Developmental Orthopedic Diseases Due to Nutritional Deficiencies (Nutritional Secondary Hyperparathyroidism, Rickets)

4. Developmental Orthopedic Diseases Due to Nutritional Deficiencies (Nutritional Secondary Hyperparathyroidism, Rickets)

Pathological fractures, including folding of the cortical bones, compression of the cancellous bone spiculae and deformation of flat bones can occur secondary to nutritional deficiencies of calcium (nutritional secondary hyperparathyroidism NSHP) or vitamin D (rickets in young dogs and osteomalacia in mature dogs). Along with pathological fractures, other clinical signs of the rarely seen rickets or hypovitaminosis D can include lethargy, muscle weakness and bulging metaphyseal areas of radius-ulna and ribs. Chronic progressive demineralization of skeletal bone with resultant loss of teeth and/or pathological and/or compression fractures can be the consequences of NSHP. As well, due to constant muscle pull on the pelvic bones, calcaneus, scapula and other prominences, the weakened bone can become misshaped. In some locations this can be seen or palpated.

Diagnosis

Developmental orthopedic diseases secondary to nutritional deficiencies may be suspected based on dietary history and physical examination. The most practical and inexpensive diagnostic technique is radiographic investigation of the long bones and axial skeleton (Riser & Shirer, 1964; Voorhout & Hazewinkel, 1987a). Although it has been demonstrated that under standardized conditions, a mineral loss of at least 30% is required before NSHP lesions are noticeable radiographically, the abnormal alignment due to greenstick and compression fractures, as well as bowing of bones due to the constant pull, is obvious. In addition, the growth plate has a normal width and the metaphyseal area is usually more radio-opaque than the rest of the bone (Figure 15). Radiographic changes of the radius and ulna can be diagnostic for rickets. Typical findings include a thin cortex, larger diameter of the medullary cavity, bowed long bones and an increase in width of the growth plates (Figure 16).

Figure 15. Nutritional secondary hyperparathyroidism. Radiograph of a dog suffering from nutritional hyperparathyroidism showing thin cortex, greenstick fracture and a normal growth plate bordered by white metaphyseal area. (© HAW Hazewinkel).

Figure 16. Hypovitaminosis D (rickets). (16A) Thin cortex, large diameter of medullary cavity and increased width of the growth plates are typical for hypovitaminosis D (rickets). (16B) Six weeks later, the radiograph shows good mineralization of both the cortices and the growth plates. (© HAW Hazewinkel).

Diagnosis can also be supported by the measurement of vitamin D metabolites and parathyroid hormone (PTH). With rickets, levels of vitamin D, 25-OH vitamin D and 24,25OH2 vitamin D will be low, whereas the 1,25 OH2 vitamin D metabolite will be in the low to normal range. In contrast, elevated PTH, increased 1,25 OH2 vitamin D and low 25-OH vitamin D may occur with NSHP. Serum biochemistry panels may also show some abnormalities with these diseases. Serum phosphate concentrations are strongly influenced by nutritional intake and this factor must be considered in the interpretation of the value. Alkaline phosphatase, abundantly available in osteoblasts and liver cells, will be markedly elevated whenever there is increased bone cell activity (including growth). Even with a low dietary calcium intake, serum calcium concentrations are kept constant. However with hypovitaminosis D, serum calcium concentrations can be in the low to normal range and serum phosphorus concentrations can be low with concurrent increased urinary phosphorus. The latter can be explained by hypocalcemia induced hyperparathyroidism, which will decrease the maximal tubular reabsorption of phosphorus.

Epidemiology

A major risk factor for development of these diseases appears to be diet. Rickets or hypovitaminosis D, rarely seen in puppies, can occur when a dog has been raised on lean meat immediately after weaning. Home-made meat-rich diets, especially those prepared from cardiac and skeletal muscle can be deficient in phosphorus and calcium resulting in NSHP. In addition, NSHP may also be induced when the diet meets all other requirements but is deficient only in its calcium content, and cannot therefore support proper skeletal mineralization. Poor availability of calcium due to complex formation with phytic acid, oxalate, high phosphate content of the food or inadequate vitamin D may cause the same symptoms.

