2 - methylene - 19 - nor - 20 ( s )- 1α , 25 - dihydroxyvitamin d 3 ( referred to herein as 2md ) was synthesized and tested . structurally , this 19 - nor analog is characterized by the general formula i previously illustrated herein . the preparation of 2 - methylene - 19 - nor - 20 ( s )- 1α , 25 - dihydroxyvitamin . d 3 having the basic structure i can be accomplished by a common general method , i . e . the condensation of a bicyclic windaus - grundmann type ketone ii with the allylic phosphine oxide iii to the corresponding 2 - methylene - 19 - nor - vitamin d analog iv followed by deprotection at c - 1 and c - 3 in the latter compound : in the structures ii , iii , and iv groups y 1 and y 2 are hydroxy - protecting groups , it being also understood that any functionalities that might be sensitive , or that interfere with the condensation reaction , be suitably protected as is well - known in the art . the process shown above represents an application of the convergent synthesis concept , which has been applied effectively for the preparation of vitamin d compounds [ e . g . lythgoe et al ., j . chem . soc . perkin trans . i , 590 ( 1978 ); lythgoe , chem . soc . rev . 9 , 449 ( 1983 ); toh et al ., j . org . chem . 48 , 1414 ( 1983 ); baggiolini et al ., j . org . chem . 51 , 3098 ( 1986 ); sardina et al ., j . org . chem . 51 , 1264 ( 1986 ); j . org . chem . 51 , 1269 ( 1986 ); deluca et al ., u . s . pat . no . 5 , 086 , 191 ; deluca et al ., u . s . pat . no . 5 , 536 , 713 ]. hydrindanones of the general structure ii are known , or can be prepared by known methods . for the preparation of the required phosphine oxides of general structure iii , a new synthetic route has been developed starting from a methyl quinicate derivative which is easily obtained from commercial ( 1r , 3r , 4s , 5r )-(−)- quinic acid as described by perlman et al ., tetrahedron lett . 32 , 7663 ( 1991 ) and deluca et al ., u . s . pat . no . 5 , 086 , 191 . the overall process of the synthesis of compound i is illustrated and described more completely in u . s . pat . no . 5 , 843 , 928 issued dec . 1 , 1998 and entitled “ 2 - alkylidene - 19 - nor - vitamin d compounds ” the specification of which is specifically incorporated herein by reference . the introduction of a methylene group to the 2 - position of the 20 ( s ) isomer of 19 - nor - 1 , 25 -( oh ) 2 d 3 had little or no effect on binding to the porcine intestinal vitamin d receptor . this compound bound equally well to the porcine receptor as compared to the standard 1 , 25 -( oh ) 2 d 3 ( fig1 ). it might be expected from these results that this compound would have equivalent biological activity . surprisingly , however , the 2 methylene and 20 ( s ) substitutions produced a highly selective analog with its primary action on bone . fig2 shows that 2md has activity similar to that of 1 , 25 - dihydroxyvitamin d 3 ( 1 , 25 ( oh ) 2 d 3 ), the natural hormone , in stimulating intestinal calcium transport . fig3 clearly demonstrates that 2md is 100 times more potent than 1 , 25 ( oh ) 2 d 3 on bone , i . e . the mobilization of bone calcium . fig4 shows that 2md is extraordinarily effective in building bone mass in ovariectomized rats as compared to the native hormone without increasing serum calcium concentration . this is as yet an unprecedented new finding for a vitamin d compound . fig5 illustrates that 2md is 50 - 100 times more potent than 1 , 25 ( oh ) 2 d 3 on hl - 60 differentiation , making it an excellent candidate for the treatment of psoriasis and cancer , especially against leukemia , colon cancer , breast cancer and prostate cancer . table 1 and fig6 a illustrate that 2md is very effective in restoring bone of ovariectomized , old female rats at 32 pmol given 2 times per week as compared to 1 , 25 ( oh ) 2 d 3 given at high doses 3 times per week . note : 2md also increases % ash in the femur . table 2 and fig6 b show that 2md increases breaking strength in the femurs ( cortical strength ) and crushing strength in the vertebra ( trabecular strength ) of animals shown in table 1 . fig7 and 8 show a six week toxicity study in rats showing that 2md appears safe at up to 30 pmol / day . further , in rhesus monkeys , a single oral dose of 27 μg does not cause significant elevation of serum calcium concentration , suggesting even greater safety in primates . competitive binding of the analogs to the porcine intestinal receptor was carried out by the method described by dame et al ( biochemistry 25 , 4523 - 4534 , 1986 ). the differentiation of hl - 60 promyelocytic into monocytes was determined as described by ostrem et al ( j . biol . chem . 