Disease-modifying osteoarthritis drugs (DMOADs): what are they and what can we expect from them?


Division of Rheumatic and Musculoskeletal Disease
University of Leeds and NIHR Leeds Musculoskeletal
Biomedical Research Unit, UK

Disease-modifying osteoarthritis drugs (DMOADs): what are they and what can we expect from them?

by A. J. Barr and P. G. Conaghan,
United Kingdom

Osteoarthritis (OA) is the most common form of arthritis and represents a huge burden on individuals and health economies. The mainstay of current therapy involves a combination of nonpharmacological and pharmacological interventions aimed at reducing pain and improving function. Current treatments do not inhibit structural deterioration of the OA joint; yet, the unmet need for this type of treatment is immense. The current definition of a disease-modifying OA drug (DMOAD) is that of a drug that inhibits structural disease progression and ideally also improves symptoms and/or function. There are currently no licensed DMOADs but there are many prospective agents under investigation. The challenges of DMOAD development include the establishment of appropriate preclinical animal models that reflect human OA, the limitations of the current radiographic standard for structural assessment, and the lack of stratification of patients in trials by phenotype or tissue involvement. Furthermore, DMOADs should probably be used in early disease before irreversible molecular and biomechanical pathology is established, as is commonly present at the time of diagnosis. DMOADs are likely to be prescribed for long periods in this chronic illness of an aging population, which demands excellent safety data in a target population with multiple comorbidities and the potential for drug interactions. Issues in DMOAD development, potential DMOADs, magnetic resonance imaging biomarkers, and lessons learned from the treatment of rheumatoid arthritis are briefly discussed in this review.

Medicographia. 2013;35:189-196 (see French abstract on page 196)

Osteoarthritis (OA) is the most common form of arthritis and represents a huge burden on both individuals and health economies. It is characterized by changes involving all the joint tissues. Affected individuals suffer pain, functional limitation, and poor quality of life. We can predict a dramatic increase in the burden of OA in aging and increasingly obese Western populations.

OA represents whole joint failure and occurs when the homeostatic equilibrium of joint tissue repair and breakdown becomes unbalanced. Risk factors for disease initiation and progression vary according to anatomical site and include age, obesity,1,2 anthropometric and anatomical characteristics, joint malalignment, and trauma.3 A genetic predisposition also contributes to OA risk; OA is a polygenic disease whose susceptibility results from the interaction of many genes.4,5 The mainstay of current therapy involves a combination of nonpharmacological and pharmacological interventions aimed at reducing pain and improving function. The pharmacological interventions include paracetamol, nonsteroidal anti-inflammatory drugs, and opiate analgesics. Their utility is limited by—at best—moderate effect size,6 or by significant toxicities, especially as OA is most prevalent in the elderly where comorbidities are more common. Current treatments do not appear to inhibit the structural deterioration of the OA joint; the unmet need for such a treatment is immense.

What are disease-modifying osteoarthritis drugs?

A disease-modifying osteoarthritis drug (DMOAD) is a drug that inhibits the structural disease progression of OA and ideally also improves symptoms and/or function. There are currently no licensed DMOADs. There are draft guidelines from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) both requiring that a DMOAD should not only slow or halt radiographic structural disease progression, but also achieve patient-reported long-term clinical benefit.7,8 Historically, attempts at developing DMOADs have focused primarily on preventing hyaline cartilage loss, thereby providing putative “chondroprotective” agents. However, and perhaps appropriately, as typical clinical OA involves multiple tissues,more recent attempts have been made at targeting other tissues including the subchondral bone, which plays an important role in OA pathogenesis.

There are a number of issues to consider in developing therapies that modify structural disease progression.

