Procollagen Type I N-terminal Propeptide Research Articles

Abstract PS9-23: Second-generation HR-pQCT analysis of bone mineral density and microstructure in women with breast cancer who underwent adjuvant endocrine therapy

Abstract Background: Adjuvant endocrine therapy for 5-10 years reduces breast cancer (BC) mortality in women with hormone receptor-positive BC. However, aromatase inhibitors (AIs) decrease bone mineral density (BMD), and increase fractures, joint stiffness, and joint pain. Although dual energy X-ray absorptiometry (DXA) is widely used to assess BMD, it is a two-dimensional method and thus cannot analyze trabecular and cortical bone microstructure. High-resolution peripheral quantitative computed tomography (HR-pQCT) allows in vivo analysis of peripheral bone microarchitecture with high spatial resolution and low radiation exposure. We used HR-pQCT to evaluate changes in volumetric bone density and microstructure consisting of trabecular and cortical bone associated with AI treatment in patients with early BC. Methods: This was a prospective single-center observational study of nonosteoporotic, postmenopausal women with hormone receptor-positive BC, whose baseline DXA lumber spine and femoral neck T-scores were > −2.5. All patients were scheduled to receive DXA and HR-pQCT at baseline and at 6 and 12 months after starting AI therapy. The primary endpoint was to examine changes in total volumetric BMD (Tt. vBMD), trabecular volumetric BMD (Tb. vBMD), cortical volumetric BMD (Ct. vBMD) change at the distal radius and the distal radius between baseline and 6 and 12 months after starting endocrine therapy. Results: Of the 20 women in the study (median age: 57.5 years; range: 55-72 years), 8 had undergone chemotherapy before registration. Their mean change in Tt. vBMD between baseline and 1 year were distal radius: −5.7% (SD: 2.5%, P<0.01); distal tibia: −3.8% (SD: 1.8%, P<0.01), Tb. vBMD distal radius: −4.0% (SD: 3.9%, P<0.01); distal tibia: −0.9% (SD: 2.4%, P<0.05), Ct. vBMD distal radius: −3.1% (SD: 1.6%, P<0.01); distal tibia: −2.9% (SD: 1.7%, P<0.01). Furthermore, at 1 year in trabecular bone, mean trabecular bone volume fraction (p<0.01), trabecular thickness (p<0.05), and trabecular number (p<0.01) were significantly decreased, and trabecular separation (p<0.01) increased, in both the distal radius and tibia. At 1 year in cortical bone, mean changes in cortical thickness (p<0.01) and cortical bone area (p<0.01) were significantly decreased in both the distal radius and tibia; however, the endocortical perimeter of cortical bone did not significantly change and cortical porosity (p<0.05) was significantly greater than that at baseline. At 1 year, DXA decreased at the total hip (−4.4%, P<0.01) and femoral neck (−0.6%, P=0.03) compared with baseline. However, no significant difference was seen in median values for lumbar spine BMD at 1 year, or for tartrate-resistant acid phosphatase-5b (TRACP-5b) or procollagen type-I N-terminal propeptide (PINP). Conclusion: Postmenopausal women who took AIs for early BC experience volumetric bone density decline and both trabecular and cortical bone deterioration. A decade of AI treatment is a standard treatment for early BC; however, healthcare professionals should monitor bone health during and after these treatments. Citation Format: Sayaka Kuba, Konosuke Watanabe, Megumi Matsumoto, Ko Chiba, Kosho Yamanouchi, Ayako Fukushima, Michi Morita, Ryota Otsubo, Hiroshi Yano, Kengo Kanetaka, Makoto Osaki, Takeshi Nagayasu, Susumu Eguchi. Second-generation HR-pQCT analysis of bone mineral density and microstructure in women with breast cancer who underwent adjuvant endocrine therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-23.

Reference intervals in Danish children and adolescents for bone turnover markers carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP)

Bone turnover markers (BTM) are gaining ground in clinical practice but to fully use their potential there is a need for establishing valid reference intervals (RI). Consequently, the purpose of the study was to establish general RI as well as suggested clinical RI for carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP) in children and adolescents. BTM were measured on Danish children and adolescents participating in the CHAMPS-study DK. A total of 762 participants were included (8-18years, 50.4% girls) contributing a total of 1410 study visits. The RI was calculated based on 2-years age spans. Participants with biochemical signs of metabolic bone disease were excluded. The differences in RI between age groups clearly reflect changes in growth with an initial increase in BTM, greatest in boys, and a subsequent decrease most pronounced in girls. β-CTX and PINP are markers most affected by these changes, compared to OC and bone ALP. The suggested clinical 95% RI included participants with vitamin D insufficiency but no biochemical signs of metabolic bone disease which did not markedly alter the RI. RI for β-CTX, PINP, OC and bone ALP varies with age and sex. β-CTX and PINP which reflect bone resorption and formation processes are mostly affected by these changes. We suggest a set of clinically applicable 95% RI for the four BTM to heighten the usefulness and generalizability of the RI.

