Histological Effects of the Combined Administration of Eldecalcitol and a Parathyroid Hormone in the Metaphyseal Trabeculae of Ovariectomized Rats

Summary Intermittent administration of human parathyroid hormone (1-34) (hPTH(1-34)) promotes anabolic action in bone by stimulating bone remodeling, while eldecalcitol, an analog of active vitamin D3, suppresses osteoclastic bone resorption, and forms new bone by minimodeling. We have examined the biological effects of combined administration of eldecalcitol and hPTH(1-34) on 9-week-old Wistar rats that underwent an ovariectomy (OVX) or Sham operation. They were divided into a Sham group, OVX with vehicle (OVX group), OVX with 10 µg/kg/day of hPTH(1-34) (PTH group), OVX with 20 ng/kg/day of eldecalcitol (eldecalcitol group) or OVX with 10 μg/kg/day of hPTH(1-34), and 20 ng/kg/day of eldecalcitol (combined group) for 4 or 8 weeks. As a consequence, the combined group showed a marked increase in bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) than OVX and had the highest bone mineral density (BMD) compared with other groups. OVX and PTH groups exhibited a high osteoblastic surface/bone surface (Ob.S/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS) indices and many TRAP-reactive osteoclasts. Contrastingly, eldecalcitol and combined groups tended to attenuate the indices of osteoclastic surface/bone surface (Oc.S/BS) and Ob.S/BS than that the other groups. The combined group revealed histological profiles of minimodeling- and remodeling-based bone formation. Thus, the combined administration of eldecalcitol and hPTH(1-34) augments their anabolic effects by means of minimodeling and remodeling.

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Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00380.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. E1183-E1188 ◽

Cited By ~ 6

Author(s):

Nabanita S. Datta ◽

Tareq A. Samra ◽

Abdul B. Abou-Samra

Keyword(s):

Parathyroid Hormone ◽

Bone Formation ◽

Physiological Role ◽

Receptor Internalization ◽

Mineral Density ◽

Trabecular Thickness ◽

Receptor Complexes ◽

Diaphyseal Bone ◽

Anabolic Action

Activation of G protein-coupled receptors by agonists leads to receptor phosphorylation, internalization of ligand receptor complexes, and desensitization of hormonal response. The role of parathyroid hormone (PTH) receptor 1, PTHR1, is well characterized and known to regulate cellular responsiveness in vitro. However, the role of PTHR1 phosphorylation in bone formation is yet to be investigated. We have previously demonstrated that impaired internalization and sustained cAMP stimulation of phosphorylation-deficient (PD) PTHR1 leads to exaggerated cAMP response to subcutaneous PTH infusion in a PD knockin mouse model. To understand the physiological role of receptor internalization on PTH bone anabolic action, we examined bone parameters of wild-type (WT) and PD knockin female and male mice following PTH treatment. We found a decrease in total and diaphyseal bone mineral density in female but not in male PD mice compared with WT controls at 3–6 mo of age. This effect was attenuated at older age groups. PTH administration displayed increased bone volume and trabecular thickness in the vertebrae and distal femora of both WT and PD animals. These results suggest that PTHR1 phosphorylation does not play a major role in the anabolic action of PTH.

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A Delphinidin-Enriched Maqui Berry Extract Improves Bone Metabolism and Protects against Bone Loss in Osteopenic Mouse Models

Antioxidants ◽

10.3390/antiox8090386 ◽

2019 ◽

Vol 8 (9) ◽

pp. 386 ◽

Cited By ~ 2

Author(s):

Masahiro Nagaoka ◽

Toyonobu Maeda ◽

Masahiro Chatani ◽

Kazuaki Handa ◽

Tomoyuki Yamakawa ◽

...

Keyword(s):