Challenges in DMOAD development

_ The current standard for structural assessment: conventional radiography
Conventional radiography is widely available and radiographic joint space width (JSW) is the traditionally used surrogate for assessing cartilage thickness. JSW can be used for both defining and measuring structural disease progression. Manual and semiautomatedmethods can be used to quantify JSW from a conventional radiographic image, providing different measures such as minimum, mean, or location-specific JSW. Joint space narrowing (JSN) is used as the primary end point in DMOAD trials in OA. Although JSN is a predictor of total joint replacement,9 the limitations of radiographic JSN should be appreciated. Indeed, while JSN is used to define cartilage loss in knee OA, magnetic resonance imaging (MRI) studies have shown that it measures a complex construct including meniscal degeneration, meniscal extrusion, and hyaline cartilage loss.10

The annual rate and variability of JSN in the natural history of OA is well described, which facilitates powering in clinical trials.11,12 However, the average annual change in JSN is approximately 0.1 to 0.2 mm per annum, with change occurring in a small group of “progressors.” The relative insensitivity to change of this surrogate measure of hyaline cartilage loss means that long trials with large numbers of patients are needed in order to adequately power a clinical study. Furthermore, the sensitivity of this measure to change may be reduced by knee repositioning variability in serial radiographic measurement of JSW, so great care must be taken in repositioning methods.12

Conventional radiography does not detect early (preradiographic) OA changes in the subchondral bone, cartilage, or menisci.13 Typically, inclusion criteria for research trials have included patients with radiographically detectable JSN (Kellgren and Lawrence grade ≥2). While this selects a group of patients who no doubt have OA, multiple large MRI studies suggest that these patients have complex multiple tissue pathologies, with gait studies suggesting a high probability of abnormal biomechanical features, meaning that these may be patients in whom pharmacological intervention alone and aimed at a single tissue would be unlikely to modify structural deterioration. A preradiographic patient cohort with milder disease may be more likely to respond. Treatment of rheumatoid arthritis according to the concept of early disease has certainly revolutionized the management of rheumatoid arthritis.

_ Magnetic resonance imaging as a potential end point
Conventional radiography cannot capture the extent of the multi-tissue involvement in OA joints. Typically, patients with Kellgren-Lawrence grade ≥2 are recruited for DMOAD trials, but these patients may lack uniformity in terms of joint tissue involvement, and this is clinically indistinguishable. Stratifying and monitoring these tissue changes among patients would require MRI.

The advantages of MRI include the ability to examine the presence and extent of pathology in all of the individual joint tissues in OA.14 There is good evidence of the reliability and responsiveness of MRI cartilage morphometry in knee OA and there is some evidence of its predictive and construct validity.15,16 This includes quantitative loss of cartilage volume being a potential predictor of total knee replacement. The assessment of subchondral bone marrow lesions and synovitis in knee OA has also demonstrated good responsiveness for semiquantitative MRI assessment.16 Further work is required to investigate the predictive validity and quantification of these noncartilage MRI pathologies. While MRI acquisition is, of course, more expensive and time-consuming than plain radiography, there are trade-offs in that increased responsiveness should result in fewer patients being required to demonstrate a structure-modifying effect.

MRI-based joint tissue measures of OA have not been routinely used as clinical outcome measures in structure-modification DMOAD trials. However, following the last decade of MRI-OA cohort studies and trials, a recent Osteoarthritis Research Society International (OARSI) working group recommended that MRI cartilage morphology assessment be used as a primary structural end point in clinical trials and noted the rapid evolution of quantitative MRI assessments of subchondral bone and synovium.17

_ Novel end points: joint arthroplasty and virtual joint arthroplasty
While pain and function outcomes are common outcomes that may be adapted for DMOAD studies from symptom-modifying trials, less frequently used measures such as quality of life and delay in time to joint replacement may also provide important information about the value of a putative agent. Rate of joint arthroplasty has been used as an end point reflecting the severity of symptoms and structural damage, but many variables influence both the decision to perform and the timing of this outcome measure. These include the surgeon’s or physician’s opinion and the patient’s comorbidities and willingness to undergo surgery, in addition to local and national health system variations in surgical waiting lists. In an attempt to overcome these confounding factors influencing the “time to total joint replacement” end point, an alternative has been proposed. This is “time to fulfilling criteria for total joint replacement” or “virtual total joint replacement,” which could be used to evaluate treatment response to DMOADs in clinical trials.18 The criteria consist of a composite index of three domains: physical function, pain, and structure19; its validity is currently being assessed in an international study although provisional reports indicate that large patient numbers would be required to detect differences between groups in DMOAD randomized control trials.20