Differential effects of abaloparatide and teriparatide on hip cortical volumetric BMD by DXA-based 3D modeling

SummaryIn postmenopausal osteoporotic women in ACTIVE, abaloparatide reduced fracture risk and increased areal bone mineral density (BMD) more than teriparatide at the hip and wrist. DXA-based 3D modeling showed significantly greater increases in hip cortical volumetric BMD with abaloparatide versus teriparatide. This may explain differences reported in aBMD by DXA.IntroductionIn ACTIVE, abaloparatide (ABL) increased bone mineral density (BMD) shown by dual-energy X-ray absorptiometry (DXA) while reducing fracture incidence in postmenopausal osteoporotic women. Changes in DXA BMD with ABL, 80 μg, were significantly greater than with open-label teriparatide (TPTD), 20 μg, at cortical sites including total hip, femoral neck, and 1/3 distal radius. The purpose of this study was to better understand the relative effects of ABL and TPTD on cortical and cancellous compartments in the proximal femur.MethodsHip DXA images from a subset of randomly selected patients in the ACTIVE trial (n = 250/arm) were retrospectively analyzed using three-dimensional modeling methods (3D-SHAPER software) to evaluate changes from baseline at months 6 and 18.ResultsSimilar significant increases in trabecular volumetric BMD (vBMD, + 9%) and cortical thickness (+ 1.5%) were observed with ABL and TPTD by 3D-DXA at 18 months. In contrast, only ABL significantly increased cortical vBMD versus baseline (+ 1.3%), and changes in both cortical vBMD and cortical surface BMD were significantly greater with ABL versus TPTD. In the TPTD group, changes in cortical vBMD were inversely correlated with changes in serum CTX (carboxy-terminal telopeptide of type I collagen) and PINP (procollagen type I N-terminal propeptide), suggesting that higher bone turnover may have attenuated cortical gains.ConclusionThese results suggest previously reported differences in areal BMD increases between ABL and TPTD may be due to differential effects on cortical vBMD. Further studies are warranted to investigate how these differences affect therapeutic impact on hip strength in postmenopausal women with osteoporosis.

The Clinical Effect of Zoledronic Acid Combined with Teriparatide in Perverting Recurrent Fracture of Osteoporotic Vertebral Compressive Fractures in the Elderly after Percutaneous Kyphoplasty

Background: Zoledronic acid and teriparatide have been proved to be effective in improving bone metabolism and preventing fractures, but there is no clear clinical report on the efficacy of their combined application. Purpose: To discuss the clinical effect of zoledronic acid combined with teriparatide in perverting recurrent fracture of osteoporotic vertebral compressive fractures (OVCF) in the elderly after percutaneous kyphoplasty (PKP). Method: A randomized clinical trial was conducted at the First Affiliated Hospital of Hebei North University in China from September 2018 and September 2019. A total of 60 patients with OVCF were enrolled in the study (zoledronic acid: 20 cases; teriparatide: 20 cases; zoledronic acid + teriparatide: 20 cases). Observe and compare the changes of bone mineral density (BMD), pro-collagen type I N-terminal propeptide (PINP) and cross-linked C-terminal telopeptide of type I collagen (β-CTX) before surgery, 6 months and 1 year after surgery. At the same time, secondary fracture events and adverse reaction events were recorded during the follow-up period. Results: After normalized treatment, the bone metabolism indexes of PINP and β-CTX were improved and BMD was increased in three groups. Adverse Reactions: There was no statistical significance in the incidence of fever, gastrointestinal reactions and myalgia among the three groups (P > 0.05). The incidence of recurrent fractures in group A was higher than that in group C (P 0.05). Conclusion: Zoledronic acid combined with teriparatide is superior to Zoledronic acid in preventing the risk of recurrent fracture after PKP for old patients with OVCF, but it has no significant advantage over teriparatide.

MiR-29c-3p reduces bone loss in rats with diabetic osteoporosis via targeted regulation of Dvl2 expression.

