scholarly journals Leptin Modulates both Resorption and Formation while Preventing Disuse-Induced Bone Loss in Tail-Suspended Female Rats

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3652-3659 ◽  
Author(s):  
Aline Martin ◽  
Raphaël de Vittoris ◽  
Valentin David ◽  
Ricardo Moraes ◽  
Martine Bégeot ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Formation Rate ◽  
Female Rats ◽  
Tail Suspension ◽  
Delayed Effect ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Positive Effects

Abstract In vitro studies have demonstrated leptin-positive effects on the osteoblast lineage and negative effects on osteoclastogenesis. Therefore, we tested the hypothesis that leptin may prevent tail-suspension-induced bone loss characterized by an uncoupling pattern of bone remodeling, through both mechanisms. Female rats were randomly tail-suspended or not and treated either with ip administration of leptin or vehicle for 3, 7, and 14 d. As measured by dual energy x-ray absorptiometry, tail-suspension induced a progressive decrease in tibia-metaphysis bone mineral density, which was prevented by leptin. Histomorphometry showed that this was related to the prevention of the transient increase in osteoclast number observed with suspension at d 7. These effects could be mediated by the receptor activator of nuclear factor κB-ligand (RANKL)/osteoprotegerin (OPG) pathway since we observed using direct RT-PCR, a suspension-induced increase in RANKL gene expression in proximal tibia at d 3, which was counterbalanced by leptin administration with a similar 3-fold increase in OPG expression and a RANKL to OPG ratio close to nonsuspended conditions. In addition, leptin prevented the decrease in bone formation rate induced by tail-suspension at d 14. The latter could be related to the role of leptin in mediating the reciprocal differentiation between adipocytes and osteoblasts, because leptin concurrently blunted the disuse-induced increase in bone marrow adipogenesis. In summary, these data suggest that peripheral administration of leptin could prevent disuse-induced bone loss through, first, a major inhibitory effect on bone resorption and, second, a delayed effect preventing the decrease in bone formation.

Bone modeling in bromocriptine-treated pregnant and lactating rats: possible osteoregulatory role of prolactin in lactation

2010 ◽  
Vol 299 (3) ◽  
pp. E426-E436 ◽  
Author(s):  
Panan Suntornsaratoon ◽  
Kannikar Wongdee ◽  
Suchandra Goswami ◽  
Nateetip Krishnamra ◽  
Narattaphol Charoenphandhu
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Trabecular Bone ◽  
Formation Rate ◽  
Bone Modeling ◽  
Mineral Density ◽  
Pregnant Rats ◽  
Bone Formation Rate ◽  
Bone Trabeculae ◽  
Bone Gain

The lactogenic hormone prolactin (PRL) directly regulates osteoblast functions in vitro and modulates bone remodeling in nulliparous rats, but its osteoregulatory roles in pregnant and lactating rats with physiological hyperprolactinemia remained unclear. Herein, bone changes were investigated in rats treated with bromocriptine (Bromo), an inhibitor of pituitary PRL release, or Bromo+PRL at different reproductive phases, from mid-pregnancy to late lactation. PRL receptors were strongly expressed in osteoblasts lining bone trabeculae, indicating bone as a target of PRL actions. By using dual energy X-ray absorptiometry, we found a significant increase in bone mineral density in the femora and vertebrae of pregnant rats. Such pregnancy-induced bone gain was, however, PRL independent and may have resulted from the increased cortical thickness. Bone trabeculae were modestly changed during pregnancy as evaluated by bone histomorphometry. On the other hand, lactating rats, especially in late lactation, showed massive bone loss in bone trabeculae but not in cortical shells. Further study in Bromo- and Bromo+PRL-treated rats suggested that PRL contributed to decreases in trabecular bone volume and number and increases in trabecular separation and eroded surface, as well as a paradoxical increase in bone formation rate in late lactation. Uncoupling of trabecular bone formation and resorption was evident in lactating rats, with the latter being predominant. In conclusion, pregnancy mainly induced cortical bone gain, whereas lactation led to trabecular bone loss in both long bones and vertebrae. Although PRL was not responsible for the pregnancy-induced bone gain, it was an important regulator of bone modeling during lactation.

