Key points

Introduction

Because OA constitutes a substantial burden to afflicted individuals and the impact on the health care system, as well as overall loss of productivity, is large and growing, its successful treatment remains a significant and increasingly unmet need. Nearly 75% of patients want better treatment of their OA. Current treatments of OA are palliative for symptoms with little demonstration of efficacy in modifying the structural changes induced by the disease or altering its clinical course. This overview intends to bring attention to a relatively recent evolution of the traditional definition of “disease modification,” provide an overview of therapeutic strategies currently in late-stage development, and give special emphasis to challenges associated with therapeutic development in this area. This introduction to a shift in thinking about broader implications of the term “disease modification” is timely because the challenges to drug development in this area have resulted in the recent exodus of most pharmaceutical companies from this area of focus, at a time when the unmet need is large and expanding annually in parallel with the growth of the mature adult population, many of whom are heavier and/or active longer in life and develop unacceptable activity-limiting OA earlier than has been the case in recent decades.

Thinking more broadly about what is considered modification of the disease to include both hard and soft tissues of the joint and neurovascular and adipose components may help reveal novel and targetable approaches to treating this debilitating disease and encourage the reinvestment of much needed resources in this area. This will of course need to be done in the context of regulatory agency acceptability to be successful, but a crucial first step in getting this process under way will be to reestablish the perceived validity of investing in OA research and development programs by producing sensible, credible, and readily translatable therapeutic targeting strategies, with a goal to improve the clinical and quality of life outcomes of affected patients, regardless of the type of tissue behavior modified in the process.

Introduction

Because OA constitutes a substantial burden to afflicted individuals and the impact on the health care system, as well as overall loss of productivity, is large and growing, its successful treatment remains a significant and increasingly unmet need. Nearly 75% of patients want better treatment of their OA. Current treatments of OA are palliative for symptoms with little demonstration of efficacy in modifying the structural changes induced by the disease or altering its clinical course. This overview intends to bring attention to a relatively recent evolution of the traditional definition of “disease modification,” provide an overview of therapeutic strategies currently in late-stage development, and give special emphasis to challenges associated with therapeutic development in this area. This introduction to a shift in thinking about broader implications of the term “disease modification” is timely because the challenges to drug development in this area have resulted in the recent exodus of most pharmaceutical companies from this area of focus, at a time when the unmet need is large and expanding annually in parallel with the growth of the mature adult population, many of whom are heavier and/or active longer in life and develop unacceptable activity-limiting OA earlier than has been the case in recent decades.

Thinking more broadly about what is considered modification of the disease to include both hard and soft tissues of the joint and neurovascular and adipose components may help reveal novel and targetable approaches to treating this debilitating disease and encourage the reinvestment of much needed resources in this area. This will of course need to be done in the context of regulatory agency acceptability to be successful, but a crucial first step in getting this process under way will be to reestablish the perceived validity of investing in OA research and development programs by producing sensible, credible, and readily translatable therapeutic targeting strategies, with a goal to improve the clinical and quality of life outcomes of affected patients, regardless of the type of tissue behavior modified in the process.

Definition of “disease modification”

Diarthrodial joints are a composite of cartilage, subchondral bone, synovial membrane, and extrasynovial tendons, ligaments, fascia, fat, and muscle. With the exception of cartilage, all of these tissues are supplied by local branches of larger peripheral blood vessel and nerves. The interior of the normal joint is bathed by a thin layer of synovial fluid, an ultrafiltrate of plasma enhanced by locally synthesized hyaluronic acid. Osteoarthritic joints exhibit a continuous cycle of whole organ metabolic and structural derangement including induction of catabolic cytokine cascades, impaired oxygenation, decreased local tissue pH, altered water balance, progressive cartilage loss, subchondral bone remodeling, osteophyte formation, local venous congestion, and mild to moderate synovial inflammation.

The precise etiopathogenesis of OA is poorly understood, and the idea that the disease can be initiated or perpetuated by any or all of the multiple tissue types in the joint is not new. A great deal of attention has been paid in the literature to most of these affected joint tissues, particularly cartilage, but also bone, meniscal degeneration, synovium, and the intracapsular but extrasynovial infrapatellar fat pad.