262 , 14164 - 14171 , 1987 ). the in vivo tests of increasing serum calcium of rats on a zero calcium diet provides an insight to osteoblastic or bone activity of 2md . the dose response curves show that 2md is at least 80 times more potent than 1 , 25 ( oh ) 2 d 3 in raising calcium in the plasma via the stimulation of the osteoblasts ( fig3 ). at the same time , the activity of 2md on intestinal calcium transport is approximately equal that of 1 , 25 -( oh ) 2 d 3 ( fig2 ). therefore , these data show 2md to have selective activity on bone . 2md is about as active as 1 , 25 ( oh ) 2 d 3 in binding to the vitamin d receptor ( fig1 ). however , it is between 10 - 100 times more active than 1 , 25 -( oh ) 2 d 3 in causing differentiation of the promyelocyte , hl - 60 , into the monocyte ( fig5 ). this result suggests that 2md will be very effective in psoriasis because it has direct cellular activity in causing differentiation and in suppressing growth . it also indicates that it will have significant activity as an anti - cancer agent , especially against leukemia , colon cancer , breast cancer and prostate cancer . the most important result , however , is that 2md is extremely effective not only in restoring bone mass of ovariectomized , old female breeder rats as shown in fig4 and 6 and tables 1 and 2 , but it causes an increase in bone mass above that of sham - operated controls . this illustrates that 2md is very likely having an anabolic effect on bone or increasing bone formation . importantly , the increased bone mass provided by 2md translates into marked increases in bone strength . this increased strength to fracture in femur shows cortical strength while increased strength to crush fractures of vertebra illustrates trabecular bone strength ( table 2 and fig6 a and 6 b ). interestingly , even the percent ash is unexpectedly increased further by 2md . of great importance is that at the dosage levels used in this study , there was no change in serum calcium of animals that showed the marked elevation of bone mass . this argues that a window of safety exists between the use of 2md to increase bone mineral content and the action of 2md in elevating serum calcium . preliminary safety tests carried out on two different occasions have revealed that female rats on a high calcium chow diet tolerate 30 pmol / day without elevating serum calcium or causing mineralization of the kidney ( see fig7 and 8 ). further , preliminary studies in rhesus monkeys indicates that primates tolerate 2md extremely well since a dose of as much as 27 μg of this compound was given as a single does to a 10 kg rhesus monkey without appreciably elevating serum calcium concentration . these and other tests indicate that primates will tolerate 2md extremely well which may give a very large window between efficacy and the danger of hypercalcemia in man . these results illustrate that 2md is an excellent candidate for an anti - osteoporosis therapy and that it may be useful in a number of other circumstances such as autoimmune diseases , cancer , and psoriasis . table 2 strength of femurs and vertebrae to mechanical stress stress value stress value group treatment femur vertebra ovx control oil vehicle / 5 ×/ week 109 . 31 ± 19 . 60 14 . 26 ± 3 . 58 sham - operated oil vehicle / 5 ×/ week 121 . 36 ± 12 . 5 13 . 67 ± 1 . 79 1 , 25 ( oh ) 2 d 3 250 pmol / day / 5 ×/ week 118 . 21 ± 19 . 85 19 . 24 ± 5 . 66 1 , 25 ( oh ) 2 d 3 500 pmol / d / 3 - 5 ×/ week 116 . 47 ± 16 . 20 17 . 14 ± 0 . 52 2md 32 pmol / d / 2 ×/ week 134 . 84 ± 14 . 12 23 . 93 ± 6 . 59 2md 65 pmol / d / 1 ×/ week 133 . 71 ± 14 . 06 17 . 07 ± 5 . 