Review

Nature Clinical Practice Rheumatology (2006) 2, 35-43
doi:10.1038/ncprheum0070  
Received 10 August 2005 | Accepted 29 September 2005

Mechanisms of Disease: is osteoporosis the obesity of bone?

Clifford J Rosen* and Mary L Bouxsein  About the authors

Correspondence *St Joseph Hospital, The Maine Center for Osteoporosis Research and Education, 360 Broadway, Bangor, ME 04401, USA

Email rofe@aol.com

Summary

Osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Interestingly, these diseases share several features including a genetic predisposition and a common progenitor cell. With aging, the composition of bone marrow shifts to favor the presence of adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. Secondary causes of osteoporosis, including diabetes mellitus, glucocorticoids and immobility, are associated with bone-marrow adiposity. In this review, we ask a provocative question: does fat infiltration in the bone marrow cause low bone mass or is it a result of bone loss? Unraveling the interface between bone and fat at a molecular and cellular level is likely to lead to a better understanding of several diseases, and to the development of drugs for both osteoporosis and obesity.

Review criteria

"Fat" and "bone" were the key search words for PubMed. All papers dating back to 1970 were examined. After "fat" and "bone", "osteoporosis" and "obesity" were used, followed by "adiposity" and "osteoblasts". Abstracts and papers were included, and both English-language and foreign-language manuscripts were noted.

Keywords:

adipocyte, bone, fat, obesity, osteoporosis

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Introduction

Two public health problems have exploded in prevalence over the past decade: osteoporosis and obesity. These disorders, once thought to be mutually exclusive, share several features and present an array of challenges to clinicians: both diseases are have a genetic basis and distinct environmental influences; both begin early in life, although the complete phenotypic presentation can take decades to be manifested; both are associated with significant morbidity and mortality; and both can be traced to dysregulation of a common precursor cell. Recently, a thorough examination of the fat–bone connection has begun, at both the molecular and clinical level. This reassessment has raised several fundamental questions. What are the systemic regulators of the fat–bone interface in the bone marrow? Does fat infiltration cause bone loss or does fat just fill the medullary space where bone once was? Are metabolism and bone mass both centrally regulated? Can osteoporosis be considered the obesity of bone? This review summarizes the evidence for and against the concept that skeletal fragility has its pathogenic roots in pleuripotent marrow stromal cells and their fate as either fat or bone cells.

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Pathogenesis of osteoporosis

Osteoporosis is a disorder characterized by enhanced skeletal fragility due to a reduction in both bone quantity and quality.1 The syndrome includes the triad of back pain, fractures without significant trauma (commonly at the spine, hip, distal radius, and proximal humerus) and low bone mineral density (BMD)1. Genetic factors account for 60–80% of the variation in adult bone mass,2 despite the fact that BMD in adults reflects the extent of bone acquisition during growth (i.e. peak bone mass) and the subsequent rate of bone loss. The majority of bone mass acquisition occurs between the ages of 12 and 18 years, when there is a critical convergence of hormonal and environmental influences interacting with an array of genes to enhance linear growth and skeletal expansion, principally by stimulating bone formation.3 Any disorder that alters bone formation, enhances bone resorption or changes the sequence of hormonal influences during this period (e.g. anorexia nervosa, growth-hormone insufficiency, delayed puberty, amenorrhea) will lead to lower peak bone mass and presumably a greater risk of fracture later in life.1 Importantly, fractures in childhood have been associated with alterations in body composition (such as increased adiposity) and bone structure, suggesting these may be the earliest signs of skeletal insufficiency.4 By about the fifth decade of life, a process of inexorable bone loss begins in both men and women, as bone resorption outpaces formation.5 Processes that accelerate osteoclast activation, such as menopause or glucocorticoid use, can further enhance the risk of fragility and fractures. Moreover, osteoblast function declines late in life, further exaggerating the imbalance between bone resorption and formation6. In summary, there is a delicate balance between resorption and formation such that perturbations in either process can result in reduced bone mass, altered bone architecture and a greater propensity for fracture. The timing of these alterations is critical for defining their ultimate impact on skeletal status.

