One often thinks of bone as biologically inert. In fact, as it is made up of hard, mineralized material, skeletal tissue externally bears the appearance of an organ with very little need for the immune system. In reality, however, the immune system plays a major role in continuously orchestrating bone remodeling. Credited with the discovery of this process is Albert von Kölliker, who in 1873 first observed giant multinucleated cells sitting along bone surfaces. As these cells were localized to pits of resorbed bone, he rightfully surmised that they played a role in bone remodeling, naming them osteoclasts, or “bone-breakers.” This close relationship between the immune system and the skeleton is known as osteoimmunology.
Osteoclasts are today recognized for the central role they play in arthritic bone disease. This is especially evident in rheumatoid arthritis, a female-biased autoimmune disease in which chronic joint inflammation culminates in bone erosion. Osteoarthritis, the other most common form of arthritis, was once framed largely as age-related “wear and tear,” but is also now understood as a whole-joint disease involving cartilage degeneration, bone remodelling, and pain. In rheumatoid arthritis, joints rich in inflammatory molecules drive osteoclasts to erode bone. Similarly, in osteoarthritis, lower-grade inflammation contributes to progressive joint failure. Both diseases disproportionately affect women, although in different ways; rheumatoid arthritis affects women two to three times more often than men, while osteoarthritis becomes especially common in women after midlife. Despite major therapeutic advances in rheumatoid arthritis, neither disease is curable, and osteoarthritis still lacks approved disease-modifying therapies.
Central to the understanding of the role of osteoclasts in arthritic diseases was their identification as immune cells. This emerged from the discovery that bone health was highly dependent on the function of the immune system. In 1997, scientists at Amgen in the United States and in Japan discovered osteoprotegerin (“bone-protector”), or OPG, a secreted molecule that could protect mice from bone loss with aging. Soon after, it began to be understood that OPG acts as a brake that makes sure osteoclast function remains balanced. By trapping survival factors such as RANKL, which act as gas pedals to drive osteoclast-driven bone breakdown forward, OPG constrains bone remodeling.
Surprisingly, however, RANKL is not only involved in bone biology – it also helps immune cells communicate. Shortly after its discovery by bone scientists, it was understood that RANKL was identical to another inflammatory cytokine being studied at the time as a mediator of inflammation driven by T cells. Evidence later uncovered that T cells promote bone loss and joint destruction through the RANK–RANKL pathway in animal models of arthritis. These discoveries fundamentally reshaped how we think about bone diseases, identifying them as immunological in nature.
Sex differences play an important role in restraining bone disease by regulating osteoclast biology. Estrogen restrains bone resorption partly by regulating the RANKL–OPG axis. Estrogen deficiency after menopause can, in turn, tilt the bone microenvironment toward a pro-osteoclastogenic environment by reducing OPG production and increasing RANKL, promoting osteoclast production, activation, and persistent secretion of inflammatory factors. Declining levels of estrogen with age in males can also contribute to skeletal fragility. However, hormones are not the only sex-dependent modulators of osteoclast function and bone disease. A mixture of sex chromosomes, pregnancy, menopause, adiposity, microbiome composition, pain processing, and environmental exposures experienced by biological females altogether shape how immune signals are translated into skeletal damage.
Despite these advances in understanding bone immunology, major questions remain about the etiology of these diseases. Why do inflammatory signals drive destructive bone erosion in some diseases, but abnormal bone formation and remodelling in others? How does this change with age, sex, or disease stage? Perhaps most importantly, why is skeletal damage irreversible in some, and completely reparable in others? These questions are especially relevant in the context of sex differences in bone disease. Estrogen clearly regulates the RANKL–OPG axis, but whether biological sex also alters the behaviour of immune cells, stromal cells, and osteoclast precursors remains less fully understood. The future of osteoimmunology lies not only in identifying immune pathways that cause bone destruction, but also in understanding why those pathways become pathogenic in different bodies, at particular ages, and in unique hormonal environments.
Jonathan Monteiro
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