Subchondral bone as a key target for osteoarthritis treatment

Abstract

Osteoarthritis (OA), the most common form of arthritis, is a debilitating and progressive disease that has become a major cause of disability and impaired quality of life in the elderly. OA is considered an organ disease that affects the whole joint, where the subchondral bone (SB) plays a crucial role. Regardless of whether SB alterations precede cartilage damage or appear during the evolution of the disease, SB is currently recognised as a key target in OA treatment. In fact, bone abnormalities, especially increased bone turnover, have been detected in the early evolution of some forms of OA. Systemic osteoporosis (OP) and OA share a paradoxical relationship in which both high and low bone mass conditions may result in induction and/or OA progression. Recent findings suggest that some drugs may be useful in treating both processes simultaneously, at least in a subgroup of patients with OA and OP. This review focuses on the role of SB in OA pathogenesis, describing relevant underlying mechanisms involved in the process and examining the potential activity as disease-modifying anti-osteoarthritic drugs (DMOADs) of certain SB-targeting agents currently under study.

Introduction

Osteoarthritis (OA) is a degenerative joint disease characterized by uneven and gradual loss of articular cartilage, osteophyte formation, subchondral sclerosis and a variety of associated abnormalities of the synovial membrane and periarticular structures. OA is a multifactorial disease characterized by pain, stiffness and functional impairment ultimately resulting in chronic disability and significant economic burden, especially in people 65 years and older [1]. Although repetitive trauma plays a crucial role in the pathogenesis of primary OA, there are other important factors that must be considered. These include genetic factors, menopause-related estrogen deficiency and aging [2].

OA has traditionally been seen as a primary articular cartilage disorder; however, the role of subchondral bone (SB) is currently believed to be of particular importance in the pathogenesis of the disease [1], [3], [4], [5], [6], [7], [8]. Nevertheless, it remains controversial whether SB alterations precede cartilage degradation or follow the damage caused by loss of cartilage during the evolution of the disease. Recent data from animal models demonstrate that microstructural SB alterations may occur before, during or after cartilage damage [5], [6], [7], [8].

In humans, the relationship between systemic bone mineral density (BMD), local subchondral BMD and OA is not clearly defined. Bone alterations may not be uniform and are dependent on the status of overlying cartilage, whether healthy or damaged, and the stage of the disease [4], [9]. Recently, data from the Multicenter OA Study (MOST) indicate that high systemic BMD increases the risk of incident knee OA, but not radiographic progression of knee OA [10]. On the contrary, experimental studies show that systemic or local OP worsens OA progression [11]. Hence, different and opposite disturbances of SB mineral density may induce incident OA or aggravate previous disease. Furthermore, the presence of low bone mass in SB does not have the same influence on healthy and diseased cartilage [9].

Thus, SB may be a potentially interesting target for OA treatment, and therefore, bone-acting agents may have favorable consequences on cartilage structure, and subsequently on OA progression.

In this review, we discuss the role of SB in OA pathogenesis and analyze the main effects of various antiresorptive and bone-forming agents on SB remodeling and their potential suitability for treating OA.