Fat metabolism is related to both arteriosclerosis and bone metabolism. Obese patients have higher risk of coronary artery disease and lower risk of osteoporosis. Recent studies by Ricci show that even moderate weight loss due to dieting in obese women leads to bone loss. A study from Denmark by Jensen found a 4.2% decrease in whole body bone mineral and 4.0% decrease in the hip in women after 6 months of a diet which resulted in 5.5% weight loss (average 94 ot 89 kg, or 207 to 196 lbs). The loss in bone density was attenuated by calcium supplementation. On the other hand, a study of 130 young women with anorexia showed a high prevalence of fractures and of low bone density. The bone density was related to weight at all skeletal sites. Bone density did not differ by use of estrogen ( Grinspoon).
Leptin is a hormone made by adipocytes which acts centrally to control body weight. Leptin appears to interact with CNS factors. Leptin inhibits NPY and AGRP and stimulates proopiomelanocortin (POMC) (Wardlaw, JCEM 01) which then inhibit eating behavior and modify energy utilization. Studies of leptin and its role in the skeletal system are conflicting. Mundy proposed that leptin regulation was responsible for increased body weight as well as increased bone density. Mice who have congenital absence of leptin (ob/ob) are obese and have very high bone density. Leptin makes them lose both fat and bone. Leptin injected into the brain of animals will inhibit bone formation at doses lower than those that cause loss of body weight (see below).
Serum leptin correlations with bone density: Yamauchi reported that plasma leptin levels were positively correlated with BMD values, and multiple regression analysis revealed that this positive relationship was still observed with BMD values of the femoral neck and of the whole body, even after %fat and age were taken into account. Moreover, plasma leptin levels but not %fat were significantly lower in women with vertebral fractures than in those without fractures. Thomas found that serum leptin correlated with BMD in women but not in men. Sato found a positive correlation between serum leptina dn calcaneal BMD in men, but the relationship became inverse if adjusted for body weight. Pasco found a signficant positive association between the BMD and serum leptin in women. Golding also found significant correlations between leptin and bone mass, but not between leptin and biochemcial markers. In a small study, Iwamoto found correlations between some skeletal sites and serum leptin, but not at the whole body, and the correlations with biochemical markers were weak. Cauley (ASBMR 2004) reported that men with higher leptin had less bone loss in a longitudinal study of 3075 elderly men and women followed for 5 years. This was not seen in women. There was no significant relation between leptin and risk of fracture, although there was a trend.
Leptin effects on bone cells and adipocyte differentiation: Ducy wrote a great review of osteoblasts, which gives more descriptions of the leptin experiments (which were done by this group). Also, this paper discusses another connection between fat and bone: marrow stromal cells can differentiate into either adipocytes or osteoblasts. One factor that is important in the differentiation of the cells into osteoblasts is the transcription factor Cbfa1 (core binding factor a1). This is further discussed in the article by Nuttall Once differentiated, the mature adipocytes produce a factor which inhibits the osteoblasts (Maurin). Corticosteroid-induced osteoporosis is a serious problem that also involves adipocytes. Wang reviews findings that show how steroids increase the number of adipocytes.
Leptin actions on bone cells: Whereas Ducy found no leptin receptors on osteoblasts, and reported that leptin acted centrally as a very potent inhibitor of bone formation, Iwamoto found that leptin was expressed in and secreted from primary cultures of human osteoblasts and promoted bone mineralization. The cells had leptin receptors, but commercially grown cells did not. Holloway reported another interaction between leptin and bone cells, showing that leptin inhibits osteoclast generation, probably by increasing osteoprotegerin messenger RNA. Consisitent with this is an in vivo study by Burguera, showing that leptin reduced ovariecotmy-induced bone loss in rats, and found significant increases in mRNA for osteoprotegerin. Cornish, J. found that leptin given peripherally increased bone strength in mice and also increased proliferation of osteoblasts in vitro.