The aim of this study was to investigate the influence of micro ribonucleic acid (miR)-29c-3p on rats with diabetic osteoporosis (DOP) and its underlying mechanism. A total of 30 specific pathogen-free (SPF)-grade male Wistar rats aged 6-week-old were randomly selected and divided into three groups according to different intervention means, including: NC group (control rats only injected with normal saline), DOP group (rats with DOP induced by injection of streptozotocin), and ME group (DOP rats injected with miR-29c-3p agonist for 4 consecutive weeks). The changes in blood glucose and body weight were recorded in the rats of each group every week. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the content of bone turnover markers (BTMs) in serum, such as alkaline phosphatase (ALP), osteocalcin (OC), and procollagen type I N-terminal propeptide (PINP). The variations in serum calcium (Ca) and phosphorus (P) levels in the abdominal aorta were determined using an atomic absorption spectrometer in the three groups. Meanwhile, bone mineral density (BMD) of femur and lumbar vertebra (L1-L4) were examined. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the changes in messenger RNA (mRNA) expressions of miR-29c-3p and Disheveled 2 (Dvl2) in the bone tissues of intervened rats. In addition, the staining and expression changes of Dvl2 protein in bone tissues were determined via immunohistochemistry. The rats in NC group had normal behavioral activities, normally increased body weight, sensitive responses, as well as normal and stable blood glucose. In DOP group, the rats manifested clinical symptoms of diabetes mellitus (DM) (i.e., polydipsia, polyphagia, polyuria, and weight loss), lackluster hairs, decreased behavioral activities, slow responses, and blood glucose at a concentration higher than 16.7 mmol/L. However, the blood glucose rose first, and then, declined and it was maintained at a level higher than normal concentration in ME group. Meanwhile, the rate of weight loss significantly decreased. The results of qRT-PCR indicated that the relative expression level of miR-29c-3p in bone tissues of DOP group was remarkably lower than that in NC group (p<0.01). However, it was significantly higher in ME group than that in DOP group (p<0.05). DOP group exhibited significantly upregulated serum BTMs (ALP, CTX-1, OC, TRACP-5b, and PIPN) when compared with NC group (p<0.05) and ME group (p<0.05). Furthermore, femoral BMD decreased in DOP group (p<0.05) while increased in ME group, showing statistically significant difference between the two groups (p<0.05). Immunohistochemistry results indicated that the bone tissues of DOP rats were deeply stained, and protein expression of Dvl2 protein was significantly higher in comparison with NC group. The bone tissues were lightly stained in ME group, and the protein expression of Dvl2 was lower than that in DOP group. Besides, qRT-PCR results demonstrated that the mRNA expression changes of Dvl2 were consistent with its protein expression trends. MiR-29c-3p reduces bone loss in rats with DOP via targeted regulation of Dvl2 expression.

Metabolic activities affect femur and lumbar vertebrae remodeling, and anti-resorptive risedronate disturbs femoral cortical bone remodeling

Metabolic activities are closely correlated with bone remodeling and long-term anti-resorptive bisphosphonate treatment frequently causes atypical femoral fractures through unclear mechanisms. To explore whether metabolic alterations affect bone remodeling in femurs and lumbar vertebrae and whether anti-osteoporotic bisphosphonates perturb their reconstruction, we studied three mouse strains with different fat and lean body masses (BALB/c, C57BL6, and C3H mice). These mice displayed variable physical activity, food and drink intake, energy expenditure, and respiratory quotients. Following intraperitoneal calcein injection, double calcein labeling of the femoral diaphysis, as well as serum levels of the bone-formation marker procollagen type-I N-terminal propeptide and the bone-resorption marker C-terminal telopeptide of type-I collagen, revealed increased bone turnover in mice in the following order: C3H > BALB/c ≥ C57BL6 mice. In addition, bone reconstitution in femurs was distinct from that in lumbar vertebrae in both healthy control and estrogen-deficient osteoporotic mice with metabolic perturbation, particularly in terms of femoral trabecular and cortical bone remodeling in CH3 mice. Interestingly, subcutaneous administration of bisphosphonate risedronate to C3H mice with normal femoral bone density led to enlarged femoral cortical bones with a low bone mineral density, resulting in bone fragility; however, this phenomenon was not observed in mice with ovariectomy-induced femoral cortical bone loss. Together, these results suggest that diverse metabolic activities support various forms of bone remodeling and that femur remodeling differs from lumbar vertebra remodeling. Moreover, our findings imply that the adverse effect of bisphosphonate agents on femoral cortical bone remodeling should be considered when prescribing them to osteoporotic patients.

Bone involvement in Gaucher disease type 1: a differential diagnosis of multiple fractures in a young patient. Case report

