Procollagen N-terminal Propeptide Research Articles

Intermittent tensile strain induces an increased response in bone formation markers compared to continuous load in mouse pre-osteoblasts when loading magnitude is matched

Intermittent and continuous mechanical loads are known to influence osteogenic activity. The present study examines the effects of matched intermittent and continuous load in vitro on bone formation markers. MC3T3 (mouse pre-osteoblasts) were cultured and placed in a bioreactor to undergo continuous, intermittent, or unloading for 1, 3 and 12 days. Loading conditions were matched for magnitude, duration and frequency. Each time point was analysed for alkaline phosphatase (ALP) activity, procollagen 1 N-terminal propeptide (PINP) and alizarin red staining (ARS). Intermittent load caused an increase in ALP activity across all time points compared to continuous loading (↑30%–59%) and unloaded conditions (↑70%–90%). PINP concentrations from intermittent load were lower than continuous load (↓112%) on day 3. However, no differences were observed in PINP concentrations between loading conditions at other time points. No differences were observed for ARS between loading conditions. Intermittent load caused an increase in bone formation marker ALP, but not PINP, when compared to continuous loading and unloaded conditions. These findings further our knowledge in bone formation response and provide additional tools for the analysis of osteogenesis in vitro.

Effect of antidepressants on bone mineral density and bone metabolism in ovariectomized depressed rats

Purpose: To investigate the effect of antidepressants on bone mineral density and bone metabolism in ovariectomized rats with depression. Methods: 48 female rats were randomly and equally assigned to six groups, namely, sham (Sn), ovariectomized depression (OD), ovariectomized depression rats treated with sertraline (ODs), citalopram (ODx), reboxetine (ODr), and venlafaxine groups (ODw). Behavioral alterations and bone-related parameters were evaluated before and after treatment. Results: After treatment, ODs, ODx, ODw, and ODr groups had higher levels of horizontal and vertical exercise scores, sugar water consumption, osteoclasts, and serum CTX-1 (p < 0.05) compared to OD group. Osteocytes, serum serotonin (5-HT), osteocalcin (BGP), and type I procollagen N-terminal propeptide (PINP) were significantly decreased (p < 0.05) after treatment in ODs, ODx, ODw, and ODr groups. A positive correlation was observed between 5-HT, BGP, PINP, and whole-body bone mineral density (r = 0.931, 0.907, and 0.843, p < 0.05) respectively, while a negative correlation was observed between collagen type I C-terminal propeptide (CTX-I) and bone mineral density (r = -0.855, p < 0.05). Conclusion: Antidepressants reduce bone mineral density and osteocyte proliferation, while increasing osteoclast proliferation. These effects are associated with reductions in 5-HT, PINP and BGP levels, and increase in CTX-I.

Predictors of bone mineral density in patients receiving glucocorticoid replacement for Addison's disease.

Patients receiving long-term glucocorticoid (GC) treatment are at risk of osteoporosis, while bone effects of substitution doses in Addison's disease (AD) remain equivocal. The project was aimed to evaluate serum bone turnover markers (BTMs): osteocalcin, type I procollagen N-terminal propeptide (PINP), collagen C-terminal telopeptide (CTX), sclerostin, DKK-1 protein, and alkaline phosphatase (ALP) in relation to bone mineral density (BMD) during GC replacement. Serum BTMs and hormones were assessed in 80 patients with AD (22 males, 25 pre- and 33 postmenopausal females) on hydrocortisone (HC) substitution for ≥3 years. Densitometry with dual-energy X-ray absorptiometry covered the lumbar spine (LS) and femoral neck (FN). Among BTMs, only PINP levels were altered in AD. BMD Z-scores remained negative except for FN in males. Considering T-scores, osteopenia was found in LS in 45.5% males, 24% young and 42.4% postmenopausal females, while osteoporosis in 9.0%, 4.0% and 21.1%, respectively. Lumbar BMD correlated positively with body mass (p = 0.0001) and serum DHEA-S (p = 9.899 × 10-6). Negative correlation was detected with HC dose/day/kg (p = 0.0320), cumulative HC dose (p = 0.0030), patient's age (p = 1.038 × 10-5), disease duration (p = 0.0004), ALP activity (p = 0.0041) and CTX level (p = 0.0105). However, only age, body mass, ALP, serum CTX, and sclerostin remained independent predictors of LS BMD. Standard HC substitution does not considerably accelerate BMD loss in AD patients and their serum BTMs: CTX, osteocalcin, sclerostin, DKK-1, and ALP activity remain within the reference ranges. Independent predictors of low lumbar spine BMD, especially ALP activity, serum CTX and sclerostin, might be monitored during GC substitution.

