In the present study, we investigated the vertebral bone-marrow fat content in healthy men and women from east China, across a spectrum of ages. We found that the vertebral bone-marrow fat content of young men was significantly higher than that of young women. With aging, fatty conversion of the bone-marrow was accelerated and progressive in women, while the fatty conversion process was slower in men, and the bone-marrow fat content of women was similar to that in men after menopause. Correlation analysis showed that the vertebral bone-marrow fat content of women was significantly positively correlated with age, and this correlation in men was significantly weaker than that in women. In addition, the bone-marrow fat content of the lower lumbar segments was higher than those of the upper segments.
Both osteoblasts and adipocytes originate from the mesenchymal stem cells, but the differentiation of mesenchymal stem cell affects the dynamic balance of bone remodeling [20–22]. As early as 1990, Moore et al. showed that the increase in bone marrow adipose tissue (BMAT) begins in childhood [1], and there are sex differences in bone metabolism from puberty, and men have higher BMAT values than women. However, Ruschke et al. considered that vertebral bone-marrow development in children showed a sex-independent cross-sectional increase of proton density fat fraction (PDFF) which correlated with the natural logarithm of age [23]. Since the subjects in the present study were adults, the sex differences in BMAT in minors cannot be verified. The findings in the present study suggested that vertebral bone-marrow fat content was positively correlated with age; bone-marrow fat content in women increased significantly during perimenopause, but the increase in the bone-marrow fat content of men was relatively stable, consistent with previous research [10, 11, 24, 25]. Bone-marrow adipocyte infiltration is thought to be part of normal aging. Studies have indicated that marrow fat content was significantly elevated in osteoporotic and osteopenic subjects, as compared to normal subjects, and osteoporosis is closely related to vertebral fragility fractures in the elderly. Van Staa et al. reported that the lifetime risk of any fracture was 53.2% at age 50 years among women, and 20.7% at the same age among men [26]. Moreover, the incidence of fractures in perimenopausal women increased exponentially, while this increase in older men was delayed by about 15 years [27]. It is likely that the age-related changes in bone-marrow fat content were mostly related to differences in hormones between the sexes in adults.
Androgens and estrogens are considered to be the chief regulators of sex differences in bone metabolism, and studies indicated that sex steroid signaling may be used as a drug target to affect bone metabolism. Animal model studies have demonstrated that androgen acts directly on trabecular bone through the androgen receptor in osteoblasts and osteocytes, which is independent of aromatization. Estrogens acting via the estrogen receptor-α in osteoblast lineage cells are crucial for men cortical and trabecular bone [28],[29]. Although the interaction between estrogen and adipose cells is complex, it is clear that estrogen reduction leads to adipocyte infiltration of the bone-marrow, and adipocytes can inhibit osteoblast activity and promote bone absorption. With aging, the composition of the bone-marrow shifts to favor the presence of adipocytes; osteoclast activity increases, and osteoblast function declines[22]. There is a significant difference in bone-marrow fat content between men and women. Young adult men have a higher androgen level than their woman counterparts. Moreover, men’ levels of estrogen, which contributes to the conversion of stem cells to adipocytes, are significantly lower than those of women. Thus, the vertebral bone-marrow fat content of men is higher than that of women. Ovarian function begins to decay before menopause, leading to a significant decline in estrogen levels in women, and a sharp increase in bone-marrow fat content in peri-menopausal women. The estrogen of postmenopausal women continues to decline gradually, and therefore the increase in bone-marrow fat content is relatively slow.
We found an anatomical variation in bone-marrow fat content, which was significantly higher in the lower lumbar segment than in the upper lumbar segment, consistent with previous studies [12, 30]. Most intervertebral disc (IVD) degeneration occurs in the lower lumbar segments, and Albert et al. reported that the prevalence of Modic changes and IVD pathology were greater in the L4/5 and L5/S1 regions than in the upper lumbar spine [31]. The lower IVDs are subjected to a greater load than the upper IVDs, and the incidence of degeneration is accordingly also higher. Therefore, vertebral adipocyte infiltration is consistent with anatomical IVD degeneration; lumbar fat content is closely related to the changes in lumbar load and stress distribution. In addition, studies by Ruschke et al. and by Baum et al. showed a decreasing PDFF from the lumbar to the cervical regions of the spine, which further confirmed segmental differences in vertebral fat distribution [23, 32].
We also found that the correlation between bone-marrow fat content and BMI was not significant, and there was no such correlation in older subjects. In a study of bone-marrow fat changes after gastric bypass surgery in obese women, nondiabetic women showed no significant mean change in bone-marrow fat [33]. Moreover, Cordes et al. reported that there were no statistically significant changes in bone-marrow FF% after a 4-week calorie restriction in obese women [34]. Furthermore, Bredella et al. suggested that bone-marrow fat was independent of BMI in young obese men and women [4]. Therefore, the small difference between the results of our study and of previous studies may be due to sampling errors; the age range of subjects in the present study was large. Overall, the process of bone-marrow fatty conversion appears to be independent of BMI.
There were several limitations to our study. First, the number of elderly subjects, i.e., those over 60 years old, especially those over 70 years old, was relatively small, and may not fully reflect the changes in bone-marrow fat in the elderly. We will expand the sample size and extend the period of observation to follow FF% in our future research. Second, we did not assess the bone mineral density. In a future study, dual-energy X-ray absorptiometry or computed tomography will be performed to evaluate the relationship between osteopenia, osteoporosis, and bone-marrow adipocytes infiltration. Third, all ROIs were manually segmented by two experienced radiologists, who ensured maximal avoidance of measurement related errors. However, future study should use a software to segment the ROIs of the vertebral bodies. Additionally, we did not have vertebral marrow biopsy specimens as a reference standard due to ethical issues in obtaining such samples from healthy people.