Despite recent recognition by various camps that bone and synovium are significant participants in OA disease manifestation and progression, the world of disease modification research and product development (see Approaches Currently Being Tested section) has largely been dominated by a cartilage-centric view. For several decades, cytokine-based cartilage culture models have been successfully used to model disease effects. Treatment of isolated chondrocytes and cartilage explants in culture with individual or combinations of cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)α/oncostatin M combinations reliably drive up serine and cysteine proteinases, as well as the aggrecanases that degrade cartilage matrix and inhibit matrix production (proteoglycan, type II collagen) at the message level. This naturally spawned the notion that these pathways were central to OA pathophysiology and disease manifestation and focused attention on the cartilage component of the disease. Historically, this led to a great deal of investment in anticytokine therapeutic strategies to help preserve cartilage, much of which has, unfortunately, been largely unrewarding. One good example of this is IL-1, the role of which has been recently reviewed in OA. Although useful as a reliable short-term inducer of OA phenotype in cell and organ culture models, the clinical trial performance of IL-1 inhibitors as therapeutics has not been strong.

Recent therapeutic development efforts ( Fig. 1 ) have recognized the potential contribution of subchondral bone to the disease process and have begun to interrogate the value of targeting this tissue therapeutically. Risedronate, a bisphosphonate intended to maintain bone integrity to support the joint surface and thus help keep the cartilage surface healthy and intact, although unsuccessful as a disease-modifying agent or symptom modifier in a large clinical trial (potentially caused in part to challenges with patient selection and unpredictable disease progression), nevertheless helped pave the way for other therapeutics with a similar strategic approach. It was recently reported that a single treatment of another bisphosphonate, zoledronic acid, resulted in significant pain reduction and decrease in pain and the size of disease progression–associated bone marrow lesions in patients with knee OA in a randomized placebo-controlled clinical study. After these findings in the clinic, the effects of this agent were shown to be disease state specific in a surgical instability model of OA in rats. Oral salmon calcitonin has also recently been in clinical development as a disease-modifying OA drug (DMOAD), seeking to reverse or slow the OA-induced disruption of the bone–cartilage unit. Although traditionally studied in the context of bone, there is mounting evidence that calcitonin has direct effects on both bone and cartilage. Calcitonin can directly inhibit matrix metalloproteinases (MMPs) and block collagen degradation in TNFα/oncostatin M–exposed cultured articular chondrocytes. Enhancement of type II collagen and proteoglycan synthesis has been demonstrated in vitro in cultured human OA cartilage. In vivo, calcitonin has demonstrated the ability to slow meniscectomy-induced damage in a rat ovariectomy model of postmenopausal OA, as well as to confer some level of protection from cartilage degradation in an mouse model of OA. A recently completed large (1169 enrolled subjects) multicenter double-blind, randomized, placebo-controlled 2-year phase III trial in Kellgren-Lawrence (K-L) grade 2–3 OA patients demonstrated significant difference in cartilage volume loss by magnetic resonance (MR) imaging in favor of calcitonin, with significant analgesic effects seen compared with placebo control. No difference was seen, however, between treated and control subjects on radiographic joint space width change, still considered a critical endpoint by regulatory agencies.

Recent OA disease–modifying therapeutic strategies in development.

Another approach that may have effects on both cartilage and bone is treatment with vitamin D, being the subject of trials that are now either complete or nearing completion, including a randomized, double-blind placebo-controlled study being conducted in Australia in subjects with low plasma vitamin D levels and OA for at least 6 months. The rationale for this treatment includes multiple facets, including direct chondrocyte effects and association of low vitamin D level with diminution in muscle strength, known to be associated with OA. Further, low vitamin D levels have been shown to negatively influence bone formation, metabolism, and mineral deposition, as well as osteoblast activity.

