Pathogenesis
Vitamin D deficiency reflects inadequate biosynthesis with insufficient acquisition from the diet, sometimes coupled with losses into the gastrointestinal tract. Primary (‘nutritional’) rickets or osteomalacia is a human- made disorder due to social, economic, and/ or cultural factors that prevent sufficient exposure to sunlight for photo synthesis of vitamin D3 in the skin. In modernity, hypovitaminosis D may also reflect too little intake from dietary (nutritional) sources or supplements containing vitamin D. Secondary deficiency could be from intestinal malabsorption of vitamin D3 or D2. Increased vitamin D clearance can result from accelerated catabolism, mainly in the liver, or increased loss via the intestine or the kidneys.
Vitamin D3 synthesis in the skin requires UV light with a maximal effective wave length between 290 and 310 nm, and is affected by the intensity of the radiation, surface area of the exposed skin, and intrinsic properties of the epidermis. At extreme latitudes during winter, almost no UV light reaches the ground. In the north of the United States, Canada, and north- western Europe, practically no vitamin D3 is produced by exposed skin between October and March. Clothing, smog, window glass, plastic, and sunscreens effectively block UV radiation and prevent cutaneous synthesis of vitamin D3. Furthermore, vitamin D3 production is less in people with dark skin (because melanin absorbs UV radiation), and in older people despite ‘thin’ skin. Nevertheless, it has been estimated that 20- minute exposure thrice times weekly of the skin of the head and arms to summer sunshine prevents vitamin D deficiency in older people.
Vitamin D content of various unfortified food substances is very low, with the exception of cod liver oil and fatty fish such as herring and mackerel. During unfortified food consumption, it is estimated that less than 20% of total circulating 25- hydroxyvitamin D is from dietary sources. In some countries, therefore, dietary vitamin D is increased by supplementation of certain food products. In the United States, milk is fortified with 400 IU per quart. Improved vitamin D intake could result from multivitamins, which usually contain 400 IU or 800 IU per capsule, or some Ca2+ salt preparations that also contain vitamin D. These supplements will increase the relative contribution of dietary vitamin D to the total body pool, and be beneficial when cutaneous production is limited. Now in the United States, substantially higher doses of vitamin D can be obtained in various shops without a prescription.
Diagnosis
Hypovitaminosis D is diagnosed by assaying the serum concentration of 25- hydroxyvitamin D, which is a reliable measure of vitamin D status in almost all clinical situations. However, the necessary level of circulating 25- hydroxyvitamin D and the terms used to de scribe various low- end serum concentrations are not recognized universally. In fact, many of the clinical signs and symptoms and biochemical perturbations reflecting bone and mineral metabolism from hypovitaminosis D are shared among the disorders of vitamin D action and Ca2+ deficiency (Tables 1 and 2), including the subsequent low to low- normal serum Ca2+ levels, secondary hyperparathyroidism, hypocalciuria, hypophosphataemia, and the hyperphosphatasaemia that seems to reflect enhanced willingness of the skeleton to ossify. Therefore, these biochemical parameters can support but not establish the diagnosis of rickets or osteomalacia, help assess the severity, and direct vitamin D dosing depending on the severity of the vitamin D requirement and the response to treatment. Importantly, circulating levels of 1,25- dihydroxyvitamin D can vary from low to elevated (Table 2), and thus are un helpful for establishing this particular diagnosis.
Table1. Biochemical parameters of mineral and skeletal homeostasis in rickets/ osteomalacia, by aetiology
Table2. Serum levels of vitamin D metabolites in disorders of vitamin D action, by aetiology
In 1998, investigation of patients on a general medicine ward in Boston, Massachusetts, USA revealed that secondary hyperparathyroidism was common when serum 25- hydroxyvitamin D levels were at or below 15 ng/ ml. This led to studies to define vitamin D ‘insufficiency’ and ‘deficiency’. Population- based reference values for serum 25- hydroxyvitamin D levels have been, for a considerable time, debatable. They could reflect age, geography, season, dress, eating habits, confinement to bed or home, local regulations concerning food fortification, and customs of vitamin supplementation. An alternative, however, was to define health- based concentrations (i.e. circulating 25- hydroxyvitamin D levels below which adverse health outcomes could occur). This would represent an intervention threshold to prevent detrimental effects on the skeleton, including relatively mild hypovitaminosis D not sufficient to compromise matrix mineralization but instead disrupt mineral homeostasis, cause secondary hyperparathyroidism, increase bone turnover, and lead to bone loss. Multiple studies aimed to define serum 25- hydroxyvitamin D concentrations below which serum PTH levels increase, or for which vitamin D supplementation significantly de creased serum PTH concentrations. Both approaches yielded similar functional thresholds. Accordingly, vitamin D ‘adequacy’ is accepted by most clinicians as serum 25- hydroxyvitamin D at or above 75 nmol/ L (30 ng/ ml), whereas some argue that the threshold level is instead between 50 and 75 nmol/ L (20 and 30 ng/ ml). However, serum 25- hydroxyvitamin D below 50 nmol/ L (20 ng/ ml) is considered ‘inadequacy’. Vitamin D inadequacy has been subdivided into vitamin D ‘insufficiency’ when levels are between 25 nmol/ L (10 ng/ ml) and the threshold value, and vitamin D ‘deficiency’ when levels are below 25 nmol/ L (10 ng/ ml). Vitamin D deficiency represents a state in which Ca2+ homeostasis begins to fail (i.e. de creased serum Ca2+ levels despite increased serum PTH concentrations), with the high risk of developing rickets or osteomalacia. The same serum 25- hydroxyvitamin D threshold of ~75 nmol/ L (30 ng/ ml) was observed for additional physiological variables, such as intestinal Ca2+ absorption, changes in bone mineral density, and lower extremity physical performance. Reduction of falls and fractures was positively correlated to the serum 25- hydroxyvitamin D level (up to a certain concentration).
