Metabolic, Nutritional, and Endocrine Bone Disorders

Metabolic diseases of the skeleton can be due to inborn errors of metabolism or be acquired. The former includes abnormalities in collagen synthesis and, as a consequence, abnormal growth or mineralization of the skeleton, whereas the latter includes a variety of hormonal diseases with or without a nutritional cause. Here we will limit ourselves to three examples of collagen disease, which are important to recognize as the differential diagnoses of diseases of endogenous and of nutritional origin.

Multiple Epiphyseal Dysplasia

Although different types exist, the major features of multiple epiphyseal dysplasia are irregular epiphyseal growth, with little vertebral involvement and a mild dwarfism, and an irregularly shaped acetabulum [1]. In humans, this genetic trait is autosomal dominant as well as recessive, whereas in dogs it seems to be autosomal recessive.

The clinical signs become obvious at the age of 2 to 3 months and are seen in a variety of breeds including Labrador retrievers, Vizslas, and Rottweilers. The owner will notice that the dog does not grow as fast as the litter mates. The elbow joints may be abducted and the gait abnormal in cases with joint deformities, however, this is not always the case. The dog will have short legs and a normal skull and vertebral column. Radiology will reveal shortening of the long bones when compared with litter mates and, in some cases, abnormal joint alignment (Fig. 99-1A). Concomitantly, osteochondrosis and other developmental diseases can be present, but so far we have not seen it in conjunction with ocular diseases like retina dysplasia.

Figure 99-1. Metabolic bone disorders. (A) Disproportional Labrador pup with multiple epiphyseal dysplasia revealing short long-bones, abnormal physeal growth, and irregularly shaped acetabulum with normally shaped vertebrae. (B) Dachshund pup with osteogenesis imperfecta with poor mineralization of long bones and slight widening of growth plates. (C) Offspring of Scottish fold cat with osteochondrodysplasia revealing short misshapen distal limbs with exostosis plantar to and distal of the calcaneus.  

In cases of abnormal joint alignment, the prognosis is extremely poor. In other cases, the disturbed growth will not have a major impact on the dog’s well-being [2].

Osteogenesis Imperfecta

The disorder is first noticed at about 3 to 4 weeks of age, when dogs with osteogenesis imperfecta (OI) reveal a reluctance to move. They are well proportioned, with blue sclera, translucent and fragile teeth, and legs with hyperlaxity at different joints and possibly with multiple fractures. Blood biochemistry and calciotropic hormone plasma levels are normal. The etiology is a genetic defect, probably autosomal recessive, which encodes for procollagen molecules of collagen type I, resulting in an abnormal collagen structure affecting the formation and stability of bone mineral associated with this collagen [3]. Because collagen type I represents 90% of the organic substance of bones, teeth, and tendons, this genetic defect has consequences for osteoid and dentin mineralization, and for connective-tissue strength at multiple sites including the chordae tendineae. The rupture of the latter may cause sudden death of the patient. The disease has been reported in golden retrievers, collies, poodles, beagles, Bedlington terriers, dachshunds, and domestic cats [4].

The diagnosis can be made by a clinical and radiologic investigation. Radiographs show poorly mineralized bones (long bones and ribs) with only some contrast in the area bordering the growth plates, which are of normal width, and fractures of long bones and ribs (Fig. 99-1B). The diagnosis can be confirmed by pathologic investigation, which reveals regular growth plates, with some disturbed mineralization of the primary mineralization zone, but with absence of secondary spongiosa, as well as with irregularly arranged woven bone without Haversian systems in lamellar bone [4]. Sometimes dentinogenesis imperfecta, owing to poor mineralization of collagen type I of the dentine, is concomitantly present. Differential diagnoses include (1) alimentary secondary hyperparathyroidism (discussed later), although this does not go together with flexible joints, blue sclera, or transparent teeth, and the diet of the patient does not differ from that of its normal litter mates; (2) hypovitaminosis D, although that is characterized by the increased width of growth plates; (3) hypothyroidism, although these patients are mobile, do not have fractures, and reveal delayed skeletal maturation with otherwise normal mineralization.

Treatment of osteogenesis imperfecta for human patients includes bisphosphonate supplementation to strengthen the bone, and allogeneic mesenchymal stem cell or bone-marrow transplantation with acceptable success [5]; but for companion animals, the prognosis is poor.

Osteochondrodysplasia in Cats

Osteochondrodysplasia is a generalized skeletal disease characterized by short, misshapen distal limbs; exostosis plantar to the calcaneus; and round joints of distal limbs with diffuse osteopenia of adjacent bone; and short, thick inflexible tails (Fig. 99-1C). It occurs in offspring of both genders originating from the mating of a Scottish fold with a normal cat. The Fold-ear is a dominant trait but does not always coincide with these skeletal abnormalities. The patient reveals lameness, a stiff gait, and a reluctance to jump, starting at a young age. Histologically, cartilage maturation seems to be disturbed [6]. Differential diagnosis is hypervitaminosis A, although this reveals exostosis around the proximal joints.

