Zoledronic acid could improve the clinical outcome in elderly patients receiving total hip arthroplasty or hemiarthroplasty for osteoporotic femoral neck fracture in the 1-year prospective study.

Introduction: To validate the therapeutic efficacy of zoledronic acid (ZOL) in elderly patients with femoral neck fracture who received total hip arthroplasty (THA) or hemiarthroplasty (HA).

Methods: Included in this study were 95 elderly patients with femoral neck fractures who received THA/HA between August 2015 and June 2018. They were randomized into a ZOL group and a control group. Patients in ZOL group received a yearly single dose of 5 mg ZOL intravenous injection plus 0.5 μg/day calcitriol and 1000 mg/day calcium carbonate 2 days before THA or HA. Patients in the control group were treated with the same dose of calcitriol and calcium carbonate only without ZOL. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Bone metabolism markers including the total extension of the peptide type I collagen amino end (P1NP) and beta collagen degradation product (β-CTX) were obtained by serum examination. The postoperative functional outcome was assessed using Harris Hip Score (HHS).

Results: During the follow-up period, BMD in the ZOL group was improved and significantly higher than that in the control group at 6 and 12 months post-operation. Bone metabolism markers P1NP and β-CTX in ZOL group remained at a relatively low level as compared with that in the control group at 6 months after treatment. No significant difference in the mean HHS and the excellent/good rate of joint function was observed during the follow-up period between the two groups. The occurrence of adverse events in the ZOL group was significantly higher than that in the control group.

Conclusions: A single infusion of ZOL shows promise in improving BMD of the healthy side of the femoral neck, lumbar spine, and total hip and decreasing the level of bone markers, which may improve the clinical outcome of patients with osteoporotic femoral neck fractures receiving THA/HA.

Keywords: Hip arthroplasty; Osteoporosis; Osteoporotic femoral neck fracture; Zoledronic acid.

Objectives: The present study determined time-course changes in plasma bone-specific and -related markers following a bout of maximal eccentric contractions (MaxEC) of bilateral knee extensors (KE) and flexors (KF).

Methods: Sedentary young men (n=30) performed a bout of 10 sets of 10 MaxEC (30°/s) of KE and KF with each leg, respectively. Maximal voluntary isometric contraction (MVC) torque, muscle soreness (SOR), plasma creatine kinase (CK) activity, insulin, leptin, tumor necrosis factor-α (TNF-α), undercarboxylated-osteocalcin (ucOCN), carboxy-terminal crosslinking telopeptide of type I collagen (CTX-1) and procollagen type I N-terminal propeptide (P1NP) concentrations were measured from before to 7 days after MaxEC.

Results: Significant changes in MVC (KE: -28%, KF: -38%), SOR and plasma CK activity (peak: 39,163 IU/L) following MaxEC were evident (P<0.05) compared to baseline. Plasma leptin (17%) concentrations decreased at 1 day after MaxEC. In bone related markers, plasma ucOCN concentrations (20%) increased at 7 days after MaxEC, and plasma CTX-1 concentrations decreased at 2, 4 and 7 days after MaxEC (6~7%; P<0.05).

Conclusion: These results demonstrate that a lean effect of bone generation and an enhanced energy anabolism can be induced by a single bout of MaxEC.

Keywords: Bone Metabolism; Delayed Onset Muscle Soreness; Lengthening Contractions; Muscle Damage; Plasma Creatine Kinase Activity.

Objective: To assess the association between the atherogenic index of plasma (AIP) and the trabecular bone score (TBS) in postmenopausal women. Furthermore, to analyze its relationship with bone mineral density (BMD), and serum concentrations of 25OHD, PTH, and bone turnover markers.

Study design: Cross-sectional study nested in a population-based cohort of 1,367 postmenopausal women aged 44-94 years. Participants were classified according to TBS values (<1.230, between 1.230-1.310 and >1.310) and regarding a widely accepted cut-off point of ≥0.11 for AIP. We analyzed TBS, BMD, serum levels of 25OHD, PTH, P1NP, CTX, and clinical covariates. A multivariate analysis was performed to assess the adjusted association between AIP and TBS.

