Original ArticleContribution of Serum Inflammatory Markers to Changes in Bone Mineral Content and Density in Postmenopausal Women: A 1-Year Investigation
Introduction
Bone is a dynamic tissue and is continually being remodeled. In adult humans, it is estimated that about 10% of total bone mass is replaced per year (1). Bone turnover is regulated by a plethora of systemic factors, such as estrogen, serum calcium, vitamin D status, and physical activity, as well as genetics (2). The activity of the bone matrix is governed by bone forming osteoblasts and bone resorbing osteoclasts, which are both equally important in maintaining bone homeostasis. An imbalance in bone turnover caused by excessive osteoclastogenesis can lead to bone loss and osteoporosis (3).
Osteoimmunology examines the interaction between bone and the immune system (4). Immune and bone cells share developmental pathways that arise from hematopoietic stem cells derived from the bone marrow. The differentiation of hematopoietic stem cells is regulated by bone and immune cell interactions. Immune cells may alter the balance of osteoclast and osteoblast cells by secreting immunoregulatory cytokines that affect the differentiation of bone precursor cells (5). The inflammatory disease rheumatoid arthritis is a classic example of this interaction. Macrophages and T-cells secrete inflammatory cytokines that activate osteoclasts, which leads to joint destruction and bone loss in rheumatoid arthritis patients (6).
During and after menopause, women lose a significant percentage of bone because of reduced estrogen production. Estrogen plays an important role in regulating the production and activity of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) (7). In an estrogen deficiency state or condition, these cytokines typically increase and activate osteoclastogenesis, thus leading to bone loss. Serum inflammatory cytokines have been shown to be higher in postmenopausal women compared with premenopausal women (8). Additionally, short term or acute inflammation as measured by C-reactive protein (CRP), compared with chronic inflammatory processes responsible for cytokine production, may also influence the degree or rate of bone loss during menopause.
Because of the lack of estrogen production and high turnover of bone in postmenopausal women, understanding the relationship between inflammation and bone is important in clinical conditions such as osteoporosis. The focus of this analysis was to examine the relationship of serum inflammatory markers and white blood cell count (WBC) to bone mineral content (BMC) and density (BMD) in healthy postmenopausal women not receiving hormone therapy. The serum inflammatory markers examined were IL-1β, IL-6, TNF-α, CRP, and WBCs. We included WBCs to account for the likelihood of concomitant infection, which may result in an acute inflammatory response.
Section snippets
Subjects
We enrolled healthy postmenopausal women (45.8–65.0 yr of age) as part of a randomized, double-blind, placebo-controlled multicenter (Iowa State University [ISU], Ames, IA and University of California at Davis [UCD], Davis, CA) clinical trial. The parent study (Soy Isoflavones for Reducing Bone Loss; SIRBL) was designed to examine the effect of 2 doses of isoflavones extracted from soybeans on bone loss during the course of 3 yr in at-risk postmenopausal (e.g., less than 10 yr since their last
Results
Descriptive characteristics of the women, and inflammatory marker values and bone parameters at baseline are presented in Table 1. Median values for inflammatory markers were within the range reported in the literature. However, 65 women had low WBC (<4.5 but >2.3 × 109/L), and none of the women had elevated WBC. Fifty women (20.6%) had nondetectable values for IL-1β and 4 women (1.7%) had nondetectable values for IL-6. Hence, we replaced these nondetectable values with 0.01 pg/mL (lowest
Discussion
Inflammatory markers are key players in bone biology and are involved in the regulation of osteocytes; as a result, the dynamic balance of bone formation and resorption are influenced by inflammatory markers. Of the serum inflammatory markers we examined, we found IL-6 and TNF-α to be the cytokines most often associated with percent change in BMC and BMD across a variety of bone sites. Additionally, the use of stepwise multiple regression analysis allowed us to evaluate the proportion of the
Acknowledgments
All authors have reviewed this article and contributed substantively to it.
Author contributions: Study concept and design, secured funding: Alekel, Van Loan; Acquisition of data: Alekel, Gertz, Hanson, Stewart, Van Loan, Wise, Silverman; Study supervision: Alekel, Van Loan; Administrative, technical support: Alekel, Hanson, Stewart, Van Loan; Statistical analysis and support: Van Loan; Analysis and interpretation of data: Gertz, Van Loan; Drafting of manuscript: Gertz, Van Loan, Alekel,
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Trial registration: NIH clinicaltrials.gov Identifier: NCT00043745.