Treatment of single cases varies from expectative, radiation of exostosis [7] and pantarsal arthrodesis [8], to injections with pentosan with oral dosage of glycosaminoglycans [6], all of which have been described as producing some success. However, breeding with Fold-eared cats can be prevented, because prognosis of this disease is poor.

Vitamin A

Vitamin A is essential in bone metabolism, especially in reducing chondrocyte proliferation in growth plates, decreasing periosteal osteoblast activity, and stimulating osteoclast activity, in addition to a variety of functions in reproduction, epithelization, and retina integrity. Vitamin A is present in animal fat, for example in ground beef (1400 IU/kg dm), raw egg (40,000 IU/kg dm), bovine liver (1,500 000 IU/kg dm), and cod liver oil (850,000 IU/kg dm). In dogs, but not in cats, vitamin A (C20H29OH) can be synthesized out of β-carotene (C40H56) by cleavage with the aid of carotenase present in the intestinal mucosa and liver cells. Approximately 1 μg of carotene is equivalent to 0.5 IU of vitamin A. Therefore, the dietary requirement of vitamin A for cats is higher than for dogs (10,000 IU and 5000 IU per kg dm food, respectively). The upper limit of vitamin A for cats is reported to be 100,000 IU/ kg dry matter (i.e., 10 times the requirement). Another difference between dogs and cats regarding vitamin A metabolism is in the inactivation; dogs but not cats can form retinyl esters to inactivate vitamin A and are able to excrete 15 to 60% of the daily intake as retinyl palmitate in the urine. Therefore, hypervitaminosis A is seen more frequently in cats than in dogs, especially at an older age (3 to 13 years).9

Hypervitaminosis A

Hypervitaminosis A can be caused in kittens and puppies after several weeks of over-supplementation. They reveal reduced growth in length and osteoporosis of long bones together with flaring of metaphyseal regions. Hypervitaminosis A in dogs results in anorexia, decreased weight gain, narrowing growth plate cartilage, decreased new bone formation, and thin cortices. Concentrations of vitamin A in plasma serum exceed the normal ranges for dogs (i.e., 1800-18,000 IU/L).

Hypervitaminosis A in cats may produce a stiff neck and/or enlarged joints in the front and hind legs (mainly elbow and stifle joint) owing to ankylosis, dull hair coat, change in character (probably owing to hypersensitivity and/or bone pain), anorexia, and weight loss (see Fig. 114-3 in Nutrition in Orthopedics). To confirm the diagnosis bone biopsies can be taken, but a liver biopsy, which is easier, will show fatty infiltration [9]. In addition, retinol levels of the liver are increased, in contrast to plasma retinol levels, which were normal in 20% of the cases in a study in cats with hypervitaminosis A [10].

In dogs, a history of supplementation with cod liver oil will help to make the diagnosis. In cats, the history can indicate a prolonged preference for raw fish, raw liver, or supplements, but this is not always the case, suggesting an individual predisposition [9]. On the other hand, a diet with 106 IU vitamin A per kg given to adult cats failed to produce the classic skeletal signs of hypervitaminosis A in 2 years’ time [11]. Both 0.5* 106 and 106 IU vitamin A per kg diets (92% dm) given to pregnant queens coincided with a 1.7- and 9-fold incidence increase of kittens with malformations, including neural tube defects, cleft palate, and pelvic hypoplasia, when compared with controls receiving 19,800 IU vitamin A per kg food [11].

The therapy should be instituted as soon as the diagnosis is made and includes analgesia and food adaptation. Because all commercially available balanced foods include at least the required amount of vitamin A, it is better to prescribe a balanced homemade diet without vitamin A added to it. Such a diet should have a low animal-fat content (lean meat such as veal, lamb, or poultry, or cottage cheese). Per 100 g of cooked meat (including its boiling water with taurine in it) and 60 g of cooked rice should be added 2 tsp of corn oil, 0.5 tsp iodized salt, and 1 tsp bone meal to prevent deficiencies [12]. Because cats will often have hepatic lipidosis, the dosage of analgesia should be on the lower side. General improvement can be seen 4 weeks after the start of the therapy; ankylosis will not disappear so the cats will stay lame, although not from pain [9].

