Edited by: Basem M. Abdallah, University of Southern Denmark, Denmark
Reviewed by: Katherine Brooke-Wavell, Loughborough University, UK; Chantal Chenu, Royal Veterinary College, UK
Specialty section: This article was submitted to Bone Research, a section of the journal Frontiers in Endocrinology
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In this review, we will first discuss the concept of bone strength and introduce how fat at different locations, including the bone marrow, directly or indirectly regulates bone turnover. We will then review the current literature supporting the mechanistic relationship between marrow fat and bone and our understanding of the relationship between body fat, body weight, and bone with emphasis on its hormonal regulation. Finally, we will briefly discuss the importance and challenges of accurately measuring the fat compartments using non-invasive methods. This review highlights the complex relationship between fat and bone and how these new concepts will impact our diagnostic and therapeutic approaches in the very near future.
We will briefly review how the definition of osteoporosis has evolved to integrate other parameters in addition to bone mineral density (BMD) measurements. We will then review the makeup of the bone microenvironment and the distribution of fat within and outside the bone compartment. Finally, we will briefly summarize how muscle and its fat composition may have impact on bone strength.
At the National Institutes of Health (NIH) Consensus Conference in 2000, osteoporosis was defined as a skeletal disorder characterized by compromised bone strength that predisposes to an increased risk of fracture (
The World Health Organization defines osteoporosis as two and a half SD below the peak bone mass [i.e., the maximum amount acquired post bone maturation around the age of 18 in women (
Bone strength is highly dependent on its structural and material properties. The balance between bone formation and resorption, also called bone turnover, greatly influences the material properties of bone such as tissue mineral density and collagen cross-linking. Enhanced bone turnover, as seen with a lack of estrogen in postmenopausal women, influences the structural and material properties that lead to bone microdamage. With aging, the reduction in bone strength is further compounded by progressive muscle weakness and the increased risk for falls due to lack of balance and coordination. Maintenance of bone mineralization within a relatively narrow range is also critical to the maintenance of bone strength (
The bone microenvironment is comprised of several compartments, including hematopoietic cells, bone cells, and stromal cells (
In humans, white adipose tissue (WAT) is principally located beneath the skin (subcutaneous fat) and around internal organs (visceral fat or abdominal fat). The main cellular component of WAT is the adipocyte but other cell types are also present, including fibroblasts, macrophages, and blood vessels. Its main function is energy storage. Adipose tissue also accounts for a significant proportion of the breast tissue and is found around other organs (such as pericardial and gonadal fat) providing protective padding. Adipocytes are also found in small amounts outside adipose tissues, including muscle, liver, pancreas, and heart, which are also referred as ectopic fat. Fat cells are also found in the bone marrow, “MF,” and have been the subject of enormous research interest to explore their relationship with the bone microenvironment.
Another form of adipose tissue is known as brown fat or brown adipose tissue (BAT) located mainly around the neck and large blood vessels of the thorax of neonates whose main function is to generate heat and protect neonates against cold (
Many studies have clearly demonstrated the positive impact of muscle strength on bone strength, but we will not cover this important area of research here. However, an interesting, but much less explored, area is the relationship between muscle fat and muscle strength and by extension its impact on bone strength. Fat accumulation in muscle may also have indirect effects on bone. Intermuscular adipose tissue accumulation occurs during aging or in pathological conditions such as Duchenne muscular dystrophy, which has been linked to decreased muscle strength, a known risk factor for osteoporosis and fractures (
In this section, the origin, clinical significance, and the factors that influence MF accumulation will be discussed.
As we age, the cortex of the bones become thinner encircling concomitantly larger marrow cavities filled with fat, but whether this is a result of a passive accumulation of fat as bone is lost and marrow space increases or an age-related shift in MSC differentiation with predominant adipogenesis against osteoblastogenesis is difficult to elucidate.
Meunier et al. studied 81 iliac crest biopsies from elderly women and found that bone marrow samples from women with osteoporosis had a pronounced accumulation of adipocytes, relative to levels in healthy young subjects (
Marrow stromal cells isolated from postmenopausal osteoporotic patients express more adipocytic differentiation markers than those with normal bone mass and are more likely to enter an adipocyte than an osteoblast differentiation program (
Pluripotent bone marrow MSCs have the ability to become osteoblasts, chondrocytes, myocytes, or adipocytes under the influence of specific cell-derived differentiation factors (
Data from pathological specimens and imaging studies have consistently observed a reciprocal relationship between bone mass and increased marrow adiposity in elderly humans (
In summary, mounting evidence supports a mechanistic relationship between MF accumulation and bone loss, pointing out the potential to target this pathway to prevent or even reverse the process of bone aging.
In this section, we will summarize the current knowledge and conflicting data linking body fat, bone mass, and fracture rate.
