18.1

Introduction

• 1.
  

  Obesity and osteoporosis are two important problems affecting global health with a high impact on both mortality and morbidity.

  
  
• 2.
  

  Both have multifactorial aetiologies, including genetic and environmental components, with potential interactions between them.

  
  
• 3.
  

  Obesity is a condition of excessive body fat due to an imbalance when energy intake exceeds energy expenditure over a prolonged period.

  
  
  
  
  • a.
    

    In healthy adults, body weight is tightly regulated by several environmental, nutritional, and hormonal factors.

    
    
  • b.
    

    Postmenopausal women often show increased body weight, likely due to a decrease in basal metabolism, alteration of hormonal levels, and reduced physical activity.

    
    
  • c.
    

    They are often affected by hypertension, dyslipidaemia, diabetes mellitus (DM), and cardiovascular disease and also have an increased risk of developing some cancers.

  
  

• 1.
  

  Osteoporosis is a metabolic bone disease that is characterised by excessive skeletal fragility (due to a reduction in both bone quantity and quality) leading to an increased risk of developing spontaneous and traumatic bone fractures and even death.

  
  
  
  
  • a.
    

    It is characterised by a reduction in bone mass; it is typically defined in an individual with a bone mineral density (BMD) T-score that is 2.5 or more SD values below normal (T-score −2.5 or less).

    
    
  • b.
    

    Normal aging is associated with a high incidence of osteoporosis and bone marrow adiposity. Bone remodelling and adiposity are both regulated through the hypothalamus and sympathetic nervous system. Adipocytes (the cell for storing energy) and osteoblasts (the bone from a common progenitor)—the mesenchymal stem cell.

  
  
  
  
• 2.
  

  Interestingly, obese women have always been considered protected against osteoporosis.

  
  
  
  
  • a.
    

    Increased mechanical loading, associated with increased body weight, contributes to increases in bone mass.

    
    
  • b.
    

    One potential problem with these phenotypic studies is that the correlation between body weight (or BMI) and bone mass may not necessarily represent a correlation between obesity per se and osteoporosis, because it is excessive fat mass rather than total body weight that defines obesity.

    
    
  • c.
    

    Body weight is a heterogeneous phenotype consisting of fat, lean muscle, and bone mass. Fat mass accounts for approximately 16% and 25% of total body weight in normal-weight men and women, respectively; the majority of the remaining body composition is lean mass.

    
    
  • d.
    

    Conclusions from studies about the relationship between obesity and bone mass may be confounded by the mechanical loading effects of total body weight on the skeletal system.

  
  

18.2

Normal bone metabolism

Osteoblasts, osteoclasts, and osteocytes are the main cells of the bone.

• 1.
  

  Osteoblasts are nonproliferative bone building cells that originate from osteoblast progenitor cells and aid in the formation of the bone matrix by secreting osteoid, a substance responsible for bone mineralisation. It plays the most important role in bone formation

  
  
• 2.
  

  Osteocytes (mature osteoblast) are unable to divide and no longer secrete matrix components.

  
  
• 3.
  

  Osteoclasts originate from macrophage monocyte cell lineage and participate in bone resorption, ultimately leading to decreased bone mass.

  
  
• 4.
  

  Preosteoblasts express receptors for different types of growth factors, pro-inflammatory cytokines, and hormones, including bone morphogenic proteins, Wnt, transforming growth factor-beta, parathyroid hormone (PTH), interleukin-6 (IL-6), 5-HT, insulin/insulin-like growth factor, and tumour necrosis factor (TNF).

  
  
• 5.
  

  Binding of these ligands with their receptors induces the activation of different types of transcription factors responsible for osteoblast differentiation, maturation, and survival.

18.3

Epidemiology of osteoporosis and obesity

• 1.
  

  Osteoporosis has become a significant health problem as approximately 200 million people worldwide are estimated to have osteoporosis.

  
  
  
  
  • a.
    

    There are estimated 10 million aged more than 50 years in the United States with osteoporosis.

