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Exercise and Diet: Uncovering Prospective Mediators of Skeletal Fragility in Bone and Marrow Adipose Tissue

Abstract

Purpose of Review

To highlight recent basic, translational, and clinical works demonstrating exercise and diet regulation of marrow adipose tissue (MAT) and bone and how this informs current understanding of the relationship between marrow adiposity and musculoskeletal health.

Recent Findings

Marrow adipocytes accumulate in the bone in the setting of not only hypercaloric intake (calorie excess; e.g., diet-induced obesity) but also with hypocaloric intake (calorie restriction; e.g., anorexia), despite the fact that these states affect bone differently. With hypercaloric intake, bone quantity is largely unaffected, whereas with hypocaloric intake, bone quantity and quality are greatly diminished. Voluntary running exercise in rodents was found to lower MAT and promote bone in eucaloric and hypercaloric states, while degrading bone in hypocaloric states, suggesting differential modulation of MAT and bone, dependent upon whole-body energy status. Energy status alters bone metabolism and bioenergetics via substrate availability or excess, which plays a key role in the response of bone and MAT to mechanical stimuli.

Summary

Marrow adipose tissue (MAT) is a fat depot with a potential role in—as well as responsivity to—whole-body energy metabolism. Understanding the localized function of this depot in bone cell bioenergetics and substrate storage, principally in the exercised state, will aid to uncover putative therapeutic targets for skeletal fragility.

An Inverse Relationship Between Adipocytes and Other Cells in the Bone Marrow Niche Led to Initial Scientific Investigations

Marrow adipose tissue (MAT), a depot that rises in states of skeletal fragility like osteoporosis, associates with reduced bone quantity and increased fracture risk [1,2,3,4]. As a responsive component of the marrow microenvironment, MAT and its physiologic function have garnered increased interest. Distinct from white and brown adipose depots, adipocytes anatomically join hematopoietic and mesenchymal precursors and related cells within the marrow niche and may play a key role in hematopoietic function [5,6,7]. MAT’s locus within bone, as well as a limited ability to access and isolate it from other bone marrow components, led to a knowledge gap in the scientific community’s understanding of MAT physiology vis-à-vis that of other fat depots.

Initial studies noted that marrow adiposity might serve as a filler tissue—i.e., a depot that occupies space and lacks physiologic purpose. In the 1930s, MAT’s rise with aging was referred to as a conversion from “red” to “yellow” marrow, suggesting that as hematopoietic cells diminish with aging, adipose tissue take up space as a “cushion” [8]. An early report from 1971 by Meunier and colleagues posed, “is the decline in bone volume occurring in parallel with changes in the volume of marrow cell populations?” [9]. In the 1980s, “yellow” marrow or marrow adipocytes were shown to be the product of terminal differentiation of mesenchymal stem cell (MSC) progenitors within bone [10, 11]. In sum, the field was initially focused on understanding the connection between MAT and hematopoietic cells and, in this setting, the inverse relationship of marrow adipocytes and bone began to be investigated.

The earliest quantitative analyses of marrow adipocytes in the late 1980s, at the University of Barcelona, noted the very problem facing researchers today, as they attempted to extrapolate two dimensional histologic data into the three-dimensional plane using geometry and statistical techniques to calculate marrow adipocyte number and diameter per cubic millimeter [12, 13]. These early quantitative analyses of marrow adipocytes emerged more than a decade after similar inquiry had been published in adipocytes in muscle [14], highlighting the uniqueness of this depot. It would be many years later that osmium staining combined with μCT was applied to visualize fat in rodent bones, facilitating region-of-interest quantification [15], and eventually a volumetric whole-bone, advanced medical image analysis workflow [16, 17] that can also be harnessed to analyze MAT via high-resolution MR imaging [18, 19]. As we solve methodologic challenges in the field, work begins to quantify and phenotype MAT which may uncover its physiologic function.

The initial discovery of the relationship between MAT and bone in osteoporosis sparked further interest in the link between bone, lean mass, body weight, and MAT [20, 21]. In recent years, our knowledge about bone in the setting of aging and disease has expanded via experiments that apply dietary and exercise interventions to ask fundamental questions about this depot’s functional purpose. A PubMed search using common MeSH terms for MAT yields 5041 results, of which 77% were published in the last 20 years, demonstrating a steep rise in interest in this field. Early studies demonstrating an inverse relationship between MAT and bone raised questions about the purpose of the MSC-derived adipocytes, prompting cell culture, translational, and clinical investigations which begin to shed light on mechanisms and targets for osteoporosis.

Marrow Adipose Tissue Accrues in Well-Perfused Trabecular Sites and Is Responsive to Exercise, Aging, and Caloric Intake

Histological assessment of marrow adipocytes (Fig. 1) identifies cellular “ghosts,” typically via staining of paraffin-embedded specimens. As noted above, recent advances in the quantification of MAT include imaging techniques, like osmium staining combined with μCT, as well as 9.4T MRI with advanced volumetric image analysis [16, 17, 19, 22]. In-depth characterization at the cellular level has been performed via 3D electron microscopy of marrow adipocytes at the proximal tibial metaphysis, revealing polarized deposits with a dense mitochondrial network—Robles et al. describe these cells as having the hallmarks of metabolically active cells [23]. Interestingly, analysis at the caudal vertebra was limited due to the extremely high density of adipocytes at that site. These findings lend credence to recent detection of regional variance in marrow adipocytes, which associates with presence or absence of hematopoietic cells [24]. We and others have evaluated MAT at hematopoietic sites adjacent to joints that experience a high degree of mechanical loading, like the femoral and tibial metaphyses and vertebrae [24, 25].

Fig. 1
figure1

Methods for quantification and visualization of marrow adipose tissue (MAT). Histological assessment of femoral marrow adipocytes via hematoxylin staining of paraffin-embedded specimens from 11-week-old B6 mice randomly allocated to ad libitum diet (CTL) or 30% caloric restriction (CR) ± voluntary running exercise for 6 weeks. a Adipocyte number (#/mm) and size (μm2) quantified via ImageJ. b For volumetric quantification of MAT, 9.4T MRI of femoral water and fat maps with a 2-dimensional RARE imaging sequence. Water images were manually contoured to generate femoral bone masks using Insight SNAP; masks were used to separate bone from other image portions in water/fat maps. Average fat maps for each group were computed in the common space and superimposed on the common, average water image for visualization of group fat maps. Fat map intensities are represented with a colored heat map in 3D Slicer for visualization. For quantification, intensity-weighted volume of MAT can be quantified via regional (e.g., metaphyseal, diaphyseal) fat histograms. *Adapted from McGrath et al. [18••]

MAT expansion typically occurs with aging and is exacerbated by high fat feeding and obesity [25, 26]. MAT content is maximal at the growth plate, and the accumulation of MAT occurs progressively outwards from the metaphysis towards the diaphysis. Importantly, the addition of one average size adipocyte (~ 5.5 × 104 μm3) to the bone marrow niche displaces ~ 30 hematopoietic cells in mice [27]. In fact, a 20% increase in MAT can displace ~ 50,000 hematopoietic cells, though the full extent of how MAT accumulation impacts hematopoiesis, both at a cellular level and clinically, has not yet been elucidated [27].

Marrow Adipocyte Locularity Resembles White Adipocytes, yet Function Remains to Be Elucidated

Marrow adipocytes physically resemble white adipose tissue, exhibiting a unilocular morphology akin to that seen in white fat depots and contrasting with the multilocular morphology of brown fat depots. MAT gene expression may overlap with beige/brown adipose (Table 1), though differing reports exist, which may depend on animal models applied [32]. Recent analyses suggest that marrow fat might not be enriched in brown/beige-like genes and may be metabolically unique based on experiments in rabbits and humans [32].

Table 1 Summary of brown adipose tissue–associated gene expression in marrow adipose tissue (MAT) and bone

In brown adipose tissue, and other cell types with a high energy demand (e.g., skeletal muscle), tethering of lipid droplets to mitochondria occurs via Perilipin (PLIN) 1 [34, 35]. Mitochondrial tethering to lipid droplets is hypothesized to serve as an efficient way to drive lipid-dependent ATP production [34]. Tethered lipid droplets may display fundamental differences in metabolism than non-tethered counterparts [34]. Increased PLIN5 induces lipid droplet-mitochondrial tethering, though mitochondrial binding partner of PLIN5 has not been identified [34]. Tethering is reduced with cold exposure–induced brown adipogenesis, while starvation increases tethering [36, 37]. Marrow adipocytes, like brown adipocytes, exhibit a dense mitochondrial network [23], yet little is known about tethering in MAT. PLIN1 and PLIN5 are not only expressed by marrow adipocytes, but both PLIN1 and PLIN5 are increased in whole tibia in hypercaloric settings, suggesting that the tethering of lipid droplets to mitochondria may occur in MAT [19, 28]. The full extent of the physiologic role mitochondrial tethering plays in the regulation of metabolism in adipose depots, and its role specifically in MAT, remains to be elucidated.

Marrow adipocytes exhibit relatively high expression of genes involved in early adipocyte differentiation (e.g., C/ebpβ) and inflammatory cytokines (e.g., TNFα, IL6) and relatively low expression of adipocyte specific genes (e.g., Pparg, Fabp4) [28]. MAT is composed predominantly of triglycerides, like WAT, and few have noted a difference in terms of lipid saturation in the marrow [33, 38]. Bone marrow has also been noted to demonstrate evidence of de novo lipogenesis [36]; however, this was post-irradiation in mice and thus it is unknown if this is physiologically relevant in the non-irradiated state. If de novo lipogenesis is ongoing in bone marrow, glucose uptake might serve this purpose as well. Questions remain about the metabolic function of adipocytes in the marrow and the purpose they might serve in normal as well as osteoporotic states.

Metabolic Functionality of Marrow Adipose Tissue: a Potential Mediator of Fracture Risk?

MAT is known to increase not only in states of skeletal fragility, like anorexia and calorie restriction, but also in states like obesity, where there is an association with greater bone mass, rather than skeletal fragility. It remains unknown how the mechanisms through which MAT accumulates and contributes to bone remodeling differ across disease states. Recent image analysis techniques in humans (e.g. 1H-MRS) have put forth marrow lipid unsaturation index as a correlate with skeletal integrity [37], with a lower unsaturation index linked to osteoporosis and fragility fractures [30, 39]. In fact, unsaturation of marrow adipocytes may be a by-product of marrow adipose tissue dysfunction, which induces declines in metabolic function [40,41,42]. Fat metabolism may be a key mediator in the crosstalk between fat and bone, particularly in the case of impaired fat metabolism seen in obesity [43]. While improved metabolic and adipose tissue function are correlated with improved bone quality [44], little research has been performed to understand marrow adipose tissue dysfunction and its contribution to bone loss and fracture risk. Pharmacologic therapies (i.e., bisphosphonates, denosumab) reduce MAT while increasing bone density in patients with bone fragility, like osteoporosis [45,46,47,48]. MAT, found in patients with increased risk of fracture [1,2,3,4], is likely distinct from MAT in other states such as obesity. Much remains unknown about the causal relationship governing MAT’s association with fracture risk despite this being a central question in studies of marrow adipocytes.

Cellular Bioenergetics in the Marrow Niche

Metabolic pathways provide fuel in the form of adenosine triphosphate (ATP) to active, growing, and differentiating cells. Tremendous energy is required for musculoskeletal anabolism with recent work focused on understanding the metabolic capacity of cells in the bone marrow niche as well as their preferred metabolic pathways, thus enabling an improved understanding of marrow adipocytes and their relationship with bone and hematopoietic cells. Oxidative phosphorylation, occurring primarily in the mitochondria, provides ATP more efficiently than other pathways, such as anaerobic glycolysis [64], though glycolysis may impart other advantages, like lower levels of oxidative stress [65]. Understanding the metabolic requirements of cells housed in bone will facilitate our ability to promote these anabolic pathways, particularly in disease states. Here we discuss bioenergetic pathways of key cells in the bone marrow niche and the clinical implications of these processes to bone health (Table 2).

Table 2 Cellular bioenergetics in bone. #A pathway that is utilized during periods of high metabolic activity, such as differentiation and proliferation; PPP, pentose phosphate pathway

Mesenchymal Lineage Cells Exhibit Metabolic Switching in Quiescent Versus Active State

Mesenchymal stem cells (MSC) were noted in cell culture to rely on glycolysis during quiescence and active—i.e., proliferating or differentiating—states [66]. In fact, glucose-free media added to cultured MSC lead to rapid cell death [67]. However, glycolysis is not solely used by MSC; when active, MSC upregulate oxidative phosphorylation while maintaining similar level of glycolysis in vitro [66]. Further, mitochondria within MSC change in morphology from disparate organelles to a connected network during differentiation, consistent with activation of oxidative phosphorylation [66]. Undifferentiated MSC possess high levels of hypoxia-inducible transcription factor 1α (HIF-1α), a known inhibitor of oxidative phosphorylation [68], which is downregulated when MSC become active [66]. Hypoxia signaling pathways in MSC and other stem cell populations, including hematopoietic stem cells (HSC), are integral to facilitate metabolic switching between glycolytic and oxidative metabolism [69].

Osteoblasts rely on both glucose as well as fatty acids for energy needs [49,50,51, 70]. In mice, glucose uptake is mediated in osteoblasts predominantly by glucose transporter 1 (GLUT1) [49,50,51], as the deletion of GLUT1 suppresses osteoblast differentiation in vitro and in vivo [50]. Regulation of substrate utilization (e.g., glucose, amino acids, fatty acids) by osteoblasts occurs via Wnt signaling. Substrate usage activation via Wnt appears to be dependent upon the stage of osteoblast development, with Wnt signaling promoting glycolysis and glutaminolysis via mTORC in osteoblast progenitor and bone lining cells [50, 52, 53]. In mature osteoblasts, oxidative phosphorylation is promoted via Wnt-Lrp5 co-activation, which induces downstream accumulation of β-catenin and ultimately activates gene expression required for oxidation of long-chain fatty acids [54, 70]; mature osteoblasts also exhibit significantly greater mitochondrial density than both progenitors and bone lining cells [55, 71]. Loss and gain of function in Lrp5 co-receptors in osteoblasts confirm the reliance of mature osteoblasts on oxidative phosphorylation [54], as do work in mutated carnitine palmitoyltransferase 2, an enzyme integral for fatty acid oxidation, in osteoblasts and osteocytes [72]. In exercising mice, bone formation is upregulated alongside genes associated with oxidative phosphorylation, such as PLIN3, and MAT is reduced, further suggesting osteoblasts utilize fat as a substrate [19, 70, 72]. The metabolism of osteocytes, terminally differentiated osteoblasts embedded in bone matrix, has, to date, not been investigated. Given their origin, it is likely that osteocytes exhibit a similar metabolic profile to osteoblasts, though the unique confines of the osteocytic environment may outweigh their origin. Recent methodological advances, such as the development of cell culture models like the stem cell–derived osteocyte model, will allow for future research into osteocyte metabolism [56].

Marrow adipocyte transcriptional control is thought to be unique and to favor oxidative phosphorylation over glucose metabolism, though the exact balance is not known on a “whole-organism” level due to complexity in isolating this depot from surrounding tissues [29, 32, 57, 73]. In addition to MAT’s function in energy storage, it may also be a source of circulating factors, like Kit ligand, mediating metabolism of HSC [7, 74]. Selective deletion of Kit ligand from marrow adipocytes impairs hematopoietic function, providing evidence for MAT as a potential regulator of hematopoiesis [7••].

Hematopoietic Lineage Cells Differentially Utilize Glycolytic and Oxidative Metabolism

Hematopoiesis, bone cells, and MAT are highly interconnected components of the marrow niche, with bone and MAT thought to be integral for HSC function [5, 7, 74]; similarly, HSC-derived osteoclasts are integral for bone metabolism. HSC rely predominantly on glycolysis during quiescent periods. Glycolysis results in low levels of reactive oxygen species and low oxidative stress is essential for survival of quiescent HSC [75]. HSC may rely on FOXO3, a key regulator of oxidative stress, for this coupling of mitochondrial metabolism and HSC homeostasis [75], though HSC metabolism is also regulated via HIF-1α, as a potent inducer of anaerobic metabolism. Similar to MSC, HSC exhibit metabolic switching to oxidative phosphorylation when active via downregulation of HIF-1α [58, 75]. Erythrocyte progenitors, responsible for production of the most abundant blood cell and terminally differentiated HSC lineage cell, rely predominantly on glucose via the pentose phosphate pathway, glutamine, and iron metabolism to produce ~ 2.4 million erythrocytes per second [59, 60].

Osteoclasts, like HSC and MSC, have been shown to exhibit metabolic switching of substrate utilization, dependent upon the stage of differentiation and maturation [61, 76]. Osteoclastogenesis strongly relies on mitochondrial oxidative phosphorylation, consistent with the dense mitochondrial network observed in mature osteoclasts [77, 78]. In vitro work has documented significant reductions in cellular proliferation of osteoclasts in high glucose media (e.g., 20–100 mM) [62]. The inhibition of oxidative phosphorylation in vitro drastically reduced osteoclast differentiation, while the absence of glucose did not [62], suggesting that osteoclast differentiation can occur without glucose as a substrate, but not without oxidative phosphorylation. Interestingly, bone resorption requires both glucose and glutamine as substrates, in addition to oxidative phosphorylation, though evidence for this has only been demonstrated in vitro [77, 78]. Metabolically, both osteoblasts and osteoclasts utilize oxidative phosphorylation, yet osteoblast activity is not routinely promoted simply with an abundance of fuel; and in the setting of aging, it is osteoclastic resorption that exceeds formation. Recent work by Weivoda et al. investigated energy metabolism, bone formation, and bone resorption utilizing denosumab to biologically ablate osteoclasts in post-menopausal women to identify secreted factors coupling bone resorption and formation [63]. These significant experiments applying RNA-seq of centrifuged bone biopsies—in the setting of denosumab therapy—identified genes involved in osteoblast to osteoclast coupling. Specifically, osteoclast-derived dipeptidyl peptidase IV (DPP4), a serine exopeptidase and known target for diabetes therapy, was noted to be significantly downregulated by denosumab and thus might be an important link between RANKL signaling and energy metabolism.

Whole-Body Energy Balance Emerges as Integral in Regulation of Bone and Marrow Adipose Tissue

In a hypercaloric state, the accumulation of MAT correlates well with accumulation of white fat depots in obese humans, suggesting a shared mechanism to accommodate higher caloric intake and energy storage [79]. It was previously expected that excess lipid in bone would be harmful to bone health; however, exercise-induced bone formation is promoted, even to a larger extent, in obese rodents, suggesting that MAT might be beneficial to the skeleton in this setting [19, 80]. Conversely, exercise provides a stimulus for bone growth that when combined with high fat feeding appears to promote bone quantity while limiting MAT via potential utilization of marrow adipocyte as a fuel source [19].

Intriguingly in a hypocaloric state, like anorexia and calorie restriction (CR), MAT increases while other adipose stores decline [18, 79, 81]. Modest CR leads to significant accumulation of MAT and degradation of bone alongside significant increases in CD36, a key regulator of metabolic flexibility and promotor of fatty acid uptake [18••]. Exercise during CR further exacerbates CR-induced bone loss, alongside decreased MAT [18••]. With hypocaloric intake, mechanical loading/exercise appears unable to stimulate bone formation which might be due to the quality of the marrow adipocyte depot in this state. As bone formation requires a great deal of energy, it might be advantageous, in the setting of CR, to resorb rather than form bone.

Dietary Interventions Serve to Advance Understanding of the Relationship Between MAT and Bone

Marrow Adipose Tissue Is Not Inherently Pathological in a Hypercaloric State

The relationship between bone, MAT, and caloric excess/obesity was recently elegantly reviewed in Pagnotti et al. [2]. In contrast to osteoporotic conditions, MAT volume can increase in states where bone is preserved or increased; this is well exemplified during the rapid growth of puberty, where MAT expansion and bone acquisition both increase in eucaloric and hypercaloric settings [82]. Further, MAT and bone quantity both increase in high-fat diet (HFD) feeding and obesity in humans and rodents [43, 83, 84]. We previously showed 6 weeks of HFD feeding increases MAT without decreasing bone quantity in female mice, suggesting that marrow adipocytes might function similarly to white adipocytes, converting fat calories into new and larger adipocytes [16, 85, 86]. Diet-induced obesity increases MAT expression of Fsp27, a gene involved in determining lipid storage capacity and required for efficient energy storage and for formation of unilocular lipid droplets [87]. Hence, MAT and bone quantity are not necessarily inversely proportional [88]. This suggests that MAT and its relationship with bone health are complex and may not be solely regulated by preferential biasing of MSC.

Hypocaloric States Promote Marrow Adipose Accumulation and Degradation of Bone

Modest calorie restriction (CR) is associated with increased longevity in aged mice; however, CR exerts a detrimental impact on bone health, particularly in young, growing animals. While total body fat stores are reduced with CR, MAT paradoxically accumulates. Twelve weeks of 30% CR in young male mice diminished bone mass and structure, suppressed bone turnover via reduced bone formation and enhanced bone resorption, and induced MAT accumulation [81]. In female mice, exercise combined with 30% CR further degraded bone despite reducing MAT stores [18••]. Additional energy expenditure via running exercise combined with a hypocaloric state likely negates the mechanical stimulus for bone formation and enhances bone resorption, based on Pontzer’s constrained energy expenditure model, further impairing bone health [89, 90]. CR in obese humans reduces visceral and subcutaneous depots but does not impact vertebral MAT [91]. In contrast, anorexic women exhibit greater MAT in lumbar vertebra and femora compared with normal weight controls [92]. Interestingly, 8% CR in obese mice yielded similar detrimental effects to those documented by McGrath and colleagues [18••]; however, simultaneous exercise and CR in mice mitigated both weight-loss induced deterioration of bone and accumulation MAT [93]. Taken together, these data suggest a differential modulation of bone and MAT with exercise in CR dependent upon whole-body energy status.