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Fat–bone interactions: cellular and molecular studies

The bone remodeling unit is composed of bone-forming osteoblasts, bone-resorbing osteoclasts, and osteocytes, former osteoblasts entombed within the bone matrix. This basic physiologic unit is strategically close to stromal elements of the marrow as well as the microvascular supply.7 Osteoclasts originate from hematopoietic precursors in the circulation and bone marrow, while osteoblasts are derived from bone-marrow mesenchymal stem cells (MSCs).7, 8, 9 The differentiation of these two cell lines within this milieu is coordinated during active bone remodeling, in part because MSCs are the source of a variety of cytokines that influence osteoclast differentiation. As outlined in Figure 1, macrophage and their monocytic precursors become osteoclasts under the influence of two stromal-derived cytokines, macrophage colony-stimulating factor and receptor activator of nuclear factor KB ligand (RANKL, also known as tumor necrosis factor ligand superfamily, member 11).8

Figure 1 Lineage allocation in the bone-marrow milieu.
Figure 1 : Lineage allocation in the bone-marrow milieu. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

For a mesenchymal stem cell to become an osteoblast, activation of several key factors such as runt-related transcription factor 2, bone morphogenetic protein 2, transforming growth factor-beta, and transcription factor Sp7 (osterix), are necessary, although the precise sequence of events in this cascade has not been fully clarified. In contrast, to achieve full adipocytic differentiation, there are two groups of critical factors already present in mesenchymal stem cells that need to be activated: CCAAT/enhancer binding proteins alpha, beta and delta, and peroxisome proliferative activated receptors alpha, gamma2 and delta.54 Peroxisome proliferative activated receptor gamma2 activation by endogenous (e.g. prostaglandin J2, long chain and oxidized fatty acids) or exogenous (e.g. rosiglitazone) ligands dramatically shifts allocation of mesenchymal stem cells towards the adipocytic pathway and away from the osteoblast lineage.9, 55 In vitro, this shift is characterized as an 'either/or' allocation; either the cell becomes a fat cell or it becomes a bone cell, but not both.56, 57 Inflammatory cytokines can be released from adipocytes, and circulating hormones such as leptin, adipsin, adiponectin and resistin are also produced by fat cells. The solid arrows represent confirmed networks for regulation and the dashed arrows represent potential regulatory pathways. BMP, bone morphogenetic protein; CEBP, CAAT/enhancer binding proteins; DLX, distal-less homeobox; HSC, hematopoietic stem cell; IGF, insulin-like growth factor; IGFR, insulin-like growth factor receptor; IL, interleukin; MCSF, macrophage colony stimulating factor; MSX, MSH homeobox homolog; OPG, osteoprotegerin (tumor necrosis factor ligand superfamily, member 11); PPAR, peroxisome proliferative activated receptors; RANK, receptor activator of nuclear transcription factor kappaB (tumor necrosis factor receptor superfamily, member 11a); RANKL, receptor activator of nuclear transcription factor kappaB ligand (tumor necrosis factor receptor superfamily, member 11); RUNX, runt-related transcription factor; TGF, transforming growth factor.

