New Biological Markers of Bone Metabolism in Osteoporosis Treatment

Osteoporosis is a chronic skeletal disorder characterized by low bone mass and poor bone quality. It is a major public health concern in aging society and requires life-long treatment for preventing fragility bone fracture. One of the main limitations in treatment of osteoporosis is the lack of smart surrogate markers that reflect the status of bone quality and measure the effect of a specific treatment and that correlates with the real clinical end-point of fragility fracture. For more than 20 years, serum type I collagen N-propeptide and crosslinked C-terminal telopeptide were used as markers of bone formation and bone resorption, respectively. However, these markers have several limitations. First, these markers are not bone tissue-specific. Since osteoporosis in elderly patients is often combined with another disease such as that of kidney or liver, the lack of specificity is a crucial issue in clinical use. Second, these markers cannot reflect the osteocyte activity or periosteal apposition that has been recently emphasized in maintenance of skeletal integrity. To overcome these limitations, recent studies have focused on the identification of new biological markers. In line with these efforts, in this issue of Endocrinology and Metabolism, Kim et al. [1] report the potential of plasma macrophage migration inhibitory factor (MIF) as a novel biomarker of bone metabolism. They demonstrate that higher plasma MIF level was inversely correlated with bone mineral density (BMD) and suggest that it might be a potential early biomarker of osteoporosis. This is the first clinical study to show the significant association between circulating MIF level and BMD in postmenopausal women. Although the biological relevance or cause-effect relationship between MIF and bone mass was not reported in their study, the authors suggested that estrogen-withdrawal-related inflammation might be the link between increased MIF and BMD loss [1]. Moreover, tissue resident osteal macrophages, which play a pivotal role in bone remodeling [2], could be the origin of MIF in high bone turnover status. In this point of view, MIF might be an important player or surrogate marker in bone remodeling. Recently, several protein-based biomarkers including periostin [3], shingosine-1-phosphate [4], and sclerostin [5] as well as microRNAs [6] have been intensively studied. However, none of the candidates fully satisfied the expected characteristics of (1) bone tissue specificity; (2) stability and celerity of reflecting bone metabolism; and (3) universality to reflect the multiple components of bone metabolism such as osteoblast, osteoclast, and osteocyte. MIF has been established as an inflammatory protein exerting various roles in inflammation and immune functions. To use this factor as a biomarker of bone metabolism, careful consideration is needed.