Enchondral – Within a cartilage or cartilaginous tissue.

Epiphysis - The end of a long bone that is originally separated from the main bone by a

layer of cartilage but that later becomes united to the main bone through

ossification.

Erythrocytes - Red blood cells that contains hemoglobin and transport oxygen.

Haematology – The science of the blood and the blood producing organs.

Histopathology - The science of the cell design and organizational structure of

abnormal tissue.

Hypercalcaemia - An abnormally high concentration of calcium in the blood.

Hypercalcitonism – An excess of calcitonin causing retardation of bone remodeling (Newell, C. M., 1996).

Hyperthermia - Abnormally high body temperature.

Hypertrophic - To grow or cause to grow abnormally large.

Hypertrophic osteodystrophy (HOD) – A disorder of the metaphyses in the long bones of young, growing dogs.

Hypervitaminosis - Any of various abnormal conditions in which the physiological

effect of a vitamin is produced to a pathological degree by excessive intake of the

vitamin.

Hypoparathyroidism - A condition due to a reduction or absence of the secretion of the

parathyroid hormones.

Hypovitaminosis - Insufficiency of one or more essential vitamins.

Lymphocytes - Any of the nearly colorless cells formed in lymphoid tissue.

Lymphocytosis - A condition marked by an abnormal increase in the number of

lymphocytes in the bloodstream, usually resulting from infection or inflammation.

Metaphyseal - Of or relating to a metaphysis.

Necrosis - Death of cells or tissues through injury or disorder, especially in a localized

area of the body.

Neutrophils – A neutrophil cell, especially an abundant type of granular white blood cell

that is highly destructive of microorganisms.

Osseous - Composed of, containing, or resembling bone.

Osteochondral - Relating to or composed of bone and cartilage.

Osteoclast - A large multinucleate cell found in growing bone that resorbs bony tissue, as

in the formation of canals and cavities.

Osteolysis - Dissolution or degeneration of bone tissue resulting from disorder.

Osteopathy - A disorder of the bone.

Osteodystrophy - Defective formation of bone.

Panosteitis - Inflammation of all bones.

Paramyxovirus – A group of viruses including those causing munps and measles.

Periosteum - The thick fibrous membrane covering the entire surface of a bone except its

articular cartilage and serving as an attachment for muscles and tendons.

Physes – Plural of physis (growth plate).

Proximal - Nearer to a point of reference such as an origin, a point of attachment, or the

midline of the body.

Pulmonary osteoarthropathy – Expansion of the distal ends or entire shafts of the long

bones, which is sometimes associated with erosion of the articular cartilages,

thickening of the vascular projections of the synovial membranes.

Pyoderma - A pus forming skin disorder.

Spongiosa - The part of a bone made up of spongy, porous type bone.

Subperiosteal - Situated or occurring beneath the periosteum.

Suppurative – Something that makes pus.

Systemic - Of, relating to, or affecting the entire body or an entire organism.

Tarsals - Of, relating to, or situated near the ankle of the foot.

Trabeculae - Any of the fine needlelike structures forming a network in porous bone.

Thyroxine – An iodine containing hormone produced by the thyroid gland.

Triiodothyronine – a crystalline iodine hormone derived from thyroxine.

Vaccinosis – Vaccinosis is a disorder syndrome caused by a weakness that is precipitated by vaccination. (Loops, C. E., 1998).

CHAPTER 2: REVIEW OF RELATED LITERATURE AND RESEARCH

Definition of HOD

Hypertrophic osteodystrophy is a developmental disorder of the metaphyses in long bones of young, growing dogs, usually of a large or giant breed. The exact etiology is unknown, although excessive dietary supplementation is suspected. The pathophysiology is based on metaphyseal vascular impairment leading to a failure in ossification and trabecular necrosis and inflammation. Clinical signs include bilateral metaphyseal pain and swelling in the distal radius and ulna, fever, anorexia, and depression. Clinical signs may be periodic. Angular limb deformities may develop in severely affected dogs. Radiography reveals metaphyseal bone lucencies and circumferential periosteal bone formation. Therapy is symptomatic and aimed at relieving pain (eg. NSAID), reducing dietary supplementation, and providing supportive fluid care. (Merck Veterinary Manual, 2006)

Original Studies of HOD: 1930-1970

As more researchers tried to determine the cause of hypertrophic osteodystrophy, more names were used for the disorder: skeletal scurvy, infantile scurvy, Moller-Barlow’s disease, and osteodystrophy. Some of the earliest studies of HOD were made in the 1930’s by researchers Collett, Gregoire and Morell (as cited in Meier et al., 1957). The name of Barlow’s disease was applied after assuming that the canine form was similar to human scurvy or rickets. This was a common mistake made by veterinarians at the time. It was only after continued study and follow-up of these HOD cases that it was discovered that these animals actually had different symptoms from what a vitamin C deficiency would exhibit. Once that occurred, new names were given to the disorder and new study directions began to take place.

Vitamin C Deficiency

The original studies of HOD were concentrated on the belief that a vitamin C deficiency or the lack of its synthesis was the cause of the disorder. The assumption of Meier et al. (1957) was that a vitamin C deficiency would cause the animal to develop scurvy or rickets as it does in humans. When radiographs were used to determine the extent of the damage early in the disorder, the lesions were comparable to clinical rickets. But as the disorder progressed, the lesions extended along the length of the long bones and into other areas of the body and would often reoccur thus eliminating the rickets diagnosis. Blood values were run on calcium, phosphorus, alkaline phosphatase levels and results came back as being normal. Various treatments were applied, including adding calcium, vitamin D, multivitamins, steroids, antibiotics and antihistamine applications. Sometimes they seemed to help but often there was no change or the animals became more ill. When checking for vitamin C levels in the blood, it was found that the levels were low. Vitamin C therapy was used with no results and improvement appeared only after growth had ceased. At that time, the plasma vitamin C levels became normal. They found that by applying vitamin C either intramuscularly or orally, the blood serum levels would rise only temporarily or it would not raise the blood serum levels to normal, nor would it immediately provide a remedy to the dogs. Instead, it was noted that it took several months for the vitamin C levels to rise to normal and that was only when the animals were no longer ill which was usually when they reached their adult size. Hence a diagnosis of hypovitaminosis C was given. “It was hypothesized that since the ascorbic acid levels did not persist, the vitamin C given was destroyed, excreted, or utilized more rapidly than normal” (p. 491). It was already known at that time that the dog is capable of synthesizing vitamin C and does not need it added to the diet under normal conditions, but this did not influence their deductions. They did not consider other causes for the reduction of vitamin C levels or that the levels may have actually been normal for those particular cases.