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Pluripotent bone-marrow MSCs become osteoblasts under the influence of several cell-derived transcription factors. These differentiation 'switches' control MSC fate as they enter the bone lineage. Other factors permit stromal cells to differentiate into adipocytes or hematopoietic supporting cells (Figure 1).9 In vivo, this process is complex, suggesting significant plasticity between adipocytes and osteoblasts.9 Adipocytes are not inert; rather, these cells secrete endocrine and paracrine factors that strongly influence neighboring cell function and distant activities. In particular, fat cells express the cytochrome P450 enzyme, aromatase, which can generate estradiol from testosterone. Products from this conversion restrain osteoclastogenesis within the marrow milieu, and partially explain why increased body weight in postmenopausal women is associated with slower rates of bone loss.9, 10, 11 Other factors secreted by adipocytes, including leptin, adiponectin, and adipsin, as well as proinflammatory cytokines, such as tumor necrosis factor and interleukin-6, can also affect bone remodeling.9

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Fat–bone interactions: animal models

Leptin

Seminal studies by Ducy and colleagues12 and Takeda et al.13 demonstrated that bone mass is influenced by the fat-derived hormone leptin via the sympathetic nervous system, prompting increased attention on the interaction between bone and fat. Initially, Ducy et al.12 showed that obese mice deficient in leptin (ob/ob mice) or the signaling form of its receptor (db/db mice) have increased vertebral trabecular bone volume due to increased bone formation, despite having hypogonadism and hypercortisolism. Intracerebroventricular infusion of leptin in both ob/ob and wild-type mice decreased vertebral trabecular bone mass. Takeda et al.13 expanded on these observations, demonstrating that the effects of intracerebroventricular leptin are mediated by the sympathetic nervous system, that osteoblasts express beta-adrenergic receptors, and that administration of beta-adrenergic agonists decreases trabecular bone volume by inhibiting bone formation. Recent data demonstrate that enhanced sympathetic activity also promotes bone resorption.14

These findings contradict several lines of evidence suggesting that leptin directly promotes the differentiation of osteoblasts and affects bone resorption.14, 15, 16, 17 Similar to its effects on feeding and energy expenditure, the complex actions of leptin on bone can best be explained by its ability to act positively and directly on peripheral tissues, or negatively via central mechanisms involving activation of the sympathetic nervous system. The predominance of leptin's central versus peripheral effect on bone in obese mice still remains controversial18 and might ultimately depend upon heterogeneity in bone-marrow composition, the effects of leptin resistance at the hypothalamic level, and the degree of sympathetic innervation.19, 20

An obvious concern about interpreting animal models with altered body composition is that a variety of factors influencing the skeleton are affected simultaneously. For example, in addition to having higher leptin levels, obese animals often have reduced gonadal steroid production, increased levels of pancreatic beta-cell products, such as insulin, amylin, preptin and adrenomedullin, reduced sympathetic tone, and high levels of adipocyte-derived hormones and cytokines. Attributing the resultant skeletal phenotype to just one factor therefore becomes difficult. Moreover, the impact of these factors is likely to depend on the skeletal compartment (i.e. trabecular versus cortical bone). Observations from mice deficient in one or more adrenergic receptors exemplify this point. Mice deficient for all three beta-adrenergic receptors (i.e. beta-less) have increased body weight and fat mass, and exhibit greater total body bone mass, trabecular bone volume and femoral cross-sectional size compared with wild-type controls.20 Alternatively, in comparison with wild type controls, mice deficient for beta1-adrenergic and beta2-adrenergic receptors have slightly lower body weight, lower total body bone mass, no difference in trabecular bone volume and decreased femoral cross-sectional size.21 These findings demonstrate the complex nature of the interactions between altered body composition and sympathetic activity.