Results: The mean age of participants was 63±10 years. Women with TBS values <1.230 were older, had greater BMI, greater prevalence of fractures after the age of 40 years, more years since menopause, higher values of AIP, and significantly lower levels of HDL-C, serum phosphate, and 25OHD. AIP values ≥0.11 were not associated with the presence of densitometric osteoporosis (OR=0.83, 95%CI 0.58-1.18; p = 0.30) but, in multivariate analysis, AIP values ≥0.11 were related to a degraded microarchitecture after controlling for age, BMI, smoking, diabetes status, ischemic heart disease, statin use, GFR, a fragility fracture at over 40 years of age and lumbar osteoporosis by DXA, with an adjusted OR=1.61 (95%CI 1.06-2.46; p = 0.009).

Conclusions: AIP is significantly and independently associated with a degraded bone microarchitecture as measured by TBS. In this sense, AIP might be a useful tool in the overall assessment of bone metabolism in postmenopausal women.

Keywords: Atherogenic index of plasma; BMD;, Osteoporosis; Postmenopausal women; TBS.

Background and objective: Diabetic microvascular disease (MVD) has been associated with increased bone fragility. The objective was to analyse the relationship between MVD and trabecular microstructure -assessed by the trabecular bone score (TBS)- in type 2 diabetic (T2D) patients. A second aim was to know the relationship between vitamin D and MVD.

Patients and methods: Cross-sectional study, which included men >50 years and postmenopausal women participating in a population-based cohort, diagnosed with T2D. The presence of nephropathy, neuropathy and/or retinopathy was classified as MVD+. Clinical and laboratory variables, TBS, 25(OH)D and BMD by DXA, were evaluated. Bivariate and multivariate analysis were performed.

Results: We evaluated 361 patients (51.1% women), 63.8 (9) years old. Of them, 92 were MVD+ and presented poorer metabolic control, longer duration of T2D, lower TBS [1.235 (.1) vs. 1.287 (.1); p=.007] and lower levels of 25(OH)D [18.3 (7) vs. 21.6 (8) ng/ml; p=.0001). There were no differences between MVD+ and MVD- with regard to BMD or P1NP and β-CTX markers. After adjusting for confounders, including HbA1c and duration of T2D, the TBS value in MVD+ was 1.252 (95% CI 1.230-1.274) vs. 1.281 (95% CI 1.267-1.295) in MVD- (p=.034). MVD was associated with a 25(OH)D level <20 ng ml with an adjusted OR of 1.88 (95% CI 1.06-3.31; p=.028).

Conclusions: The MVD+ patients presented a significantly lower TBS, after adjusting for confounders. Furthermore, multivariable analysis showed a significant relationship between a low 25(OH)D level and a prevalent MVD.

Keywords: 25-hidroxivitamina D; 25-hydroxyvitamin D; Bone metabolic diseases; Deficiencia de vitamina D; Diabetes mellitus tipo 2; Diabetic microangiopathy; Enfermedades metabólicas óseas; Microangiopatía diabética; Trabecular bone score; Type 2 Diabetes Mellitus; Vitamin D deficiency; Índice trabecular óseo.

Introduction: Type 2 diabetes (T2D) is related to an increased fracture risk and low bone turnover. However, the mechanisms are not elucidated. In the present study we investigate the association between glycemic variability and bone turnover markers.

Methods: 100 participants with T2D and 100 age and gender matched controls were included in this cross-sectional study. All participants with T2D were equipped with a continuous glucose monitoring (CGM) sensor for 3 days (CGMS iPro Continuous Glucose Recorder; Medtronic MiniMed). The dawn glucose levels were defined as a morning period starting 1 h before breakfast ending 1 h post ingestion. On all participants serum (s)-C-terminal cross-linked telopeptide of type-I collagen (CTX), s-procollagen type 1 amino terminal propeptide (P1NP), and s-sclerostin were measured.

Results: Participants with T2D displayed significantly lower levels of the bone resorption marker s-CTX and the bone formation marker s-P1NP compared to controls. S-CTX was significantly negatively associated with the mean amplitude of glycemic excursions (MAGE) and the dawn glucose levels whereas s-P1NP only was significantly negatively associated with the dawn glucose levels while it was borderline significantly associated with MAGE (p=0.05). S-CTX and s-P1NP were significantly lower among the 50 % with the highest dawn glucose levels compared to the 50 % lowest dawn glucose levels also after adjustment for age, gender, glycated hemoglobin A1c (HbA1c), and body mass index (BMI).

Conclusion: We observed that the amplitude of glycemic excursions and rise in dawn glucose was negatively associated with bone turnover markers. Future research is needed to determine whether reduction of the amplitude of glycemic excursions increase bone turnover markers.

Keywords: Diabetes; bone turnover; glycemic variability; sclerostin.

Autosomal Dominant Osteopetrosis type II (ADO2) is a bone disease of impaired osteoclastic bone resorption that usually results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene. We created mouse models of ADO2 by introducing a knock-in (p.G213R) mutation in the Clcn7 gene, which is analogous to one of the common mutations (G215R) found in humans. The mutation leads to severe osteopetrosis and lethality in homozygous mice but produces substantial phenotypic variability in heterozygous mice on different genetic backgrounds that phenocopy the human disease of ADO2. ADO2 is an osteoclast-intrinsic disease, and lysosomal enzymes and proteins are critical for osteoclast activity. Chloroquine (CQ) is known to affect lysosomal trafficking, intracellular signaling and the lysosomal and vesicular pH, suggesting it might improve ADO2 osteoclast function. We tested this hypothesis in cell culture studies using osteoclasts derived from wild-type (WT or ADO2^+/+) and ADO2 heterozygous (ADO2^+/-) mice and found that CQ and its metabolite desethylchloroquine (DCQ), significantly increased ADO2^+/- osteoclasts bone resorption activity in vitro, whereas bone resorption of ADO2^+/+ osteoclasts was increased only by DCQ. In addition, we exploited our unique animal model of ADO2 on 129 background to identify the effect of CQ for the treatment of ADO2. Female ADO2 mice at 8 weeks of age were treated with 5 doses of CQ (1, 2.5, 5, 7.5 and 10 mg/kg BW/day) via drinking water for 6 months. Bone mineral density and bone micro-architecture were analyzed by longitudinal in-vivo DXA and micro-CT at baseline, 3 and 6 months. Serum bone biomarkers (CTX, TRAP and P1NP) were also analyzed at these time points. CQ treatment at the doses tested failed to produce any significant changes of aBMD, BMC (whole body, femur and spine) and trabecular BV/TV (distal femur) in ADO2 mice compared to the control group (water only). Further, levels of bone biomarkers were not significantly changed due to CQ treatment in these mice. Our findings indicate that while CQ increased osteoclast activity in vitro, it did not improve the osteopetrotic bone phenotypes in ADO2 heterozygous mice.

Keywords: Bone phenotypes; Chloride channel 7; Chloroquine; Osteoclast; Osteopetrosis.

OBJECTIVE

We attempted to assess bone mineralization and the frequency of fractures occurrence in women with a history of treatment of anorexia nervosa (AN) in adolescence.

METHODS

47 women (age 20-36.8 years) were re-examined 6.33-21,2 years after the onset of AN symptoms. Bone mineral density (BMD) of total body, lumbar spine, femoral neck, total hip (DXA) and densitometric Vertebral Fracture Assessment (VFA) were performed on 46 of women and BAP, P1NP, CTX, estradiol, testosterone, cortisol, IGF-1, leptin, DHEA-S on 45 of women entered for the current study. Current BMD results were compared with available baseline results from the time of hospitalization.