_ Symptomatic improvement
The current regulatory approval standard for DMOADs requires that structural disease modification be linked with some clinical benefit. However, in observational studies in OA there is generally a weak relation between pain and/or function and JSN and radiographic structural change.21 Furthermore, cartilage is not directly attributable as the cause of the typical OA symptoms, including pain and stiffness.22 Importantly, most trials of symptom-modifying drugs have been of short duration, often only 3 months long. DMOAD trials need to monitor pain over long periods of time (1 to 2 years), where the efficacy of existing analgesics has often not been clearly demonstrated. Such long-duration trials are often associated with patient drop-out, especially in an elderly population, and robust statistical modeling will be required to cope with missing data.

_ DMOAD safety profile
Prospective DMOADs for use in established OA are likely to require long-term administration in an aging population with significant comorbidities, and will thus be prescribed alongside a variety of medications. For that reason, prospective DMOADs will be required to demonstrate a good safety profile with respect to both patient tolerance and drug interactions. Long-duration trials will therefore be needed to achieve this.

_ Preclinical models
Animal models can mimic certain aspects of human disease. However, there is no single model that reflects all of the phenotypes and components of human OA. The marked differences between animal models and human disease may result in dismissing drugs that may be viable DMOADs in humans due to preclinical failure in animal models. Existing models include primary idiopathic and secondary experimentally induced disease. Small animal models may provide us with a clearer understanding of the molecular pathways involved in the pathogenesis of OA and the effects of prospective DMOADs on these pathways.23 Although large weight-bearing models may be more relevant, they are less frequently used. Animal models generally achieve adequate severity of OA but some may exceed that seen in humans. There is a general consensus of opinion that animal models of less severe OA will be better placed to establish the efficacy of prospective human DMOADs. Furthermore, establishing animal models with relevance to human OA will require standardization of experimental techniques, disease severity, and treatment responses.24

Are there candidate DMOADs?

A number of prospective DMOADs are under investigation and some of those more advanced in development are summarized in Table I (page 192). The degradation of cartilage and that of subchondral bone are closely linked in OA. Table I describes the mechanism of action of the prospective DMOADs on cartilage, although they may also structurally modify subchondral bone.

_ Calcitonin
Calcitonin is responsible for regulating calcium homeostasis and promotes osteoblastic bone formation. It inhibits bone resorption by binding to calcitonin receptors on osteoclasts. Calcitonin is indicated for the prevention of osteoporosis in postmenopausal women. It can be administered orally, intra-nasally, or subcutaneously. Its inhibition of subchondral bone turnover may be chondroprotective and, therefore, it may inhibit the structural disease progression of OA.25 In a human trial, bone resorption and cartilage degradation markers were significantly lower in the oral salmon calcitonin group compared with placebo.26 In a 2-year phase 3 trial of knee OA, oral calcitonin modified symptoms and increased cartilage volume but did not have an effect on JSW.27

Table I
Table I. Prospective disease-modifying osteoarthritis drugs
(DMOADs) and their mechanisms of action on cartilage.

_ Bisphosphonates
Bisphosphonates are frequently used for treating conditions with osteoclastic bone resorption, especially osteoporosis. Increased subchondral bone turnover in OA is integral to the pathogenic process of OA,28 and may be associated with progressive cartilage loss.29 This disease-specific pathogenic process can be targeted using antiresorptive agents such as bisphosphonates, which hinder the bone remodeling process and could be chondroprotective. Animal models identified a beneficial effect of bisphosphonates in OA through their impact on subchondral bone, which includes inhibition of remodeling and osteophyte formation along with decreased vascular invasion of calcified cartilage.30

