Tartrate-resistant Acid Phosphatase 5b Research Articles

A Novel Variant in CLCN7 Regulates the Coupling of Angiogenesis and Osteogenesis

Autosomal dominant osteopetrosis type II (ADO II), characterized by increased bone mass and density, is caused by mutations in the chloride channel 7 (CLCN7) gene. In this study, a novel missense variant in CLCN7 (c.1678A > G; p.Met560Val) was identified in three symptomatic subjects and one carrier of a Chinese family with ADO II. Notably, bone formation markers, including osteocalcin and total procollagen type N-terminal propeptide, have increased or presented at the upper limit of the normal range in the three patients. Serum factors secreted by osteoclast lineage cells and affecting the CD31hiEMCNhi vessel formation, such as tartrate-resistant acid phosphatase 5b, platelet-derived growth factor-BB, vascular endothelial growth factor, and SLIT3, had a higher expression in three ADO II subjects than in 15 healthy age-matched and sex-matched controls. Moreover, the conditioned medium was obtained from preosteoclast induced from the ADO II patients’ peripheral blood mononuclear cells. It was found to promote the CD31hiEMCNhi vessel formation of human microvascular endothelial cells and osteogenic differentiation of bone marrow-derived stem cells. Taken together, our finding revealed a novel CLCN7 variant associated with ADO II and suggested that the sclerotic bone was potentially associated with the increase of the CD31hiEMCNhi vessel formation and bone formation.

Mass spectrometric quantitation of AGEs and enzymatic crosslinks in human cancellous bone

Advanced glycation end-products (AGEs) deteriorate bone strength. Among over 40 species identified in vivo, AGEs other than pentosidine were roughly estimated as total fluorescent AGEs (tfAGEs) due to technical difficulties. Using LC-QqTOF-MS, we established a system that enabled the quantitation of five AGEs (CML, CEL, MG-H1, CMA and pentosidine) as well as two mature and three immature enzymatic crosslinks. Human bone samples were collected from 149 patients who underwent total knee arthroplasty. Their clinical parameters were collected to investigate parameters that may be predictive of AGE accumulation. All the analytes were quantitated and showed significant linearity with high sensitivity and precision. The results showed that MG-H1 was the most abundant AGE, whereas pentosidine was 1/200–1/20-fold less abundant than the other four AGEs. The AGEs were significantly and strongly correlated with pentosidine, while showing moderate correlation with tfAGEs. Interestingly, multiple linear regression analysis revealed that gender contributed most to the accumulation of all the AGEs, followed by age, tartrate-resistant acid phosphatase-5b and HbA1c. Furthermore, the AGEs were negatively correlated with immature crosslinks. Mass spectrometric quantitation of AGEs and enzymatic crosslinks is crucial to a better understanding of ageing- and disease-related deterioration of bone strength.

Prediction of Fracture Risk From Early-Stage Bone Markers in Patients With Osteoporosis Treated With Once-Yearly Administered Zoledronic Acid.

The prevention of fractures is the ultimate goal of osteoporosis treatments. To achieve this objective, developing a method to predict fracture risk in the early stage of osteoporosis treatment would be clinically useful. This study aimed to develop a mathematical model quantifying the long‐term fracture risk after 2 annual doses of 5 mg of once‐yearly administered zoledronic acid or placebo based on the short‐term measurement of bone turnover markers or bone mineral density (BMD). The data used in this analysis were obtained from a randomized, placebo‐controlled, double‐blind, 2‐year study of zoledronic acid that included 656 patients with primary osteoporosis. Two‐year individual bone resorption marker (tartrate‐resistant acid phosphatase 5b [TRACP‐5b]) and lumbar spine (L2‐L4) BMD profiles were simulated using baseline values and short‐term measurements (at 3 months for TRACP‐5b and 6 months for BMD) according to the pharmacodynamic model. A new parametric time‐to‐event model was developed to describe the risk of clinical fractures. Fracture risk was estimated using TRACP‐5b or BMD and the number of baseline vertebral fractures. As a result, the fracture risk during the 2 years was successfully predicted using TRACP‐5b or BMD. The 90% prediction intervals well covered the observed fracture profiles in both models. Therefore, TRACP‐5b or BMD is useful to predict the fracture risk of patients with osteoporosis, and TRACP‐5b would be more useful because it is an earlier marker. Importantly, the developed model allows clinicians to inform patients of their predicted response at the initial stage of zoledronic acid treatment.