73 for treatment purposes , the compound of this invention defined by formula i may be formulated for pharmaceutical applications as a solution in innocuous solvents , or as an emulsion , suspension or dispersion in suitable solvents or carriers , or as pills , tablets or capsules , together with solid carriers , according to conventional methods known in the art . any such formulations may also contain other pharmaceutically - acceptable and non - toxic excipients such as stabilizers , anti - oxidants , binders , coloring agents or emulsifying or taste - modifying agents . the compound may be administered orally , topically , parenterally or transdermally . the compound is advantageously administered by injection or by intravenous infusion or suitable sterile solutions , or in the form of liquid or solid doses via the alimentary canal , or in the form of creams , ointments , patches , or similar vehicles suitable for transdermal applications . doses of from 0 . 1 μg to 10 μg per day of the compounds are appropriate for treatment purposes , such doses being adjusted according to the disease to be treated , its severity and the response of the subject as is well understood in the art . since the compound exhibits specificity of action , each may be suitably administered alone , or together with graded doses of another active vitamin d compound — e . g . 1α - hydroxyvitamin d 2 or d 3 , or 1α , 25 - dihydroxyvitamin d 3 — in situations where different degrees of bone mineral mobilization and calcium transport stimulation is found to be advantageous . compositions for use in the above - mentioned treatment of psoriasis and other malignancies comprise an effective amount of the 2 - methylene - 20 ( s )- 19 - nor - vitamin d compound as defined by the above formula i as the active ingredient , and a suitable carrier . an effective amount of such compound for use in accordance with this invention is from about 0 . 01 μg to about 50 μg per gm of composition , and may be administered topically , transdermally , orally or parenterally in dosages of from about 0 . 1 μg / day to about 10 μg / day . the compound may be formulated as creams , lotions , ointments , topical patches , pills , capsules or tablets , or in liquid form as solutions , emulsions , dispersions , or suspensions in pharmaceutically innocuous and acceptable solvent or oils , and such preparations may contain in addition other pharmaceutically innocuous or beneficial components , such as stabilizers , antioxidants , emulsifiers , coloring agents , binders or taste - modifying agents . the compound is advantageously administered in amounts sufficient to effect the differentiation of promyelocytes to normal macrophages . dosages as described above are suitable , it being understood that the amounts given are to be adjusted in accordance with the severity of the disease , and the condition and response of the subject as is well understood in the art . the formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients . the carrier must be “ acceptable ” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof . formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules , sachets , tablets or lozenges , each containing a predetermined amount of the active ingredient ; in the form of a powder or granules ; in the form of a solution or a suspension in an aqueous liquid or non - aqueous liquid ; or in the form of an oil - in - water emulsion or a water - in - oil emulsion . formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter , or in the form of an enema . formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient . formulations suitable for topical administration include liquid or semi - liquid preparations such as liniments , lotions , applicants , oil - in - water or water - in - oil emulsions such as creams , ointments or pastes ; or solutions or suspensions such as drops ; or as sprays . for asthma treatment , inhalation of powder , self - propelling or spray formulations , dispensed with a spray can , a nebulizer or an atomizer can be used . the formulations , when dispensed , preferably have a particle size in the range of 10 to 100μ . the formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy . by the term “ dosage unit ” is meant a unitary , i . e . a single dose which is capable of being administered to a patient as a physically and chemically stable unit dose comprising either the active ingredient as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers .