Potential utility of high preoperative levels of serum type I collagen markers in postmenopausal women with primary hyperparathyroidism with respect to their short-term variations after parathyroidectomy

We evaluated short-term changes in serum amino-terminal procollagen propeptide (P1NP) and cross-linked C-terminal telopeptide (βCTX) of type I collagen after parathyroidectomy (PTX) in 41 postmenopausal women with primary hyperparathyroidism (PHPT). Serum levels of 25-hydroxyvitamin D, intact PTH, calcium, phosphate, albumin, creatinine, P1NP, and βCTX were measured before and 2 days after PTX. Their P1NP and βCTX levels were compared with those measured in 41 normally menstruating and 30 postmenopausal controls. Fifteen of these 41 women had both pre-surgery P1NP and βCTX concentrations above the upper limit noted in our postmenopausal controls [high turnover (HT) subgroup], while βCTX levels were solely above the upper limit lastly mentioned in 11 women [high bone resorption (HBR) subgroup]. In addition, these two markers were within the postmenopausal control range in 12 of them [normal turnover (NT) subgroup]. A more significant decrease in postoperative βCTX levels was observed in the 15 HT compared with the 12 NT PHPT women. The significant postoperative increase in P1NP levels observed in the 15 HT as well as in the 11 HBR was no longer significant in the 12 NT women. In conclusion, higher pre-surgery P1NP and βCTX levels in post-menopausal PHPT women are associated with a preferential activation of bone formation over bone resorption after PTX.     

Comparison of Serum and Urine Assays for Biochemical Markers of Bone Resorption in Postmenopausal Women with and without Hormone Replacement Therapy and in Men

Biochemical markers of bone resorption have been used to characterize metabolic bone disease and assess therapeutic response. Most studies have used the urinary measurement of collagen crosslinks, but serum assays have recently been developed that may have less analytic and biologic variability. In the present study, we measured urine and serum N- and C-terminal crosslinked telopeptides of type I collagen (NTX and CTX) and serum bone sialoprotein (BSP) in postmenopausal women with or without hormone replacement therapy (HRT) and in men of similar age. In these populations, the variability of serum and urine markers was similar, except that serum NTX showed somewhat lower variability in postmenopausal women. Urine and serum assays correlated well with one another and were significantly lower in postmenopausal women on HRT compared with untreated women. The difference in women on HRT was similar for sNTX, uNTX and BSP (35–40%) and greater for sCTX and uCTX (52–53%). There was an inverse correlation between markers and bone mineral density, largely attributable to the high correlation in women not on HRT. Fractional excretion of NTX and CTX were estimated at 0.20 ± 0.07 and 0.44 ± 0.11, respectively. These values were independent of the concentration of the marker or of creatinine in the urine. We conclude that serum markers are useful measures of bone resorption in these populations, in whom the use of such markers is likely to be helpful in the management of osteoporosis. Received: 23 August 1999 / Accepted: 30 November 1999     

Physical Activity and Bone Turnover Markers: A Cross-Sectional and a Longitudinal Study

Strenuous physical activity in young individuals has an important effect on both bone mass and bone turnover but the effect of moderate physical activity in adults remains uncertain. In a large cohort (N = 530) of healthy premenopausal women, bone formation markers (osteocalcin and N-terminal propeptide of type 1 procollagen [P1NP]), but not serum C-telopeptide of type 1 collagen (sCTX), were found to be significantly associated with the level of physical activity, and this association remained significant after adjusting the data (ANCOVA) by age and body mass index. Mean spine and hip bone mineral density (BMD) values were positively associated with physical activity but this was statistically significant (P = 0.050) only for adjusted values of spine BMD. Twenty-four healthy sedentary premenopausal women, subscribing to participate in a community exercise program lasting a month, and 18 age-matched controls were included in the longitudinal study. Serum osteocalcin and P1NP, but not sCTX, rose significantly, by ca. 25%, only in the active group after a month of exercise. The changes in the two bone formation markers remained statistically significant for values adjusted for body weight, which fell significantly in the exercise group. In conclusion, both the cross-sectional and the longitudinal parts of our study demonstrate that even minor changes in physical activity are associated with a clear effect on bone formation markers.     

