PRECLINICAL STUDIES OF ALENDRONATE

1999 ◽  
Vol 03 (03) ◽  
pp. 209-216
Author(s):  
Jenny Zhao ◽  
Yebin Jiang ◽  
Harry K. Genant
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Turnover ◽  
Trabecular Bone ◽  
Bending Strength ◽  
Bone Volume ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Dose Dependent

Alendronate has been developed for the treatment of diseases characterized by increased bone resorption, such as osteoporosis. It increases metaphyseal bone density, bone volume, femoral bending strength and vertebral compressive strength, in a dose-dependent manner, in growing, intact rats. In ovariectomized (OVX) rats, alendronate increases femoral bone mass and tibial trabecular bone volume in a dose-dependent manner, and increases femoral midshaft bending strength. In rats immobilized by unilateral sciatic neurectomy, it inhibits bone loss and is dose-dependent. In rats, alendronate prevents high-turnover osteopenia induced by hyperthyroidism or by administration of immunosuppressant agent cyclosporin-A. Also in rats, treatment with prostaglandin E 2 and alendronate does not inhibit prostaglandin E 2-induced stimulation of bone formation on endocortical and periosteal surfaces. It does, however, prevent prostaglandin E 2-induced cortical bone porosity as a result of increased bone resorption, leading to an increase in cortical thickness and an increase in three-point bending strength of the femoral midshaft. At up to five times the dose used for treatment of osteoporosis in clinical trials, alendronate causes no abnormalities in bone remodeling, bone structure, or structural mechanical properties of the femur or vertebrae in intact beagles. Treatment with alendronate before or during fracture healing, or both, has no adverse effects on the union, strength, bone formation or mineralization of bone in mature beagle dogs. In intact minipigs, sodium fluoride increases and alendronate decreases bone turnover, while sodium fluoride, but not alendronate, decreases L4 strength and femoral stiffness. Small-angle X-ray scattering and backscattered electron imaging show that the trabecular bone matrix is more uniformly mineralized after alendronate treatment. In OVX baboons, which show bone changes similar to those seen in postmenopausal women, alendronate prevents an increase in bone turnover, and increases both bone volume and strength in vertebrae, in a dose-dependent manner. Alendronate also reduces the bone loss of alveolar support associated with periodontitis in monkeys. Thus, alendronate inhibits bone resorption and bone turnover, increases bone quantity accompanied by improved bone quality in some of the intact animals and in the animal models.

Running exercise alleviates trabecular bone loss and osteopenia in hemizygous β-globin knockout thalassemic mice

2014 ◽  
Vol 306 (12) ◽  
pp. E1406-E1417 ◽  
Author(s):  
Kanogwun Thongchote ◽  
Saovaros Svasti ◽  
Jarinthorn Teerapornpuntakit ◽  
Nateetip Krishnamra ◽  
Narattaphol Charoenphandhu
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Trabecular Bone ◽  
Elevated Serum ◽  
Bone Volume ◽  
Trabecular Bone Volume ◽  
Mineral Density ◽  
Trabecular Thickness ◽  
Running Exercise

A marked decrease in β-globin production led to β-thalassemia, a hereditary anemic disease associated with bone marrow expansion, bone erosion, and osteoporosis. Herein, we aimed to investigate changes in bone mineral density (BMD) and trabecular microstructure in hemizygous β-globin knockout thalassemic (BKO) mice and to determine whether endurance running (60 min/day, 5 days/wk for 12 wk in running wheels) could effectively alleviate bone loss in BKO mice. Both male and female BKO mice (1–2 mo old) showed growth retardation as indicated by smaller body weight and femoral length than their wild-type littermates. A decrease in BMD was more severe in female than in male BKO mice. Bone histomorphometry revealed that BKO mice had decreases in trabecular bone volume, trabecular number, and trabecular thickness, presumably due to suppression of osteoblast-mediated bone formation and activation of osteoclast-mediated bone resorption, the latter of which was consistent with elevated serum levels of osteoclastogenic cytokines IL-1α and -1β. As determined by peripheral quantitative computed tomography, running increased cortical density and thickness in the femoral and tibial diaphyses of BKO mice compared with those of sedentary BKO mice. Several histomorphometric parameters suggested an enhancement of bone formation (e.g., increased mineral apposition rate) and suppression of bone resorption (e.g., decreased osteoclast surface), which led to increases in trabecular bone volume and trabecular thickness in running BKO mice. In conclusion, BKO mice exhibited pervasive osteopenia and impaired bone microstructure, whereas running exercise appeared to be an effective intervention in alleviating bone microstructural defect in β-thalassemia.

