Disclosed are methods of treating vitamin D-sensitive diseases without inducing severe forms of hypercalcemia. The methods comprise administering biologically inert vitamin D prodrugs. The vitamin D prodrugs have a vitamin D-drug moiety and a pro moiety, wherein the pro moiety is selected from the group consisting of a glycone moiety and a sulfate moiety. The vitamin D prodrugs are activated by enzymes at target tissues or cells that cleave the pro moiety from the vitamin D-drug moiety, freeing the vitamin D-moiety from the pro moiety in the vicinity of the target tissues or cells. In some versions, the vitamin D-drug moiety is an active vitamin D drug that has direct therapeutic effects at target sites. In other versions, the vitamin D-drug moiety is an inactive vitamin D drug that regulates the production and/or turnover of an active vitamin D drug and, therefore, abundance of the active vitamin D drug at the target site. The methods of the invention prevent large, acute, systemic increases in the free form of the vitamin D-drug moiety that would otherwise lead to hypercalcemia. The methods can be used to treat hyperproliferative, autoimmune, or infectious diseases throughout the body, including the intestine. Compositions of the vitamin D prodrugs useful in the described methods are also disclosed.
