CA2679847A1 - Methods and compositions for promoting bone and joint health - Google Patents

Abstract

Methods and compositions that can be used to promote bone and joint health through amelioration, stabilization and repair of damage associated with various pathophysiological conditions are disclosed.

Description

METHODS AND COMPOSITIONS FOR PROMOTING BONE AND JOINT HEALTH
CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This patent application claims priority to U.S. provisional application Ser. No.
60/918,727 filed on March 19, 2007.

BACKGROLJND OF THE INVENTION
Field of the Invention [002] The present invention relates generally to mettiods and compositions that can be used to promote bone and joint health through amelioration, stabilization or repair of damage associated with various pathophysiological conditions.

Description of the Related Art [003] Millions daily suffer damage to joint and bone tissues, either from the normal bumps and bruises of every day life or as a result of various disease conditions. Osteoarthritis, rheumatoid arthritis, and osteoporosis represent the most prevalent diseases influencing bone and joint health. Furthermore, other diseases not generally associated with bone or joint health, such as systemic lupus erythematosus, for example, inay have elements affecting bones or joints structure and function.

[004] Osteoarthritis (OA) is an age-related joint disorder that affects rnore than 40 million Americans (Hinton et al, "Osteoarthritis: Diagnosis and therapeutic considerations." Am Fain Physician.65:841-8, 2002; Lawrence et al, "Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States." Arthritis Rheum.
41:778-99; 2004). The disease affects the entire joint structure, and is characterized pathologically by focal areas of articular cartilage loss in synovial joints, varying degrees of osteophyte formation (bony outgi-owths at the cartilage margins), subchondral bone change, and synovitis.
Although OA was historically regarded solely as a degenerative form of arthritis, there is increasing evidence for inflammation as a vital component of OA. Signs of synovial inflammation are present in the many symptoms of OA: joint swelling and effusion, stiffness and occasional redness, especially at proximal and distal interpharyngeal joints. Further, elevated levels of inflaminatory cytokines (interieukin-1 beta [IL-1 [3] and tumor necrosis factor alpha [TNFa]) have been observed in OA
synovial fluid. These cytokines, which are prirnarily synthesized by chondrocytes, appear to play a major part in the destruction of cartilage tissue through the induction of rnatrix metalloproteinases (MMPs), nitric oxide (NO) and prostaglandin E2 (PGE2).
(see, for example, (1) Dieppe & Lohmander, "Patliogenesis and managernent of pain in osteoarthritis."
Lancet, 365:965-73;2005; Felson et al, "Osteoarthritis: New insights". Ann Intern Med.
133:635-46;2000; Goldring, "The role of the chondrocyte in osteoarthritis." Arthritis Rheum. 43:1916-26;2000; van der Kraan & van der Berg, "Anabolic and destructive mediators in osteoarthritis."
Curr Opin Nutr Metab Care. 3:205-11;2000; Pelletier et al, "Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets."
Arthritis Rheum.
44:1237-47;2001; lannonne F, Lapadula G. "The pathophysiology of osteoartllritis." Aging Clin Exp Res, 15:364-72; 2003).

[005] Rheumatoid arthritis (RA) is a systemic inflaminatory disorder that affects 1% of the Arnerican population, and approximately three times as many women as men are affected by this disorder. RA, whicli can be a self-limiting condition or a debilitating chronic disease leading to joint destruction and deformity, is characterized by joint inflainmation, and the predominant symptoms include pain, stiffness and swelling of peripheral joints. (see, for example, Lee DM, Weinblatt ME. "Rheumatoid arthritis". Lancet, 358:903-11; 2001; Rindfleisch JA, Muller D.
"Diagnosis and management of rheumatoid arthritis." Am Fain Physician. 72:1049-50; 2005; and Doan T, and Massarotti E. "Rheumatoid arthritis: An overview of new and emerging therapies."
J Clin Pharmacol. 45:751-62; 2005).

[006] The sequence of events in RA is thought to be initiated by CD4+ T cells, which upon recognizing arthritogenic antigens in synovial tissue, activate macrophages, monocytes and synovial fibroblasts. The activated macrophages, monocytes and synovial fibroblasts then secrete nGnnerous inflannnatory cytokines like interleukin -1 (IL-1), IL-6 and tumor necrosis factor a; in addition, these activated cells also secrete matrix metalloproteinases, which are responsible for the proteolytic breakdown of bone and cartilage tissue. Other mediators of inflammation induced by the pro-inflammatory cytokines, and which contribute to the pathology in affected joints include prostaglandin E2 (PGE2) and nitric oxide. (see, for example, Lee DM, Weinblatt ME. õRheumatoid ai-thritis. " Lancet. 358:903-11; 2001; Bingham 3rd CO. "The patliogenesis of rheumatoid arthritis: Pivotal cytokines involved in bone degradation and inflammation." J Rheuinatol. 29 (suppl 65):3-9; 2002; and Doan T, and Massarotti E.
"Rheumatoid arthritis: An overview of new and emerging therapies." J Clin Pharmacol. 45:751-62; 2005).

[007] Osteoporosis is a disease characterized by low bone mass and deterioration of bone structure resulting in bone fragility and increased risk of fracture. The World Health Organization has defined osteoporosis as a bone mineral density (BMD) value more than 2.5 standard deviations below the rnean for normal young White women. Individuals with osteoporosis are at high risk of suffering one or more fractures, injuries that can often be (2) physically debilitating and potentially lead to a downward spiral in physical and mental health.
There are a variety of different types of osteoporosis. "Primary osteoporosis"
is the rnost common form of the disease and is characterized as osteoporosis that is not caused by some other specific disorder. If the bone loss has been caused by specific diseases or medications then it is referred to as "secondary osteoporosis."

10081 According to the Surgeon General of the tJnited States "the 1.5 million osteoporotic fractures in the United States each year lead to more than half a million hospitalizations, over 800,000 emergency room encounters, more than 2,600,000 physician office visits, and the placement of nearly 180,000 individuals into nursing homes.
Hip fractures are by far the most devastating type of fracture, accounting for about 300,000 hospitalizations each year. Caring for these fractures is expensive. Studies show tiiat annual direct care expendihu=es for osteoporotic fractures range from $12 to $18 billion per year in 2002 dollars. Indirect costs (e.g., lost productivity for patients and caregivers) likely add billions of dollars to this figure.
These costs could double or triple in the coming decades." See "Bone Healtli and Osteoporosis:
A Report of the Surgeon General (2004)" published at http://www.surgeongeiieral.gov/1ibrary/bonehealth/conteiit.htmI (last viewed on February 26, 2008).

[009] Newer methods and compositions for promoting bone and joint health are required since many of the conditions of impaired bone or joint health are or become chroriic in nature, thereby necessitating long term tllerapies. One area for exploration would include botanical based products having proven long term histories of safe use. Two potential candidates are berberine and substituted 1,3-cyclopentadione compounds which may either be isolated from hops or derived frorn hops.

100101 Berberine (7,8,13,13a-tetrahydro-9,10-dimethoxy-2,3-(methylenedioxy)-berbinium), an alkaloid most commonly associated with extracts from plants of the Berberis species, has a history of safety and has known widespread use in traditional medicine for the treatment of a number of conditions ranging from diabetes (See, for example, Leng, SH., et al., "Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion." Acta Pharrnacol Sin. 25(4):496-502; 2004), or for protozoal, bacterial, or fungal infections (see, for example, Sabir, M., et al., "Experimental study of the antitrachoma action of berberine", Indian J Med Res. 64(8):1160-7, 1976; Mohan, M., et al., "Berberine in h=achoma. (A
clinical trial)." Indian J Ophtlialmol. 30(2):69-75, 1982.); Mekawi, M., "Effect of berberine alkaloid on cholera Vibro and its endotoxin." J Egypt Med Assoc. 49(8):554m9, 1966; or Albal, MV., et al., "Clinical evaluation of berberine in mycotic infections." Indian J Ophthalmol.
34:91-2; 1986). Berberine has also been used septic shock and graft versus liost disease (3) (Upadhyay, S., et al., U.S. Patent Ntunber 6,291,483) and investigated for its anti-inflamniatory properties as a potential arthritis treatment modality ( Ivanovska, N., and Philipov, S., "Study on the anti-inflammatory action of Berberis vulgaris root e.xtract, alkaloid,fractions and pzrre alkaloids. ", Int. J. Immunopharmac., 18(10: 553-561, 1996).

[0011] The inventors have previously reported on a number of compounds either isolated from hops or derived from hops (alpha acids, beta acids, prenylflavonoids, chalcones, isoalpha acids, and reduced isoalpha acids) which display activity against numerous conditions including inflammation, minor pain, and arthritic conditions (see, for example, U.S.
2003/0008021; iJS 2003/0113393;i.JS 2004/0115290; or US 2004/0 1 5 1 792). The inventors have found and report lierein among other things the unexpected results that berberine may act synergistically with substituted 1,3-cyclopentadione coinpounds wliich may either be isolated from hops or derived from hops to promote bone and joint health. The inventors additionally report on combinations of botanically derived compounds which inay be used to promote joint and bone health.

SUMMARY OF THE INVENTION

[0012] The present invention relates generally to methods and compositions for promoting bone and joint health in mammals. In some instances the subject may liave a disease or condition such as osteoarthritis, rheumatoid arthritis, an autoimmune disorder, or osteoporosis.
The promotion of bone and joint health may be effecti.iated through a reduction or cessation of the conditions or factors producing deleterious effects in the affected tissue. Alternatively, the present invention may be used modulate repair mechanism processes to either retard or stabilize tissue damage or to promote repair in the affected tissues. The methods and compositions described ernploy combinations of berberine and substituted 1,3-cyclopentadione compounds (wliich may either be isolated from hops or derived from hops), or alternatively, combinations of botanically derived compounds which may be used to promote joint and bone liealtli.

100131 A first embodiment of the invention provides methods to prornote bone and joint health in a mammal in need. Here the method comprises comprising administering to the mammal a composition comprising a therapeutically effective amount of berberine or a pharmaceutically acceptable salt thereof as a first component and as a second component a therapeutically effective amount of a substituted 1,3-cyclopentadione compound selected from the group consisting of rho diliydroisoalpha acids and tetrahydroisoalpha acids or pharmaceutically acceptable salts tliereof.

[0014] A second embodiment provides compositions to promote bone and joint health in a mammal where the compositions comprise a tlier=apeutically effective arnount of berberine or (4) a pharmaceutically acceptable salt thereof as a first component and as a second component a therapeutically effective amount of a substituted 1,3-cyclopentadione compound selected from the group consisting of rho dihydroisoalpha acids and tetrahydroisoalpha acids or pharmaceutically acceptable salts thereo 100151 Methods to promote bone and joint health in a mammal in need are described in another embodiment. Here the compositions of the method comprise from about 10 -ng to about 800 mg of berberine or a pharmaceutically acceptable salt thereof and from about 10 mg to about 800 mg of a tetrahydroisoalpha acid or a pharmacer.itically acceptable salt thereof, wherein the tetrahydroisoalpha acid is selected from the group consisting of 4R,5S)-3,4-dihydroxy-2-(3 -methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyelopent-2-en-1 .-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1 -one;
(4R,5S)-3,4-dihydroxy-2-(3anethylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyelopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2--(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-I -one;
(4R,5S')-3,4-dilrydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyc lopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-, methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyelopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-I -one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en.-I -one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-rnethylpentanoyl)cyelopent-2-en-l-one;
and (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one, [00161 Composition for promoting bone and joint liealth in a mammal in need comprising from about 10 mg to about 800 mg of berberine or a pharmaceutically acceptable salt thereof and from about 10 mg to about 800 mg of a tetrahydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the tetrahydroisoalpha acid is selected from the group consisting of 4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S')-3,4-dihydroxy-2-(3-methylbutanoyl)-5.-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5,S)-3,4-(5) dihydroxy-2-( 3 -methylbutanoyl)-5-(3-methy Ibutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-metliylbutanoyl)-5-(3-methylbtityl)-4-(4-methylpentanoyl)cyclopent-2-en-I -one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5m(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4anethylpentanoyl)cyclopent-2-en-l-one;
(4R,5.S)-3,4-dihydroxy-2-(3 -methy lbutanoy l)-5-( 3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-I -one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbt.rtyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxym2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3.-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; and (4R,5S)-3,4-dihydroxy-2-(3-rnethylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one are described in yet another embodiment.