Peroxisome proliferative activated receptor bold gamma2

As noted in Figure 1, the nuclear receptor peroxisome proliferative activated receptor (PPAR) gamma2 is the dominant regulator of adipogenesis, and ligand activation of PPARgamma2 favors differentiation of MSCs into adipocytes rather than osteoblasts.11 Confirming the key role of MSC lineage allocation for the skeleton, Akune et al.22 showed that PPARgamma insufficiency led to increased osteoblastogenesis in vitro and higher trabecular bone volume in vivo. PPARgamma haploinsufficiency, however, had no effect on fully differentiated osteoblasts and osteoclasts. Furthermore, treatment of nondiabetic adult mice with rosiglitazone, an FDA-approved treatment for type II diabetes that improves insulin sensitivity by activating PPARgamma, led to a significant deterioration in trabecular architecture, a decrease in bone formation, and an increase in bone-marrow adiposity.23 Interestingly, aged mice exhibit adipocytic bone-marrow infiltration and enhanced expression of PPARgamma2 along with reduced mRNA expression of osteoblastic differentiation factors such as runt-related transcription factor 2.24 Mice with premature aging, the SAMP6 strain, also show nearly identical patterns of adipocyte infiltration with impaired osteoblastogenesis.25 Adipocytic marrow infiltration and enhanced PPARgamma2 expression was recently reported in insulinopenic diabetic mice.26 In summary, aging, or processes that accelerate aging, result in significant bone-marrow adiposity and a defect in osteoblastogenesis in mice.

Fat redistribution

Recently, we described a CONGENIC mouse that exhibited allelic suppression of skeletal and hepatic insulin-like growth factor 1, and markedly reduced trabecular bone mass.27 Interestingly, these mice have fatty infiltration of the marrow and liver, but are not obese.28 Bone formation is markedly reduced, as is the number of osteoblast progenitors, suggesting an arrest in differentiation of the osteoblast lineage with a subsequent shift towards adipocytic differentiation. The PPARgamma2 pathway is also activated in the bone marrow of these congenic mice, resulting in increased expression of multiple key factors including lipin 1, adiponectin, adipisin, sterol regulatory element binding factor 1, thyroid hormone responsive protein (THRSP, also known as SPOT14) and lipoprotein lipase.28 Data from this fascinating model suggest that fat redistribution, rather than generalized adiposity, might be a better indicator of impaired osteoblastogenesis. Thus, animal models (Table 1), particularly those produced through genetic engineering, have provided, and will continue to provide, insight into the fat–bone interface.

Table 1 Knockout and congenic mouse models used to study the interaction between fat, adrenergic signaling and bone.
Table 1 - Knockout and congenic mouse models used to study the interaction between fat, adrenergic signaling and bone.
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Fat–bone interactions: clinical observations

The link between body weight, bone mineral density and osteoporosis

A longstanding clinical theory has been that obese women do not get osteoporosis; however, some studies have challenged that tenet. DUAL-ENERGY X-RAY ABSORPTIOMETRY (DXA) has been widely used to study the relationship between BMD, body weight and body composition. Both cross-sectional and longitudinal studies in adults and children have shown that bone mass is positively related to body weight and BMI, although there is controversy as to whether lean mass or fat mass is the more important determinant of BMD.29, 30 The positive association between body weight and bone mass might be attributable to several possible mechanisms: higher body weight increases mechanical loading on the skeleton, particularly the cortical elements; the association of fat mass with the secretion of bone-active hormones from the pancreatic beta-cell (i.e. insulin, amylin, resistin and preptin); and secretion of bone-active factors from adipocytes (i.e. estrogen, leptin, and adiponectin).29

The body weight–BMD relationship, however, is complex. For example, errors in BMD determinations are common in markedly obese individuals because of fat deposition, as well as difficulties in achieving correct positioning. DXA measurements are falsely elevated by increased body fat, whereas measurements of trabecular BMD by QUANTITATIVE COMPUTED TOMOGRAPHY are decreased by greater marrow fat. Longitudinal studies of obese patients after gastric bypass operations demonstrate a greater than expected drop in BMD as a result of concomitant changes in body composition.31

Low body weight and recent weight loss are confirmed risk factors for osteoporotic fractures.32, 33 Moreover, women with more body fat have lower rates of bone resorption (an independent predictor of fracture) during menopause than thinner women.34 It is not clear, however, whether low body weight necessarily means low body fat. For example, in CUSHING SYNDROME there is a dramatic shift in fat distribution, including greater bone-marrow adiposity, with only modest changes in total body weight.35 Similarly, in the frailest elderly patients, increased abdominal fat has been associated with hip fracture risk.33