RESULTS

Currently BMD Z-score <-1 examined at any location occurred in 28 from 46 women (including Z-score <-2 in 5 women). In 11 from 12 women with reduced BMD at the time of hospitalization current total body BMD was within the normal range. Lumbar spine BMD was normalized or improved respectively in 5 and 6 from 15 women. Currently increased levels/activity of bone formation markers: P1NP in 27 (60%) and BAP in 28 women (62.2%) were observed. In 7 women (15.6%) increased values of bone formation markers with increased marker of bone resorption (CTX) occurred. Osteoporotic fractures and fractures in the spine in VFA were not observed during the observation period.

CONCLUSIONS

Despite early treatment of adolescent-onset AN and good outcomes of the treatment, decreased BMD was currently present in 60.9% of women. During follow-up normalization or significant improvement in BMD results (total body, lumbar spine) were observed in majority of cases.

This study showed that procollagen type 1 amino-terminal pro-peptide and N-MID osteocalcin significantly increased after exercise independent of the form of muscle contraction. Thus, these preliminary results will be useful for future studies that will consider bone turnover characteristics of responders and non-responders to acute and chronic aerobic exercise.

BACKGROUND

The aim of the current study was to compare the effects of acute flat running (FR) and downhill running (DHR) on bone turnover markers in men.

METHODS

Fourteen healthy young active men performed three exercise tests in a counterbalanced order, including rest condition, FR, and DHR, at 60% maximal aerobic capacity on a treadmill with 0 and - 12% inclines. Blood samples were taken in the pre-exercise, immediately post-exercise, and 24-h post-exercise periods, and bone markers included total procollagen type 1 amino-terminal pro-peptide (total PINP) and N-MID osteocalcin.

RESULTS

Total P1NP significantly increased after exercise independent of the form of muscle contraction (p>> 0.05). N-MID osteocalcin increased after DHR by 17% compared to after pre-exercise, but the difference did not reach significance (p = 0.07; partial eta square, 0.21). Biomarker responses to exercise were dependent on the exercise form and independent of hormone type in half of the participants who were classified as responders. Physiological parameters and changes in muscle voluntary contraction did not explain the differences between responders and non-responders.

CONCLUSIONS

The effect of acute DHR on bone turnover is determined by biomarker type and participant characteristics. Future studies should discriminate between the characteristics of responders and those of non-responders.

Introduction: The objectives of the present study were to determine whether simvastatin (SIM) could reverse the harmful effects on titanium rod osseointegration in ovariectomized rats fed high-fat diet (HFD).

Materials and methods: Ovariectomized female Sprague-Dawley rats were randomly allocated to three groups and received SIM treatment plus HFD for 12 weeks. We then evaluated the microstructure parameters, histological parameters, biomechanical parameters, bone turnover, and blood lipid level.

Results: After 12 weeks of treatment, SIM can significantly improve bone formation around the titanium rod and osseointegration including higher values of maximum push-out force, bone area ratio (BAR), bone-to-implant contact (BIC), bone mineral density (BMD), bone volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), mean connective density (Conn.D) when compared with the HFD group. In addition, system administration of SIM showed positive effects on collagen type 1 cross-linked C-telopeptide (CTX-1), procollagen I N-terminal propeptide (PINP), total cholesterol (TC), triglycerides (TGL), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol. Compared with the HFD group, lower values of CTX-1, P1NP, TC, TGL and LDL were observed in the SIM+HFD group (P < 0.05).

Conclusion: Our findings revealed that HFD may have an adverse effect on osseointegration in osteoporotic conditions, and the harmful effect of HFD on osseointegration could be reversed by SIM.

Keywords: High-fat diet; Osseointegration; Ovariectomized rats; Simvastatin.

