Ruminants: Vitamin D

Rickets, the primary vitamin D deficiency disease, is a skeletal disorder of young, growing animals generally characterized by decreased concentration of calcium and phosphorus in the organic matrices of cartilage and bone. Vitamin D deficiency results in clinical signs similar to those produced by deficiency of calcium and (or) phosphorus, because all three nutrients are required for proper bone formation. In the adult animal, osteomalacia is the counterpart of rickets. Cartilage growth in the adult has ceased, and thus this condition is characterized by a decreased concentration of calcium and phosphorus in the bone matrix (demineralization).

Symptoms of rickets include the following skeletal changes, varying somewhat with species depending on anatomy and severity: (1) weakened long bones, resulting in curvature and deformation; (2) enlarged, painful hock and knee joints; (3) general stiffness of gait, arched back and a tendency to drag hind legs; and (4) beaded ribs and deformed thorax.

With osteomalacia, in adults, the progressive demineralization of bones eventually results in fractures and breaks. The disturbance of calcium and phosphorus metabolism produces other symptoms such as reduced performance, hypocalcemia and reproductive failure.

Although there appear to be differences among species in the susceptibility of different bones to degenerative changes, as well as differences that probably reflect body conformation (e.g., pigs compared with sheep), there is nevertheless an apparent common pattern in vitamin D deficiency (Maynard et al., 1979). The spongy and cartilaginous parts of individual bones (mainly the bone ends or epiphysis) and bones relatively rich in this tissue, such as the ribcage, are generally the first and most severely affected. As in simple calcium deficiency, the vertebrae and the skull have the greatest degree of demineralization followed by, the scapula, sternum and ribs. The most resistant bones are the metatarsals and shafts of long bones, which would have obvious survival value to the animal.

Other clinical signs of vitamin D deficiency in ruminants are decreased appetite and growth rate, digestive disturbances, stiffness of gait, labored breathing, irritability, weakness and occasionally tetany and convulsions. These symptoms may precede the skeletal symptoms (i.e., enlargement of joints, slight arching of the back, bowing of legs, with erosion of joint surface causing difficulty in locomotion) (NRC, 1996). There can be an increase in the birth of dead, weak or deformed calves and lambs.

Grazing animals that have normal exposure to direct sunlight are normally protected from vitamin D deficiency. However, under most conditions of commercial livestock production, where animals have limited exposure to direct sunlight and where rates of growth or milk production are high, dietary supplementation with vitamin D is prudent and recommended.

Vitamin D should be supplied to growing and lactating cattle housed in confinement or with limited sun exposure. In more northern latitudes during winter months, photochemical conversion of provitamin D to its active compound (cholecalciferol) in the skin can be limited because of insufficient ultraviolet radiation. Hidiroglou et al. (1979) reported that 25-(OH)D was higher in plasma of cattle in summer than in winter. Richter et al. (1990) found higher concentrations of 25-(OH)D in blood plasma when bulls were kept outdoors as compared to indoors: 21.1 vs. 14.3 ng per ml, respectively. The normal range of plasma 25-(OH)D in cattle is 20 to 50 ng/ml, and therefore even the bulls exposed to direct sunlight in this experiment appeared to have marginal vitamin D status. Similar relationships have been observed in human populations (Romagnoli et al., 1999), where plasma 25-(OH)D was significantly higher in summer than in winter. During winter 15% of young adults, 32% of postmenopausal women and 71-82% of hospital inpatients exhibited vitamin D deficiency based on plasma levels of 25-(OH)D.

Clinical signs of vitamin D deficiency in calves involving the skeleton begin with thickening and swelling of the metacarpal or metatarsal bones (Illus. 1 and 2). As the disease progresses, the forelegs bend forward or sideways. In severe or prolonged vitamin D deficiency, the force exerted by normal muscle tension results in bending and twisting of long bones and the characteristic bone deformity. There is enlargement of bone ends (epiphyses) from deposition of excess cartilage, giving the characteristic "beading" effect along the sternum at the point of attachment of the ribs (NRC, 1996; 1989).