Vitamin D

The importance of vitamin D (vitD) for skeletal development was reported in dogs even before it was described in humans [13]. The skeletal abnormalities, including thin cortices, curved bones, and enlarged growth plates, that developed in dogs raised on oatmeal could be prevented and cured by the administration of cod liver oil. Sunlight was found to prevent rickets in children and to cure rickets in a goat based on the ability to synthesize cholecalciferol in the skin under the influence of ultraviolet-B light. This ability has been developed in amphibians, reptiles, birds, herbivores, and omnivores, but not in dogs and cats [14]. The cutaneous level of the vitamin D3 precursor 7-dehydrocholesterol (7-DHC) is low [14], because of a high level of 7-DHC reductase, an enzyme with high activity converting 7-DHC into cholesterol [15]. Thus, dogs and cats are solely dependent on dietary resources to meet their vitamin D requirement. Balanced dog and cat food does not need any vitamin D supplementation, irrespective of the season or the latitude.

Vitamin D3 is absorbed in the intestine by passive diffusion, transported in plasma bound to chylomicrons, lipoproteins, and vitD-binding proteins (DBP), and routed to the liver where 40% to 60% will be absorbed [16]. Here vitD3 is hydroxylated into 25-hydroxy-cholecalciferol (25OHvitD3). Eventually, this metabolite is further hydroxylated at different places, thus forming a variety of metabolites with different or no activity. Two metabolites are considered to be the most active: 1,25dihydroxy-cholecalciferol (1,25 (OH)2vitD3) and 24,25dihydroxy-cholecalciferol (24,25(OH)2vitD3). Other metabolites are considered metabolites of the oxidation pathway and can be increased in case of vitamin D intoxication [17]. A 1000-fold difference in plasma concentration exists between 25OHvitD3 (nmol/L) and 24,25(OH)2vitD3 (nmol/L), versus 1,25(OH)2vitD3 (pmol/L), but the latter is the most active metabolite. Under normal circumstances, only 0.4% of the latter is not bound to transport proteins and thus it is biologically active. In vitD intoxication, 1,25(OH)2vitD3 is freed from the binding protein, resulting in high vitD activity without a severe increase of the total plasma concentration of 1,25(OH)2vitD3 [18]. The hydroxylation into 24,25 or 1,25(OH)2vitD3 in the kidneys is reflected in the plasma concentration, whereas other hydroxylation sites (such as intestine, growth plates, and placenta) are not. A variety of factors, related to breed, age, and dietary contents, influence the plasma concentrations of these main metabolites (Table 99-1) [19-27]. The main role of 1,25(OH)2vitD3, the biologically most active metabolite, is the mineralization of newly formed cartilage and osteoid. Its increase of active intestinal and renal calcium and phosphorous absorption and its stimulation of the parathyroid hormone-induced osteoclastic bone resorption should be seen in the light of making calcium and phosphorous available for the mineralization process. The main role of 25OHvitD3, the most abundant metabolite in plasma, is to become hydroxylated, although it has biologic activity, which mainly increases active calcium absorption. The main roles of 24,25(OH)2vitD3 are decreasing the actions of 1,25(OH)2vitD3 on the intestine, but working in concert in cartilage maturation and possibly suppression of osteoclast activity [19].

Hypovitaminosis D

Hypovitaminosis D in young growing animals is called rickets. It is characterized by thin cortices, wide growth plates, broad osteoid seams, and a low plasma concentration of most of the vitamin D metabolites. Rickets is seen only under extreme circumstances, including in dogs fed unsupplemented vegetarian food, in dogs with an inability to absorb fat and thus also vitamins soluble in fat [23], and in dogs with inborn errors of vitamin D3 metabolism.

The diagnosis can be made with radiographs, revealing thin cortices and wide ("mushroom shaped") growth plates (see Fig. 114-1C of Nutrition in Orthopedics). Because active calcium and phosphorous absorption will be decreased in hypovitaminosis D, plasma concentrations of these minerals will be lowered. As a consequence, more PTH will be synthesized and secreted, thus increasing activity of 1a-hydroxylase. However, owing to the lack of sufficient substrate, the total 1,25(OH)2vitD3 plasma concentration will be lowered (with even less unbound, biologically active metabolite). Under the influence of hyperparathyroidism, the osteoclasts will increase bone resorption to compensate for the decreased active calcium absorption, and thus osteoblasts will increase osteoid production as well. Osteoid will seal off the mineralized bone, preventing osteoclasts from resorbing more bone; the decreased bone and increased amount of collagen explain the bowing of the legs rather than the pathologic fracturing seen in hyperparathyroidism.

Treatment depends on the underlying cause. Because the vegetarian diet is often unbalanced at multiple points, a balanced diet is the treatment of choice. Restoration of the skeleton can be noticed in 3 weeks’ time because cartilage and osteoid are present and ready to become mineralized [14]. Atresia of the bile bladder can be corrected surgically [23]. Inborn error of vitamin D metabolism is resistant to even prolonged vitamin D therapy.