Profile of changes in bone turnover markers during once-weekly teriparatide administration for 24 weeks in postmenopausal women with osteoporosis

Summary

Changes in bone turnover markers with weekly 56.5 μg teriparatide injections for 24 weeks were investigated in women with osteoporosis. Changes in bone turnover markers 24 h after each injection of teriparatide were constant. During the 24 week period, bone formation markers increased and baseline bone resorption marker levels were maintained.

Introduction

This study aimed to clarify the changes in bone turnover markers during 24 weeks of once-weekly teriparatide injections in postmenopausal women with osteoporosis.

Methods

The 24 h changes in pharmacokinetics (PK), calcium metabolism, and bone turnover markers (serum osteocalcin, procollagen type I N-terminal propeptide (P1NP), urinary cross-linked N-telopeptide of type I collagen (NTX), deoxypiridinoline (DPD)) after each injection of 56.5 μg teriparatide at the data collection weeks (0, 4, 12, and 24 weeks) were investigated. The changes were evaluated by comparison with the data at 0 h in each data collection week.

Results

Similar 24 h changes in each parameter after injection of teriparatide were observed in each data collection week. Serum calcium increased transiently, and intact PTH decreased 4–8 h after injection; serum calcium subsequently returned to baseline levels. Calcium and intact PTH levels decreased for 24 weeks. Although serum osteocalcin decreased at 24 h, it was significantly increased at 4 weeks. P1NP decreased transiently and then increased significantly at 24 h. P1NP was significantly increased at 4 weeks. Urinary NTX and DPD were significantly increased transiently and then decreased at 24 h. The urinary DPD level decreased significantly at 4 weeks.

Conclusions

Twenty-four hour changes in PK, calcium metabolism, and bone turnover markers showed the same direction and level after once-weekly teriparatide injections for 24 weeks, with no attenuation of the effect over time. After 24 weeks, the bone formation marker, serum osteocalcin, increased significantly, but the serum P1NP, did not. Bone resorption markers decreased or remained the same.     

An immunoassay for type I collagen alpha 1 helicoidal peptide 620-633, a new marker of bone resorption in osteoporosis

Type I collagen fragments are the most sensitive markers of bone resorption in osteoporosis. Currently, all available type I collagen-related bone resorption markers detect in serum and/or urine fragments arising from the telopeptide region of the molecule. Our aim was to evaluate the technical and clinical performances of a new assay detecting in urine a degradation fragment originating from the helical part of type I collagen and consisting of the 620-633 sequence of the alpha1 chain. Urinary helical peptide was measured with a new ELISA (Metra Helical peptide, Quidel Corporation). Results were compared with those of urinary C-terminal cross-linking type I collagen of type I collagen (CTX), an established bone resorption marker. We measured urinary helical peptide levels in 89 healthy women (age 31-89 years) and in 59 postmenopausal women involved in two randomized studies of the efficacy of alendronate (10 mg/day; n = 20) and transdermal 17beta estradiol (50 microg/day; n = 39). The within-run and between-run CVs were < or = 7.3 and 8.7%, respectively. In 59 healthy women, urinary helical peptide levels highly correlated with those of urinary CTX (r = 0.78, P < 0.0001). The long-term intraindividual variability assessed over 6 months in 18 untreated postmenopausal women was 24%. Compared to 24 premenopausal women, urinary helical peptide was 42% (P < 0.0001) higher in 65 postmenopausal women (mean age, 60 years), an increase comparable to that of urinary CTX (+ 47%, P < 0.0001). Urinary helical peptide levels decreased by 72% (P < 0.0001) after 3 months of alendronate treatment and by 59% (P < 0.0001) after 6 months of transdermal estrogen therapy. These changes were of similar magnitude to those of urinary CTX (-69 and -62%, respectively; NS compared with changes in helical peptide). In women treated with transdermal 17beta estradiol, the percentage of change of urinary helical peptide and urinary CTX at 6 months significantly correlated with the change in spinal bone mineral density after 2 years (r = -0.58, P = 0.002, and r = -0.52, P = 0.006, for urinary helical peptide and CTX, respectively). This new assay for type I collagen helical peptide has demonstrated adequate analytical performance and was highly correlated with urinary CTX, an established type I collagen C-telopeptide bone resorption marker. The test was a sensitive indicator of the antiresorptive effects of bisphosphonate and estrogens in postmenopausal women. This new bone resorption marker should be useful for the clinical investigation of patients with osteoporosis.     