Gaucher disease type 1 (GD1) is a rare inherited disease caused by mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase, leading to decreased enzyme activity and the consequential accumulation of its substrate, glucosylceramide, within macrophages. Bone involvement in GD1 may include avascular necrosis, bone infarcts, fragility fractures, lytic or sclerotic bone lesions and osteomyelitis. Bone pain can manifest as an acute and very painful bone crisis or a chronic pain that might vary in intensity, usually caused by fractures or avascular necrosis with progressive collapse of bone and joints. Hence, this report aims to describe a case of Gaucher disease type 1 and discuss its diagnosis, bone involvement and management, since late diagnosis or inadequate therapy can lead to clinical worsening, irreversible mobility impairment and increased morbidity. AGR, a 32-year-old male patient, was admitted to the Rheumatology Service with a previous history of diffuse bone pain, episodic hyperemia in the lower limbs since the age of 9 and two low-impact fractures. He had an initial non-confirmed diagnostic hypothesis of chronic recurrent multifocal osteomyelitis and was taking dipyrone and tramadol to reduce pain. His physical examination evinced overweight (body mass index: 29.7 kg/m2) and hepatosplenomegaly. Laboratory tests shown thrombocytopenia, with platelet count 103,000/mm3 (reference value [RV]: 140,000-450,000/mm3), serum phosphorus 4.7 mg/dL (RV: 2.7-4.5 mg/dL), C-reactive protein 88.8 mg/dL (RV: &lt; 5 mg/dL) and ferritin 1336 ng/mL (RV: 30-400 ng/mL). Biochemical and bone turnover markers were normal, including serum total calcium and magnesium, parathyroid hormone, 25-OH vitamin D, alkaline phosphatase, procollagen type-I N-terminal propeptide and C-terminal telopeptide of type I collagen. Conventional radiographies and magnetic resonance imaging were performed and confirmed previous fractures in the right humerus and the right acetabulum. They also showed sclerotic lesions in the left femur and Erlenmeyer flask deformities in the distal femurs and the proximal tibias. Bone scintigraphy indicated a bone infarct area in the left tibia. Areal bone mineral density (BMD) evaluated by bone densitometry showed a left total femur Z-score of +4.3 and left femoral neck Z-score of +4.5. Differently, the bone microarchitecture and volumetric BMD, evaluated by a high-resolution peripheral quantitative computed tomography (HR-pQCT) at distal radius and distal tibia, demonstrated an impairment of cortical compartment with lower cortical thickness and lower cortical volumetric BMD, possibly contributing to the low-impact fractures. Considering the compatible radiological findings, associated with hepatosplenomegaly and thrombocytopenia, Gaucher disease type 1 became the major hypothesis. It was confirmed after enzymatic dosage, which showed low residual glucocerebrosidase activity and high serum chitotriosidase. Enzyme replacement therapy was started with taliglucerase alfa, a recombinant enzyme preparation that aims to supply the lacking glucocerebrosidase in lysosomes. After 6 months of treatment, patient reported a significant improvement in bone pain and general quality of life. Therefore, clinicians should be alert to young patients with multiple low-impact fractures and further evaluate other possible bone involvement, as GD1 may be a differential diagnosis. Since it needs specific treatment, early diagnosis can be crucial to avoid permanent bone damage and morbidity.

Fusion Potential of Human Osteoclasts In Vitro Reflects Age, Menopause, and In Vivo Bone Resorption Levels of Their Donors-A Possible Involvement of DC-STAMP.

It is well established that multinucleation is central for osteoclastic bone resorption. However, our knowledge on the mechanisms regulating how many nuclei an osteoclast will have is limited. The objective of this study was to investigate donor-related variations in the fusion potential of in vitro-generated osteoclasts. Therefore, CD14+ monocytes were isolated from 49 healthy female donors. Donor demographics were compared to the in vivo bone biomarker levels and their monocytes’ ability to differentiate into osteoclasts, showing that: (1) C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels increase with age, (2) the number of nuclei per osteoclast in vitro increases with age, and (3) there is a positive correlation between the number of nuclei per osteoclast in vitro and CTX levels in vivo. Furthermore, the expression levels of the gene encoding dendritic cell-specific transmembrane protein (DCSTAMP) of osteoclasts in vitro correlated positively with the number of nuclei per osteoclast, CTX levels in vivo, and donor age. Our results furthermore suggest that these changes in gene expression may be mediated through age-related changes in DNA methylation levels. We conclude that both intrinsic factors and age-induced increase in fusion potential of osteoclasts could be contributing factors for the enhanced bone resorption in vivo, possibly caused by increased expression levels of DCSTAMP.

Bone turnover markers in children living with HIV remaining on ritonavir-boosted lopinavir or switching to efavirenz.

We previously found lower bone mass but similar bone turnover in pre-pubertal children living with HIV (CLWH) on a ritonavir-boosted lopinavir (LPV/r)-based vs. efavirenz-based antiretroviral therapy regimen 2years after switch. Here, we evaluate if bone turnover differed between the groups close to the time of switch. Samples from 108 children remaining on LPV/r and 104 children switched to efavirenz were available for analysis 8weeks post-randomization. Bone turnover markers, including C-telopeptide of type 1 collagen (CTx), procollagen type-I N-terminal propeptide (P1NP), and osteocalcin were measured. Markers of immune activation were also measured, including IL-6, TNF-alpha, soluble CD14 and high-sensitivity C-reactive protein (CRP). Eight weeks post-randomization, we did not detect differences in CTx (1.42 vs. 1.44ng/mL, p=0.85) or P1NP concentrations (622 vs. 513ng/mL, p=0.68) between treatment groups. At 8weeks, the treatment groups also had similar levels of IL-6, TNF-alpha, soluble CD14 and high-sensitivity CRP. Osteocalcin (ng/mL) was higher in the LPV/r than efavirenz group both at 8weeks (88.6 vs. 67.3, p=0.001) and 2years (67.6 vs. 49.8, p=0.001). Overall, we failed to detect difference in bone turnover by P1NP and CTx in virologically-suppressed CLWH on different regimens at a time point close to the switch. We did observe higher levels of total osteocalcin in children remaining on LPV/r compared to children switched to efavirenz. Future studies should focus on uncovering the mechanism and determining whether perturbation in undercarboxylated osteocalcin could explain some of the bone side effects noted with protease inhibitors.

Are the Effects of Oral and Vaginal Contraceptives on Bone Formation in Young Women Mediated via the Growth Hormone-IGF-I Axis?

