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Ruggiero, C. Obesity and Bone. Encyclopedia. Available online: https://encyclopedia.pub/entry/17743 (accessed on 16 November 2024).
Ruggiero C. Obesity and Bone. Encyclopedia. Available at: https://encyclopedia.pub/entry/17743. Accessed November 16, 2024.
Ruggiero, Carmelinda. "Obesity and Bone" Encyclopedia, https://encyclopedia.pub/entry/17743 (accessed November 16, 2024).
Ruggiero, C. (2022, January 04). Obesity and Bone. In Encyclopedia. https://encyclopedia.pub/entry/17743
Ruggiero, Carmelinda. "Obesity and Bone." Encyclopedia. Web. 04 January, 2022.
Obesity and Bone
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms222413662

The increase in body weight causes an increase in BMD (bone mineral density), both for a mechanical effect and for the greater amount of estrogens present in the adipose tissue. Nevertheless, despite an apparent strengthening of the bone witnessed by the increased BMD, the risk of fracture is higher.

BMD (bone mineral density) Bone Fractures Obesity

1. Increased Bone Fragility

1.1. Metabolic Association

Obesity is a condition of chronic dysfunction characterized by a low-grade, systemic inflammatory state. This pathological condition predisposes to the onset of some diseases, such as diabetes, hyperlipidemia, and hypertension. MetS (metabolic syndrome) is mainly characterized by obesity, hyperglycemia, hyperlipidemia, and hypertension, even if its definition has undergone changes over time [1][2][3]. Adipose tissue must be considered an endocrine organ, which regulates many body functions and has a critical role in energy homeostasis, producing, for example, several biologically active substances, like adipokines. Just as adipose tissue can be considered a real organ that acts on the body’s metabolism, bone tissue can also represent an organ that exerts an action on many other organs.
Leptin: Leptin is secreted by the white adipose tissue. Hyperleptinemia found in the obese subject seems to be one of the causes of bone weakening. In fact, leptin has a dual effect on bone. One of these effects is positive: in vitro, leptin stimulates stromal cells to differentiate into osteoblasts, stimulates the proliferation of the latter and inhibits the formation of osteoclasts [4][5][6]. It has also been shown that a knockout of the leptin gene causes a reduction in BMD and bone volume [7]. The negative effect seems to prevail over the positive one [8][9]. This negative effect would be exerted via the central nervous system. Leptin would cause decreased production of serotonin in the hypothalamic neurons, resulting in decreased bone formation [10][11]. In mice lacking leptin or leptin receptors, several authors found a decrease of femur bone mass and an increase of femur bone marrow fat [10][11]. Jansson et al. [12] based on their animal study in rats and mice, hypothesize that, in addition to the action of Leptin, which would have the ability to reduce body weight, also through a reduced food intake [13][14] there would be a homeostat, called “gravitostat” by the authors, located in the weight-bearing lower extremities, which would be activated with the increase in body weight, producing a decrease in fat mass regardless of leptin. The same group of authors, in a more recent paper [15] found that the gravitostat regulates fat mass in obese mice, while leptin regulates fat mass in lean mice, concluding that the gravitostat protects against obesity, whereas undernutrition induces low levels of leptin, with subsequent weight gain. The findings of these two studies lead to an interesting conclusion: obesity has an effect on bone, but bone also has an effect on body weight.