Age, sex and ethnicity influences

Most population studies of body composition have examined middle-aged white men and women with a mean BMI greater than 25 kg/m2. In contrast, a study of 921 African-American, Asian, Latino and Caucasian women, aged 20–25 years, found that lean mass rather than fat mass was more positively related to BMD.30 Even more surprising, in a recent study of more than 13,000 Chinese men and women with significantly lower mean BMI than other cohorts (21 kg/m2), percentage body fat was inversely related to BMD as measured by DXA at the spine and hip and total body.36 These conflicting results suggest there is a complex relationship between fat mass and bone mass, which is likely to depend on the patient's age, sex and ethnicity. To date, relatively few studies have examined the relationship between fat mass and distinct skeletal compartments (i.e. trabecular and cortical) using 3D techniques for bone assessment, such as CT or MRI.37

Around 35 years ago, Meunier studied 81 iliac crest biopsies from elderly women and found that bone-marrow samples from women with osteoporosis had a pronounced accumulation of adipocytes, relative to levels in healthy young subjects.38 This finding was confirmed in subsequent studies that showed increased bone-marrow adiposity in postmenopausal women with osteoporosis, and a negative association between bone-marrow fat and rate of bone formation.39, 40, 41 Despite the observation of increased bone-marrow adiposity in iliac crest biopsies from osteoporotic individuals, fatty infiltration in the bone marrow was until recently considered an inconsequential part of normal aging.

MRI has provided additional support for the earlier observations in iliac biopsies, and provided a noninvasive, accurate means of identifying bone-marrow fat throughout the skeleton. Wehrli et al.37 first reported that MRI assessment of increased bone-marrow fat in the vertebral bodies of older women with low bone mass conferred an additional risk for compression fracture beyond that associated with low BMD (Figure 2). Schellinger et al.42 employed MRI spectroscopy and also found increased marrow fat in older women with osteoporosis (as noted by end-plate compression). Yeung and colleagues43 recently showed that postmenopausal women have more than twice the bone-marrow fat compared with premenopausal women, and that age-matched women with low BMD had significantly greater bone-marrow fat than those with normal BMD. Remarkably, these authors also found that there was a shift towards greater saturated lipid content in bone marrow in those women with osteoporosis compared to those without.43 Several lines of evidence therefore suggest that fat infiltration in the bone marrow is associated with skeletal fragility, although the underlying mechanisms remain to be elucidated.

Figure 2 (A) MRI of the radius in a 34-year-old healthy woman and (B) in a 64-year-old osteoporotic woman.
Figure 2 : (A) MRI of the radius in a 34-year-old healthy woman and (B) in a 64-year-old osteoporotic woman. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

The black striations within the radius and ulna represent trabecular bone. Note the marked loss of trabecular structure in the osteoporotic woman. Both images demonstrate fatty infiltration of the marrow space, an early occurrence in the appendicular skeleton. Indeed, the fat signal on T1-weighted images by MRI in the axial and appendicular skeleton is quite pronounced, increases markedly with age in the axial skeleton, and is often not reported because it is so common. (Images courtesy of David Newitt PhD, University of California, San Francisco.)

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Clinical correlates of increased marrow fat

The increased fracture risk associated with several clinical conditions might have its origins in the interface between bone-marrow fat and bone. For instance, individuals with type 1 and type 2 diabetes mellitus tend to have low BMD, and therefore a higher risk of fracture.44 The mechanisms underlying this increased risk are unknown, yet one might posit that increased adiposity, insulin resistance and effects of thiazolidinedione treatment enhance skeletal fragility in these individuals. Secondly, both exogenous glucocorticoid use and endogenous overproduction of cortisol for a prolonged period are associated with low BMD and a significantly greater risk of fracture, as well as with marked bone-marrow infiltration by adipocytes.45, 46, 47