The Peroxisome Proliferator-Activated Receptor-γ Agonist Rosiglitazone Increases Bone Resorption in Women with Type 2 Diabetes: A Randomized, Controlled Trial

In previous studies, with up to 16 weeks of exposure to rosiglitazone or pioglitazone, circulating markers of bone formation [procollagen I N-terminal propeptide (P1NP), osteocalcin, and bone-specific alkaline phosphatase] decreased but no change in bone resorption markers was found. We examined the effect of rosiglitazone on bone resorption and formation markers when used for 24 weeks. This post-hoc analysis of a double-blind, placebo-controlled, randomized trial evaluated the effects of 6 months of rosiglitazone use versus placebo on circulating markers of bone turnover in 111 patients with type 2 diabetes and cardiovascular disease or additional cardiac risk factors. The principal end points for analysis were changes in bone formation and resorption markers, measured by P1NP and carboxy-terminal cross-links (CTX), respectively. There were 111 subjects who completed the study and had baseline and 6-month data; mean age was 56, including 41% women and 67% nonwhite (50 black, 18 Hispanic, and six other), and subjects were evenly distributed between placebo and rosiglitazone groups. Women treated with rosiglitazone had higher CTX levels (0.43 ng/mL) than those who received placebo (0.23 ng/mL) (P = 0.007), with no significant differences in P1NP or OPG. Overall, in stratified analyses of men and in stratified analyses among different ethnicities, there were no statistically significant differences observed in CTX, P1NP, OPG, PTH, or 25-OHD between the treatment groups. Women taking rosiglitazone had higher circulating markers of bone resorption, which is contrary to prior studies of shorter duration, where the principal observation was a decrease in markers of bone formation.     

IL-33与绝经后骨质疏松女性骨密度和骨代谢指标相关性研究

目的 探索血清白细胞介素-33(IL-33)与绝经后骨质疏松女性骨密度和骨代谢指标相关性。方法 采用酶联免疫吸附法测定50例绝经后骨质疏松患者和50例正常绝经后妇女血清IL-33水平。采用双能X线骨密度仪(DXA)测量患者和对照组的骨密度(BMD)。检测维生素D、钙、碱性磷酸酶(ALP)、甲状旁腺激素(PTH)水平,以及1型胶原C末端肽(CTX)和1型前胶原N端前肽(P1NP)等骨转换指标。结果 在绝经后骨质疏松症女性中,IL-33水平显著低于健康对照组[(3.53±2.45) pg/mL vs (13.72±5.39) pg/mL,P=0.007];Spearman相关分析表明血清IL-33水平与年龄、BMI、PTH、CTX和P1NP水平呈负相关,与腰椎BMD和股骨颈BMD呈正相关。多元回归分析表明,年龄、BMI、腰椎BMD、PTH、股骨颈BMD和血清CTX和P1NP水平是骨质疏松症患者血清IL-33水平降低的独立预测因子。结论 血清IL-33降低是绝经后骨质疏松患者股骨颈和腰椎骨密度降低和骨转换增速的危险因素。     

The benefits of a high-intensity aquatic exercise program (HydrOS) for bone metabolism and bone mass of postmenopausal women

This study aimed to evaluate the 24-week effects of a high-intensity aquatic exercise program on bone remodeling markers and bone mass of postmenopausal women. In this randomized, controlled trial we studied 108 women (58.8 ± 6.4 years), randomized into Aquatic Exercise Group (AEG), n = 64, performing 24 weeks of aquatic exercises, and Control Group (CG), n = 44, sedentary. They had their fasting morning blood sample collected for the measures of intact parathyroid hormone (iPTH), procollagen type 1 amino-terminal propeptide (P1NP) and carboxy-terminal cross-linking telopeptide of type I collagen (CTx). Bone mass was measured by dual-energy X-ray absorptiometry before and after the intervention. Participants of both groups received a daily supplementation of 500 mg of elementary calcium and 1,000 IU of vitamin D (cholecalciferol). Results showed an augment in bone formation marker (P1NP) only in the AEG (15.8 %; p = 0.001), and although both groups experienced significant enhancements in bone resorption marker (CTx), this increase was less considerable in the AEG (15 % in the AEG and 29 % in the CG). IPTH was increased by 19 % in the CG (p = 0.003) at the end. The femoral trochanter BMD presented a 1.2 % reduction in the CG (p = 0.009), whereas in the AEG no change was observed (p = 0.069). The proposed aquatic exercise program was efficient in attenuating bone resorption raise and enhancing bone formation, which prevented the participants in the AEG from reducing the femoral trochanter BMD, as happened in the CG.     