Effects of the linagliptin, dipeptidyl peptidase-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus in obese mice.

Recently, it has been suggested that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), which play important roles in the homeostasis of glucose metabolism, could be involved in the regulation of bone metabolism. Inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades GIP and GLP-1, are widely used clinically as a therapeutic agent for diabetes. However, the effects of DPP-4 inhibitors on bone metabolism remain unclear. In this study, we investigated the effects of linagliptin, a DPP-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus (T2DM). Non-diabetic mice were used as controls, and T2DM mice were administered linagliptin orally on a daily basis for 12 weeks. In T2DM mice, decreased bone mineral density was observed in the lower limb bones along with low serum osteocalcin levels and high serum tartrate-resistant acid phosphatase-5b (TRAP) levels. In contrast, the decreased serum osteocalcin levels and increased serum TRAP levels observed in T2DM mice were significantly suppressed after the administration of linagliptin 30 mg/kg. Bone histomorphometric analysis revealed a reduced osteoid volume and osteoblast surface with an increase in the eroded surface and number of osteoclasts in T2DM mice. This decreased bone formation and increased bone resorption observed in the T2DM mice were suppressed and trabecular bone volume increased following the administration of 30 mg/kg linagliptin. Collectively, these findings suggest that linagliptin may improve the microstructure of trabecular bone by inhibiting both a decrease in bone formation and an increase in bone resorption induced by T2DM.

Absence of αβ T cells accelerates disuse bone loss in male mice after spinal cord injury.

Whether T cells promote bone loss following immobilization after spinal cord injury (SCI) remains undetermined. Therefore, wild-type (WT) and T cell-deficient (Tcrb-/- ) male mice underwent sham or contusion SCI to cause hindlimb paralysis. Femurs were isolated and distal and midshaft regions were evaluated by microcomputed tomography scanning. Bone marrow (BM) levels of bone turnover markers, as well as receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG), were measured by ELISA. At 2 weeks post-SCI, immobilization resulted in marked reduction in trabecular fractional bone volume (55%), thickness (40%), connectivity, and cortical thickness only in the Tcrb-/- animals (interaction with P < 0.05). BM analysis revealed lower bone formation (procollagen type 1 intact N-terminal propeptide), higher bone resorption (tartrate-resistant acid phosphatase-5b), and a higher RANKL/OPG ratio in the Tcrb-/- SCI animals. At 5 weeks post-SCI, while both WT and Tcrb-/- paralyzed animals showed deterioration of all indices of bone structure, they were more severe in Tcrb-/- animals. In summary, unlike other skeletal disorders, loss of αβ T cells compromises, rather than preserves, skeletal integrity under conditions of immobilization.

Effects of paprika carotenoid supplementation on bone turnover in postmenopausal women: a randomized, double-blind, placebo-controlled, parallel-group comparison study.

BackgroundPaprika (Capsicum annuum L.) is a good source of carotenoids, including capsanthin, β-carotene, β-cryptoxanthin, and zeaxanthin. Several epidemiological studies have shown a beneficial association of intake of these carotenoids or their blood concentration with bone mineral density (BMD) and fracture risk. However, little information is available regarding the effect of intake of these carotenoids on bone metabolism in postmenopausal women.ObjectiveThe objective of the present study was to investigate the effects of paprika carotenoid extract (PCE) on bone turnover in healthy, postmenopausal women.DesignWe conducted a randomized, double-blind, placebo-controlled, parallel-group comparison study. One hundred participants were randomly assigned to PCE or placebo groups. Each group was given a 20 mg PCE (equivalent to 1.4 mg of carotenoids) a day or a placebo for 24 weeks. We measured bone resorption markers (tartrate-resistant acid phosphatase 5b [TRACP-5b] and serum type I collagen cross-linked N-telopeptide [sNTX]) at 12 and 24 weeks and bone formation markers (bone alkaline phosphatase and osteocalcin) at 24 weeks.ResultsThe percentage decrease of TRACP-5b at 24 weeks was significantly higher for PCE than the placebo. There were no significant differences in sNTX or bone formation markers, although PCE decreased each marker compared with the placebo.ConclusionOur findings suggest that PCE supplementation suppresses bone resorption and contributes to maintaining bone quality in postmenopausal women.