Bone Loss ◽

Bone Formation ◽

Bone Metabolism ◽

Mouse Models ◽

Bone Morphogenetic Protein 2 ◽

Bone Surface ◽

Bone Formation Rate ◽

Trabecular Thickness ◽

Tissue Volume ◽

Maqui Berry

In our previous investigation, delphinidin, one of the most abundant anthocyanins found in vegetables and berry fruits, had been shown to inhibit osteoclasts and prevent bone loss in mouse models of osteoporosis. In the present study, we investigated whether a delphinidin glycoside-enriched maqui berry extract (MBE, Delphinol®) exhibits beneficial effects on bone metabolism both in vitro and in vivo. MBE stimulated the osteoblastic differentiation of MC3T3-E1 cells, as indicated by enhanced mineralized nodule formation, and increased alkaline phosphatase activity, through the upregulation of bone morphogenetic protein 2 (Bmp2), runt-related transcription factor 2 (Runx2), Osterix (Osx), osteocalcin (Ocn), and matrix extracellular phosphoglycoprotein (Mepe) mRNA expression. Immunostaining and immunoprecipitation assays demonstrated that MBE suppressed NF-κB transnucleation through acting as a superoxide anion/peroxynitrite scavenger in MC3T3-E1 cells. Simultaneously, MBE inhibited both osteoclastogenesis in primary bone marrow macrophages and pit formation by maturated osteoclasts on dentine slices. Microcomputed tomography (micro-CT) and bone histomorphometry analyses of femurs demonstrated that the daily ingestion of MBE significantly increased BV/TV (ratio of bone volume to tissue volume), Tb.Th (trabecular thickness), Tb.N (trabecular number), N.Nd/N.Tm (node to terminus ratio), OV/TV (ratio of osteoid volume to tissue volume), BFR/TV (bone formation rate per tissue volume), and significantly decreased Tb.Sp (trabecular separation), ES/BS (ratio of eroded surface to bone surface) and N.Oc/BS (number of osteoclast per unit of bone surface), compared to vehicle controls in osteopenic mouse models. These findings suggest that MBE can be a promising natural agent for the prevention of bone loss in osteopenic conditions by not only inhibiting bone resorption, but also stimulating bone formation.

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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 ◽

10.1210/en.2002-221061 ◽

2003 ◽

Vol 144 (5) ◽

pp. 2008-2015 ◽

Cited By ~ 76

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.

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Preventive and Therapeutic Effects of Acupuncture on Bone Mass in Osteopenic Ovariectomized Rats

The American Journal of Chinese Medicine ◽

10.1142/s0192415x04002089 ◽

2004 ◽

Vol 32 (03) ◽

pp. 427-443 ◽

Cited By ~ 13

Author(s):

Wenping Zhang ◽

Masayuki Kanehara ◽

Torao Ishida ◽

Yi Guo ◽

Xiuyun Wang ◽

...

Keyword(s):

Lumbar Vertebrae ◽

Ovariectomized Rats ◽

Control Group ◽

Acupuncture Points ◽

Therapeutic Effects ◽

Mineral Density ◽

Bone Formation Rate ◽

Trabecular Thickness ◽

Ovx Rats ◽

Model Control

This study was designed to (1) test the preventive and therapeutic effects of acupuncture on osteopenia in ovariectomized (OVX) rats, and (2) assess whether treatment of different acupuncture points causes different effects on tibiae, femora or lumbar spines. Thirty-five female Sprague-Dawley rats were divided into four groups: Sham (sham-operated, non-acupuncture); Model (OVX, non-acupuncture); Acp-A [OVX, bilateral needling of points Tsu-San-Li (ST-36) and San-Yin- Chiao (SP-6)]; and Acp-B (OVX, bilateral needling of P'i-Shu (Bl-20) and Shen Shu (Bl-23)). Operations were performed at 8 weeks of age, 1 week later the study was started and continued for 16 weeks. Ovariectomy resulted in decreased bone mineral density (BMD) compared to the sham group over time, and Acp-A tended to have higher BMD than the other OVX groups, especially for tibiae. In addition, the bone ash weight of the Acp groups tended to be heavier than the model group. Deoxypyridinoline, the urinary marker of bone resorption, also appeared to be decreased in both acupuncture groups. Similarly, microarchitecture and bone morphometry of lumbar vertebrae and tibiae, such as bone volume, trabecular thickness, trabecular number, mineralizing surface, bone formation rate, mineral apposition rate, number of nodes and number of node-terminus struts, also showed the same improvement in the acupuncture groups as compared to the model control group. Our findings showed that acupuncture may prevent the development of osteopenia in rats induced by ovariectomy. Needling of Tsu-San-Li (ST-36) and San-Yin- Chiao (SP-6) seems more effective than needling of P'i-Shu (Bl-20) and Shen Shu (Bl-23) in bone anabolic regulation.

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Effect of Minocycline on Osteoporosis

Advances in Dental Research ◽

10.1177/08959374980120012401 ◽

1998 ◽

Vol 12 (1) ◽

pp. 71-75 ◽

Cited By ~ 17

Author(s):