Postmenopausal women have the ability to produce estrogens from the peripheral conversion of testosterone to estradiol in fat tissues. Adipocytes express the cytochrome P450 enzyme, aromatase, which can produce estradiol from testosterone. This peripheral production of estradiol has been proposed as protective mechanism against bone loss in overweight women (
Bone mineral density measured by dual-energy X-ray absorptiometry (DXA) is positively related to body weight and BMI (
A meta-analysis indicates that a high BMI appears to protect against fractures at any site in both men and women (
In this section, we will review the major hormonal regulators controlling fat and bone, with particular attention on the mechanisms underlying the reciprocal relationship between MF and bone.
Hyperinsulinemia is a hallmark of the metabolic syndrome characterized by accumulation of visceral fat (
Administration of glucagon-like peptide-1 (GLP-1) to diabetic mice results in an insulin-independent anabolic effect on bone (
Leptin is primarily produced by adipocytes and initially discovered as an appetite suppressant (
However, subsequent studies demonstrated the potent effect of leptin on bone in animal studies (
Adiponectin is another adipokine produced by adipocytes whose role is to increase insulin sensitivity. Its blood levels are decreased in obese and diabetic individuals (
PPARγ2 is the most important regulator of adipogenesis.
The canonical Wnt/beta-catenin pathway and non-canonical Wnt signaling have been implicated in this reciprocal regulation
Duque et al. provided
Excessive production or supre-physiological administration of GC excess results in inhibition of osteoblastogenesis and accelerated adipogenesis (
Vitamin D insufficiency is a worldwide phenomenon affecting even the sunniest areas (
Vitamin D (from skin irradiation or in the diet) must be metabolically activated first by the liver 25 hydroxylase (CYP2R1) to 25hydroxyvitamin D (25OHD) and then by the kidney 1αhydroxylase to its active form 1,25dihydroxyvitamin D [1,25(OH)2D]. The role of vitamin D on bone and mineral homeostasis is well known, but its role in other tissue function including fat is still the subject of considerable debate.
The relationship between vitamin D and fat has been the subject of many studies in recent years. Several studies found a strong and inverse correlation between circulation levels of 25OHD and weight but also BMI (
However, a causal relationship supporting the role of vitamin D as a regulator of fat metabolism and distribution in humans has been difficult to prove. In support of this theory, Ortega et al. found that baseline 25OHD levels are predictive of the efficacy of weight loss regimen and that the vitamin D status potentiates the effect of low caloric diet (
An unexplored effect of vitamin D action on bone could come from its effect on fat accumulation in muscle. Vitamin D is also a major determinant of skeletal muscle function (
Our studies showing that vitamin D is inversely related to fat infiltration in muscle (
Most vitamin D supplementation trials on muscle strength have been done in the elderly and found a reduction in falls, improvements in balance and body sway, and/or resolution of myalgia in statin-treated patients with treatment periods as short as 8–12 weeks (
Two vitamin D supplementation studies have been done in girls; one found improvements in muscle function in the vitamin D-treated group but no significant differences in bone measures using DXA and peripheral quantitative computed tomography (CT), while the other found increases in DXA measures of lean mass and spine bone mineral content (
Parathyroid hormone is a major regulator of calcium and bone homeostasis, but studies on its effect of fat have been so far limited. Two epidemiological studies suggest a possible positive association between circulating levels of PTH and fat mass. The first showed that circulating PTH concentrations are directly correlated with fat mass (
Much of this review focused on the interaction between white fat and bone, which is by far the most studied. In contrast, the literature on BAT and bone is almost non-existent except for two correlative studies showing that a positive relationship exists between BAT and bone volume in children and adolescent boys and girls (
In this section, we will briefly summarize the recent progress in non-invasive measurement of MF and body using imaging technologies.
Studies assessing MF–bone interactions have been hindered by the difficulty of independently examining different tissues at the same site. The most commonly employed method to assess bone and body composition has been DXA, which cannot analyze muscle or MF. In contrast, CT and MRI provide accurate measures of bone, muscle, and fat independently (
Possible differences in the distribution of fat accumulation in children have been difficult to establish due to the limitations and the risks of the techniques used. While there are many techniques, including underwater weighing, anthropometry, body water dilution, impedance, and DXA, to estimate total body fat content, it has not been possible to differentiate between subcutaneous and visceral fat until the advent of CT and MRI (
The interactions between fat and bone are complex and new emerging concepts regarding their relationship have the potential of transforming our therapeutic targeting of the skeleton. The inverse relationship between MF and bone is an enthralling area of research based on the very origin of bone and fat cell differentiation from MSC. The obesity epidemic has also brought new challenges in terms of prevention and treatment of common illnesses, such as type 2 diabetes. Here again, the interactions between body weight, body fat, and bone are much more complex, and the influence of clinical context, age, sex, and ethnicity should be considered when examining this relationship. Overall, bone and fat may not be such an odd couple but rather a very important one that deserves to be examined in all its facets as it represents a unique challenge for future health.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by National Institutes of Health Grant 1R01 AR052744-01, Department of the Army Grant DAMD17-01-1-0817, and Canadian Institutes of Health Research Grant MT-10839, Department of Defense Grant BCRP 142405.