Minodronate in the treatment of osteoporosis: A systematic review and meta-analysis.

Background:The goal of this study was to review relevant randomized controlled trials or case-control studies to determine the clinical efficacy of minodronate in the treatment of osteoporosis.Method:The relevant studies were identified on PubMed, Cochrane, and Embase databases using appropriate keywords. Pertinent sources in the literature were also reviewed, and all articles published through October 2019 were considered for inclusion. For each study, we assessed odds ratios, mean difference, and 95% confidence interval (95% CI) to evaluate and synthesize outcomes.Result:Thirteen studies comprising 3740 patients were included in this study. Compared with other drugs, minodronate significantly decreased N-telopeptide of type I collagen/creatinine (weighted mean difference [WMD]: –13.669, 95% confidence interval [CI]: –23.108 to –4.229), bone alkaline phosphatase (BAP) (WMD: –1.26, 95% CI: –2.04 to –0.47) and tartrate-resistant acid phosphatase 5b (WMD: –154.11, 95% CI: –277.85 to –30.37). Minodronate combined with other drugs would significantly decrease BAP (WMD: –3.10, 95% CI: –5.20 to –1.00) than minodronate. Minodronate-naïve would significantly decrease BAP (WMD: –3.00, 95% CI: –5.47 to 0.53) and tartrate-resistant acid phosphatase 5b (WMD: –128.20, 95% CI: –198.11 to –58.29) than minodronate-switch. The incidence of vertebral fracture was significantly decreased in the minodronate group than the other drugs (relative risk: 0.520, 95% CI: 0.363–0.744).Conclusion:Minodronate has better clinical efficacy in the treatment of osteoporosis than other drugs (alendronate, risedronate, raloxifene, or eldecalcitol).

Impact of whole-body vibration exercise on physical performance and bone turnover in patients with monoclonal gammopathy of undetermined significance

ObjectiveMonoclonal Gammopathy of Undetermined Significance (MGUS) is a risk factor for reduced physical performance, osteoporosis, and fractures due to compromised musculoskeletal metabolism. In this condition it is unknown whether whole-body vibration (WBV) exercise favorably alters physical performance and bone metabolism. MethodsTo evaluate the effect of three-months WBV exercise (30 min; 2x/week) including an optional three-month extension on physical performance, bone metabolism and bone mineral density. Endpoints included functional assessments, bone turnover markers and bone mineral density assessed by peripheral quantitative computed tomography of the tibia. ResultsFifteen MGUS patients (median age 62.0, nine female) completed the first three months of which ten completed the three-month extension. Measures of physical functioning including chair rise test, timed up and go and 6-minute walk test improved (p = 0.007; p = 0.009; p = 0.005) after three and six months of WBV exercise. Total tibial bone mineral density remained unaltered (p > 0.05). WBV exercise tended to increase levels of sclerostin (p = 0.093) with a transient increase in osteoclast resorption markers (N-terminal telopeptide of collagen type 1, tartrate resistant acid phosphatase 5b) after three months while Dickkopf-1 (p = 0.093), procollagen I N-terminal propeptide (p = 0.074) and total alkaline phosphatase (p = 0.016) appeared to decline. No exercise-related adverse events were reported. ConclusionWBV exercise in MGUS patients improves indicators of physical performance. Observed trends in bone turnover markers and changes in distal tibial bone mineral density may indicate a regulatory effect of WBV exercise on bone metabolism and warrants further evaluation by large scale studies.

Early clinical effects, safety, and appropriate selection of bone markers in romosozumab treatment for osteoporosis patients: a 6-month study.

Romosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody which increases bone formation and suppresses bone resorption. In this study, we analyzed the actual clinical effects, adverse effects, and the optimal way to evaluate the treatment. Romosozumab was administered as subcutaneous injection of 210mg once every 4weeks. We conducted pre-post study in 185 patients treated for 6months. We focused on the incidence of new vertebral fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers. We evaluated BMD before romosozumab treatment and after 4 to 6months and performed the serum analysis before romosozumab treatment, after 1, 3, and 6months. There was no new fracture during treatment, and there was no fatal adverse event including cardiovascular disease. Since percent changes from baseline of the spine and total hip BMD were 6.34% and 1.53% after 4- to 6-month treatment, the treatment was effective for spine osteoporosis. Tartrate-resistant acid phosphatase 5b (TRACP-5b) and intact type I procollagen N-terminal propeptide (iP1NP) had significant changes during romosozumab treatment (p < 0.05). Percent change from baseline of TRACP-5b and iP1NP after 1month correlated with percent change from baseline of BMD after 4 to 6months of treatment. Romosozumab is effective in preventing fractures and useful for increasing the spine BMD. Also, romosozumab is relatively safe to use. It is especially effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP.

Quercetin prevents bone loss in hindlimb suspension mice via stanniocalcin 1-mediated inhibition of osteoclastogenesis.

Recent studies demonstrate that diet quercetin (Quer) has obvious bone protective effects on ovariectomized rodents but thus far there is no direct evidence to support the inhibitory effect of Quer on bone loss caused by long-term unloading. In the present study, we investigated whether Quer could prevent bone loss induced by unloading in mice. Mice were subjected to hindlimb suspension (HLS) and received Quer (25, 50, 100 mg· kg-1 ·day-1, ig) for 4 weeks. Before euthanasia blood sample was collected; the femurs were harvested and subjected to MicroCT analysis. We showed that Quer administration markedly improved bone microstructure evidenced by dose-dependently reversing the reduction in bone volume per tissue volume, trabecular number, and bone mineral density, and the increase of trabecular spacing in mice with HLS. Analysis of serum markers and bone histometric parameters confirmed that Quer at both middle and high doses significantly decreased bone resorption-related markers collagen type I and tartrate-resistant acid phosphatase 5b, and increased bone formation-related marker procollagen 1 N-terminal propeptide as compared with HLS group. Treatment with Quer (1, 2, 5 μM) dose-dependently inhibited RANKL-induced osteoclastogenesis through promoting the expression of antioxidant hormone stanniocalcin 1 (STC1) and decreasing ROS generation; knockdown of STC1 blocked the inhibitory effect of Quer on ROS generation. Knockdown of STC1 also significantly promoted osteoclastogenesis in primary osteoclasts. In conclusion, Quer protects bones and prevents unloading-caused bone loss in mice through STC1-mediated inhibition of osteoclastogenesis. The findings suggest that Quer has the potential to prevent and treat off-load bone loss as an alternative supplement.

Three-year results of denosumab treatment for osteoporosis in women with rheumatoid arthritis and primary osteoporosis: A clinical observational study

Introduction This study investigated the results of 3 years of denosumab treatment for osteoporosis in women with rheumatoid arthritis (RA) and primary osteoporosis (PO). Materials and methods This study enrolled 112 women with RA (RA group) and 104 women with a PO group who received 60 mg denosumab for 3 years. Bone mineral densitiy (BMD) of the lumbar spine, total hip and femoral neck as well as levels of bone turnover markers [N-terminal propeptide of type I procollagen (P1NP) and tartrate-resistant acid phosphatase-5b (TRACP-5b)] were measured at years 1, 2, and 3. Results The percent changes (Δ) in BMD values at years 1, 2, and 3 were as follows: RA group: 6.7 ± 6.2%, 8.9 ± 6.5%, and 9.8 ± 8.2% and PO group: 6.0 ± 4.8%, 8.9 ± 7.5%, and 12.6 ± 8.7% for the lumbar spine; RA group: 4.5 ± 4.6%, 5.2 ± 5.1%, and 6.8 ± 5.9% and PO group: 3.8 ± 4.5%, 4.6 ± 7.4%, and 6.8 ± 4.6% for the total hip; and RA group: 2.7 ± 5.1%, 4.1 ± 6.8%, and 4.3 ± 6.7% and PO group: 3.6 ± 8.0%, 4.5 ± 10.9%, and 5.7 ± 10.5% for the femoral neck, respectively. The ΔBMD for the lumbar spine, total hip, and femoral neck as well as ΔP1NP and ΔTRACP-5b did not differ significantly between the two groups at any time points. Conclusion Denosumab treatment for osteoporosis had a similar efficacy over 3 years among women with RA and PO. A better understanding of denosumab treatment for this patient population is important in clinical practice.