S. Williams ◽

A. Wakisaka ◽

Q.Q. Zeng ◽

J. Barnes ◽

S. Seyedin ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Trabecular Bone ◽

Formation Rate ◽

Inhibitory Effect ◽

Mineral Apposition Rate ◽

Mineral Density ◽

Bone Formation Rate ◽

Trabecular Thickness ◽

Trabecular Bone Area

The effect of oral minocycline on osteopenia in ovariectomized (OVX) old rats was examined in this study. Rats were divided into 4 groups: sham-operated, OVX followed by treatment with vehicle, minocycline, or 17β-estradiol. The treatment was initiated one day after OVX and proceeded for 8 wks. OVX reduced bone mineral density (BMD) in the whole femur and in the femoral regions that are enriched in trabecular bone. Treatment with minocycline or estrogen prevented a decrease in BMD. Femoral trabecular bone area, trabecular number, and trabecular thickness were reduced, and trabecular separation was increased by OVX. Treatment with minocycline or estrogen abolished the detrimental effects induced by OVX. OVX also reduced indices that reflect the interconnectivity of trabecular bone, and the loss of trabecular connectivity was prevented by treatment with minocycline or estrogen. Based on the levels of urinary pyridinoline, we showed that the effect of estrogen, but not minocycline, was primarily through its inhibitory effect on bone resorption. Analysis of bone turnover activity suggests that OVX increased parameters associated with bone resorption (eroded surface) and formation (osteoid surface, mineralizing surface, mineral apposition rate, and bone formation rate). Treatment with minocycline reduced bone resorption modestly and stimulated bone formation substantially. In contrast, treatment with estrogen drastically reduced parameters associated with both bone resorption and formation. We have concluded that oral minocycline can effectively prevent the decrease in BMD and trabecular bone through its dual effects on bone resorption and formation.

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Teriparatide [rhPTH (1-34)], But Not Strontium Ranelate, Demonstrated Bone Anabolic Efficacy in Mature, Osteopenic, Ovariectomized Rats

Endocrinology ◽

10.1210/en.2010-1112 ◽

2011 ◽

Vol 152 (5) ◽

pp. 1767-1778 ◽

Cited By ~ 23

Author(s):

Yanfei L. Ma ◽

Qing Q. Zeng ◽

Leah L. Porras ◽

Anita Harvey ◽

Terry L. Moore ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Formation ◽

Bone Mineral ◽

Strontium Ranelate ◽

Formation Rate ◽

Ovariectomized Rats ◽

Mineral Density ◽

Bone Formation Rate ◽

Ovx Rats ◽

Dose Dependent

We compared teriparatide (TPTD) and strontium ranelate (SR) efficacy on bone formation activity in a mature rat model of estrogen-deficiency bone loss. Rats were ovariectomized (OVX) at age 6 months and permitted to lose bone for 2 months to establish osteopenia before initiation of treatment with TPTD (5 or 15 μg/kg · d sc) or SR (150 or 450 mg/kg · d oral gavage). After 3 wk, RT-PCR analyses of bone formation genes in the distal femur metaphysis showed significant elevation of collagen 1α2, osteocalcin, bone sialoprotein, alkaline phosphatase, and Runx2 gene expression at both TPTD doses, relative to OVX controls. SR had no significant effect on expression of these genes. TPTD treatment for 12 wk dose dependently increased lumbar vertebral (LV) and femoral midshaft bone mineral content (BMC) and bone mineral density over pretreatment and age-matched OVX controls. SR 150 increased BMC, and SR 450 increased BMC and bone mineral density of femoral midshaft and LV over OVX controls. There were significant dose-dependent TPTD increases of LV and femoral neck strength, and TPTD 15 also increased midshaft strength compared with pretreatment and age-matched OVX controls. SR did not enhance bone strength relative to pretreatment or age-matched OVX controls. Histomorphometry of the proximal tibial metaphysis showed dose-dependent effects of TPTD on trabecular area, number, width, and osteoblast surface, bone mineralizing surface, and bone formation rate relative to pretreatment and age-matched OVX controls, whereas SR had no effect on these parameters. These findings confirmed the bone anabolic efficacy of teriparatide, but not SR in mature, osteopenic, OVX rats.

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Skeletal Effects of the Saturated 3-Thia Fatty Acid Tetradecylthioacetic Acid in Rats

PPAR Research ◽

10.1155/2011/436358 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Astrid Kamilla Stunes ◽

Irene Westbroek ◽

Reidar Fossmark ◽

Rolf Kristian Berge ◽

Janne Elin Reseland ◽

...

Keyword(s):

Whole Body ◽

Sham Operation ◽

Peroxisome Proliferator ◽

Mineral Density ◽

Femoral Bone Mineral Density ◽

Peroxisome Proliferator Activated Receptor ◽

Trabecular Thickness ◽

Tetradecylthioacetic Acid ◽

Femoral Metaphysis ◽

Skeletal Effects

This study explores the skeletal effects of the peroxisome proliferator activated receptor (PPAR)pan agonist tetradecylthioacetic acid (TTA). Rats, without (Study I) and with ovariectomy (OVX) or sham operation (Study II), were given TTA or vehicle daily for 4 months. Bone markers in plasma, whole body and femoral bone mineral density and content (BMD and BMC), and body composition were examined. Histomorphometric and biomechanical analyses (Study I) and biomechanical and μCT analyses (Study II) of the femur were performed. Normal rats fed TTA had higher femoral BMD and increased total and cortical area in femur compared to controls. The ovariectomized groups had decreased BMD and impaired microarchitecture parameters compared to SHAM. However, the TTA OVX group maintained femoral BMC, trabecular thickness in the femoral head, and cortical volume in the femoral metaphysis as SHAM. TTA might increase BMD and exert a light preventive effect on estrogen-related bone loss in rats.