Other risk factors may be breed and breed size. Under experimental conditions, pathological fractures may occur in small breed dogs when fed a diet with extremely low calcium content, whereas Great Danes may exhibit pathological fractures when the dietary calcium content is 50% of the recommended amount. In adult dogs, Krook et al. (1971) described severe hyperparathyroidism in adult Beagles fed 1.2 mg calcium per kg diet (DMB), whereas in adult Golden Retrievers fed a diet with 1 g calcium per kg diet (Hedhammar et al., 1980) and adult mongrels fed a diet with 1.3 g per kg diet did not develop clinical signs of osteoporosis (Gershoff et al., 1958).

Pathophysiology

Up to 95% of ingested calcium may be absorbed following long term feeding of a calcium deficient diet (Gershoff et al., 1958; Hazewinkel et al., 1991). This increase in absorption efficiency is achieved by an increase in formation of the most active metabolite of vitamin D. This metabolite is formed in the kidney under the influence of PTH (Figure 17).

Figure 17. Vitamin D Metabolism (modified after Hazewinkel & Tryfonidou 2002). After ingestion of vitamin D3 in food, it is hydroxylated into 25(OH)D3 in the liver and subsequently to 1,25(OH)2D3 or 24,25(OH)2 D3 in various organs, mainly the kidneys. The second hydroxylation takes place under the influence of 1-a-hydroxylase and 24-hydroxylase, respectively, whose activity is stimulated (+) or decreased (-) by a variety of hormones: parathyroid hormone (PTH), Growth Hormone (GH), Insulin-like Growth Factor (IGF-I) and minerals (Calcium-Ca and Phosphorus-P). In addition to specific actions on intestine and kidneys 1,25(OH)2D3 acts together with 24,25 (OH)2D3 on cartilage and bone cells.

A low calcium uptake stimulates PTH synthesis and secretion. Both elevated vitamin D3 levels and hyperparathyroidism will increase the number, as well as the activity, of the bone resorbing osteoclasts (Hazewinkel et al., 1987a). Osteoclasis will be augmented at the sites where osteoclasts are normally active in young growing bone, i.e., at the medullary aspect of cortical bone and at the periphery of the cancellous bone spiculae. The circulating calcium level is kept constant and is sufficient not to disturb other process in the body, including mineralization of the newly formed cartilage of growth plates.

Vitamin D metabolites stimulate calcium and phosphate absorption in the intestine and reabsorption in the renal tubules as well as stimulate osteoclasts and are necessary for mineralization of the newly formed osteoid and cartilage. Vitamin D is absorbed in the intestine as one of the fat soluble vitamins, transported to and hydroxylated in the liver and then further hydroxylated in the kidney to 24,25 OH2 vitamin D or 1,25 OH2 vitamin D (Fraser, 1980). It has been demonstrated that dogs do not synthesize adequate vitamin D in their skin when radiated with ultraviolet B-light, unlike herbivores and other omnivores (Table 5). Under experimental conditions, young dogs developed the signs of rickets when fed a vitamin D deficient diet with adequate amounts of calcium, phosphorus and other constituents according to the NRC 1974 guidelines. Daily exposure with ultraviolet B-light did not prevent or heal the hypovitaminosis D (Hazewinkel et al., 1987b).

Therefore, dogs rely on the vitamin D in foodstuffs including liver, fish, egg, milk and commercial available dog foods to meet their requirements (Table 6). Synthesis of the most active metabolite (1,25-OH2 vitamin D) is stimulated by the influence of PTH, low serum calcium and phosphorus levels and during growth, pregnancy and lactation.

Nutritional Therapy

Developmental orthopedic diseases secondary to nutritional deficiencies are highly responsive to nutritional intervention. Nutritional therapy should be begun immediately and usually involves feeding a commercial dog food. Commercial dog foods contain adequate amounts of calcium and phosphate and are well above the recommended allowance of vitamin D (i.e., 3.4 µg or 136 IU/ 1000 kcal - NRC 2006). In hypovitaminosis D, after 3 weeks of dietary therapy, mineralization of the growth plates should be almost normal and there should be an improvement in mineralization of cortical and cancellous bone, as well as callus formation around pathological fractures. Mineralization will be complete after several more weeks. If mineralization has not improved within the first 3 weeks, then the diagnosis should be reevaluated: collagen diseases like osteogenesis imperfecta or an inability to hydroxylate vitamin D metabolites should be considered. Vitamin D injections carry the risk of over supplementation and are not recommended when dietary measures are employed (Hazewinkel et al., 1987b). Corrective surgery should be postponed until mineralization of the skeleton is complete.

