OBJECTIVE: To examine the effects of ursolic acid (UA) on mitigating retinoic acid (RA)-induced osteoporosis in rats. METHODS: Fifty female Sprague-Dawley rats were randomly divided into the control group (n=10) and the osteoporosis group (n=40). The 40 osteoporosis rats were induced by 75 mg/(kg•d) RA once daily for 2 weeks, and then were randomly assigned to vehicle control (model), low-, middle-, and high-dose UA [(UA-L, UA-M, UA-H; 30, 60, 120 mg/(kg•d), respectively] groups (10 rats each). UA were administered once daily to the rats from the 3rd weeks for up to 4 weeks by gavage. Bone turnover markers [serum alkaline phosphatase (ALP), osteocalcin (OCN), urine deoxypyridinoline (DPD)] and other parameters, including serum calcium (S-Ca), serum phosphorus (S-P), urine calcium (U-Ca), urine phosphorus (U-P), and bone mineral density (BMD) of the femur, 4th lumbar vertebra and tibia, bone biomechanical properties and trabecular microarchitecture, were measured. RESULTS: The osteoporosis in rats was successfully induced by RA. Compared with the model group, UA-M and UA-H significantly reversed the RA-induced changes in S-P, U-Ca, U-P, ALP, OCN and urine DPD ratio and markedly enhanced the BMD of right femur, 4th lumbar vertebra and tibia (Plt;0.05 or Plt;0.01). Further, biomechanical test and microcomputed tomography evaluation also showed that UA-H drastically improved biomechanical properties and trabecular microarchitecture (Plt;0.05 or Plt;0.01). CONCLUSION UA could promote bone formation, increase osteoblastic activity and reduce osteoclastic activity in rats, indicating that UA might be a potential therapeutic of RA-induced acute osteoporosis.
Animals ; Biomechanical Phenomena ; Bone Density ; drug effects ; Bone Remodeling ; drug effects ; Female ; Osteoporosis ; diagnostic imaging ; drug therapy ; Rats ; Rats, Sprague-Dawley ; Tretinoin ; toxicity ; Triterpenes ; pharmacology ; therapeutic use ; X-Ray Microtomography

The interplay between mechanoresponses and a broad range of fundamental biological processes, such as cell cycle progression, growth and differentiation, has been extensively investigated. However, metabolic regulation in mechanobiology remains largely unexplored. Here, we identified glucose transporter 1 (GLUT1)-the primary glucose transporter in various cells-as a novel mechanosensitive gene in orthodontic tooth movement (OTM). Using an in vivo rat OTM model, we demonstrated the specific induction of Glut1 proteins on the compressive side of a physically strained periodontal ligament. This transcriptional activation could be recapitulated in in vitro cultured human periodontal ligament cells (PDLCs), showing a time- and dose-dependent mechanoresponse. Importantly, application of GLUT1 specific inhibitor WZB117 greatly suppressed the efficiency of orthodontic tooth movement in a mouse OTM model, and this reduction was associated with a decline in osteoclastic activities. A mechanistic study suggested that GLUT1 inhibition affected the receptor activator for nuclear factor-κ B Ligand (RANKL)/osteoprotegerin (OPG) system by impairing compressive force-mediated RANKL upregulation. Consistently, pretreatment of PDLCs with WZB117 severely impeded the osteoclastic differentiation of co-cultured RAW264.7 cells. Further biochemical analysis indicated mutual regulation between GLUT1 and the MEK/ERK cascade to relay potential communication between glucose uptake and mechanical stress response. Together, these cross-species experiments revealed the transcriptional activation of GLUT1 as a novel and conserved linkage between metabolism and bone remodelling.
Animals ; Biomechanical Phenomena ; Blotting, Western ; Bone Remodeling ; drug effects ; Cells, Cultured ; Glucose Transporter Type 1 ; antagonists & inhibitors ; genetics ; Humans ; Hydroxybenzoates ; pharmacology ; Immunohistochemistry ; MAP Kinase Signaling System ; drug effects ; Mice ; Mice, Inbred C57BL ; Osteoprotegerin ; metabolism ; Periodontal Ligament ; cytology ; RANK Ligand ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Tooth Movement Techniques ; Transcriptional Activation