Purpose: Combined hormonal contraceptive therapy has been associated with negative bone mineral density outcomes that may be route-dependent [i.e., combined oral contraception (COC) vs. contraceptive vaginal ring (CVR)] and involve the hepatic growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. The objective of the pilot study was to assess the impact of route of contraceptive administration on IGF-I and procollagen type I N-terminal propeptide (PINP) responses to an IGF-I Generation Test. We hypothesized that the peak rise in IGF-I and PINP concentration and area under the curve (AUC) would be attenuated following COC, but not CVR, use.Methods: Healthy, premenopausal women not taking hormonal contraception were recruited. Women were enrolled in the control group (n = 8) or randomly assigned to COC (n = 8) or CVR (n = 8) for two contraceptive cycles. IGF-I Generation Tests were used as a probe to stimulate IGF-I release and were completed during the pre-intervention and intervention phases. Serum IGF-I and PINP were measured during both IGF-I Generation Tests. The study was registered at ClinicalTrials.gov (NCT02367833).Results: Compared to the pre-intervention phase, peak IGF-I concentration in response to the IGF-I Generation Test in the intervention phase was suppressed in the COC group (p < 0.001), but not the CVR or Control groups (p > 0.090). Additionally, compared to the pre-intervention phase, PINP AUC during the intervention phase was suppressed in both COC and CVR groups (p < 0.001), while no difference was observed in the control group (p = 0.980).Conclusion: These data suggest that changes in recombinant human GH-stimulated hepatic IGF-I synthesis in response to combined hormonal contraception (CHC) use are dependent on route of CHC administration, while the influence on PINP is route-independent. Future research is needed to expand these results with larger randomized control trials in all age ranges of women who utilize hormonal contraception.Clinical Trial Registration: www.ClinicalTrials.gov registration NCT02367833.

Status of circulating bone turnover markers in elderly osteoporosis/osteopenia patients in comparison with healthy subjects

Abstract Background In the aging individuals, osteoporosis is a major health problem. Due to the various limitations of dual X-ray absorptiometry (DEXA) for diagnosis osteoporosis, serum-based biochemical markers have been suggested for the discrimination between the patients and healthy subjects. Objective To investigate the serum levels of bone turnover markers in elderly osteoporosis patients. Methods The serum samples from elderly subjects (osteoporosis (n = 28), osteopenia (n = 28), and healthy ones (n = 28) were collected from Amirkola Health and Ageing Project study. Furthermore, serum levels of bone formation and bone resorption markers as well as estrogen and progesterone were measured by enzyme-linked immunosorbent assay. Kruskal–Wallis test and receiver operating characteristic curve analysis were used for statistical analysis using SPSS. Results Levels of bone alkaline phosphatase (B-ALP) and procollagen type I N-terminal propeptide (PINP) differed between groups (P = 0.003 and 0.009, respectively). Furthermore, PINP and B-ALP levels had the best area under the curve, sensitivity, and specificity for the discrimination between patients with osteoporosis and healthy individuals. Conclusion In conditions in which we are not able to assess the bone mineral density by DEXA, analysis of the B-ALP and PINP levels may be a helpful tool.

Comparison of Bone Turnover Markers between Young Adult Male Smokers and Nonsmokers.

BackgroundThis study aims to compare the differences in the means of bone formation and resorption markers between young adult male smokers and nonsmokers.MethodsThis study employed a cross-sectional, descriptive design. Thirty-five smokers and 38 nonsmokers were recruited. All participants completed self-reported questionnaires about demographics, physical activity, and smoking status. In addition, blood specimens were collected to determine serum levels of bone turnover markers.ResultsRegarding bone formation markers, the least square means (LSM) for osteoprotegerin (OPG) and procollagen type I N-terminal propeptide (PINP) were similar for smoking and nonsmoking groups. Regarding bone resorption markers, the LSM serum carboxyl-terminal telopeptide of collagen type I (CTXI) level was found to be significantly lower in smokers than nonsmokers [0.82 ± 0.83 vs. 1.30 ± 0.82 ng/mL, F (1, 66) = 5.73, p = 0.020]. The LSM for soluble-receptor activator of nuclear factor-kappa B ligand (sRANKL) [1.64 ± 0.60 vs. 1.69 ± 0.62 ng/mL, F (1,64) = 10.74, p = 0.002] and RANKL/OPG [2.62 ± 1.09 vs. 2.81 ± 1.10 ng/mL, F (1,65) = 5.88, p = 0.018] were different for smoking and nonsmoking groups. Exploration of the moderating influence of physical activity on smoking effects revealed significant effect for the interaction between smoking status and physical activity on sRANKL [F (2, 64) = 8.63, p = 0.001] and RANKL/OPG ratio [F (2, 65) = 5.49, p = 0.006].ConclusionOur study provides evidence for the effect of smoking on bone resorption markers in young adult males. Such effects should be carefully considered side by side with other lifestyles that may lead to poor bone health and increased risk for osteoporosis.

Combined antisclerostin antibody and parathyroid hormone (1-34) synergistically enhance the healing of bone defects in ovariectomized rats.