100171 In still fiirther embodiments of the invention, methods to prornote bone and joint health in a mammal in need are described wliere the compositions of the metliods comprise from about 9 mg to about 720 mg of berberine or a pharmaceutically acceptable salt thereof and from about 20 mg to about 1600 mg of a rho d'rhydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the rho dihydroisoalpha acid is selected from the group consisting of (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-I-one; (4R,-5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent.-2-en-l-one;
(4R,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l -yl)cyclopent-2-en- I -one; (4R,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l -yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l -one;
(4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-I-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one;
(4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-1-yi)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[( l R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-,methylbutanoyl)-5-(3Mmethylbut-2-en-l-yl)cyclopent--2-en-l-one;
(4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-I-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-metlrylpent-3-en-l-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one;

(6) (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylhutanoyl)-5.-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(IS)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-4-[( I S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-1 --yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4S,.5R)-3,4-dihydroxy-4-[( I R)-hydroxy-4-methylpent-3-en-1--y1]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-I -one; (4S,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-1-y1]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-I -one; (4S,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylpropanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-I -one; (4S,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l -yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(IR)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en- I -yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1 R)-lrydroxy-4-methylpent-3-en-1 -yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-I -yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one;
and (4S,5S)-3,4-dihydroxy-4-[(IS)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one.

[0018] Additionally, compositions to promote bone and joint health in a mammal in need wherein the composition comprises from about 9mg to about 720 mg of berberine or a pharmaceutically acceptable salt thereof and fi-om about 20 mg to about 1600 mg of a rho dihydroisoalpha acid or a pharmaceutically acceptable salt thereof are described, wherein the rho dihydroisoalpha acid is selected from the group consisting of (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4anethylpent-3-en-l-yl]-2-(3-methylbutanoyl)-.5-(3-methylbut-2-en-l -yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[( I R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one; (4R,5R)--3,4-dihydroxy-4-[( I S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-I -yl)-2-(2-(7) methylpropanoyl)cycloperrt-2-en-I-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-.5-(3-methylbut-2-en-l-yl)cyclopent-2-en-1 --one; (4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-rnethylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[( I R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-rnethylbutanoyl)-5-(3-methylbr.rt-2-en-1-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2m methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[( I S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-= 1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l -yl)cyclopent-2-en-I -one; (4S,5R)-3,4-dihydroxy-4-[( I R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-1-yl)-2-(2anethylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(IS)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1.S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylpropanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-lrydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-rnethylbut-2-en-1-yl)cyclopent-2-en-l-one; (4S,.5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one;
and (4S,5S)-3,4-dihydroxy-4-[(IS)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut--2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one.

[00191 Another embodiment fLu=ther describes methods to promote bone and joint health in a maminal in need. The methods of this embodiment comprise administering to the mamrnal a composition comprising therapeutically effective amounts of at least two members selected from the group consisting of Abelmoschus, Acacia extract, African Devil's claw, Arthred bovine, Arthred porcine, Astragalus, Berberine, Black cohosh, Bonepep, Bonestein, Chicken Collagen, Curcumin, Devil's Claw, DHEA, Dioscorea, Flaxseed, FOS, Fructus Ligustri, Genistein, Glabridin, Glucosamine, Green tea, Green Tea Polyphenols, Hesperidin, Hyaluronic Acid, Inulin, lprif7avone, Linoleic Acid, MBP, MCHA, Oleanolic Acid, Oleuropein, Olive oil, Osteosine, Partliinolide, Perilla oil, Phloridzin, Puerariae radix, Punica granatum, Quercetin, Red yeast rice, Resveratrol, RIAA, Rosemary, Rutin, THIAA, Vitamin K2, and Withania.

(8) [0020] A further embodiment provides compositions to proinote bone and joint health in a mammal in need. These compositions comprise therapeutically effective amounts of at least two members selected from the group consisting of Abelmoschus, Acacia extract, African Devil's claw, Arthred bovine, Arthred porcine, Astragalus, Berberine, Black cohosh, Bonepep, Bonestein, Chicken Collagen, Curcumin, Devil's Claw, DHEA, Dioscorea, Flaxseed, FOS, Fruch.is Ligustri, Genistein, Glabridin, Glucosamine, Green tea, Gi-een Tea Polyphenols, Hesperidin, Hyaluronic Acid, Inulin, Ipriflavone, Linoleic Acid, MBP, MCHA, Oleanolic Acid, Oleuropein, Olive oil, Osteosine, Parthinolide, Perilla oil, Phloridzin, Puerariae radix, Punica granatum, Quercetin, Red yeast rice, Resveratrol, RLAA, Rosemary, Rutin, THIAA, Vitamin K2, and Withania.

BRIEF DESCRIPTION OF THE FIGiJRES

[0021] Figure 1 graphically displays the cliemical structure of 7,8,13,13a-tetrahydro-9,1Q-dimethoxy-2,3-(methylenedioxy)-berbinii.un; also known as berberine.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention relates generally to methods and compositions for promoting bone and joint health in mammals in need. In some instances the subject may have a disease or condition such as osteoai-tllritis, rheumatoid arthritis, an autoimmune disorder, or osteoporosis. The promotion of bone and joint health may be effectuated through a reduction or cessation of the conditions or factors producing deleterious effects in the affected tissue.
Alternatively, the present invention may be used modulate repair rnechanism processes to either retard or stabilize tissue damage or to promote repair in the affected tissues. The methods and compositions described employ combinations of berberine and substituted 1,3--cyclopentadione compotmds (which may either be isolated from hops or derived from liops), or alternatively, combinations of botanically derived cornpounds which may be used to promote joint and bone health.

[0023] The patents, published applications, and scientific literature referred to herein establish the knowledge of those with skill in the art and are hereby incorporated by reference in their entirety to the same extent as if each was specifically and individually indicated to be incorporated by reference. Any conflict between any reference cited herein and the specific teachings of this specification shall be resolved in favor of the latter.
Likewise, any conflict between an art-understood definition of a word or phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter.

(9) [0024] Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of DNA technology include Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, New York (1989); and Kaufman et al., Eds., Handbook of Molecular and Cellular Methods in Biology in Medicine, CRC Press, Boca Raton (1995).
Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 11th Ed., McGraw Hill Companies Inc., New York (2006).

[0025] In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. As used in this specification, the singular forms "a," "an" and "the" specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise. Additionally, as used herein, unless specifically indicated otherwise, the word "or" is used in the "inclusive"
sense of "and/or" and not the "exclusive" sense of "either/or." The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjumction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to rnodify a nuunerical value above and below the stated value by a variance of 20%.

[0026] As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value of the numerical range, including the end-points of the range.
Similarly, for a variable which is inherently continuous, the variable can be equal to any real value of the numerical range, including the end-points of the range. As an example, a variable which is described as having values between 0 and 2, can be 0, 1 or 2 for variables which are iniierently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables which are inherently continuous.

100271 Reference is made hereinafter in detail to specific embodiments of the invention.
While the invention will be described in conjunction with these specific embodiments, it will be understood that it is not intended to limit the invention to such specific embodiments. On the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims. In the following description, numerous specific details are set forth in order to provide a thorough understanding (10) of the present invention. The present invention may be practiced without some or all of these specific details. In other instances, well known process operations have not been described in detail, in order not to unnecessarily obscure the present invention.

[0028] Any suitable materials and/or methods known to those of skill can be utilized in carrying out the present invention. However, preferred materials and methods are described.
Materials, reagents and the like to which reference are rnade in the following description and examples are obtainable from commercial sources, unless otherwise noted.

[0029] The methods and compositions of the present invention are intended for use with any mammal that may experience the benefits of the methods of the invention.
Foremost among such mammals are hurnans, although the invention is not intended to be so limited, and is applicable to veterinaiy uses. Thus, in accordance with the invention, "rnammals" or "mammal in need" include htunans as well as non-human mammals, particularly domesticated animals including, without limitation, cats, dogs, and horses.

[00301 A first embodiinent of the invention describes methods to promote bone and joint health in a mainmal in need. In this embodiment the methods comprise administering to the mammal a composition comprising a therapeutically effective amoumt of berberine or a pharmaceutically acceptable salt thereof as a first component and as a second component a therapeutically effective atnount of a substituted 1,3-cyclopentadione compound selected from the group consisting of rho dihydroisoalpha acids and tetrahydroisoalpha acids or pharmaceutically acceptable salts thereof.

100311 In some aspects of this embodiment, the cornposition of the method comprises a first component and a second component in a synergistic ratio.

[0032] In other aspects, the rho dihydroisoalplia acid is selected from the group consisting of (4S,SS)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-I -yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent--3-en-I-yl]-2-(2-methylbutanoyl)-5-(3--methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)--3,4--dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-metliylbut-2-en-1 -yl)-2-(2-methylpropanoyl)cyclopent.-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-.5-(3-methylbut-2-en-l-yl)cyclopent-2-en-I -one; (4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbt.rtanoyl)-5-(3-methylbut.-2-en-1-yl)cyclopent-2-en-l-one; (4R,SR)-3,4-dihydroxy-4-[(1S)-hydroxy-4-rnethylpent-3-en-l-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-metliylpropanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-(11) [(1R)-hydroxy-4anethylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3anethylbut-2-en-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbi.rt-2-en-l-yl)cyclopent-2-en-I -one; (4R,5S)-3,4--dihydroxy-4-, [(1 R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[( I S)-hydroxy-4anethylpent-3-en-1-yl]-2-(3-rnethylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-I-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(IR)-hydroxy-4-methylpent-3-en-l-yl]-2-(2--methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(l R)-hydroxy-4-methylpent-3-en~-l-yl]-5-(3-methylbut-2-en-I -yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3Tmethylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en- I -one;
(4S,5R)-3,4-dihydroxy-4-[( I S)-hydroxy-4anethylpent-3-en-l-yl]-2-,(2-rnethylpropanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-metlrylbut-2-en-I-yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-metlrylbutanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-i -yl]-2-(2-methyibutanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(IS)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-I-yl)cyclopent-2-en-l-one; and (4S,5S)-3,4-dihydroxy-4-[( I S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-metirylbut-2-en-I -yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one.

[00331 In still other aspects of this embodiment, the tetrahydroisoalplia acid is selected from the group consisting of 4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-I -one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbi.rtyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoy l)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-metlrylbutanoyl)-5-(3-methylbutyl)-4--(4-methylpentanoyl)cyclopent-2-en-I -one; (4R,5S)-3,4-dihydroxy-2-( 3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-rnethylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-(12) dihydroxy-2-(3anethylbutanoyl)-5-(3-methylbutyl)=-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1 --one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5,S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3anethylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R, 5S')-3,4-dihydroxy-2-(3-methy lbutanoy 1)-5-(3-methy lbuty 1)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l -one; and (4R,.5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one.
[0034] In some aspects the second component is derived from hops, while in other aspects the compositions fi.irther comprise a pharmaceutically acceptable excipient selected from the group consisting of coatings, isotonic and absorption delaying agents, binders, adhesives, lubricants, disintergrants, coloring agents, flavoring agents, sweetening agents, absorbants, detergents, and emulsifying agents. In yet other aspects the composition further comprises one or more members selected fi=om the group consisting of antioxidants, vitamins, minerals, proteins, fats, and carbohydrates.