    
    
  • b.
    

    In a Brazilian study, the prevalence of fragility fracture in women and men aged higher than 40 years was 15.1% and 12.8%, respectively was reported.

  
  
  
  
• 2.
  

  The WHO’s World Health Statistics (2015) shows the obesity rate among adults in Europe is 21.5% in males and 24.5% in females.

  
  
• 3.
  

  It is projected that 60% of the world’s population, that is, 3.3 billion people, could be overweight (2.2 billion) or obese (1.1billion) by 2030 if recent trends continue.

  
  
• 4.
  

  Age and female gender increase the risk of developing both obesity and osteoporosis.

  
  
  
  
  • a.
    

    Age-related changes in body composition, metabolic factors, and hormonal levels after menopause, accompanied by a decline in physical activity, may all provide mechanisms for the propensity to gain weight.

    
    
  • b.
    

    Increase in fat mass often characterised by replacement of lean mass (LM) by adipose tissue.

    
    
  • c.
    

    The process of bone loss begins soon after menopause due to increased bone resorption by osteoclasts that exceed bone formation by osteoblasts.

    
    
  • d.
    

    Osteoblast function declines with aging, determining the imbalance between bone resorption and bone formation.

  
  

• 5.
  

  Premenopausal women with increased central adiposity had poorer bone quality and stiffness and markedly lower bone formation.

  
  
• 6.
  

  Most recent studies have reported that BMD appears to be a better long-term predictor of death than blood pressure or cholesterol.

18.4

Relationship between fat and bone: epidemiologic and clinical observations

• 1.
  

  The most powerful determinant of fracture risk is the amount of bone in the skeleton, as defined by either BMD or BMC

  
  
  
  
  • a.
    

    Extensive data have shown that high body weight or BMI is correlated with high BMD or BMC and a decrease in body weight leads to bone loss.

    
    
  • b.
    

    There is also evidence to support the view that fat mass, a component of total body weight and one of the most important indices of obesity, has a similar beneficial effect on increasing bone mass, thereby reducing the risk of osteoporosis.

    
    
  • c.
    

    In normal pre- and postmenopausal women, total body fat was positively related to BMD throughout the skeleton, and this effect was found in both White and Japanese subjects

    
    
  • d.
    

    Study showed that “rapid” bone losers had significantly lower fat mass than the “slow” bone losers.

  
  
  
  
• 2.
  

  However, in contrast to the abovementioned reported results, other independent groups have shown that excessive fat mass may not protect against decreases in bone mass.

  
  
  
  
  • a.
    

    In a large-scale study of Chinese and White subjects, when the mechanical loading effect of total body weight was statistically removed, then fat mass was negatively correlated with bone mass, thus suggesting that fat mass actually has a detrimental effect on bone.

    
    
  • b.
    

    A study conducted on evaluation of BMD in individuals with high body mass index has shown that obese patients have a significant reduction in bone mineral mass for age and BMI. It also showed the evidence that morbid obesity may not be considered a protective factor against osteoporosis in both female and male population.

  
  
  
  
• 3.
  

  Evidence from environmental factors and medical interventions also support an inverse correlation between fat mass and bone mass.

  
  
  
  
  • a.
    

    Physical exercise increases bone mass while reducing fat mass.

    
    
  • b.
    

    Consumption of milk which is a good source of highly absorbable calcium has been shown to increase peak bone mass at puberty, slow bone loss, and reduce the incidence of osteoporotic fractures in the elderly.

    
    
  • c.
    

    Menopause has also been associated with increased bone loss, increased fat mass, and decreased LM.

    
    
  • d.
    

    Hormone replacement therapy is an effective means of attenuating loss of LM and bone and reversing menopause related obesity in postmenopausal women.

    
    
  • e.
    

    Osteoporosis and obesity are side effects of treatment with gonadotropin-releasing hormone agonists.

    
    
  • f.
    

    The clinical use of glucocorticoids has been shown to cause decreased bone mass and an increase in central obesity.

  
  

• 4.
  