The Relevance of Osteoclastic and Osteoblastic Activity Markers Follow-Up in Patients on Antiresorptive Osteoporosis Treatment

In general, markers of bone formation and markers of bone resorption are changing synergistically, so the monitoring of any osteoclastic and any osteoblastic marker should reflect the rate of bone transformation. The aim of the study is to monitor the bone metabolism markers in postmenopausal women with osteoporosis and osteopenia along with the variations caused by the effects of bisphosphonate therapy. The study involved 55 women of average age of 57.95 years, with osteopenia or osteoporosis. The patients with osteoporosis were treated with bisphosphonates (75?mg once a week); the laboratory tests were performed before the treatment and 6 months later. Patients with osteopenia were evaluated at the first assessment and 6 months later. The tests included bone densitometry, dual-energy X-ray absorptiometry, osteocalcin, alkaline phosphatase, collagen 1 N-terminal pro-peptide (P1NP), and beta C telopeptide of type I collagen (CTX). The mean T-score was ?2.80?±?0.63 before therapy and ?2.64?±?0.45 6 months later (p?<?0.001). Women with osteoporosis had elevated levels of osteocalcin and P1NP at the first assessment, whereas the alkaline phosphatase level did not change with the treatment. After the introduction of antiresorptive therapy, the levels of osteocalcin and P1NP significantly decreased (p?<?0.001). In the group with osteopenia, the biochemical markers activity were increased in both assessments. In patients with osteoporosis, Beta-CTX was increased in the first evaluation, and decreased after treatment (p = 0.001). The results indicate that the assessment of biochemical markers of bone metabolism show excellent results in the assessment of prognosis, monitoring the course and the response to various treatment regimens of osteoporosis and evince strong correlation with standard densitometry and dual-energy X-ray absorptiometry procedures. P1NP and CTX show better diagnostic applicability compared with osteocalcin and alkaline phosphatase. The analysis of the activity of biochemical markers may obtain early information on the therapeutic response, before definitive assessment by bone density measurements.     

Are bone turnover markers associated with volumetric bone density,size, and strength in older men and women? The AGES–Reykjavik study

Summary

Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density.

Introduction

The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN).

Methods

A total of 1745 older individuals (773 men and 972 women, aged 66–92 years) from the Age, Gene/Environment Susceptibility (AGES)–Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression.

Results

Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1–10 %).

Conclusion

Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.

     

Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: A randomized,double‐blind,placebo‐controlled,multiple‐ascending‐dose phase I trial

Src is a nonreceptor tyrosine kinase thought to be essential for osteoclast function and bone resorption. We investigated the effect of the orally available Src inhibitor saracatinib (AZD0530) on bone turnover in healthy men. The study was part of a randomized, double‐blind, placebo‐controlled multiple‐ascending‐dose phase I trial of saracatinib. Fifty‐nine healthy men (mean age 34.6 years) were divided into five cohorts; four with 12 subjects and one with 11 subjects, and randomized within each cohort in the ratio 3:1 to receive a single dose of saracatinib or placebo, respectively, followed 7 to 10 days later with daily doses for a further 10 to 14 days. Dosing levels of saracatinib ascended by cohort (60 to 250 mg). Markers of bone turnover were measured predose and 24 and 48 hours after the initial single dose and immediately before and 24 and 48 hours and 10 to 14 days after the final dose. Data from 44 subjects were included in the analysis. There was a dose‐dependent decrease in bone resorption markers [serum cross‐linked C‐telopeptide of type I collagen (sCTX) and urinary cross‐linked N‐telopeptide of type I collagen normalized to creatinine (uNTX/Cr)]. At a dose of 250 mg (maximum tolerated dose), sCTX decreased by 88% [95% confidence interval (CI) 84–91%] and uNTX/Cr decreased by 67% (95% CI 53–77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. There were no significant adverse events. We conclude that inhibition of Src reduces osteoclastic bone resorption in humans. Saracatinib is a potentially useful treatment for diseases characterized by increased bone resorption, such as metastatic bone disease and osteoporosis. © 2010 American Society for Bone and Mineral Research     

Bone markers during acute burn care: Relevance to clinical practice?

