Treatment of bone disorders with skeletal anabolic drugs

Abstract

Disclosed herein are methods for the prevention and treatment of a variety of mammalian conditions manifested by loss of bone mass, including osteoporosis. The present invention provides methods of using PTHrP, or analogs thereof, for the treatment of metabolic bone disorders that are both effective and have an increased safety.

1 .- 21 . (canceled) 
     
     
         22 . A method of increasing bone mass in a human patient in need thereof, said method comprising administering intermittently to said patient parathyroid hormone-related protein (PTHrP) at a dosage of at least 600 μg/day for a period of at least one month, wherein the bone mass density of said patient increases at a rate of at least 1% per month. 
     
     
         23 . The method of  claim 22 , wherein the bone mass density of said patient increases at a rate of at least 1.5% per month over a period of at least three months. 
     
     
         24 . The method of  claim 23 , wherein said human patient is afflicted with, or at risk of, primary or secondary osteoporosis. 
     
     
         25 . The method of  claim 23 , wherein said human patient is afflicted with, or at risk of, a metabolic bone disorder selected from the group consisting of: osteomalacia, renal osteodystrophy, and other types of skeletal disorders with associated bone loss. 
     
     
         26 . The method of  claim 23 , wherein PTHrP is administered subcutaneously. 
     
     
         27 . A method of treating a human patient afflicted with osteoporosis, said method comprising administering intermittently parathyroid hormone-related protein (PTHrP) to said patient at a dosage of at least about 600 μg/day for a period of about 1 to about 36 months, wherein the bone mass density of said patient increases at a rate of at least 1% per month. 
     
     
         28 . The method of  claim 27 , wherein the bone mass density of said patient increases at a rate of at least 1.5% per month over a period of at least three months. 
     
     
         29 . The method of  claim 28 , wherein said PTHrP is administered subcutaneously. 
     
     
         30 . The method of  claim 28 , wherein said PTHrP is administered by the route of administration selected from the group consisting of: oral, intravenous, intraperitoneal, intramuscular, buccal, rectal, vaginal, intranasal, and aerosol administration. 
     
     
         31 . The method of  claim 28 , wherein said PTHrP is administered until the bone mass density of said patient is restored. 
     
     
         32 . The method of  claim 23 , wherein the period of administration is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 30, and 36 months. 
     
     
         33 . The method of  claim 22 , wherein the bone mass density of the patient increases at a rate selected from the group consisting of at least 1.1% per month, at least 1.2% per month, at least 1.3% per month, at least 1.4% per month, at least 1.5% per month, and at least 1.6% per month over a period of at least three months. 
     
     
         34 . The method of  claim 23 , wherein the method results in a reduction in fractures selected from the group consisting of at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and at least 95%. 
     
     
         35 . The method of  claim 23 , wherein the intermittent administration is selected from the group consisting of once daily, once every two days, once every three days, once weekly, twice weekly biweekly, twice monthly, monthly, and a combination thereof. 
     
     
         36 . The method of  claim 23 , further comprising co-administering, either simultaneously or sequentially with PTHrP, a bone resorption inhibiting agent. 
     
     
         37 . The method of  claim 36 , wherein the bone resorption-inhibiting agent is selected from the group consisting of a bisphosphonate, estrogen, a selective estrogen receptor modulator, a selective androgen receptor modulator, calcitonin, a vitamin D analog, a calcium salt, alendronate, risedronate, etidronate, pamidronate, tiludronate, zoledronic acid, raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, levonneloxifene, and conjugated estrogens. 
     
     
         38 . The method of  claim 23 , wherein the PTHrP has an amino acid sequence as shown in SEQ ID NO:2. 
     
     
         39 . The method of  claim 23 , wherein the PTHrP is naturally-occurring PTHrP, synthetic PTHrP, or recombinant PTHrP. 
     
     
         40 . The method of  claim 23 , wherein the PTHrP has an amino acid sequence which differs from that shown in SEQ ID NO:2 by one or more conservative amino acid substitutions. 
     
     
         41 . The method of  claim 23 , wherein the PTHrP has an amino acid sequence which is at least 90% homologous to the amino acid sequence of SEQ ID NO:2. 
     
     
         42 . The method of  claim 23 , wherein the PTHrP has an amino acid sequence which is at least 95% homologous to the amino acid sequence of SEQ ID NO:2. 
     
     
         43 . The method of  claim 22 , wherein the PTHrP is human PTHrP. 
     
     
         44 . A method of increasing bone mass in a human patient in need thereof, said method comprising administering intermittently to said patient parathyroid hormone-related protein (PTHrP) at a dosage of at least 600 μg/day for a period of at least one month, wherein the bone mass density of said patient increases at a rate of at least 1% per month over a period of at least three months. 
     
     
         45 . A method of treating a human patient afflicted with osteoporosis, said method comprising administering intermittently parathyroid hormone-related protein (PTHrP) to said patient at a dosage of at least about 600 μg/day for a period of about 1 to about 36 months, wherein the bone mass density of said patient increases at a rate of at least 1% per month over a period of at least three months.