MAT Accumulation and Bone Loss in a Eucaloric State

With whole-body energy homeostasis, or a eucaloric state, bone loss can occur and, while linked to mechanical loading/unloading and energy status, bone fragility can be additionally mediated by a multitude of factors including: aging, genetic, hormonal, or nutritional status. In such states, mechanisms of bone loss are diverse and beyond the scope of this review. Control diet and sedentary groups in experimental manipulation of caloric intake and expenditure (e.g., exercise) provide insights for mechanisms of bone loss in a eucaloric state. Conclusions made from such experiments, however, may not be generalizable to other states of skeletal fragility. Exercise in the eucaloric state promotes trabecular and cortical bone formation alongside reductions in MAT volume, suggesting utilization of MAT to fuel bone formation [16, 19, 94].

Vitamin and Mineral Intake May Impact Bone and MAT Independently of Whole-Body Energy Status

Vitamins and minerals influence bone health independent of energy status and can alter the effects of dietary and activity interventions. For example, dietary phosphate restriction significantly impairs bone mass and enhances MAT accumulation via suppression of osteogenic genes and activation of adipogenic genes [95]. Similarly, vitamin D, calcium, and potassium deficiencies, as well as trace minerals like magnesium, negatively impact bone mass and mineralization [96,97,98], though impacts on MAT have not been well characterized.

Mechanical Loading and Unloading Interventions to Understand Exercise Regulation of MAT and Bone

While metabolic factors play a central role in maintaining healthy tissue, especially those compromised by poor diet and sedentary lifestyles, one of the principal and universal components derived from physical exertion in general, and various exercise modalities, is the mechanical loading environment. Whether high-magnitude (e.g., weight-lifting, running) or low-magnitude (e.g., balance, vibration), mechanical loading has the unique ability to suppress adiposity while providing regulatory cues of musculoskeletal anabolism and/or homeostatic regulation of bone and muscle [99,100,101,102,103]. In contrast, without mechanical input, cells will default to a state of energy conservation (i.e., adipogenic over osteogenic) rather than utilization. This discrepancy in MSC lineage outcome highlights the interdependency of the mechanical loading environment and bone homeostasis. Further, mechanical loading highlights crosstalk within the musculoskeletal system, whereby muscle and bone signaling is integral for proper function of both tissues. While beyond the scope of this review, the intersection of muscle, muscle-bone crosstalk, and fat metabolism is an integral component of exercise regulation of the musculoskeletal system (reviewed in [2]).

Mechanical Unloading of the Skeleton Induces Marrow Adipose Accumulation and Bone Loss

Severe loss of muscle and bone due to disuse or mechanical unloading, clinically termed osteo-sarcopenia, is correlated with high morbidity and mortality [45, 104]. Musculoskeletal tissue dependency on mechanical forces is well illustrated in circumstances where mechanical forces are absent, as exemplified by chronic bedrest, disuse, and through conditions of microgravity [105, 106]. Exposure to microgravity and resulting unloading-induced bone loss was first documented following astronaut missions in the late 1970s. Early studies using rodents flown in space were the first to demonstrate increased MAT at the humeral and femoral metaphases with just 18.5 days of weightlessness [107]. Ground-based models of unloading, using tail suspension, induce reduction of femoral bone mass and volume and accumulation of MAT via suppression of dynamic markers of bone formation (marrow apposition rate, mineralizing surface, bone formation rate) and enhancement of relative osteoclast surface and number [108, 109]. Osteocyte apoptosis, assessed via the percentage of empty lacunae, resulting from tail suspension or targeted ablation of osteocytes, occurs alongside MAT accumulation and bone loss [110, 111]. Gene expression in the femora of unloaded mice reveals the downregulation of bone formation markers osteocalcin, type 1 collagen, and Cbfa1 and upregulation of adipocyte markers Pparg, Cebpα, and Cebpβ [109]. Keune and colleagues document exacerbated loss of trabecular bone with 2 weeks of hindlimb unloading in MAT-deficient mice, achieved via loss of function in cKit receptor (KitW/W-v), though KitW/W-v mice have higher baseline bone volume and connective density of trabecular bone [109]. Surprisingly, osteoblast perimeter, marrow apposition rate, and bone formation rate are elevated in unloaded MAT-deficient mice relative to genotype and loading controls, which contrasts with significant trabecular bone loss. It is worth noting that this study was conducted at thermoneutral temperature (32 °C), rather than room temperature (22 °C), which suppresses MAT accumulation, measured via adipocyte number, and BAT-like gene expression in rodents [112]. Further, Kit ligand, also known as stem cell factor, has been recently elucidated as a mediator of metabolic regulation of HSC and loss of Kit ligand function significantly impairs hematopoietic function [7, 74].

As experienced by astronauts subjected to sustained microgravity and chronic bed-rest analogs, skeletal unloading results in significant, and potentially irreversible, bone loss, though the degree to which this is observed is highly variable between individuals [113, 114]. In addition to bone loss, skeletal unloading has been documented to directly correlate with increased MAT in aging, osteoporosis, and bed-rest models [115,116,117]. Healthy young women and men exposed to 60 days of bed rest experienced significant increases in MAT at the lumbar vertebrae at the expense of bone [115, 116]. Intriguingly, vertebral MAT accumulation after 60 days of bed rest in healthy young women was maintained 1 year later alongside reductions in hematopoietic markers, suggesting irreversible changes to the vertebral niche [115].

Mechanical Loading of the Skeleton Induces Differential Effects on Marrow Adipose Tissue and Bone Dependent upon Mode of Exercise

Endurance Exercise

Voluntary wheel running, a frequently applied model of physical activity in rodents, improves trabecular and cortical bone mass and structure with concurrent reductions in marrow adiposity in states of hypercaloric or eucaloric intake [16, 17, 19, 118,119,120]; though this is not the case in hypocaloric states. Exercise benefits from wheel running are equally as evident in the setting of HF feeding; however, reductions in MAT occur here via reduced adipocyte size, rather than number [16, 17, 19]. HF feeding, in sedentary and exercising mice, is associated with greater Fsp27, a promoter of fat storage, and PLIN5, a promoter of beta-oxidation, while PLIN1, a promoter of fat utilization during starvation, is greater with exercise irrespective of diet [19]. Metabolically, greater utilization of fat stores and upregulation of beta oxidation likely fuel bone formation in wheel running mice with MAT as a local fuel source [19, 70, 72]. In sum, voluntary wheel running consistently improves bone mass while reducing MAT in hyper- and eucaloric, but not hypocaloric, states.

Running in rodents additionally affects bone deferentially depending on whether it is voluntary (e.g., wheel running) or forced (e.g., treadmill running), graded (e.g., level, uphill, downhill), and short- or long-term, among other variables. Downhill treadmill running of 10° or more appears to be consistently detrimental to bone, while uphill running promotes large gains in bone mass, volume, and structure [121, 122]. In fact, ground reaction forces to the hindlimbs, measured in cats, are lesser with a downhill slope than level running, while an uphill slope results in larger ground reaction forces [123]. Given the degree of mechanical input is the principal determinant of the stimulus for bone growth, this likely explains the differential effect of slope on bone outcomes. Level running, while less anabolic than uphill running, beneficially impacts bone [122, 124,125,126] and lessens MAT [126]. Interestingly, Wallace and colleagues report that, despite greater peak strains engendered at the forelimbs during level treadmill running in young female rats, minimal changes are seen in microarchitecture and geometry of the humerus, radius, and ulna, while the tibia and femur undergo significant and widespread improvements to trabecular and cortical bone [124]. The differential response of the forelimbs documented by Wallace et al. coincided with reduced MSC responsiveness in the forelimbs, suggesting that responsivity to loading may be more important for bone growth [124]. Mechanical stimuli promote MSC lineage selection towards osteogenesis and suppress adipogenesis in vitro, and treadmill running may elicit a similar response in vivo. In fact, 4 and 8 weeks of treadmill running reduced MAT at the proximal tibial metaphysis relative to sedentary controls, though bone mass remained unchanged [127]. Treadmill running exercise, whether level or uphill, across young to old rodent ages, consistently improves trabecular bone mass, volume, and structure of the hindlimbs in rodents.

Human studies have demonstrated a similar relationship to what is noted in rodents, between exercise and MAT. Human studies have largely focused on MAT at vertebral sites due to methodologic imaging restrictions. Bone marrow fat fraction at the lumbar vertebrae, but not the femur, was inversely associated with physical activity over a certain threshold (> 2 h/week) [128]. Notably, long-distance runners (> 50 km/week), but not habitual joggers (20–40 km/week) or high-volume cyclists (> 150 km/week), demonstrated significantly reduced vertebral MAT compared with controls (< 150 min/week of moderate activity) [129]. Long-distance running and high-volume cycling are regarded as comparable in terms of exertion, suggesting that mechanical loading of the spine, not aerobic exercise per se, suppresses adipogenesis in vertebrae.

Resistance Exercise

Progressive resistance training exercise, typically conducted via ladder climbing, jump training, or squat training, widely promotes bone formation, trabecular bone volume, and bone strength and suppresses bone resorption in aging and osteoporosis models, as well as in young, growing rats [130,131,132,133]. Ladder climbing with progressive loading up to 75% of body weight significantly improved femoral BMD, cortical cross-sectional area, and mechanical properties via increased mRNA of Runx2, Osterix, Bmp2, Bsp, and Osteocalcin and decreased expression of Pparg and Osteoprotegerin [132]. MAT has yet to be assessed in “resistance-trained” rodents, though the simulation of such exercise in an animal model poses experimental challenges which to date have not been resolved.

Exercise interventions which enable sufficient mechanical loading on the skeleton have demonstrably improved bone mass in young, old, osteoporotic, and obese humans [134,135,136]. Low bone mass older men and post-menopausal women undergoing high-intensity resistance and impact training for 8 months significantly improved lumbar spine and femoral neck BMD, as well as cortical thickness at the femoral neck [137••, 138]. These LIFTMOR exercise trials are of strong clinical and translational importance, as previously exercise programs were regarded as unsafe for older individuals with low bone mass or osteoporosis. The minimal frequency, intensity, and duration required to improve and maintain bone mass have yet to be delineated. Further, the response of MAT to resistance exercise interventions in healthy individuals and disorders of skeletal fragility remains largely unknown.

Low-Intensity Vibration

Despite the large body of evidence supporting the benefits of exercise in lessening MAT while improving bone, there are distinct patient populations, for reasons of bone fragility, muscle weakness, or general unwillingness, who are unable to participate in exercise regimens. The administration of lower magnitude forces in the form of whole-body-delivered low-intensity vibration (LIV) has been applied as a therapeutic surrogate to mechanical loading/exercise. Investigated as a measure to protect against ovariectomy-induced bone loss, LIV administration in rodents was found to mitigate ovariectomy-induced bone loss [139, 140]. Such studies document preservation of trabecular bone volume and microarchitecture, as well as suppression of MAT [139,140,141]. As with in vitro mechanical stimulation, rest days improved bone-related outcomes in high frequency, low magnitude (HFLM) whole-body vibration in ovariectomized female rats and healthy male rats [140, 142, 143]. Interestingly, the impact of HFLM on bone may differ in a sex-dependent manner [143, 144]. With LIV, applied frequency and signal amplitude are integral to stimulating bone formation; however, Zhang et al. utilized a higher frequency and noted negative impacts to bone; thus, there must exist a range of adequate signal parameters and differential sex-dependent responses to HFLM vibration exposure [144, 145].