Initially, a phase 2 study of risedronate31 reported promising findings with a trend toward inhibition of JSN in knee OA. However, a subsequent phase 3 study of risedronate in knee OA reported no significant change in JSN or symptom severity.32 As yet, no study has accounted for the heterogeneity of the OA population regarding subchondral bone abnormalities when selecting patients. The insensitivity to change of conventional radiography used as an outcome measure (vide supra) for structural change suggests that the above-mentioned studies were significantly underpowered to show a response.33 Some potentially beneficial effects have nonetheless been observed. A reduction in biomarkers of cartilage degradation at 6 months of therapy was noted, along with slower knee OA progression.34

Zoledronic acid is a long-acting bisphosphonate that is licensed for postmenopausal osteoporosis. Along with other bisphosphonates, zoledronic acid has demonstrated chondroprotective effects in animal models of OA35 in conjunction with its impact on subchondral bone. In a 1-year randomized placebo controlled trial of zoledronic acid in patients with knee OA, zoledronic acid demonstrated a reduction in bone marrow edema (a marker associated with structural disease progression) and knee pain.36 As it improves symptoms and a marker of structural disease progression at the same time, zoledronic acid represents an important prospective DMOAD.

_ Strontium ranelate
Strontium ranelate is a drug used in the treatment of osteoporosis with antiresorptive and anabolic effects on the subchondral bone. Strontium ranelate influences bone remodeling through calcium-sensing receptors on osteoclasts and osteoblasts in subchondral bone and by an antiresorptive action via inhibition of osteoclastogenesis.37 In vitro studies suggest that strontium ranelate has anabolic effects on cartilage by directly promoting the formation of human cartilage matrix.38 In studies of human osteoporosis, strontium ranelate reduces cartilage degradation markers and inhibits clinical symptoms and radiographic features of spinal OA, indicating its potential as a DMOAD.39 A double-blind, placebo-controlled, randomized, international 3-year study of knee OA demonstrated a chondroprotective effect and symptomatic improvement in WOMAC (Western Ontario and McMaster Universities) index scoring.40

_ Bone morphogenetic protein
Human bone morphogenetic protein-7 (BMP-7)—also known as osteogenic protein-1 (OP-1)—is a transforming growth factor with a broad range of effects on a variety of cells, including cartilage. It signals through transmembrane serine-threonine kinase receptors, and is involved in cartilage homeostasis and repair via anticatabolic and anabolic properties.41 In animal models, BMP-7 demonstrated reparative effects on cartilage lesions.42 Human chondrocytes also promote cartilage formation in response to BMP-7 treatment.43 Clinical trials investigating the efficacy of BMP-7 in human knee OA have commenced.

_ Inducible nitric oxide synthase
Nitric oxide is considered to play a pathogenic role in cartilage degradation and pain in OA.44 Nitric oxide—along with its metabolites—induces cartilage degradation and cytotoxic tissue damage via inhibition of proteoglycan and collagen synthesis, apoptosis of chondrocytes, and activation of matrix metalloproteinases (MMPs).

In animal models, selective inhibition of one isoform of nitric oxide synthase (iNOS) significantly reduces articular cartilage degradation and the number of osteophytes.45 There is also a significant reduction in the severity and incidence of OA in iNOS knock-out mice, indicating a potential role of iNOS in human OA. However, in a recent 2-year randomized, double- blind, placebo-controlled trial of an oral selective iNOS inhibitor, cindunistat, there was only a transient slowing of JSN in Kellgren-Lawrence grade 2 OA, which was not sustained at 2 years, and no significant evidence of inhibition of structural progression was seen in OA of greater radiographic severity.46

_ Matrix metalloproteinase inhibitors
MMPs are collagenases that cleave type II collagen and result in loss of biomechanical integrity of normal human articular cartilage. This important pathogenic process in OA can be inhibited using MMP inhibitors. However, these MMP inhibitors have failed early clinical trials due to the frequent development of a painful musculoskeletal syndrome (MSS). This has been attributed to the broad spectrum of MMP inhibition. MMP-13 appears to be an important collagenase in human OA and specific inhibitors targeting it are in development.47 This more targeted approach will, hopefully, avoid MSS.