Leptin and sympathetic nervous system: Takeda, S. reported that leptin acted via the sympathetic nervous system, and inhibition of beta-adrenergic neurons results in leptin-resistent high bone mass. Schlienger, R. G. and Pasco, J. A. have both reported that the risk of fractures was decreased in patients taking beta-blockers for hypertension. At the 2004 ASBMR, several abstracts discussed beta-adrenergic knock-out mice, but the results were conflicting about whether bone formation was depressed or not in these animals. Ke reported that isoproterenol induced bone loss but the mechanism was increased osteoclast action, not reduced osteoblast activity.
Adiponectin: This is another hormone produded by adipocytes, and levels are lower in obese patients. Cauley (ASBMR 2004) reported that elderly people (age 70-79) with increased adiponectin levels had a trend towards higher fracture risk (p=.07) that was independent of body weight.
Pasco, J. A.(2004). Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Geelong Osteoporosis Study. J Bone Miner Res 19: 19-24.
Reid, I. R.(2002). Relationships among body mass, its components, and bone1. Bone 31: 547-55.
Cornish, J.(2002). Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo. J Endocrinol 175: 405-15.
Takeda, S.(2002). Leptin regulates bone formation via the sympathetic nervous system. Cell 111: 305-17.
Simha, V.(2002). Effect of subcutaneous leptin replacement therapy on bone metabolism in patients with generalized lipodystrophy. J Clin Endocrinol Metab 87: 4942-5.
Khosla, S.(2002). Leptin-central or peripheral to the regulation of bone metabolism? Endocrinology 143: 4161-4.
Ruhl, C. E.(2002). Relationship of serum leptin concentration with bone mineral density in the United States population. J Bone Miner Res 17: 1896-903.
Thomas, T.(2002). Is leptin the link between fat and bone mass? J Bone Miner Res 17: 1563-9.
Hoybye, C.(2002). Metabolic profile and body composition in adults with Prader-Willi syndrome and severe obesity. J Clin Endocrinol Metab 87: 3590-7.
Kaufman, B. A.(2002). Bone density and amenorrhea in ballet dancers are related to a decreased resting metabolic rate and lower leptin levels. J Clin Endocrinol Metab 87: 2777-83.
Burguera, B.(2001). Leptin reduces ovariectomy-induced bone loss in rats. Endocrinology 142: 3546-53.
Ducy, P.(2000). The osteoblast: a sophisticated fibroblast under central surveillance. Science 289: 1501-4.
Goulding, A.(1998). Plasma leptin values in relation to bone mass and density and to dynamic biochemical markers of bone resorption and formation in postmenopausal women. Calcif Tissue Int 63: 456-8.
Holloway, W. R.(2002). Leptin inhibits osteoclast generation. J Bone Miner Res 17: 200-9.
Iwamoto, I.(2000). Relationships between serum leptin level and regional bone mineral density, bone metabolic markers in healthy women. Acta Obstet Gynecol Scand 79: 1060-4.
Karsenty, G.(2000). The Central Regulation of Bone Remodeling. Trends Endocrinol Metab 11: 437-439.
Pasco, J. A.(2001). Serum leptin levels are associated with bone mass in nonobese women. J Clin Endocrinol Metab 86: 1884-7.
Reseland, J. E.(2001). Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. J Bone Miner Res 16: 1426-33.
Ricci, T. A.(2001). Moderate energy restriction increases bone resorption in obese postmenopausal women. Am J Clin Nutr 73: 347-352.
Sato, M.(2001). Association between Serum Leptin Concentrations and Bone Mineral Density, and Biochemical Markers of Bone Turnover in Adult Men. J Clin Endocrinol Metab 86: 5273-6.
Thomas, T.(2001). Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women. Bone 29: 114-20.
Yamauchi, M.(2001). Plasma leptin concentrations are associated with bone mineral density and the presence of vertebral fractures in postmenopausal women. Clin Endocrinol (Oxf) 55: 341-7.