Hypovitaminosis D in mature dogs is called osteomalacia. It can be expected in mature dogs raised on a vegetarian diet (without sufficient vitD supply) or in case of severe kidney failure with decreased 1a-hydroxylation of the 25-OHvitD metabolite. The latter can occur despite the renal secondary hyperparathyroidism. Because of hypovitaminosis D, newly formed osteoid will not mineralize, but in older animals this activity is reduced, leaving alone the osteoclast activity. Generalized osteoporosis will occur. This will seldom cause clinical problems, because the animal will already be suffering from its renal failure, but microscopically widened osteocyte lacunae can be noticed. Especially in the jaw, bone resorption can cause noticeable weakening (the "rubber jaw syndrome") with loosening of elements.

Hypervitaminosis D

Hypervitaminosis D in dogs is not easy to induce. Dogs developed an efficient 24-hydroxylase-induced mechanism to increase hydroxylation of 1,25(OH)2vitD3 in case of its overproduction owing to increased vitD intake [20]. Only after 3 months of very high levels of dietary vitD content (100 times the required amount of 500 IU/ kg food) was the 24-hydroxylation mechanism not efficient, eventually leading to increased calcium absorption. In the dogs with the excessive vitD intake, bone trabeculae were thicker, bone remodeling was decreased, and endochondral ossification was severely disturbed, the latter even before calcium absorption increased (Fig. 99-2A) [20]. This led to the conclusion that excessive vitD intake is a direct cause of disturbance of endochondral ossification, and that the mechanism is not via hypercalcemia as was hypothesized earlier [20]. Disturbance of endochondral ossification in distal growth plates of the ulna caused radius curvus syndrome in most of these dogs.

Figure 99-2. Nutritional bone disorders. (A) Young dogs with access at weaning to food with high calcium content developed panosteitis at the age of 4 months, characterized radiologically by increased mineral density in the medulla at different sites [32]. (B) Excessive calcium intake causing hypophosphatemia and hypoparathyroidism with decreased activation of 25OHvitD3 caused rickets-like disease with poorly mineralized cortical and cancellous bone and increased width of growth plates [33]. (See also Fig. 114-1C of Nutrition in Orthopedics). (C) Excessive vitamin D intake causes disturbances of endochondral ossification including retained cartilage cones in (especially fast growing) growth plates, even before it causes increased calcium absorption with hypercalcemia [20]. (See also Figure. 114-1D of Nutrition in Orthopedics).

Parathyroid Hormone

Parathyroid hormone (PTH) is synthesized in and secreted from the four parathyroid glands, lying in or near the thyroid glands. Its synthesis is increased by decreasing plasma concentrations of calcium; chronic calcium deficiency causes enhanced synthesis per chief cell as well as hyperplasia of chief cells. Phosphorus does not have a direct effect on chief cell activity, whereas 1,25(OH)2vitD3 executes a negative feedback on chief cell activity. In case of decreasing plasma 1,25(OH)2vitD3 concentration, PTH acts directly on bone and kidneys to mobilize and reabsorb calcium, respectively. The second phase is increased osteoclast activity; PTH has no direct effect on osteoclasts but acts indirectly via the shrinkage of osteoblasts, thus exposing bone to the osteoclasts. Osteocytes under the influence of PTH enlarge their lacunae, indicating osteocytic osteolysis [27]. Owing to coupling of osteoclast and osteoblast activity, mediated by local factors, osteoblast activity eventually increases. An important effect of PTH on renal tubules is the decrease of the tubular maximum for phosphorus.

Alimentary Secondary Hyperparathyroidism (or All-Meat Syndrome)

In fast growing animals the calcium requirement is much higher than in mature animals. Insufficient chronic calcium intake, owing to imbalanced food (especially meat based) will induce hyperparathyroidism with increased osteoclastic and osteocytic bone resorption and increased osteoblast activity: bone turnover is severely increased. This explains the radiologic and pathologic findings in the skeleton: normal growth in width of the bone, but an excessively increased osteoclastic bone removal especially in the endosteum and in the areas of cancellous bone (i.e., metaphyses, diaphyses, vertebrae). The cortex can become so thin that it cannot withstand normal muscle contraction or the bodyweight of the animal, leading to pathologic fractures (i.e., greenstick and compression fractures) (see Fig. 114-1B in Nutrition in Orthopedics). Compression fractures of vertebrae can cause paralysis and can determine the prognosis of the animal, although complete restoration can occur when additional trauma is prevented and adequate therapy is instituted [9]. The increased 1,25(OH)2vitD3 plasma level in alimentary secondary hyperparathyroidism (ASH) explains the normal mineralization of the growth plate cartilage, visible as a white area bordering the growth plates of normal width [16]. This is the most important clinical finding to differentiate between rickets (wide growth plates) and ASH (narrow growth plates), both with thin cortices and possibly greenstick fractures.