Osteoporotic bones heal more slowly and ineffectively than normal bones. Acombination of antibodies against sclerosing protein (Scl-Ab), and parathyroid hormone 1-34 (PTH 1-34) may improve healing. Astandard osteoporotic rat model was established 12weeks after bilateral ovarian resection (OVX). Bone defects were created in the right femora of 80rats, which were randomly divided into 4 groups: control, Scl-Ab (25 mg/kg twice weekly), PTH (60 μg/kg of PTH 1-34 three times aweek) and PTH plus Scl-Ab. After 12weeks of treatment the rats were sacrificed and blood and the distal femora were harvested for biochemical evaluation, histology, microcomputed tomography and biomechanical testing. Compared to the control group, monotherapy and combination therapy with PTH and/or Scl-Ab promoted the formation of new bone, enhanced maximum femoral loading and increased the levels of procollagen typeI N‑terminal propeptide (PINP) and osteocalcin. The administration of PTH + Scl-Ab maximally enhanced bone defect healing. Combination treatment was better than either treatment alone, indicating asynergistic effect.

Higher concentration of serum C-terminal cross-linking telopeptide of type I collagen is positively related with inflammatory factors in postmenopausal women with H-type hypertension and osteoporosis.

ObjectiveTo investigate the changes of inflammatory factors and bone metabolism markers in postmenopausal women with H‐type hypertension and to assess the relationship between them.MethodsPostmenopausal women who were diagnosed with osteoporosis were selected as observation objects. Participants were divided into three groups: only osteoporosis group (osteoporosis group), hypertension combined with osteoporosis group (hypertension group), and H‐type hypertension combined with osteoporosis group (H‐type hypertension group). The changes in bone mineral density and bone metabolic markers (osteocalcin [OC], procollagen type I N‐terminal propeptide (PINP), and C‐terminal cross‐linking telopeptide of type I collagen [CTX]) and inflammatory factors (interleukin‐6 [IL‐6] and tumor necrosis factor‐α [TNF‐α]) were compared among three groups.ResultsIn the hypertension group and the H‐type hypertension group, the bone mineral density of the lumbar spine (0.647 ± 0.038 vs 0.638 ± 0.034 vs 0.668 ± 0.047, P < 0.05) and the femoral neck (0.567 ± 0.047 vs 0.552 ± 0.053 vs 0.618 ± 0.059, P < 0.05) was significantly lower than that in the osteoporosis group. The concentrations of CTX (266.61 ± 64.65 vs 293.09 ± 72.34 vs 235.48 ± 62.85, P < 0.05), IL‐6 (44.36 ± 6.45 vs 48.05 ± 8.04 vs 39.06 ± 7.95, P < 0.05) and TNF‐α (30.53 ± 6.28 vs 34.52 ± 7.15 vs 28.66 ± 6.19, P < 0.01) in the hypertension group and in the H‐type hypertension group were significantly higher than those in the osteoporosis group. The concentrations of OC (30.59 ± 6.43 vs 27.10 ± 6.51, P < 0.05) and PINP (36.36 ± 6.16 vs 33.16 ± 6.77, P < 0.05) in the H‐type hypertension group were increased dramatically. The concentration of CTX was positively correlated with the concentration of IL‐6 (r = 0.587, P < 0.01) and TNF‐α (r = 0.474, P < 0.01) and negatively related with the concentration of OC (r = −0.591, P < 0.01) and PINP (r = −0.646, P < 0.01) and the bone mineral density of the lumbar spine (r = −0.470, P < 0.01) and the femoral neck (r = −0.509, P < 0.01).ConclusionHigher concentration of serum CTX is found in postmenopausal women with H‐type hypertension, which is positively correlated with inflammatory factors. Besides, H‐type hypertension could further enhance the activity of osteoclasts and increase the expressions of inflammatory factors, resulting in the aggravation of osteoporosis.

Therapeutic effect of percutaneous kyphoplasty combined with anti-osteoporosis drug on postmenopausal women with osteoporotic vertebral compression fracture and analysis of postoperative bone cement leakage risk factors: a retrospective cohort study

BackgroundThe purpose of this study is to explore the therapeutic effect of percutaneous kyphoplasty (PKP) combined with anti-osteoporosis drug, zoledronic acid, on postmenopausal women with osteoporotic vertebral compression fracture (OVCF) and to perform an analysis of postoperative bone cement leakage risk factors.MethodsA total of 112 OVCF patients, according to therapeutic regimens, were divided into control group (n = 52, treated with PKP) and observation group (n = 60, treated with PKP and zoledronic acid injection).ResultsPostoperative tumor necrosis factor-α and interleukin-6 levels were significantly decreased in the two groups, compared with those before treatment (both P < 0.05); bone mineral density (BMD), serum bone gla protein (BGP), and vertebral height ratio of injured vertebrae were significantly increased, and procollagen type I N-terminal propeptide (PINP), Cobb angle, visual analogue scale/score (VAS), and Oswestry disability index (ODI) were significantly decreased compared with those before treatment (all P < 0.05). There were significantly higher changes in difference value of BMD, PINP, BGP, vertebral height ratio of injured vertebrae, Cobb angle, VAS, and ODI levels and significantly better therapeutic effect in the observation group than those in the control group (all P < 0.05). Multivariate logistic regression analysis showed that the use of zoledronic acid, vertebral height ratio of injured vertebrae, and ODI were independent factors affecting the therapeutic effect, and that the dosage of bone cement, and peripheral vertebrae wall damage were independent risk factors causing postoperative bone cement leakage. There were no significant differences in postoperative bone cement leakage rate between the two groups.ConclusionsPeripheral vertebrae wall damage and the dosage of bone cement are independent risk factors causing bone cement leakage in OVCF patients treated with PKP. PKP combined with zoledronic acid has an improvement effect on the condition of postmenopausal women with OVCF and reduces the inflammation and pain in patients, which is beneficial to clinical treatment.