scholarly journals New Bone Formation with Teriparatide [Human Parathyroid Hormone-(1–34)] Is Not Retarded by Long-Term Pretreatment with Alendronate, Estrogen, or Raloxifene in Ovariectomized Rats

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 2008-2015 ◽  
Author(s):  
Yanfei L. Ma ◽  
Henry U. Bryant ◽  
Qingqiang Zeng ◽  
Allen Schmidt ◽  
Jennifer Hoover ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Formation Rate ◽  
Prior Exposure ◽  
Ovariectomized Rats ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Teriparatide Treatment ◽  
Antiresorptive Agents ◽  
Ovx Rats

With the ready availability of several osteoporosis therapies, teriparatide [human PTH-(1–34)] is likely to be prescribed to postmenopausal women with prior exposure to agents that prevent bone loss, such as bisphosphonates, estrogen, or selective estrogen receptor modulators. Therefore, we evaluated the ability of once daily teriparatide to induce bone formation in ovariectomized (Ovx) rats with extended prior exposure to various antiresorptive agents, such as alendronate (ABP), 17α-ethinyl estradiol (EE), or raloxifene (Ral). Sprague Dawley rats were Ovx and treated with ABP (28 μg/kg, twice weekly), EE (0.1 mg/kg·d), or Ral (1 mg/kg·d) for 10 months before switching to teriparatide 30 μg/kg·d for another 2 months. Analysis of the proximal tibial metaphysis showed that all three antiresorptive agents prevented ovariectomy-induced bone loss after 10 months, but were mechanistically distinct, as shown by histomorphometry. Before teriparatide treatment, ABP strongly suppressed activation frequency and bone formation rate to below levels in other treatment groups, whereas these parameters were not different from sham values for EE or Ral. Trabecular area for ABP, EE, and Ral were greater than that in Ovx controls. However, the trabecular bone effects of ABP were attributed not only to effects on the secondary spongiosa, but also to the preservation of primary spongiosa, which was prevented from remodeling. After 2 months of teriparatide treatment, lumbar vertebra showed relative bone mineral density increases of 18%, 7%, 11%, and 10% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Histomorphometry showed that trabecular area was increased by 105%, 113%, 36%, and 48% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Teriparatide enhanced mineralizing surface, mineral apposition rate, and bone formation rate in all groups. Compression testing of vertebra showed that teriparatide improved strength (peak load) and toughness in all groups to a proportionately similar extent compared with 10 month levels. These data showed a surprising ability of the rat skeleton to respond to teriparatide despite extensive pretreatment with ABP, EE, or Ral. Therefore, the mature skeleton of Ovx rats remains highly responsive to the appositional effects of teriparatide regardless of pretreatment status in terms of cancellous bone area or rate of bone turnover.

scholarly journals DSS-induced colitis produces inflammation-induced bone loss while irisin treatment mitigates the inflammatory state in both gut and bone

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Corinne E. Metzger ◽  
S. Anand Narayanan ◽  
Jon P. Elizondo ◽  
Anne Michal Carter ◽  
David C. Zawieja ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Therapeutic Potential ◽  
Negative Impact ◽  
Formation Rate ◽  
Inflammatory Factors ◽  
Sprague Dawley ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Gut Inflammation

Abstract Chronic pediatric inflammatory bowel disease (IBD) leads to lack of bone accrual, bone loss, and increased fractures. Presently there is no cure, and many IBD treatments incur negative side effects. We previously discovered treatment with exogenous irisin resolved inflammatory changes in the colon, gut lymphatics, and bone in a mild IBD rodent model. Here we assess irisin treatment in severe IBD induced via dextran sodium sulfate (DSS). Male Sprague Dawley rats (2-mo-old) were untreated (Con) or given 2% DSS in drinking water. In week two, half of each group (Con + Ir and DSS + Ir) received injections of recombinant irisin (i.p., 2x/wk). After 4 weeks, gut inflammation was associated with declines in bone mineral density and cancellous bone volume. Furthermore, elevated osteocyte TNF-α, interleukin-6, RANKL, OPG, and sclerostin corresponded with higher osteoclast surfaces and lower bone formation rate in DSS animals as well as lower ultimate load. While irisin treatment improved colon inflammation, there were no improvements in bone density or bone mechanical properties; however, irisin elevated bone formation rate, decreased osteoclast surfaces, and reduced osteocyte pro-inflammatory factors. These data highlight the negative impact of chronic gut inflammation on bone as well as the therapeutic potential of irisin as an anti-inflammatory treatment.