Fucoidan, as a marine bioactive substance, has shown great potential in regulating the bone-gut axis

Fucoidans exhibit numerous biological activities, including anti-inflammatory and hypolipidemic effects. Although its potential in regulating intestinal flora has been demonstrated, studies on its impact on bone metabolism and its relationship with the bone-gut axis remain limited. Therefore, this study was undertaken to explore the effects of fucoidan on the gut-bone axis in ovariectomized mice with osteoporosis. Twenty-one SPF ICR female mice were used in this study, distributed as follows: sham-operated (7), ovariectomized (7), and ovariectomized + fucoidan (200 mg/kg, 7). Subsequently, body indices, blood chemistry, bone specimens, short-chain fatty acids, fecal microbiota content, transmission electron microscopy, and RNA-seq transcriptome analysis were assessed, and statistical analysis was performed. The efficacy of fucoidan in treating osteoporosis was demonstrated in this study. Fucoidan treatment led to a significant increase in bone mineral density and procollagen N-terminal propeptide levels and a significant decrease in body weight and C-terminal peptide of human type I collagen and triglyceride levels (P < 0.05). Fucoidan promoted the health of ovariectomized mice, possibly by regulating the gut-bone axis. It significantly decreased the abundance of Ruminococcaceae UG-014, Parasutterella, and Muribaculum and increased the abundance of Akkermansia and Dubosiella (P < 0.05). Moreover, fucoidan protected the intestinal barrier and increased the acetic acid ratio. These changes in microbiota were significantly correlated with clinical features of osteoporosis (P < 0.05). Lipid metabolism emerged as a pivotal factor in the association between the intestinal microbiota and osteoporosis. Notably, intestinal transcriptome sequencing revealed significant changes in the expression of genes related to lipid metabolism (Adipoq, Angptl4, Adrb3, and C3ar1) and bone metabolism (Clec3b, Nrtn, Bpnt2, Ccn3, and Lama2) (P < 0.05). Overall, this study provides valuable insights into the unexplored microbiome-based mechanism by which fucoidan improves bone quality in ovariectomized mice, possibly by regulating the gut-bone axis.

Number of contiguous vertebral cross-links in the spine indicates bone formation: a cross-sectional study

BackgroundAs an indicator to evaluate the risk of fracture in diffuse idiopathic skeletal hyperostosis, the maximum number of vertebral bodies’ bone cross-linked with contiguous adjacent vertebrae (max VB) was developed. This study retrospectively investigates the relationship between max VB, bone mineral density (BMD), and bone metabolic markers (BMM).MethodsIn this cross-sectional study (from April 2010 to January 2022), males (n = 114) with various max VB from the thoracic vertebra to the sacrum, measured using computed tomography scans, were selected to assess femur BMD and BMM. The association of max VB with the total type I procollagen N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and bone turnover ratio (BTR = TRACP-5b/P1NP) as well as its relationship with femur BMD with P1NP and TRACP-5b, were investigated. Furthermore, the relationship between P1NP and TRACP-5b was investigated.ResultsP1NP increased in proportion to max VB and TRACP-5b increased in proportion to P1NP. Moreover, BTR was inversely proportional to max VB. Finally, femur BMD was inversely proportional to P1NP and TRACP-5b.ConclusionAs max VB increased with P1NP—a potential osteogenesis indicator—and BTR was inversely proportional to max VB with compensatory TRACP-5b increase, max VB can be considered as a possible predictor of bone fusion.

Lipid Peroxidation as a Possible Factor Affecting Bone Resorption in Obese Subjects-Preliminary Research.