_ Tissue inhibitors of metalloproteinases
Aggrecan is an important protein found in articular cartilage that is degraded as part of the pathogenesis of OA. This process occurs as a result of the action of a variety of different aggrecanases, including a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). Endogenous inhibitors of MMPs include the tissue inhibitor of metalloproteinase TIMP-3, which can inhibit the action of these aggrecanases.48 Greater cartilage degradation was noted in TIMP-3 knockout mice compared with wild-type mice.49 Therefore, tissue inhibitors of metalloproteinases represent a prospective DMOAD target.

_ Vitamin D
Vitamin D is required for normal cartilage and bone metabolism. It regulates the expression of MMPs by chondrocytes.50 Vitamin D insufficiency is common and is associated with reduced osteoblast activity and reduced bone quality, which may explain its association with structural progression of OA.51 Several clinical trials are investigating the effect of vitamin D on structural disease progression

_ Fibroblast growth factor 18
Fibroblast growth factor 18 (FGF-18) is involved in cartilage and bone development during skeletal maturation.52 In animal models, it has been shown to promote chondrogenesis, cartilage repair, and subchondral bone remodelling.53 It represents an important potential DMOAD and is currently undergoing phase 2 clinical trials examining changes in cartilage volume.

_ Interleukin 1 inhibitors
Interleukin 1 (IL-1) has been proposed to be involved in the degradation of articular hyaline cartilage based upon preclinical studies. Inhibition of the enzyme that activates the proinflammatory cytokine IL-1β, interleukin-1 beta-converting enzyme (ICE), has been achieved with a highly selective caspase-1 inhibitor called pralnacasan. In animal models, a reduction in joint damage was demonstrated.54 However, in human OA, monoclonal antibody IL-1 inhibitors have failed to demonstrate an improvement in symptoms.55

_ Neutraceuticals and supplements
Glucosamine, an amino sugar, is a substrate for the formation of glycosaminoglycans, and chondroitin sulfate is a sulfated glycosaminoglycan. Glycosaminoglycans are important constituents of articular cartilage. The availability of these substrates may limit the formation of cartilage and therefore glucosamine and chondroitin were used in trials as prospective DMOADs. A recent meta-analysis of glucosamine and chondroitin concluded that there is no structural modifying effect of these agents based upon trials using JSN as a clinical end point.56

Collagen hydrolysate is another dietary supplement. It is formed as a result of collagen hydrolysis and has only demonstrated small clinical improvement in OA. Phase 2/3 trials with collagen hydrolysate are yet to be published.

_ Doxycycline
Although there is no evidence to support an infectious etiology in OA, doxycycline has demonstrated potential as a DMOAD based on preclinical data. Possible mechanisms of action include inhibition of type XI cartilage degradation, inhibition of collagenase activity and a decrease in iNOS mRNA transcription. A randomized, placebo-controlled, double-blind trial of doxycycline of over 30 months that included 431 obese women with unilateral radiographic knee OA reported a small reduction in the rate of JSN in knees with established OA.11 Doxycycline is not currently recommended for the treatment of OA.

_ Cathepsin K
Cathepsin K, a cysteine proteinase, appears to play a role in the pathogenesis of OA.57 In preclinical models, cathepsin K inhibition reduced evidence of cartilage degradation.58 It is, therefore, a prospective DMOAD.

Can we learn lessons from disease modification in rheumatoid arthritis?

There may be some lessons to be learned from the management of rheumatoid arthritis, although the DMOADs that are used in the treatment of established OA are likely to differ from disease-modifying anti-rheumatic drugs (DMARDs) in some respects. DMARDs are typically used in a younger population where toxicity may be better tolerated and the absence of co- morbidities and concurrent therapies to treat them permits the use of agents with greater potential toxicity. DMOADs for established OA will require excellent toxicity profiles in light of the greater prevalence of comorbidities and potential for drug interactions. However, DMOADs, like DMARDs, are likely to require chronic administration. OA affects a significantly greater proportion of the population than rheumatoid arthritis and, therefore, its treatment may represent a significant burden to health services. Ideally, DMOADs should be inexpensive, patient- administered, and require little or no monitoring in comparison with DMARDs such as tocilizumab and infliximab.