[0035] In another aspect, the method comprises administering to the mammal a composition which comprises from about 10 mg to about 800 mg of berberine or a pharmaceutically acceptable salt thereof and from about 10 mg to about 800 mg of a tetraliydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the tetrahydroisoalpha acid is selected fi=om the group consisting of 4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-I -one;
(4R,5.S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-.5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-metlrylpentanoyl)cyclopent-2-en-l -one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-I-one; (4R,5S)-.3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-I -one;
(4R,5S)-3,4-dillydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-(13) methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methy lbutyl)-4-(4-methylpentanoyl)cyc lopent-2-en-l-one;
and (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbr.ltyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one.

[0036] In yet another aspect, the inethod comprises administering to the mammal a cornposition wliich comprises frorn about 9 mg to about 720 mg of berberine or a pharmaceutically acceptable salt thereof and from about 20 ing to about 1600 mg of a rho dihydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the rho dihydroisoalpha acid is selected from the group consisting of (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbi.it-2-en-l-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(IR)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-rnetlrylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 ,)-hydroxy-4-methylpent-,3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-I -yl)cycloperrt-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1.5)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(l R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbtrtanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-I -one; (4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-I -yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3anethylbut-2-en-yl)cyclopent-2-en-l-one; (4R,5,9-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-rnethylbut-2-en-l-yl)cyclopent-2-en.-l-one; (4R,5S)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dilrydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbuut-2-en-l-yl)cyclopent-2-en-l-one; (4S,-5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-I -one; (4S,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl].-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[( I S)-hydroxy-4-rrrethylpent-3-en-1-y1]-2-(2-(14) methylpropanoyl)-5-(.3anethylbut-2-en-l-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-I -yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methy lpent-3 -en-1-y 1]-2-(2-methy l bt.rtanoy l)-5 -(3 -methy lbut-2-en-1-y 1)cyc l opent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[( I
S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one;
and (4S,5S)-3,4-dihydroxy-4-[(1,S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one [0037] As used herein, the phrase "promote bone healtli" shall refer to those conditions wherein the methods and compositions of the invention may result in (a) reduced localized pain and inflammation at a site of bone dainage; (b) stabilization of bone structure and integrity; (c) modulation of the mechanism(s) to prevent cell based destruction of bone tissue; (d) enhancing repair of damaged bone tissue by increasing bone mineralization; or (e) modulation of the equilibrium between normal bone deposition and reforination. Representative diseases or conditions wherein use of the methods and compositions of the invention include, without Iimitation, osteoporosis, osteopenia, rickets, osteoarthritis, autoimmune diseases, and rheumatoid arthritis.
[0038] As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonyrnously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising"
means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or compounds, but may also include additional features or compounds.

[0039] As used herein, the terms "derivatives" or a matter "derived" refer to a chemical substance related structurally to another substance and theoretically obtainable from it, i.e. a substance that can be made from another substance. Derivatives can include compounds obtained via a chemical reaction.

[0040] As used herein, "berberine" refers to 7,8,13,13a-tetrahydro-9,10-dimethoxy-2,3-(methylenedioxy)-berbinium. Berberine, an alkaloid, is rnost commonly associated with but not limited to extracts from plants of the Berheris species.

(15) [0041] As used herein, "substituted 1,3-cyclopentadione compotmds" refers to those compounds generally described as reduced isoalpha acids commonly associated with hops and beer production. The substituted 1,3-cyclopentadione compounds refers to the diiiydroisoalplia acids (RIAA), tetraliydroisoalpha acids ("THIAA") and hexahydroisalpha acids ("HHIAA").
Examples of reduced isoalpha acids (RIAA) include without lirnitation dihydroisoalplia acids, more specifically Rho dihydroisoalpha acids (Table 1), tetrahydroisoalpha acid (Table 2), and hexahydroisoalpha acids (Table 3), and their derivatives. "Rho" refers to those reduced isoalpha acids wherein the reduction is a reduction of the carbonyl group in the 4-methyl-3-pentenoyl side chain.

Table I

Rlio dihydroisoalpha acids Chemical Name S non m Structure (4S,5S')-3,4-dihydroxy-4-[(1S')-hydroxy-4- rho (6S) cis n iso-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5- alplia acid Ho"oH
(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one Ho' ~, o 0 (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4- rlio (6R) cis n methylpent-3-en-I-yl]-2-(3-methylbutanoyl)-5- iso-alpl-a acid Ho~~ oH
(3-methylbut-2-en-l -yl)cyclopent-2-en-I -one Ho 0 o (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4- i.lio (6R) trans n methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5iso alpha acid H.
= OH
(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one Ho"~~
(4R,5S)-3,4-dihydroxy-4-[( l S')-hydroxy-4 rho (6S) trans n methylpent-3-en-I-yl]-2-(3-methylbutanoyl)-5 iso al Ho - oH
(3-methylbut-2--en-l-yl)cyclopent-2-en.-l-one pha acid Ho (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4- rho (6R) cis rho n metliylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5- iso-alpha acid HO = OH
(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one Ho*"~

(16) (4R'5R)-3'4-dihydroxy4-[(1 hydroxY4 rho (6S) cis n iso- o '~-methylpent-3-en-l-yl]-2-(3-rnethylbutanoyl)-5 alpha acid HO : OH
(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one H= 1~

o (4S,5R)-3,4-dihydroxy-4-[(IS)-hydroxy-4- (6S) trans rho n methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5- iso-alplia acid H"= OH
(3-methylbut-2-en-l-yl)cyc loperrt-2-en-I -one Ho="
(4S,5R)-3,4-dihYdroxY-4-[(1 R) hYdroxY-4- o rho (6R) trans n methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5- iso-alpha acid Ho OH
(3-methylbut-2-en-I-yl)cyclopent-2-en-l-one Ho (4S,5,S)-3,4-dihydroxy-4-[(1,9-hydroxy-4-methylpent-3-en-l-yl]-5-(3anethylbut-2-en-l- rho (6S) cis co 1 2-2-meth 1 ro ano 1 c clo ent-2-en-1- iso-al~haacid H === o"
Y)- ( Y p p Y) Y p l Ho==' one (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4- ~,.
inethylpent-3-en-l-yl]-5-(3-methylbut-2-en-1- rho (6R) cis co Ha,., OH
yl)-2-(2-methylpropanoyl)cyclopent-2-en-1- iso-alpha acid HO
one (4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4- o methylpent-3-en-l-yl]-5-(3-methylbut-2-en-1- riio (6R) trans co , yl)-2-(2-methylpropanoyl)cyclopent-2-en-1- iso-alplia acid O = OH
one HO' ~y (4R,5S)-3,4-dihydroxy-4-[( l S)-hydroxy-4-methylpent-3-en.-I-yl]-5-(3-methylbut-2-en-I- rho (6S) trans co 1 2-2aneth 1 ro ~ano 1 c clo ent-2-en-l - iso-al ha acid NQ o"
Y)- ( Y p 1 Y) Y P p Ho =
one ~
(4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-metliylpent-3-en-l-yl]-5-(3-methylbut-2-en-I- rho (6R) cis co 1 2 2-meth I ro ano 1 c clo ent-2-en-1- iso-al ha acid HO ' H
Y)- ( Yp p Y) Y p p Ho one ~ y (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4- ~OHO
methylpent-3-en-l-yl]--5-(3-methylbut-2-en-I- rho (6S) cis co 1 2-2-meth 1 ro ano 1 c clo~ent-2-en-1- iso-al lia acid Y)- ( Y P P Y) Y ~ P H
=
one ~/

(17) (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4- rho (6,S) trans co rnethylpent-3-en-1-yl]-2-(2=-methylpropanayl) iso-alpha acid Ho,, OH
5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4- 0 methylpent-3-en-l-yl]-5-(3-methylbut-2-en-1- rlio (6R) trans co I 2-2-meth 1 ia ano 1)c clo ent-2-en-1- iso-al1~haacid NO H
Y)- ( Y P' p Y Y p HO
one O
(4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbr.rtanoyl)-5.- rho (6S) cis ad H OH
(3-rnethylbut-2-en-l-yl)cyclopent-2-en- l-one iso-alpha acid H õ
(4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4 rho (6R) cis ad rnethylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5- iso alpha acid Ho, H
(3-methylbut-2-en-l-yl)cyc lopent-2-en-l-one (4R,5S)-3,4-dihydroxy-4-[(IR)-hydroxy-4 iho (6R) trans ad methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5 iso alpha acid Hp OH
(3-methylbut-2-en-l-yl)cyclopent-2-en-=1-one ~

(4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4 rho (6S) trans ad methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5- iso-al ha acid HQ H
(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one p HO"=' ~
(4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4- rho (6R) cis ad methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5 iso alpha acid Ho H
(3-methylbut-2-en-l-yl)cyclopent-2-en-1 ==one O"y q O
(4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4- rho (6S) cis ad methylpent-3 en-1 yl] 2-(2-methylbutanoyl) 5 iso-alpha acid No= OH
(3-rnethylbut-2-en-l-yl)cyclopent-2-err-l-one "'y (4S,5R)-3,4-dihydroxy-4-[(lS)-hydroxy-4- rho (6S) trans ad methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5 iso alpha acid Ho,.= OH
(3-~methylbut-2-en-1 -yl)cyclopent-2-en-l-one (18) (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4- l.lio (6R) trans ad o 0 methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5 iso alpha acid Ho" H
(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one Table 2 Tetrahydroisoalpha acids Chemical Name Synon m Structure C
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5- tetraliydro cis n (3-methylbi.ityl)-4-(4 Ho~ oH
methylpentanoyl)cyclopent-2-en-l-one ~so alpha acid o (4S,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5 tetrahydro trans n (3-methylbutyl)-4-(4- iso-alpha acid Ho = OH
methylpentanoyl)cyclopent-2 en 1 one o~
o p (4S,5R)-3,4-dihydroxy-2-(3-methylbutanoyl)-5- tetralhydro cis n (3 methylbutyl) 4(4 iso-alpha acid Hof oH
methylpentanoyl)cyclopent-2-en-l -one (4R,5R)-3,4-dihydroxy-2--(3-methylbutanoyl)-5- tetrahydro trans n (3-methylbutyl)-4-(4- iso alpha acid Ho~~ oH
methylpentanoyl)cyclopent-2-en~-l-one ~ o 0 (4R,5S),-3,4-dihydroxy-5-(3-methylbutyl)-4-(4 methylpentanoyl)-2-(3- tetrahydro cis co Ho,, oH
methylpropanoyl)cyclopent-2-en-l-one iso alpha acid o (4S,5S)-3,4-dihydroxy-5-(3-methylbutyl)-4-(4 tetrahydro trans oH
methylpentanoyl)-2-(3- co iso-alpha acid OH
methylpropanoyl)cyclopent-2-en-l-one (19) o (4S,5R)-3,4-dihydroxy-5-(3-methylbutyl)-4-(4 methylpentanoyl)-2-(3- tetrahydro cis co HQ

methylpropanoyl)cyclopent-2-en-l-one iso-alpha acid H

(4R,5R)-3,4-dihydroxy-5-(3-methylbutyl)-4-(4-methylpentanoyl)-2-(3 tetraliydro trans "o,, co iso-alpha acid o"
methylpropanoyl)cyclopent-2-en-l-one (4R,5S)-3,4-dihydroxy-2-(2-methylbutanoyl)-5- tetrahydro cis ad (3-methylbutyl)-4-(4- iso-alpha acid Ho H
methylpentanoyl)cyclopent-2-en-l-one p 0 (4S,5S)-3,4-dihydroxy-2-(2-methylbutanoyl)-5- tetrahydro trans (3-methylbutyl)-4-(4- ad iso-alpha acid H o"
methylpentanoyl)cyclopent-2-en-l-one o (4S,5R)-3,4-dihydroxy-2-(2~-methylbutanoyl)--5- tetrahydro cis ad (3-methylbutyl)-,4-(4- HO = o"

methylpentanoyl)cyclopent-2-en-l-one iso-alpha acid (4R,5R)-3,4-dihydroxy-2-(2-methylbutanoyl)-5- tetrahydro trans (3-rnethylbutyl)-4-(4- NO"' o"
metlrylpentanoyl)cyclopent-2-en-l-one ad iso alpha acid o Table 3 Hexahydroisoalpha acids Cliernical Name S non m Structure (4S,5S)-3,4-dihydroxy-4-[(1S)-1-hydroxy-4- hexahydro (6S) cis methylpentyl]-2-(3-methylbutanoyl)-5-(3- n iso-alpha acid HO H
methylbutyl)cyclopent-2-en-l -one HO"' (20) ~ ~ o (4S,5S)-3,4-dihydroxy-4-[( I R)-1-hydroxy-4- hexahydro (6R) cis methylpentyl]-2-(3-methylbutanoyl)-5-(3- n iso-alplia acid HO pH
methylbutyl)cyclopent-2-en-l-one Ho (4R,5S)-3,4-dihydroxy-4-[(1R)-1-hydroxy-4- hexaliydro (6R) ; `
methylpentyl]-2-(3-methylbutanoyl)-5-(3- trans n iso-alplia HO ; H
"",,y methylbutyl)cyclopent-2-en-l-one acid H