Oxidative stress, which promotes bone catabolism, also affects the quality of bone tissue. We aimed to assess the impact of metabolic disorders and oxidant-antioxidant imbalance associated with primary obesity on bone resorption and formation processes. Anthropometric parameters, metabolic variables, oxidative stress indicators (malondialdehyde, vitamins A and E, uric acid, superoxide dismutase, catalase, glutathione peroxidase, type 1 paraoxonase, iron-reducing plasma antioxidant power) and markers of bone turnover (type I procollagen N-terminal propeptide and the type I collagen C-terminal cross-linked telopeptide; P1NP and CTX) were assessed in 108 Polish participants. Under the influence of oxidative stress, both enzymatic and non-enzymatic defense mechanisms were stimulated in obese subjects, especially in women, who had increased lipid peroxidation and activity of catalase (particularly in first-degree obesity) and decreased vitamin E concentration. The process of lipid peroxidation, as well as the weakening of the bone formation, was strongly manifested in women at a BMI range of 35.0-39.9 kg/m2 but not at BMI > 40.0 kg/m2, but it had a comprehensive negative impact on bone turnover in obese men. Obesity and its degree of advancement significantly affected the decrease in the concentration of the marker of bone formation-P1NP-only in the plasma of women. Excessive body weight had no effect on the value of the bone resorption marker in plasma, regardless of gender. Our results confirm the existence of the "obesity paradox" in the aspect of bone tissue metabolism and suggest that a specific body weight threshold changed the molecular response of the tissue.

Do patients with type 2 diabetes have impaired hip bone microstructure? A study using 3D modeling of hip dual-energy X-ray absorptiometry.

Patients with type 2 diabetes (T2DM) have more risk of bone fractures. However, areal bone mineral density (aBMD) by conventional dual-energy x-ray absorptiometry (DXA) is not useful for identifying this risk. This study aims to evaluate 3D-DXA parameters determining the cortical and trabecular compartments in patients with T2DM compared to non-diabetic subjects and to identify their determinants. Case-control study in 111 T2DM patients (65.4 ± 7.6 years old) and 134 non-diabetic controls (64.7 ± 8.6-year-old). DXA, 3D-DXA modelling via 3D-Shaper software and trabecular bone score (TBS) were used to obtain aBMD, cortical and trabecular parameters, and lumbar spine microarchitecture, respectively. In addition, biochemical markers as 25-hydroxyvitamin d, type I procollagen N-terminal propeptide (P1NP), C-terminal telopeptide of type I collagen (CTX), and glycated haemoglobin (HbA1c) were analysed. Mean-adjusted values showed higher aBMD (5.4%-7.7%, ES: 0.33-0.53) and 3D-DXA parameters (4.1%-10.3%, ES: 0.42-0.68) in the T2DM group compared with the control group. However, TBS was lower in the T2DM group compared to the control group (-14.7%, ES: 1.18). In addition, sex (β = 0.272 to 0.316) and body mass index (BMI) (β = 0.236 to 0.455) were the most consistent and positive predictors of aBMD (p ≤ 0.01). BMI and P1NP were negative predictors of TBS (β = -0.530 and -0.254, respectively, p ≤ 0.01), while CTX was a positive one (β = 0.226, p=0.02). Finally, BMI was consistently the strongest positive predictor of 3D-DXA parameters (β = 0.240 to 0.442, p<0.05). Patients with T2DM present higher bone mass measured both by conventional DXA and 3D-DXA, suggesting that 3D-DXA technology is not capable of identifying alterations in bone structure in this population. Moreover, BMI was the most consistent determinant in all bone outcomes.

Assessment of the Necessity of Osteoporosis Treatment for Patients with Low Bone Density in Diffuse Idiopathic Skeletal Hyperostosis.