Calcitonin is a small peptide hormone secreted from the parafollicular cells of the thyroid gland in response to an increase in serum calcium. The inhibition of osteoclastic resorption is the main mechanism by which calcitonin quickly decreases circulating calcium levels. Although calcitonin pharmacologically acts on osteoclasts to prevent bone resorption, the results of studies on genetically modified animals have shown that the physiological effect of calcitonin is in the inhibition of osteoblastic bone formation. Because the calcitonin receptor is only expressed in osteoclasts, the effect of calcitonin on osteoblasts maybe indirect and mediated via osteoclasts. Wnt ligands are involved in various aspects of skeletal biology, including bone remodeling and endochondral bone formation. Wnt10b has recently been recognized as a clastokine, and is potentially a therapeutic target for treating bone disorders. However, the extent to which Wnt signaling is involved in bone physiology and disease is not yet fully understood. We hypothesize that calcitonin indirectly increases osteoblastic bone formation by inducing Wnt10b expression in osteoclasts. Micro-CT analysis revealed reduced bone loss in calcitonin-treated ovariectomized rats. The serum of animals treated with calcitonin had decreased TRAP5b and CTX-1 but increased osteocalcin, P1NP, and Wnt10b. Immunohistochemistry staining showed that the level of Wnt10b in the femur was increased in calcitonin-treated groups as compared with control groups. Hematopoietic mononuclear cells were separated from rat femur and tibia bone marrow, and were induced into osteoclasts following treatment with M-CSF and RANKL. In these cells, immunoconfocal microscopy and Western blot analysis showed that calcitonin induced an increase in Wnt10b expression. In a culture of osteoblasts isolated from neonatal rat calvariae, the calcitonin-treated osteoclast supernatant showed an increase in mineralization, as indicated by ALP and alizarin red staining. Taken together, these results indicate that calcitonin induces bone formation by increasing the expression of Wnt10b in osteoclasts in ovariectomy-induced osteoporotic rats. The present study provides in-depth information about the effects of calcitonin on bone remodeling and will thus help in the development of future potential therapeutic strategies for postmenopausal osteoporosis.

Keywords: Wnt10b; calcitonin; osteoclasts; osteoporosis; ovariectomy.

Objective: Diabetic osteopathy is a common comorbidity of diabetes mellitus, with skeletal fragility, osteoporosis and bone pain. The aim of our study was to highlight the role of sema3a on osteoblast differentiation of MC3T3-e1 in high-glucose condition and explore its therapeutic effect of diabetic osteopathy in vitro and vivo. Methods: In our study, the expression of osteogenesis-related makers, such as ALP, OCN, OPG, β-catenin and Runx2, were analyzed in MC3T3 osteoblastic cells to explore the effect of sema3a on osteoblast differentiation in high-glucose condition, and as was the staining of ALP and Alizarin Red S. In a diabetic animal model, the expression of serum bone metabolic markers, such as ALP, P1NP, OCN, and β-CTX, were analyzed and micro-CT was used to detect bone architecture, including Tb.N, Tb.Th, Tb.Sp, Tb.Pf, BS/BV, and BV/TV after the treatment of sema3a. Results: High glucose significantly inhibited osteogenic differentiation by decreasing the expression of osteogenesis-related makers, sema3a and its receptor of Nrp-1 in a dose-dependent manner in MC3T3. In high-glucose condition, exogenous sema3a (RPL917Mu01) increased the expression of ALP, OCN, OPG, Runx2, β-catenin, and the positive proportion of ALP and Alizarin Red S staining. In addition, in diabetic animal model, exogenous sema3a could increase bone mass and bone mineral density, and downregulate the expression of ALP, P1NP, OCN, and β-CTX. Conclusion: High glucose suppresses osteogenic differentiation in MC3T3 and sema3a may take part in this process. The application of exogenous sema3a alleviates high glucose-induced inhibition of osteoblast differentiation in diabetic osteopathy.

Aims: The aim of the present study was to evaluate umbilical cord N-terminal procollagen of type l collagen (P1NP) and beta C-terminal telopeptide (βCTX) levels in term pregnancies with vitamin D deficiency.

Materials and methods: Ninety-two pregnant women between 19 and 35-years-old who delivered at term gestational age were included in the study and divided into deficient (n = 32), insufficient (n = 30), and normal (control) vitamin D levels (n = 30).