In contrast to animal models, clinical trials utilizing whole-body vibration had equivocal effects in older adults with bone loss [146,147,148,149]. Younger women, though, demonstrated significant bone density improvements following vibration, highlighting the fact that age might play a role in the mechanical responsiveness of the skeleton [150]. For example, a 12-month trial of 15–20-year-old women with low bone mass found 2–3% increases in trabecular bone at the lumbar vertebra and cortical bone at the femoral diaphysis [150], which has been similarly reported in young disabled children pre- and post-puberty [151]. Further, children in cancer remission exhibited increased T-scores after 1 year of LIV [152]. In sum, human studies point to vibration as a potential augmenter of bone in younger individuals, though there is much that remains unknown.

In vitro Loading of Bone Cells Biases MSC Lineage Selection Towards Osteogenesis and Away from Adipogenesis

Applied at the level of the cell, the administration of biaxial strain or other mechanical loads to MSC largely downregulate adipogenesis [31, 153,154,155,156]. TGFβ1/Smad2 signaling, upregulated by strain, may also play a role in the mechanical repression of adipogenesis [31]. β-catenin is required for mechanical strain–induced inhibition of adipogenesis [156], and recent work demonstrates that β-catenin promotes the stemness of MSC via the activation of EZH2, a key epigenetic enzyme that silences genes [157]. Though most cell culture work has demonstrated mechanical input represses adipogenesis, some have also demonstrated correlative increase in osteogenesis with MSC undergoing cyclic stretch [155]. Despite extensive in vitro work showing biasing away from the adipogenic lineage, it remains unclear if this translates in vivo and whether the mechanical diminution of MAT is driven by similar pathways that regulate lineage selection.

The Role of Endogenous Sex Hormones in Regulation of Bone and Marrow Adipose Tissue

While diet and physical activity attenuate MAT and bone, other circulating factors may elicit increases in marrow adiposity at the expense of bone. Endogenous sex hormones, such as estrogens and androgens, are known to independently impact musculoskeletal anabolism and fat metabolism in bone and muscle [158, 159]. Age or pharmacologically induced deprivation of estrogens and/or androgens stimulates bone loss in post-menopausal women and older men [160,161,162,163], and waning sex hormone synthesis is associated with fat accumulation in bone and muscle [164, 165]. Factors such as sclerostin, glucocorticoids, pref-1, adiponectin, and leptin have been investigated, and yet, causality in mediating MAT or MAT’s interaction with bone has not been firmly established [79, 166,167,168]. Hormones such as insulin, IGF-1, and IGF-binding proteins are central to metabolic processes discussed herein, and their significance to the musculoskeletal system has previously been well-reviewed [169,170,171,172]. The significance of these hormonal factors to MAT is unclear and deserves further investigation.

Aging-induced replacement of viable bone with MAT, linked to waning sex hormone synthesis, may be further linked to a higher incidence of breast and prostate cancer in these populations [160,161,162,163]. Pharmacologic modalities to suppress estrogens and androgens in these disorders highlight a molecular dependency for sex hormones in preventing bone loss and MAT accrual, as well as preventing degradations in bone quality and strength [164, 165]. Recent work suggests that MAT could play a role in metastatic homing of cancer cells to the bone, highlighting a great need to define and maintain a healthy marrow microenvironment [173,174,175]. In-depth assessment of these mechanisms is reviewed elsewhere in this topical collection on Bone Marrow and Adipose Tissue from Current Osteoporosis Reports [176, 177]. Ongoing efforts are underway to understand the relationship between MAT, bone, and cancer, though much remains to be elucidated.

Conclusions

Marrow adipocytes accumulate in bone in hypercaloric (calorie excess; e.g., diet-induced obesity) and hypocaloric (calorie restriction; e.g., anorexia) states, despite an opposing effect on bone (Fig. 2). Bone quantity remains largely unaffected with hypercaloric intake, whereas in the hypocaloric state, bone quantity and quality are greatly diminished. Endurance exercise prevents MAT accumulation and increases bone in eucaloric and hypercaloric states, while further diminishing bone in hypocaloric states, suggesting differential modulation of MAT and bone, dependent upon whole-body energy status. Energy status alters bone metabolism and bioenergetics via substrate availability or excess, playing a key role in the response of bone and MAT to exercise/mechanical stimuli.

Fig. 2
figure2

Summary of bone and MAT response in hypercaloric and hypocaloric settings, with and without exercise. a Hypercaloric intake (e.g., diet-induced obesity) promotes MAT accumulation and trabecular bone loss in sedentary rodents and humans, particularly at the distal femoral (DFM) and proximal tibial metaphysis (PTM). The addition of exercise/mechanical loading, applied in tandem with the onset of a hypercaloric state, suppresses MAT volume and improves bone mass at these sites. b In contrast, hypocaloric intake (e.g., anorexia) promotes MAT accumulation and trabecular bone loss in sedentary rodents and humans, similar to that observed in hypercaloric states; however, exercise (e.g., endurance running) modestly suppresses MAT volume while further promoting bone loss at these sites

In summary, MAT’s response to whole-body energy requirements in the setting of exercise may supply adjacent osteoblasts energy required for exercise-induced bone formation, though in the hypocaloric state, MAT’s function has yet to be illuminated. Investigations applying physiologic interventions such as diet and exercise provide critical mechanistic insights about poorly understood tissues, serving to identify potential targets for future therapies.

Data Availability

Not applicable.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.

    Pagnotti GM, Styner M. Exercise regulation of marrow adipose tissue. Front Endocrinol (Lausanne). 2016;7:94. https://doi.org/10.3389/fendo.2016.00094.

    Article  Google Scholar 

  2. 2.

    Pagnotti GM, Styner M, Uzer G, Patel VS, Wright LE, Ness KK, et al. Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity. Nat Rev Endocrinol. 2019;15(6):339–55. https://doi.org/10.1038/s41574-019-0170-1.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Paccou J, Hardouin P, Cotten A, Penel G, Cortet B. The role of bone marrow fat in skeletal health: usefulness and perspectives for clinicians. J Clin Endocrinol Metab. 2015;100(10):3613–21. https://doi.org/10.1210/jc.2015-2338.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Devlin MJ. Why does starvation make bones fat? Am J Hum Biol. 2011;23(5):577–85. https://doi.org/10.1002/ajhb.21202.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460(7252):259–63. https://doi.org/10.1038/nature08099.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Zhou BO, Yu H, Yue R, Zhao Z, Rios JJ, Naveiras O, et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat Cell Biol. 2017;19(8):891–903. https://doi.org/10.1038/ncb3570.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    •• Zhang Z, Huang Z, Ong B, Sahu C, Zeng H, Ruan HB. Bone marrow adipose tissue-derived stem cell factor mediates metabolic regulation of hematopoiesis. Haematologica. 2019;104(9):1731–43. https://doi.org/10.3324/haematol.2018.205856Stem cell factor, a MAT-secreted hormone, acts as an integral mediator for metabolic regulation of hematopoietic stem cells and its absence significantly impairs hematopoiesis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Oehlbeck LW, Robscheit-Robbins FS, Whipple GH. Marrow hyperplasia and hemoglobin reserve in experimental anemia due to bleeding. J Exp Med. 1932;56(3):425–48. https://doi.org/10.1084/jem.56.3.425.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Meunier P, Aaron J, Edouard C, Vignon G. Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. Clin Orthop Relat Res. 1971;80:147–54. https://doi.org/10.1097/00003086-197110000-00021.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Lanotte M, Scott D, Dexter TM, Allen TD. Clonal preadipocyte cell lines with different phenotypes derived from murine marrow stroma: factors influencing growth and adipogenesis in vitro. J Cell Physiol. 1982;111(2):177–86. https://doi.org/10.1002/jcp.1041110209.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Kodama HA, Amagai Y, Koyama H, Kasai S. A new preadipose cell line derived from newborn mouse calvaria can promote the proliferation of pluripotent hemopoietic stem cells in vitro. J Cell Physiol. 1982;112(1):89–95. https://doi.org/10.1002/jcp.1041120114.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Rozman C, Feliu E, Berga L, Reverter JC, Climent C, Ferran MJ. Age-related variations of fat tissue fraction in normal human bone marrow depend both on size and number of adipocytes: a stereological study. Exp Hematol. 1989;17(1):34–7.

    CAS  PubMed  Google Scholar 

  13. 13.

    Rozman C, Reverter JC, Feliu E, Berga L, Rozman M, Climent C. Variations of fat tissue fraction in abnormal human bone marrow depend both on size and number of adipocytes: a stereologic study. Blood. 1990;76(5):892–5.

    CAS  Article  Google Scholar 

  14. 14.

    Hood RL, Allen CE. Cellularity of bovine adipose tissue. J Lipid Res. 1973;14(6):605–10.

    CAS  PubMed  Google Scholar 

  15. 15.

    Scheller EL, Troiano N, Vanhoutan JN, Bouxsein MA, Fretz JA, Xi Y, et al. Use of osmium tetroxide staining with microcomputerized tomography to visualize and quantify bone marrow adipose tissue in vivo. Methods Enzymol. 2014;537:123–39. https://doi.org/10.1016/B978-0-12-411619-1.00007-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Styner M, Thompson WR, Galior K, Uzer G, Wu X, Kadari S, et al. Bone marrow fat accumulation accelerated by high fat diet is suppressed by exercise. Bone. 2014;64:39–46. https://doi.org/10.1016/j.bone.2014.03.044.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Uzer G, Thompson WR, Sen B, Xie Z, Yen SS, Miller S, et al. Cell Mechanosensitivity to extremely low-magnitude signals is enabled by a LINCed nucleus. Stem Cells. 2015;33(6):2063–76. https://doi.org/10.1002/stem.2004.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    •• McGrath C, Sankaran JS, Misaghian-Xanthos N, Sen B, Xie Z, Styner MA, et al. Exercise degrades bone in caloric restriction, despite suppression of marrow adipose tissue (MAT). J Bone Miner Res. 2020;35(1):106–15. https://doi.org/10.1002/jbmr.3872Moderate calorie restriction induced MAT accumulation and trabecular bone loss, while combined restriction and exercise modestly suppressed MAT and further degraded bone.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Styner M, Pagnotti GM, McGrath C, Wu X, Sen B, Uzer G, et al. Exercise decreases marrow adipose tissue through β-oxidation in obese running mice. J Bone Miner Res Off J Am Soc Bone Miner Res. 2017. https://doi.org/10.1002/jbmr.3159.

  20. 20.

    Wang MC, Bachrach LK, Van Loan M, Hudes M, Flegal KM, Crawford PB. The relative contributions of lean tissue mass and fat mass to bone density in young women. Bone. 2005;37(4):474–81. https://doi.org/10.1016/j.bone.2005.04.038.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    De Laet C, Kanis JA, Odén A, Johanson H, Johnell O, Delmas P, et al. Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int. 2005;16(11):1330–8. https://doi.org/10.1007/s00198-005-1863-y.

    Article  PubMed  Google Scholar 

  22. 22.