Although patients with diffuse idiopathic skeletal hyperostosis (DISH) do not have low bone density, it is a risk factor for spine fractures associated with DISH. We investigated the characteristics and bone metabolism markers of patients with DISH having low bone density to assess whether osteoporosis medication is necessary to prevent fractures. A cross-sectional study was conducted between April 1, 2008, and March 31, 2019. The 86 patients included were divided into two groups according to their T-scores-one group had low bone density and DISH, and the other group did not. Group A (T-score≤-1) and B (T-score>-1) data were adjusted for confounding factors and compared for differences in age, body weight, maximum number of vertebral bodies with bony bridges between adjacent vertebrae (max VB), and previous history (hypertension, malignant tumors, diabetes mellitus, cardiac diseases, chronic renal failure, and spinal fractures). In Group A, multiple linear regression was used to investigate relationships among max VB, femur bone mineral density (BMD), total type I procollagen N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b (TRACP-5b). Group A had 36, and Group B had 50 male patients with DISH. Patients in Group B were heavier than those in Group A. The mean femur BMD in Group A was age-appropriate, and that in Group B was higher than the age-appropriate femur BMD. The mean values of P1NP and TRACP-5b were within the normal range. Max VB was positively correlated with total P1NP in Group A. Total P1NP was significantly and positively correlated with TRACP-5b. The DISH group with a T-score of ≤-1 was age-appropriate. The group with a T-score of >-1 had higher BMD because of their higher body weight. The group with a T-score of ≤-1 had good bone metabolism and did not require aggressive osteoporosis treatment.

Experimental Exposure to Bisphenol A Has Minimal Effects on Bone Tissue in Growing Rams-A Preliminary Study.

Simple SummaryBisphenol A (BPA) is a well-known synthetic compound that belongs to the group of chemicals that disrupt the endocrine system in humans and animals. Although bones represent a potential target for these compounds, studies investigating BPA-related effects in bones in large farm animals are limited. We exposed young rams aged 9–12 months to BPA through feed for 64 days and investigated the effects of BPA on bone length, mass, microscopic structure, mineral content, strength, and serum bone parameters. We discovered that BPA had no significant effects on most of the parameters studied. Only manganese was decreased, and copper increased in the femurs of the BPA-exposed rams. These results suggest that a 2-month, low-dose exposure to BPA in growing rams did not affect the macro- and microstructure, metabolism, and biomechanical behavior of femur bones; however, it did affect the composition of microelements in bone, which could affect the bone in the long term.Bisphenol A (BPA) is a well-known synthetic compound that belongs to the group of endocrine-disrupting chemicals. Although bone tissue is a target for these compounds, studies on BPA-related effects on bone morphology in farm animals are limited. In this preliminary study, we investigated the effects of short-term dietary BPA exposure on femoral morphology, metabolism, mineral content, and biomechanical behavior in rams aged 9–12 months. Fourteen rams of the Istrian Pramenka breed were randomly divided into a BPA group and a control group (seven rams/group) and exposed to 25 µg BPA/kg bw for 64 days in feed. Blood was collected for determination of bone turnover markers (procollagen N-terminal propeptide, C-terminal telopeptide), and femurs were assessed via computed tomography, histomorphometry, three-point bending test, and mineral analysis. BPA had no significant effects on most of the parameters studied. Only mineral analysis showed decreased manganese (50%; p ≤ 0.05) and increased copper content (25%; p ≤ 0.05) in the femurs of BPA-exposed rams. These results suggest that a 2-month, low-dose exposure to BPA in growing rams did not affect the histomorphology, metabolism, and biomechanical behavior of femurs; however, it affected the composition of microelements, which could affect the histometric and biophysical properties of bone in the long term.

Value of Biochemical Indexes of Bone Metabolism in Predicting Osteoporotic Lumbar Fractures.

Objective To investigate the value of bone metabolism indexes such as type I procollagen N-terminal propeptide (P1NP), 25-hydroxyvitamin D (25(OH)D), osteocalcin (OSTEOC), and parathyroid hormone (PTH) in predicting osteoporotic lumbar fractures. Methods 120 female patients with osteoporosis treated in our hospital were selected as research objects. There were 76 cases in the fracture group and 44 cases in the nonfracture group. The relationship between the levels of P1NP, 25(OH)D, OSTEOC, and PTH and the incidence of osteoporotic lumbar fractures were detected and compared between the two groups. The predictive value of biochemical indexes of bone metabolism in patients with osteoporosis was analyzed by ROC curve. Results The levels of P1NP and PTH in the fracture group were significantly higher than those in the nonfracture group, while 25(OH)D and OSTEOC levels were lower than those in the nonfracture group. Moreover, the levels of P1NP, 25(OH)D, OSTEOC, and PTH are important factors affecting the pathogenesis of osteoporosis. The area under the curve (AUC) of fracture in patients with osteoporosis predicted by the combination of P1NP, 25(OH)D, OSTEOC, and PTH levels was 0.886, which was greater than the AUC predicted by each index (0.796, 0.753, 0.670, and 0.824). The best sensitivity and specificity of comprehensive prediction of each index were 78.95% and 79.10%, respectively. Conclusion The abnormal changes of P1NP, 25(OH)D, OSTEOC, and PTH in female patients with osteoporotic lumbar fracture are closely related to the occurrence of the disease. The combination of these indicators has relatively significant application value in predicting the occurrence of fracture, which is helpful to formulate and guide relevant preventive measures for female patients with osteoporotic lumbar fracture and improve the prognosis.