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Keel-bone fractures are associated with bone quality differences in laying hens

Animal Welfare ◽

10.7120/09627286.30.1.071 ◽

2021 ◽

Vol 30 (1) ◽

pp. 71-80

Author(s):

HD Wei ◽

YJ Chen ◽

XY Zeng ◽

YJ Bi ◽

YN Wang ◽

...

Keyword(s):

Bone Quality ◽

Laying Hens ◽

Bone Fractures ◽

Quality Parameters ◽

Bone Volume ◽

Tartrate Resistant Acid Phosphatase ◽

Bone Surface ◽

Mineral Density ◽

Trabecular Thickness ◽

Trap Activity

This study aimed to investigate the relationship between bone quality in terms of metabolism, homeostasis of elements, bone mineral density (BMD), and microstructure and keel-bone fractures in laying hens (Gallusgallusdomesticus). One hundred and twenty 17 week old Lohmann White laying hens with normal keel bones were individually housed in furnished cages for 25 weeks. Birds were then euthanased and dissected to assess keel-bone status at 42 weeks. Serum and keel-bone samples from normal keel (NK) and fractured keel (FK) hens were collected to determine the previously mentioned bone quality parameters. The results showed FK hens to have higher levels of the components of osteocalcin, greater alkaline phosphatase activity in serum and keel bones, and greater tartrate-resistant acid phosphatase (TRAP) activity in keel bones, compared to NK hens. Additionally, FK hens also had higher concentrations of Li, B, K, Cu, As, Se, Sn, Hg, and Pb, but lower concentrations of Na, P, and Ca. Moreover, FK hens showed decreased bone microstructural parameters including bone volume/tissue volume, trabecular number, degree of anisotropy, connectivity density, and BMD, but increased trabecular separation. Meanwhile, no differences were detected in serum TRAP activity, trabecular thickness, bone surface, or bone surface/bone volume. Results showed laying hens with keel-bone fractures to have differences in bone metabolism, elements of homeostasis, bone microstructure parameters, and BMD. These results suggest that keel-bone fractures may be associated with bone quality.

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The Effects of Signaling-Selective Parathyroid Hormone Analogs on Osteoporotic Osteocyte Apoptosis

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2904 ◽

2022 ◽

Vol 12 (2) ◽

pp. 316-322

Author(s):

Meng-Sheng Song ◽

Xiao Yu ◽

Peng-Ze Rong ◽

Qing-Jiang Pang

Keyword(s):

Parathyroid Hormone ◽

Immunohistochemical Staining ◽

Micro Computed Tomography ◽

Mineral Density ◽

Femoral Bone Mineral Density ◽

Trabecular Thickness ◽

Osteocyte Apoptosis ◽

Trabecular Bone Microstructure ◽

Hormone Analogs ◽

Trabecular Number

Objectives: To compare the effects of signaling-selective parathyroid hormone analogs [G1, R19]hPTH(1–28) [GR(1–28)] and [G1, R19]hPTH(1–34) [GR(1–34)] on osteoporotic osteocyte apoptosis, and to explore the mechanism of the anti-osteoporotic difference. Methods: The osteoporosis model was established in eighty adult female C57BL/6 mice aged 12 weeks. The mice were subcutaneously administered with GR(1–28) and GR(1–34) 5 days per week for 8 weeks. Bilateral femur samples were collected at 4 and 8 weeks, and micro-computed tomography (CT), H&E staining and immunohistochemical staining analyses were performed. Results: From micro-CT analysis, GR(1–34) increased proximal femoral bone mineral density (BMD) and relative bone volume (BV/TV), which was higher than GR(1–28) did. In addition, more trabecular number (Tb.N), thinner trabecular thickness (Tb.Th) and wider trabecular separation (Tb.Sp) were measured at week 8 using GR(1–34). From H&E and immunohistochemical staining, a stronger apoptosis inhibition was induced by GR(1–34) with more Bcl-2 secretion but less Bax expression, as opposed to GR(1–28). Conclusions: GR(1–34) shows better anti-osteoporotic effects than GR(1–28), which appears to be attributed to the activation of the PLC-independent PKC signaling pathway triggered by the former, inhibiting osteocyte apoptosis through up-regulation of Bcl-2 and down-regulation of Bax to increase bone mass and improving trabecular bone microstructure to enhance bone quality by reducing trabecular number, increasing trabecular thickness and trabecular space.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.281.2.e283 ◽

2001 ◽

Vol 281 (2) ◽

pp. E283-E288 ◽

Cited By ~ 33

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.

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