    Sankaran JS, Sen B, Dudakovic A, Paradise CR, Perdue T, Xie Z, et al. Knockdown of formin mDia2 alters lamin B1 levels and increases osteogenesis in stem cells. Stem Cells. 2020;38(1):102–17. https://doi.org/10.1002/stem.3098.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Robles H, Park S, Joens MS, Fitzpatrick JAJ, Craft CS, Scheller EL. Characterization of the bone marrow adipocyte niche with three-dimensional electron microscopy. Bone. 2019;118:89–98. https://doi.org/10.1016/j.bone.2018.01.020.

    Article  PubMed  Google Scholar 

  24. 24.

    Scheller EL, Doucette CR, Learman BS, Cawthorn WP, Khandaker S, Schell B, et al. Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues. Nat Commun. 2015;6:7808. https://doi.org/10.1038/ncomms8808.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Cuminetti V, Arranz L. Bone marrow adipocytes: the enigmatic components of the hematopoietic stem cell niche. J Clin Med. 2019;8(5). doi:https://doi.org/10.3390/jcm8050707.

  26. 26.

    Yu EW, Greenblatt L, Eajazi A, Torriani M, Bredella MA. Marrow adipose tissue composition in adults with morbid obesity. Bone. 2017;97:38–42. https://doi.org/10.1016/j.bone.2016.12.018.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Turner RT, Martin SA, Iwaniec UT. Metabolic coupling between bone marrow adipose tissue and hematopoiesis. Curr Osteoporos Rep. 2018;16(2):95–104. https://doi.org/10.1007/s11914-018-0422-3.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Liu LF, Shen WJ, Ueno M, Patel S, Kraemer FB. Characterization of age-related gene expression profiling in bone marrow and epididymal adipocytes. BMC Genomics. 2011;12:212. https://doi.org/10.1186/1471-2164-12-212.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Suchacki KJ, Tavares AAS, Mattiucci D, Scheller EL, Papanastasiou G, Gray C, et al. Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis. Nat Commun. 2020;11(1):3097. https://doi.org/10.1038/s41467-020-16878-2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Yeung DK, Griffith JF, Antonio GE, Lee FK, Woo J, Leung PC. Osteoporosis is associated with increased marrow fat content and decreased marrow fat unsaturation: a proton MR spectroscopy study. J Magn Reson Imaging. 2005;22(2):279–85.

    Article  Google Scholar 

  31. 31.

    Li R, Liang L, Dou Y, Huang Z, Mo H, Wang Y, et al. Mechanical stretch inhibits mesenchymal stem cell adipogenic differentiation through TGFbeta1/Smad2 signaling. J Biomech. 2015;48(13):3665–71. https://doi.org/10.1016/j.jbiomech.2015.08.013.

    Article  PubMed  Google Scholar 

  32. 32.

    Krings A, Rahman S, Huang S, Lu Y, Czernik PJ, Lecka-Czernik B. Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes. Bone. 2012;50(2):546–52. https://doi.org/10.1016/j.bone.2011.06.016.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Tavassoli M, Houchin DN, Jacobs P. Fatty acid composition of adipose cells in red and yellow marrow: a possible determinant of haematopoietic potential. Scand J Haematol. 1977;18(1):47–53. https://doi.org/10.1111/j.1600-0609.1977.tb01476.x.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Bohnert M. New friends for seipin - implications of seipin partner proteins in the life cycle of lipid droplets. Semin Cell Dev Biol. 2020. https://doi.org/10.1016/j.semcdb.2020.04.012.

  35. 35.

    Tarnopolsky MA, Rennie CD, Robertshaw HA, Fedak-Tarnopolsky SN, Devries MC, Hamadeh MJ. Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity. Am J Physiol Regul Integr Comp Physiol. 2007;292(3):R1271–8. https://doi.org/10.1152/ajpregu.00472.2006.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Kozubik A, Sedlakova A, Pospisil M, Petrasek R. In vivo studies of the relationship between the activation of lipid metabolism, postirradiation bone marrow cell proliferation and radioresistance of mice. Gen Physiol Biophys. 1988;7(3):293–302.

    CAS  PubMed  Google Scholar 

  37. 37.

    Valentinitsch A, Patsch JM, Burghardt AJ, Link TM, Majumdar S, Fischer L, et al. Computational identification and quantification of trabecular microarchitecture classes by 3-D texture analysis-based clustering. Bone. 2013;54(1):133–40. https://doi.org/10.1016/j.bone.2012.12.047.

    Article  PubMed  Google Scholar 

  38. 38.

    Griffith JF, Yeung DKW, Antonio GE, Wong SYS, Kwok TCY, Woo J, et al. Vertebral marrow fat content and diffusion and perfusion indexes in women with varying bone density: MR evaluation. Radiology. 2006;241(3):831–8. https://doi.org/10.1148/radiol.2413051858.

    Article  PubMed  Google Scholar 

  39. 39.

    Patsch JM, Li X, Baum T, Yap SP, Karampinos DC, Schwartz AV, et al. Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures. J Bone Miner Res. 2013. https://doi.org/10.1002/jbmr.1950.

  40. 40.

    Stout MB, Swindell WR, Zhi X, Rohde K, List EO, Berryman DE, et al. Transcriptome profiling reveals divergent expression shifts in brown and white adipose tissue from long-lived GHRKO mice. Oncotarget. 2015;6(29):26702–15. https://doi.org/10.18632/oncotarget.5760.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Palmer AK, Kirkland JL. Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol. 2016;86:97–105. https://doi.org/10.1016/j.exger.2016.02.013.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Picard F, Guarente L. Molecular links between aging and adipose tissue. Int J Obes. 2005;29(Suppl 1):S36–9. https://doi.org/10.1038/sj.ijo.0802912.

    CAS  Article  Google Scholar 

  43. 43.

    Lecka-Czernik B, Stechschulte LA, Czernik PJ, Dowling AR. High bone mass in adult mice with diet-induced obesity results from a combination of initial increase in bone mass followed by attenuation in bone formation; implications for high bone mass and decreased bone quality in obesity. Mol Cell Endocrinol. 2015. https://doi.org/10.1016/j.mce.2015.01.001.

  44. 44.

    Rahman S, Lu Y, Czernik PJ, Rosen CJ, Enerback S, Lecka-Czernik B. Inducible brown adipose tissue, or beige fat is anabolic for the skeleton. Endocrinology. 2013. https://doi.org/10.1210/en.2012-2162.

  45. 45.

    Bonnet N, Bourgoin L, Biver E, Douni E, Ferrari S. RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass. J Clin Invest. 2019;129(8):3214–23. https://doi.org/10.1172/JCI125915.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Hanley DA, Adachi JD, Bell A, Brown V. Denosumab: mechanism of action and clinical outcomes. Int J Clin Pract. 2012;66(12):1139–46. https://doi.org/10.1111/ijcp.12022.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Zebaze RM, Libanati C, Austin M, Ghasem-Zadeh A, Hanley DA, Zanchetta JR, et al. Differing effects of denosumab and alendronate on cortical and trabecular bone. Bone. 2014;59:173–9. https://doi.org/10.1016/j.bone.2013.11.016.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Harris KB, Nealy KL, Jackson DJ, Thornton PL. The clinical use of denosumab for the management of low bone mineral density in postmenopausal women. J Pharm Pract. 2012;25(3):310–8. https://doi.org/10.1177/0897190012442061.

    Article  PubMed  Google Scholar 

  49. 49.

    Thomas DM, Maher F, Rogers SD, Best JD. Expression and regulation by insulin of Glut 3 in UMR 106-01, a clonal rat osteosarcoma cell line. Biochem Biophys Res Commun. 1996;218(3):789–93. https://doi.org/10.1006/bbrc.1996.0140.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Wei J, Shimazu J, Makinistoglu MP, Maurizi A, Kajimura D, Zong H, et al. Glucose uptake and Runx2 synergize to orchestrate osteoblast differentiation and bone formation. Cell. 2015;161(7):1576–91. https://doi.org/10.1016/j.cell.2015.05.029.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Zoch ML, Abou DS, Clemens TL, Thorek DL, Riddle RC. In vivo radiometric analysis of glucose uptake and distribution in mouse bone. Bone Res. 2016;4(December 2015):16004. https://doi.org/10.1038/boneres.2016.4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Esen E, Chen J, Karner CM, Okunade AL, Patterson BW, Long F. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab. 2013;17(5):745–55. https://doi.org/10.1016/j.cmet.2013.03.017.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Karner CM, Esen E, Okunade AL, Patterson BW, Long F. Increased glutamine catabolism mediates bone anabolism in response to WNT signaling. J Clin Invest. 2015;125(2):551–62. https://doi.org/10.1172/JCI78470.

    Article  PubMed  Google Scholar 

  54. 54.

    Frey JL, Li Z, Ellis JM, Zhang Q, Farber CR, Aja S, et al. Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast. Mol Cell Biol. 2015;35(11):1979–91. https://doi.org/10.1128/MCB.01343-14.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Pritchard JJ. A cytological and histochemical study of bone and cartilage formation in the rat. J Anat. 1959;86:259–77.

    Google Scholar 

  56. 56.

    Thompson WR, Uzer G, Brobst KE, Xie Z, Sen B, Yen SS, et al. Osteocyte specific responses to soluble and mechanical stimuli in a stem cell derived culture model. Sci Rep. 2015;5:11049. https://doi.org/10.1038/srep11049.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Lecka-Czernik B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone. 2012;50(2):534–9. https://doi.org/10.1016/j.bone.2011.06.032.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010;7(3):380–90. https://doi.org/10.1016/j.stem.2010.07.011.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Oburoglu L, Tardito S, Fritz V, de Barros SC, Merida P, Craveiro M, et al. Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification. Cell Stem Cell. 2014;15:169–84. https://doi.org/10.1016/j.stem.2014.06.002.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Oburoglu L, Romano M, Taylor N, Kinet S. Metabolic regulation of hematopoietic stem cell commitment and erythroid differentiation. Curr Opin Hematol. 2016;23(3):198–205. https://doi.org/10.1097/MOH.0000000000000234.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Morten KJ, Badder L, Knowles HJ. Differential regulation of HIF-mediated pathways increases mitochondrial metabolism and ATP production in hypoxic osteoclasts. J Pathol. 2013;229:755–64. https://doi.org/10.1002/path.4159.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Karner CM, Long F. Glucose metabolism in bone. Bone. 2018;115:2–7. https://doi.org/10.1016/j.bone.2017.08.008.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Weivoda MM, Chew CK, Monroe DG, Farr JN, Atkinson EJ, Geske JR, et al. Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism. Nat Commun. 2020;11(1):87. https://doi.org/10.1038/s41467-019-14003-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Schmidt-Rohr K. Oxygen is the high-energy molecule powering complex multicellular life: fundamental corrections to traditional bioenergetics. ACS Omega. 2020;5(5):2221–33. https://doi.org/10.1021/acsomega.9b03352.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Brand K. Aerobic glycolysis by proliferating cells: protection against oxidative stress at the expense of energy yield. J Bioenerg Biomembr. 1997;29(4):355–64. https://doi.org/10.1023/a:1022498714522.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Shum LC, White NS, Mills BN, Bentley KL, Eliseev RA. Energy metabolism in mesenchymal stem cells during osteogenic differentiation. Stem Cells Dev. 2016;25(2):114–22. https://doi.org/10.1089/scd.2015.0193.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Mylotte LA, Duffy AM, Murphy M, O’Brien T, Samali A, Barry F, et al. Metabolic flexibility permits mesenchymal stem cell survival in an ischemic environment. Stem Cells. 2008;26(5):1325–36. https://doi.org/10.1634/stemcells.2007-1072.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Du W, Zhang L, Brett-Morris A, Aguila B, Kerner J, Hoppel CL, et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun. 2017;8(1):1769. https://doi.org/10.1038/s41467-017-01965-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3(3):187–97. https://doi.org/10.1016/j.cmet.2006.01.012.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Kushwaha P, Wolfgang MJ, Riddle RC. Fatty acid metabolism by the osteoblast. Bone. 2018;115(November):8–14. https://doi.org/10.1016/j.bone.2017.08.024.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Komarova SV, Ataullakhanov FI, Globus RK. Bioenergetics and mitochondrial transmembrane potential during differentiation of cultured osteoblasts. Am J Physiol Cell Physiol. 2000;279(4):C1220–9. https://doi.org/10.1152/ajpcell.2000.279.4.C1220.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Kim SP, Li Z, Zoch ML, Frey JL, Bowman CE, Kushwaha P, et al. Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner. JCI Insight. 2017;2(16):1–16. https://doi.org/10.1172/jci.insight.92704.