Peripartum changes in serum activities of three major alkaline phosphatase isoenzymes in Holstein dairy cows.

This study investigated changes in serum levels of hepatic, bone, and intestinal alkaline phosphatase (ALP) isoenzymes (ALP2, ALP3, and ALP5, respectively) in Holstein cows around parturition. Tartrate-resistant acid phosphatase 5b (TRAP5b) activity and calcium (Ca) concen-trations were also measured. We analyzed blood samples from 11 late-pregnant heifers (primipa-rous group) and 13 multiparous (2-4 lactations; multiparous group) cows at 3 weeks (18-24 days prepartum; -3 weeks), 2 weeks (17-11 days prepartum; -2 weeks), and 1 week (10-4 days prepar-tum; -1 weeks) before parturition; the day of calving (within 12 h post-calving; day 0); and 5 days postpartum (5 days). ALP3 activity was significantly higher in the primiparous group than in the multiparous group, whereas the activities decreased significantly in both groups after 5 days. ALP2 and ALP5 activities did not change, whereas ALP2 activity was significantly higher in the primiparous group than in the multiparous group. TRAP5b activity was significantly higher in the primiparous group than in the multiparous group and showed a transient significant increase at day 0. Ca concentration significantly decreased at day 0 in both groups; the Ca level at day 0 was significantly higher in the primiparous group than in the multiparous group. These data show that ALP3 activity in serum may indicate a change in osteoblastic bone forma-tion after calving, but further study is needed to determine the clinical application for measuring ALP isoenzymes in bovine medicine.

Effects of denosumab treatment in chronic liver disease patients with osteoporosis.

BACKGROUNDEffective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease (CLD) patients. Denosumab has been shown to increase bone mineral density (BMD) and decrease the risk of osteoporotic fracture in the general population. However, there are few reports evaluating the efficacy of denosumab in CLD patients.AIMTo investigated the effects and safety of denosumab in CLD patients with osteoporosis.METHODSSixty CLD patients with osteoporosis were subcutaneously administered denosumab once every 6 mo. The study period for evaluating efficacy and safety was 12 mo. Changes from baseline in BMD at the lumbar spine, femoral neck, and total hip were evaluated at 12 mo of denosumab treatment. Bone turnover and quality were assessed by measuring serum tartrate-resistant acid phosphatase-5b (bone resorption marker), serum total procollagen type I N-terminal propeptide (bone formation maker), and plasma pentosidine (bone quality marker).RESULTSAmong the 405 CLD patients, 138 (34.1%) patients were diagnosed with osteoporosis; among these, 78 patients met the exclusion criteria and thus 60 patients were finally included in the present study. The median percentage changes from baseline to 12 mo of denosumab treatment in BMD at the lumbar spine, femoral neck, and total hip were +4.44%, +3.71%, and +4.03%, respectively. Denosumab significantly improved BMD, regardless of sex, patient age, and presence of liver cirrhosis. Serum tartrate-resistant acid phosphatase-5b and procollagen type I N-terminal propeptide levels constantly and significantly declined after denosumab treatment (P < 0.001). Plasma pentosidine levels were also significantly lower at 12 mo of treatment (P = 0.010). No patients experienced fractures and moderate-to-severe adverse events, except for transient hypocalcemia.CONCLUSIONDenosumab treatment was safe and increased BMD, suppressed bone turnover, and improved bone quality marker levels in CLD patients with osteoporosis, irrespective of differences in baseline characteristics.

Short-Term Impact of Staying Home on Bone Health in Patients With Osteoporosis During a State of Emergency Declaration Due to COVID-19 in Kanagawa, Japan.