Excess of Calcium or Vitamin D

Three groups of Great Danes were studied by Riser and Shirer (1965) to determine developmental changes caused by different calcium levels. The puppies were put on various diets containing high, normal and low levels of calcium through ages seven to twenty-one weeks. They found that feeding both high and low calcium diets caused a multitude of growth disturbances in the bones, particularly of the long bones. The puppies that were fed the high calcium diets had retardation in the development of the long bones (HOD). The puppies that were fed the low calcium diets developed severe nutritional hyperparathyroidism. It was also noted that home supplementations had usually been fortified with vitamin D, often the irradiated form. One milligram of irradiated vitamin D is equal to fourteen teaspoons of pure cod liver oil in its metabolic effect. Vitamin D toxicity depends upon the calcium to phosphorus ratio. “Each increase in the diet of calcium results in an increased severity of hypervitaminosis D. The greater the amount of calcium available for absorption, the greater the hypercalcemia and metastatic calcification” (p. 63). If vitamin D is increased without increasing the calcium levels, the cortical bone is drawn from to provide the blood calcium levels required. When they found a seven month old Great Dane with hypertrophic osteodystrophy also exhibiting ossification of the endocardium, aorta and kidneys, it verified their position that HOD is caused by vitamin D toxicity.

Newer Studies of HOD: 1970-1990

Vitamin C Deficiency Supported

During the 1970’s, the nutrient that received the most attention in feeding studies was vitamin C. Multiple studies proclaimed contradictory results of either vitamin C being deficient or it was not a factor in the disorder. While acknowledging that dogs can synthesis their own vitamin C requirements and do not need its addition to the diet, Bennett (1976) still agrees with the supposition that the disorder is most likely caused by a lack of vitamin C. He mentions that increased requirements, antagonist actions, utilization failure, storage failure and excessive urinary excretion of the vitamin as being possible reasons to consider vitamin C deficiency as the cause of the disorder. But antirachitic therapy not only did not cure the disorder, it also made it worse. He does include the possibility that the diet may also be over supplemented with minerals and vitamins, thereby causing the condition due to lack of proper nutritional balance. Väänänen & Wikman (1979) also support the vitamin C deficiency theory with clinical cases performed on two dogs that came in with HOD. Based on previous case studies, they gave 3000 mg of ascorbic acid intravenously each day. Both dogs had been previously fed homemade rations with calcium levels of up to 5 times higher than the proper level. When the diet was corrected and the vitamin C was added, the dogs soon became better and the vitamin C therapy was attributed to their recovery. The corrected diet was not considered as the “real” reason for the recovery. They did mention the possibility of an infectious agent being the instigator of the disorder due to the additional symptoms of diarrhea and fever, supported by the idea that a vitamin C deficiency would lower immunity and increase risk of infection, even though antibiotic therapy did not correct the symptoms.

Vitamin C Deficiency Contraindicated

Vitamin C deficiency has been disproved to the point of contraindicating its supplementation for an animal with HOD. It has now been shown that not only does the addition of vitamin C not help cure the disorder; it can result in a higher serum calcium level which in turn, through hypercalcitoninism, can significantly diminish bone resorption even more than the original HOD. Grondalen (1976) maintains that vitamin C was not a causative factor. He states that the low vitamin C plasma levels could possibly be related to “exercise, food intake as well as the presence of stress conditions. Due to the disease, the dogs suffering from MO were under stress, and food intake had been limited” (p. 733). Pain will cause stress and stress has been found to reduce vitamin C levels. The food limitation alone could have been the healing factor by cutting the amount of calories and calcium, but it was not considered. The mineral and vitamin overloading theory was discounted and an infective origin was suggested as the cause of HOD, mainly due to the fevers and diarrheal symptoms. Sixteen of twenty-four dogs had diarrhea the week prior to HOD symptoms and had also been vaccinated for canine distemper and canine infectious hepatitis within the first six weeks before symptom onset. Three of the dogs treated with antibiotics, corticosteroids and ascorbic acid were euthanized and another died. Eight other dogs that were treated with antibiotics or antibiotics and corticosteroids recovered. Six that were not given any treatment also recovered. He compared children with rickets who responded well to vitamin C therapy to dogs with HOD on vitamin C therapy which did not respond. “Based on these observations, the theory of vitamin C avitaminosis as the only aetiological factor in the disease, seems unreasonable” (p. 733). That is because the dogs with HOD had very high fevers in comparison to the low fevers that children have had with skeletal scurvy. When vitamin C was given, no improvement occurred. Teare, Krook, Kallfelz, & Hintz (1979) followed up with a study on ascorbic acid levels in both normal adult and normal growing Labrador Retrievers. Before beginning the feeding study, they took blood samples from all of the dogs for their baseline data and found that the young, growing group of dogs had significantly higher plasma ascorbic acid levels than the adults. They then fed the Labrador puppies rations high in protein, energy and calcium content which resulted in the typical skeletal disorders of over-nutrition, including HOD. The puppies were tested and found to have a reduced level of vitamin C during the disorder process. They gave these puppies half a gram of ascorbic acid orally twice a day. This not only did not help relieve the HOD symptoms, it caused an increase in higher serum calcium values (hypercalcemia) which created hypercalcitoninism which then caused even less bone resorption by lowering the parathyroid activity. It also aggravated the osseous lesions of HOD causing more inflammation to the joint areas. They attributed the decreased vitamin C levels to the stress caused by the pain from the illness the animals endured. As time passed and other studies proved that vitamin C did not help HOD, different causes began to be investigated.

Excesses in Nutrition

Excess nutrition is playing out as being the strongest factor that could be causing HOD. Within this generalization are the subsets of ad libitum feeding, the excess intake of calcium to phosphorus ratio, and excess calories in general.

Ad Libitum Feeding

Ad libitum versus restricted feeding practices were first studied by Hedhammar et al. (1974). They found that bone deformation occurred within 3 weeks of an ad libitum diet. The epiphyseal plates closed earlier, the metaphyses broadened and increased in density and further extension of the secondary spongiosa occurred along with the excessive nutrition the dogs ate when they were allowed to have however much food they wanted. They also found that the increased calcium ingested caused an increase in the gastrin production which in turn caused hypercalcitoninism. This inhibited cartilage maturation and the remodeling of the cortical bone into osteonic bone was delayed, causing the typical radius and ulna epiphyseal-metaphyseal enlargements. Mismanagement of the dog’s diet by allowing it to be fed ad libitum can create not only obese animals and damaged joints and ligaments during growth, but ad libitum feeding can also cause excess nutrition and energy intake even when feeding foods prepared for large breed puppies. These foods have been formulated to provide more nutrition in less volume but have also been formulated to taste very good. This causes the ad libitum animal to over eat, thus taking in excess calories and nutrients (Kronfeld, 1985).

Calcium Excess

In an effort to find out if calcium was the culprit for the developmental damage on young bones, Hazewinkel, Goedegebuure, Poulos, & Wolvekamp (1985) conducted a study by increasing the calcium in the diet of young, growing puppies to almost 300% above normal while keeping all other nutrient levels at the National Research Council’s Nutrient Requirements of Dogs recommendations. They determined that excess calcium (without proportionately balancing with phosphorus) causes a narrowing of the spinal column, radius curvus syndrome, hypercalcemia, hypophosphatemia, hypermineralization of osteoid, decreased osteoclastic activity and insufficient remodeling of the growing skeleton. Enchondral ossification is disturbed, cartilage maturation is retarded and bone resorption is decreased. Excess calcium also caused higher amounts of calcitonin producing C-cells in the now under active thyroid gland.