In calves, the mandible becomes thick and soft, and in the worst cases, calves have difficulty eating. In calves so affected, there can be slobbering, inability to close the mouth and protrusion of the tongue (Craig and Davis, 1943). Joints (particularly the knee and hock) become swollen and stiff, the pastern straight and the back arched. In severe cases, synovial fluid accumulates in the joints (NRC, 1989). Posterior paralysis may also occur as the result of fractured vertebrae. The structural weakness of the bones appears to be related to poor mineralization. The advanced stages of the disease are marked by stiffness of gait, dragging of the hind legs, irritability, tetany, labored and rapid breathing, weakness, anorexia and cessation of growth. Calves born to vitamin D-deficient dams may be born dead, weak or deformed (Rupel et al., 1933).

In older animals with vitamin D deficiency (osteomalacia), bones become weak and fracture easily, and posterior paralysis may accompany vertebral fractures. For dairy cattle, milk production may be decreased and estrus inhibited by inadequate vitamin D (NRC, 1989). Cows fed a vitamin D-deficient diet and kept out of direct sunlight showed definite signs of vitamin D deficiency within six to 10 months (Wallis, 1944). Functions that deplete vitamin D are high milk production and advancing pregnancy, especially during the last few months before calving. The visible signs of vitamin D deficiency in dairy cows are similar to those of rickets in calves. The animal begins to show stiffness in her limbs and joints, which makes it difficult to walk, lie down and get up. The knees, hocks, and other joints become swollen, tender and stiff. The knees often spring forward, the posterior joints straighten, and the animal is tilted forward on her toes. The hair coat becomes coarse and rough and there is an overall appearance of unthriftiness (Wallis, 1944). As the deficiency advances, the spine and back often become stiff, arched and humped. In deficient herds, calving rates are lower, and calves can be born dead or weak. Hypocalcemia, either milk fever (parturient hypocalcemia) or unexplained lactational hypocalcemia and paresis, may also be observed as a result of chronic vitamin D deficiency in dairy cattle. These signs are also produced by calcium, phosphorus or electrolyte deficiency or imbalances and are therefore not specific to vitamin D deficiency.

1. Milk Fever in Dairy Cattle (Parturient Paresis)
Milk fever (parturient paresis) is a metabolic disease characterized by hypocalcemia at or near parturition in dairy cows. Goff et al. (1991b) and Horst et al. (1994) discussed milk fever and calcium metabolism of dairy cattle in detail. In essence, milk fever is a failure of calcium homeostasis in the face of increased metabolic demand for calcium. Causative and risk factors are partly, but not completely, understood (Enevoldsen, 1993; Horst et al., 1994; Liesegang et al., 1998). Milk fever is related to factors such as (a) previous calcium and phosphorus intakes, (b) previous vitamin D intake, (c) previous intakes and dietary ratios of potassium, chloride, magnesium, sulfur and sodium, and (d) age and breed of cow. Cows that develop milk fever are unable to meet the sudden demand for calcium brought about by the initiation of lactation. Milk fever usually occurs within 72 hours after parturition and is manifested by circulatory collapse, generalized paresis, depression and eventually coma and death. The most obvious and consistent clinical sign is acute hypocalcemia in which serum calcium decreases from a normal 8 to 10 mg % to 3 to 7 mg % (average 5 mg %). Initially a cow may exhibit some unsteadiness of gait. More commonly, the cow is observed lying on her sternum with her head turned sharply toward her flank in a characteristic posture. The eyes are dull and staring, and the pupils fixed and dilated. If treatment is delayed, paresis will progress into coma, which becomes progressively deeper, leading to death. Treatment with intravenous calcium boro-gluconate is an extremely effective treatment. Some cows will relapse, sometimes with multiple episodes of paresis that indicate a severe failure of the calcium regulatory system or in some cases, severe depletion of body calcium stores. Oral calcium pastes and gels are also used both prophylactically and as an adjunct to intravenous calcium treatment.