  The finding that all of these interventions have opposite effects on fat vs. bone mass supports the concept that there is an inverse correlation between fat and bone mass and that fat does not have a protective effect on the bone.

  
  
• 5.
  

  LM is the strongest predictor of BMD at all sites. It is important that LM should also be the target for improvement when considering prevention and/or management of osteoporosis.

18.5

Hormonal effect of obesity and osteoporosis

18.6

Adipocyte hormones

• 1.
  

  Adipocyte is not just an inert organ for energy storage but it expresses and secretes a variety of biologically active molecules, such as oestrogen, resistin, leptin, adiponectin, and IL-6 that affect human energy homeostasis and bone metabolism.

  
  
• 2.
  

  Adipocyte is an oestrogen-producing cell particularly in postmenopausal women. Oestrogen inhibits bone turnover by reducing osteoclast-mediated bone resorption and by stimulating osteoblasts-mediated bone formation.

  
  
• 3.
  

  In postmenopausal women extragonadal oestrogen synthesis in fat tissue becomes the dominant oestrogen source. The role of adipocyte as oestrogen producers may become more important for the bone metabolism in postmenopausal women.

  
  
• 4.
  

  Women with premature menopause who lose bone rapidly have lower levels of both oestrone and oestradiol than slow losers, and this may be accounted for by their lower body fat.

18.7

Obesity of the bone

• 1.
  

  Bone marrow mesenchymal stromal cells are the common precursors for both osteoblasts and adipocytes.

  
  
• 2.
  

  Aging may shift the composition of bone marrow by increasing adipocytes, osteoclast activity, and decreasing osteoblasts activity, resulting in osteoporosis.

18.8

Clinical and diagnostic implication of the concept obesity of the bone

• 1.
  

  Errors in BMD determinations commonly seen in markedly obese individuals are because of fat deposition in bone marrow.

  
  
• 2.
  

  Dual-energy X-ray absorptiometry measurements may be falsely elevated by increased body fat, whereas measurements of trabecular BMD by quantitative computed tomography may be decreased by greater marrow fat.

  
  
• 3.
  

  Increase in bone marrow adiposity may explain secondary causes of osteoporosis such as Cushing’s syndrome, DM, glucocorticoids levels, and immobility, which are associated with obesity.

18.9

Treatment implications of the concept obesity of the bone

• 1.
  

  The present treatment options for osteoporosis primarily are either antiosteoblastogenesis or proosteoblastogenesis in nature.

  
  
• 2.
  

  Decreased levels of vitamin D are a hallmark of osteoporosis and bone fractures.

  
  
• 3.
  

  Vitamin D has been shown to act by:

  
  
  
  
  • a.
    

    inhibiting bone marrow adipogenesis as an additional mechanism beside its known actions on bone;

    
    
  • b.
    

    affecting body fat mass by inhibiting adipogenic transcription factors and lipid accumulation during adipocyte differentiation; and

    
    
  • c.
    

    influencing adipokine production and the inflammatory response in adipose tissue.

  
  
  
  
• 4.
  

  High-fat diet has a pivotal role in bone formation because it markedly reduces the rate of Ca21 absorption by the intestine and thereby decreases the availability of Ca21 required for osteogenesis.

  
  
• 5.
  

  Vitamin D deficiency in the serum prevents intestinal uptake of Ca21 from the diet and hereby signals the parathyroid gland to secret increased levels of PTH.

  
  
• 6.
  

  Increased secretion of PTH induces osteolysis and prevents osteogenesis by supplying adequate levels of calcium and phosphorus in the blood necessary for metabolic processes and neuromuscular function.

  
  
• 7.
  

  Alendronate is a widely used bisphosphonate that stimulates osteoblastic differentiation while inhibiting adipogenesis in vitro, thereby suggesting an anabolic effect on bone through the differentiation of mesenchymal stem cells.

  
  
• 8.
  

  PTH also has been shown in the past to induce osteoblasts differentiation, inhibit adipogenesis, and suppress osteoclasts apoptosis.

