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Osteoporos Int. Author manuscript; available in PMC 2009 September 1.
Published in final edited form as: Osteoporos Int. 2008 September ; 19(9): 1323–1330. doi:10.1007/s00198-008-0574-6.

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Effects of Estrogen Therapy on Bone Marrow Adipocytes in Postmenopausal Osteoporotic WomenFarhan A. Syed, Ph.D., Merry Jo Oursler, Ph.D., Theresa E. Hefferan, Ph.D., James. M. Peterson, M.S., B. Lawrence Riggs, M.D., and Sundeep Khosla, M.D. Endocrine Research Unit and Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Rochester, MN.

Introduction—Aging is associated not only with bone loss but also with increases in bone marrow adipocytes. Since osteoblastsand adipocytes are derived from a common precursor, it is possible that with aging, there is a preferential “switch” in commitment of this precursor to the adipocyte over the osteoblast lineage. We tested the hypothesis that the apparent “age-related” increase in marrow adipocytes is due, at least in part, to estrogen (E) deficiency. Methods—Reanalysis of bone biopsies from a randomized,placebo-controlled trial involving 56 postmenopausal osteoporotic women (mean age, 64 years) treated either with placebo (PL, n = 27) or transdermal estradiol (0.1 mg/d, n = 29) for 1 year. Results—Adipocyte volume/tissue volume (AV/TV) and adipocyte number (Ad#) increased (by ∼ 20%, P < 0.05) in the PL group, but were unchanged (Ad#) or decreased (AV/TV, by −24%, P < 0.001) in the E group. E treatmentalso prevented increases in mean adipocyte size over 1 year. Conclusions—These findings represent the first in vivo demonstration in humans that not only ongoing bone loss, but also the increase in bone marrow adipocyte number and size in postmenopausal osteoporotic women may be due, at least in part, to E deficiency. Keywords Osteoporosis; adipocytes; bone

Age-related bone loss inwomen and men and postmenopausal bone loss in women is due principally to an imbalance between bone resorption and bone formation (1). The impaired bone formation with aging was demonstrated in human iliac crest bone biopsies by Lips and colleagues (2) who measured mean wall thickness, an index of the work done by the team of osteoblasts in each basic multicellular unit (BMU), and found that thisdecreased by 43% over life. Dunnill and colleagues were the first to demonstrate an age-related increase in vertebral marrow fat and a decrease in bone volume as a function of age (3). Concomitant with an agerelated decrease in bone formation at the BMU level, Meunier and colleagues (4) established over three decades ago that there was a parallel increase in bone marrow adipose volume with age.Using iliac crest bone biopsies, these investigators showed that, between the ages of 20 and 90 years, trabecular bone volume decreased by 40% and this was accompanied by a 300% increase in marrow adipose volume in both women and men.

Address all correspondence to Sundeep Khosla, M.D., 5−194 Joseph, Endocrine Research Unit, Mayo Clinic College of Medicine, 200 First Street SW, Rochester,Minnesota 55905;

Syed et al.

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Osteoblasts and adipocytes are believed to be derived from a common progenitor in the bone marrow mesenchymal stromal compartment (5). A number of in vitro studies using primary bone marrow stromal cells and stromal cell lines have established the existence of a bipotential osteoblast/adipocyte precursor (6,7) The commitment of thisprecursor cell to the osteoblast or adipocyte lineages is determined by the expression and/or activity of lineage-specific transcription factors. For example, runx2 and osterix promote osteoblastic (8,9) and C/EBPß and PPARγ promote adipocytic commitment and differentiation (10). That the balance between such lineage-specific nuclear transcription factors is important was highlighted by findings...
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