Aged cows are at the greatest risk of developing milk fever. Heifers rarely develop milk fever, which is borne out by their superior calcium status at parturition (Shappell et al., 1987). Jersey cattle are generally more susceptible than Holsteins. Older animals have a decreased response to dietary calcium stress due to both decreased production of 1,25-(OH)D and a decreased responsiveness to the 1,25-(OH)2D.

In older cows, fewer osteoclasts exist to respond to hormonal stimulation, which delays the bone contribution of calcium to the plasma calcium pool (Goff et al., 1989, 1991b). The aging process is also associated with reduced renal 1-alpha-hydroxylase response to hypocalcemia, therefore, reducing the amount of 1,25-(OH)2D produced from 25-(OH)D (Goff et al., 1991b; Horst et al., 1994). Tissue receptors for 1,25-(OH)2D decline at parturition (Goff et al., 1995), although there was not a significant difference between paretic and nonparetic cows. Osteoblast activity also appears to be decreased during late pregnancy and around parturition (Naito et al., 1990). This may be related to the reduced plasma calcitonin concentrations around parturition and especially in hypocalcemic, aged cows (Shappell et al., 1987). Low magnesium status is also a risk factor for parturient hypocalcemia as well as hypomagnesemia (Van de Braak et al., 1987; Van Mosel et al., 1991). Infection with the common brown stomach worm (Ostertagia) has been strongly implicated as a causative agent of milk fever and displaced abomasum in dairy cows (Axelsson, 1991), apparently due to an anaphylactic reaction at parturition.

Parturient paresis can be prevented effectively by feeding a low-calcium and adequate-phosphorus diet for the last several weeks prepartum, followed by a high-calcium diet after calving (Horst et al., 1994). Feeding low-calcium diets prepartum is associated with increased plasma PTH and 1,25-(OH)2D concentrations during the peripartum period (Kichura et al., 1982; Green et al., 1981). Green et al. (1981) suggested that the increased PTH and 1,25-(OH)2D concentrations resulted in "prepared" and effective intestinal absorption and bone resorption of calcium at parturition that prevents parturient paresis. Phosphorus deficiency did not affect plasma concentrations of vitamin D3 or its 25-OH or 1,25-OH active metabolites, but did elevate plasma calcium and appeared to increase 1,25-(OH)2D3 receptor binding in the duodenum of phosphorus- depleted lactating goats (Schroder et al., 1990).

Prepartal dietary cation-anion balance (DCAD) influences the degree and incidence of milk fever (Ender et al., 1971; Block, 1984; Gaynor et al., 1989; Oetzel et al., 1988; Enevoldsen, 1993). Dietary excess of cations, especially sodium and potassium, relative to anions, primarily chloride and sulfur, tends to induce milk fever, while anionic diets can prevent milk fever. The cation-anion balance of the diet affects acid-base status of the animal, with cationic diets producing a more alkaline state and anionic diets a more acid state of metabolism. Mild metabolic acidosis in turn promotes calcium mobilization and excretion (Lomba et al., 1978; Fredeen et al., 1988; Won et al., 1996). Anionic diets increase the amount of 1,25-(OH)2D produced per unit increase in parathyroid hormone (Goff et al. 1991a). Debate remains as to the mechanisms of action and the relative importance of individual mineral ions (Enevoldsen, 1993; Horst et al., 1994).

Used correctly, anionic diets prepare the cow's metabolism for a sudden demand for calcium at calving and reduce the incidence of subclinical hypocalcemia and paresis (Horst et al., 1994). Because most legumes and grasses are high in potassium, typical dry cow rations are alkaline. Addition of anions, usually as anionic salts, to the diet for two to four weeks prepartum has been used successfully to reduce the incidence of milk fever. Goff et al. (1991a) concluded that low calcium diets, anionic diets and PTH administration all increase renal 1-alpha hydroxylase activity, resulting in increased production of 1,25-(OH)2D and prevention of milk fever. Increased plasma 1,25-(OH)2D3 concentration in response to feeding acidified diets prepartum was reported by Phillippo et al. (1994).