scholarly journals Increased bone mass in adult prostacyclin-deficient mice

2009 ◽  
Vol 204 (2) ◽  
pp. 125-133 ◽  
Author(s):  
Chalida Nakalekha ◽  
Chieko Yokoyama ◽  
Hiroyuki Miura ◽  
Neil Alles ◽  
Kazuhiro Aoki ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Bone Metabolism ◽  
Potential Effect ◽  
Prostaglandin E ◽  
Dependent Manner

Prostaglandins (PGs) are key regulatory factors that affect bone metabolism. Prostaglandin E2 (PGE2) regulates bone resorption and bone formation. Prostacyclin (PGI2) is one of the major products derived from arachidonic acid by the action of cyclooxygenase and PGI2 synthase (PGIS). Unlike PGE2, there are few reports about the role of PGI2 in bone regulation. Therefore, we investigated the potential effect of PGI2 on bone metabolism. We used PGIS knockout (PGIS−/−), PGIS heterozygous (PGIS+/−), and wild-type mice to investigate the role of PGI2. Notably, PGIS−/− mice gradually displayed an increase in trabecular bone mass in adolescence. Adult PGIS−/− mice showed an increase in trabecular bone volume/tissue volume. Histomorphometric analysis showed that PGIS−/− mice displayed increases in both bone formation and bone resorption parameters. Levels of serum osteocalcin and C-telopeptides were increased in adult PGIS−/− mice. Furthermore, the increased bone mass patterns were rescued in PGIS−/tg mice. In conclusion, adult PGIS−/− mice displayed an overall increase in the levels of both bone formation and bone resorption parameters, which suggests that PGI2 deficiency accelerates high bone turnover activity with a greater increase in bone mass in aging. These results indicated that PGI2 may contribute to the maintenance of normal bone mass and micro-architecture in mice in age-dependent manner. Our findings demonstrate for the first time that PGI2 is involved in bone metabolism in vivo.

scholarly journals Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

2021 ◽  
Vol 22 (9) ◽  
pp. 4717
Author(s):  
Jin-Young Lee ◽  
Da-Ae Kim ◽  
Eun-Young Kim ◽  
Eun-Ju Chang ◽  
So-Jeong Park ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Map Kinases ◽  
Osteoclast Differentiation ◽  
Dependent Manner ◽  
Dual Action ◽  
Dose Dependent ◽  
Resorptive Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.

scholarly journals Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

2018 ◽  
Vol 238 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Thomas Funck-Brentano ◽  
Karin H Nilsson ◽  
Robert Brommage ◽  
Petra Henning ◽  
Ulf H Lerner ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Bone Strength ◽  
Bending Test ◽  
Bone Homeostasis ◽  
Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

5 alpha-Dihydrotestosterone partially restores cancellous bone volume in osteopenic ovariectomized rats

1994 ◽  
Vol 267 (6) ◽  
pp. E853-E859 ◽  
Author(s):  
J. H. Tobias ◽  
A. Gallagher ◽  
T. J. Chambers
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Cancellous Bone ◽  
Bone Growth ◽  
Bone Volume ◽  
Ovariectomized Rats ◽  
Trabecular Thickness ◽  
Longitudinal Bone Growth ◽  
Periosteal Bone Formation

Although androgens are thought to be important for skeletal maintenance in females and males, little is known about the mechanisms involved. To investigate this question further, we examined the effects of administering 0.01, 0.1, or 1.0 mg/kg 5 alpha-dihydrotestosterone (DHT) for 60 days on the skeleton of ovariectomized rats. Treatment was delayed until 90 days after ovariectomy to enable bone loss to stabilize. We found that ovariectomy markedly reduced cancellous bone volume of the proximal tibial metaphysis due to a combination of loss and thinning of trabeculae. Cancellous bone volume was partially restored by all doses of DHT, with trabecular thickness, but not number, returning to that of sham-operated animals. DHT also stimulated longitudinal bone growth and endosteal and periosteal bone formation and suppressed histomorphometric indexes of cancellous bone resorption. This suggests that DHT influences skeletal metabolism in osteopenic ovariectomized rats both by stimulating bone formation and suppressing resorption, although it is unclear which, if any, of these actions predominate at cancellous sites.