The therapy includes strict rest to prevent more damage and normalization of the diet. Normalization of the diet can be accomplished with a complete, balanced food; extra calcium carbonate (50 mg calcium per kg body weight per day) can be added. Because the endogenous 1,25(OH)2vitD3 is increased in hyperparathyroidism, calcium absorption is highly efficient and extra vitamin D is contraindicated in order to avoid further increasing osteoclast activity [9].

Fractures should be treated only conservatively, i.e., even splints cannot be applied, because the bone will break at the proximal margin of the splint. After mineralization of the skeleton, which is completed within a month, corrective surgery can be considered.

Differential diagnoses are rickets, osteogenesis imperfecta, and renal hyperparathyroidism.

Calcitonin

In the dog calcitonin (CT) is synthesized mainly in the parafollicular or C-cells in the thyroid glands. The synthesis of calcitonin is increased in case of calcium intake and gastrin. Chronic excessive calcium intake, especially at a young age, caused hyperplasia of C-cells [28]. Phosphorus has no known effect on the C-cells, whereas 1,25(OH)2vitD suppresses CT gene expression [29].

The main function of CT is the storage of calcium in the skeleton. thus preventing (post-)prandial hypercalcemia. It does so via an instant release of secretory granules filled with CT after stimulation by calcium or gastrin followed by instant retraction of the ruffle border of osteoclasts. Chronic hypercalcemia causes hypercalcitoninism, characterized by an increased CT plasma concentration and/or increased response on calcium intake, not directly related to the total amount of absorbed calcium [30]. As a consequence, osteoclast activity is decreased. In addition, chronic hypercalcemia will suppress parathyroid synthesis and activity, including suppressed osteoclasia.

Nutritional Hypercalcitoninism

Induction of hypercalcitoninism depends on the growth rate of the dog, the age of the animal when the excessive calcium intake starts, and the duration of the period the excessive calcium intake lasts.

Miniature poodles (MPs) raised on a diet with excessive calcium content (3.3% calcium on dry matter base [dmb], which is 3 times the calcium requirement according to NRC 1974 and 6 times the requirement of NRC 1985 (based on an average growing beagle puppy) developed no clinical or radiologically detectable skeletal abnormalities [31].

Great Dane (GDs) puppies with access to the bitch’s diet, which had increased calcium (3.3% on dmb) in order to prevent eclampsia puerperalis (milk fever), during only the period of partial weaning (i.e., 3-6 weeks of age) developed hyperplasia of C cells with excessive response of CT release following a calcium bolus injection. Despite the fact that at 6 weeks of age all pups got standard food (with 1.1% calcium), the dogs with access to the calcium supplanted food at partial weaning revealed this excessive response until 4 months of age. All these dogs developed enostosis (panosteitis eosinophilic) characterized by shifting lameness and white confluent areas in the medullary cavities (Fig. 99-2B), whereas the pups with access to the control food from partial weaning onward had normal skeletal development [32].

GDs with access to the above described bitch’s diet (3.3% calcium on dmb) during partial weaning and continued thereafter, developed severe hypercalcemia, hypophosphataemia, and hypoparathyroidism. Calcification of newly formed osteoid and cartilage was much disturbed both as a result of the hampered phosphate absorption causing hypophosphataemia and the disturbed vitamin D metabolism owing to hypoparathyroidism (Fig. 99-2C). The skeleton revealed rickets-like abnormalities with thin cortices and wide growth plates. After normalization of the diet, the chief cells became active again and the skeleton mineralized completely [33].

GDs raised on food with an increased calcium or calcium plus phosphorous content (i.e., 3.3% calcium and 0.9% phosphorous or 3.3% calcium and 3.0% phosphorous, respectively) starting at weaning (i.e., 6 weeks of age) revealed decreased bone remodeling owing to decreased osteoclast activity and disturbances in endochondral ossification, i.e., osteochondrosis. Decreased remodeling was not expressed as a proportional widening of foramina in the cervical area, leading to the so-called wobbler syndrome, as was also described by Hedhammar et al. (1974) [37]. who raised GDs with excessive food intake and compared them with restrictedly fed dogs [34]. The disturbances of endochondral ossification were noticed as osteochondrosis in joint cartilage (in the centro-caudal area of the humeral head) and as retained cartilage in the growth plates of ribs, distal ulnae, distal radius, and crus. Disturbances in growth in length developed in these dogs with radius curvus syndrome, elbow incongruities, and deviation of the hind paws [33,35]. (see Fig. 114-1D and Fig. 114-4 of Nutrition in Orthopedics).