Adiponectine: Adiponectine, secreted by white adipose tissue, is an adipokine that has been proven to stimulate bone formation. It has been shown that adiponectin stimulates osteoblastic proliferation, with an increase in the activity of alkaline phosphatase, and the formation of type I collagen and osteocalcin, all markers of differentiation and maturation of osteoblasts. The osteogenesis of mesenchymal stem cells stimulated by adiponectin is mediated by the adipoR1 phosphorylation of P38 MAPK, which enhances COX-2 (cyclooxygenase2) and BMP2 expression (bone morphogenetic protein 2), a cytokine with considerable osteogenic potential [16][17][18]. In obesity, a low concentration of adiponectin is usually present [19]. This condition induces the reduction in osteoblastogenesis and the increase in osteoclastogenesis [20], through the mechanisms described above and, overall, through a mechanism mediated by inflammation markers. The chronic inflammatory condition present in obesity is likely to be partly linked to the lack of adiponectin. Adiponectin deficiency is also found in insulin-resistant diabetes [19]. This could be one of the links between obesity and diabetes.
The concentration of adiponectin is inversely proportional to that of numerous inflammatory cytokines, such as C-reactive protein (CRP), IL-6, and TNF-α. It is therefore presumable that the chronic inflammatory state present in obesity expresses a high concentration of these inflammation markers, which are potent inhibitors of adiponectin expression [21].
TNF-α: As already mentioned, in the obese subject there is a greater expression of TNF-α (GK57). TNF-α, through multiple mechanisms, leads to an increase in RANKL (RANK-Ligand) [22][23][24]. The latter promotes an osteoclastic bone resorption process. TNF-α also stimulates the production of osteoprotogerin [25].
IL-6: Just as in the case of TNF-α, obesity and insulin resistance cause an increase in interleukin 6 (IL-6) [26], through its overproduction by adipocytes and fibroblasts. IL-6, like TNF-α, also induces osteoclastogenesis and bone resorption [27][28][29].
Resistin: Resistin, a hormone of protein origin produced by visceral adipocytes and macrophages, has a controversial effect on bone. If it seems to favor the proliferation of osteoblasts, it also seems to favor osteoclastic proliferation and the release of inflammatory cytokines [30]. A high concentration of resistin is found in obese people [31].
Peroxisome proliferator-activated receptor gamma (PPARg): According to some authors, the peroxisome proliferator-activated receptor gamma (PPARg), together with its agonists, the thiazolidinediones, can act in the obese subject producing a negative effect on the bone. In fact, PPARgs have the property of promoting the differentiation of mesenchymal cells into adipocytes and blocking the transformation of mesenchymal cells into osteoblasts [32].
Lipid metabolism: The review by Kim et al. [33] carefully examines how the alterations in lipid metabolism present in the obese subject can negatively affect bone metabolism. The lipid alterations to which such consequences can be attributed are different and complex, with the involvement of SREBP, cholesterol, LXRs and RXRs, fatty acids, statins. The latter can impact the phenotype of osteoclasts and osteoblasts in pathological conditions.
Vitamin D: Vitamin D deficiency causes a reduction of calcium resorption and, consequently, osteoporosis and osteomalacia. In the obese, the serum levels of vitamin D are significantly lower than in non-obese [34][35][36]. However, as researchers have previously reported, the obese patient’s BMD is higher. The incongruity of this phenomenon can be explained by the fact that a wide amount of vitamin D in the obese is stored in the largely represented adipose tissue, causing a serum hypovitaminosis D. This hypovitaminosis is only apparent though, since vitamin D in the adipose deposits is always available and, therefore, the obese subjects are not affected by the negative effects of the deficiency of this vitamin [37]. In obese patients, it is very common (43% of the morbidly obese adults) to observe a secondary hyperparathyroidism, that can negatively impact skeletal health [38][39].
Peptide YY: Not strictly related to metabolism, is the level of Peptide YY. Although it must be confirmed, the role of this peptide seems to have an influence both on obesity and bone mass. Peptide YY promotes satiety. PYY-deficient mice (Pyy(−/−)) have osteopenia with a reduction in trabecular bone mass and a deficit in bone strength. PYY levels are lower in obese adults and the elevation of PYY seen after a meal in lean subjects is blunted in obesity [40][41].