scholarly journals Genetic Sost Deletion and Pharmacological Inhibition of Sclerostin Prevent Multiple Myeloma-Induced Bone Loss without Affecting Tumor Growth

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1136-1136 ◽  
Author(s):  
Jesus Delgado-Calle ◽  
Judith Anderson ◽  
Meloney D. Cregor ◽  
Dan Zhou ◽  
Lilian I. Plotkin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Tumor Growth ◽  
Bone Disease ◽  
Dependent Manner ◽  
Osteolytic Lesions ◽  
Pharmacological Inhibition ◽  
The Impact

Abstract In Multiple myeloma (MM) plasma cells grow in the bone marrow and induce localized lytic lesions due to increased bone resorption and suppressed bone formation. High levels of Sclerostin, a potent inhibitor of bone formation, are found in sera of MM patients. The expression of Sost/Scleorstin by osteocytes is also increased in mice bearing MM tumors, suggesting that Sclerostin might play a role in MM-induced bone disease. The goal of this study was to examine the impact of Sost/Sclersotin on tumor growth and MM-induced bone disease. We first examined the effect of genetic deletion of Sost. Therefore, we generated global Sost KO mice in an immunodeficient background (SCID), which exhibited the expected high bone mass phenotype associated with Sost deficiency. 6-wk-old SostKO or WT control littermates mice were injected intratibially with 105 JJN3 human MM (hMM) cells or saline (n=7-10/group), and sacrificed after 4wks. Sost KO and WT mice injected with hMM had equivalent tumor engraftment as demonstrated by serum human kappa light chain levels. hMM-injected WT mice exhibited ~50% decrease in tibia cancellous bone volume (BV/TV) and trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). In contrast, hMM-injected Sost KO mice displayed no changes in BV/TV or bone architecture. Importantly, X-ray analysis revealed that the number and area of osteolytic lesions was reduced in Sost KO by 60% and 74%, respectively, compared to WT mice. We next examined the effect of pharmacological inhibition of Sclerostin in an immunocompetent preclinical model of established MM. 6-wk-old C57BLKalwRij mice were injected intratibially with 105 5TGM1 murine MM cells (mMM) or saline. After 4wks mMM-injected mice had a 2-fold increase in the serum tumor engraftment marker IgG2b. Saline or mMM-injected mice were then treated with a Sclerostin neutralizing antibody (Scl-Ab; 15mg/kg/wk) or control antibody (IgG; n=6-10/group). After 4wks of treatment, serum IgG2b levels were similar in mMM-injected mice receiving Scl-Ab or IgG. mMM-injected mice receiving IgG injections had ~35% decreased BV/TV, Tb.N, and increased Tb.Sp. In contrast, mMM-injected mice receiving Scl-Ab displayed increased trabecular BV/TV (52%), Tb.N (22%), Tb.Th (33%) and decreased Tb.Sp (14%), results that did not differ from saline-injected mice treated with Scl-Ab. Moreover, the number of osteolytic lesions was reduced by 46% in Scl-Ab treated mice when compared to the IgG-treated group. Further, mMM-injected mice treated with IgG or Scl-Ab showed similar increases in the bone resorption markerCTX in the circulation, whereas mMM-injected mice treated with Scl-Ab had a smaller decrease in the bone formation marker P1NP in sera compared to IgG-treated mice (22 vs 45%). Consistent with the lack of effect of the Scl-Ab on MM tumor growth in vivo, Scl-Ab did not affect the proliferation or viability of MM cells in vitro. We then examined next if Scl-Ab alters the anti-myeloma activity of dexamethasone (DEX), bortezomib (BOR) and the Notch inhibitor GSIXX. As expected, DEX, BOR and GSIXX increased the number of dead mMM and hMM cells in a time- and dose-dependent manner. Importantly, the increase in the number of dead hMM and mMM cells induced by DEX, BOR and GSIXX remained unchanged when Scl-Ab was co-administered. Taken together, these results demonstrate that increased Scl production by osteocytes inhibits bone formation and contributes to MM-induced bone loss. Further, our data shows that pharmacological inhibition of Scl does not alter tumor growth or the activity of anti-myeloma drugs. These findings provide the rationale for combining Scl-Ab with anti-tumor drugs to simultaneously prevent tumor growth and the bone diseases in MM patients. Disclosures Roodman: Amgen: Consultancy.