(4R,5S)-3,4-dihydroxy-4-[(IS)-1-hydroxy-4- hexahydro (6S) rrrethylpentyl]-2-(3-methylbutanoyl)-5-(3- trans n iso-alpha H : N
"~
methylbutyl)cyclopent-2-en-l-one acid H "

(4R,5R)-3,4-dihydroxy= 4-[(1 R)- I -hydroxy-4 methylpentyl]-2-(3-methylbutanoyl)-5-(3 hexahydro (6R) cis HO _ m O",r ethylbutyl)cyclopent-2-en-l-one n iso-alpha acid HO OH

(4R,5R)-3,4-dihydroxy-4-[(1 S)-1-hydroxy-4 methylpentyl]-2-(3-methylbutanoyl)-5-(3 hexahydro (6.S) cis HO
methylbutyl)cyclopent-2-en-l-one iso-alplia acid HO=, OH

(4S,5R)-3,4-dihydroxy-4-[(1 S)-I-hydroxy-4- hexahydro (6S) methylpentyl]-2-(3-rnethylbutanoyl)-5-(3- trans n iso-alplia Ho"' H
methylbutyl)cyclopent-2-en-I -one acid HO =

o r (4S,5R)-3,4-dihydroxy-4-[(1R)-1-hydroxy-4- hexaiiydro (6R) rnethylpentyl]-=2-(3-methylbutanoyl)-5-(3- trans n iso-alpha HO' rnethylbutyl)cyclopent-2-en-I-one acid HO

(4S,5S')-3,4-dihydroxy-4-[(1S)-hydroxy-4- 0 metliylpent-3-en-I-yl]-5-(3--methylbr.rt-2-en-1- hexahydro (6S) cis l 2 2-meth 1 ro ano 1 c cla ent-2-en-I- co iso-al ha acid HQ, N
Y)- ( Yp p Y) Y p P Ha"
one (4S,5S)-3,4-dihydroxy-4-[(lR)-hydroxy-4- 0 0 inethylpent-3-en-l-yl]-5-(3-anethylbut-2-en-1- hexahydro (6R) cis HO'" OH
yl)-2-(2-methylpropanoyl)cyclopent-2-en-1- co iso-alpha acid HO
one (21) (4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4 o methylpent-3-en-l-yl]-5-(3-methylbut-2-en-I- hexahydro (6R) HO ; H
1 2 2-rneth 1 io ano 1 c clo ent-2-en-1- trans co iso-alpha Y)- ( Y P' P Y) Y P acid "o one ~, (4R'53'4-dihydroxy4-[(1 hydroxy4-'~ '~- hexahydro (6S) methylpent-3-en-l-yl]-5-(3-methylbut-2-en-1- trans co iso-alpha HO
Q"' yl)-2-(2-methylpropanoyl)cyclopent-2-en-1- acid 1i~
one r (4R,5R)-3,4-dihydroxy-4-[(lR)-hydroxy-4-metliylpent-3-en-l-yl]-5-(3-methylbut-2-en-1- liexahydro (6R) cis HO , OH
yl)-2-(2-methylpropanoyl)cyclopent-2-en-1 - co iso-alpha acid HO"ly one (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4- ~IHO
methylpent-3-en-l~-yl]-5-(3-methylbut-2-en-1- hexahydro (6S) cis 1 2-2-meth 1 ro ano 1 c clo ent-2-en-I- co iso-al ha acid HO Y)- ( Y P P Y) Y
P P Ho"=
one ~
4S 5R 3 4-dih drox 4 l h drox 4 ( ~ ) ~ Y Y [( ~ Y Y hexahydro (6S) methylpent-3-en--l-yl]-2-(2-methylpropanoyl) trans co iso al ~ha HOl=
5-(3-methylbut-2-en-l-yl)cyclopent-2-en-1 1 " '"
acid one (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4- hexahydro (6R) methylpent-3-en-I-yl]-5.-(3anethylbut-2-en-1 trans co iso-alpha HO H
HO`
yl)-2-(2-methylpropanoyl)cyclopent-2-en-1- acid one (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4- 0 methylpent-3-en-I-yl]-2-(2-methylbutanoyl)- hexahydro (6S) cis 3-meth Ibut-2-en-1 1 c clo ent-2-en-1- ad iso-al ha acid HO H
( Y Y) Y P P HU"
one (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)- hexaliydro (6R) cis HO~"' 5-(3-rnethylbut-2-en-I-yl)cyclopent-2-en.-I- ad iso-alpha acid HO
o"
one (4R,5S)--3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)- hexahydro (6R) trans ad isa alpha HO OH
5-(3-methylbut-2-en-I-yl)cyclopent-2-en-1- acid one ~.

(22) (4R,5S)-3,4-dihydroxy-4-[(1,9-hydroxy-4- o hexahydro(6S) methylpent-3-en-l-yl]-2-(2-methylbi.rtanoyl)- trans ad iso-alpha Ho : H
5-(3-methylbut-2-en-l-yl)cyclopent-2-en-1 acid "o"
one (4R,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4- o methylpent-3-en-l-yl]-2-(2-methylbutanoyl)- hexahydro (6R) cis 5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1- ad iso-alpha acid Ho OH
one ~
(4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4- o methylpent-3-en-l-yl]-2-(2-rnethylbutanoyl)- hexahydro (6S) cis (3-methYIbut-2-en-1 Y1)cYcloPent-2-en-I- ad iso-alPha acid HO ` o"
one (~

4S,5R)-3,4-dihYdroxY-4 L(1 S)-hYdroxY-4- hexahydro (6S) 0 methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-trans ad iso alpha Hoõ' OH
5-(3-methylbut-2-en-l-yl)cyclopent-2-en-1- acid one (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4- hexahydro (6R) 0 0 methylpent-3-en-l-yl]-2-(2-methylbutanoyl)- trans ad iso-alpha Ho oH
5-(3-methylbut-2-en-l-yl)cyclopent-2-en-1- acid HQ
one [0042] In some instances the compotmds of the second component are derived from hops. See Verzele, M. and De Keukeleire, D., Developments in Food Science 27:
Chemistry and Analysis of Hop and Beer Bitter Acids, Elsevier Science Pub. Co., 1991, New York, USA, herein incorporated by reference in its entirety, for a detailed discussion of hops chemistry.

[0043] The term "pharmaceutically acceptable" is i.ised in the sense of being compatible with the other ingredients of the compositions and not deleterious to the recipient thereof.

[0044] As used lierein, "compounds" may be identified eitlier by their chemical structure, chernical name, or common name. When the chemical structure and chemical or common name conflict, the chemical structure is determinative of the identity of the compound.
The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isoiners (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including (23) the stereoisomerically pure form (e.g., geornetrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral syrnthesis tecluliques well known to the skilled artisan. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated or identified compounds. The compoGmds described also encompass isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally fotmd in nature. Examples of isotopes that rnay be incorporated into the compounds of the invention include, but are not limited to, ZH, 3 H,13C,111C, 15N, 180, 1'O, etc, Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be liydrated, solvated or N-oxides. Certain cornpounds may exist in inultiple crystalline or amorphous forms. Also contemplated within the scope of the invention are congeners, analogs, hydrolysis products, metabolites and prectu-sor or prodrugs of the compound. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

[0045] Compounds according to the invention may be present as salts. In particular, pharmaceutically acceptable salts of the compounds are conteinplated.
A"pliarmaceutically acceptable salt" of the invention is a combination of a compound of the invention and eitlier an acid or a base that forms a salt (such as, for example, the magnesium salt, denoted herein as "Mg" or "Mag") with the compound and is tolerated by a subject under therapeutic conditions.
In general, a pharmaceutically acceptable salt of a compound of the invention will have a therapeutic index (the ratio of the lowest toxic dose to the lowest therapeutically effective dose) of I or greater. The person skilled in the art will recognize that the lowest therapeutically effective dose will vary from subject to subject and from indication to indication, and will thus adjust accordingly.

[0046] As used herein "hop" or "hops" refers to plant cones of the genus Hunzulus which contains a bitter arornatic oil which is used in the brewing industry to prevent bacterial action and add the characteristic bitter taste to beer. More preferably, the liops used are derived from Hunztilus lupulus.

[0047] The compounds according to the invention are optionally forrnulated in a pharmaceutically acceptable vehicle with any of the well known pharmaceutically acceptable carriers, including diluents and excipients (see Remington's Pharinacei.rtical Sciences, 18th Ed., Gennaro, Mack Publishing Co., Easton, PA 1990 and Remington: The Science and Practice of (24) Pharmacy, Lippincott, Williams & Wilkins, 1995). While the type of pharinaceutically acceptable carrier/vehicle employed in generating the compositions of the invention will vary depending upon the mode of administration of the composition to a mammal, generally pharmaceutically acceptable carriers are physiologically inert and non-toxic.
Formulations of compositions according to the invention may contain more than one type of compound of the invention), as well any other pharmacologically active ingredient useful for the treatment of the symptom/condition being treated.

100481 The compositions of the invention can be administered by standard routes. The coinpositions of the invention include those suitable for oral, inhalation, rectal, ophthalmic (including intravitreal or intracameral), nasal, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intratracheal). In addition, polymers may be added according to standard methodologies in the art for sustained release of a given cotnpound.

[0049] It is contemplated within the scope of the invention that compositions used to treat a disease or condition will use a pharmaceutical grade coinpound and that the composition will further comprise a pharmaceutically acceptable carrier. It is further contemplated that these compositions of the invention may be prepared in unit dosage forms appropriate to both the route of administration and the disease and patient to be treated. The compositions may conveniently be presented in dosage unit form be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the vehicle which constitutes one or more auxiliary constituents, In general, the compositions are prepared by uniformly and intimately bringing the active ingredient into association witll a liquid vehicle or a finely divided solid vehicle or both, and then, if necessary, shaping the product into the desired composition.

[0050] The terin "dosage unit" is understood to mean a unitary, i,e. a single dose which is capable of being adrninistered to a patient, and which may be readily handled and packed, remaining as a physically and che-nically stable unit dose comprising either the active ingredient as such or a mixture of it with solid or liquid pharmaceutical vehicle materials.