1.2. Fat Bone Marrow

Bone marrow is an important deposit of fat, at the level of the “yellow” areas. Marrow adipose tissue (BAT) is estimated to occupy 70% of the marrow space by adulthood [42] and accounts for about 8% of total fat mass [43]. In the obese subject, bone marrow fat fraction (BMFF) was shown to be higher than in the normal weight subject [44]. The adipocytes of the bone marrow are responsible for the secretion of adipokines, some of which induce the release of various inflammatory cytokines mentioned above, such as TNFα and IL-6.
The correlation between obesity and bone fragility can also originate from the adipose bone marrow, which has been shown to interfere with bone metabolism. It is not a coincidence that BMFF increases in obesity, in old age and in osteoporosis, especially in postmenopausal women [45]. Actually, adipocytes and osteoblasts have a common origin, which are pluripotential, bone marrow-derived mesenchymal stem cells [46]. It cannot be ruled out that the inability of the latter cells to differentiate into osteoblasts leads to an increased differentiation into adipocytes. The literature widely demonstrates that the presence of a greater amount of fat in the bone marrow induces osteoporosis [47][48][49][50][51][52]. Indeed, an increase in marrow fat content has been demonstrated in obese women with low BMD, and Wehrli et al. reported that bone marrow adipose tissue in the lumbar spine is an independent predictive factor of fracture [44][53][54][55].
It is also important to mention the importance of palmitate, reported by some authors [56]. According to these authors, the lipotoxic effect of BAT is mainly due to the action of palmitate, which would have its toxic effect, especially on bone cells, mainly osteoblasts.

1.3. Genetic Predisposition

In some subjects, obesity is dependent on a mutation of the FTO (FaT mass and Obesity-associated protein) gene [57]. It has been demonstrated that the deletion of FTO in mice leads to increased death of osteoblasts and bone loss [58]. It could be inferred that subjects carrying the FTO gene mutation are more predisposed to osteoporosis due to the depletion of osteoblasts.

2. Type of Adiposity

Abdominal fat is composed of abdominal subcutaneous fat and intraabdominal fat. Intraabdominal adipose tissue is composed of visceral, or intraperitoneal, fat [57] and its accumulation is the cause of central adiposity. Abdominal obesity is an index of visceral (or central) adiposity and can be measured through the waist circumference. It must be distinguished from obesity in general, which is measured with BMI. From the literature it emerges that, more than obesity, evaluable with BMI, it is the excess of visceral adiposity that induces damage of bone microstructure. Visceral adipose tissue (VAT) has been associated with lower trabecular bone volume, lower bone formation rate, lower stiffness, and higher cortical porosity [59]. Numerous papers published in the literature highlight that VAT is an independent negative determining factor of bone density in obesity [44][60][61][62]. A Korean study on a large population of postmenopausal women (n = 3058) found that the prevalence of osteoporosis in women with waist circumference (WC) obesity (>80 cm) was higher than in women with BMI obesity (>25 kg/m2) [63]. A study by Cao et al. showed low levels of IGF-1 in VAT. IGF-1 has an anabolic action on osteoblasts [64]. Some authors report that an increase in VAT causes a higher release of pro-inflammatory molecules such as TNF and IL-6, which are very important in the genesis of osteoporosis [65][66].
It is interesting what some authors report, arguing that visceral fat has an adverse effect on bone mass, while subcutaneous fat would have beneficial effects [62].

3. Age and Sex

It is not easy to draw conclusions regarding the differences in bone quantity and quality and the risk of fracture in obese subjects based on age and sex. It is well known that postmenopausal women have a much higher risk of osteoporosis than premenopausal women and men, although there are numerous studies that conclude that osteoporosis in men should not be underestimated [67]. As regards the influence of age and sex in the relationship between obesity and bone fragility, biasing factors are unavoidable in the assessment of fracture risk: the risk of osteoporosis and fractures increases with age, independently from body weight, and, in menopause, the abrupt decrease of estrogens is the main cause of osteoporosis.
In the literature, it is possible to find conflicting data on the responsibility of obesity on bone health based on age and sex. Several studies conducted by Asian authors deal with metabolic syndrome in general. In two retrospective studies on populations of over 50, it appears that MetS has a protective effect on bone in men but not in women [68][69]. These conclusions are confirmed by the studies of Eckstein et al. and Hernandez et al. [70][71]. Totally opposite results emerge from some studies carried out on the Korean population [72][73][74]. Zhou et al., in their meta-analysis in which nine studies were selected for a total population of 18,380, confirm that MetS has more harmful effects on bone in men than in women [75]. Even considering the “menopause” factor influencing the results, it appears that obesity determines a significantly higher BMD increase in postmenopausal women than in premenopausal women [76][77][78].