Skeletal unloading due to immobilization or inactivity has been associated with a conversion of stromal cells to adipocytes rather than osteoblasts, leading to reduced bone formation.48 Finally, recent data show that obese women have lower rates of bone formation as measured by the serum biochemical marker, propeptide of type I collagen, suggesting that increased body fat suppresses new collagen formation.49

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Role of adipocytes in marrow

Several studies have examined the function of adipocytes in bone marrow. Marrow stromal cells isolated from postmenopausal osteoporotic patients express more adipocytic differentiation markers than those with normal bone mass,50 and are more likely to enter an adipocyte differentiation program than an osteoblast one.51 Importantly, fat in bone marrow might not only suppress osteoblastogenesis, but might promote bone resorption because marrow adipocytes, much like fat cells elsewhere, secrete inflammatory cytokines capable of recruiting osteoclasts.52 The interaction between estrogen (a key hormone for bone health) and fat appears to be complex. Martin et al.53 showed there was pronounced fatty bone-marrow infiltration in rats following oophorectomy, suggesting that estrogen must play an important role in regulating adipocyte recruitment. On the other hand, the presence of aromatase in fat cells permits higher intramarrow conversion of testosterone to estrone or estradiol which, in turn, can restrain bone resorption.9

The mere presence of fat in bone marrow does not mean that osteoblast precursors are being exclusively forced down the adipocyte pathway. For instance, some thiazolidinedione derivates that can activate PPARgamma enhance bone-marrow adiposity without altering BMD (B Lecka-Czernik, personal communication). One unresolved question, therefore, is what ultimately determines bone-marrow stromal-cell fate? That is, are there clones of stem cells that are predetermined to become osteoblasts under any circumstances, or are there environmental cues, or particular niches within the bone marrow, that are permissive for cell entrance into a particular lineage?

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Conclusions and future directions

The evidence for a significant yet complex interaction between fat and bone is summarized in Table 2. Research has clearly established that there is central regulation of bone remodeling through the hypothalamus and sympathetic nervous system, a pathway that also regulates the metabolic fate and distribution of adipose tissue. Moreover, adipocytes and osteoblasts arise from a common precursor cell, and their destinies, although not mutually exclusive, are intertwined and share a variety of genetic, hormonal and environmental factors. On the other hand, there is a protective role for fat in the skeleton, particularly with respect to fracture risk and bone loss during and immediately after menopause. There is mounting evidence, however, that at the extremes of life, puberty and old age, fat infiltration in the bone marrow might not be good for skeletal strength, nor for the optimal function of the bone remodeling unit. Nevertheless, many questions remain. For example, is fatty infiltration in the bone marrow of older individuals the cause of reduced bone formation, or does it merely fill a vacuum created by the reduction in osteoblastogenesis? Does adipocyte expansion occur at the expense of another bone-marrow constituent? What physiologic role does the adipocyte play in the bone-marrow milieu? How does estrogen regulate bone-marrow fat allocation? How does bone-marrow fat affect skeletal strength? If allocation down the osteoblast lineage is not mutually exclusive with adipogenesis, what factors ultimately determine bone cell fate in vivo? To answer these and other questions, new model systems and more extensive studies at the genetic, molecular and cellular level are needed.

Table 2 Support for and against the hypothesis that fat is protective for the skeleton.
Table 2 - Support for and against the hypothesis that fat is protective for the skeleton.
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Key points

  • Bone-marrow stromal cells can differentiate into adipocytes or osteoblasts

  • Bone-marrow adiposity increases with age in mammalian species

  • The function of fat in the bone marrow is unknown; it may be protective or detrimental

  • Increased bone-marrow fat as detected by MRI might be associated with greater fracture risk

  • The master controls over stem-cell lineage allocation are still not well defined

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Acknowledgments

The authors are supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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Competing interests

The authors declared no competing interests.

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