The bioavailability of calcium is affected by vitamin D, phosphorus, protein, fat, lactose, fiber, acidity and alkalinity. Phosphorus in phytic acid or phytin is unavailable for absorption and hinders the intake of calcium, iron and zinc. The absorption of phosphorus is directly affected by the absorption of calcium. Kronfield (1985) recommends feeding the National Research Councils’ suggested ratio of calcium to phosphorus (1.1:.9). When feeding meat which has a high calcium to phosphorus ratio (.02:.04) or corn grain (.03:.3), supplemental calcium needs to be added to correct the ratios. Feeding corn based foods will cause a protein deficiency if not corrected. Soybean meal is often added but it contains phytin which will depress the calcium availability, so a lot of calcium is supplemented to these diets, but excessive calcium impairs the absorption of zinc, copper and iodine and may cause vitamin D toxicity.

Infectious Agents

The symptoms of HOD do include high fever, upper respiratory symptoms and diarrhea. Because these symptoms often indicate an infection is present, studies were run to try to determine if indeed there was an infection and what caused it. Grondalen (1976), Woodard (1982), and Lenehan and Fetter (1985) all postulated that an infection may be present due to the fever, diarrhea, and the band of viral cell infiltration in the metaphysis, although they could not identify the source of the infections.

Gregory (n.d.) contends that symptoms of a blood infection or septicemia, which she has named “Pseudo-HOD” (para. 3) and HOD symptoms are almost the same. She claims that the cause is myelitis and that the use of chloromycetin, generically called Chloramphenicol, should be given to wipe out the infection. Chloromycetin is the only antibiotic that crosses Mother Natures’ barrier which protects the brain, the spinal cord, mammary glands and bone marrow. She performed no scientific studies, but instead, relied upon her experiences with her own dogs and anecdotal reports from other dog owners.

Vaccines and Immunodeficiency

Vaccines first came under scrutiny in the late 1960s. A study by Wiktor, Doherty and Koprowski (1977) on immunosuppression with regard to rabies in mice found that not only did the live virus cause the immune response to fail, but the killed virus had the same effect. It had always been previously thought that because the virus was killed, there would be no immunosuppressive effects. Immunosuppression is not restricted to virulent viruses. The vaccines for measles, mumps, rubella, polio, yellow fever and influenza also have immunosuppressive effects. Vaccines have lately been more commonly offered in polyvalent form containing multiple viral and bacterial components. What few studies already existed covered only the monovalent vaccines. Little was known about the vaccine virus interactions and their immunosuppressive until Phillips, Jensen, Rubino, Yang, and Schultz (1989) found that the polyvalent vaccines significantly suppressed the lymphocyte count and response to mitogens and that these effects lasted up to a month or longer. When the vaccines were given individually, this did not occur. When canine distemper virus (CDV) was combined with canine adenovirus type-1 or type-2, significant suppression again occurred. Those results indicated that combining CDV with canine adenovirus type-1 (CAV1) or canine adenovirus type-2 (CAV2) in polyvalent vaccines induced significant lymphocyte suppression. It was determined that such immunosuppression could allow the animals to exhibit clinical signs, especially if the animal was already in a partially immunosuppressed condition such as being nutritionally deficient. This could cause an underlying disorder or infection to become clinically apparent.

Recent Studies of HOD: 1991-2007

Vaccines, Vaccinosis and Immunosuppression

The issue of vaccinosis has continued to grow and is now considered as a rather large factor in causing HOD for many dogs, Weimaraners in particular. Studies have shown that other breeds such as the Boxer, Great Dane, Irish Setter, and German Shepherd often succumb shortly after receiving their polyvalent vaccines. Unfortunately, the majority of veterinarians discount the idea or even the possibility of the existence of vaccinosis. The average veterinarian builds his/her practice around an annual vaccination program that is generally required of every client’s animal. A major source of their income would be lost if those vaccines are not given on a yearly basis. As the public becomes more educated on what vaccines can and cannot do for their animals, these practices will begin to suffer from clients withdrawing and searching for veterinarians more amendable to newer practices. Once veterinarians accept that vaccines can and do cause acute and chronic illnesses, they would be able to redesign their practices to embrace preventative medicine with a more holistic approach, employing “wellness” checkups, titering immune levels and vaccinating only when there is a need instead of pushing frequent, unnecessary or harmful vaccines, particularly on dogs already ill, which is contrary to label instructions. This new approach would bring in more clients due to the more caring presence of the vet and the more inclusive alternative options the veterinary practitioner offers. A State of the American Pet Survey of 2001 dog and cat owners sponsored by Health Pets 21 Consortium found that “41% of pet owners had considered or tried various alternative therapies, including nutritional supplements (29%), herbal remedies (7%) and homeopathy (4%)” (as cited in Brown, 2001, para.3). This huge number of owners looking for alternative health care for their pets could be harnessed by a forward thinking veterinarian offering such amenities. Rather than loosing cliental with vaccination reductions, there would be an increase, thereby boosting income with a more holistic practice.

Continuing to work with the viral theory, Mee et al. (1992) examined the bone cells in the metaphyses of dogs infected with distemper and found the canine distemper virus in the marrow, the osteoblasts and the osteoclasts, suggesting that this virus may be a cause of HOD. Mee et al. (1993) then took this another step forward and studied bone samples of HOD dogs. They found CDV in the osteoblasts, osteoclasts and the bone marrow of two dogs that were infected with CDV and in dogs with HOD. A paramyxovirus was isolated in one dog that died with HOD. During that animal’s treatment, they found that corticosteroids may be contraindicated for treatment of HOD, which supported Grondalen’s theory in which the blood of dogs with HOD caused clinical CDV infection in recipient dogs. Finally Mee, Hoyland, Baird, Bennett, and Sharpe (1995) determined that CDV infection induces interleukin-6 and c-Fos mRNA in osteoclast-like cells, causing immunosuppression in these same cells. Osteoblasts, osteoclasts, osteocytes and bone marrow cells of the infected dogs had CDV RNA. This established a clear link between the CDV virus infection and HOD. Young puppies were actually infected with the canine distemper virus (Baumgartner et al., 1995) and it was discovered that the virus antigen was already implanted into the marrow and bone cells within five days on infection. The immunopositive cell count dropped rapidly and they were completely gone by day 41. The bone lesions were most prominent between days eight and 32 and were concentrated within the metaphyseal bone cells. Necrosis of the osteoclasts, and atrophied and necrotic osteoblasts and marrow cells occured.