4. Obese’s Fracture Site Paradox

In fact, the published scientific data highlight that the increased risk does not concern all fractures, but only some sites are affected by a higher incidence of fractures. This site-specificity of fracture risk could be called “obese’s fracture site paradox” (in analogy with the “obesity paradox” mentioned above), since the increased risk of fracture paradoxically does not concern the typical sites of osteoporotic fractures [79][80] but other, less common, sites. Specifically, most of the available evidence supports a lower risk of hip, vertebral, and wrist fractures in obese adults [81][82], whereas a higher risk of ankle, upper leg, and humerus fractures has been found [83][84][85][86]. In a study carried out by Compston et al. on 3628 fractures in 52,939 post-menopausal women followed for 3 years, the authors concluded that BMI was protective for hip and wrist, whereas the risk of ankle fractures increased (HR 1.05 [1.02–1.07]) (p < 0.01) [83].
One wonders what the reasons for this anomalous distribution of these fractures may be. The hypotheses that can be formulated are essentially related to the mechanism of falling. A first factor could be the hip padding, that is, the presence of an abundant fat pad around the pelvis that could protect obese individuals from hip fractures, while at the level of the legs and upper limb the protection by fat is minimal [87][88][89]. Another factor could be how obese people fall, since they are more prone to fall backward or sideward [90]. A further hypothesized factor is the tendency of the obese to excessive introversion and extroversion of the ankle and lower leg. That would predispose to sprains and fractures of the ankle [91].

5. High-Fat Diet

In order to better understand the relationship between obesity and bone health, the analysis of the numerous studies on the effects of high-fat diet (HFD) can be interesting. Most of the findings on the effects of high fat diet come from animal studies.
Ionova-Martin et al. report that obesity induced in C57BL/6 mice by HFD is associated with an increased bone quantity (larger bone size and mineral content), but also with a decrease in bone quality, as evidenced by lower size-independent mechanical properties [92]. Other demonstrations of the deleterious effect of HFD in mice are reported by Fujita et al., who showed the reduction of trabecular bone density and by Patch et al., which reported an increase in bone resorption [93][94]. Several other studies have confirmed the decreased bone mass in mice following HFD [94][95][96][97][98][99][100], although some studies in rats reported opposite results [101][102][103][104]. However, most of the studies report harmful effects of high-fat diet on bone. It has been shown that the component of the bone tissue that suffers mostly from this type of dietary intake is the cancellous bone. Several authors found that the consequences of HFD are the decrease of bone trabecular density [93] and of bone trabecular volume fraction, bone mineral content, and quantity [99]. The studies on cortical bone do not have comparable evidence [64][105][106]. This can be explained by the fact that cancellous bone is more sensitive to bone turnover, as it has a greater remodeling action, likely due to its larger surface to volume ratio [107]. Another reason may be the fact that cortical bone is less affected by bone resorption because the body weight load mainly acts on the cortical bone, strengthening it. HFD, in addition to exerting a deleterious action on bone structure, has also a harmful effect on the cellular component: it induces osteoclast hyperactivity and bone resorption [108] mainly through the RANKL/RANK/OPG signaling pathway. Shu et al. (2015) found an increased osteoclast number in the femoral metaphyseal sections of HFD-fed mice, associated with the finding of RANKL, TNF, and PPARγ in bone marrow cells [98]. In fact, an increase in osteoblast function was also noted in the same study. To explain these findings, it can be hypothesized that, despite the harmful effect of HFD on bone by changing the bone marrow microenvironment, the weight gain of animals gives the bone a greater biomechanical stimulus, which only partially reduces bone fragility.