Results: Maternal demographic characteristics and biochemical parameters were similar among groups. The mean umbilical cord P1NP level was 221.4 (211.7-231.0, 95%CI) pg/mL in the vitamin D deficiency group, 282.5 (271.2-293.8, 95%CI) pg/mL in the vitamin D insufficiency group, and 280.9 (270.9-290.8, 95%CI) pg/mL in the control group and significantly lower in vitamin D deficiency group than others (p < .001). Umbilical cord P1NP level was similar in the vitamin D insufficiency group and control group (p = .971). The mean umbilical cord βCTX level was 5530, 9 (5511.5-5550.3, 95%CI) pg/mL in the vitamin D deficiency group, 5516.3 (5498.4-5534.2, 95%CI) pg/mL in the vitamin D insufficiency group, and 5510 (5491.4-5528.5, 95%CI) pg/mL in the control group, which was statistically similar among the groups (p = .251).

Conclusion: Our results indicated that vitamin D deficiency during pregnancy affects fetal bone osteoblast activity.

Keywords: C-terminal telopeptide; N-terminal procollagen of type l collagen (P1NP); Vitamin D deficiency; βCTX.

BRIL (bone-restricted IFITM-like), is a short transmembrane protein expressed almost exclusively in osteoblasts. Although much is known about its bone-restricted gene expression pattern and protein biochemical and topological features, little information is available for BRIL physiological function. Two autosomal dominant forms of osteogenesis imperfecta (OI) are caused by distinct, but recurrent mutations in the BRIL gene. Yet, the underlying mechanisms by which those mutations lead to OI are still poorly understood. A previous report indicated that BRIL knockout (KO) mice had bone deformities, shortened long bones, and reproductive problems. Here we generated and systematically analyzed the skeletal phenotype of a new global Bril KO/LacZ knockin mouse model. KO mice reproduced and thrived normally up to 12 month of age. The skeletal phenotype of KO and WT littermates was assessed at embryonic (E13.5 to E18.5) and postnatal (2 days, 3 weeks, 3 months and 8 months) time-points. Embryos from E13.5 through to E18.5 showed significant X-Gal staining in all skeletal elements without any apparent patterning anomalies. Although bone deformities were never observed at any postnatal ages, minor and transient differences were noted in terms of bone length and static uCT parameters, but not systematically across all ages and genders. These changes, however, were not accompanied by significant alteration in bone material properties as assessed by a 3-point bending test. In addition, no changes were detected in circulating serum markers of bone turnover (P1NP, CTX-I, and osteocalcin). Gene expression monitoring also revealed no major impact of the loss of BRIL. Further, when mice were challenged with a surgically-induced fracture in tibia, bones repaired equally well in the KO mice as compared to WT. Finally, we showed that BRIL C-terminus is not a bona fide binding site for calcium. In conclusion, our in depth analysis suggest that skeletal patterning, bone mass accrual and remodeling in mice proceeded independent of BRIL.

Exercise combined with protein and calcium has been shown to benefit bone turnover and bone metabolism. Greek yogurt (GY) contains important nutrients that support bone but has yet to be studied with exercise for this purpose. Thirty untrained, university-aged, males were randomized to 2 groups (n=15/group): GY (20g protein, 208mg calcium/dose) or Placebo Pudding (PP; 0g protein, 0g calcium/dose) consumed 3x/d on training days and 2x/d on non-training days. Both groups underwent a resistance/plyometric training program for 12 weeks. Blood was obtained at weeks 0, 1 and 12 to measure procollagen-type-I-N-terminal-propeptide (P1NP) and C-terminal-telopeptide (CTX). After outlier treatment, P1NP increased more over time in GY versus PP (P=0.002; interaction). Both groups decreased CTX over time (P=0.046; time effect). Following one week of training, there was a trend towards a significant increase in CTX in PP with no change in GY (P=0.062; interaction). P1NP changed more in GY than PP (wk12-baseline; P=0.029) as did the P1NP:CTX ratio (P=0.015) indicating a greater increase in formation with GY. Thus, GY added to a high-load, high-impact exercise program positively shifted bone turnover towards increased formation while attenuating resorption. GY could be a plausible post-exercise food to support bone health in young adult males. ●Greek yogurt, with exercise, increased bone formation in young adult males over 12 weeks. ●After 1 week of an osteogenic exercise program, Greek yogurt tended to blunt a rise in bone resorption seen with the placebo. ●Greek yogurt is a plausible post-exercise food that supports bone.