The diagnosis of hypercalcitoninism can only be confirmed by a provocation test with determination of the plasma calcitonin concentration, which warrants a homologous radioimmunoassay for CT [36]. A thorough history with special emphasis on diet composition will not even be informative in many cases, because the calcium intake at pre-weaning is not known to many owners. After weaning calcium intake is often not known either because labels of commercial dog food usually state the "minimal content" rather than the actual content of calcium, unlike special diets with a maximum-claim for calcium (per kg food or per energy content). The diagnosis of hypercalcitoninism refers to the known cause of a series of entities characterized by decreased skeletal remodeling (panosteitis, canine wobbler syndrome) and disturbed endochondral ossification (osteochondrosis, retained cartilage cones) in growth plates and joint cartilage. Although genetics may play a role in the occurrence of these entities (although this is not yet proven), high calcium intake plays an important role in their expression and so far no other causative factor has been indicated.

Therapeutic measures should include normalization of the diet. With osteochondrosis and radius curvus syndrome surgery may be indicated.

Growth Hormone

Growth hormone (GH) originates from the somatotrophic cells in the anterior lobe of the pituitary. Its release is characterized by rhythmic pulses, reflecting the pulsatile delivery of growth hormone-releasing hormone, and intervening troughs. The GH level is under primary control of somatotropin-release inhibiting factor, both of which originate from the hypothalamus. The effects of GH can be divided into rapid or metabolic and slow or hypertrophic actions. The rapid effect includes insulin resistance, inducing enhanced lipolysis and restricted glucose transport across cell membranes. The slow effects are mediated through insulin-like growth factor I (IGF-I), which is synthesized in the liver and in other GH-target cells including chondrocytes. At growth plate level, GH stimulates cell differentiation after clonal expansion through the locally produced IGF-I. IGF-I reached higher levels in growing dogs fed free choice compared with restricted feed controls, whereas dietary protein or carbohydrate content fed iso-energetically to growing dogs did not influence IGF-I levels [37,38].

GH Excess

Basal plasma concentrations of GH are significantly higher in young dogs of large breeds than in dogs of the same age but of small or miniature breed [39]. The levels of GH in large breed dogs decrease during maturation and are not significantly different from that of small breed dogs at 6 months of age 38 and reach the level range for adult dogs [38]. Prior to that time the pups of giant breed dogs go through a period of plasma GH concentrations comparable with those known to cause acromegaly in adult dogs. The plasma IGF-I levels are higher in large breed young dogs and, although decreasing during life, stay higher in large than in small breed dogs [38]. The heavy overgrowth features known in young puppies of giant breeds are the result of transient juvenile gigantism [39].

Research dogs, receiving supraphysiologic doses of porcine GH (which has a structure identical to canine GH) in a dosage of 0.5 IU per kg body per day, revealed a steep 2.5- to 3.5-fold increase in plasma IGF-I levels immediately after starting administration of GH at the age of 13 weeks. In addition, a significant increase in weight gain (112 ± 15 vs. 76 ± 10 g in controls [p< 0.05]), in alkaline phosphatase, and in mineralization but not in bone resorption could be noticed at 21 weeks of age [21]. This uncoupling of mineralization and resorption may be the cause that, in 2 out of 5 GH-treated dogs and none of the controls, panosteitis-like lesions were noticed on the radiographs. The length of the radius and ulna were 10% greater in the GH-treated dogs than in the controls at 21 weeks of age, with microscopically noticeable thickening of the growth plates without any signs of osteochondrosis. This finding makes it likely that it is not the physiologic transient juvenile gigantism in puppies of large breeds that makes them susceptible to osteochondrosis [21]. Long-term administration of IGF-I did not result in increased body size in miniature poodles [40].

GH-excess is known as acromegaly and occurs in middle-aged female dogs and middle-aged and elderly, predominantly male, cats. Acromegaly in companion animals is characterized by soft-tissue overgrowth rather than by bony overgrowth, as is characteristic for acromegaly in humans. In dogs, endogenous progesterone or exogenous progestogens induce GH secretion from hyperplastic ductular epithelium in the mammary gland. In dogs, soft-tissue hypertrophy of the mouth, tongue, and pharynx may cause snoring, thickening of the skin, and prognatism, and owing to that, wide interdental spaces [37,38]. In cats, GH excess originates from primary pituitary adenomas and reveals less pronounced physical changes than in dogs with GH excess. In cats, acromegaly may be complicated by diabetes mellitus, neurologic signs owing to tumor growth, and degenerative arthritis with periarticular periosteal reaction [38]. The diagnosis is made by measuring plasma GH concentrations or, even better, by measuring the less fluctuating plasma IGF-I concentration, although hyperglycemia (in cats) and high alkaline phosphatase levels in mature dogs can be indicative. The medical history in dogs and imaging techniques in cats can support the diagnosis. Discontinuation of exogenous progestins and/or ovario(hyster)ectomy in dogs, and hypophysectomy in cats are indicated [33,41].