The efficacy of denosumab in Korean male patients with osteoporosis.

Background/AimsDespite the prominence of denosumab as the number one prescribed anti-osteoporosis drug in Korea, the effects of denosumab in male osteoporosis patients were not researched sufficiently. Moreover, concerns on rebound vertebral fractures associated with poor denosumab adherence exist.MethodsWe retrospectively evaluated 147 Korean male osteoporosis patients treated with denosumab. After 12 months of treatment, 60 patients were lost during follow-up, and eight were excluded due to missing data. Out of the initial 147 patients, 79 were considered eligible for the analysis of the efficacy of denosumab. 54 patients were initially drug-naïve, and 25 had previously received bisphosphonate therapy.ResultsIn 54 drug-naïve patients, significant increases in bone mineral density (BMD) were observed in all measurement sites: 5.2% ± 3.7% in the lumbar spine, 2.3% ± 2.8% in the femoral neck, and 1.9% ± 2.8% in the total hip (p < 0.01, respectively). Trabecular bone score showed an increase of 0.5% ± 5.8% in drug-naïve patients. Likewise, in 25 patients with previous bisphosphonate treatment, increase in BMD were observed as well: 4.8% ± 3.5% in the lumbar spine, 1.4% ± 3.6% in the femoral neck, and 0.8% ± 2.1% in the total hip (p < 0.01, p = 0.06, p = 0.06, respectively). Significant declines of −55.1% ± 31.8% in C-terminal telopeptide of type 1 collagen (CTX), and −62.9% ± 21.3% in total procollagen 1 N-terminal propeptide (P1NP), in drug-naïve patients; and −37.7% ± 41.5%, in CTX and −55.4% ± 30.1%, in P1NP in patients with previous bisphosphonate treatment were exhibited after 12 months of treatment. The adherence rates of the second and third dosing schedules were 79.9% and 56.8%, respectively.ConclusionsOur study indicates that denosumab is effective in increasing BMD in Korean osteoporosis males regardless of prior bisphosphonate treatment.

Menopausal Transition: Prospective Study of Estrogen Status, Circulating MicroRNAs, and Biomarkers of Bone Metabolism.

ObjectiveOsteoporosis is associated with an impaired balance between bone resorption and formation, which in turn leads to bone loss and fractures. Many recent studies have underlined the regulatory role of microRNAs (miRNAs) in bone remodeling processes and their potential as biomarkers of osteoporosis. The purpose of this study was to prospectively examine the association of circulating miRNAs and bone biomarkers with estrogen status in women before and after oophorectomy, as well as in oophorectomized women on estrogen therapy.MethodsIn this prospective study, we included 11 women before oophorectomy and hysterectomy and at 201 ± 24 days after the surgery. Another 11 women were evaluated 508 ± 127 days after oophorectomy and hysterectomy and after an additional 203 ± 71 days of estradiol treatment. Serum miRNAs were profiled by sequencing. Estrogen status and biomarkers of bone metabolism were quantified. Bone mineral density was assessed in the lumbar spine.ResultsOur analysis revealed 17 miRNAs associated with estrogen levels. Of those miRNAs that were upregulated with estrogen deficiency and downregulated after estrogen therapy, miR-422a correlated with serum beta-carboxy-terminal type I collagen crosslinks (β-CTX) and procollagen 1 N-terminal propeptide (P1NP); and miR-1278 correlated with serum β-CTX, P1NP, osteocalcin, sclerostin, and Dickkopf-1(Dkk1). In contrast, we found an inverse association of miR-24-1-5p with estrogen status and a negative correlation with serum β-CTX, P1NP, osteoprotegerin, and sclerostin levels.ConclusionThe reported miRNAs associated with estrogen status and bone metabolism could be potential biomarkers of bone pathophysiology and would facilitate studies on the prevention of postmenopausal osteoporosis. Our findings require validation in an extended cohort.