Prevalence of Vitamin D Insufficiency and Deficiency
Although the biosynthetic and bioactivation pathways for vitamin D are known, primary deficiency still seems common worldwide. In the United Kingdom, hypovitaminosis D resurged in the 1970s within the immigrant Asian community [13]. Those most vulnerable cannot move freely, and are at the beginning or end of life. In multiple studies worldwide, vitamin D deficiency was detected in 35 to 65% of older people; more so in institutionalized individuals. In people hospitalized for an osteoporotic fracture, deficiency was recorded in 20– 68%; only 1– 3% had levels above 75 nmol/ L (30 ng/ ml). However, any age can be affected, especially when there are physical or mental handicaps. Additionally, the ‘safety net’ created in some countries by fortifying certain foods with vitamin D may not be available [13, 30]. Among adults, institutionalized or housebound individuals, the poor, older people, food faddists, and some religious groups (because of diet and dress) are at enhanced risk. Infants who are breastfed beyond 6 months of age or drink non- fortified milk or formula are also susceptible. In some populations, low dietary Ca2+ intake can be an important or exacerbating factor (‘calciopaenic rickets’).
In postmenopausal women treated for osteoporosis in various regions of the world, vitamin D ‘inadequacy’; that is, serum 25- hydroxyvitamin levels <75 nmol/ L (30 ng/ ml), was found in 52% of those in North America, 58% in Europe, 53% in Latin America, 71% in Asia, and 82% in the Middle East. Pronounced differences in prevalences were observed among countries, ranging from 30% in Sweden in the summer to ~ 90% in Japan and South Korea in the winter and summer. Vitamin D ‘deficiency’ was, however, much less common; ~1% in North America, and ~6% and 8% in Latin America and the Middle East, respectively. Values below 25 nmol/ L (10 ng/ ml) were reported in ~40% of those tested in Sri Lanka and Beijing, and 18% in Hong Kong. But, serum levels below 50 nmol/ L (20 ng/ ml) were observed in 78% of healthy hospital staff in India, and 90% of young women in Beijing and Hong Kong.
Of special concern is the high prevalence, in some geographic regions, of vitamin D deficiency in pregnant women, their children, and adolescent girls. Maternal serum 25- hydroxyvitamin D levels correlate positively with 25- hydroxyvitamin D levels in cord blood.
Fortunately, the prevalence of osteomalacia from hypovitaminosis D is lower than for the vitamin itself, but depends on the criteria for diagnosis (i.e. clinical, biochemical, bone histology, or bone histomorphometry). In a review of multiple publications describing histomorphometry of the femoral head or iliac crest in approximately 1400 patients with hip fracture, osteomalacia ranged from none to over 30% of patients. Perhaps this reflects different populations and magnitudes and durations of vitamin D deficiency, but also the histological criteria used to define osteomalacia.
Treatment
Although patient or parent education and correction of causal socioeconomic factors might seem best for preventing and treating primary vitamin D deficiency, this is often difficult to achieve. Fortunately, pharmacological or supplementation therapy should be inexpensive, effective, and work rapidly. Vitamin D deficiency should be treated using vitamin D2 or D3. Although 25- hydroxyvitamin D3, 1α- hydroxyvitamin D3, and 1,25- dihydroxyvitamin D3 are more potent and act more rapidly than cholecalciferol or ergocalciferol, these active metabolites do not correct the depleted stores of vitamin D and their therapeutic windows are narrow and may not be sustained.
Adequate vitamin D intake has been recommended by the National Osteoporosis Foundation of the USA to be 800– 1000 IU/ day in adults age 50 years or older. The recommendation for infants was increased to 400 IU/ day of vitamin D3. However, these goals are often unachievable unless certain foods are fortified with vitamin D.