[0051] Compositions suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets, soft gels or lozenges, each containing a predetermined amount of the active irngredient; 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, such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Such oils may be edible oils, such as e.g.
cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for (25) aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, gum arabic, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose and polyvinylpyrrolidone. The active ingredient may also be administered in the form of a bolus, electuary or paste.

[0052] Transdermal compositions may be in the form of a plaster, microstructured arrays, sometimes called microneedles, iontophoresis (which uses low voltage electrical current to drive cliarged drugs through the skin), electroporation (which uses short electrical pulses of high voltage to create transient aqueous pores in the skin), sonophoresis (which uses low frequency ultrasonic energy to disrupt the stratum corneum), and thermal energy (wllich uses heat to make the skin more permeable and to increase the energy of drug molecules), or via polymer patch.

[0053] Liposomal compositions or biodegradable polymer systems may also be used to present the active ingredient for ophthalmic administration.

[0054] Compositions suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, gels, and oil-in-water or watcr-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.

[0055] In addition to the compositions described above, the compositions of the invention may also be formulated as a depot preparation. Such long-acting compositions may be adrninistered by implantation (e.g, subcutaneously, intraabdominally, or intramuscularly) or by intramuscular injection. Thus, for exarnple, the active ingredient inay be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in a pliarrnaceutically acceptable oil), or an ion exchange resin.

[0056] As used herein, by "treating" is meant reducing, preventing, and/or reversing the symptoms in the individual to which a compound of the invention has been administered, as compared to the symptoms of an individual not being treated according to the invention. A
practitioner will appreciate that the compounds, compositions, and rnethods described herein are to be used in concomitance with continuous clinical evaluations by a skilled practitioner (physician or veterinarian) to determine subsequent therapy. Hence, following treatment the practitioners will evaluate any improvement in the treatment of the pulmonary inflammation according to standard methodologies. Such evaluation will aid and inform in evaluating whether to increase, reduce or continue a particular treatment dose, mode of administration, etc.

[0057] It will be understood that the subject to which a compound of the invention is administered need not suffer from a specific traurnatic state. Indeed, the compounds of the invention may be adininistered prophylactically, prior to any development of symptoms. The (26) term "therapeutic," "therapeutically," and permutations of these terms are used to encompass therapeutic, palliative as well as propliylactic uses. Hence, as used herein, by "treating or alleviating the symptoms" is meant reducing, preventing, and/or reversing the symptoms of the individual to which a compound of the invention has been administered, as compared to the symptoms of an individual receiving no such administration.

[0058] The term "therapeutically effective amount" is used to denote ti-eatments at dosages effective to aciiieve the ther=apeutic result sought. Furthermore, one of skill will appreciate that the therapeutically effective amount of the compound of the invention may be lowered or increased by fine tuning and/or by administering more than one compound of the invention, or by administering a compound of the invention with another campound. See, for example, Meiner, C.L., "Clinical Trials: Design, Conduct, and Analysis,"
Monographs in Epidemiology and Biostatistics, Vol. 8 Oxford IJniversity Press, IJSA (1986).
The invention therefore provides a method to tailor the administration/treatment to the particular exigencies specific to a given mammal. As illustrated in the following examples, tlherapeutically effective amounts may be easily deterinined for example einpirically by starting at relatively low amounts and by step-wise increments with concurrent evaluation of beneficial effect.

[0059] It will be appreciated by those of skill in the art that the number= of administrations of the compounds according to the invention will vary from patient to patient based on the particular medical status of that patient at any given time including other clinical factors such as age, weight and condition of the mammal and the route of administration chosen.
[0060] As used herein, "symptom" denotes any sensation or change in bodily function that is experienced by a patient and is associated with a particular disease, i.e., anything that accompanies "X" and is regarded as an indication of "X"'s existence. It is recognized and understood that symptoms will vary from disease to disease or condition to condition.

[0061] A second embodiment of the invention describes compositions to promote bone and joint health in a mammal. Here the compositions comprise a therapeutically effective amount of berbei-ine or a pharmaceutically acceptable salt thereof as a first component and as a second component a therapeutically effective amount of a substituted 1,3-cyclopentadione compound selected from the group from the group consisting of rho dihydroisoalpha acids and tetrahydroisoalpha acids or pharmaceutically acceptable salts thereof.

[0062] hn some aspects of this embodiment the first component and the second component are in a synergistic ratio.

(27) [00631 The rho dihydroisoalpha acid is selected from the group consisting of (4S,5,S')-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbtrtanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[( I R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4anethylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(.3-metlrylbut-2-en-1-yl)cyclopent-2-en-1 -one; (4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3anethylbi.itanoyl)-5-(3-methylbLrt-2-en-l-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methy Ipent-3-en-1-y 1]-2-(2-methy lbutanoy l)-5-(3-methy lbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,-5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-I-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en--l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]--5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbt.rt-2-en-l-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3--en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l--one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[( I S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylpropanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en--l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-rnethylbutanoyl)-5-(3-methylbut-2-en-I -yl)cyclopent-2-en-i -one; (4S,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(lR)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-y l)cyclopent-2-en-l-one;
and (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one is utilized in other aspects of this embodiment.

(28) [0064] In another aspect of tiiis embodiment the tetrahydroisoalpha acid is selected from the group consistirig of 4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylperrtanoyl)cyclopent-2-en-l-one; (4R,.5S)-3,4-dihydroxy-2-(3-metlrylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5,S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methy Ibutanoy 1)-5-(3anethy lbutyl)-4-(4-methy ]pentanoy l)cyc lopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopentm2-en-I -one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-.5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3anethylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methyibutyl)-4-(4-methyipentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3anethylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,.5S)-3,4-dihydroxy-2-(.3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1 -one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyc lopent-2-en-l-.one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylperrtanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-_5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; and (4R,5,S)-3,4-dihydroxy-2-(3-methylbutanoyl)-.5-(3-methylbutyl)-4-(4anethylpentanoyl)cyclopent-2-en-l-one.
[0065] In some aspects the second component of the composition is derived from hops while in other aspects the composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of coatings, isotonic and absorption delaying agents, binders, adhesives, lubricants, disintergrants, coloring agents, flavoring agents, sweetening agents, absorbants, detergents, and emulsifying agents. Additionally, in still other aspects the composition further comprises one or more members selected from the group consisting of antioxidants, vitamins, minerals, proteins, fats, and carbollydrates.

[00661 Anotlier aspect describes compositions comprising from about 10 mg to about 800 mg of berberine or a pharrnaceutically acceptable salt tllereof and from about 10 mg to about 800 mg of a tetrahydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the tetrahydroisoalpha acid is selected froin the group consisting of 4R,5S)-3,4-dihydroxy-2-(3-rnethylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S')-3,4-d ihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4--(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R, 5S)-3,4-d ihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-I -one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-(29) methylbutanoyl)-5-(3-rnethylbutyl)-4-(4-rnethylpentarroyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3anethylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbi.ityl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-.3,4-dihydroxy-2-(.3anethylbutanoyl)-5-(3-methylbutyl)m4-(4-methylpentanoyl)cyclopent-2-en-l -one; (4R,5.S')-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3--methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one; (4R,.5.S)-3,4-dihydroxy-2-(3-methylbutanoyl)-.5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one;
(4R,5S)-3,4-di hydroxy-2-(3-methy 1 butanoy 1)-5-(3 -anethy Ibuty1)-4-(4-methy lpentanoy 1)cyc lopent-2-en-l-one;
and (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-.5-(3-rnethylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-l-one.

100671 In yet another aspect, the composition comprises from about 9mg to about 720 mg of berberine or a pharmaceutically acceptable salt thereof and from about 20 rng to about 1600 rng of a rllo dihydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the rho dihydroisoalpha acid is selected fi-om the group consisting of (4S,5S)-3,4-dihydroxy-4-[(IS)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-rnethylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-enTl -one; (4R,5R)-3,4-dihydroxy-4-[(I R)-hydroxy-4anethylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent 2 en 1-one; (4R,5R)-3,4-dihydroxy-4-[( IR)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 ,S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l -yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4R,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1 -one; (4R,5S)-3,4-dihydroxy-4-[( I R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3anethylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one;
(4R,5S)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-.5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-5-(3-rnethylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4R,5S')-3,4-dihydroxy-4-[( I S)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-rnethylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(IS)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4R,5S)-3,4-dihydroxy-4-[(1 S)--(30) hydroxy-4-methylpent-3-en-l-yl]-5-(3-methylbut-2-en-l-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-I-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-rnethylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1 R)-hydroxy-4-methylpent-3-en-l-yl]-5-(.3-methylbut-2-en-I-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[( I S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[( I S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylpropanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1 S)-hydroxy-4-methylpent-3-en-l -yl]-2-(2-methylbutanoyl)-5-(3anethylbut-2-en-I -yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4=-[( I R)-hydroxy-4-methylpent-3-en-l-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-I-yl)cyclopent-2-en-l-one; (4S,5S)-3,4-dihydroxy-4-[(IR)-hydroxy-4-methy lpent-3-en-1-y l]-2-(2-methy lbutanoy l)-5-(3-methy lbt.rt-2-en-1-y l)cyc lopent-2-en- I-one; (4S,5S)-3,4-dihydroxy-4-[( I R)-hydroxy-4-methylpent-3-en- I-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-I-one; (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-l-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-l-yl)cyclopent-2-en-I -one;
and (4S,5S)-.3,4-dilrydroxy.-4-[(IS)-hydroxy-4-methylpent-3-en-l -yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en- I -one.

[00681 Another embodirnent of the invention describes methods to promote bone and joint health in a mammal in need where the method comprises administering to the mammal a composition comprising therapeutically effective amounts of at least two members selected from the group consisting of Abelmoschus, Acacia extract, African Devil's claw, Arthred bovine, Arthred porcine, Astragalus, Berberine, Black cohosh, Bonepep, Bonestein, Chicken Collagen, Curcumin, Devil's Claw, DHEA, Dioscorea, Flaxseed, FOS, Fructus Ligustri, Genistein, Glabridin, Glucosamine, Green tea, Green Tea Polyphenols, Hesperidin, Hyaluronic Acid, Inulin, Ipriflavone, Linoleic Acid, MBP, MCHA, Oleanolic Acid, Oleuropein, Olive oil, Osteosine, Partllinolide, Perilla oil, Phloridzin, Puerariae radix, Punica granatwn, Quercetin, Red yeast rice, Resveratrol, Rosemary, Rutin, Vita-nin K2, and Withania.

100691 In some aspects of the embodiment the composition utilized is a medical food.
100701 A further embodiment describes compositions to promote bone and joint health in a tnarnmal in need. In this embodiment the compositions comprise therapeutically effective amounts of at least two rnembers selected from the group consisting of Abelmoschus, Acacia extract, African Devil's claw, Arthred bovine, Arthred porcine, Astragalus, Berberine, Black cohosh, Bonepep, Bonestein, Chicken Collagen, Curcumin, Devil's Claw, DHEA, Dioscorea, Flaxseed, FOS, Fructus Ligustri, Genistein, Glabridin, Glucosamine, Green tea, Green Tea (31) Polyphenols, Hesperidin, Hyaluronic Acid, Inulin, Ipriflavone, Linoleic Acid, MBP, MCHA, Oleanolic Acid, Oleuropein, Olive oil, Osteosine, Parthinolide, Perilla oil, Phloridzin, Puerariae radix, Punica granatum, Quercetin, Red yeast rice, Resveratrol, Rosemary, Rutin, Vitamin K2, and Withania. In some aspects of this embodiment the composition is a medical food.

[0071] As used herein, "medical food" refers to those eompositions wherein all of the components are generally regarded as safe (GRAS) and the composition meets the statutory and regulatory requirements for a medical food witliin the jurisdiction of enforcement..