One study of vaccinated HOD afflicted puppies involved six Weimaraner pups, five of which were related (Abeles et al., 1999). The dam of two of the puppies had been vaccinated with a polyvalent vaccine which included the modified live distemper virus, hepatitis, parvovirus, and parainfluenza vaccines with a leptospirosis bacterin during her pregnancy. All six dogs had clinical signs of HOD between the ages of eleven and sixteen weeks. Five of them developed signs four to ten days after a second vaccination with a modified live parvovirus vaccine. The pups’ owners observed the dogs as having anorexia, lethargy, depression, difficulty in standing and walking, diarrhea, vomiting, and ocular and nasal discharges. The veterinary exams found fever, symmetrical metaphyseal swelling and pain, respiratory sounds increased, enamel hypoplasia, ataxia and head tremors above and beyond the original signs. Chest x-rays showed bronchial pneumonia and pleuritis. One of the dogs relapsed five days after receiving a third dose of a modified live parvovirus vaccine. Radiographs showed HOD in both of the forelegs and hind legs. They deduced that vaccination protocols should be altered for the Weimaraner breed. “Vaccination is most effective when the concentration of maternal antibodies is low or they have disappeared; measuring maternal antibodies and vaccinating only when their level is low should be considered in order to minimize the number of vaccinations given” (p. 133). They suggest using separated vaccines, using a measles vaccine in lieu of a modified live CDV, or using only killed vaccines. They noted that their animals responded better to corticosteroid therapy, suggesting that the breed has a genetic tendency to express immunodeficiency. Vaccination protocols on two groups of client owned Weimaraners were studied by Harrus et al. (2002), specifically to try to determine if the vaccines would cause HOD and how effective the immunizations were. All of the pups were first vaccinated at eight weeks of age. The first group was vaccinated with a modified live canine parvovirus (CPV) and two weeks later they were vaccinated with a trivalent vaccine composed of a modified live canine distemper virus, adenovirus type 2 and Leptospira bacterin (DHL). The CPV and DHL vaccines were given twice more at two week intervals. The second group was vaccinated with a multivalent vaccine containing modified live CDV, CPV, parainfluenza and adenovirus type 2 combined with Leptospira bacterin for three consecutive times at four week intervals. Three dogs in group one developed HOD while all five dogs in group two developed HOD. Group two dogs had more reoccurring episodes of HOD and developed lower antibody titers to parvovirus and CDV compared to the dogs in group one. Only two out of the ten dogs developed protective antibody titers to parvovirus. The results illustrate that different vaccination protocols can affect the appearance of HOD and the effectivity of immunizations.

Post-vaccination immunization testing on puppies that were previously vaccinated with CPV and CDV was performed by Waner, Noam and Mazar (2003) to determine their levels of immunity, as well as to find those that did not respond to the vaccines. The intent was to see if the immunoassay test kit (ELISA) would provide adequate information regarding their vaccination status. The ELISA kit was found to be suitable for use in the clinic, providing veterinarians the ability to test immune levels in-house, possibly allowing prevention of the over-vaccination of animals which causes vaccination failure and pup mortality. Stating that annual vaccinations may not be beneficial and in some cases may even be deleterious, Waner (2004) encourages and recommends veterinarians to determine what is best for the individual patient and to tailor a vaccination program for this purpose. One of the side effects of frequent vaccinations is metaphyseal osteopathy.

Speculating that not only is HOD largely genetically predisposed, Lanting (2001) asserts that it affects more males than females, due to the female being able to accept more stress. He also suggests that distemper or distemper vaccines may be causing many cases of HOD, as the disorders occur shortly after distemper vaccinations. Distemper and measles viruses are very similar to each other; the latter commonly modified and used to vaccinate very young puppies before their maternal immunity disappears. He notes that measles vaccines have caused humans to have bone disorders very similar to HOD.

Diets that are deficient in protein, energy, minerals, vitamins and essential fatty acids will impair immunity, but Hayek, Massimino, and Ceddia (2002) contend that the immune cells are also especially susceptible to free radical damage due to their cell membranes containing high levels of polyunsaturated fatty acids which are more easily damaged. While omega-3 fatty acids reduce inflammatory potential, diet-derived antioxidants such as vitamin E, beta-carotene and lutein help to protect against free radical damage. What was particularly interesting to the author was that they found prolonged exercise is associated with the decrease of neutrophil and macrophage functioning ability which suppresses lymphocyte proliferation and increases free radical damage while only mild exercise is beneficial.

Nutritional Factors

Excess Energy and Nutrition

Richardson and Toll (1997) report that genetics, environment, nutrition, nutritional components, specific nutrients, rate of growth, food amounts consumed and feeding methods can all contribute to developmental disorders. They argue against free choice (ad libitum) feeding and hold that excess energy and calcium intake are the biggest nutritional factors causing disorders. They deduce that food should be of a growth type with limiting factors for puppies and that owners should weigh and evaluate pups at least every 2 weeks, adjusting food quantities accordingly. Dietary fat is the primary contributor to excessive energy and they suggest that a growth food should have 22% protein. They maintain that an absolute level of calcium rather than an imbalance causes problems during growth, believing that puppies are unable to regulate calcium intake. Excess calcium of 3.3% paired with a normal .9% or high 3% phosphorus causes bone disorders. If the food is altered to a low calorie maintenance food in an effort to avoid excessive calcium, this change can often cause high calcium intake when the animal consumes more food attempting to get enough calories. The theory that a high level of energy intake promotes an excessive rate of growth in the large breed puppy is supported by Lepine (1998; 2001). The high growth rate increases the potential for skeletal disorder and he suggests that such puppies would best be served with a diet of 26% protein, 14% fat, .80% calcium and .67% phosphorus. Richardson and Zicker (1999) relate that developmental orthopedic disorders increase in large and giant breeds of dogs fed a well balanced, highly palatable, energy dense food, presumably due to the dogs’ genetic propensity for rapid growth. The skeletal system is more susceptible to physical, nutritional, and metabolic damage during the first year of life. Overfeeding energy affects growth velocity directly through nutrient supply and indirectly through growth hormone, insulin-like growth factor 1 (IGF-1), triiodothyronine (T₃), thyrocine (T₄), and insulin. The epiphyseal spongiosa of giant breed dogs is inherently less dense, thus it is considered less strong than that of smaller breeds. This condition may worsen if the dog is overfed, thus ad libitum feeding methods may lead to a mismatch of bone to body growth, causing small cartilaginous lesions in the immature bone due to the excess weight and muscle pull.

Describing how the thickness of the growth plates parallel the growth velocity of young puppies, Hazewinkel (2001) explains that the growth velocity and closure of the growth plates depends upon age, breed, location, and hormonal and nutritional factors. He discusses the fact that measuring the blood levels of certain suspect nutrients does not give the proper indication of what the absorption rate, availability or source was for that nutrient. Some nutrient levels such as calcium and alkaline phosphatase may be increased due to the age of the animal and not to any nutritional imbalance. Some tests are very specialized and will only provide information if they are taken many times. Because of the poor nutritional information such testing provides, he suggests: “A thorough history taking focused on the food composition and daily ration will support making a diagnosis in nutrition related orthopaedic disorders” (p. 30). Only by asking such questions of an animals’ caretaker will one obtain the crucial data required to be able to determine if the animal is receiving the proper quality and amount of nutrition for its age and weight. This is extremely invaluable when a disorder is caused by nutrition and can be corrected with good nutrition. It can prevent invasive treatments, pain from such treatments or from excessive time living with the disorder, and unnecessary expense to the animals’ owner.