Erythropoietin Stimulates Bone Resorption Via Direct Activation of the Monocytic Lineage and Via Increased RANKL Production By B Cells and Osteoblasts

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 247-247
Author(s):  
Sahar Hiram-Bab ◽  
Naamit Deshet ◽  
Tamar Liron ◽  
Moshe Mittelman ◽  
Max Gassmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Bone Loss ◽  
Bone Formation ◽  
Formation Rate ◽  
Serum Levels ◽  
Bone Formation Rate ◽  
Negative Effect ◽  
Monocytic Lineage

Abstract The negative effect of hypoxia on bone metabolism is well established but its mechanism of action is not fully understood. Hypoxia triggers the production of erythropoietin (EPO), a hormone most recognized for its hematopoietic function. An increasing number of roles unrelated to red blood cell production have been attributed to EPO, many of which are mediated by non-erythroid cells. In light of the controversy on the effect of increased serum levels of EPO on the skeleton, we investigated here the effect of the hormone on bone metabolism using EPO overexpressing (Tg6), and EPO-administered adult mice. In these models, the increase in EPO levels is similar to its physiologic increase at high altitude without the confounding direct effect of hypoxia on bone cells. Using microcomputed tomography, histology and serum markers we found that high EPO levels result in a severe trabecular bone loss (-32 to -61% decrease in bone density in Tg6 and EPO-injected animals, respectively; p<0.05 versus their respective controls throughout), due to increased bone resorption (+28 to +18% in TRAP5b serum levels) and reduced bone formation rate (-19 to -74%). This bone loss consisted of reduced trabecular number, but not thickness, with no effect on the cortical bone compartment. A similar bone response was observed with high and low doses of EPO, with no difference between intermittent and continuous administration modes. Using flow cytometry analysis and specific cell surface markers, we found that EPO (both overexpression and injection) targets the monocytic lineage by increasing the number of CD115+CD265- monocytes/macrophages by 43 and 57% (p<0.05), CD115+ CD265+ pre-osteoclasts by 2 and 4-fold (p=0.02) and mature osteoclasts (TRAP positive) by 64 and 88% (p<0.05, Figure 1A) in bones, compared to WT and diluent controls, respectively. EPO has direct stimulatory effects in vitro on both macrophages and preosteoclasts thus coupling immune and skeletal systems, Activation of purified BM-derived macrophages with EPO, led to a 33% increase (p=0.01) in phagocytosis of 5T33 multiple myeloma cells. EPO strongly stimulated osteoclastogenesis (TRAP staining, Figure 1B) and pit resorption (measured in calcium-phosphate-coated wells) in a cell-autonomous manner. Furthermore, our data indicate that EPO receptor (EPO-R) signaling in osteoclast precursors involves the Jak2 and PI3K pathways, but is independent of the MAPK/MEK pathway. In addition to the direct effect of EPO on monocyte derived cells, high EPO also led to a 1.6 fold (p=0.03) increase in the transcript levels of the osteoclastogenic cytokine RANKL in total bone marrow. Notably, the major sources of RANKL are B cells and osteoblasts, and our data indicate that both cell types express EPO-R, suggesting that they are direct targets of EPO. Accordingly we found an EPO-related increase in membrane bound RANKL on B cells (1.8-fold, p=0.0003) and osteoblasts (1.16-fold, p=0.001) isolated from bone marrow (Figure 1C). To test whether EPO-R on osteoblasts also mediates the attenuation of bone formation, we treated isolated osteoblasts with EPO. However, EPO treatment in vitro did not inhibit osteoblast differentiation and activity, as demonstrated by RT-qPCR of marker genes and mineralization assays. Taken together, these findings demonstrate that EPO strongly regulates bone mass by stimulating osteoclastogenesis and attenuating bone formation. The osteoclastogenic action of EPO is mediated both directly by EPO-R on the monocytic lineage and indirectly via EPO-R signaling on B cells and osteoblasts. Regarding bone formation, the negative effect of EPO on bone formation rate in vivo was not reproduced in isolated cells, thus implying the involvement of cells beyond the osteoblastic lineage. We also propose a new mechanism for hypoxia-induced bone loss that involves EPO action on monocytic, B cell and osteoblastic lineages. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Palm Tocotrienol Supplementation Enhanced Bone Formation in Oestrogen-Deficient Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Ima Nirwana Soelaiman ◽  
Wang Ming ◽  
Roshayati Abu Bakar ◽  
Nursyahrina Atiqah Hashnan ◽  
Hanif Mohd Ali ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Type I Collagen ◽  
Formation Rate ◽  
Serum Levels ◽  
Female Rats ◽  
Mineral Apposition Rate ◽  
Type I ◽  
Bone Biomarkers ◽  
Bone Formation Rate