6. Gut Microbiota

Microbiome science is relatively new and evolving. Gut microbiota (GM) dysbiosis has been identified in various diseases, such as hypertension, Alzheimer disease, type 2 diabetes, depression, and also in obesity [109][110][111][112][113][114]. Several studies have also shown a relationship of GM dysbiosis with bone health [115]. It can be inferred that the relationship between obesity and bone can also be conditioned by GM. In an animal study by Wang et al. [116][117], the GM dysbiosis induced by the transfer of feces from osteoporotic senile rats to young rats, made the latter osteoporotic. From the study by Zhou et al. on 264 obese or overweight subjects [118], it emerges that the gut microbiota-related metabolite trimethylamine N-oxide (TMAO) protects against BMD reduction during weight loss. An important study on this topic is that of Fernández-Murga et al. [117].
The experiment was conducted on two groups of mice: both groups of mice were fed a high-fat diet (HFD) for 14 days, but in one of the two groups the diet was supplemented with Bifidobacterium pseudocatenulatum CECT 7765. In HFD-fed mice, bone alterations were detected, such as reduced volumetric bone mineral density in the trabecular bone and deteriorated trabecular architecture in bone volumetric fraction, trabecular number, and trabecular pattern factor at the level of the distal femur. In HFD-fed mice supplemented with B. pseudocatenulatum CECT 7765, the findings were the following: low negative effect on bone microstructure, increased Wnt/β-catenin pathway gene expression (which improves BMD), and decreased serum C-terminal telopeptide (CTX) and parathormone. These findings demonstrate the protective effect of B. pseudocatenulatum CECT 7765 on bone in obese mice.

7. Effect of Weight Loss

From what has been said so far, it can be inferred that the increase of body weight generally induces an increase of BMD, but that the bone is not protected by it, on the contrary, its microstructure is damaged and the risk of fracture increases. What happens when the obese subject loses weight? It is interesting to analyze the studies that deal with this topic.

8. Bariatric Surgery

Strictly connected with the effect of weight loss are the consequences of bariatric surgery, on which numerous papers have been published.
The most performed surgical techniques in bariatric surgery are the following: laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy (SL), roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD/DS) [119].
Related to this topic, available evidence suggests the following conclusions about the consequences of bariatric surgery: (1) decrease in BMD and areal BMD (aBMD) [120][121][122][123][124][125][126][127][128][129], with endocortical resorption, evidenced by the decrease in the number of trabeculae and a great increase of cortical porosity [130][120][125]; (2) early and dramatic increase of biochemical markers of bone turnover, such as serum C-terminal telopeptide (CTx), especially after RYGB [122][123][129][131][132]; (3) as far as the type of surgery is concerned, these consequences seem to be rare after LAGB [133], while they are frequent after RYGB and BPD-DS [134][135][136][137]; (4) the risk of fracture increases, but the most frequent fracture sites are different from those typically found in the obese subjects. In detail, the mostly incident fractures reported are wrist, humerus, spine, hip, femur [134][135][136], clavicle, scapula, sternum, foot [137]; (5) The risk of fracture increases at a longtime distance from the operation (it starts to increase between 2 and 5 years after surgery) [134][135][136][137]; (6) The negative consequences on bone can be mitigated with exercise [138].
It should be kept in mind that most of the patients who undergo bariatric surgery are women between the ages of 30 and 40 [108]. It follows that the risk of fracture in that age group is low, but it is, however, increased after this type of surgery.
There are several hypotheses on the etiopathogenesis of the negative influence of bariatric surgery on bone. The etiopathogenesis is presumably multifactorial, and mechanisms may involve nutritional factors, mechanical unloading, hormonal factors, and changes in body composition and bone marrow fat. The first indisputable factor is hypovitaminosis D, which occurs in the operated subject. Already before surgery, as previously described, the patient is probably deficient in vitamin D, because of their obesity, but in the postoperative period, this deficiency worsens and, unfortunately, the therapeutic intake of vitamin is unable to compensate for the deficit, with persistence of a serum concentration of 25OHD below 30 ng/mL [139]. As a result, there is severe calcium malabsorption, which is reduced by up to 7% after RYGB by 6 months from surgery [129]. Another consequence is that subjects undergoing bariatric surgery almost always have high levels of parathyroid hormone [140][141]. Another conceivable cause is that the patient’s sudden weight loss can significantly affect the bone stoke as a result of mechanical unloading. This last factor can contribute to the increment of bone fragility, but it cannot be considered the most important, also because it would not explain the increase in fractures in sites not subjected to load, such as the upper limb.
In patients submitted to bariatric surgery, several hormonal changes have been detected. In particular, the increase of adiponectin and peptide YY and the reduction in estradiol, leptin, insulin, and ghrelin (the latter not always increases) causes a decrease of bone mass, while the increase in testosterone, GLP-1, and IGF-1 is able to induce bone gain [127][128][142][143].
Another hypothesized mechanism to explain bone loss after bariatric surgery is the reduction of lean mass, which would lead to a decline in aBMD [120][128][144][145].