OBJECTIVES: This postmarketing, observational study evaluated the safety and effectiveness of monthly intravenous (IV) ibandronate in Japanese patients with osteoporosis. METHODS: Eligible patients received monthly IV ibandronate 1mg for 12 months. Adverse drug reactions (ADRs) were evaluated. Changes in bone mineral density (BMD) and bone turnover markers (BTMs) were assessed using matched t-test analysis. Cumulative fracture rates were analyzed by Kaplan-Meier methodology. RESULTS: In total, 1062 patients were enrolled, of whom 1025 (n = 887 women, n = 138 men) were treated. Mean patient age was 77 years. Seventy-five ADRs were reported in 54 patients (5.26%). Four patients (0.39%) experienced serious ADRs, including one case of osteonecrosis of the jaw. Acute-phase reactions occurred in 21 patients (2.04%), and half of them arose after the first ibandronate injection. No new safety concerns were identified. Significant increases in BMD at 12 months relative to baseline were observed at the lumbar spine (4.84%, n = 187; 95% confidence interval [CI], 3.47%–6.21%), femoral neck (2.73%, n = 166; 95% CI, 1.46%–4.01%), and total hip (1.93%, n = 133; 95% CI, 0.80%–3.07%). Significant reductions were observed in all BTMs at 12 months (n = 174 in tartrate-resistant acid phosphatase-5b, n = 101 in procollagen type 1 N-terminal propeptide at baseline). The cumulative incidence of nontraumatic, new vertebral and nonvertebral fractures was 3.16% (95% CI, 2.12%–4.70%). Analyses in women only showed similar results to the overall population. CONCLUSIONS: These findings confirm the favorable safety and consistent effectiveness of ibandronate, and indicate that monthly IV ibandronate would be beneficial in daily practice for the treatment of Japanese patients with osteoporosis.
Asian Continental Ancestry Group ; Bone Density ; Bone Remodeling ; Drug-Related Side Effects and Adverse Reactions ; Female ; Femur Neck ; Hip ; Humans ; Incidence ; Japan ; Jaw ; Observational Study ; Osteonecrosis ; Osteoporosis ; Procollagen ; Prospective Studies ; Spine

BACKGROUND/AIMS: Proton pump inhibitors (PPIs) act by irreversibly binding to the H+-K+-ATPase of the proton pump in parietal cells and may possibly affect the vacuolar H+-ATPase in osteoclasts. METHODS: We investigated the effect of 8 weeks of PPI treatment on the parameters of bone turnover and compared PPI with revaprazan, which acts by reversibly binding to H+-K+-ATPase in proton pumps. This study was a parallel randomized controlled trial. For 8 weeks, either a PPI or revaprazan was randomly assigned to patients with gastric ulcers. The parameters of bone turnover were measured at the beginning of and after the 8-week treatment period. RESULTS: Twenty-six patients (PPI, n=13; revaprazan, n=13) completed the intention-to-treat analysis. After the 8-week treatment period, serum calcium and urine deoxypyridinoline (DPD) were increased in the PPI group (serum calcium, p=0.046; urine DPD, p=0.046) but not in the revaprazan group. According to multivariate linear regression analysis, age > or =60 years was an independent predictor for the changes in serum calcium and urine DPD. CONCLUSIONS: In elderly patients, administering a PPI for 8 weeks altered bone parameters. Our study suggested that PPIs might directly alter bone metabolism via the vacuolar H+-ATPase in osteoclasts.
Aged ; Amino Acids/drug effects/urine ; Bone Remodeling/*drug effects ; Bone and Bones/*metabolism ; Calcium/blood ; Female ; Humans ; Intention to Treat Analysis ; Linear Models ; Male ; Middle Aged ; Multivariate Analysis ; Osteoclasts/*metabolism ; Prospective Studies ; Proton Pump Inhibitors/*pharmacology ; Pyrimidinones/*pharmacology ; Tetrahydroisoquinolines/*pharmacology