GH Deficiency

Congenital growth hormone deficiency causes a retardation of growth. This genetic disease, with autosomal recessive inheritance, is seen in different dog breeds but mainly German shepherd and Carelian bear dogs, as well as in cats [38]. A deficiency exists in both GH and thyroid-stimulating hormone, resulting in short but proportional statue (Fig. 99-3A) with growth-plate closure before 1 year of age. Owing to concomitant deficiency of luteinizing hormone and follicle-stimulating hormone, female dwarfs come frequently into heat without ovulating, thus preventing breeding, whereas males produce motile sperm. Owing to developing hypothyroidism, the hair coat is lost and the dogs become dull and inactive at a later age [37,38].

Figure 99-3. Endocrine bone disorders. (A) Congenital growth-hormone deficiency results in proportional dwarfism as revealed from the skeleton and phenotype, respectively, of two adult German shepherd dogs with this genetic disease. (B) Hypothyroidism in a 6-month-old St. Bernard with mental retardation, puffy facial features, and a skeleton with delayed maturation. Skeletal development normal for its age could be reached in 1 month of thyroxine therapy (see anconeal process which should be fused at 6 months of age). (C) Bilateral femoral neck metaphyseal osteopathy in a 14-month-old, early castrated, male cat with gradual progression of lameness and radiologically demonstrated lucency in the femoral necks, which may result in pathologic fractures.

The diagnosis is made based on the typical habitus, and the low GH- and IGF-I-plasma levels. Differential diagnosis is cretinism owing to hypothyroidism (but those dwarfs are disproportional (legs too short), dull, and have a retarded skeletal maturation) and a variety of cardiac, hepatic, gastrointestinal, and renal diseases causing growth failure [42]. Treatment with porcine GH is advocated, but limited experience is available. Progestins, known to induce GH secretion in the mammary gland in both genders with release into systemic circulation, can be used with growth-stimulating effects on the skeleton and hair coat [37]. Without therapy, the prognosis is poor because most dwarfs die at an average age of 4 years from a variety of dysfunctions.

Thyroid Hormones

The thyroid glands secrete tetraiodothyronine (L-thyroxine or T4) and triiodothyronine (T3) in a ratio of 5:1, with T3 being 3 to 4 times more biologically potent than T4. Iodine is actively transported from the extracellular fluid into the thyroid follicular cells. In iodine excess, organic binding in the thyroids is blocked, whereas in iodine deficiency thyroid function is increased. Thyroid hormone in circulation is coupled to binding proteins. The iodine content of meat is less than 10 μg per 100 gram on dmb and decreases even more after cooking, whereas dry dog food has an iodine content of 50 to 100 μg per 100 gram on dmb; for cats the requirement is at least 100 μg per 100 gram on dmb [7,38].

Hypothyroidism in Young Animals

Hypothyroidism at a young age is characterized by disproportionate dwarfism and mental retardation (cretinism). It can be caused by iodine deficiency (owing to a strict carnivore diet without supplementation), lymphocytic thyroiditis, or congenital hypothyroidism (owing to thyroid dysgenesis or defective thyroid hormone synthesis) as described in dogs and cats [38]. In complete athyrosis, symptoms manifest at 2 to 2 months of age with hypoactivity, hypothermia, puffy and retarded facial features, retarded growth in length, and delayed loss of puppy hair (Fig. 99-3B). The skull is broadened, the tongue may be too big for the mouth, and mental dullness and retardation are reported by the owners. Since thyroid hormone influences both the activity of chondrocyte progenitors and the maturation of chondrocytes during endochondral ossification, hypothyroidism leads to skeletal abnormalities. Radiographic investigation of long bones and vertebral bodies reveal retarded skeletal maturation with delayed appearance of secondary ossification centers, delayed growth in length, but normal cortices and growth plates [43].

Differential diagnoses can include dwarfism (although proportional and lively), owing to GH deficiency, rickets (with thin cortices, wide growth plates), secondary hyperparathyroidism (thin cortices, normal growth plate) and chondrodysplasia (normal cortices, normal growth plate, abnormal alignment and/or joint congruities).

The diagnosis can be made by measuring plasma concentrations of thyroid hormone, thyroid scintigraphy, measuring an increased endogenous thyroid-stimulating hormone plasma level, and by comparing radiographs of the patient with breed- and age-matched controls [38].

The therapy includes normalization of the diet (in case of iodine deficiency) or thyroxine therapy at a dose rate of 10 μg/kg body weight twice daily for dogs and half that dosage for cats [38]. After 1 month the skeleton is expected to reach the stage of the biologic age of the animal (Fig. 99-3B), although radiologic control may reveal pathologic abnormalities, and mental retardation can stay manifest.