DMARDs are often prescribed in combination to improve the efficacy of treatment in terms of symptoms and structural disease progression. Similarly, DMOADs may also need to be prescribed in combination, particularly if a single joint tissue is targeted by the DMOAD. It is important to recognize that OA is a whole joint disease involving pathophysiological interactions between subchondral bone, cartilage, synovium, and ligaments and it is likely that an individual DMOAD will only target a single tissue, thereby increasing the need for combination therapy.

The cornerstone of DMARD therapy has been effective targeting of synovitis. While the synovium is only one of the tissues involved in OA pathogenesis, synovitis may contribute to disease progression.59 Therapies that modify synovitis could therefore potentially modify OA structural progression. Studies in this area are ongoing.


OA is the most common form of arthritis and is a chronic and progressive disease of the whole joint with only moderately effective treatment options currently available. There are a number of prospective targets for structural and symptomatic disease modification in patients with established OA, early OA, or at the time of acute joint injury, with a view to preventing structural progression, improving symptoms and function, and avoiding the need for total joint replacement. DMOADs are the highest unmet need in the field of OA and prospective DMOADs will need to demonstrate excellent safety profiles in view of their target population. However, DMOAD trials will require improved biomarkers and clinical end points to appropriately demonstrate the construct of OA structure modification. _

