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Methods and compositions for stimulating bone growth using nitric oxide releasing bisphosphonate conjugates (no-bisphosphonate)

a technology of nitric oxide and bisphosphonate, which is applied in the direction of phosphorous compound active ingredients, drug compositions, biocides, etc., can solve the problems of reducing bone growth, reducing bone density, and reducing bone density, so as to promote bone growth, and enhance bone formation or bone mineral density

Inactive Publication Date: 2008-05-08
GARRETT I ROSS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a method to enhance bone formation or mineral density, or treat bone or joint conditions in a vertebrate subject. This is achieved by administering a nitric oxide-attached bisphosphonate compound (NO-bisphosphonate) to the subject. The NO-bisphosphonate can be used alone or in combination with other compounds that promote bone growth or inhibit bone resorption. The combination can include other bone enhancers or resorption inhibitors such as bone morphogenetic factors, anti-resorptive agents, osteogenic factors, cartilage-derived morphogenetic proteins, growth hormones, estrogens, bisphosphonates, statins, differentiating factors, compounds that inhibit NF-κB, anti-NF-κB antibodies, compounds that inhibit proteasomal activity, and antisense oligos. The patent also describes pharmaceutical compositions and kits containing the NO-bisphosphonate compound.

Problems solved by technology

Further bone deterioration associated with post-menopausal osteoporosis has been treated with estrogens or bisphosphonates, which may have drawbacks for some individuals.
Thus, bisphosphonates seem to be non-biodegradable, both in animals and in solution.
Although the nitrogen-containing bisphosphonates such as alendronate and pamidronate, have been shown to be effective in preventing bone loss, these drugs also appear capable of causing injury to the upper gastrointestinal tract, and there have been several case reports of severe esophagitis in patients treated with alendronate.
Alendronate has also been shown to cause erosions and ulcers in the human stomach and to interfere with the healing of pre-existing lesions when given to healthy volunteers at doses that are prescribed for the treatment of osteoporosis and Pagets disease of bone.

Method used

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  • Methods and compositions for stimulating bone growth using nitric oxide releasing bisphosphonate conjugates (no-bisphosphonate)
  • Methods and compositions for stimulating bone growth using nitric oxide releasing bisphosphonate conjugates (no-bisphosphonate)

Examples

Experimental program
Comparison scheme
Effect test

example 1

High Throughput Screening

[0076] In this screen, the standard positive control was the compound 59-0008 (also denoted “OS8”), which is of the formula:

[0077] In more detail, the 2T3-BMP-2-LUC cells, a stably transformed osteoblast cell line described in Ghosh-Choudhury et al., Endocrinology (1996) 137:331-39, referenced above, was employed. The cells were cultured using α-MEM, 10% FCS with 1% penicillin / streptomycin and 1% glutamine (“plating medium”), and were split 1:5 once per week. For the assay, the cells were resuspended in a plating medium containing 4% FCS, plated in microtiter plates at a concentration of 5×103 cells (in 50 μl) / well, and incubated for 24 hours at 37° C. in 5% CO2. To initiate the assay, 50 μl of the test compound or the control in DMSO was added at 2× concentration to each well, so that the final volume was 100 μl. The final serum concentration was 2% FCS, and the final DMSO concentration was 1%. Compound 59-0008 (10 μM) was used as a positive control.

[00...

example 2

In Vitro Bone Formation

[0079] Selected compounds and appropriate controls were assayed in vitro (ex vivo) for bone formation activity (described above in “Techniques for Neonatal Mouse Calvaria Assay (in vitro)). Histomorphometrical assessments of ex vivo calvaria were carried out using an OsteoMetrics bone morphometry measurement program, according to the manufacturer's instructions. Measurements were determined using either a 10- or 20-fold objective with a standard point counting eyepiece graticule.

[0080] New bone formation was determined (using a 20× objective) by measuring the new bone area formed in one field in 3 representative sections of each bone (4 bones per group). Each measurement was carried out ½ field distance from the end of the suture. Both total bone and old bone area were measured. Data were expressed as new bone width in mm.

[0081] Osteoblast numbers are determined by point counting. The number of osteoblast cells lining the bone surface on both sides of the b...

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Abstract

The invention relates to compositions and methods for use in treating skeletal system disorders in a vertebrate at risk for bone loss, and in treating conditions that are characterized by the need for bone growth, in treating fractures, and in treating cartilage disorders. More specifically, the invention concerns the use of NO-bisphosphonate assembly for enhancing bone growth.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 428,309, filed May 2, 2003, now U.S. Pat. No. 7,288,535, which claims the benefit of U.S. Provisional Application Ser. No. 60 / 377,898, filed May 2, 2002. The contents of each of these documents are incorporated herein by reference in their entirety.TECHNICAL FIELD [0002] The invention relates to compositions and methods for use in treating skeletal system disorders in a vertebrate at risk for bone loss, and in treating conditions that are characterized by the need for bone growth, in treating fractures, and in treating cartilage disorders. More specifically, the invention concerns the use of NO-bisphosphonate activity, e.g., a NO-bisphosphonate compound, for enhancing bone growth. BACKGROUND OF THE INVENTION [0003] Bone is subject to constant breakdown and re-synthesis in a complex process mediated by osteoblasts, which produce new bone, and osteoclasts, which destroy bo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/663C07F9/38A61P43/00A61K45/00A61K31/675A61P19/08A61P19/10
CPCA61K31/663A61K31/675A61K47/48084A61K2300/00A61K47/548A61P19/00A61P19/08A61P19/10A61P43/00
Inventor GARRETT, I. ROSS
Owner GARRETT I ROSS
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