Objective

Bone changes are increasingly described after burn. How bone markers could help to detect early bone changes or to screen burn patients at higher risk of demineralization is still not made clear. We performed an observational study assessing the changes in serum bone markers after moderate burn.

Change of cross-linked telopeptide of type I collagen (ICTP) and other bone resorption markers in patients with bone fragility fractures

Background The serum concentration of cross-linked telopeptide of type I collagen (ICTP) has been reported to be a useful marker and for both diagnosis and monitoring of bone metastasis. This study was performed to clarify the changes in various bone turnover markers, including ICTP, after bone fragility fracture. Methods Seventy-six bone fragility fracture patients (14 men and 62 postmenopausal women; mean age, 77.0 years) were evaluated for bone resorption markers, including serum ICTP. We measured urinary N-terminal telopeptides of type I collagen (NTX) several times after fracture. Furthermore, serum ICTP, serum NTX, urinary deoxypyridinoline (DPD), and urinary C-telopeptide-cross-linked type I collagen (CTX) were measured at the times of both minimum and maximum urinary NTX. Results Urinary NTX was increased significantly from 86.4 ± 57.9 to 214.3 ± 137.2 nmol BCE/mmol Cr following fracture. Serum ICTP showed a similar significant increase from 7.6 ± 4.7 to 10.4 ± 5.5 ng/ml in bone fragility fracture patients. Furthermore, other markers also showed similar increases. The level of increase in urinary NTX (148.0%) was especially high compared with other bone resorption markers. On the other hand, the level of increase in serum ICTP (36.8%) was similar to that in serum NTX (39.8%). Serum ICTP levels were significantly correlated with other bone resorption markers, with an especially strong correlation between serum ICTP and serum NTX (r = 0.647, P < 0.001). The percentage of cases in which ICTP exceeded the cutoff value for suspected bone metastasis in postmenopausal women was 73.6%. Conclusions The value of ICTP increases with bone fragility fracture and is correlated with other bone resorption markers, and ICTP obviously exceeded the reference value as compared with other bone resorption markers.     

Serum type I collagen breakdown product (serum CTX) predicts hip fracture risk in elderly women: the EPIDOS study

We report the predictive value for hip fracture of a new marker of bone resorption, serum C-telopeptide of type I collagen (CTX), measured on a new automated analyzer, Elecsys. Baseline urinary and serum samples from 212 patients who subsequently had a hip fracture and from 642 controls were analyzed in a nested case control study within the EPIDOS prospective cohort. Each fracture patient was matched with three control patients of the same age who did not fracture. Mean follow-up was 3.3 years (maximum 4.9 years). We measured urinary CTX, urinary free deoxypyridinoline, and serum CTX. Urinary markers were assessed to know whether the magnitude of prediction of hip fracture by this serum marker was similar compared with that given by urinary markers. In the whole group, serum CTX was not predictive of hip fracture risk. When the analysis was restricted to samples taken in the early afternoon (between 1 and 2 P.M.), representing 115 fracture cases and 293 controls, serum CTX was significantly predictive with a relative hazard of 1.86 (95% confidence interval 1.01-3.76) for values above the premenopausal range (mean + 2 SD). For comparison, in the whole group, the relative hazard for fracture of women having a T-score >/= 2 for urinary CTX and free deoxypyridinoline was 1.67 (1.19-2.32), and 2. 07 (1.49-2.9), respectively. Serum CTX from morning samples did not predict hip fractures probably because it was not controlled for time and fasting/nonfasting state. We conclude that serum CTX sampled under controlled conditions significantly predicts the subsequent risk of hip fracture in ambulatory elderly women, with the same magnitude as urinary markers of resorption.     