Efficacy and Safety of Oral Ibandronate versus Intravenous Zoledronic Acid on Bone Metabolism and Bone Mineral Density in Postmenopausal Japanese Women with Osteoporosis.

There are no published clinical reports comparing ibandronate (IBN) treatment and zoledronic acid (ZOL) treatment in Japanese postmenopausal osteoporotic patients. This investigation therefore compared the efficacy and safety of the drugs on improving bone metabolism and bone mineral density (BMD) in Japanese postmenopausal women with primary osteoporosis. Eighty-two treatment-naïve primary osteoporotic female patients were randomly divided into IBN-treated or ZOL-treated groups. Bone turnover markers and BMD were examined immediately prior to treatment (baseline) and at 6, 12, 18, 24, and 30 months of therapy. Compared with baseline levels, the values of type 1 procollagen N-terminal propeptide, bone-specific alkaline phosphatase (BAP), urinary type-I collagen amino-terminal telopeptide (NTX), and tartrate-resistant acid phosphatase 5b were all significantly decreased at every time point in both groups apart from BAP at 30 months in the ZOL group, urinary NTX at 12 months in the ZOL group and at 24 and 30 months in both groups. Lumbar BMD values were significantly increased at 6, 12, 18, and 24 months in the IBN group and at 6 and 12 months in the ZOL group compared with pre-treatment levels. Hip BMD values were also significantly increased at 6, 12, 18, and 24 months in the IBN group and at 6, 12, and 18 months in the ZOL group compared with baseline values. The percentage changes of hip BMD at 18 and 24 months in the ZOL group were significantly higher than those in the IBN group (both p < 0.05). No remarkable adverse events were noted in either group. In conclusion, both IBN and ZOL significantly and safely improved bone turnover markers and BMD during 30 months of treatment in Japanese osteoporosis patients. The ZOL group tended to exhibit greater gains in BMD as compared with the IBN group, which merits further investigation.

Sex Differences In Bone Metabolism During An Arduous Military Field Exercise

Military personnel are often exposed to arduous exercise and energy deficits. Acute and severe periods of energy deficit increase bone resorption and decrease bone formation. Evidence for the effect of energy deficit on bone metabolism in military personnel is limited, and sex differences in these responses are unknown. PURPOSE: To investigate sex differences in bone metabolism during an arduous military field exercise. METHODS: Twenty-seven British Army Officer cadets (women [n = 14]: 23 ± 1 y, 1.67 ± 0.67 m, 61.6 ± 6.6 kg; men [n = 13]: 23 ± 2 y, 1.81 ± 0.62 m, 81.5 ± 7.1 kg) completed a field exercise covering 70 km over undulating terrain in 24 hours carrying 15 kg (women) or 20 kg (men) of load. Circulating markers of bone resorption and formation were measured at baseline (BASE), and 12 h (POST12) and 48 h (POST48) post-field exercise. RESULTS: Procollagen 1 N-terminal propeptide (P1NP) decreased from BASE to POST12 (−13.4 μg·L-1; p < 0.001) and increased from POST12 to POST48 (5.9 μg·L-1; p = 0.033); POST48 was also lower than BASE (−7.6 μg·L-1; p = 0.001). There was no difference in P1NP between men and women (main effect of sex, p = 0.210; sex × time interaction, p = 0.309). Parathyroid hormone (PTH) increased from BASE to POST12 (0.7 pmol·L-1; p = 0.012), and decreased from POST12 to POST48 (−0.5 pmol·L-1; p = 0.027); BASE and POST48 were not different (p = 0.081). There was no difference in PTH between men and women (main effect of sex, p = 0.776; sex × time interaction, p = 0.927). Testosterone decreased from BASE to POST12 (−7.1 nmol·L-1; p < 0.001) and increased from POST12 to POST48 (4.9 nmol·L-1; p < 0.001) in men only; POST48 was also lower than BASE (−2.2 nmol·L-1; p < 0.001). Testosterone did not change in women. Testosterone was higher in men than women (19 nmol·L-1, p < 0.001). The field exercise had no effect on beta C-telopeptide cross-links of type 1 collagen (time: p = 0.155; sex: p = 0.560; sex × time interaction: p = 0.579) or cortisol (time: p = 0.110; sex: p = 0.117; sex × time interaction: p = 0.836). CONCLUSION: Men and women have similar bone metabolic responses to an extreme model of exercise where they are likely to be in energy deficit. The decrease in bone formation was likely mediated by the severe energy deficit, and takes more than 48 h to recover to baseline.