Postmenopausal osteoporosis is the commonest cause of osteoporosis. It is associated with increased free radical activity induced by the oestrogen-deficient state. Therefore, supplementation with palm-oil-derived tocotrienols, a potent antioxidant, should be able to prevent this bone loss. Our earlier studies have shown that tocotrienol was able to prevent and even reverse osteoporosis due to various factors, including oestrogen deficiency. In this study we compared the effects of supplementation with palm tocotrienol mixture or calcium on bone biomarkers and bone formation rate in ovariectomised (oestrogen-deficient) female rats. Our results showed that palm tocotrienols significantly increased bone formation in oestrogen-deficient rats, seen by increased double-labeled surface (dLS/Bs), reduced single-labeled surface (sLS/BS), increased mineralizing surface (MS/BS), increased mineral apposition rate (MAR), and an overall increase in bone formation rate (BFR/BS). These effects were not seen in the group supplemented with calcium. However, no significant changes were seen in the serum levels of the bone biomarkers, osteocalcin, and cross-linked C-telopeptide of type I collagen, CTX. In conclusion, palm tocotrienol is more effective than calcium in preventing oestrogen-deficient bone loss. Further studies are needed to determine the potential of tocotrienol as an antiosteoporotic agent.

IGF-binding protein-5 stimulates osteoblast activity and bone accretion in ovariectomized mice

2001 ◽  
Vol 281 (2) ◽  
pp. E283-E288 ◽  
Author(s):  
Dennis L. Andress
Keyword(s):  
Bone Formation ◽  
Binding Protein ◽  
Formation Rate ◽  
Bone Matrix ◽  
Secretory Protein ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Ovariectomized Mice ◽  
Osteoblast Activity

Insulin-like growth factor binding protein-5 (IGFBP-5) is an osteoblast secretory protein that becomes incorporated into the mineralized bone matrix. In osteoblast cultures, IGFBP-5 stimulates cell proliferation by an IGF-independent mechanism. To evaluate whether IGFBP-5 can stimulate osteoblast activity and enhance bone accretion in a mouse model of osteoblast insufficiency, daily subcutaneous injections of either intact [IGFBP-5 (intact)] or carboxy-truncated IGFBP-5 [IGFBP-5-(1–169)] were given to ovariectomized (OVX) mice for 8 wk. Femur and spine bone mineral density (BMD), measured every 2 wk, showed early and sustained increases in response to IGFBP-5. Bone histomorphometry of cancellous bone showed significant elevations in the bone formation rate in both the femur metaphysis [IGFBP-5- (1)] only) and spine compared with OVX controls. IGFBP-5 also stimulated osteoblast number in the femur IGFBP-5-(1–169) only) and spine. These data indicate that IGFBP-5 effectively enhances bone formation and bone accretion in OVX mice by stimulating osteoblast activity. The finding that IGFBP-5-(1–169) is bioactive in vivo indicates that the carboxy-terminal portion is not required for this bone anabolic effect.

scholarly journals Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis

2008 ◽  
Vol 205 (5) ◽  
pp. 1145-1153 ◽  
Author(s):  
Luc Malaval ◽  
Ndéyé Marième Wade-Guéye ◽  
Maya Boudiffa ◽  
Jia Fei ◽  
Ralph Zirngibl ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Growth ◽  
Formation Rate ◽  
Bone Sialoprotein ◽  
Tail Suspension ◽  
Wild Type ◽  
Hematopoietic Progenitors ◽  
Bone Formation Rate ◽  
Osteoblast Markers ◽  
Resorptive Activity