BackgroundOn April 16, 2020, the Japanese government declared a state of emergency due to the spread of COVID-19 infection, leading prefectural governors to announce a stay-at-home order for 39 days until May 25, 2020. As physical inactivity is a risk factor for osteoporosis, we investigated the short-term impact of the stay-at-home order on bone health among patients with osteoporosis in our hospital in Kanagawa prefecture.MethodsThirty patients with osteoporosis with no delays in their regular medication who received care at our hospital’s osteoporosis outpatient clinic within one month after the end of the state of emergency were included. Lumbar spine and femur proximal bone mineral density (BMD) were measured at the last follow-up date (May 25 to June 30, 2020; 0M) and six (6M) and 12 months (12M) before the last follow-up using dual-energy X-ray absorptiometry. Bone alkaline phosphatase (BAP), Tartrate-resistant Acid Phosphatase 5b (TRACP5b), calcium and phosphorus were assessed at the same time points.ResultsSerum BAP concentrations were significantly lower at 0M than 12M (p=0.040), but were comparable between 0M and 6M (p=0.527). Serum TRACP5b was significantly lower at 6M than 12M (p=0.009), but was similar between 0M and 6M (p=1.000). Serum calcium and phosphorus did not differ among the time points (p=0.516 and p=0.358, respectively). Similarly, lumbar spine and femoral neck BMD were comparable (p=0.679 and p=0.076, respectively).ConclusionBone health in patients with osteoporosis was maintained during the short-term COVID-19 stay-at-home order among patients who experienced no delays in medication. However, larger and long-term studies are needed.

Sodium-Glucose Co-Transporter 2 Inhibitors Increase Serum Level of Total Procollagen Type 1 Amino-Terminal Propeptide and Bone Strength in Japanese Patients With Type 2 Diabetes Mellitus

Background: Diabetes mellitus is known to be associated with an increased risk of bone fracture. We investigated the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on bone strength and density in type 2 diabetic patients. Methods: Nineteen Japanese patients with type 2 diabetes mellitus were administered 2.5 mg/day of luseogliflozin or 5 mg/day of dapagliflozin for 6 months. Serum levels of tartrate-resistant acid phosphatase 5b (TRACP-5b), an osteoclastic marker, and total procollagen type 1 amino-terminal propeptide (P1NP), a bone formation marker, were measured and compared with those before the treatment. Bone strength was measured by quantitative ultrasound (QUS), and bone density was evaluated by dual-energy X-ray absorptiometry (DEXA). Results: SGLT2 inhibitors significantly increased the calcaneal bone strength as measured by QUS compared to that in young adult mean. However, there was no effect in the lumbar spine density as measured by DEXA after administration. The drug treatment had no effect on serum TRACP-5b, but significantly increased serum P1NP. Conclusions: The results imply that the SGLT2 inhibitors improve bone strength while the inhibitors had no effect on bone density. These results suggest that the increase in bone strength was due to improved bone quality through an increase in serum P1NP level. J Endocrinol Metab. 2020;10(3-4):89-93 doi: https://doi.org/10.14740/jem683

Atorvastatin promotes bone formation in aged apoE\u2013/\u2013 mice through the Sirt1\u2013Runx2 axis

BackgroundStatins are the most widely used drugs in elderly patients; the most common clinical application of statins is in aged hyperlipemia patients. There are few studies on the effects and mechanisms of statins on bone in elderly mice with hyperlipemia. The study is to examine the effects of atorvastatin on bone phenotypes and metabolism in aged apolipoprotein E-deficient (apoE–/–) mice, and the possible mechanisms involved in these changes.MethodsTwenty-four 60-week-old apoE–/– mice were randomly allocated to two groups. Twelve mice were orally gavaged with atorvastatin (10 mg/kg body weight/day) for 12 weeks; the others served as the control group. Bone mass and skeletal microarchitecture were determined using micro-CT. Bone metabolism was assessed by serum analyses, qRT-PCR, and Western blot. Bone marrow-derived mesenchymal stem cells (BMSCs) from apoE–/– mice were differentiated into osteoblasts and treated with atorvastatin and silent information regulator 1 (Sirt1) inhibitor EX-527.ResultsThe results showed that long-term administration of atorvastatin increases bone mass and improves bone microarchitecture in trabecular bone but not in cortical bone. Furthermore, the serum bone formation marker osteocalcin (OCN) was ameliorated by atorvastatin, whereas the bone resorption marker tartrate-resistant acid phosphatase 5b (Trap5b) did not appear obviously changes after the treatment of atorvastatin. The mRNA expression of Sirt1, runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and OCN in bone tissue were increased after atorvastatin administration. Western blot showed same trend in Sirt1 and Runx2. The in vitro study showed that when BMSCs from apoE–/– mice were pretreated with EX527, the higher expression of Runx2, ALP, and OCN activated by atorvastatin decreased significantly or showed no difference compared with the control. The protein expression of Runx2 showed same trend.ConclusionsAccordingly, the current study validates the hypothesis that atorvastatin can increase bone mass and promote osteogenesis in aged apoE−/− mice by regulating the Sirt1–Runx2 axis.