Systematic Review of the Long-Term Effects of Transgender Hormone Therapy on Bone Markers and Bone Mineral Density and Their Potential Effects in Implant Therapy.

This study seeks to evaluate the long-term effects of pharmacologic therapy on the bone markers and bone mineral density of transgender patients and to provide a basis for understanding its potential implications on therapies involving implant procedures. Following the referred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and well-defined PICOT (Problem/Patient/Population, Intervention, Comparison, Outcome, Time) questionnaires, a literature search was completed for articles in English language, with more than a 3 year follow-up reporting the long-term effects of the cross-sex pharmacotherapy on the bones of adult transgender patients. Transgender demographics, time under treatment, and treatment received were recorded. In addition, bone marker levels (calcium, phosphate, alkaline phosphatase, and osteocalcin), bone mineral density (BMD), and bone turnover markers (Serum Procollagen type I N-Terminal pro-peptide (PINP), and Serum Collagen type I crosslinked C-telopeptide (CTX)) before and after the treatment were also recorded. The considerable variability between studies did not allow a meta-analysis. All the studies were completed in European countries. Transwomen (921 men to female) were more frequent than transmen (719 female to male). Transwomen’s treatments were based in antiandrogens, estrogens, new drugs, and sex reassignment surgery, meanwhile transmen’s surgeries were based in the administration of several forms of testosterone and sex reassignment. Calcium, phosphate, alkaline phosphatase, and osteocalcin levels remained stable. PINP increased in transwomen and transmen meanwhile, CTX showed contradictory values in transwomen and transmen. Finally, reduced BMD was observed in transwomen patients receiving long-term cross-sex pharmacotherapy. Considering the limitations of this systematic review, it was concluded that long-term cross-sex pharmacotherapy for transwomen and transmen transgender patients does not alter the calcium, phosphate, alkaline phosphatase, and osteocalcin levels, and will slightly increase the bone formation in both transwomen and transmen patients. Furthermore, long-term pharmacotherapy reduces the BMD in transwomen patients.

Comparison of bone biomechanical properties after bone marrow mesenchymal stem cell or alendronate treatment in an osteoporotic animal model.

The aim of this study was to explore the effects of bone marrow mesenchymal stem cells (BMMSCs) and alendronate sodium (ALN) intervention on osteoporosis (OP). Sixty-eight 6-month-old healthy female Sprague Dawley (SD) rats were used to generate an OP model by removal of the ovaries. After 12 weeks, rats were treated with BMMSCs (BMMSC group) or ALN (ALN group) for 5 weeks. Serum type I collagen C terminal peptide (CTX_1), procollagen type I N-terminal propeptide (PINP), and bone alkaline phosphatase (BALP) were tested along with the femur bone density and other properties, including bone mineral density (BMD), BALP, percent trabecular area (BV/TV), trabecular thickness (Tb.Th), trabecular number (TbN), maximum load, maximum stress, maximum strain, and elastic modulus. BMD, BALP, BV/TV, Tb.Th, TbN, maximum load, maximum stress, maximum strain, and elastic modulus values were higher in the BMMSC group versus the ALN group relative to the control group (p < 0.05); CTX_1, PINP, trabecular separation (Tb.Sp), and osteoclast number (OC.N) were lowest in the BMMSC group versus the ALN group relative to the control group (p < 0.05). Both BMMSCs and ALN could improve the metabolic function and bone quality in osteoporotic mice while restoring the strength and toughness of bones. The intervention effects of BMMSCs are better than ALN in this model.

LncRNAp21 promotes osteogenic differentiation of mesenchymal stem cells in the rat model of osteoporosis by the Wnt/β-catenin signaling pathway.