Bone sialoprotein (BSP) and osteopontin (OPN) are both highly expressed in bone, but their functional specificities are unknown. OPN knockout (−/−) mice do not lose bone in a model of hindlimb disuse (tail suspension), showing the importance of OPN in bone remodeling. We report that BSP−/− mice are viable and breed normally, but their weight and size are lower than wild-type (WT) mice. Bone is undermineralized in fetuses and young adults, but not in older (≥12 mo) BSP−/− mice. At 4 mo, BSP−/− mice display thinner cortical bones than WT, but greater trabecular bone volume with very low bone formation rate, which indicates reduced resorption, as confirmed by lower osteoclast surfaces. Although the frequency of total colonies and committed osteoblast colonies is the same, fewer mineralized colonies expressing decreased levels of osteoblast markers form in BSP−/− versus WT bone marrow stromal cultures. BSP−/− hematopoietic progenitors form fewer osteoclasts, but their resorptive activity on dentin is normal. Tail-suspended BSP−/− mice lose bone in hindlimbs, as expected. In conclusion, BSP deficiency impairs bone growth and mineralization, concomitant with dramatically reduced bone formation. It does not, however, prevent the bone loss resulting from loss of mechanical stimulation, a phenotype that is clearly different from OPN−/− mice.

scholarly journals Leucine rich amelogenin peptide prevents ovariectomy-induced bone loss in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259966
Author(s):  
Naoto Haruyama ◽  
Takayoshi Yamaza ◽  
Shigeki Suzuki ◽  
Bradford Hall ◽  
Andrew Cho ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bone Turnover ◽  
Fluorescent Protein ◽  
Tooth Enamel ◽  
Quantitative Polymerase Chain Reaction ◽  
Periodontal Ligament Cells ◽  
Mineral Density ◽  
Entry Site

Amelogenins, major extra cellular matrix proteins of developing tooth enamel, are predominantly expressed by ameloblasts and play significant roles in the formation of enamel. Recently, amelogenin has been detected in various epithelial and mesenchymal tissues, implicating that it might have distinct functions in various tissues. We have previously reported that leucine rich amelogenin peptide (LRAP), one of the alternate splice forms of amelogenin, regulates receptor activator of NF-kappa B ligand (RANKL) expression in cementoblast/periodontal ligament cells, suggesting that the amelogenins, especially LRAP, might function as a signaling molecule in bone metabolism. The objective of this study was to identify and define LRAP functions in bone turnover. We engineered transgenic (TgLRAP) mice using a murine 2.3kb α1(I)-collagen promoter to drive expression of a transgene consisting of LRAP, an internal ribosome entry site (IRES) and enhanced green fluorescent protein (EGFP) to study functions of LRAP in bone formation and resorption. Calvarial cell cultures from the TgLRAP mice showed increased alkaline phosphatase (ALP) activity and increased formation of mineralized nodules compared to the cells derived from wild-type (WT) mice. The TgLRAP calvarial cells also showed an inhibitory effect on osteoclastogenesis in vitro. Gene expression comparison by quantitative polymerase chain reaction (Q-PCR) in calvarial cells indicated that bone formation makers such as Runx2, Alp, and osteocalcin were increased in TgLRAP compared to the WT cells. Meanwhile, Rankl expression was decreased in the TgLRAP cells in vitro. The ovariectomized (OVX) TgLRAP mice resisted bone loss induced by ovariectomy resulting in higher bone mineral density in comparison to OVX WT mice. The quantitative analysis of calcein intakes indicated that the ovariectomy resulted in increased bone formation in both WT and TgLRAP mice; OVX TgLRAP appeared to show the most remarkably increased bone formation. The parameters for bone resorption in tissue sections showed increased number of osteoclasts in OVX WT, but not in OVX TgLRAP over that of sham operated WT or TgLRAP mice, supporting the observed bone phenotypes in OVX mice. This is the first report identifying that LRAP, one of the amelogenin splice variants, affects bone turnover in vivo.

scholarly journals Bone microstructural defects and osteopenia in hemizygous βIVSII-654knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function