    Article  Google Scholar 

  73. 73.

    Shockley KR, Lazarenko OP, Czernik PJ, Rosen CJ, Churchill GA, Lecka-Czernik B. PPARgamma2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J Cell Biochem. 2009;106(2):232–46. https://doi.org/10.1002/jcb.21994.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Li Z, Macdougald OA. Stem cell factor: the bridge between bone marrow adipocytes and hematopoietic cells. Haematologica. 2019;104(9):1689–91. https://doi.org/10.3324/haematol.2019.224188.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Rimmelé P, Liang R, Bigarella CL, Kocabas F, Xie J, Serasinghe MN, et al. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO 3. EMBO Rep. 2015;16(9):1164–76. https://doi.org/10.15252/embr.201439704.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Kim JM, Jeong D, Kang HK, Jung SY, Kang SS, Min BM. Osteoclast precursors display dynamic metabolic shifts toward accelerated glucose metabolism at an early stage of RANKL-stimulated osteoclast differentiation. Cell Physiol Biochem. 2007;20:935–46. https://doi.org/10.1159/000110454.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Lemma S, Sboarina M, Porporato PE, Zini N, Sonveaux P, Di Pompo G, et al. Energy metabolism in osteoclast formation and activity. Int J Biochem Cell Biol. 2016;79(August):168–80. https://doi.org/10.1016/j.biocel.2016.08.034.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Indo Y, Takeshita S, Ishii KA, Hoshii T, Aburatani H, Hirao A, et al. Metabolic regulation of osteoclast differentiation and function. J Bone Miner Res. 2013;28(11):2392–9. https://doi.org/10.1002/jbmr.1976.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Bredella MA, Torriani M, Ghomi RH, Thomas BJ, Brick DJ, Gerweck AV, et al. Vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 in obese women. Obesity (Silver Spring). 2011;19(1):49–53. https://doi.org/10.1038/oby.2010.106.

    CAS  Article  Google Scholar 

  80. 80.

    McCabe LR, Irwin R, Tekalur A, Evans C, Schepper JD. Exercise prevents high fat diet-induced bone loss , marrow adiposity and dysbiosis in male mice. Bone. 2019;118:20–31. https://doi.org/10.1016/j.bone.2018.03.024.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Devlin MJ, Cloutier AM, Thomas NA, Panus DA, Lotinun S, Pinz I, et al. Caloric restriction leads to high marrow adiposity and low bone mass in growing mice. J Bone Miner Res. 2010;25(9):2078–88. https://doi.org/10.1002/jbmr.82.

    Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Bredella MA. Perspective: the bone-fat connection. Skelet Radiol. 2010;39(8):729–31. https://doi.org/10.1007/s00256-010-0936-y.

    Article  Google Scholar 

  83. 83.

    Amrein K, Amrein S, Drexler C, Dimai HP, Dobnig H, Pfeifer K, et al. Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J Clin Endocrinol Metab. 2012;97(1):148–54. https://doi.org/10.1210/jc.2011-2152.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Lavet C, Martin A, Linossier MT, Bossche AV, Laroche N, Thomas M, et al. Fat and sucrose intake induces obesity-related bone metabolism disturbances: kinetic and reversibility studies in growing and adult rats. J Bone Miner Res. 2016;31(1):98–115. https://doi.org/10.1002/jbmr.2596.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Heinonen S, Saarinen L, Naukkarinen J, Rodriguez A, Fruhbeck G, Hakkarainen A, et al. Adipocyte morphology and implications for metabolic derangements in acquired obesity. Int J Obes. 2014;38(11):1423–31. https://doi.org/10.1038/ijo.2014.31.

    CAS  Article  Google Scholar 

  86. 86.

    Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, et al. Dynamics of fat cell turnover in humans. Nature. 2008;453(7196):783–7. https://doi.org/10.1038/nature06902.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Nishino N, Tamori Y, Tateya S, Kawaguchi T, Shibakusa T, Mizunoya W, et al. FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J Clin Investig. 2008;118(8):2808–21. https://doi.org/10.1172/JCI34090.

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Fazeli PK, Bredella MA, Freedman L, Thomas BJ, Breggia A, Meenaghan E, et al. Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa. J Bone Miner Res. 2012;27(9):1864–71. https://doi.org/10.1002/jbmr.1640.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Pontzer H. Constrained total energy expenditure and the evolutionary biology of energy balance. Exerc Sport Sci Rev. 2015;43(3):110–6. https://doi.org/10.1249/JES.0000000000000048.

    Article  PubMed  Google Scholar 

  90. 90.

    Pontzer H. Energy constraint as a novel mechanism linking exercise and health. Physiology. 2018;33(6):384–93. https://doi.org/10.1152/physiol.00027.2018.

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Cordes C, Dieckmeyer M, Ott B, Shen J, Ruschke S, Settles M, et al. MR-detected changes in liver fat, abdominal fat, and vertebral bone marrow fat after a four-week calorie restriction in obese women. J Magn Reson Imaging. 2015;42(5):1272–80. https://doi.org/10.1002/jmri.24908.

    Article  PubMed  Google Scholar 

  92. 92.

    Bredella MA, Fazeli PK, Miller KK, Misra M, Torriani M, Thomas BJ, et al. Increased bone marrow fat in anorexia nervosa. J Clin Endocrinol Metab. 2009;94(6):2129–36. https://doi.org/10.1210/jc.2008-2532.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Cao JJ. Caloric restriction combined with exercise is effective in reducing adiposity and mitigating bone structural deterioration in obese rats. Ann N Y Acad Sci. 2018;1433(1):41–52. https://doi.org/10.1111/nyas.13936.

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Styner M, Pagnotti GM, Galior K, Wu X, Thompson WR, Uzer G, et al. Exercise regulation of marrow fat in the setting of PPARgamma agonist treatment in female C57BL/6 mice. Endocrinology. 2015;156(8):2753–61. https://doi.org/10.1210/en.2015-1213.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Ko FC, Martins JS, Reddy P, Bragdon B, Hussein AI, Gerstenfeld LC, et al. Acute phosphate restriction impairs bone formation and increases marrow adipose tissue in growing mice. J Bone Miner Res. 2016;31(12):2204–14. https://doi.org/10.1002/jbmr.2891.

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Lips P, Van Schoor NM. The effect of vitamin D on bone and osteoporosis. Best Pract Res Clin Endocrinol Metab. 2011;25(4):585–91. https://doi.org/10.1016/j.beem.2011.05.002.

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Zofkova I, Davis M, Blahos J. Trace elements have beneficial, as well as detrimental effects on bone homeostasis. Physiol Res. 2017;66(3):391–402. https://doi.org/10.33549/physiolres.933454.

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Price CT, Langford JR, Liporace FA. Essential nutrients for bone health and a review of their availability in the average North American diet. Open Orthop J. 2012;6(1):143–9. https://doi.org/10.2174/1874325001206010143.

    Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Ozcivici E, Luu YK, Adler B, Qin YX, Rubin J, Judex S, et al. Mechanical signals as anabolic agents in bone. Nat Rev Rheumatol. 2010;6(1):50–9. https://doi.org/10.1038/nrrheum.2009.239.Mechanical.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Rubin C, Lanyon L. Regulation of bone formation by applied dynamic loads. J Bone Joint Surg. 1984;66A:397–402.

    Article  Google Scholar 

  101. 101.

    Rubin C, Turner AS, Bain S, Mallinckrodt C, McLeod K. Low mechanical signals strengthen long bones. Nature. 2001;412(6847):603–4. https://doi.org/10.1038/35088119.

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Rubin J. Regulation of skeletal remodeling by biomechanical input. Osteoporos Int. 2003;14(Suppl 5):S43–S5. https://doi.org/10.1007/s00198-003-1472-6.

    Article  PubMed  Google Scholar 

  103. 103.

    Thompson WR, Rubin CT, Rubin J. Mechanical regulation of signaling pathways in bone. Gene. 2012;503(2):179–93. https://doi.org/10.1038/jid.2014.371.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Phu S, Bani Hassan E, Vogrin S, Kirk B, Duque G. Effect of denosumab on falls, muscle strength, and function in community-dwelling older adults. J Am Geriatr Soc. 2019;67(12):2660–1. https://doi.org/10.1111/jgs.16165.

    Article  PubMed  Google Scholar 

  105. 105.

    Gross TS, Rubin CT. Uniformity of resorptive bone loss induced by disuse. J Orthop Res. 1995;13(5):708–14. https://doi.org/10.1002/jor.1100130510.

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Judex S, Garman R, Squire M, Busa B, Donahue LR, Rubin C. Genetically linked site-specificity of disuse osteoporosis. J Bone Miner Res. 2004;19(4):607–13. https://doi.org/10.1359/JBMR.040110.

    Article  PubMed  Google Scholar 

  107. 107.

    Jee S, Wronski E, Morey J, Kimmel D. Effects of spaceflight on trabecular bone in rats. Am J Phys. 1983;244:4310–4.

    Google Scholar 

  108. 108.

    Hino K, Nifuji A, Morinobu M, Tsuji K, Ezura Y, Nakashima K, et al. Unloading-induced bone loss was suppressed in gold-thioglucose treated mice. J Cell Biochem. 2006;99(3):845–52. https://doi.org/10.1002/jcb.20935.

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Keune JA, Wong CP, Br AJ, Iwaniec UT, Turner RT. Bone marrow adipose tissue deficiency increases disuse-induced bone loss in male mice. Sci Rep. 2017;7(46325). doi:https://doi.org/10.1038/srep46325.

  110. 110.

    Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 2007;5(6):464–75. https://doi.org/10.1016/j.cmet.2007.05.001.

    CAS  Article  Google Scholar 

  111. 111.

    Aguirre JI, Plotkin LI, Stewart SA, Weinstein RS, Parfitt AM, Manolagas SC, et al. Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss. J Bone Miner Res. 2006;21(4):605–15. https://doi.org/10.1359/jbmr.060107.

    Article  PubMed  Google Scholar 

  112. 112.