The aim of this study was to explore the promoting effect of long non-coding ribonucleic acid p21 (lncRNAp21) on the osteogenic differentiation of mesenchymal stem cells in the rat model of osteoporosis (OP) through the Wnt/β-catenin signaling pathway. A total of 30 healthy female rats were selected and randomly divided into three groups, including the lncRNAp21 group, OP model group (model group) and normal group. Rats in the lncRNAp21 group were given a certain quantity of lncRNAp21 inhibitors for gavage. Rats in the model group were regularly given 0.9% NaCl for gavage every day after the removal of bilateral ovaries. Meanwhile, rats in the normal group were fed normally without any changes. Bone mineral density (BMD) was measured after 12 weeks of modeling. The levels of procollagen type I N-terminal propeptide (PINP), serum estradiol (E2), osteocalcin (OC), bone alkaline phosphatase (BALP), C-terminal cross-linking telopeptide of type I collagen (CTX) and tartrate-resistant acid phosphatase 5b (TRACP-5b) in the bone and serum of rats were measured by enzyme-linked immunosorbent assay (ELISA). Besides, quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blotting were adopted to detect the mRNA and protein expressions of Wnt1 and β-catenin in bone tissues, respectively. Compared with the normal group and lncRNAp21 group, the serum level of E2 in the model group decreased significantly (p<0.05). BMD and phosphorus (P) content in the model group were both markedly lower than those of the normal group and lncRNAp21 group. However, calcium (Ca) content was remarkably higher than that of the normal group and lncRNAp21 group (p<0.05). The serum levels of bone resorption markers (including TRACP-5b and CTX) in the model group were prominently higher than those of the normal group (p<0.05). However, the levels of the two markers in the lncRNAp21 group were significantly lower than the model group (p<0.05). Additionally, bone formation markers (including OC, PINP and BALP) in the serum of rats in the model group were notably higher than those in the normal group and lncRNAp21 group (p<0.05). QRT-PCR and Western blotting results revealed that the mRNA and protein expressions of Wnt1 and β-catenin in bone tissues of the model group were markedly lower than those of the normal group. However, the mRNA and protein expressions of Wnt1 and β-catenin in the lncRNAp21 group were remarkably higher than the model group (p<0.05). Low expression of lncRNAp21 activates the Wnt/β-catenin signaling pathway by increasing E2 secretion, eventually stimulating bone formation and increasing osteogenic differentiation of mesenchymal stem cells in OP model rats.

Bone Status in Obese, Non-diabetic, Antipsychotic-Treated Patients, and Effects of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide on Bone Turnover Markers and Bone Mineral Density.

Background: Low bone mineral density (BMD) may constitute an underestimated comorbidity in schizophrenia patients undergoing long-term antipsychotic treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists are antidiabetic drugs, which may also affect bone turnover.Methods: In planned secondary analyses of a 3 months, double-blind, randomized, placebo-controlled trial (n = 45), we explored effects of the GLP-1 receptor agonist exenatide 2 mg once-weekly (n = 23), or placebo (n = 22) on bone turnover markers (BTMs) and BMD in chronic, obese, antipsychotic-treated patients with schizophrenia spectrum disorder. Baseline BTMs were compared to sex- and age-adjusted reference values from a Danish population cohort, and T- and Z-scores were calculated for BMD.Results: In women (n = 24), all baseline BTM measurements of procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were within reference values. In men (n = 21), 5% displayed lower PINP and 14% displayed lower CTX. One patient displayed BMD Z-score < −2, and 23% of patients (17% of women and 29% of men) displayed −2.5 < T-scores < –1 indicating osteopenia, but none had osteoporosis. After treatment, PINP decreased at trend level significance (P = 0.05), and body mass index BMD increased for L2–L4 (P = 0.016). No changes in bone markers were significant after correction for mean prolactin levels.Conclusions: Sex- and age-adjusted measures of bone status in chronic, obese, antipsychotic-treated patients appeared comparable to the reference population. Subtle changes in bone markers during 3 months exenatide treatment may suggest beneficial effects of GLP-1 receptor agonists on bone status in antipsychotic-treated patients, and further studies should consider the potential influence of prolactin.

Exploration of gender differences in correlation between iron metabolism and bone turnover markers in elderly patients with fragility fractures

Objective To explore the gender differences in the association between iron metabolism and bone turnover markers in elderly patients with fragility fracture. Methods A total of 271 patients admitted in our hospital from Aug 2014 to Oct 2017 with osteoporotic fractures were divided into two groups: 109 males and 162 females, aged from 60 to 92 years.Both groups were further divided into 3 age groups(60 to 70, 71 to 80, and ≥81 year group). Biochemical indicators, serum ferritin and bone turnover markers were detected eight hours after admission. Results In the male group, there were no statistical differences in serum ferritin and serum procollagen type I N-terminal propeptide(PINP)among age groups(all P>0.05). Serum β-carboxy terminal telopeptide of collagen type I β-CTX(β-CTX)was elevated with ageing.In the female group, serum ferritin, PINP, and β-CTX were elevated with ageing.There was a significant positive correlation between serum ferritin and β-CTX in two gender groups(all P<0.05)without gender difference.Gender difference was observed in the correlation between serum ferritin and PINP between two gender groups: a significant positive correlation in the female group(r=0.255, P=0.001)whereas a significant negative correlation in the male group(r=-0.207, P=0.031). Conclusions There are gender differences in correlations of serum ferritin with bone turnover markers.Increased iron accumulation in postmenopausal women is closely correlated with high bone turnover rate. Key words: Fractures, bone; Bone turnover markers; Iron metabolism disorders