BACKGROUND/AIMS: Our aim was to assess whether short-term treatment with soluble tumor necrosis factor (TNF) receptor affects circulating markers of bone metabolism in rheumatoid arthritis (RA) patients. METHODS: Thirty-three active RA patients, treated with oral disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids for > 6 months, were administered etanercept for 12 weeks. Serum levels of bone metabolism markers were compared among patients treated with DMARDs at baseline and after etanercept treatment, normal controls and naive RA patients not previously treated with DMARDs (both age- and gender-matched). RESULTS: Bone-specific alkaline phosphatase (BSALP) and serum c-telopeptide (CTX)-1 levels were lower in RA patients treated with DMARDs than in DMARD-naive RA patients. After 12 weeks of etanercept treatment, serum CTX-1 and sclerostin levels increased. In patients whose DAS28 improved, the sclerostin level increased from 1.67 +/- 2.12 pg/mL at baseline to 2.51 +/- 3.03 pg/mL, which was statistically significant (p = 0.021). Increases in sclerostin levels after etanercept treatment were positively correlated with those of serum CTX-1 (r = 0.775), as were those of BSALP (r = 0.755). CONCLUSIONS: RA patients treated with DMARDs showed depressed bone metabolism compared to naive RA patients. Increases in serum CTX-1 and sclerostin levels after short-term etanercept treatment suggest reconstitution of bone metabolism homeostasis.
Adult ; Alkaline Phosphatase/blood ; Arthritis, Rheumatoid/blood/diagnosis/*drug therapy ; Biological Markers/blood ; Bone Morphogenetic Proteins/blood ; Bone Remodeling/*drug effects ; Collagen Type I/blood ; Female ; Genetic Markers ; Homeostasis ; Humans ; Immunoglobulin G/*administration & dosage ; Immunosuppressive Agents/*administration & dosage ; Inflammation Mediators/blood ; Male ; Middle Aged ; Peptides/blood ; Receptors, Tumor Necrosis Factor/*administration & dosage ; Time Factors ; Treatment Outcome ; Tumor Necrosis Factor-alpha/antagonists & inhibitors

Zoledronic acid has been used for prevention of osteolytic and osteoblastic bone metastasis. This case report illustrates an undesirable consequence from prolonged usage of zoledronic acid in bone metastasis prevention. Periprosthetic acetabular fracture in a patient treated with zoledronic acid for 7 years was reported. The clinical presentation, radiographic and pathological results were described. This is a rare complication after total hip arthroplasty which should not be ignored especially in patients who received long term bisphosphonate.
Acetabulum/*injuries/pathology/surgery ; Aged ; Arthroplasty, Replacement, Hip/*adverse effects ; Bone Density Conservation Agents/*adverse effects/pharmacology ; Bone Neoplasms/prevention & control/secondary ; Bone Remodeling/drug effects ; Breast Neoplasms/pathology ; Diphosphonates/*adverse effects/pharmacology ; Female ; Fractures, Spontaneous/chemically induced/etiology ; Hip Prosthesis ; Humans ; Imidazoles/*adverse effects/pharmacology ; Osteoarthritis, Hip/*surgery ; Periprosthetic Fractures/*chemically induced/etiology ; Prosthesis Failure ; Reoperation

BACKGROUNDThe association of long-term bisphosphonate treatment for osteoporosis and related safety problems such as atypical fractures were not clearly defined. This study was to evaluate the structural, densitometric and biomechanical properties of the prolonged bisphosphonate-loaded bones.