Hypothyroidism in Adults

Often as a result of autoimmune disease, thyroid tissue disappears, leading to a slowly occurring hypothyroidism, characterized by slowing of mental and physical activities, disinterest, thin hair coat, thick skin with puffy appearance owing to myxedema. The patient can reveal lameness because of myositis in the skeletal muscles and increased plasma creatinine kinase activity [38]. It has been demonstrated that skeletal muscle in a hypothyroid cat is more fatigable, with changes in the isometric twitch speed properties [44]. In addition, lameness characteristic for osteoarthrosis can be seen owing to mucopolysaccharide accumulation in the joint capsules; often this occurs in multiple joints, leading to a stiff gait rather than to lameness. In some cases severe front leg lameness, eventually non-weight bearing, is seen owing to myxedema formation in the carpal tunnel, with median nerve entrapment as can occur around the facial nerve. It is the author’s experience that the front legs are never equally affected. The diagnosis is made by excluding tumors (e.g., osteosarcoma, neurofibroma) in the affected leg and by diagnosing hypothyroidism [43].

With medical treatment of hypothyroidism (see earlier) the prognosis for animals with myositis and nerve impingement is good, whereas it is guarded for those with osteoarthrosis. In fact, the dog will improve mentally earlier than its joint capsules heal, and thus over-use can make the complaint of osteoarthrosis even worse. In the healing period, the dog should be leash restricted [43]. Other neurologic disorders that may coincide with hypothyroidism (including myasthenia gravis, vestibular disease, laryngeal paralysis) may not result in resolution of the signs [45].

Sex Hormones

Skeletal growth and puberty are connected as the sex hormones testosterone and estrogen play a role in cartilage growth and endochondral ossification. Although both hormones are not essential, they play a role in growth, skeletal development, and maintenance of the adult skeleton. Androgens stimulate both chondrocyte hyperplasia and maturation. The anabolic effects of testosterone are associated with augmentation of pulsatile GH secretion. This drives longitudinal bone growth and epiphyseal growth-plate maturation, which culminates in cessation of skeletal elongation. The effect of estrogens (following aromatization of androgens and stimulation of estrogen receptors) depends on its concentration: low concentration stimulates cartilage growth, whereas high concentration stops cartilage growth. It has been demonstrated that many of the growth-promoting effects of the sex steroids are mediated through estrogens rather than androgens. In addition, skeletal maturation with growth-plate closure is also estrogen-dependent in both sexes [46]. Androgens stimulate osteoblast proliferation and antagonize osteoclast-activating effects of PTH, leading to increased cortical bone formation. Estrogens repress osteoclastogenesis and stimulate endosteal and trabecular bone formation, both increasing bone strength [46].

Sex Hormone Deficiency

Estrogen or testosterone deficiency owing to castration occurs soon after surgery. Especially in female dogs, investigations have been performed to study bone strength and composition following ovariohysterectomy, as a model for osteoporosis in postmenopausal women. However, dogs differ considerably in this regard, perhaps owing to the mean estric cycle of 6 months in dogs. In a study in beagle dogs it revealed that 10 months post-ovariohysterectomy, cancellous bone remodeling was not significantly different from presurgical levels [47]. No reports show that early castration will cause osteoporosis or its related pathologic fractures in companion animals.

In a study comparing early (at 7 weeks), late (at 7 months), and no castration in dogs, it revealed that growth-plate closure was postponed in case of castration, even more so in early castration. Because growth velocity did not differ among groups, but the growth period was elongated, the final bone length was increased in both sexes especially in the early castrated dogs [48]. Similarly, in cats, gonadectomy in both genders either at 7 weeks or 7 months of age revealed a delayed closure of the distal radial physis compared with the intact cats [49]. In cats, the growth plates of the proximal femur normally close at 7 to10 months of age, but this occurs much later in early gonadectomized males. This can increase the vulnerability of early castrated cats for physeal fractures in the proximal or distal femur even at adult age.

Femoral neck metaphyseal osteopathy is seen incidentally, mainly in early castrated male cats. The cat has a vague onset of hind-limb lameness with progression to severe lameness with pain on extension of the hip. Radiologic investigation reveals lucency in the proximal metaphyseal area of the femur with pathologic fracture in a limited number of cases (Fig. 99-3C). Histopathologic evaluation may reveal thickening and splitting of the articular cartilage with necrotic bone and vascular congestion at the epiphysis, with an increased number of osteoclasts. Damage to the blood supply of the femoral head and neck is hypothesized with secondary osteoporosis and pathologic fracture [50], although the pathophysiology of this entity needs to be further elucidated.