1. Office for National Statistics. National population projections, 2008-based. ONS. 2009.
2. Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88.
3. Sellam J H-BG, Berenbaum F. Osteoarthritis: pathogenesis, clinical aspects and diagnosis. In: Bijlsma JW, Burmester GR, da Silva JA, Faarvang KL, Hachulla E, Mariette X, eds. EULAR compendium on rheumatic diseases. London, UK: BMJ Publishing Group; 2009:444-463.
4. Loughlin J. The genetic epidemiology of human primary osteoarthritis: current status. Expert Rev Mol Med. 2005;7(9):1-12.
5. Panoutsopoulou K, Southam L, Elliott KS, et al. Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study. Ann Rheum Dis. 2011;70(5):864-867.
6. Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage. 2010;18(4):476-499.
7. Food and Drug Administration. Guidance for industry: Clinical development programs for drugs, devices, and biological products intended for the treatment of osteoarthritis (OA). 1999. FDA document 07/1999.
8. EuropeanMedicines Agency. Guideline on clinical investigation ofmedicinal products used in the treatment of osteoarthritis. 2010.
9. Maillefert JF, Gueguen A, Nguyen M, et al. Relevant change in radiological progression in patients with hip osteoarthritis. I. Determination using predictive validity for total hip arthroplasty. Rheumatology (Oxford). 2002;41(2):142-147.
10. Hunter DJ, Zhang YQ, Tu X, et al. Change in joint space width: hyaline articular cartilage loss or alteration in meniscus? Arthritis Rheum. 2006;54(8):2488- 2495.
11. Brandt KD, Mazzuca SA, Katz BP, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2005;52(7):2015-2025.
12. Le Graverand MP, Vignon EP, Brandt KD, et al. Head-to-head comparison of the Lyon Schuss and fixed flexion radiographic techniques. Long-term reproducibility in normal knees and sensitivity to change in osteoarthritic knees. Ann Rheum Dis. 2008;67(11):1562-1566.
13. Hunter DJ, Arden N, Conaghan PG, et al. Definition of osteoarthritis on MRI: results of a Delphi exercise. Osteoarthritis Cartilage. 2011;19(8):963-969.
14. Conaghan PG, Felson D, Gold G, Lohmander S, Totterman S, Altman R. MRI and non-cartilaginous structures in knee osteoarthritis. Osteoarthritis Cartilage. 2006;14(suppl A):A87-A94.
15. Hunter DJ, Zhang W, Conaghan PG, et al. Systematic review of the concurrent and predictive validity of MRI biomarkers in OA. Osteoarthritis Cartilage. 2011; 19(5):557-588.
16. Hunter DJ, Zhang W, Conaghan PG, et al. Responsiveness and reliability of MRI in knee osteoarthritis: a meta-analysis of published evidence. Osteoarthritis Cartilage. 2011;19(5):589-605.
17. Conaghan PG, Hunter DJ, Maillefert JF, Reichmann WM, Losina E. Summary and recommendations of the OARSI FDA Osteoarthritis Assessment of Structural Change Working Group. Osteoarthritis Cartilage. 2011;19(5):606-610.
18. Maillefert JF, Hawker GA, Gossec L, et al. Concomitant therapy: an outcome variable for musculoskeletal disorders? Part 2: total joint replacement in osteoarthritis trials. J Rheumatol. 2005;32(12):2449-2451.
19. Gossec L, Hawker G, Davis AM, et al.OMERACT/OARSI initiative to define states of severity and indication for joint replacement in hip and knee osteoarthritis. J Rheumatol. 2007;34(6):1432-1435.
20. Manno RL, Bingham CO 3rd, Paternotte S, et al. OARSI-OMERACT initiative: defining thresholds for symptomatic severity and structural changes in disease modifying osteoarthritis drug (DMOAD) clinical trials. Osteoarthritis Cartilage. 2012;20(2):93-101.
21. Creamer P. Osteoarthritis pain and its treatment. Curr Opin Rheumatol. 2000; 12(5):450-455.
22. Felson DT. The sources of pain in knee osteoarthritis. Curr Opin Rheumatol. 2005;17(5):624-628.
23. van den Berg WB. Lessons from animal models of osteoarthritis. Curr Rheumatol Rep. 2008;10(1):26-29.
24. Poole R, Blake S, Buschmann M, et al. Recommendations for the use of preclinical models in the study and treatment of osteoarthritis. Osteoarthritis Cartilage. 2010;18(suppl 3):S10-S16.
25. Manicourt DH, Altman RD,Williams JM, et al. Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions. Arthritis Rheum. 1999;42(6):1159-1167.
26. Karsdal MA, Byrjalsen I, Henriksen K, et al. The effect of oral salmon calcitonin delivered with 5-CNAC on bone and cartilage degradation in osteoarthritic patients: a 14-day randomized study. Osteoarthritis Cartilage. 2010;18(2):150-159.
27. KarsdalMA, Alexandersen P, JohnMR, et al. Oral calcitonin demonstrated symptom- modifying efficacy and increased cartilage volume: results from a 2-year phase 3 trial in patients with osteoarthritis of the knee. Osteoarthritis Cartilage. 2011;19(suppl 1):S1-S35.
28. Hayami T, Pickarski M, Zhuo Y, Wesolowski GA, Rodan GA, Duong le T. Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone. 2006;38(2):234-243.
29. Kothari A, Guermazi A, Chmiel JS, et al. Within-subregion relationship between bone marrow lesions and subsequent cartilage loss in knee osteoarthritis. Arthritis Care Res (Hoboken). 2010;62(2):198-203.