METHODSBone mineral density (BMD) at hip and femoral midshaft, bone cross-sectional area, moment of inertia of both femurs, bone formation and resorption biochemical markers were compared between 28 elderly with at least 4 years of bisphosphonate treatment from 2002 through 2006 and age-matched group of 37 elderly.

RESULTSThe total hip BMD and t-score were found not different between two groups. However, bisphosphonate treated patients were found to have significantly lower bone mineral content in the femoral shaft (P < 0.05); morphological study showed lower cross-sectional area in subtrochanteric and mid-diaphyseal region and thus significantly lower moment of inertia (P < 0.01). High resolution-peripheral quantitative computed tomography showed significantly decreased trabecular density, bone volume ratio, trabecular number but increased trabecular spacing in tibia and distal radius. Finite element analysis further confirmed significantly lower stiffness and failure load in tibia. Biochemical studies also showed lower bone resorption and severely suppressed bone formation activity (P < 0.001).

CONCLUSIONSThe unchanged total hip BMD between two groups confirmed the beneficial effects of bisphosphonate on trabecular bone, thus preventing osteoporotic fractures at large in previous studies. However, the inferior structural, densitometric and biomechanical properties at cortical bones, especially femur midshaft, need a special attention to look into the association between long-term bisphosphonate intake and the occurrence of stress fractures. When patients taking bisphosphonate complain of proximal thigh pain or discomfort, plain X-ray film can be the first line screening. All patients prescribed with bisphosphonate should be informed of such a complication though we must stress its rarity.

Aged ; Aged, 80 and over ; Biomechanical Phenomena ; Bone Density ; drug effects ; Bone Density Conservation Agents ; adverse effects ; Bone Remodeling ; drug effects ; Densitometry ; Diphosphonates ; adverse effects ; Female ; Finite Element Analysis ; Humans ; Male ; Middle Aged ; RANK Ligand ; blood

PURPOSE: Our aim was to determine the effects of infliximab on bone mineral metabolism in rheumatoid arthritis (RA) patients and analyze the relationship between inflammatory markers of acute phase thought to play a major role in bone remodeling. MATERIALS AND METHODS: 36 patients with established RA were investigated. All patients underwent physical examination and blood and urinary analysis at baseline, 2 weeks, 14 weeks, 6 months and 12 months after the initiation of treatment. The serum levels of: tumor necrosis factor alpha (TNF-alpha), tumor necrosis factor alpha receptor 1 (TNFR1), TNFR2, interleukin 6 (IL-6), IL-17, IL-23 and markers of bone remodeling such as osteocalcin (BGP), deoxypyridynoline (Dpd), and N-telopeptide of type I collagen (NTx) were measured by ELISA. RESULTS: The results showed significant decrease of all the above cytokines levels in RA patients in comparison with those after 2 weeks of treatment. After 6 months, the markers of bone formation and resorption decreased compared to baseline values. We found positive correlation between the levels of NTx and the levels of IL-6, IL-17 and TNFR1, and between the levels of Dpd and IL-6 and Dpd and TNFR2, whereas negative correlation between BGP and IL-23. After 12 months the positive association was found at the BGP level and IL-6 as well as Dpd and the level of IL-6. We also observed a positive relation between Dpd and TNF-alpha and negative between BGP and TNFR1. CONCLUSION: We suggest that infliximab treatment may limit the risk of osteoporosis in RA patients.
Adult ; Aged ; Antibodies, Monoclonal/*therapeutic use ; Antirheumatic Agents/therapeutic use ; Arthritis, Rheumatoid/blood/complications/*drug therapy ; Biological Markers/metabolism ; Bone Remodeling/*drug effects ; Bone Resorption ; Cytokines/*metabolism ; Female ; *Gene Expression Regulation ; Humans ; Interleukin-17/metabolism ; Interleukin-6/metabolism ; Middle Aged ; Osteoporosis/complications/prevention & control ; Receptors, Tumor Necrosis Factor, Type I/metabolism

OBJECTIVETo study the effects of low pre-pregnant lead exposure level on the mobilization of lead and calcium in maternal skeleton during gestation and lactation in mice.