Protein levels in dog foods can vary greatly depending upon the quality and the digestibility of the protein sources which could be derived from plants, animal hair, horn or hooves, reducing the bioavailability to the dog. The high protein dog foods should have a high fat content as well because the two must be kept in a balanced 2:1 ratio. Believing that the dog will regulate its food intake based on its energy requirements, Nap (2001) points out that the requirements of all other ingredients and components comprising a complete and balanced nutritional diet should be met in order to avoid health issues.

A mismatch between the body and the bone growth rates of the dog is caused by ad libitum feeding of young animals. Zentek (2001) discovered that: “The epiphyseal spongiosa in the bones of giant dogs is less dense and therefore probably less strong compared to the structures in smaller breeds” (p. 5). This factor may be exaggerated by excess nutrition and energy intake. Overfeeding affects the endocrine regulation of an insulin-like growth factor-1 (IGF-1) and the thyroid hormones. The IGF-1, thyroxine and triiodothyronine levels increase, causing higher growth rates of chondrocytes in the epiphyseal tissues. “Restricted energy supply by avoiding ad libitum feeding of large breed puppies and adequate diet composition are the essentials, that can be recommended to dog owners” (p. 6). Controlling the diet will not totally eliminate developmental disorders, but it will greatly reduce their occurrences in the young dog.

Improper feeding during growth is associated with several skeletal disorders in large and giant breed dogs. Coffman (2002) made note that dogs that weigh over 50 pounds have a higher chance of developing bone problems caused by nutrition. “About 22% of dogs less than one year of age are affected by developmental skeletal disorders and more than 90% of these cases are influenced by nutrition” (p. 30). He contends that two of the main causes of these disorders are free choice (ad libitum) feeding and supplementing with calcium. New owners of giant breeds often think that “bigger is better” leading the owners to feed excess calories to their puppies during the crucial growth phase. This causes rapid, unhealthy growth rates which in turn cause developmental disorders. Ad libitum feeding promotes the intake of excess energy or calories and while this method of feeding is simple for the owner, it is extremely damaging to the animal.

Vitamin C

By the 1990s, it was well documented that the role of vitamin C in the dog’s diet is not a factor in developmental disorders because the dog produces its own vitamin C. The studies by Richardson and Toll (1997) and Richardson and Zicker (2000) concluded that vitamin C is needed for hydroxylation of praline and lysine during biosynthesis of collagen, which is a major component of ligaments and bones. However, when feeding foods lacking vitamin C to puppies for up to 154 days, it neither affected growth nor caused skeletal lesions, so there is no requirement to add vitamin C to the diet.

At their clinic, Özer et al. (2004) treated 18 HOD stricken puppies. The animals had infectious type symptoms of diarrhea, tonsillitis, pyoderma, and pneumonia along with significant lymphocytosis. The puppies were treated with antibiotics and aspirin, and relapsed when these medications were stopped. They surmised that the high fevers were due to protein resorption following extensive hemorrhaging rather than infection because the fevers were decreased with aspirin while the antibiotics had no effect. They also think that the diarrhea may have been caused by altered intestinal absorption. The dogs had low serum vitamin C levels of which a deficiency would prevent collagen formation, but they would not recommend giving vitamin C because it is absent in almost every painful disorder due to stress and is considered a secondary factor. Mere stress, such as when animals experience pain, can cause vitamin C levels to drop. They also knew that supplementing with vitamin C will aggravate the osseous lesions in HOD.

Calcium Excess

A study on rats found that the amount of calcium absorbed in the intestines depended upon the regular amount of calcium intake (Bronner and Pansu, 1998). When intake is low, the active transcellular calcium transport in the duodenum is increased. A larger proportion of calcium is absorbed by the active process than by the passive paracellular process that occurs in the jejunum and ileum. Bioavailability of the source (digestibility and solubilization) plays a roll under conditions of low calcium intake but it is relatively unimportant when calcium intakes are high. They theorized that the same results would apply to humans and dogs.

Calcium plays a very significant part in the skeletal development of large and giant breed puppies. Carey and Lepine (2000) note that a high level of calcium affects the bone development by causing cartilage cones to be retained, increasing the minerals in the bone, and delaying bone remodeling. They pointed out that the Iams Company evaluated three diets containing 26% protein and 14% fat but with three different calcium to phosphorus levels (2.7 % to 2.2%, .80% to .67%, .48% to .40%) on Great Danes until they were eighteen months of age. The .80% calcium to .67% phosphorus level was the resulting ideal mineral level for healthy growth and the least amount of bone disorders. In their own work with giant and large breed puppies, Weber et al. (2000) to tried to find a safety range for calcium. After raising these dogs from weaning to thirty four weeks of age on two diets with differing calcium and phosphorus levels of .8%/.6% versus 1.5%/1.23%, they found that neither diet induced any adverse effects on growth and skeletal development. This allows us to conclude that these levels of calcium could define a safety range for growing dogs of large breeds. Overfeeding dogs with excess amounts of dietary calcium may impair the absorption of trace elements and phosphorus, which will then hamper the regulatory mechanisms of calcitonin and vitamin D (Zentek 2001). Balanced diets must take into account the mineral levels in relation to the energy density, which is closely related to the fat content. The mineral intake influences tissue development, electrolyte balance and the acid base equilibrium.

It was believed that young dogs below 5 months of age could not control their digestibility of calcium regardless of the amounts fed (Dobenecker, 2002). This meant that even more precision would be required in the feeding of the younger animal to prevent excesses or deficiencies of calcium than merely providing a balanced food would provide. Countering with their own study regarding intestinal calcium absorption and its’ effects on age and breed, Tryfonidou, Broek, Brom, and Hazewinkel (2002) used two breeds of growing dogs that differed in their growth rates – Great Danes and Miniature Poodles. They concluded that weaned dogs can regulate calcium absorption during long periods of deficient or excessive availability, no matter what their growth rate was.

“This analysis rebuts previous assumptions and revealed that there were no essential differences between giant and small breed dogs concerning the intestinal Ca handling in the period after weaning until the age of 27 weeks on diets containing .33-3.3 g Ca/100 g diet (dry matter). This leaves other considerations such as growth rate and disturbance of calciotropic hormones as possible etiological factors” (p. 3367).

Active calcium absorption undergoes developmental changes, whereas passive absorption accounts for 53% of absorption of the available calcium and is age-independent. During a diet deficient in calcium, active absorption contributed to a large part of the total calcium absorbed. But during diets with excess calcium, active calcium absorption was negligible and passive absorption played the larger part. Intestinal calcium absorption was not related to body size or growth rate.