Treatment should recognize those at greatest risk. Vitamin D supplementation for infants up to 1 year of age is required in many countries. However, supplementation may not be routine for older people. Nursing home residents, institutionalized and hospitalized elderly, patients with hip fractures, and those with neurological dis orders are among those in greatest jeopardy.
For vitamin D treatment to be fully effective, the recommended daily Ca2+ allowance should be achieved, including by Ca2+ salt supplementation if necessary. In fact, low dietary Ca2+ intake, especially common in some regions of Africa and North China, may itself cause rickets (‘calciopaenic rickets’) or exacerbate vitamin D- deficiency rickets.
The typical oral maintenance dose of vitamin D is 800 to 1000 IU daily. For patients with severe vitamin D deficiency causing symptomatic hypocalcaemia, it is helpful to administer a ‘loading dose’ of vitamin D2 to replete body stores rapidly. Ca2+ intake must also be supplemented. Insufficient Ca2+ for a suddenly mineralizing skeleton could exacerbate the hypocalcaemia. A single oral dose of 5000 IU of vitamin D per kg body weight can be given. For a 70 kg adult, this is 350 000 IU of vitamin D. Although this quantity of vitamin D seems great, it illustrates the body’s storage capacity for vitamin D. With symptomatic hypocalcaemia, Ca2+ can be given intravenously over 24 hours (as much as 20 mg of elemental Ca2+ per kg of body weight per day). Ca2+ infusions should be administered continuously, or slowly in portions, and always regulated by serum Ca2+ levels determined several times daily. Oral Ca2+ supplementation (1– 2 g of elemental Ca2+ each day) can be initi ated at this time. For patients who are not lactose intolerant and no longer hypocalcaemic, three to four glasses of milk each day will provide both Ca2+ and Pi to help remineralize the skeleton. In severe vitamin D deficiency, 4000– 8000 IU could be given daily for the first 4– 6 weeks. Alternatively, 50 000 IU of vitamin D could be ad ministered two or three times a week for the first 2 weeks, followed by lower doses. Because vitamin D is stored in fat and released slowly, and the circulating half- life of 25- hydroxyvitamin D is 2– 3 weeks, dosing can be once weekly, monthly, or every 3– 6 months. An oral dose of 100 000 IU every 4 months for 5 years increased serum 25- hydroxyvitamin D to adequate levels. This approach can improve compliance by seeing the prescribed dose taken, both for independent elderly and for dependent institutionalized patients. However, experience with this high- dose regimen is relatively limited.
The response to vitamin D supplementation will depend on the severity of its deficiency and the consequent changes in mineral and skeletal homeostasis. Serum 25- hydroxyvitamin D should return to normal, but the timeframe will reflect the severity of the initial vitamin D deficiency. When the rickets or osteomalacia is severe, symptoms, signs, and laboratory parameters can change rapidly. Bone pain and muscle weakness will improve quickly, pseudofractures can heal, and serum Ca2+, Pi, and PTH should return towards normal levels. In mild vitamin D deficiency or insufficiency, the response can be more subtle. Bone mineral density can increase, and the incidence of fractures should decrease and their rate of healing improve.
For infants and young children with vitamin D- deficiency rickets, liquid preparations of vitamin D2 are available (Table 3) and can be dosed at 4000 IU (100 µg) orally each day for several months. If capsules can be chewed or swallowed directly, one 50 000 IU (1.25 mg) dose of vitamin D2 orally each week for three or four doses is an inexpensive and straightforward regimen. It seems prudent that the physician observe that at least the first capsule is swallowed. Biochemical and radiographic improvement then typic ally occurs within just a few weeks.
Table3. Pharmaceutical preparations of vitamin D and active metabolites
After healing their rickets, children who have inadequate sunlight exposure should receive 400 IU vitamin D2 or D3 per day, either by consuming fortified foods or using an over- the- counter multi vitamin or vitamin D supplement.
Failure to show biochemical and radiographic improvement with persistently low serum 25- hydroxyvitamin D levels could reflect failed compliance or malabsorption. Use of inexpensive vitamin D capsules may help to assure that the medication is taken. Alternatively, and if available, a single intramuscular injection of vitamin D in sesame oil will assure long- term access to antirachitic activity if patient compliance for oral treatment is poor, or if there is malabsorption (Table 3). Visits to a ‘tanning salon’ have also proved effective. If skeletal disease persists despite sustained correction of circulating 25- hydroxyvitamin D levels, calciopaenia, or one of the vitamin D- dependent or resistant syndromes must be considered.
Prophylaxis against vitamin D- deficiency rickets could involve outdoor activity in sufficient sunshine but without sunburn, consumption of vitamin D- fortified foods, vitamin D supplements, or brief direct exposure to UV light wearing protective goggles. ‘Stoss’ therapy, used in Europe for children, consists of one depot intramuscular injection of 600 000 IU of vitamin D2 during the autumn. However, this dose given once orally has caused hypercalcaemia and renal damage.