9. Osteosarcopenic Obesity Syndrome

“Sarcopenic obesity” is characterized by loss of muscle mass due to obesity [146][147][148]. The combination of osteoporosis/osteopenia and sarcopenia has been called “osteosarcopenia” [149][150][151]. The “osteosarcopenic obesity syndrome”, first described by Ilich et al. [152], is a syndrome characterized by the combination of three conditions: adiposity, with infiltration of fat in muscle tissue and bone, sarcopenia, and osteopenia/osteoporosis. The condition that most of all induces the other two is obesity, as a form of low chronic inflammation that causes the release of numerous cytokines harmful to the bone and muscle and produces fatty infiltration of the muscles, making the latter less strong and efficient [152][153][154]. In sarcopenia, it has also been observed the release of specific muscle cytokines, such as myostatin, which can inhibit osteogenic differentiation of BMSCs, as well as osteoblast differentiation and mineralization [154][155][156].
Sarcopenic obesity is a highly prevalent condition in the elderly. According to data from the European Working Group on Sarcopenia in Older People (EWGSOP), the prevalence of sarcopenia increases by 11% in subjects between 50 and 59 years of age and by 37% in subjects aged 80 and over [157]. Sarcopenic obesity sums up the effects of obesity and sarcopenia on elevation of fracture risk. Scott et al. report that older adults with sarcopenic obesity have a three times greater risk of fracture than older adults with nonsarcopenic obesity and controls (no sarcopenia, no obesity) [158]. It has also been shown that older adults with sarcopenic obesity have higher percentage of nonvertebral fractures, compared with those with sarcopenia alone and those with obesity alone [158][159].

10. Obesity and Falls

One of the causes of the increased risk of fractures in the obese subject is the greater tendency to fall compared to the non-obese.
The increased risk of falling in obese people is reported by various authors [160][161][162][163][164]. In a meta-analysis published in 2019, which analyzed 31 observational studies [165], it emerges that obese people not only have a greater risk of falling than non-obese, but also that obese subjects have a significantly greater tendency to experience multiple falls.
Several causes for the greater risk of falling in obese people are reported in the literature: (1) excessive body weight reduces the subject’s agility and therefore his ability to move skillfully avoiding obstacles [166] and slows down the reaction time in supporting the body mass during falling [167][168][169]. (2) Postural instability. The body center stability is lower in obese people [163][164], especially in older women with central adiposity [170]. In a cross-sectional study conducted on 201 older adults, Azevedo-Garcia et al. [171] concluded that obesity is associated with postural balance on unstable surfaces. The lower stability was also associated with the greater pressure on the heels exerted by the obese subject, which decompensates the load distribution and alters the correct dynamics of the gait [172]. (3) The poorer physical activity performed on average by obese subjects [173][174] also influences their lower balance capacity, both because of the lower muscle strength and the lower agility related to the poor daily exercise [175]. (4) The term “dynapenic obesity” is referred to the association of obesity with lower muscle strength, due to fatty infiltration of the muscles [159][175][176][177]. This leads to a greater predisposition to falls. Dynapenic obesity is also present in “sarcopenic obesity”, a highly prevalent condition in the elderly which, as already explained in a previous paragraph, involves a greater risk of falls and fractures [153][178][160][179][180]. (5) Obesity is associated with some diseases, of which it can be cause or effect, such as diabetes, cardiovascular diseases, chronic pulmonary diseases, sleep apnea, hypertension [166]. These conditions can be associated to peripheral neuropathy, orthostatic hypotension, general weakness, all predisposing to falls [181].

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