Vitamin D Excess

Further nutritional studies were conducted on vitamin D metabolites which regulate calcium metabolism and therefore skeletal development. These metabolites aid in the absorption of calcium and phosphorus from the gut, increasing bone cell activity and influencing endochondral ossification and calcium excretion. Commercial pet foods often have from 2 to 10 times more vitamin D than the AAFCO recommendations. Excess vitamin D can cause hypercalcemia, hyperphosphatemia, generalized soft tissue mineralization and lameness. It can cause marked skeletal deformity due to increased calcium and phosphorus absorption. How, Hazewinkel and Mol (1994) found that canines must take in vitamin D via dietary means (usually animal fats) as their skin does not process UV rays as other animals do. Vitamin D is often supplemented by the pet owner in their attempts to grow an exceptionally large animal. Unfortunately it can easily become toxic, based on Ca:P intake, when over supplemented. Vitamin D can be obtained in its natural state and in its’ unnatural irradiated form. Tryfonidou, Stevenhagen et al. (2002) studied the effects of vitamin D₃ on the hormonal regulation of intestinal calcium absorption in growing Great Danes from six weeks to four months of age. Calcium absorption, calciotropic and growth-regulating hormones were measured after feeding diets either high in vitamin D₃ or a diet with NRC recommended rates. The high vitamin D₃ intake had major affects on the formation of the biologically important vitamin D₃ metabolites and resulted in lowered intestinal calcium absorption. Following up with another study on calcium and vitamin D_3, Tryfonidou, Holl et al. (2003) involved young growing Great Danes and Miniature Poodles aged six to twenty one weeks. It was determined that giant breed dogs are more susceptible to skeletal disorders than the smaller breed dogs when raised on a diet either deficient or excessively supplemented with calcium. Even at optimum calcium intake, the giant breed dogs had more irregular growth plates with moderate disorders of endochondral ossification than the smaller breed dogs. This may have been related to differential regulation of calcium homeostasis and skeletal growth between the breeds. Giant breed dogs grow rapidly and have higher plasma concentrations of growth-regulating factors, which in turn may influence vitamin D₃ metabolism. A deficiency in vitamin D₃may be a cause for the increased incidence of skeletal disorders.

Protein Levels

The dog generally regulates its food intake based upon its energy requirements. When these energy requirements are met, all of the other ingredients and components of a complete and balanced diet need to be met as well, or the nutrient intake will not be adequate. When evaluating protein levels, it is important to look at the fat level first, since this indicates the energy density of the product. High fat diets need high protein levels to balance the protein to energy ratio of almost two to one. High protein intake does not influence final height, calcium metabolism or skeletal development (Nap, 2001).

Lepine (1998; 2001) suggests that the diet should consist of 26% high quality animal protein source, 14% fat, .80% calcium and .76% phosphorus. However, Richardson and Zicker (2000) contend that protein should be from 25-30%, fat 12% and calcium should be from .9 to 1.5% with phosphorus at .8 to 1.4% respectively with the calcium levels. In addition, they point out that low levels of zinc, alkaline phosphatase, iodine, vitamin D and manganese can cause more growth disorders. There are disparities between these two research groups regarding optimal nutrient levels, but either diet could probably be followed without any detriment to the animals.

Zinc Deficiency

A zinc deficiency can show up within days of its omission exhibiting symptoms resulting in skin defects, depression, growth disorders and an impaired immune system. Zinc is a cofactor in more than 100 enzymes including those for connective tissue metabolism. Fraker, King, Laakko and Vollmer (2000) found that a zinc deficiency “reduced the ability of the immune system to replenish the peripheral blood and secondary immune tissues with adequate numbers of lymphocytes” (p.1402S) creating a rapid depletion of marrow and thymus precursor T and B cells. This deficiency also causes chronic production of glucocorticoids which induces the death genes and apoptosis. It is possible that zinc could inhibit apoptosis and the death signal itself, but high levels can be toxic. Wang, Fosmire, Gay, and Leach (2002) followed up with yet another study concerning zinc deficiency (with chickens) and found that within 3 days the serum levels were 65% lower and chondrocyte proliferation was significantly inhibited. Chondrocyte differentiation was accelerated and cell apoptosis was induced. Changes were noted primarily in areas furthest from the blood vessels in the growth plate. Because the growth plate in animals has very few blood vessels, their study suggests that longitudinal bone growth may be especially sensitive to zinc levels.

Aluminum Toxicity

In another study that involved chickens being fed low calcium diets (Cox & Dunn 2001), aluminum toxicity was found to alter the regulation of the intestinal calbindin mRNA and aluminum may inhibit the expression of vitamin D-dependent genes causing a decreased response to the active form of vitamin D. Calcium has been shown to inhibit the uptake of aluminum in the intestines. Diets adequate in calcium may be protective against the inhibitory effects of aluminum on calbindin mRNA expression

Genetics

Genetic studies regarding HOD began surfacing in the early ‘90s, beginning with Dammrich, (1991) who determined that large and giant breed dogs already have an inherent capacity for rapid skeletal growth. The epiphyseal spongiosa is less dense and less strong per unit area than of dogs of smaller breeds. These characteristics would tend to predetermine the bone developmental problems that the larger breeds have. If a dog already genetically has weaker bones, extreme growth rates and weight would consistently cause more damage. Carey and Lepine (2000) prompt more discussion concerning growth rate and adult size being programmed into the genes. Puppies from very large boned parents may also have large bones and be more apt to develop bone growth disorders. Puppies from parents who were rapidly growing are more likely to grow rapidly, too. Increasing the energy intake to a puppy can push the growth rate to its upper limits and thus increase the likelihood of certain skeletal disorders. Angles (2001) is trying to discover a DNA marker for HOD in the Weimaraner. He has found that HOD in the Weimaraner has a heritability of 0.35 and has an autosomal recessive mode of inheritance. But there is yet no way to detect carriers other than by test matings. Weimaraners are the breed most genetically affected by HOD, rather than nutritionally affected.

Hedhammar (2001) holds that large sized dogs that are already affected by developmental and degenerative skeletal disorders “should be fed restricted amounts of a balanced diet to decrease rate of growth and to reduce weight” and “should not be used for breeding” (p. 11). He maintains that feeding a balanced diet that is neither deficient nor excessive with the nutrient levels should also be restricted to promote a moderate rate of growth and optimal skeletal development rather than attempting to maximize the growth and impairing the skeletal health.

A ten year study by LaFond, Breur, & Austin (2002) involved collecting reports from ten veterinary teaching hospitals which were participating in the Veterinary Medical Database from 1986 to 1995. These reports showed that out of 160 HOD cases, there were 8 breeds involved and their order of frequency was “Great Danes (31), Labrador Retrievers (18), Golden Retrievers (15), German Shepherd Dogs (13), mixed breeds (11), and Weimaraners, Irish Setters and Boxers each with seven” (p. 470). This implies that the larger breeds of dogs may be genetically predisposed to have more developmental disorders than any other breeds. The genome of the dog involves 38 canine autosomes and was completed in the last decade. The first 21 were studied by the conventional cytogenetics and molecular cytogenetic techniques were used on the remaining 17 pairs. Swanson, Schook and Fahey (2003) insist that although genetic components exist, nutrition must play a major role in the development and treatment of many disorders. Diets should be formulated based on genotype and statistical analyses will detect important correlations between gene expression and diet changes with consequent metabolism. “Several functional ingredients are already making their way into pet foods” (p. 3038). Such ingredients include glucosamine, chondroitin sulfate, green-lipped mussel, vitamin E, beta-carotene, fatty acids, and probiotics. The study of nutritional genomics and proteomics will be crucial in areas such as nutrient requirement determination, disorder prevention and treatment, functional ingredient testing and others.

