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OA/RA Drug Development

Bone Turnover Markers in Joint Disease

Bone Turnover Markers in Joint Disease 
There is now an extensive body of literature on the use of biochemical markers of bone turnover in the clinical development of drugs that affect bone metabolism, such as bisphosphonates, parathyroid hormone, and selective estrogen receptor modulators (1-4). Biochemical markers of bone turnover are also important in assessing disease activity in both osteoarthritis and rheumatoid arthritis (5-8).

Biochemical markers of bone turnover fall into two categories:

  • Markers of bone formation
  • Markers of bone resorption (degradation)

Bone formation markers include serum osteocalcin, serum bone-specific alkaline phosphatase, and serum levels of N- and C- propeptides of type I procollagen (PINP and PICP). These markers generally reflect osteoblastic activity, and in the case of PINP and PICP actually reflect the synthesis of type I collagen, the major structural protein of bone.

Bone resorption markers include urinary pyridinoline and deoxypyridinoline, and urinary and serum levels of the N- and C- telopeptides of type I collagen (NTX and CTX). These markers generally reflect osteoclastic activity and in each case represent degradation products of type I collagen. Of these, CTX (also referred to as CTX-I or CrossLaps®) is thought to be the most specific because the epitope is a unique crosslinked, β- isomerized peptide that is highly enriched in bone.

Osteoarthritis (OA) is characterized not only by progressive cartilage destruction but also by alterations in bone, such as subchondral bone remodeling and osteophyte formation. In a rat model of OA, treatment with alendronate (a bone resorption inhibitor) resulted in inhibition of subchondral bone remodeling and osteophyte formation, as well as decreased cartilage damage (9). In human OA, markers of bone resorption and formation have been shown to correlate significantly with arthritis (5, 6).

Bone Turnover Markers are Decreased in Knee OA 
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Recently, markers of bone turnover have been measured in patients with rheumatoid arthritis (RA). In a study involving 318 RA patients divided into those with or without joint destruction, serum osteocalcin and CTX-I levels were analyzed (7). CTX-I levels were significantly increased in destructive RA compared to controls but were unchanged in the nondestructive group. Osteocalcin levels were significantly reduced in both destructive and nondestructive RA compared to controls. Therefore, bone formation is broadly reduced in RA, whereas bone resorption is specifically increased only in patients with joint destruction and is positively correlated with indices of disease activity.

In a second study, urinary CTX-I and urinary CTX-II (a marker of cartilage degradation) were measured in 110 patients with early RA enrolled in the COBRA study evaluating traditional DMARDs. Increased baseline urinary CTX-I and CTX-II levels were found to be strong independent predictors of radiologic progression over 4 years, especially in those patients without initial radiologic joint damage (8).

From these data, it can be anticipated that markers of bone turnover can provide useful information about progression of joint damage, especially when combined with markers of cartilage turnover. The most useful marker of bone resorption is CTX-I; for bone formation osteocalcin can be recommended or, alternatively, PINP, which has also emerged as a robust bone formation marker (10).

References

1. Eastell, R. et al. J. Bone Min. Res. 18: 1051-1056, 2003. 2. Bone, H.G. et al. N. Engl. J. Med. 350: 1189-1199, 2004. 3. Black, D.M. et al. N. Engl. J. Med. 349: 1207-1215, 2003. 4. Sambrook, P.N. et al. J. Intern. Med. 255: 503-511. 5. Garnero, P. et al. Ann. Rheum. Dis. 60: 619-626, 2001. 6. Garnero, P. et al. Ann. Rheum. Dis. 62: 939-943, 2003. 7. Garnero, P. et al. Bone 24: 381-385, 1999. 8. Garnero, P. et al. Arthritis Rheum. 46: 2847-2856, 2002. 9. Hayami, T. et al. Bone 32: S83, 2003. 10. Fink, E. et al. Osteoporos. Int. 11: 295-303, 2000.

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