Influence Of Hormonal Contraceptive Use On Bone Metabolic Responses To British Army Officer Basic Training

Hormonal contraceptives are commonly used by servicewomen. Hormonal contraceptives contain ethinyl oestradiol and progestogen, or progestogen only, and act by altering the endogenous production of 17β-Oestradiol. 17β-Oestradiol plays an important role in the regulation of bone metabolism. PURPOSE: To investigate differences in the bone metabolic responses to 44-weeks British Army Officer basic training between women not using any hormonal contraceptive and women using the combined oral contraceptive pill (ethinyl oestradiol and progestogen: COCP) or a progestogen-only contraceptive (pill, subdermal implant, intramuscular injection: POC). METHODS: Venous blood samples were obtained after an overnight fast from 51 women during week 1, 28, and 44 of training (non-users, n = 11; COCP users, n = 18; POC users, n = 17; other, n = 5; mean ± SD, age 24 ± 3 y, height 1.66 ± 0.06 m, body mass 64.3 ± 7.7 kg; p ≥ 0.079 between groups). Blood samples were analysed for biochemical markers of bone resorption and formation. RESULTS: Albumin-adjusted calcium increased from week 1 to week 28 (0.05 mmol·L-1) and week 44 (0.05 mmol·L-1) in all women (p ≤ 0.045). Procollagen 1 N-terminal propeptide (P1NP), bone-specific alkaline phosphatase, beta C-telopeptide cross-links of type 1 collagen, sclerostin, phosphate, or total 25-hydroxyvitamin D were not different between timepoints (p ≥ 0.096). P1NP was higher in POC users than COCP users at week 1 (mean [IQR], 81.8 [68.9, 115.1] vs 61.3 [50.5, 77.5] μg·L-1, p = 0.012). Sclerostin was higher in POC users than COCP users at week 1 (40.9 [37.0, 50.6] vs 33.0 [28.9, 40.6] pmol·L-1) and week 44 (43.2 [41.3, 47.4] vs 30.8 [27.8, 41.7] pmol·L-1) (p ≤ 0.018). There were no other effects of hormonal contraceptive use on markers of bone metabolism (p ≥ 0.053). CONCLUSIONS: POCs may inhibit new bone formation in response to mechanical loading through disinhibition of the WNT-signalling pathway. The mechanism is likely due to low endogenous and exogenous oestradiol. Bone metabolism is a dynamic process, and frequent measures of bone markers are recommended to capture biochemical responses to mechanical loading.

Anti-Mullerian hormone was a serum biomarker for early knee osteoarthritis - Iwaki cohort study

Anti-Mullerian hormone was a serum biomarker for early knee osteoarthritis - Iwaki cohort study

Non-oxidized parathyroid hormone (PTH) measured by current method is not superior to total PTH in assessing bone turnover in chronic kidney disease