A study of 109 female volunteers in good health and reproductive life, the mean age was 38.5 years, the volunteers had no intake of any kind of medicine before blood examination. The mean value of PINP is 44.57 ng/ml, standard deviation= 19.91, standard error= 1.9 with 95% confident interval = 40.79 to 48.35 ng/ml The PINP is a bone formation marker which is secreted by osteoblast, the advantage of the present study was helping the evaluation of bone status after bone forming agents therapy. In addition PINP showed the status of bone turnover when compared to bone resorption marker (CTx).

TNFα inhibitors (TNFαI) exert positive effects on disease activity in rheumatoid arthritis (RA). Bone involvement is a major determinant of functional impairment in this disease. Here we investigated the short-term effects of TNFαI therapy on bone metabolism and density. We studied 54 patients with RA starting a TNFαI biologic drug, in whom any factor known to interfere with bone metabolism was excluded or rigorously accounted for. We measured at baseline and after 6-month therapy bone turnover markers: N-propeptide of type I collagen (P1NP), and bone alkaline phosphates for bone formation and serum C-terminal telopeptide of type I collagen (CTX) for bone resorption. We also evaluated bone mineral density (BMD) at hip and lumbar by dual-energy X-ray absorptiometry. All bone markers rose significantly and these changes were not dependent on steroid dosage. A significant decrease in femoral neck BMD was also observed. These results indicate that TNFαI therapy in RA over 6 months is associated with an early increase in bone turnover and a decline in hip BMD.

Breast cancer (BC) is the most frequent malignancy and the first cause of cancer-related death in women. The majority of patients with advanced BC develop skeletal metastases which may ultimately lead to serious complications, termed skeletal-related events, that often dramatically impact on quality of life and survival. Therefore, the identification of biomarkers able to stratify BC patient risk to develop bone metastases (BM) is fundamental to define personalized diagnostic and therapeutic strategies, possibly at the earliest stages of the disease. In this regard, the advent of "omics" sciences boosted the investigation of several putative biomarkers of BC osteotropism, including deregulated genes, proteins and microRNAs. The present review revisits the current knowledge on BM development in BC and the most recent studies exploring potential BM-predicting biomarkers, based on the application of omics sciences to the study of primary breast malignancies.

Keywords: ADAMTS1, a disintegrin-like and metalloproteinase with thrombospondin type 1; ALP, alkaline phosphatase; BALP (BSAP), bone-specific alkaline phosphatase; BC, breast cancer; BM, bone metastases; BOLCs, breast osteoblast-like cells; BTM, bone turnover markers; Biomarkers; Bone metastases; Breast cancer; CAPG, capping-protein; CCN3, cellular communication network factor 3; CDH11, cadherin-11; CNV, copy number variation; CTGF, connective tissue-derived growth factor; CTSK, cathepsin K; CTX, C-telopeptide; CXCL, C-X-C-ligand; CXCR, C–X–C motif chemokine receptor; DEGs, differentially expressed genes; DOCK4, dedicator of cytokinesis protein 4; DPD, deoxypyridoline; DTC, disseminated tumour cells; EMT, epithelial-to-mesenchymal transition; ER, estrogen receptor; ERRα, estrogen-related receptor alpha; FAK, focal adhesion kinase; FGF, fibroblast growth factor; FST, follistatin; GIPC1, PDZ domain-containing protein member 1; HR, hazard ratio; Her, human epidermal growth factor; ICAM-1, intercellular adhesion molecule 1; IGF, insulin-like growth factor; IHC, immunohistochemistry; IL, interleukin; LC/MS/MS, liquid chromatography/mass spectrometry/mass spectrometry; MAF, v-maf avian muscolo aponeurotic fibro-sarcoma oncogene homolog; MDA-MB, MD Anderson metastatic BC; MMP1, matrix metalloproteinase-1; NTX, N-telopeptide; OPG, osteoprotegerin; Omics sciences; Osteotropism; P1CP, pro-collagen type I C-terminal; P1NP, pro-collagen type I N-terminal; PDGF, platelet-derived growth factor; PRG1, proteoglycan-1; PTH-rP, parathyroid hormone-related protein; PYD, pyridoline; PgR, progesterone receptor; PlGF, placental growth factor; RANK, receptor activator of nuclear factor к-B; RT-PCR, real time-PCR; SILAC-MS, stable isotope labelling by amino acids in cell culture-mass spectrometry; SNPs, single nucleotide polymorphisms; SPP1, osteopontin; SREs, skeletal-related events; TCGA, the cancer genome atlas; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor-α; TRACP-5b, tartrate resistant acid phosphatase-5b; VEGF, vascular endothelial growth factor; ZNF217, zinc-finger protein 217; miRNAs, microRNAs; ncRNAs, noncoding RNA.