    Iwaniec UT, Philbrick KA, Wong CP, Gordon JL, Kahler-Quesada AM, Olson DA, et al. Room temperature housing results in premature cancellous bone loss in growing female mice: implications for the mouse as a preclinical model for age-related bone loss. Osteoporos Int. 2016;27(10):3091–101. https://doi.org/10.1007/s00198-016-3634-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    LeBlanc A, Schneider V, Shackelford L, West S, Oganov V, Bakulin A, et al. Bone mineral and lean tissue loss after long duration space flight. J Musculoskelet Neuronal Interact. 2000;1(2):157–60.

    CAS  PubMed  Google Scholar 

  114. 114.

    Lang T, Leblanc A, Evans H, Lu Y, Genant H, Yu A. Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight. J Bone Miner Res. 2004;19(6). doi:https://doi.org/10.1359/JBMR.040307.

  115. 115.

    Trudel G, Payne M, Madler B, Ramachandran N, Lecompte M, Wade C, et al. Bone marrow fat accumulation after 60 days of bed rest persisted 1 year after activities were resumed along with hemopoietic stimulation: the Women International Space Simulation for Exploration study. J Appl Physiol. 2009;107(2):540–8. https://doi.org/10.1152/japplphysiol.91530.2008.

    Article  PubMed  Google Scholar 

  116. 116.

    Trudel G, Coletta E, Cameron I, Belavy DL, Lecompte M, Armbrecht G, et al. Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men. J Appl Physiol. 2012;112(11):1824–31. https://doi.org/10.1152/japplphysiol.00029.2012.

    Article  PubMed  Google Scholar 

  117. 117.

    Ambrosi TH, Scialdone A, Graja A, Saraiva LR, Schulz TJ. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell. 2017;20:771–84. https://doi.org/10.1016/j.stem.2017.02.009.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Hinton PS, Nigh P, Thyfault J. Effectiveness of resistance training or jumping-exercise to increase bone mineral density in men with low bone mass: a 12-month randomized, clinical trial. Bone. 2015;79:203–12. https://doi.org/10.1016/j.bone.2015.06.008.

    Article  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Hinton PS, Shankar K, Eaton LM, Rector RS. Obesity-related changes in bone structural and material properties in hyperphagic OLETF rats and protection by voluntary wheel running. Metab Clin Exp. 2015;64(8):905–16. https://doi.org/10.1016/j.metabol.2015.04.004.

    CAS  Article  PubMed  Google Scholar 

  120. 120.

    Newhall KM, Rodnick KJ, van der Meulen MC, Carter DR, Marcus R. Effects of voluntary exercise on bone mineral content in rats. J Bone Miner Res. 1991;6(3):289–96.

    CAS  Article  Google Scholar 

  121. 121.

    Hamann N, Kohler T, Müller R, Brüggemann GP, Niehoff A. The effect of level and downhill running on cortical and trabecular bone in growing rats. Calcif Tissue Int. 2012;90(5):429–37. https://doi.org/10.1007/s00223-012-9593-6.

    CAS  Article  PubMed  Google Scholar 

  122. 122.

    Tamakoshi K, Nishii Y, Minematsu A. Upward running is more beneficial than level surface or downslope running in reverting tibia bone degeneration in ovariectomized rats. J Musculoskelet Neuronal Interact. 2018;18(4):493–500.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Gregor RJ, Smith DW, Prilutsky BI. Mechanics of slope walking in the cat: quantification of muscle load, length change, and ankle extensor EMG patterns. J Neurophysiol. 2006;95(3):1397–409. https://doi.org/10.1152/jn.01300.2004.

    Article  PubMed  Google Scholar 

  124. 124.

    Wallace IJ, Pagnotti GM, Rubin-Sigler J, Naeher M, Copes LE, Judex S, et al. Focal enhancement of the skeleton to exercise correlates with responsivity of bone marrow mesenchymal stem cells rather than peak external forces. J Exp Biol. 2015;218(19):3002–9. https://doi.org/10.1242/jeb.118729.

    Article  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Huang TH, Su IH, Lewis JL, Chang MS, Hsu AT, Perrone CE, et al. Effects of methionine restriction and endurance exercise on bones of ovariectomized rats: a study of histomorphometry, densitometry, and biomechanical properties. J Appl Physiol. 2015;119(5):517–26. https://doi.org/10.1152/japplphysiol.00395.2015.

    CAS  Article  PubMed  Google Scholar 

  126. 126.

    Baker JM, De Lisio M, Parise G. Endurance exercise training promotes medullary hematopoiesis. FASEB J. 2011;25(12):4348–57. https://doi.org/10.1096/fj.11-189043.

    CAS  Article  PubMed  Google Scholar 

  127. 127.

    Yuasa Y, Miyakoshi N, Kasukawa Y, Nagahata I, Akagawa M, Ono Y, et al. Effects of bazedoxifene and low-intensity aerobic exercise on bone and fat parameters in ovariectomized rats. J Bone Miner Metab. 2020;38(2):179–87. https://doi.org/10.1007/s00774-019-01045-5.

    CAS  Article  PubMed  Google Scholar 

  128. 128.

    Bertheau RC, Lorbeer R, Nattenmuller J, Wintermeyer E, Machann J, Linkohr B, et al. Bone marrow fat fraction assessment in regard to physical activity: KORA FF4-3-T MR imaging in a population-based cohort. Eur Radiol. 2020;30(6):3417–28. https://doi.org/10.1007/s00330-019-06612-y.

    CAS  Article  PubMed  Google Scholar 

  129. 129.

    Belavy DL, Quittner MJ, Ridgers ND, Shiekh A, Rantalainen T, Trudel G. Specific modulation of vertebral marrow adipose tissue by physical activity. J Bone Miner Res. 2018;33(4):651–7. https://doi.org/10.1002/jbmr.3357.

    CAS  Article  PubMed  Google Scholar 

  130. 130.

    Mori T, Okimoto N, Sakai A, Okazaki Y, Nakura N, Notomi T, et al. Climbing exercise increases bone mass and trabecular bone turnover through transient regulation of marrow osteogenic and osteoclastogenic potentials in mice. J Bone Miner Res. 2003;18(11):2002–9. https://doi.org/10.1359/jbmr.2003.18.11.2002.

    Article  PubMed  Google Scholar 

  131. 131.

    Gomes RM, Junior MDF, Francisco FA, Moreira VM, de Almeida DL, Saavedra LPJ, et al. Strength training reverses ovariectomy-induced bone loss and improve metabolic parameters in female Wistar rats. Life Sci. 2018;213(October):134–41. https://doi.org/10.1016/j.lfs.2018.10.032.

    CAS  Article  PubMed  Google Scholar 

  132. 132.

    Singulani MP, Stringhetta-Garcia CT, Santos LF, Morais SR, Louzada MJ, Oliveira SH, et al. Effects of strength training on osteogenic differentiation and bone strength in aging female Wistar rats. Sci Rep. 2017;7(February):42878. https://doi.org/10.1038/srep42878.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Swift JM, Gasier HG, Swift SN, Wiggs MP, Hogan HA, Fluckey JD, et al. Increased training loads do not magnify cancellous bone gains with rodent jump resistance exercise. J Appl Physiol. 2010;109(6):1600–7. https://doi.org/10.1152/japplphysiol.00596.2010.

    CAS  Article  PubMed  Google Scholar 

  134. 134.

    Marín-Cascales E, Alcaraz PE, Ramos-Campo DJ, Rubio-Arias JA. Effects of multicomponent training on lean and bone mass in postmenopausal and older women: a systematic review. Menopause. 2018;25(3):346–56. https://doi.org/10.1097/GME.0000000000000975.

    Article  PubMed  Google Scholar 

  135. 135.

    Sañudo B, De Hoyo M, Del Pozo-Cruz J, Carrasco L, Del Pozo-Cruz B, Tejero S, et al. A systematic review of the exercise effect on bone health: the importance of assessing mechanical loading in perimenopausal and postmenopausal women. Menopause. 2017;24(10):1208–16. https://doi.org/10.1097/GME.0000000000000872.

    Article  PubMed  Google Scholar 

  136. 136.

    Lambert C, Beck BR, Harding AT, Watson SL, Weeks BK. Regional changes in indices of bone strength of upper and lower limbs in response to high-intensity impact loading or high-intensity resistance training. Bone. 2020;132(July 2019):115192. https://doi.org/10.1016/j.bone.2019.115192.

    Article  PubMed  Google Scholar 

  137. 137.

    •• Harding AT, Weeks BK, Lambert C, Watson SL, Weis LJ, Beck BR. A comparison of bone-targeted exercise strategies to reduce fracture risk in middle-aged and older men with osteopenia and osteoporosis: LIFTMOR-M Semi-Randomized Controlled Trial. J Bone Miner Res. 2020;35(8):1404–14. https://doi.org/10.1002/jbmr.4008Older men with low bone mass participating in an 8-month high-intensity resistance and impact training program significantly improved lumbar spine and femoral neck BMD, as well as cortical thickness at the femoral neck, proving the safety and efficacy of strength training for osteoporosis prevention.

    Article  PubMed  Google Scholar 

  138. 138.

    Watson SL, Weeks BK, Weis LJ, Harding AT, Horan SA, Beck BR. High-intensity resistance and impact training improves bone mineral density and physical function in postmenopausal women with osteopenia and osteoporosis: the LIFTMOR randomized controlled trial. J Bone Miner Res. 2018;33(2):211–20. https://doi.org/10.1002/jbmr.3284.

    Article  PubMed  Google Scholar 

  139. 139.

    Krishnamoorthy D, Frechette DM, Adler BJ, Green DE, Chan ME, Rubin CT. Marrow adipogenesis and bone loss that parallels estrogen deficiency is slowed by low-intensity mechanical signals. Osteoporos Int. 2016;27(2):747–56. https://doi.org/10.1007/s00198-015-3289-5.

    CAS  Article  PubMed  Google Scholar 

  140. 140.

    Ma R, Zhu D, Gong H, Gu G, Huang X, Gao JZ, et al. High-frequency and low-magnitude whole body vibration with rest days is more effective in improving skeletal micro-morphology and biomechanical properties in ovariectomised rodents. Hip Int. 2012;22(2):218–26. https://doi.org/10.5301/HIP.2012.9033.

    Article  PubMed  Google Scholar 

  141. 141.

    Rubin CT, Capilla E, Luu YK, Busa B, Crawford H, Nolan DJ, et al. Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals. Proc Natl Acad Sci U S A. 2007;104(45):17879–84. https://doi.org/10.1073/pnas.0708467104.

    Article  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Styner M, Sen B, Xie Z, Case N, Rubin J. Indomethacin promotes adipogenesis of mesenchymal stem cells through a cyclooxygenase independent mechanism. J Cell Biochem. 2010;111(4):1042–50. https://doi.org/10.1002/jcb.22793.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Gong H, Zhang R, Gao J, Zhang M, Liu B, Zhang M, et al. Whole body vibration with rest days could improve bone quality of distal femoral metaphysis by regulating trabecular arrangement. Sci China Life Sci. 2019;62(1):95–103. https://doi.org/10.1007/s11427-017-9253-x.

    CAS  Article  PubMed  Google Scholar 

  144. 144.