METHODSSeventy Kunming female mice were randomly divided into the lead exposure or control groups, 36 mice were exposed to lead by drinking water (50 mg/L) and 36 mice were exposed to deionized water for 4 weeks. The levels of calcium and lead in blood and femurs were measured on the 1st, 7th and 14th days during gestation and on the 1st,10th and 21st days during lactation with atomic absorption spectrophotometry using a heated graphite atomizer or flame atomic absorption spectrophotometry.

RESULTSAs compared with the pre-pregnant, at the end of lactation in exposure group the levels of calcium in blood and bones significantly decreased 18.5% and 17.75%, respectively, the levels of lead in blood significantly increased 65.22% and the levels of lead in bones significantly decreased 28.45% (P < 0.05). There was a significant negative correlation between the blood lead level and the bone lead level during gestation and lactation in exposure group (r = -0.904, P < 0.01). There were significant differences of lead and calcium levels during the gestation and lactation between exposure group and control group (P < 0.05).

CONCLUSIONThe lead mobilization in maternal bone occurred during gestation and lactation in mice, which could be accelerated by the low pre-pregnant lead exposure.

Animals ; Bone Remodeling ; drug effects ; Bone and Bones ; drug effects ; metabolism ; Calcium ; blood ; metabolism ; Calcium, Dietary ; Female ; Lactation ; Lead ; blood ; toxicity ; Mice ; Mice, Inbred Strains ; Pregnancy ; Prenatal Exposure Delayed Effects

BACKGROUND: Estrogens act on estrogen receptors distributed in articular cartilages, synovial membrane, and ligaments, which are thought to be related with degenerative changes. Meanwhile, progesterone is known to have a weak anabolic action on bone formation This study evaluates the effects of estrogen and progesterone hormone on bone/cartilage turnover in ovariectomized (OVX) rats. METHODS: Thirty-five 7-month-old female Sprague-Dawley rats were randomly divided into 5 groups and then ovariectomized bilaterally except the sham control group. The first and the second group acting as controls did not receive hormonal therapy, the third group received estrogen, the fourth group received progesterone, and the fifth group received combination of both hormones 10 weeks after surgery. Evaluations were done using the serum levels of cartilage oligomeric matrix protein (COMP) for cartilage turnover, collagen type I C-telopeptide (CTX-1) and osteocalcin (OC) for bone turnover at 11, 15, 19 weeks after OVX and histology using the Osteoarthritis Research Society International (OARSI) osteoarthritis (OA) cartilage histopathology assessment system. RESULTS: Significantly less cartilage degradation (decreased levels of COMP) was found in the combined hormone treated group in comparison with OVX group. Similarly, both hormonal treatment resulted in increased bone formation and decreased bone resorption i.e., a low overall bone turnover status (decrease in the serum OC and CTX-1 levels). CONCLUSIONS: Combined estrogen and progesterone therapy was found to be convincing in terms of reducing the severity of OA in this experimental model.
Animals ; Biological Markers/blood/metabolism ; Bone Remodeling/*drug effects ; Bone and Bones/chemistry/drug effects ; Cartilage/chemistry/*drug effects ; Collagen Type I/blood/metabolism ; Disease Models, Animal ; Estrogens/*pharmacology ; Extracellular Matrix Proteins/blood/metabolism ; Female ; Glycoproteins/blood/metabolism ; Histocytochemistry ; Hormone Replacement Therapy/*methods ; Osteoarthritis/blood/*drug therapy ; Osteocalcin/blood/metabolism ; Ovariectomy ; Progesterone/*pharmacology ; Rats ; Rats, Sprague-Dawley