OBJECTIVE

Epidemiologic data suggest older adults receiving serotonergic antidepressants may have accelerated bone loss. We examined bone turnover marker changes and patient-level variables associated with these changes in older adults receiving protocolized antidepressant treatment.

METHODS

Open-label, protocolized treatment study.

METHODS

Medical centers in Pittsburgh, St Louis, and Toronto.

METHODS

Older adults with major depression (N = 168).

METHODS

Serum levels of the bone resorption marker C-terminal cross-linking telopeptide of type 1 collagen (CTX) and the bone formation marker procollagen type 1 N propeptide (P1NP) were assayed before and after 12 weeks of treatment with venlafaxine. Whether CTX and P1NP changes were associated with depression remission and duration of depression and genetic polymorphisms in the serotonin transporter (5HTTLPR) and 1B receptor (HTR1B) were also examined.

RESULTS

CTX increased and P1NP decreased during venlafaxine treatment, a profile consistent with accelerated bone loss. Two individual-level clinical variables were correlated with bone turnover; participants whose depression did not go into remission had higher CTX levels, and those with chronic depression had lower P1NP levels. HTR1B genotype predicted P1NP change, whereas 5HTTLPR genotype was unrelated to either biomarker.

CONCLUSIONS

Bone turnover markers change with antidepressant treatment in a pattern that suggests accelerated bone loss, although the clinical significance of these changes is unclear. These data are preliminary and argue for a larger, controlled study to confirm whether antidepressants are harmful to bone metabolism and whether certain individuals might be at increased risk.

Evidence from several studies indicates that the long-term treatment of selective serotonin reuptake inhibitors (SSRIs) is associated with a decrease in bone mass and increase the risk of fractures. The present work evaluated and compared the effect of treatment with two SSRIs viz. fluoxetine and escitalopram on bone biomarkers (P1NP and βCTX) in male Wistar rats. In addition, the effect of these drugs on bone microarchitecture of lumbar and tibia bones was carried out. Fluoxetine (8.2 mg/kg) treatment for 40 days significantly reduced (P < 0.01) the levels of the P1NP while escitalopram (2.0 mg/kg) was without such effects. Both drugs were devoid of any effects on bone resorption marker βCTX. The pCREB levels were reduced by both the antidepressants but the reduction was significantly (P < 0.001) marked in case of fluoxetine. The micro-CT data revealed that fluoxetine, but not escitalopram, treatment resulted in reduced bone volume fraction, trabecular thickness and number while increased trabecular separation, trabecular pattern factor and connectivity density in the proximal tibial metaphysis. No significant changes were, however, discernible in lumbar bones. The study shows that fluoxetine reduces bone formation possibly through reduced pCREB mediated by the action of gut serotonin in osteoblasts and that escitalopram can be a better treatment option as far as adverse effects on bone are concerned.