[0072] The following examples are intended to further illustrate ce1-tain preferred embodiments of the invention and are not limiting in nature. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experunentation, numerous equivalents to the specific substances and procedures described herein.

EXAMPLES
Example 1 Modified hop extracts and herbal extracts modulate TNFa induced MMP-13 expression in huanan chondrocyte cell line, SW1353.

[0073] The Model - The SW 1353 human chondrocyte cell line was used as described below.

[0074] Materials - All test materials were provided by Metagenics Inc (San Clemente, CA). Test compounds were prepared in dimethyl sufoxide (DMSO) and stored at -20 C. Human TNFa was purchased from Sigma Chemicals (St. Louis, MO). MMP-13 kits were purchased from Amersham Biosciences (Piscataway, NJ).

[0075] Cell Culture and treatment - The human chondrocyte cell line, SW 1353 was purchased from ATCC (Manassas, VA) and maintained in L-15 medii.un in the presence of 10%
serum according to manufacturer instructions. Cells were grown and subcultured in 96-well plates at a density of 8x104 cells per well and allowed to reach -80%
confluence overnight. Test compounds in medium were added to the cells at a final concentration of 0.1%
DMSO.
Following one hour of incubation with the test compounds, TNFa (10ng/ml) or medium alone was added to the cell wells and incubation continued for 24 hours. The supernatant rnedia was subsequently collected for MMP-13 determination.

(32) 100761 Determination of MMP-13: A commercial, non-radioactive procedure for quantification of MMP-13 was used according to the manufacturer's instructions using MMP-13 as a standard. A miniinum of 3 wells were used for each test condition.

[0077] Statistical analysis - The amount of MMPm13 release into the rnedium was determined by comparison of the MMP-1 3 generated in the presence or absence of TNFa and test compounds. A minimum of three wells were used for each test condition.
The basal MMP-13 levels without TNFa stimulation was subtracted from TNF stimulation to determine the TNFa induced MMP-13 expression in the medium and the levels normalized to 100%. The percent activity of test compounds was measured in the presence of TNFa and referred as TNFa induced MMP-13 expression.

[0078] Results - Test compounds at 10 g /ml or 20 g/ml were modulated TNFa induced MMP-13 expression (Table 4) in human chondrocyte cells, SW 1353.

(33) Table 4:

Effect of modified hop extracts and herbal extracts on TNFa induced MMP-13 expression TNFa Stimulated TNFa Stimulated Test Compounds ug/mL average SD Test Compounds ug/mL average SD
TNF Neg - 0% 17% Black cohosh 20 63% 20%
TNF os 0 100% 28% Salvia 20 118% 17%
RIAA 10 20% 11% Red yeast rice 20 85% 50%
RIAA 20 0% 7% Glabridin 20 79% 61%
Kaprex 10 37% 12% Resveratrol 20 -42% 6%
THIAA 10 34% 34% lpriflavone 20 -42% 7%
THIAA 20 3% 24% Abelmoschus 20 56% 53%
Tetrex 10 26% 11% DHA 20 265% 41%
Acacia 10 73% 7% Perilla oil 20 100% 61%
Rosemary 10 25% 14% Pelicosanol 20 489% 687%
Oleanolic Acid 10 17% 23% Camellia Sinensis 20 159% 13%
Curcumin 10 -11% 0% Green Tea 20 74% 16%
Trimax 10 -8% 4% Dioscorea 20 48% 54%
H aluronic Acid 20 105% 55% Quercetin 20 -65% 18%
Glucosamine 20 77% 41% Hesperidin 20 13% 29%
Green Tea Polyphenols 20 53% 15% Berberine 20 -39% 63%
Punica granatum 20 84% 30% Flaxseed 20 -24% 1%
African Devil's claw 20 58% 9% Oleuro ein 20 -31% 18%
Parthenolide 20 28% 22% Olive oil 20 -23% 6%
Vitamin C 20 370% 94% Rutin 20 -7% 49%
MBP 20 90% 38% FOS 20 -12% 12%
Bonepep 20 114% 65% Inulin 20 33% 61%
Bonistein 20 -30% 16% Linoleic Acid 20 23% 22%
Genistein 20 27% 18% Astra alus 20 -8% 44%
Vitamin K2 20 56% 41% Chicken Collagen 20 -6% 15%
DHEA 20 -2% 45% Arthred Bovine 20 109% 143%
Withania 20 -11% 11% Arthred Porcine 20 -12% 22%
Potassium Citrate 20 95% 26% Osteosine 20 -4% 43%
Fructus Ligustri 20 56% 26% MCHA 20 11% 31%
Phloridzin 20 77% 40% Prune PE 20 321% 130%
Puerariae radix 20 70% 37%

*formula components:
Kaprex (RIAA: Rosernary: Oleanolic acid; 225:112.5:1) Tetrex (THIAA: Rosemary: Oleanolic acid; 225:112.5:1) Trimax (RIAA: Curcumin: Rasemary; 2:2:1) (34) Example 2 Modified hop extracts and herbal extracts dose dependently rnodulate TNFa induced MMP-13 eVression in human chondrocyte cell line, SW1353.

[0079] The Model - The SW1353 human chondrocyte cell line model as described in Exainple 1.

[0080] Cell Czdture and treatment - Standard chemicals used were described in Example 1. Following one hour of incubation with the test compounds (RIAA, ci.ircumin, DHEA
withania, resveratrol, ipriflavone, astragalus, purariae radix, bonistein and partlianolide at multiple concentrations (20, 10, 5 and lug/m1)), the human chondrocyte cell line, SW 1353 was stimulated with TNFa (l Ong/ml) for 24 lirs. MMP-13 levels were measured in the medium as described in the Example 1.

[0081] Determination of MMP-13 expression- The MMP-13 levels in the medium were measured as described in Example 1.

[0082] Calculations - The percent of MMP-13 levels in the medium was measured as described in Example I in the presence and absence of TNFa.

[0083] Median Effect Calculations - Median effect calculations were performed using CalcuSyn (Biosoft, Ferguson, MO). This program utilizes the Median Effects Model of Chou and Talalay (Adv Enzym Regul (1984) 22:27-55) and fits the equation:

log C = (3o + (3 I log [fa/(1-f)] = E

where fa is the factional inhibition of the reaction. A minimum of three concentrations were used to determine the dose-response curve and a median inhibitory concentration (IC50)=

[0084] Results - Test compounds RIAA, curcumin, DHEA, withania, resveratrol, ipriflavone, astragalus, purariae radix, bonistein and parthanolide were dose dependently (20, 10, and lug/ml) inhibited TNFa induced MMP-13 expression (Table 5).

(35) Table 5:
Screening of test cornpounds for MMP-13 expression at multiple doses TNFa Stimulated TNFa Stimulated Test Compounds ug/mL average SD Test Compounds ug/mL n=1 TNF Neg 0% 1% TNF Neg - 0%
TNF pos 100% 14% TNF pos 100%
RIAA 20 45% 6% Berberine 20 -4%
74% 5% 10 -4%
5 94% 2% 5 -4%
1 120% 7% 1 -1%
Curcumin 20 -2% 0% THIAA 20 -4%
10 -1% 1% 10 14%
5 11% 3% 5 58%
1 89% 2% 1 101%
Bonistein 20 1% 1% Rosemary 20 8%
10 23% 4% 10 33%
5 71% 4% 5 55%
1 109% 7% 1 93%
DHEA 20 5% 3% Oleanolic acid 20 26%
10 64% 1% 10 43%
5 108% 17% 5 38%
1 111% 8% 1 95%
Whithania 20 76% 8% Glucosamine 20 105%
10 94% 12% 10 107%
5 136% 18% 5 137%
1 178% 21% 1 126%
Resveratol 20 45% 12%
10 53% 13%
5 88% 11 /a 1 96% 15%
Ipriflavone 20 3% 2%
10 0% 2%
5 20% 3%
1 86% 16%
Astragalus 20 82% 12%
10 88% 14%
5 79% 2%
1 92% 13%
Puerariae radix 20 61% 4%
10 76% 15%
5 67% 4%
1 81% 24%
Parthenolide std 20 47% 3%
10 72% 3%
5 101% 8%
1 119% 1%

(36) Example 3 Modified hop extract RIAA and herbal extracts dose dependently modulate TNFa induced MMP-13 expression in hurnan chondrocyte cell line, SW1353.

[0085] The Model - The SW1353 lir.unan chondrocyte cell line inodel as described in Exarnple 1.

[0086] Cell Culture and treatment - Standard cliemicals used were described in Example 1. Following one hour of incubatian with the various test compaunds as listed in the table (table 3) human chondrocyte cell line, SW 1353 was stimulated witli TNFa (IOng/ml) for 24 hrs and MMP.-13 were measured in the medium as described in the Example 1.

[0087] Determination of MMP-13 expression- The MMP-13 levels in the meditun was measured as described in Example 1.

[0088] Median Effect Calculations - Median effect calculations and inhibitory concentrations (IC50) were performed using CalcuSyn as described in Example 2.

[0089] Results - Test compotmds RIAA, berberine sulfate, barberry stem bark (10: l), coptis chinensis extract (20%) and Oregon grape root extract (4: 1) were dose dependently rnodulated TNFa induced MMP-13 expression (Table 6) in human chondrocyte cells, SW 1353.

(37) Table 6:

Test compounds dose dependently inhibited TNFa induced MMP-13 expression.
Test Compounds ug/mL TNFa Stimulated % Activity IC50 average SD ug/mL
TNF Neg 0 0% 0% (95% CI) TNF pos 100% 7%
RIAA 20 44% 3% 25.79 75% 14% (9.2-72.0) 5 83% 8%
1 91% 13%
Berberine sulfate 1 -1% 0% 0.15 0.5 4% 2% (0.05-0.5) 0.1 50% 6%
0.05 99% 13%
Barberry stem bark10:1 5 15% 8% 2.00 2.5 37% 8% (1.6-2.5) 1.0 74% 5%
0.1 101% 5%
Coptis Chinensis extract 20% 5 -2% 1% 0.48 2.5 3% 2% (0.3-0.8) 1.0 28% 3%
0.1 97% 14%
Oregon grape root extract 4:1 5 130% 13%
2.5 121% 1%
1.0 192% 9%
0.1 180% 14%

(38) Example 4 Modified hop extract THIAA and berberine sul ate synergistically inhibited TNFa induced MMP-13 expression in hurnan chondrocyte cell line, SW1353.

[0090] The Model - The SW 1353 human chondrocyte cell line was used as described in Example 1, [0091] Materials -All test materials were provided by Metagenics Inc (San Clemente, CA). All other chemicals used as described in Example 1.

[0092] Cell Culture and treatment- The human chor-drocyte cell line, SW 1353 were maintained and treatinents conditions were described in Example 1. THIAA and berberine was used at various ratios (10:0; 1:10; 5:1; 2:1; 1:1; 1:2; 1:5; 1:10; 0: 10) and added to the cells in medium at a final concentration of 0.1% DMSO. Following one hour of incubation with various concentrations of test compounds, TNFa (l Onghnl) was added to the cell wells and ineubation continued for 24 hours, the supernatant media was collected for MMP-13 determination.

[0093] Determination of MMP-13 expression- The MMP-13 levels in the medium was measured as described in Example 1.

[0094] Statislical analysis and Median Effect Calculations - Median effect calculations were performed using CalcuSyn (Biosoft, Ferguson, MO). This program utilizes the Median Effects Model of Chou and Talalay (Adv Enzyrn Regul (1984) 22:27-55) and fits the equation:

log C = [3o + [3 I log [f,/(1-fa)] = s where , is the factional inhibition of the reaction. A minimum of three concentrations were used to determine the dose-response curve and a median inhibitory concentration (IC50).