Parathyroid hormone (PTH) is a key regulator of bone turnover but can be oxidized invivo, which impairs biological activity. Variable PTH oxidation may account for the rather poor correlation of PTH with indices of bone turnover in chronic kidney disease. Here, we tested whether non-oxidized PTH is superior to total PTH as a marker of bone turnover in 31 patients with kidney failure included from an ongoing prospective observational bone biopsy study and selected to cover the whole spectrum of bone turnover. Receiver Operating Characteristic (ROC) curves, Spearman correlation and regression analysis of non-oxidized PTH, total PTH and bone turnover markers (bone-specific alkaline phosphatase, procollagen N-terminal pro-peptide and tartrate-resistant acid phosphatase 5b) were used to assess the capability of non-oxidized PTH vs. total PTH to discriminate low from non-low and high from non-high bone turnover, as assessed quantitatively by bone histomorphometry. Serum levels of non-oxidized PTH and total PTH were strongly and significantly correlated. Histomorphometric parameters of bone turnover and the circulating bone turnover markers showed similar correlation coefficients with non-oxidized PTH and total PTH. The area under the ROC (AUROC) values for discriminating between low/non-low turnover for non-oxidized PTH and total PTH were significant and comparable (0.82 and 0.79, respectively). For high/non-high turnover the AUROCs were also significant and of the same magnitude (0.76 and 0.80, respectively). Thus, measuring non-oxidized PTH using the currently available method provides no added value compared to total PTH as an indicator of bone turnover in patients with kidney failure.

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.

Synovial fluid fingerprinting in end-stage knee osteoarthritis: a novel biomarker concept.

AimsThe lack of disease-modifying treatments for osteoarthritis (OA) is linked to a shortage of suitable biomarkers. This study combines multi-molecule synovial fluid analysis with machine learning to produce an accurate diagnostic biomarker model for end-stage knee OA (esOA).MethodsSynovial fluid (SF) from patients with esOA, non-OA knee injury, and inflammatory knee arthritis were analyzed for 35 potential markers using immunoassays. Partial least square discriminant analysis (PLS-DA) was used to derive a biomarker model for cohort classification. The ability of the biomarker model to diagnose esOA was validated by identical wide-spectrum SF analysis of a test cohort of ten patients with esOA.ResultsPLS-DA produced a streamlined biomarker model with excellent sensitivity (95%), specificity (98.4%), and reliability (97.4%). The eight-biomarker model produced a fingerprint for esOA comprising type IIA procollagen N-terminal propeptide (PIIANP), tissue inhibitor of metalloproteinase (TIMP)-1, a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), monocyte chemoattractant protein (MCP)-1, interferon-γ-inducible protein-10 (IP-10), and transforming growth factor (TGF)-β3. Receiver operating characteristic (ROC) analysis demonstrated excellent discriminatory accuracy: area under the curve (AUC) being 0.970 for esOA, 0.957 for knee injury, and 1 for inflammatory arthritis. All ten validation test patients were classified correctly as esOA (accuracy 100%; reliability 100%) by the biomarker model.ConclusionSF analysis coupled with machine learning produced a partially validated biomarker model with cohort-specific fingerprints that accurately and reliably discriminated esOA from knee injury and inflammatory arthritis with almost 100% efficacy. The presented findings and approach represent a new biomarker concept and potential diagnostic tool to stage disease in therapy trials and monitor the efficacy of such interventions.Cite this article: Bone Joint Res 2020;9(9):623–632.

Aging and menopause reprogram osteoclast precursors for aggressive bone resorption

Women gradually lose bone from the age of ~35 years, but around menopause, the rate of bone loss escalates due to increasing bone resorption and decreasing bone formation levels, rendering these individuals more prone to developing osteoporosis. The increased osteoclast activity has been linked to a reduced estrogen level and other hormonal changes. However, it is unclear whether intrinsic changes in osteoclast precursors around menopause can also explain the increased osteoclast activity. Therefore, we set up a protocol in which CD14+ blood monocytes were isolated from 49 female donors (40–66 years old). Cells were differentiated into osteoclasts, and data on differentiation and resorption activity were collected. Using multiple linear regression analyses combining in vitro and in vivo data, we found the following: (1) age and menopausal status correlate with aggressive osteoclastic bone resorption in vitro; (2) the type I procollagen N-terminal propeptide level in vivo inversely correlates with osteoclast resorption activity in vitro; (3) the protein level of mature cathepsin K in osteoclasts in vitro increases with age and menopause; and (4) the promoter of the gene encoding the dendritic cell-specific transmembrane protein is less methylated with age. We conclude that monocytes are “reprogrammed” in vivo, allowing them to “remember” age, the menopausal status, and the bone formation status in vitro, resulting in more aggressive osteoclasts. Our discovery suggests that this may be mediated through DNA methylation. We suggest that this may have clinical implications and could contribute to understanding individual differences in age- and menopause-induced bone loss.