  
  
• 9.
  

  PTH-related protein has been shown to induce a mild osteogenic effect and inhibit the adipocytic effect in human mesenchymal stem cells, thereby helping in osteoporosis beside its known action to modulate bone formation through promoting osteoblasts differentiation.

  
  
• 10.
  

  Strontium ranelate has both antiresorptive and anabolic effects on bone. However, it has been recently shown that adipogenesis is negatively affected in the presence of strontium ranelate with a concomitant dose-dependent decrease in the expression of adipogenic markers and changes in adipokine profile, thereby generating a favourable osteogenic effect within the bone marrow milieu.

  
  
• 11.
  

  Dietary relevant mixtures of isoflavones and their metabolites, lignans and their metabolites, coumestrol, and a mixture containing all of them have been shown to inhibit adipocyte differentiation as their additional mechanism of action in preventing osteoporosis independent of their concentration.

18.10

Bariatric surgery and bone health

• 1.
  

  Bariatric surgery adversely affects bone health. The skeletal effects of bariatric surgery are presumably multifactorial, and mechanisms may involve nutritional factors, mechanical unloading, hormonal factors, and changes in body composition and bone marrow fat.

  
  
• 2.
  

  The Roux-en-Y gastric bypass (RYGB) procedure combines restriction and malabsorption techniques and involves creating both a small gastric pouch and a deviation of a segment of the small intestine.

  
  
• 3.
  

  Metabolic bone disease (osteomalacia and osteoporosis) is a well-documented long-term complication of obesity surgery.

  
  
• 4.
  

  Abnormalities in calcium and vitamin D metabolism begin shortly after gastrointestinal bypass operations but clinical and biochemical evidence of metabolic bone disease may not be detected until many years later.

  
  
• 5.
  

  RYGB has significant impact on calcium and vitamin D metabolism. Diet restriction reduces the exogenous load of calcium and vitamin D and decreases intake of macronutrients that positively affect their absorption. In RYGB the proximal jejunum is bypassed, excluding an important site of calcium absorption, which contributes to the decreased calcium load.

  
  
• 6.
  

  In addition, the reduction in food intake leads to increased release of cortisol and decrease in IGF-I serum levels, both adaptations potentially impair calcium absorption.

18.11

Management after Roux-en-Y gastric bypass

• 1.
  

  Follow-up includes careful examination to detect subclinical fracture.

  
  
• 2.
  

  Patient stature should be measured before and at regular intervals after surgery.

  
  
• 3.
  

  Patients undergoing RYBG should be screened for osteoporosis with bone density measurement.

  
  
• 4.
  

  Laboratory evaluation includes calcium, albumin, magnesium, PTH, and 25(OH) D.

  
  
• 5.
  

  Operated patients should be encouraged to perform regular weight-bearing physical exercise. Physical activity is part of the strategy to reduce fracture risk.

  
  
• 6.
  

  Calcium and vitamin D supplementation should be prescribed in all bariatric patients. Patients should be advised to take slightly higher daily doses of vitamin D and Calcium than RDI recommendations: 1500 mg calcium and 2000 IU vitamin D.

  
  
• 7.
  

  25(OH) D serum levels should be checked every 2 months to ensure adequate levels. One should consider pharmacological treatment in patients if BMD is below 21.5.

18.12

Pragmatic approach for obese women

18.13

Conclusion

• 1.
  

  The relationship between fat mass and bone is confounded by complex genetic backgrounds and by interactions between metabolic factors and regulatory pathways influencing both obesity and osteoporosis.

  
  
• 2.
  

  The previous concept that obesity is protective for osteoporosis may not stand up to careful scrutiny as the new concept of bone marrow fat deposition seen in obesity has emerged, supporting the detrimental effect of obesity for bone health. Thus obesity, especially central obesity, may not be considered protective for osteoporosis.

  
  
• 3.
  

  Considering that obesity can be associated with fracture and that obesity treatment also can damage the skeleton, it is reasonable to conclude that the primary target should be obesity prevention.