[0095] Synergy- Combinational Index (CI) values were measured using CalcuSyn (Biosoft, Ferguson, MO). CI values less than I represent synergy and more than 1 represent non-synergy combinations (Greco, W. R., Bravo, G., and Parsons, J. C. (1995).

[0096] Results - Cl value less than I showed synergy. All the combinations of THIAA
and berberine sulfate exhibited synergy for TNFa induced MMP-13 expression at one or more eoncentrations tested (Table 7A). Non syneigistic combinations were liighlighted. THIAA and berberine sulfate inhibited TNFa induced MMP-13 expression witli IC50 of 16.424 and 0.254ug/ml respectively (Table 7B).

(39) Table 7A:

Synergistic effect of THIAA and berberine TNFa induced MMP-13 expression in human chondrocyte cell line SW1353 G THIAA Berberine CI 'LHIAA Berberin CI THIAA Berb rin CI THIAA Berberin CI
THIAA Berberine CI THTTr~ erberine CI THIAA Berberine u/m u/m u/m u m u/M u/ml u Im! u/ml u m u/ml u/ml u/mi u/ml u/ml 0.597 0.003 0.026 0.470 0.004 0.020 1.192 0:025 "D.050 0.454 0.019 0.019 0.121 0.009 0.005 0.675 0.115 0.023 0.395 0.111 0.011 0.574 0,004 0.038 0.462 0.006 0.030 1;099 0.036 0.072 0.456 0.029 0,029 0.167 0.021 0.010 0.623 0.173 0.035 0.402 0.192 0,019 0.558 0.005 0.052 0.456 0.008 0.042 1:032 0.047 0.095 0.460 0.042 0.042 0.217 0.038 0.019 0.589 0.238 0.048 0.413 0.294 0.029 0.548 0.006 0.063 0.453 0.010 0.052 0.994 0.057 0.113 0.462 0.052 0.052 0.256 0.056 0.028 0.571 0.290 0.058 0.422 0.384 0.038 0.540 0.007 0.073 0.450 0.012 0.061 0.966 0.064 0.129 0.464 0.061 0.061 0.290 0.075 0.037 0.559 0.337 0.067 0.430 0.469 0.047 0.534 0.008 0.082 0.448 0.014 0.069 0.943 0.072 0,144 0.466 0.070 0.070 0.321 0,095 0.047 0.550 0.382 0.076 0.438 0.553 0.055 0.529 0.009 0.091 0.446 0.015 0.077 0.924 0.079 0.158 0.467 0.079 0.079 0.351 0.117 0.058 0.542 0.425 0.085 0.445 0.639 0,064 0.524 0.010 0.100 0.444 0.017 0.085 0.907 0.086 0.172 0.469 0.088 0.088 0.381 0.141 0.070 0.535 0.469 0.094 0.452 0.729 0.073 0.520 0.011 0.110 0.443 0,019 0.093 0.891 0.093 0.187 0.470 0.098 0.098 0.412 0.168 0,084 0.529 0.514 0.103 0.458 0.824 0.082 0.515 0.012 0.119 0.442 0.020 0.102 0.877 0,101 0.202 0.472 0.108 0.108 0.443 0.199 0.099 0.524 0.561 0.112 0.465 0.926 0.093 0.511 0.013 0.130 0.440 0.022 0.111 0.863 0.109 0218 0.473 0.118 0.118 0.477 0.235 0117 17 0.518 0.611 0.122 0.472 1.039 0.104 0.507 0.014 0.141 0.439 0.024 0.122 0.849 0.117 0.235 0.475 0.130 0.130 0.512 0.277 0.139 0.513 0.666 0.133 0.480 1.166 0.117 0.503 0.015 0.154 0.437 0,027 0.133 0.835 0.127 0.253 0.476 0.144 0144 0.552 0.328 0.164 0.508 0.728 0.146 0.488 1.312 0.131 0.499 0.017 0.168 0.436 0.029 0.146 0.821 0,137 0.275 0.478 0.159 0.159 0.596 0.392 0.196 0.504 0.798 0.160 0.496 1.483 0.148 0.495 0.018 0.185 0.434 0.032 0.162 0.806 0.150 0.299 0.480 0.177 0.177 0.64B
0.473 0.237 0.498 0.880 0.176 0.506 1.691 0.169 0.490 0.021 0.205 0.433 0.036 0.181 0.790 0.165 0.329 0.482 0.200 0,200 0.710 0.583 0,291 0,493 0.980 0.196 0.517 1.953 0.195 0.484 0.023 0.231 0.431 0.041 0.205 0.772 0.184 0.367 0.484 0.229 0.229 0.789 0.739 0.370 0.487 1.108 0.222 0.530 2.304 0.230 0.478 0.027 0.267 0.428 0.048 0.240 0.751 0.209 0.419 0.487 0.270 0.270 0.896 0.986 0.493 0.480 1.287 0.257 0.547 2.814 0.281 0.469 0.032 0.324 0.425 0,059 0.294 0,724 0.249 0.498 0.491 0.337 0.337 1.061 1.445 0.723 0.472 1.570 0.314 0.572 3.670 0.367 0,456 0.044 0.443 0.421 0.082 0.408 0.682 0.330 0.661 0.497 0.481 0.481 1.396 2.681 1.340 0.459 2.163 0,433 0.615 5.635 0.564 0.428 0.088 0.881 0.410 0.169 0.846 0.598 0.616 1.232 0.513 1.054 1.054 2.563 1D.497 5.248 0.434 4.393 0.879 0.730 14.536 1,454 Non-synergistic combinations are highlighted.

Table 7B:

THIAA and berberine sulfate inhibited TNFa induced MMP-- 13 expression Drug Dm r THIAA 16.42401 0.98789 Berberine sulfate 0.25411 0.99815 (40) Example S

Modified hop extracts and herbal extracts modulate sRANKL mediated osteoclastogenesis [0097] The Model - sRANKL, mediated osteoclastogenesis as described by Rahman, M.M., et al., (Conjugated linoleic acid inliibits osteoclast differentiation of RAW264.7 cells by modulating RANKL signaling. J. Lipid Res. 47(8): 1739 - 1748, 2006).

[00981 Materials - All test compounds were provided by Metagenics Inc (San Clemente, CA). Test compounds were prepared in dimetliyl sufoxide (DMSO) and stored at -20 C. sRANKL (Receptor activated NF-icB ligand), was purchased froin Peprotecli (Rockey Hill, NJ). TRAP activity measurement kit was purchased from Sigma Chemicals (St Louis, MO) [0099] Cell Culture and treatment- The murine macrophage cell line, RAW 264.7 was purchased from ATCC (Manassas, VA) and maintained in a-MEM containing 10% FBS
and plated at a concentration of 1x104/well in 48 well culture plate (Corning, NY). Next day, test compounds (10 and 5 g/ml) were added to the cells in medium at a final concentration of 0,1 %
DMSO. Following overnight incubation with the test compounds, sRANKL (50ng/ml) or medium alone was added to the cell wells. The medii.im was replaced after 2 days with test compounds and sRANKL and incubation was continued for 3 additional days.

[001001 Determination of TRAP (tartrate resistant acid phsophatase) activity -The cells were washed twice with ice cold PBS and lysed in 150 l of 0.2% triton x-100 in PBS. TRAP
activity in cell lysates was determined by using TRAP solution from the kit (Sigma 387A1 kit), according to the manufacturers instructions. A l 00 1 cell lysates was added to I00 1 of TRAP
solution in 96 well plate and incubated at 37 C for 1 hr. The absorbance was measured at 555nm usir-g a plate reader. The protein concentration was estimated using BCA
reagent (Sigma) and the final activity was normalized for equal protein.

[001011 Statistical analysis - Inhibition of TRAP activity was determined by comparison of the TRAP activity in the presence of with and with out test compounds in sRANKL activated osteoclasts. Aminirnum of two wells were used for each concentration.

[001021 Results - Test compounds which inodulated sRANKL mediated TRAP
activity are presented in Table 8.

(41) Table 8:
Modulation of sRANKL mediated TRAP activity % TRAP Activity % TRAP Activity Test Compounds uglmL average SD Test Compounds uglmL average SD
Control 0% 0% Black cohosh 10 38% 17%
RANKL 100% 23% 5 45% 1%
RIAA 10 65% 4% Salvia miltiorrhiza 10 87% 7%
78% 9% 5 69% 4%

Kaprex 10 22% ~ 3% Red Yeast Rice ~10 54% 3%
5 36% 11% 5 76% 4%
THIAA 10 0% 3% Glabridin 10 75% 4%
5 54% 4% 5 82% 0%
Tetrex 10 8% 2% Resveratol 10 2% 4%
5 46% 2% 511% 7%
Acacia 10 64% 7% Abelmoschus manihot 10 83% 16%
5 110% 3% 5 108% 13%
Rosemary 10 0% 6% DHA 10 105o/o 9%
5 23% 3/0 5 120% 8/0 nleanol'rc Acid 10 35% 1% Perilla oil 10 84% 0%
5 61% 1% 5 71% 3%
Curcumin 10 -22% 0% Camellia sinesis 10 94% 1%
5 -17% 3% 5 113% 9%
Hyaluronic Acid 10 2% 5% Green tea 10 73% 16%
5 35% 17% 5 88% 11%
GlUcosamine 10 48% 20% Dioscorea spogiosa 10 71% 4%
5 75% 20% 5 67% 1%
Green Tea 10 79% 11 % Quercetin 10 62% 5%
Polyphenols 5 65% 4% 5 73% 4%
Punica Granatum 10 240% 33% Hesperidin 10 76% 2%
5 215% 26% 5 81% 2%
Devil's Claw 10 67% 2% Berberine 10 -8% 2%
5 67% 13% 5 4% 6%
Parthenolide 10 8% 1% Flax seed extract 10 102% 0%
5 50% 2% 5 97% 4%
MBP 10 101% 7% Oleuropein 10 81% 1%
5 99% 2% 5 82% 10%
Bonepep 10 89% 3% Olive oil 10 61% 6%
5 79/0 7/0 5 74 /0 15%
Bonestein 10 -3% 2% Rutin 10 74% 7%
5 128% 37% 5 106% 20%
Genistein 10 72% 3% FOS 10 98% 22%
5 91% 2% 5 79% 2%
DHEA 10 33% 6% tnulin 10 69% 1%
5 46% 0% 5 87% 4%
~
Fructus Ligustri 10 81% 6% Arthred bovine 10 66% 17%
5 77% 5/0 5 100% 33%
Phloridizin 10 150% 10% Arthred porcine 10 72% 7%
5 103% 20% 5 68% 0%
Puerariae radix 10 43% 8%
5 49% 11%

(42) Example 6 Modi ied hop extracts and herbal extracts dose dependently inodulate sRANKL
osteoclastogenes is [00103] The Model - sRANKL mediated osteoclastogenesis as described in Example 5.
[00104] Materials - All test compounds were provided by Metagenics hlc (San Clemente, CA). Purchase of other chem'rcals was described in Example 5.

[00105] Cell Culture and treatment- The maintenance of murine macrophage cell line, RAW 264.7 and cell treatment was described in Example 5. Multiple concentration of test compounds (10, 5 and 1 g/ml) were used to determine the effect on sRANKL
induced TRAP
activity.

[00106] Determination of TRAP activity - Determination of TRAP activity was described in Example S.

[00107] Statistical analysis - Inhibition of TRAP activity was determined by comparison in the presence of with and with out test compounds in sRANKL activated osteoclasts. A
minimum of two wells were used for each concentration. The basal TRAP activity levels with out sRANKL stimulation was subtracted from sRANKL, stimulation to get the sRANKL induced TRAP activity and the activity was normalized to 100%. The percent activity of test compounds was measured in the presence of sRANKL and referred as sRANKL induced TRAP
activity.
1001081 A minimum of three concentrations were used to determine median inhibitoiy concentration (IC5o). IC50 values were measured using CalcuSyn program (Biosoft, Fergusson, MO) as described in Example 2.

