Treatment of conditions that present with low bone mass by continuous combination therapy with selective prostaglandin ep4 receptor agonists and an estrogen

A method of treating a condition which presents with low bone mass in a patient presenting with low bone mass, the method comprising continuously administering to the patient presenting with low bone mass a synergistically effective combination of a first compound and a second compound, the first compound being of the formula I

• a prodrug thereof, a pharmaceutically acceptable salt of said compound or said prodrug or a stereoisomer or diastereomeric mixture of said compound, prodrug or salt, wherein:
• the dotted line is a bond or no bond;
• X is —CH2— or O;
• Z is —(CH2)3—, thienyl, thiazolyl or phenyl, provided that when X is O, then Z is phenyl;
• Q is carboxyl, (C1-C4)alkoxylcarbonyl or tetrazolyl;
• R2 is —Ar or —Ar1—V—Ar2;
• V is a bond, —O—, —OCH2— or —CH2O—;
• Ar is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or fully saturated ring or bicyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
• and
• Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, said partially or fully saturated ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
• said Ar moiety is optionally substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, or on one or both rings if the moiety is bicyclic, with up to three substituents per ring each independently selected from hydroxy, halo, carboxy, (C1-C7)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C7)alkyl, (C2-C7)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,N′- or tri-N,N,N′-(C1-C4)alkyl substituted aminocarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl and mono-N- or di-N,N-(C1-C4)alkylaminosulfinyl, wherein said alkyl and alkoxy substituents in the definition of Ar are optionally substituted on carbon with up to three fluoro;
• and
• said Ar1 and Ar2 moieties are independently optionally substituted on carbon or nitrogen with up to three substituents each independently selected from hydroxy, halo, carboxy, (C1-C7)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C7)alkyl, (C2-C7)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,N′- or tri-N,N,N′-(C1-C4)alkyl substituted aminocarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl and mono-N- or di-N,N-(C1-C4)alkylaminosulfinyl, wherein said alkyl and alkoxy substituents in the definition of Ar1 and Ar2 are optionally substituted on carbon with up to three fluoro;
• provided that (a) when X is (CH2)— and Z is —(CH2)3—, then R2 is not thienyl, phenyl or phenyl monosubstituted with chloro, fluoro, phenyl, methoxy, trifluoromethyl or (C1-C4)alkyl;
• and (b) when X is (CH2)—, Z is —(CH2)3—, and Q is carboxyl or (C1-C4)alkoxycarbonyl, then R2 is not (i) (C5-C7)cycloalkyl or (ii) phenyl, thienyl or furyl each of which may be optionally monosubstituted or disubstituted by one or two substituents selected, independently in the latter case, from halogen atoms, alkyl groups having 1-3 carbon atoms which may be substituted by one or more halogen atoms, and alkoxy groups having 1-4 carbon atoms;
• and
• wherein the second compound is an estrogen, or a pharmaceutically acceptable salt thereof.