    Zhang T, Gao J, Fang J, Gong H. Multiscale investigation on the effects of additional weight bearing in combination with low-magnitude high-frequency vibration on bone quality of growing female rats. J Bone Miner Metab. 2018;36(2):157–69. https://doi.org/10.1007/s00774-017-0827-6.

    Article  PubMed  Google Scholar 

  145. 145.

    Judex S, Lei X, Han D, Rubin C. Low-magnitude mechanical signals that stimulate bone formation in the ovariectomized rat are dependent on the applied frequency but not on the strain magnitude. J Biomech. 2007;40(6):1333–9. https://doi.org/10.1016/j.jbiomech.2006.05.014.

    Article  PubMed  Google Scholar 

  146. 146.

    Luo X, Zhang J, Zhang C, He C, Wang P. The effect of whole-body vibration therapy on bone metabolism, motor function, and anthropometric parameters in women with postmenopausal osteoporosis. Disabil Rehabil. 2017;39(22):2315–23. https://doi.org/10.1080/09638288.2016.1226417.

    Article  PubMed  Google Scholar 

  147. 147.

    Rubin C, Recker R, Cullen D, Ryaby J, McCabe J, McLeod K. Prevention of postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J Bone Miner Res. 2004;19(3):343–51. https://doi.org/10.1359/JBMR.0301251.

    Article  PubMed  Google Scholar 

  148. 148.

    Kiel DP, Hannan MT, Barton BA, Bouxsein ML, Sisson E, Lang T, et al. Low-magnitude mechanical stimulation to improve bone density in persons of advanced age: a randomized, placebo-controlled trial. J Bone Miner Res. 2015;30(7):1319–28. https://doi.org/10.1002/jbmr.2448.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Slatkovska L, Alibhai SMH, Beyene J, Hu H, Demaras A, Cheung AM. Effect of 12 months of whole-body vibration therapy on bone density and structure in postmenopausal women: a randomized trial. Ann Intern Med. 2011;155(10):668–79. https://doi.org/10.7326/0003-4819-155-10-201111150-00005.

    Article  PubMed  Google Scholar 

  150. 150.

    Gilsanz V, Wren TA, Sanchez M, Dorey F, Judex S, Rubin C. Low-level, high-frequency mechanical signals enhance musculoskeletal development of young women with low BMD. J Bone Miner Res. 2006;21(9):1464–74. https://doi.org/10.1359/jbmr.060612.

    Article  PubMed  Google Scholar 

  151. 151.

    Ward K, Alsop C, Caulton J, Rubin C, Adams J, Mughal Z. Low magnitude mechanical loading is osteogenic in children with disabling conditions. J Bone Miner Res. 2004;19(3):360–9. https://doi.org/10.1359/JBMR.040129.

    Article  PubMed  Google Scholar 

  152. 152.

    Mogil RJ, Kaste SC, Ferry RJ, Hudson MM, Mulrooney DA, Howell CR, et al. Effect of low-magnitude, high-frequency mechanical stimulation on BMD among young childhood cancer survivors a randomized clinical trial. JAMA Oncol. 2016;2(7):908–14. https://doi.org/10.1001/jamaoncol.2015.6557.

    Article  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Sen B, Xie Z, Case N, Styner M, Rubin CT, Rubin J. Mechanical signal influence on mesenchymal stem cell fate is enhanced by incorporation of refractory periods into the loading regimen. J Biomech. 2011;44(4):593–9. https://doi.org/10.1038/jid.2014.371.

    CAS  Article  PubMed  Google Scholar 

  154. 154.

    Styner M, Meyer MB, Galior K, Case N, Xie Z, Sen B, et al. Mechanical strain downregulates C/EBPbeta in MSC and decreases endoplasmic reticulum stress. PLoS One. 2012;7(12):e51613. https://doi.org/10.1371/journal.pone.0051613.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155.

    David V, Martin A, Lafage-Proust MH, Malaval L, Peyroche S, Jones DB, et al. Mechanical loading down-regulates peroxisome proliferator-activated receptor γ in bone marrow stromal cells and favors osteoblastogenesis at the expense of adipogenesis. Endocrinology. 2007;148(5):2553–62. https://doi.org/10.1210/en.2006-1704.

    CAS  Article  PubMed  Google Scholar 

  156. 156.

    Sen B, Xie Z, Case N, Ma M, Rubin C, Rubin J. Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable β-catenin signal. Endocrinology. 2008;149(12):6065–75. https://doi.org/10.1210/en.2008-0687.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Sen B, Paradise CR, Xie Z, Sankaran J, Uzer G, Styner M, et al. β-Catenin preserves the stem state of murine bone marrow stromal cells through activation of EZH2. J Bone Miner Res Off J Am Soc Bone Miner Res. 2020. https://doi.org/10.1002/jbmr.3975.

  158. 158.

    Nedergaard A, Henriksen K, Karsdal MA, Christiansen C. Musculoskeletal ageing and primary prevention. Best Pract Res Clin Obstet Gynaecol. 2013;27(5):673–88. https://doi.org/10.1016/j.bpobgyn.2013.06.001.

    Article  PubMed  Google Scholar 

  159. 159.

    Brown M. Skeletal muscle and bone: effect of sex steroids and aging. Am J Physiol Adv Physiol Educ. 2008;32(2):120–6. https://doi.org/10.1152/advan.90111.2008.

    Article  Google Scholar 

  160. 160.

    Syed FA, Oursler MJ, Hefferanm TE, Peterson JM, Riggs BL, Khosla S. Effects of estrogen therapy on bone marrow adipocytes in postmenopausal osteoporotic women. Osteoporos Int. 2008;19(9):1323–30. https://doi.org/10.1007/s00198-008-0574-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab. 2012;23(11):576–81. https://doi.org/10.1016/j.japh.2018.02.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Clarke BL, Khosla S. Androgens and bone. Steroids. 2009;74(3):296–305. https://doi.org/10.1385/1-59259-388-7:221.

    CAS  Article  PubMed  Google Scholar 

  163. 163.

    Mistry SD, Woods GN, Sigurdsson S, Ewing SK, Hue TF, Eiriksdottir G, et al. Sex hormones are negatively associated with vertebral bone marrow fat. Bone. 2018;108(1):20–4. https://doi.org/10.1016/j.bone.2017.12.009.

    CAS  Article  PubMed  Google Scholar 

  164. 164.

    Gavin KM, Sullivan TM, Kohrt WM, Majka SM, Klemm DJ. Ovarian hormones regulate the production of adipocytes from bone marrow-derived cells. Front Endocrinol (Lausanne). 2018;9(MAY):276. https://doi.org/10.3389/fendo.2018.00276.

    Article  Google Scholar 

  165. 165.

    Wright LE, Harhash AA, Kozlow WM, Waning DL, Regan JN, She Y, et al. Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo. Oncotarget. 2017;8(5):8406–19. https://doi.org/10.18632/oncotarget.14139.

    Article  PubMed  Google Scholar 

  166. 166.

    Cawthorn WP, Scheller EL, Parlee SD, Pham HA, Learman BS, Redshaw CM, et al. Expansion of bone marrow adipose tissue during caloric restriction is associated with increased circulating glucocorticoids and not with hypoleptinemia. Endocrinology. 2016;157(2):508–21. https://doi.org/10.1210/en.2015-1477.

    CAS  Article  PubMed  Google Scholar 

  167. 167.

    Khosla S. Leptin-central or peripheral to the regulation of bone metabolism? Endocrinology. 2002;143(11):4161–4. https://doi.org/10.1210/en.2002-220843.

    CAS  Article  PubMed  Google Scholar 

  168. 168.

    Devlin MJ, Brooks DJ, Conlon C, Vliet M, Louis L, Rosen CJ, et al. Daily leptin blunts marrow fat but does not impact bone mass in calorie-restricted mice. J Endocrinol. 2016;229(3):295–306. https://doi.org/10.1530/JOE-15-0473.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Ackert-Bicknell CL, Shockley KR, Horton LG, Lecka-Czernik B, Churchill GA, Rosen CJ. Strain-specific effects of rosiglitazone on bone mass, body composition, and serum insulin-like growth factor-I. Endocrinology. 2009;150(3):1330–40. https://doi.org/10.1210/en.2008-0936.

    CAS  Article  PubMed  Google Scholar 

  170. 170.

    Clemmons DR. Role of IGF-binding proteins in regulating IGF responses to changes in metabolism. J Mol Endocrinol. 2018;61(1):T139–T69. https://doi.org/10.1530/JME-18-0016.

    CAS  Article  PubMed  Google Scholar 

  171. 171.

    Tian F, Wang Y, Bikle DD. IGF-1 signaling mediated cell-specific skeletal mechano-transduction. J Orthop Res. 2018;36(2):576–83. https://doi.org/10.1002/jor.23767.

    CAS  Article  PubMed  Google Scholar 

  172. 172.

    Xi G, Shen X, Rosen CJ, Clemmons DR. IRS-1 functions as a molecular scaffold to coordinate IGF-I/IGFBP-2 signaling during osteoblast differentiation. J Bone Miner Res Off J Am Soc Bone Miner Res. 2016;31(6):1300–14. https://doi.org/10.1002/jbmr.2791.

    CAS  Article  Google Scholar 

  173. 173.

    Diedrich JD, Rajagurubandara E, Herroon MK, Mahapatra G, Hüttemann M, Podgorski I. Bone marrow adipocytes promote the warburg phenotype in metastatic prostate tumors via HIF-1α activation. Oncotarget. 2016;7(40):64854–77. https://doi.org/10.18632/oncotarget.11712.

    Article  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Morris EV, Edwards CM. Bone marrow adipose tissue: a new player in cancer metastasis to bone. Front Endocrinol (Lausanne). 2016;7(JUL):90. https://doi.org/10.3389/fendo.2016.00090.

    Article  Google Scholar 

  175. 175.

    Luo G, He Y, Yu X. Bone marrow adipocyte: an intimate partner with tumor cells in bone metastasis. Front Endocrinol (Lausanne). 2018;9(JUL):339. https://doi.org/10.3389/fendo.2018.00339.

    Article  Google Scholar 

  176. 176.

    Diedrich JD, Herroon MK, Rajagurubandara E, Podgorski I. The lipid side of bone marrow adipocytes: how tumor cells adapt and survive in bone. Curr Osteoporos Rep. 2018;16(4):443–57. https://doi.org/10.1007/s11914-018-0453-9.

    Article  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Reagan MR. Critical assessment of in vitro and in vivo models to study marrow adipose tissue. Curr Osteoporos Rep. 2020;18(2):85–94. https://doi.org/10.1007/s11914-020-00569-4.

    Article  PubMed  Google Scholar 

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Funding

This review was supported by funds from the NIH/NIAMS R01AR073264 and NIH/NCATS KL2TR002490.

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Correspondence to Sarah E. Little-Letsinger.

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Little-Letsinger, S.E., Pagnotti, G.M., McGrath, C. et al. Exercise and Diet: Uncovering Prospective Mediators of Skeletal Fragility in Bone and Marrow Adipose Tissue. Curr Osteoporos Rep 18, 774–789 (2020). https://doi.org/10.1007/s11914-020-00634-y

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Keywords

  • Mesenchymal stem cell (MSC)
  • Marrow adipose tissue (MAT)
  • Exercise
  • Bone marrow cells
  • Caloric restriction