30. Hayami T, Pickarski M, Wesolowski GA, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 2004;50(4):1193-1206.
31. Bingham CO 3rd, Buckland-Wright JC, Garnero P, et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum. 2006;54(11):3494-3507.
32. Spector TD, Conaghan PG, Buckland-Wright JC, et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Res Ther. 2005;7(3): R625-R633.
33. Hellio Le Graverand-Gastineau MP. OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed? Osteoarthritis Cartilage. 2009;17(11):1393-1401.
34. Garnero P, Aronstein WS, Cohen SB, et al. Relationships between biochemical markers of bone and cartilage degradation with radiological progression in patients with knee osteoarthritis receiving risedronate: the Knee Osteoarthritis Structural Arthritis randomized clinical trial. Osteoarthritis Cartilage. 2008; 16(6):660-666.
35. Muehleman C, Green J,Williams JM, Kuettner KE, Thonar EJ, Sumner DR. The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage. Osteoarthritis Cartilage. 2002;10(3):226-233.
36. Laslett LL, Dore DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis. 2012;71(8):1322-1328.
37. Brennan TC, Rybchyn MS, Green W, Atwa S, Conigrave AD, Mason RS. Osteoblasts play key roles in the mechanisms of action of strontium ranelate. Br J Pharmacol. 2009;157(7):1291-1300.
38. Henrotin Y, Labasse A, Zheng SX, et al. Strontium ranelate increases cartilage matrix formation. J Bone Miner Res. 2001;16(2):299-308.
39. Bruyere O, Delferriere D, Roux C, et al. Effects of strontium ranelate on spinal osteoarthritis progression. Ann Rheum Dis. 2008;67(3):335-339.
40. Reginster J CR, Christiansen C, Genant H, Bellamy N, Bensen W. Structure modifying effects of strontium ranelate in knee osteoarthritis. Osteoporosis Int. 2012;23(suppl 2):S58.
41. Chubinskaya S, Hurtig M, Rueger DC. OP-1/BMP-7 in cartilage repair. Int Orthop. 2007;31(6):773-781.
42. Jelic M, Pecina M, Haspl M, et al. Regeneration of articular cartilage chondral defects by osteogenic protein-1 (bone morphogenetic protein-7) in sheep. Growth Factors. 2001;19(2):101-113.
43. Gavenis K, Heussen N, Schmidt-Rohlfing B. Effects of low concentration BMP-7 on human osteoarthritic chondrocytes: comparison of different applications. J Biomater Appl. 2012;26(7):845-859.
44. Abramson SB. Nitric oxide in inflammation and pain associated with osteoarthritis. Arthritis Res Ther. 2008;10(suppl 2):S2.
45. Pelletier JP, Jovanovic D, Fernandes JC, et al. Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase. Arthritis Rheum. 1998;41(7):1275-1286.
46. Hellio le Graverand MP, Clemmer R, Brunell RM, Hayes CW, Miller CG, Vignon E. Considerations when designing a disease-modifying osteoarthritis drug (DMOAD) trial using radiography. OARSI OA Biomarker Meeting 2012. http: //www.oarsi.org/pdfs/biomarkers/MP_Hellio_le_Graverand_2.pdf.
47. Baragi VM, Becher G, Bendele AM, et al. A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models. Arthritis Rheum. 2009;60(7):2008-2018.
48. Kashiwagi M, Tortorella M, Nagase H, Brew K. TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem. 2001;276(16):12501-12504.
49. Sahebjam S, Khokha R, Mort JS. Increased collagen and aggrecan degradation with age in the joints of Timp3(-/-) mice. Arthritis Rheum. 2007;56(3):905- 909.
50. Tetlow LC, Woolley DE. Expression of vitamin D receptors and matrix metalloproteinases in osteoarthritic cartilage and human articular chondrocytes in vitro. Osteoarthritis Cartilage. 2001;9(5):423-431.
51. McAlindon TE, Felson DT, Zhang Y, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med. 1996;125(5):353-359.
52. Haque T, Nakada S, Hamdy RC. A review of FGF18: Its expression, signaling pathways and possible functions during embryogenesis and post-natal development. Histol Histopathol. 2007;22(1):97-105.
53. Moore EE, Bendele AM, Thompson DL, et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage. 2005;13(7):623-631.
54. Rudolphi K, Gerwin N, Verzijl N, van der Kraan P, van den BergW. Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage. 2003;11(10):738- 746.
55. Cohen SB, Proudman S, Kivitz AJ, et al. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res Ther. 2011;13(4):R125.
56. Wandel S, Juni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ. 2010;341:c4675.
57. Kozawa E, Nishida Y, Cheng XW, et al. Osteoarthritic change is delayed in a Ctsk-knockout mouse model of osteoarthritis. Arthritis Rheum. 2012;64(2): 454-464.
58. Hayami T, Zhuo Y,Wesolowski GA, Pickarski M, Duong le T. Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis. Bone. 2012;50(6):1250-1259.
59. Conaghan PG, D’Agostino MA, Le Bars M, et al. Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3-year, prospective EULAR study. Ann Rheum Dis. 2010;69(4):644-647.

Keywords: biomarker; cartilage; DMOAD; subchondral bone; structure