[00109] Results - Test coinpounds inhibited sRANKL mediated TRAP activity as indicated in Table 9 below.

(43) Table 9:

Hop and herbal extracts dose dependently modulated sRANKL mediated TRAP
activity.
% TRAP activity % TRAP activity Test Compounds uglmL average SD Test Compounds ug/mL average SD
Withania somnifera 10 69% 0%
Control 0 0% 1% 5 87% 9%
RANKL 0 100% 16% 1 120% 0%
69% 6% Puerariae radix 10 87% 6%
RIAA 5 112% 5% 5 108% 0%
1 90% 52% 1 114% 9%
10 4% 3% Black Cohosh 10 103% 14%
THIAA 5 65% 4% 5 128% 15%
1 113% 8% 1 154% 2%
10 22% 15% Resveratol 10 16% 2%
HHIAA 5 104% 1% 5 17% 30%
1 120% 16% 1 117% 1%
10 7% 5% Ipriflavone 10 82% 5%
Rosemary 5 39% 3% 5 164% 34%
1 117% 10% 1 168% 5%
10 32% 1% Policosanol 10 103% 1%
Oleanolic acid 5 63% 6% 5 139% 6%
1 139% 1% 1 152% 15%
10 91% 17% Berberine 10 7% 1%
Acacia 5 176% 14% 5 15% 5%
1 169% 1% 1 68% 9%
Conjugated Linoleic 5 -1% 9% acid 10 79% 15%
Curcumin 2.5 46% 25% 5 81% 8%
1 92% 17% 1 86% 1%
Chicken Collagen 5 70% 14% Type II Kolla2 10 87% 9%
Parthenolide Std 2.5 85% 12% 5 125% 4%
1 117% 45% 1 102% 8%
10 111% 17% OsteoSine 10 38% 5%
Hyaluronic acid 5 130% 1% 5 53% 1%
1 122% 4% 1 68% 6%
10 269% 188% MCHA 10 105% 17%
Glucosamine 5 183% 13% 5 111% 1%
1 179% 58% 1 105% 1%
10 119% 31% Prune (PLUM) PE 10 142% 3%
African Devil's claw 5 197% 43% 5 141% 11%
1 153% 19% 1 101% 4%
10 29% 6% Epimedium 10 77% 3%
Parthenolide 5 78% 3% 5 89% 4%
1 106% 10% 1 84% 2%
10 18% 45% Black rice 10 72% 4%
Bonistein 5 346% 13% 5 20%
1 184% 1% 1 63% 2%

(44) Example 7 Clinical effects on pain reduction and flexibility of a berberine /
tetrahydroisoalpha acid com osp ition 1001101 The purpose of this experiment was to deterrnine the effects of a berberine /
tetraliydroisoalpha acid composition on joint pain and flexibility in volunteers, 1001111 A small, open label, non-controlled study was conducted on 12 volunteer subjects whose clinical history and exam indicated that additional therapeutics were necessary beyond bodywork (here chiropractic manipulation). Examples included patients in whom bodywork had only been of brief lielp previously requiring repeated adjustments, patients with active inflammatory challenges including chronic and acute pain states, and patients with poor tissue integrity secondary to clu=onicity, fibrosis (fibromyalgia), and liypothyroidism.

1001121 Questionnaires were administered at baseline prior to body work and administration of two tablets prior to initial manipulation of a composition comprising 100 mg of berberine and 100 mg of tetrahydroisoalpha acids as the active moieties, and thereafter immediately following body work, and at I hour, 6 hours, 24 hours, and 7 days time points after body work (1 - 3 tablets per day). Subjects were asked to score using Likert scales of 1- 10 the severity of their pain and lack of flexibility. On the pain scale, a score of 10 represented the highest level of pain. On the flexibility scale, a score of I represented the least level of flexibility. The results are presented in Table 10 below.

(45) Table 10 Clinical effects on pain reduction and flexibility of a berberine /
tetrahydroisoalpha acid composition Likert Scores Pain Flexibility Averages BEFORE Visit: 6.67 4,08 IMMEDIATELY AFTER
Visit: 2.67 6.58 -1 HOUR AFTER Visit: 2.67 6.58 -6 HOURS AFTER Visit: 2.92 6.58 Visit: 3.50 6.83 -7 DAYS AFTER Visit: 3.92 Visit:
% change BEFORE
IMMEDIATELY AFTER -Visit: 60.0% 61.2%
-1 HOUR AFTER Visit: 60.0% 61.2%
-6 HOURS AFTER Visit: 56.3% 61.2%

Visit: 47.5% 67.3%
-7 DAYS AFTER Visit: 41.3%

[00113] The significant reduction in pain (41-60%) and improvements in flexibility (61%-67%) and the persistence of this benefit were considered to represent a significant clinical response.

[00114] Side effects noted by 2 subjects were minimal GI discomfort after taking the product on an empty stomach. This was addressed by taking with food. One subject had more persistent GI discomfort including a presumed episode of GERD.

[00115] Tliree subjects were followed for 2 -3 week intervals as they used the product.
Moderate clinical improvement was noted by the clinician. His comments included "that with less trigger point tenderness, he was more effectively able to address the issue using body work"
in one case.

(46)

Claims (22)

1. A method to promote bone and joint health in a mammal in need thereof, said method comprising administering to the mammal a composition comprising a therapeutically effective amount of berberine or a pharmaceutically acceptable salt thereof as a first component and as a second component a therapeutically effective amount of a substituted 1,3-cyclopentadione compound selected from the group consisting of rho dihydroisoalpha acids and tetrahydroisoalpha acids or pharmaceutically acceptable salts thereof.

2. The method of Claim 1, wherein the composition comprises a first component and a second component in a synergistic ratio.

3. The method of Claim 1, wherein the rho dihydroisoalpha acid is selected from the group consisting of (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy,-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one;
(4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,-5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-(47) methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-y 1]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylpropanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-

4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; and (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one.

4. The method of Claim 1, wherein the tetrahydroisoalpha acid is selected from the group consisting of 4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; and (4R,5S)-3,4-(48) dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one.

5. The method according to Claim 1, wherein the second component is derived from hops.

6. The method according to Claim 1, wherein the composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of coatings, isotonic and absorption delaying agents, binders, adhesives, lubricants, disintergrants, coloring agents, flavoring agents, sweetening agents, absorbants, detergents, and emulsifying agents.

7. The method according to Claim 1, wherein the composition further comprises one or more members selected from the group consisting of antioxidants, vitamins, minerals, proteins, fats, and carbohydrates.

8. A composition to promote bone and joint health in a mammal in need thereof, said composition comprising a therapeutically effective amount of berberine or a pharmaceutically acceptable salt thereof as a first component and as a second component a therapeutically effective amount of a substituted 1,3-cyclopentadione compound selected from the group from the group consisting of rho dihydroisoalpha acids and tetrahydroisoalpha acids or pharmaceutically acceptable salts thereof.

9. The composition of Claim 8, wherein the first component and the second component are in a synergistic ratio

10. The composition according to Claim 8, wherein the rho dihydroisoalpha acid is selected from the group consisting of (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one;
(4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-y1]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one;
(4R,5R)-3,4-dihydroxy-4-[(1,S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-(49) one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylpropanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; and (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one.

11. The composition according to Claim 8, wherein the tetrahydroisoalpha acid is selected from the group consisting of 4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-(50) methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; and (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one.

12. The composition according to Claim 8, wherein the second component is derived from hops.

13. The composition according to Claim 8, wherein the composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of coatings, isotonic and absorption delaying agents, binders, adhesives, lubricants, disintergrants, coloring agents, flavoring agents, sweetening agents, absorbants, detergents, and emulsifying agents.

14. The composition according to Claim 8, wherein the composition further comprises one or more members selected from the group consisting of antioxidants, vitamins, minerals, proteins, fats, and carbohydrates.

15. The method according to Claim 1, wherein the composition comprises from about 10 mg to about 800 mg of berberine or a pharmaceutically acceptable salt thereof and from about 10 mg to about 800 mg of a tetrahydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the tetrahydroisoalpha acid is selected from the group consisting of 4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(51) (3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; and (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one.

16. The composition according to Claim 8, wherein the composition comprises from about mg to about 800 mg of berberine or a pharmaceutically acceptable salt thereof and from about 10 mg to about 800 mg of a tetrahydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the tetrahydroisoalpha acid is selected from the group consisting of 4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one;
(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(52) (3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; and (4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one.

17. The method according to Claim 1, wherein the composition comprises from about 9 mg to about 720 mg of berberine or a pharmaceutically acceptable salt thereof and from about 20 mg to about 1600 mg of a rho dihydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the rho dihydroisoalpha acid is selected from the group consisting of (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-S-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one;
(4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,SS)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-l-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-(53) methylpropanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; and (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one.

18. The composition according to Claim 8, wherein the composition comprises from about 9mg to about 720 mg of berberine or a pharmaceutically acceptable salt thereof and from about 20 mg to about 1600 mg of a rho dihydroisoalpha acid or a pharmaceutically acceptable salt thereof, wherein the rho dihydroisoalpha acid is selected from the group consisting of (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one;
(4R,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4R,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-(54) methylpropanoyl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylpropanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5R)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(3-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1R)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one; (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-2-(2-methylbutanoyl)-5-(3-methylbut-2-en-1-yl)cyclopent-2-en-1-one; and (4S,5S)-3,4-dihydroxy-4-[(1S)-hydroxy-4-methylpent-3-en-1-yl]-5-(3-methylbut-2-en-1-yl)-2-(2-methylpropanoyl)cyclopent-2-en-1-one.

19. A method to promote bone and joint health in a mammal in need thereof, said method comprising administering to the mammal a composition comprising therapeutically effective amounts of at least two members selected from the group consisting of Abelmoschus, Acacia extract, African Devil's claw, Arthred bovine, Arthred porcine, Astragalus, Berberine, Black cohosh, Bonepep, Bonestein, Chicken Collagen, Curcumin, Devil's Claw, DHEA, Dioscorea, Flaxseed, FOS, Fructus Ligustri, Genistein, Glabridin, Glucosamine, Green tea, Green Tea Polyphenols, Hesperidin, Hyaluronic Acid, Inulin, Ipriflavone, Linoleic Acid, MBP, MCHA, Oleanolic Acid, Oleuropein, Olive oil, Osteosine, Parthinolide, Perilla oil, Phloridzin, Puerariae radix, Punica granatum, Quercetin, Red yeast rice, Resveratrol, Rosemary, Rutin, Vitamin K2, and Withania.

20. The method according to Claim 19, wherein the composition is a medical food.

21. A composition to promote bone and joint health in a mammal in need thereof, said composition comprising therapeutically effective amounts of at least two members selected from the group consisting of Abehnoschus, Acacia extract, African Devil's claw, Arthred bovine, Arthred porcine, Astragalus, Berberine, Black cohosh, Bonepep, Bonestein, Chicken Collagen, Curcumin, Devil's Claw, DHEA, Dioscorea, Flaxseed, (55) FOS, Fructus Ligustri, Genistein, Glabridin, Glucosamine, Green tea, Green Tea Polyphenols, Hesperidin, Hyaluronic Acid, Inulin, Ipriflavone, Linoleic Acid, MBP, MCHA, Oleanolic Acid, Oleuropein, Olive oil, Osteosine, Parthinolide, Perilla oil, Phloridzin, Puerariae radix, Punica granatum, Quercetin, Red yeast rice, Resveratrol, Rosemary, Rutin, Vitamin K2, and Withania.

22. The composition according to Claim 21, wherein the composition is a medical food.
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