2015 ◽  
Vol 309 (11) ◽  
pp. E936-E948 ◽  
Author(s):  
Kanogwun Thongchote ◽  
Saovaros Svasti ◽  
Jarinthorn Teerapornpuntakit ◽  
Panan Suntornsaratoon ◽  
Nateetip Krishnamra ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Histomorphometry ◽  
Formation Rate ◽  
Computer Assisted ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Male And Female ◽  
Female Mice ◽  
Growing Period ◽  
Microstructural Defects

β-Thalassemia, a hereditary anemic disorder, is often associated with skeletal complications that can be found in both males and females. The present study aimed to investigate the age- and sex-dependent changes in bone mineral density (BMD) and trabecular microstructure in βIVSII-654knockin thalassemic mice. Dual-energy X-ray absorptiometry and computer-assisted bone histomorphometry were employed to investigate temporal changes in BMD and histomorphometric parameters in male and female mice of a βIVSII-654knockin mouse model of human β-thalassemia, in which impaired splicing of β-globin transcript was caused by hemizygous C→T mutation at nucleotide 654 of intron 2. Young, growing βIVSII-654mice (1 mo old) manifested shorter bone length and lower BMD than their wild-type littermates, indicating possible growth retardation and osteopenia, the latter of which persisted until 8 mo of age (adult mice). Interestingly, two-way analysis of variance suggested an interaction between sex and βIVSII-654genotype, i.e., more severe osteopenia in adult female mice. Bone histomorphometry further suggested that low trabecular bone volume in male βIVSII-654mice, particularly during a growing period (1–2 mo), was primarily due to suppression of bone formation, whereas both a low bone formation rate and a marked increase in osteoclast surface were observed in female βIVSII-654mice. In conclusion, osteopenia and trabecular microstructural defects were present in both male and female βIVSII-654knockin thalassemic mice, but the severity, disease progression, and cellular mechanism differed between the sexes.

scholarly journals Increased Marrow Adiposity in Premenopausal Women with Idiopathic Osteoporosis

2012 ◽  
Vol 97 (8) ◽  
pp. 2782-2791 ◽  
Author(s):  
Adi Cohen ◽  
David W. Dempster ◽  
Emily M. Stein ◽  
Thomas L. Nickolas ◽  
Hua Zhou ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Formation Rate ◽  
Premenopausal Women ◽  
Micro Computed Tomography ◽  
Mineral Density ◽  
Marrow Fat ◽  
Bone Formation Rate ◽  
Idiopathic Osteoporosis ◽  
Marrow Adiposity

Abstract Context: We have previously reported that premenopausal women with idiopathic osteoporosis based on fractures (IOP) or idiopathic low bone mineral density (ILBMD) exhibit markedly reduced bone mass, profoundly abnormal trabecular microstructure, and significant deficits in trabecular bone stiffness. Bone remodeling was heterogeneous. Those with low bone turnover had evidence of osteoblast dysfunction and the most marked deficits in microstructure and stiffness. Objective: Because osteoblasts and marrow adipocytes derive from a common mesenchymal precursor and excess marrow fat has been implicated in the pathogenesis of bone fragility in anorexia nervosa, glucocorticoid excess, and thiazolidinedione exposure, we hypothesized that marrow adiposity would be higher in affected women and inversely related to bone mass, microarchitecture, bone formation rate, and osteoblast number. Design: We analyzed tetracycline-labeled transiliac biopsy specimens in 64 premenopausal women with IOP or ILBMD and 40 controls by three-dimensional micro-computed tomography and two-dimensional quantitative histomorphometry to assess marrow adipocyte number, perimeter, and area. Results: IOP and ILBMD subjects did not differ with regard to any adipocyte parameter, and thus results were combined. Subjects had substantially higher adipocyte number (by 22%), size (by 24%), and volume (by 26%) than controls (P &lt; 0.0001 for all). Results remained significant after adjusting for age, body mass index, and bone volume. Controls demonstrated expected direct associations between marrow adiposity and age and inverse relationships between marrow adiposity and bone formation, volume, and microstructure measures. No such relationships were observed in the subjects. Conclusions: Higher marrow adiposity and the absence of expected relationships between marrow adiposity and bone microstructure and remodeling in women with IOP or ILBMD suggest that the relationships between fat and bone are abnormal; excess marrow fat may not arise from a switch from the osteoblast to the adipocyte lineage in this disorder. Whether excess marrow fat contributes to the pathogenesis of this disorder remains unclear.

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