Image Source: Mayo Clinic
An hypothesis was offered roughly a decade ago that osteoporosis might be considered the obesity of the bone.(1) The reason I find this hypothesis so engaging and interesting is that because for years obesity and overweight were considered to be protective against osteoporosis. Today’s blog will be focused on a more recent paper(2) that reviews obesity and osteoporosis as well as the hypothesis that rather than protective against osteoporosis, osteoporosis should be considered the obesity of bone.
As obesity and osteoporosis have had an increasing prevalence and both have significant impacts on mortality and morbidity, more research has been focused on these two topics. Additionally, the expanding body of data has revealed that what was once assumed (obesity being protective against osteoporosis) may in fact be the opposite of the truth. That is, “the latest epidemiological and clinical studies, have shown that a high level of fat mass might be a risk factor for osteoporosis and fragility fractures” (2, p. 273).
Age and female gender have increased risk of developing both obesity and osteoporosis. As such, we should briefly review the adipose tissue-derived hormones and serum mediators that could have a role in osteoporosis and obesity. For example, we know that after menopause hormone levels change, there are age-related changes in body composition, metabolic factors, and decreased physical activity may all be important mechanisms for increased risk of weight gain.
Fat had long been considered a passive energy reservoir; however, we now know that there are adipose tissue hormones and serum mediators. We now consider adipose tissue to be an active endocrine organ that is
“involved in the modulation of the energy homeostasis. Adipose tissue, in fact, secretes various inflammatory cytokines, including interleukin 6 (IL-6) and tumor necrosis factor α (TNFα), which are thought to have adverse metabolic, skeletal, and cardiovascular consequences. Moreover, as IL-6, other fat-derived mediators, which include resistin, leptin, and adiponectin, affect human energy homeostasis and are involved in bone metabolism, contributing to the complex relationship between adipose and bone tissue” (p. 273-4).
Fat is also a major source of aromatase, an enzyme that synthesizes estrogens from androgen precursors. Estrogens are hormones that have a pivotal role in maintain skeletal homeostasis. It is known that in obese postmenopausal women, “increased estrogen synthesis by adipose tissue has been suggested as one of the potential mechanisms for the protective effect of fat mass on bone” (p. 274). This could be wrong, for if the process to maintain skeletal homeostasis is corrupt, the skeleton may easily be altered. In other words, adipose tissue produces several cytokines and hormones that are active in bone remodeling, either bone formation or resorption.
While fat is now considered an active endocrine organ, bone cells express several hormone receptors. As such, the skeleton is now considered an endocrine target organ; bone-derived factors osteocalcin (OCN) and osteopontin (OPN) affect body weight control as well as glucose homeostasis. Therefore, bone is also an endocrine organ itself, not just a target. Finally, these hormones and factors lead to cross talk between bone and fat that seems to provide a homeostatic feedback system. As we saw in Obesity and Stem Cells, Part III, adipocytes and osteoblasts originate from the same progenitor, the medicinal signaling cell (MSC). As such, this makes the topic of obesity and bone interesting from the perspective of stem cells.
In the paper, Greco et al review several clinical studies on bone mineral density (BMD) and fracture risk in obesity. I will pull a few from their table (Table 1). In a study published in 1995 of premenopausal women with eumenorrhea (>36 years) it was found that bone density was only associated with fat mass in sedentary women but BMD was not associated with fat mass in exercisers. In 2013, another study found that lower abdomen fat was significantly associated with higher fracture risk in women. In a large study of 139,419 old men, multiple rib fractures were more frequent in overweight and obese. In fact, obesity was associated with reduced spine, hip, pelvis and wrist fracture, but increased risk for multiple rib fractures. A 2014 study of 60,393 obese women aged 55 and older, obesity increase the risk of fractures in ankle and lower leg. Another study in 2014 of 52,939 women found inverse linear relationships between BMI or weight and spine, hip, and wrist fracture. Additionally, a meta-analysis of 44 studies with 15,260 women and 20,226 men (ages ranged from 18 to 92 years) found that lean mass exerts a greater effect on BMD than fat mass in men and women. In 2015 a study of 19,918 postmenopausal women and 23, 061 men found that abdominal obesity was associated with great risk of hip fracture. In other words, the past few decades has found that rather than a protective effect, obesity has a negative effect on bone health and density and that “…obesity, based on the amount of fat mass, can affect bone metabolism leading to osteoporosis” (p. 274). Increased abdominal fat should also be considered a risk factor for decreased BMD and osteoporosis in both women and men.
Additionally, Greco et al discuss adipokines. Adipokines are bioactive compounds secreted by adipocytes; many adipokines are proinflammatory peptides (we have already discussed the chronic inflammation that occurs because of obesity). Dysregulation of adipokines is a strong determinant of the chronic, low-grade inflammation of obesity. This then leads to promotion of a cascade of metabolism altering events that have cardiovascular complications, insulin resistance, diabetes, and bone loss. For example, adiponectin naturally exerts a protective role on the cardiovascular system as well as glucose metabolism. However, serum levels of adiponectin are reduced in those with obesity and diabetes. Low adiponectin levels can be raised with weight loss. Adiponectin increases bone mass by activating osteoblastogenesis and inhibiting osteoclasts for resorbing bone. Additionally, TNFα is elevated in obesity and TNFα is a proinflammatory cytokine that promotes bone loss through increased osteoclastogenesis. Similar results are found with the obesity-increased IL-6 production.
As can be clearly observed, there is an interplay between obesity and bone tissue health. The skeleton has a critical role in energy balance and fat metabolism. Moreover, the connection between fuel (calorie) utilization and skeletal remodeling appears to begin in the bone marrow, and we have seen the effects of obesity in the bone marrow. As such, obesity has a significantly negative impact on skeletal remodeling. Finally, fatty bone marrow is a sign of both aging and is frequently found in osteoporosis with the likely pathway being MSCs to differentiate toward adipocytes rather than osteoblasts. This increases the fatty content of the bone marrow and provides insufficient numbers of osteoblasts for proper bone remodeling and health.
As both obesity and osteoporosis are major global health problems worldwide, research on these topics has increased. With the increased research, we seeing a picture of their relationship painted before our eyes. In fact, the once-held view that obesity is protective against osteoporosis has come into question with large epidemiological, clinical, and scientific studies. Rather than a protective effect, it now appears that obesity actually is a major risk factor for osteoporosis and fragility fractures. Without doubt, the fat and bone interplay is complex and involves numerous molecules, but the existence of the crosstalk and feedback demonstrates a bone-adipose axis that is the opposite of what was once thought.
Whether the reader is a clinician or one suffering with obesity, it is hoped that this blog will further the discussion and perhaps bring old thoughts about potential benefit of obesity to the modern era of understanding it is the opposite of what was once thought with respect to bone health and density.
Rosen C and Bouxein M. (2006). Mechanisms of disease: is osteoporosis the obesity of bone? Nat Clin Pract Rheumatol; 2:35-43.
Greco EA, Lenzi A, and Migliaccio S. (2015). The obesity of bone. Ther Adv Endocrinol Metab; 6:273-86.