scholarly journals Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1314-1320 ◽  
Author(s):  
JM Muir ◽  
M Andrew ◽  
J Hirsh ◽  
JI Weitz ◽  
E Young ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Bone Resorption ◽  
Trabecular Bone ◽  
Serum Alkaline Phosphatase ◽  
Bone Volume ◽  
Trabecular Bone Volume ◽  
Histomorphometric Analysis ◽  
Epiphyseal Growth Plate ◽  
Heparin Treatment ◽  
Dose Dependent

Long-term heparin treatment causes osteoporosis through an as yet undefined mechanism. To investigate this phenomenon, we treated rats with once daily subcutaneous injections of heparin (in doses ranging from 0.25 to 1.0 U/g) or saline for 8 to 32 days and monitored the effects on bone both histomorphometrically and by serial measurements of urinary type 1 collagen cross linked-pyridinoline (PYD) and serum alkaline phosphatase, markers of bone resorption and formation, respectively. Histomorphometric analysis of the distal third of the right femur in the region proximal to the epiphyseal growth plate showed that heparin induces both a time- and dose-dependent decreased in trabecular bone volume, with the majority of trabecular bone loss occurring within the first 8 days of treatment. Thus, heparin doses of 1.0 U/g/d resulted in a 32% loss of trabecular bone. Heparin-treated rats also showed a 37% decrease in osteoblast surface as well as a 75% decrease in osteoid surface. In contrast, heparin treatment had the opposite effect on osteoclast surface, which was 43% higher in heparin- treated rats, as compared with that in control rats. Biochemical markers of bone turnover showed that heparin treatment produced a dose- dependent decrease in serum alkaline phosphatase and a transient increase in urinary PYD, thus confirming the histomorphometric data. Based on these observations, we conclude that heparin decreases trabecular bone volume both by decreasing the rate of bone formation and increasing the rate of bone resorption.

scholarly journals Role of Osteoblast Gi Signaling in Age-Related Bone Loss in Female Mice

Endocrinology ◽  
2017 ◽  
Vol 158 (6) ◽  
pp. 1715-1726 ◽  
Author(s):  
Susan M. Millard ◽  
Liping Wang ◽  
Lalita Wattanachanya ◽  
Dylan O’Carroll ◽  
Aaron J. Fields ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bending Strength ◽  
The Elderly ◽  
Bone Volume ◽  
Littermate Control ◽  
Female Mice ◽  
Age Related ◽  
Aging Women ◽  
G Protein Coupled

Abstract Age-related bone loss is an important risk factor for fractures in the elderly; it results from an imbalance in bone remodeling mainly due to decreased bone formation. We have previously demonstrated that endogenous G protein–coupled receptor (GPCR)-driven Gi signaling in osteoblasts (Obs) restrains bone formation in mice during growth. Here, we launched a longitudinal study to test the hypothesis that Gi signaling in Obs restrains bone formation in aging mice, thereby promoting bone loss. Our approach was to block Gi signaling in maturing Obs by the induced expression of the catalytic subunit of pertussis toxin (PTX) after the achievement of peak bone mass. In contrast to the progressive cancellous bone loss seen in aging sex-matched littermate control mice, aging female Col1(2.3)+/PTX+ mice showed an age-related increase in bone volume. Increased bone volume was associated with increased bone formation at both trabecular and endocortical surfaces as well as increased bending strength of the femoral middiaphyses. In contrast, male Col1(2.3)+/PTX+ mice were not protected from age-related bone loss. Our results indicate that Gi signaling markedly restrains bone formation at cancellous and endosteal bone surfaces in female mice during aging. Blockade of the relevant Gi-coupled GPCRs represents an approach for the development of osteoporosis therapies—at least in the long bones of aging women.

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