Obesity is traditionally thought to be beneficial to bone and, thus, to protect against osteoporosis [5, 54, 55]. Mechanical loading stimulates bone formation by decreasing apoptosis and increasing proliferation and differentiation of osteoblasts and osteocytes [56] through the Wnt/β-catenin signaling pathway [57, 58]. Therefore, mechanical loading conferred by body weight is part of the assumption that has led to widespread belief that obesity may prevent bone loss and osteoporosis [59–63].

However, recent reports have shown that excessive fat mass may not protect humans from osteoporosis and in fact, increased fat mass is associated with low total bone mineral density and total bone mineral content [64–67]. In a cross-sectional study of 60 females between 10 and 19 years of age, the percent of body fat was linked to suboptimal attainment of peak bone mass [68]. Increased adiposity may also be linked to the increased risk of bone fracture. For example, in a case-control study of 100 patients with fractures and 100 age-matched fracture-free control subjects aged 3 to 19 years, high adiposity are associated with increased risk of distal forearm fractures [69]. In another large cross-sectional study of about 13,000 adult men, pre- and post-menopausal women, percentage of body fat was positive associated with osteopenia and nonspine fractures [66].

In a leptin-deficient (ob/ob) mouse model for obesity, mice weighed twice as much as lean mice but had lower femoral bone mineral density, cortical thickness, and trabecular bone volume [70]. Obviously the positive effect of mechanical loading of increased body weight could not overcome the detrimental effect of leptin-deficiency (or possibly obesity) on bone in these mice. The apparent competing effects of adiposity and mechanical loading on bone metabolism remain an active research area. Research findings suggest that factors other than body weight are involved in the final outcome of obesity on bone health.

While research with obese animal model has established the negative effects of adiposity on bone metabolism, studies with human subjects continue to be controversial. Human obesity is a complex issue which in general involves excessive consumption of other nutrients, such as protein and minerals, known to influence bone metabolism [71]. Findings of the effects of obesity on bone health in humans have been based on statistical correlation or modeling rather than controlled trials. Thus, controlled studies with the obese animal model are useful for dissecting the mechanisms upon which excessive fat accumulation affect on bone metabolism.

Using a diet-induced obese mouse model, we demonstrated that feeding mice a high-fat diet (45% energy as fat) for 14 wks decreases trabecular bone volume and trabecular number in the proximal tibia despite a substantial increase in body weight and bone formation markers in cultured BMSC [72]. These structural changes are accompanied by increases in serum leptin and TRAP levels, the ratio of RANKL/OPG expression in cultured osteoblasts, and the number of TRAP-positive osteoclasts [72, 73]. Increased osteoclast activity and decreased expression of IL-10, an anti-inflammatory cytokine, by bone marrow-derived macrophages in diet-induced obese mice have also been reported by others [74]. High fat-induced obese animals exhibited increased bone marrow adiposity accompanied by reduced BMD in different skeletal sites, up-regulation of peroxisome proliferator-activated receptor γ, cathepsin k, IL-6 and TNF-α [75].

Based on available literature, obesity appears to affect bone metabolism through several mechanisms. Obesity may decrease bone formation (osteoblastogenesis) while increasing adipogenesis because adipocyte and osteoblasts are derived from a common multi-potential mesenchymal stem cell (Figure 1) [76]. For example, mechanical loading promotes osteoblast differentiation and inhibits adipogenesis by down-regulating peroxisome proliferator-activated receptor gamma (PPARγ) or by stimulating a durable beta-catemin signal [12, 13]. Activation of PPARγ by thiazolidinediones decreased osteoblast differentiation, bone mineral density and trabecular bone mass while increasing adipocytes differentiation and bone marrow adipose tissue volume [11, 77, 78].

Obesity may increase bone resorption through upregulating proinflammatory cytokines such as IL-6 and TNF-α. These proinflammatory cytokines are capable of stimulating osteoclast activity through the regulation of the RANKL/RANK/OPG pathway [49, 50]. Obesity is significantly associated with degenerative and inflammatory musculoskeletal system [79]. Bone marrow adipocytes also may directly regulate the osteoclast progenitors, hematopoietic cells [80]. For example, when expressed with a dominant-negative form of CCAAT-enhancer-binding proteins (C/EBP) under the adipocyte fatty-acid-binding protein 4 promoter, mice cannot form adipocytes [81]. These mice lack white adipose tissue and have increased bone mineral density [82].

Obesity may affect bone metabolism directly or indirectly through adipocyte-derived cytokines such as leptin and adiponectin. Obesity is associated with significant increase in serum leptin [32, 33] and decrease in adiponectin [35]. The action of leptin on bone appears to be complex and both positive [83, 84] and negative [85, 86] effects have been reported. It appears that its action may depend on current leptin status and the mode of the action (central or peripheral effects). Overproduction of leptin, as seen in obese animal models, may have negative effects on bone metabolism [73]. Increased serum leptin level has been found a negative regulator of bone mass in a mouse model [85]. Adiponectin is another cytokine secreted by adipocytes and has anti-inflammatory effect [34]. In animal model, adiponectin has been reported to inhibit osteoclastogenesis, reduce bone resorption, and increase bone mass [87]. Obese subjects have low serum adiponectin concentrations as compared to those normal subjects [35]. Increased secretion of leptin (and/or decreased production of adiponectin) by adipocytes may also contribute to macrophage accumulation by simulating transport of macrophages to adipose tissue [88] and promoting adhesion of macrophages to endothelial cells, respectively [89].

Finally, a high-fat diet, often a cause of obesity, has been reported to interfere with intestinal calcium absorption. Free fatty acids can form unabsorbable insoluble calcium soaps and therefore contributing to low calcium absorption [90–92].

Increased body weight associated with obesity may counteract the detrimental effects of obesity on bone metabolism. It is well established that body weight or body mass index (BMI) is positively correlated with bone mineral density or bone mass [59, 93] and low body weight or BMI is a risk factor for low bone mass and increased bone loss in humans [60]. However, studies indicate the positive effects of body weight could not completely offset the detrimental effects of obesity on bone, at least in obese animal models.