Targeting other joint tissues, including synovial or neovascularization pathologies, is a path less well traveled. Certainly there is overlap between anticatabolic strategies intended to preserve cartilage and those that influence synovial production of degradative cytokines. Inducible nitric oxide synthase (iNOS) inhibition, a strategy recently interrogated in a phase III clinical trial, could be considered a good example of an agent likely to influence both synovial and cartilage nitric oxide production and to reduce pathologic effects in both tissues. iNOS is the enzyme responsible for cytokine-induced production of oxidatively toxic nitric oxide by chondrocytes under pathologic stress. Experimentally, iNOS inhibition can reduce the size of cartilage lesions and osteophytes while reducing synovial production of IL-1β, MMPs, and prostaglandins, all potential drivers of structural damage and/or pain sensitization. A large (1048 study completers of 1457 randomized subjects) 2-year multinational multicenter randomized double-blind trial was recently completed to evaluate the potential of iNOS to slow progression of radiographic joint space narrowing in the medial tibiofemoral joint compartment to a greater degree than placebo control. In the overall analysis, joint space width was not significantly different between treated and placebo control groups, whereas in discrete subanalyses by OA radiographic severity, K-L grade 2 subjects demonstrated significantly lower rates of joint space narrowing during the first 48 weeks of treatment but K-L grade 3 subjects did not, which the investigators indicate suggests either that iNOS plays a more significant role in OA pathologic conditions earlier in the disease process or that late-stage disease has advanced biomechanically too far to be amenable to treatment with this inhibitor, or potentially both.

Other strategies that could prove useful include inhibition of such OA-related pathologic conditions as vascular leakage, neovascularization, neuronal cell death, osteophyte formation, and bone marrow lesion formation and growth. The potential value of these types of less-traditional approaches for either symptom or structure modification remains to be explored.

Other approaches under active consideration

A review summarizing active clinical trials published in early 2010 shows a pipeline dominated by anticatabolic strategies, including inhibition of IL-1, TNFα, iNOS, MMPs, and aggrecanases. More recently, emphasis has been placed more on anabolic strategies, such as growth factors and cells as approaches to slow or stop joint degeneration in OA. A similar review of active late-stage clinical trials published in 2011 shows what may be considered a shifting landscape for active clinical trials from that published in early 2010. Anticatabolic strategies such as those targeting serine and cysteine proteinases, aggrecanases, interleukins, and members of the mitogen-activated protein kinase signaling pathway have for the most part been dropped from the therapeutic pipeline. Fibroblast growth factor-18 (FGF-18), a chondrogenic factor for chondrocytes and stem cells that can promote extracellular matrix synthesis, has been the subject of a recent clinical proof-of-concept trial. This factor has also been shown to have some catabolic activity in OA chondrocytes. Supporting this dual role is a microarray analysis of the effects of FGF-18 on IL-1–stimulated human articular chondrocytes in culture, which demonstrated increased gene expression of cartilage protective factors aggrecan, bone morphogenetic protein-2, and COL2A1 with concomitant upregulation of catabolic factors such as the aggrecanases ADAMTS-4 and -5, IL-1β, IL-6, and MMP-13. It remains to be seen if this balance between anabolic and catabolic activities promotes anabolism with beneficial structural remodeling of newly formed repair tissue or results in either little effect or a disorganized or inconsistent response. Clinically, in a randomized, double-blind, placebo-controlled, multicenter study evaluating intra-articular injection of FGF-18 in patients with OA, total cartilage volume was significantly increased in the treated group versus placebo, with most of the change seen in the lateral femorotibial compartment. Similar to other studies of this type, as described earlier for iNOS and salmon calcitonin, radiographic joint space width was not different between groups.

Osteogenic protein-1 (also known as bone morphogenetic protein-7), is a powerful bone and cartilage matrix anabolic factor expressed by adult human chondrocytes that may also demonstrate some level of IL-1 inhibitory activity. Similar to other members of the transforming growth factor-β superfamily, osteogenic protein -1 markedly drives up proteoglycan and collagen production by chondrocytes and may help to prevent chondrocytes from terminally differentiating and becoming hypertrophic as OA progresses. This agent was in trial for pain-relieving effects and structural change, and although early clinical data seemed to hold promise, successful pain endpoints were not achieved in a larger later-stage trial.

Multiple small exploratory autologous and allogeneic cell therapy–based clinical trials with both pain and structure endpoints are currently registered ( clinicaltrials.gov ) evaluating efficacy of OA treatment. The mechanism of action of stem cells in a disease such as OA may be linked to the pluripotent differentiation capability of these cells providing additional stem cells and chondrocytes that are geared toward restoration of damaged tissues, but these cells are also factories for balanced levels of growth factors, cytokines, chemokines, and other factors that influence tissue repair, remodeling, and inflammation. This latter paracrine capacity is currently considered the primary mechanism of action of these therapies. Although this mechanistic complexity may make cell-based therapy a more biologically relevant treatment option, it will also hinder its regulatory and commercial acceptability. As for other biologic approaches, the therapeutic potential of these strategies remains to be proved.