The study for genetic influences on calcium balances during growth surmise that a breed-dependent difference in calcium metabolism exists which may lead to different responses to calcium excesses. This may explain the inconsistent reports from past literature (Dobenecker, 2004). Hawthorne, Booles, Nugent, Gettinby, and Wilkinson (2004), support the existing feeding guidelines of commercially available, nutritionally complete diets for breeds of different sizes but suggest “additional breed specific differences in growth patterns may occur even in dogs of similar size” (p. 2029S).

New Tools for Research

We are now able to study the vascular system around the growth plates using new tools. Cornell researchers Cornelia Farnum and Rebecca Williams are using multiphoton microscopy to map the vascular system of the growth plates in the bones of transgenic mice. This will allow determination of the flow of nutrients and chemical signals that contribute to bone elongation. By determining how the process works in normal conditions, researchers may soon find out why it sometimes breaks down and be able to offer improved therapeutic approaches to clients. All previous hypotheses have been based on necropsies. Blood flow to cartilage is not evident in necropsies. The use of the multiphoton microscope allows a look into in vivo – actual living tissue. During this study, they found that tetracycline chelates with calcium, preventing it from being available to the body. Because of this finding, tetracycline should never be used during pregnancy or growth. This could play a big part in causing HOD if tetracycline is administered to young dogs (Wheatley, 2004).

CHAPTER 3: RESULTS AND FINDINGS

The purpose of this paper was to help determine the cause of hypertrophic osteodystrophy by collecting previous research studies and compiling and deciphering that information into useful and accurate data in one location. The results of over 70 years of research have brought to light even more issues that may be causing HOD rather than reducing them. A few of the studies have dismissed some of the original assumptions, but with the new methods of research presently available, more possible causes are being explored. The reason for this is because nothing yet has been proven to be the sole cause of HOD. It may be that there is more than one cause for this disorder; therefore studies continue to be pursued in all directions.

Hypertrophic osteodystrophy is a disorder that affects the young, growing larger breeds of dogs between the ages of two and eight months. It usually affects the metaphyseal areas of the long bones but may be involved in other areas of the body such as the ribs and the jaw with even soft body parts including the heart, lungs and kidneys being involved. The affected boney areas become larger from the thickened periosteum, hot to the touch and very painful, usually causing a refusal to walk. The animals suffer from weight loss, anorexia, fever, diarrhea, and depression. The disorder is presently being treated symptomatically. Treatments vary widely with some researchers advocating using steroids and others promoting antibiotics or NSAIDs. The death rate of the afflicted animals is generally low, except when the Weimaraner breed is involved.

Research Questions and Results

What Are the True Causes of Hypertrophic Osteodystrophy?

This question is still unanswerable. But through this research, the author has narrowed the answer down to three categories: genetics, excess nutrition mainly consisting of calcium, vitamin D and energy, and immunodeficiencies caused by vaccinations.

What Can Be Done To Prevent HOD?

Precautions can be taken to help prevent HOD from raising its ugly head. Particular attention should be given to the genetic history, vaccination methods and feeding methods. When looking to acquire a dog, prospective owners might investigate the genetic propensity for disorders of the breed that they are interested in. Boxers, Great Danes, Irish Setters, German Shepherds, and Weimaraners are more susceptible to HOD than any other breed. Potential owners could ask about any related animals that may carry inherited traits or deficiencies that have been shown to trigger HOD and verify whether or not the related animals had HOD when growing up. Owners can be more involved with the medical applications by reducing the number of vaccinations that are given. The avoidance of the use of trigger vaccines such as distemper, rabies and polyvalent vaccines may help reduce the incidence of HOD. Veterinarians can titer for exposure levels, which can determine if a vaccine is truly required. A measles vaccine may be used in lieu of the distemper vaccine, and administer monovalent vaccines in lieu of polyvalent ones. Close attention to providing balanced foods and avoiding supplementing with vitamin C, calcium or vitamin D to a growing puppy should greatly lower the chances of the puppy developing HOD. Ad libitum feeding of a puppy has been proven to induce HOD and should be discouraged.

Does Excess Nutrition Cause HOD?

Overfed, thus overweight dogs do not necessarily get HOD. But they do get more nutrients and energy than required. This can lead to an excess intake of calcium or vitamin D as well as calories. Ad libitum feeding can promote excess nutritional intake, particularly when being fed foods made for larger breeds (nutrient and calorie rich and very tasty). Overfeeding energy also affects IGF-1, thyroid growth hormones T₃, T₄ and insulin. The potential for developing HOD due to a large intake of nutrients such as calcium or vitamin D is increased exponentially when the animal is allowed to be fed ad libitum.

Does Excess or Deficient Calcium or Vitamin D Cause HOD?

Multiple studies have shown that when puppies are fed large amounts of calcium and/or vitamin D, they quickly develop growth disorders, including HOD. Feeding low calcium diets will cause hyperparathyroidism. These minerals and vitamins (and many others) work synergistically and imbalances will create distortion in growth. This is why feeding a young animal a properly balanced diet is critical to its health.

Does Vaccinosis Cause HOD?

Many recent studies support this. Canine distemper virus has been found in the metaphyseal areas of the bones shortly after vaccines were administered. The immune system quickly deteriorates and HOD occurs. The implication in those studies is that the virus/vaccine is causing the HOD.

Does Vaccinosis Cause Poor Immune Systems?

Vaccines are causing a drastic reduction in the immunosuppressive response of the immune system. A compromised immune system does not protect the body well enough to fight viral and bacterial infections or the bone deterioration that settles in after the vaccine was given. The author proposes that this is the true root cause of HOD in those animals that develop the disorder shortly after receiving their vaccinations, regardless of their genetic propensity.

Does a Poor Immune System Cause Vaccinosis?

It is probable that an already compromised immune system will continue to get worse after vaccinations are given. Studies have suggested that it would be expected to plummet to no protection whatsoever. Most of the studies support the theory that the vaccines themselves are causing the immunosuppressive responses. Studies do not hold that a poor immune system will cause vaccinosis.

Does Thymus Gland Failure Cause a Poor Immune System?

Studies seem to indicate this. A zinc deficiency can have far reaching effects on the immune system. Besides zinc, low levels of alkaline phosphatase, iodine, manganese and vitamin D can cause growth disorders and all are synergistic with the thymus gland, which is the main organ that delivers immune support by creating T-lymphocytes. These cells help other cells recognize and destroy bacteria, viruses, abnormal cell growth such as cancer and other foreign bodies. Failure of the thymus gland will almost certainly cause failure of the immune system.