In the acute phase of NSHP, therapy involves good nursing care and feeding a diet which fulfils the dog's nutritional requirements for its age and size without any injections of calcium or vitamin D. Commercial dog foods would be appropriate and contain adequate calcium content if chosen for correct age and size. The amount of calcium needed exceeds the amount which can be safely injected by 1000 fold. The 1,25 OH2 vitamin D level is expected to be elevated and vitamin D injections would not be beneficial (Figure 18).

Figure 18. Greenstick fracture. (18A) Ventrodorsal view of the pelvis and femurs of a 7 month old crossbred dog raised on a home made diet based on chicken meat, revealing folding fractures of the long bones and the pelvis and compression fractures of the sixth lumbal vertebra.

(18B) The mediolateral view of the left femur shows the abnormal alignment, the thin cortex and wide medulla and the poor contrast when compared with the surrounding soft tissues.

In the acute phase, affected bones cannot withstand the load of a splint or cast and will form another greenstick fracture just proximal to its margin. Compression of the vertebrae with compression of the spinal cord, especially in the lumbar area can occur and cause posterior paralysis in severe cases.

Figure 18c. Vitamin D.

Influence of Increased Vitamin D Intake in Puppies

Under normal circumstances with a vitamin D3 intake of 500 - 1000 IU per kg food, the 24,25(OH)vitamin D3 plasma concentration is 10 times higher in small breed dogs than in large breed dogs of the same age (70 µg/L vs. 7 µg/L), due to excess growth hormone (GH) and insulin-like growth factor (IGF-I) in large breed dogs (Hazewinkel & Tryfonidou, 2002). The 1,25(OH) vitamin D3 plasma concentration in large breed dogs is higher than in small breed dogs (250 pmol/L vs 200 pmol/L) when raised on the same food (Tryfonidou et al., 2002a), mainly due to a lower activity of 24-hydroxylase in large breed dogs.

However, with high vitamin D3 intake, increased hydroxylation occurs in the liver with conversion into the25(OH) vitamin D3 form. The high plasma concentration of 25(OH) vitamin D3 stimulates both the activity of 24-hydroxylase and 1alpha-hydroxy-lase. As a consequence more 1,25 (OH)2 vitamin D3 will be synthesized but immediately further hydroxylated into 1,24,25(OH) tri-hydroxy-vitamin D3 and other products of oxidation. This results in an increased 24,25(OH)2 vitamin D3 plasma concentration and a decreased 1,25(OH)2 vitamin D3 plasma concentration (Tryfonidou et al., 2002). These changes do not alter the absorption rate of is calcium or phosphate, but it does cause severe abnormalities in cartilage maturation, known as osteochondrosis, in Great Danes less than 6 months of age. The latter is probably the result of an imbalance between 24,25(OH)2 vitamin D3 and the available 1,25(OH)2 vitamin D3 at the site of the growth plate (Tryfonidou et al., 2003; Boyan et al., 2001).

Therefore excessive vitamin D intake for a long period should be avoided (Table 5), since it might have deleterious effect on cartilage development in young dogs. Some dog foods may have high vitamin D levels, due to both the ingredients and additional pre-mixture with a standard amount of vitamin D and minerals (Kallfelz & Dzanis, 1989).

Vitamin D intoxication due to vitamin D over supplementation or cholecalciferol poisoning will cause an increase in serum calcium levels by reabsorption of calcium and increased osteoclastic activity.

As a consequence of the increased serum calcium, PTH levels will decrease. There will be an increased threshold for phosphate in combination with phosphate derived from osteoclasia. An increased plasma phosphate level will also be seen with vitamin D intoxication. Calcium phosphate will precipitate in the stomach, lungs, and kidneys with severe clinical consequences.

The long bones may be abnormally shaped and need surgical correction after mineralization is completed, to allow for normal use. Although the prognosis should be guarded, posterior paralysis may disappear two weeks after installation of therapy. Abnormal alignment of the pelvic bones may cause repetitive obstipation which will continue after restoration of the mineralization status of the skeleton. Fracture treatment or corrective osteotomies must be postponed till the skeleton is firmly mineralized.