Assessment of Bone Turnover Biomarkers in Lead-Battery Workers with Long-Term Exposure to Lead.

Background: The major portion of lead in the body resides in skeletal system. The bone turnover affects the release of lead into the circulation from bones. The bone turnover biomarkers (BTM) in lead-battery workers with long-term exposure to lead have not been explored yet. Objective: To evaluate the BTM (formation and resorption) in lead-battery workers with long-term exposure to lead in lead-battery manufacturing plant. Methods: 176 male lead-exposed workers and 80 matched comparison group were studied. All participants were examined for blood lead levels (BLLs), bone formation biomarkers—serum osteocalcin (OC), alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP)—and bone resorption biomarkers—serum pyridinoline (PYD), deoxypyridinoline (DPYD), tartarate-resistant acid phosphatase-5b (TRACP-5b), and urinary hydroxyproline (UHYP). Results: We found a significantly higher bone formation biomarkers such as BALP (p=0.007) and bone resorption biomarkers, eg, PYD (p=0.048), TRCAP-5b (p=0.001), and UHYP (p=0.001) in lead-exposed workers. A significant (p=0.041) negative correlation (ρ -0.128) was noted between BLLs and OC. A significant positive correlation was noted between BLLs and TRACP-5b (ρ 0.176, p=0.005) and UHYP (ρ 0.258, p=0.004). Serum OC (p=0.040) and UHYP (p=0.015) levels changed significantly with BLL level. Bone resorption biomarkers levels—PYD, TRACP-5b, and BALP—were higher among those with higher BLLs levels. The duration of exposure was significantly associated with BALP (p=0.037), DPYD (p=0.016), TRACP5b (p=0.001), and UHYP (p=0.002) levels. Conclusion: Long-term lead exposure affects the bone turnover.

The influence and clinical significance of proteasome inhibitor on serum bone metabolite markers in patients with myeloma bone disease

Objective: To investigate the influence and clinical significance of proteasome inhibitor on serum bone metabolite markers including tartrate-resistant acid phosphatase 5b isoenzyme (TRACP-5b), type I collagen carboxy terminal peptide β(β-CTX), type I procollagen amino terminal prolongation peptide (PINP) and vitamin D3 in patients with myeloma bone disease (MBD). Methods: From April 2015 to June 2018, 68 patients with newly diagnosed MBD who admitted to our hospital were treated with proteasome inhibitor-based regimen. Serum concentration of TRACP-5b、β-CTX、PINP and vitamin D3 were measured before treatment and after 4 and 8 cycles of chemotherapy, and imaging changes were observed. Results: After 4 and 8 cycles of chemotherapy, serum levels of TRACP-5b, β-CTX and vitamin D3 were decreased significantly (P<0.05). The serum concentration of PINP was (78.1±44.9) ng/L before chemotherapy, while after 4 cycles, it turned to (94.5±56.1) ng/L without significant difference (t=-1.871, P=0.063). Moreover, it increased to (173.3±80.5) ng/L after 8 cycles of chemotherapy with significant difference (t=-8.272, P<0.001). The proportion of imaging classification ≥3 among all patients was 66.2%, and it decreased to 60.3% after 4 cycles of chemotherapy without significant difference (χ(2)=0.569, P=0.477). The proportion of imaging classification ≥3 after 8 cycles of chemotherapy decreased to 44.5%, which was significantly lower than that before treatment (χ(2)=6.260, P=0.012). After 8 cycles of chemotherapy, 63 patients were evaluable, of which 50 were effective and 13 were ineffective. Serum concentration of PINP in the effective group was higher than that in the ineffective group ((190.7±78.5) ng/L vs (106.5±47.3) ng/L,t=5.762, P<0.001), and the serum concentration of vitamin D3 in the effective group was lower than that in the ineffective group ((11.7±4.8) μg/L vs (15.6±5.5) μg/L, t=-2.478, P=0.016). The proportion of patients with more than grade 3 bone disease of the effective group was also significantly lower than that of the ineffective group (38.0% vs 69.2%, χ(2)=4.076, P=0.044). There was no significant difference in the serum concentration of TRACP-5b and β-CTX between two groups. Conclusion: After treatment with the proteasome inhibitor -based regimen, the serum concentrations of TRACP-5b, β-CTX and vitamin D3, which reflect osteoclast activity in MBD patients were decreased, the serum concentration of PINP indicating osteoblast activity was increased, and the grade of imaging of bone disease was decreased.