Supplemental vitamin D has been used to prevent parturient paresis in dairy cows for a number of years (Hibbs and Conrad, 1976, 1983; Littledike and Horst, 1982). Feeding or injecting massive doses of vitamin D has been an effective preventive of milk fever, but toxicity symptoms and death have occurred as well. In some cows, milk fever has been induced by the treatment. Due to the toxicity of vitamin D3 in pregnant cows and the low margin of safety between vitamin D3 doses that prevent milk fever and those that induce milk fever, Littledike and Horst (1982) concluded that injecting vitamin D3 prepartum is not a practical solution to milk fever. However, more recent reports from the same laboratory have provided data suggesting that injection of 24-F-1,25-(OH)2D (fluoridation at the 24 position) delivered at seven-day intervals prior to parturition can effectively reduce incidence of parturient paresis (Goff et al., 1988). Hodnett et al. (1992) used a combination of 25-(OH)D3 and 1-alpha-hydroxy D3 to reduce parturient paresis in dairy cows fed high dietary calcium. The incidence of the disease was reduced from 33% to 8%.

Feeding high doses of vitamin D has been more successful than parental administration in preventing milk fever without inducing toxicity (Hibbs and Conrad, 1976). Feeding 20 million to 30 million IU of vitamin D2 for three to eight days prepartum prevented 80% of expected milk fever cases in aged, Jersey cows (Hibbs and Conrad, 1976). However, prolonging the treatment to 20 days prepartum has resulted in toxicity. The same authors fed cows 100,000 to 580,000 IU vitamin D2 per day on a continuous, year-round basis and reported a reduction in milk fever in cows with a history of the disease but not in cows without a history of milk fever. The most practical approach to controlling milk fever today appears to be through optimizing macro-mineral levels in the diet and providing continuous supplementation with vitamin D at normal levels.

Clinical signs of vitamin D deficiency in sheep and goats are similar to those of cattle, including rickets in young animals and osteomalacia in adults (NRC, 1981; 1985) (Illus. 3). An early report of rickets in Scotland referred to the condition as "bent leg," which occurred in ram lambs seven to 12 months of age (Elliot and Crichton, 1926). The condition was prevented by administration of small amounts of vitamin D in the form of cod liver oil. Newborn lambs can receive enough vitamin D from their dams to prevent early rickets if the ewes have adequate vitamin D status (Church and Pond, 1974). Newborn kids develop rickets if the doe is fed a diet deficient in vitamin D during pregnancy (NRC, 1981).

Vitamin D deficiency has been observed in young lambs or goat kids kept in complete confinement without access to sun-cured roughage. Hidiroglou et al. (1978) reported the clinical history of a flock of sheep kept in total confinement that showed a high incidence (8%) of an osteodystrophic condition which was vitamin D-responsive. A form of osteodystrophia has also been produced experimentally in goats (NRC, 1981).

Parturient paresis occurs in ewes. It is a disturbance of calcium metabolism in pregnant and lactating ewes and is characterized by acute hypocalcemia and the rapid development of hyperexcitability, ataxia, paresis, coma and death. The disease occurs any time from five weeks before to 10 weeks after lambing, principally in overconditioned, older ewes at pasture. The onset is often triggered by abrupt changes in diet, sudden weather changes or periods of stress and fasting imposed by circumstances such as shearing or transportation. The extent of involvement of vitamin D in calcium metabolism in paretic ewes is unclear. Maternal calcium homeostasis is under stress in pregnant ewes (Paulson and Langman, 1990). Sheep differ from all other species studied thus far in that pregnancy does not result in an increase in circulating levels of 1,25-(OH)2D3 (Paulson and Langman, 1990). The signs (e.g., hyperexcitability) and conditions under which this disorder occur (lush pasture, stressful events) suggest that hypomagnesemia is also involved.

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