Vitamin D deficiency due to enhanced clearance is usually explained by systemic disorders (e.g. protein- losing nephropathy, intestinal malabsorption) or increased liver catabolism sometimes caused by certain drugs (e.g. barbiturates, other antiepileptics, etc.). Gastrointestinal malabsorption interferes with uptake of fat- soluble vitamin D from the gut, but sometimes disrupted enterohepatic re circulation of vitamin D metabolites contributes to the loss. Thus, intestinal malabsorption may decrease input and increase excretion of vitamin D.
Vitamin D deficiency from malabsorption may overcome normal amounts of sunlight exposure. Gastrointestinal, pancreatic, or hepatobiliary disease may be at fault, but the mechanism for the vitamin D deficiency and associated derangements in mineral metabolism is often complex. Malabsorption by the gut may also interfere with the uptake of dietary minerals.
Vitamin D is a fat- soluble secosterol, bile salts enable its ab sorption, and there is enterohepatic circulation of vitamin D and its derivatives [2, 3]. Hence, hepatobiliary or pancreatic disease or short bowel syndrome can cause deficiency of bile salts, steatorrhoea, and malabsorption leading to depletion of vitamin D stores. Furthermore, the small bowel mediates dietary Ca2+ up take, and malabsorption of Ca2+ can exacerbate the consequences from vitamin D deficiency. With secondary hyperparathyroidism, conversion of 25- hydroxyvitamin D to both 1,25- and 24,25- dihydroxyvitamin D is enhanced, and 25- hydroxyvitamin D is depleted also by this mechanism. In fact, vitamin D deficiency and its clinical and biochemical consequences may be the first sign of occult malabsorption due, for example, to coeliac disease (non- tropical sprue). Nevertheless, in some conditions where osteomalacia might be anticipated (e.g. primary biliary cirrhosis), the associated osteopathy is often osteoporosis. Iliac crest histology is especially useful for such patients.
Although the pathogenesis of secondary vitamin D- deficiency rickets or osteomalacia can be complicated, pharmacological therapy with appropriate follow- up should give gratifying results. As these patients reflect heterogeneous disturbances of wide- ranging severity, individualized therapy is key. Assay of serum 25- hydroxyvitamin D documents vitamin D status and is essential for monitoring progress. Doses of vitamin D2 or D3 given orally should prove sufficient to correct any deficiency, and are relatively inexpensive. Repletion of vitamin D stores is a principal goal. Then, cholecalciferol or ergocalciferol can be converted to 25- hydroxyvitamin D, even if there is parenchymal liver disease (2, 3). Here too, a single oral ‘loading’ dose of about 125 µg (5000 IU) of vitamin D per kg of body weight can expedite treatment prior to maintenance dosing. Intravenous Ca2+ for symptomatic hypocalcaemia (as much as 20 mg of elemental Ca2+ per kg of body weight daily) over 24 hours by continuous infusion, or slowly in divided doses, is regulated by frequent measurements of serum Ca2+ and would be helpful for ‘hungry bones. Serum Mg2+ should be assayed for newly diagnosed hypocalcaemia, and treated if levels are low, as this may cause peripheral resistance to PTH or impair PTH biosynthesis.
After the loading dose(s) of vitamin D, patients with secondary vitamin D deficiency will require supplemental vitamin D unless the primary disorder can also be corrected. If not, it is impossible to predict the maintenance dose, and therefore clinical and biochemical follow- up is mandatory. Initially, outpatients should be evaluated every few weeks. Adjustments in dosing will be needed when the rickets or osteomalacia heals, or the gastrointestinal, hepatobiliary, or pancreatic disturbance evolves or responds to treatment, but considerable time may pass before the patient achieves a ‘steady state’ of vitamin D repletion.
For mild disease, a reasonable starting dose of vitamin D2 or D3 is 50 000 IU (1.25 mg) orally twice weekly. Assay of the circulating 25- hydroxyvitamin D level about 1 month later, and about every 4 months thereafter, will determine what dose of vitamin D proves useful. Serum 25- hydroxyvitamin D levels should be maintained somewhat above a threshold value of 75 nmol/ L (30 ng/ ml). If hypocalcaemia with secondary hyperparathyroidism is persisting, Ca2+ supplements can be added. Then, assay periodically of the Ca2+ and creatinine content of a 24- h urine collections, aiming for a normal calcium/ creatinine ratio, can be used to optimize therapy. Attention to urinary Ca2+ levels will help to guard against vitamin D toxicity manifesting as hypercalciuria. This approach should show correction of hypocalciuria unless circulating levels of PTH (which reclaims urinary Ca2+) are persistently elevated due to parathyroid gland hyperplasia and do not suppress with treatment. In this situation, assay of serum rather than urine Ca2+ levels becomes especially important.
Although oral vitamin D therapy at some dose is nearly always successful (unless there has been almost complete resection of the small intestine requiring total parenteral nutrition), intramuscular injection (if available) of depot vitamin D2 in oil can be an alternative. Here, 12.5 mg of vitamin D2 (500 000 IU) dissolved in 1 ml of sesame oil (Table 1) will provide sustained bioavailability of vitamin D [36]. An increment in the circulating 25- hydroxyvitamin D level may not appear for several weeks after the injection, but vitamin D2 release will persist for months. Injections of 500 000 IU of vitamin D2 every few months should provide effective and continuous supplementation for an adult, but biochemical monitoring is important.
Hypophosphataemia due to secondary hyperparathyroidism with renal Pi wasting contributes importantly to the pathogenesis of defective mineralization of skeletal matrix in most patients, but is not treated directly. Notably, some individuals with hypocalcaemia alone from hypoparathyroidism or pseudohypoparathyroidism develop rickets or osteomalacia despite elevated serum Pi levels.
Table1. Pharmaceutical preparations of vitamin D and active metabolites