High bone turnover state under osteoporotic changes induces pain-like behaviors in mild osteoarthritis model mice.

Our previous studies demonstrated that a high bone turnover state under osteoporotic changes decreased the threshold of skeletal pain. Recent studies reported that the incidence of joint pain due to osteoarthritis (OA) in postmenopausal women was higher than that in males even with the same radiographic OA grade. The aim of this study was to evaluate whether a high bone turnover state affects the induction of pain-like behaviors in mild OA model mice. We established mild OA model mice with accompanying osteoporotic changes by monosodium iodoacetate injection after ovariectomy. We assessed pain-like behaviors by von Frey test and paw-flick test; histological changes in OA joints; the expression of Runx2, Osterix, Osteocalcin, and Rankl; bone micro-architecture by μCT and measured serum tartrate-resistant acid-phosphatase 5b levels in the model mice. Pain-like behaviors in mice with OA and osteoporotic changes were significantly increased in comparison with those in OA mice without osteoporotic changes. The severity of histological OA changes did not differ significantly between the OA mice with and without osteoporotic changes. Bisphosphonate significantly improved pain-like behaviors accompanied with improvement in the high bone turnover state in the OA mice with osteoporosis, while it had no significant effect on pain-like behaviors in the OA mice without osteoporosis. In addition, the improvement was maintained for more than 4weeks even after the discontinuation of bisphosphonate treatment. These results indicated that a high bone turnover state under osteoporotic changes could affect the induction of pain-like behaviors in mild OA model mice.

Effects of denosumab as compared with parathyroidectomy regarding calcium, renal, and bone involvement in osteoporotic patients with primary hyperparathyroidism.

To evaluate the effects of denosumab (Dmb) on calcium, renal, and bone involvement in osteoporotic patients with primary hyperparathyroidism (PHPT) and compare with those who underwent a parathyroidectomy (PTX) procedure. This retrospective, longitudinal study included patients treated with Dmb (60 mg) once every 6 months (n = 19) and those who successfully underwent a PTX procedure (n = 19) corrected calcium (cCa), eGFR, bone mineral density (BMD) in the lumbar spine (LS), total hip (TH), and femoral neck (FN) and LS-trabecular bone score (TBS) changes at 1 year after beginning Dmb or undergoing PTX were measured. Dmb group had older age, and showed milder disease activity and lower eGFR as compared with PTX group. In PTX group, cCa and eGFR were significantly decreased following surgery, while those were stable in Dmb group. There were significant increases in LS, TH, and FN-BMD in both Dmb (LS: 6.0 ± 0.8%, TH: 3.7 ± 1.0%, FN: 4.3 ± 1.5%) and PTX (LS: 11.2 ± 1.5%, TH: 7.5 ± 1.5%, FN: 7.9 ± 2.1%) groups. In Dmb group, LS-TBS was significantly improved by 3.0 ± 1.0%, while TBS change in PTX group approached significance (2.8 ± 1.5%). Percent change in TH-BMD was significantly correlated with baseline tartrate-resistant acid phosphatase-5b (TRACP-5b) in both groups. Dmb treatment not only increased BMD, dependent on bone turnover status, the same as PTX, but also improved LS-TBS. In addition, it did not decrease the level of eGFR, whereas PTX did. These results suggest that Dmb treatment help in the clinical management of osteoporotic patients with PHPT who do not undergo surgery as alternative to PTX.