Survey Results

The author created two different online surveys on HOD (see Appendix A). One survey was made for the dog owner and the other survey was designed for the veterinarian. The survey links were posted to the MyMentors Great Dane Yahoo list of over 420 members and passed on to other Yahoo list groups as well as being placed on the authors’ personal web page. Considering the large number of people on the Great Dane list that complain about having dogs affected by HOD, the author was quite surprised and very disappointed that only seventeen entries were submitted by dog owners and none by veterinarians. Of those seventeen, only twelve were Great Danes. The remaining five were Weimaraners. Even with this small number of respondents, the survey results validated most of the findings from many of the HOD experiments done by the researchers in this paper.

The average age that most of the dogs first exhibited HOD symptoms was three and a half months with the range being from two months to six months (see Appendix A). The symptoms reported were high fever (82.4%), extremely painful joints (88.2%), refusal to eat (70.6%), depression (58.8%), refusing to stand (52.9%), enlarged joints (64.7%), mild lameness (52.9%), alternating lameness (23.5%), periods of remission (5.9%) and “other” (17.6%). “Other” included extreme lameness, drooling, surgery recommended, no recurrences for five weeks and wetting the bed (see Appendix B). Ten (58.8%) of the respondents stated that their dog had received a vaccination within three weeks of the onset of HOD (see Appendix C). All of the respondents had their dogs on kibble foods and one added canned food. The amount of food being fed was extremely erratic, but most were being overfed with such examples as the two month old being fed three meals for a total of six cups a day and a three and a half month old getting four meals for a total of twelve cups a day. These amounts are more than double the normal requirements at these ages. Final outcomes showed seven dogs (43.8%) gaining total recovery, three dogs (18.8%) had recovered but with resulting skeletal deformities, five dogs (31.25%) have not yet recovered and one dog (6.25%) died. One respondent skipped the final outcome question.

Findings

Vitamin C deficiency and excess protein have been ruled out as causes for HOD. But an excess or a deficiency of calcium or vitamin D can play major roles in bone development. Providing too many nutrients overall also creates havoc on a young, growing body.

Studies have shown that the act of injecting viral components (vaccines) into the body disables the immune system and sets up the body for cellular damage and destruction which may never be overcome. There is new technology to help study and learn how the body works that has become available now. Cell activity can now be watched “live” instead of having to rely on necropsies. Live cell responses to nutrition, environment, and foreign bodies can be studied in actual real time. The author expects much new information to come from being able to study the body processes using the multiphoton microscopy. The information that we presently have may soon change due to its use.

The canine genome has been identified and researchers can now begin to trace which gene is responsible for what action. Applying genetic information to breeding for a better, healthier animal is becoming much more common practice for the hobby breeder as well as the serious breeder. Making the genetic and health information available to the purchasing public will enhance and improve the breed as well as encourage the breeder to produce better animals.

Summary

Despite the many years of research, studies still have not positively identified one cause of hypertrophic osteodystrophy as being the only cause of the disorder. Perhaps there is none. Perhaps the body’s genetic makeup, chemistry, function, the environment it is subjected to and the nutrition that supports it must be encompassed holistically to understand and determine the true cause(s) of HOD. Until that happens, the author proposes that the application of proper nutrition based on age and weight, the use of healthy breeding stock and the individualization of health procedures for each animal can reduce and possibly eliminate the occurrence of hypertrophic osteodystrophy from the canine world.

CHAPTER 4: CONCLUSIONS, IMPLICATIONS AND RECOMMENDATIONS FOR FURTHER RESEARCH

Conclusions

The results show that there is likely more than one cause for HOD. Those causes are still being investigated and narrowed down by researchers. Presently, they consist of nutritional excesses of calcium, vitamin D, and excess nutrition in general, vaccinosis along with excess vaccination regimens, and the genetic propensity of the animal. All of these factors play majors roles in the dog’s overall health and well being.

Implications

If dog food manufacturers, veterinarians, dog breeders and dog owners use the information gleaned from these studies regarding nutrition, vaccines and genetics, they will be able to control and possibly wipe out any more occurrences of HOD. If a genetic marker is found for HOD, then breeders would be able to stop its spread by selecting only breeding stock that does not carry the marker. Dog owners and veterinarians already have control over nutrition and vaccinations by carefully choosing their products and services. Educating the dog food manufacturers, the general dog owning public and veterinarians regarding large breed nutritional requirements and adjusting vaccine types and schedules should be the goal in reducing future HOD cases.

Great strides can be made in conquering this disorder by paying attention to these issues individually and applying the lessons learned from previous studies. But the information needs to be looked at as a whole as well, because everything is connected in one way or another. Hypertrophic osteodystrophy cannot be addressed with just simple nutrition, or a single mineral, or a single vaccine. This must be addressed holistically with nutrition, medical applications, genetic inheritances and environmental issues all taken into account.

Recommendations

The primary cause of HOD would be eliminated by assuring feeding of the proper amount of balanced diets formulated for growing, large breed puppies and preventing the addition of supplements which would then imbalance the diet.

There would be less ‘unknowns’ to deal with if the genetic background of the puppy and of the breed in general were researched to expose any possible genetic predisposition for HOD or other growth disorders. If the familial line has had HOD, then more stringent action can be taken to watch for and prevent HOD from developing, as well as preventing the breeding of affected animals.

The application of vaccines and the possibility of vaccinosis occurring can and should be carefully monitored, particularly if the family line has previously had HOD triggered by vaccines. Weimaraners are notorious for this, but Great Danes are showing a propensity in this regard as well. Avoidance of certain vaccines or how often they are given should help reduce the occurrence of HOD. The author suggests that dogs that succumb to HOD due to vaccinosis or due to genetic predisposition should be neutered or spayed to prevent further generations from developing the disorder.

APPENDIX A

ONLINE HOD SURVEY

17 results as of March, 1, 2007

Breed age at first sign amount fed time of care vaccine w/i 3 wks outcome

1 Dane 3.5 months 12 cups/day .5 month vet care no ongoing

2 Weim 5 months 4 cups/day 2.5 months vet care CR SD

3 Weim 5 months 5 cups/day 1 month vet care vaccine FR

4 Weim 3 months 3 cups/day .5 month vet care vaccine FR

5 Weim 3 months 3 cups/day .5 month vet care vaccine FR

6 Weim 3.5 months 3 cups/day .5 month vet care vaccine FR

7 Dane unknown unknown unknown unknown SD

8 Dane 6 months 6 cups/day 2 month vet care no FR

9 Dane 5 months 2 cups/day 2 month vet care yes SD

10 Dane unknown unknown unknown no unknown

11 Dane 6 months 6 cups/day .5 month vet care no ongoing

12 Dane 2 months 6 cups/day 2 month vet care vaccine FR

13 Dane 3 months 6 cups/day 2 days vet care vaccine E

14 Dane 4 months 4 cups/day 1 month vet care vaccine ongoing

15 Dane 5 months 6 cups/day 4 days vet care no FR

16 Dane 4 months unknown 1 month vet care vaccine surgery

17 Dane 4.5 months 4 cups/day 1 month vet care vaccine FR

CR – cannot remember

SD – skeletal deformity

FR – full recovery

E – euthanized

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