Markers of bone turnover are reduced in patients with CF related diabetes; the role of glucose

BackgroundCystic fibrosis(CF) related diabetes(CFRD) and osteoporosis are prevalent in adult patients with CF. We aimed to evaluate if CFRD and markers of glucose metabolism and inflammation are associated with bone turnover in CF.MethodsCross sectional study at the adult section at the Copenhagen CF Center from January–October 2017. Fasting blood samples, including bone turnover markers(BTMs) and cytokines, Dual-x-ray absorptiometry scan and oral glucose tolerance test were performed. Lung-transplanted participants and patients in antiosteoporotic treatment were excluded from analyses.Results102 patients were included of whom 19 had a prior CFRD diagnosis. CFRD patients had lower procollagen type 1 N-terminal propeptide(P1NP) and C-Terminal cross-linked Telopeptide(CTX) levels compared to CF patients without diabetes (median[IQR]) 49.5 μg/l [29.6,57.1] vs 56.9 μg/l [38.2,74.3], p = .03 and 0.2 μg/l [0.1,0.3] vs 0.4 μg/l [0.3,0.6], p < .01, respectively. Fasting plasma glucose(FPG) was negatively associated with the bone formation markers P1NP and osteocalcin and bone resorption marker CTX. In multivariate linear regression FPG remained a significant predictor of P1NP -1.07 [−1.09;-0.01] and CTX -1.13 [−1.21;-1.06]. Bone mineral density Z-score was not different between patients with and without CFRD but FPG was negatively associated with hip and femoral neck Z-score. There was no consistent association between inflammatory cytokines and BTMs.ConclusionsBone turnover markers are reduced in CF patients with CFRD and negatively associated with glucose levels. Extra attention towards frequent hyperglycemia in CF patients should be taken when evaluating decreased BMD. Glycemia may be a future target for improving outcome in CFBD.     

Reference intervals of biochemical bone turnover markers for Saudi Arabian women: A cross-sectional study

Biochemical bone turnover markers (BTMs) provide important information on the diagnosis, therapy and monitoring of metabolic bone diseases including osteoporosis. One goal of antiresorptive therapy in women is to decrease biochemical BTMs to the lower half of reference intervals for healthy pre-menopausal counterparts, using newly developed automated assays of such markers. The main objectives of the present study were to: (1) establish reference interval values for the following biochemical BTMs: serum osteocalcine (s-OC), bone alkaline phosphatase (s-bone ALP), procollagen type 1 N-terminal propeptide (s-PINP), crosslinked C-terminal telopeptide of Type 1 collagen (s-CTX), tartarate-resistant acid phosphatase isoform 5b (s-TRACP-5b) and urinary: CTX (u-CTX), N-telopeptides of type 1 collagen (u-NTX), pyridinoline (u-PYD) and deoxypyridinoline (u-DPD) in randomly selected Saudi healthy pre-menopausal women; (2) study the changes in biochemical BTMs in relation to age in pre- and post-menopausal women and the factors reported to influence bone turnover and (3) determine the effect of menopausal status on BTMs. A total of 2125 women were studied [including (n = 1557) pre-, and (n = 568) post-menopausal women, respectively, aged 20–79 years]. A total of 765 healthy pre-menopausal women (aged 35–45 years) were used to establish reference intervals for biochemical BTMs. All women studied were medically examined and had their bone mineral density (BMD) values obtained for the lumbar spine (L₁–L₄) and femoral neck according to detailed inclusion criteria. In all women, values of biochemical BTMs, decreased with increasing age up to the age of 45 years, increased steeply among women in their 50s and remained increased in post-menopausal women. Significant increases were evident in all biochemical BTMs in post-menopausal women with > 5 years since menopause with the exception of s-OC, u-DPD, and u-PYD. Using stepwise multiple linear regression analysis, several variables were identified (depending on the BTM) as determinants of BTMs including age, BMI, parity, FSH, LH, PTH, s-Ca, s-Mg, s-PO₄ and 25(OH)D. In the reference intervals group, there are no significant correlations between any of the biochemical BTMs and age of menarche, day of menstrual cycle, physical activity, total daily dietary calcium and caffeine intakes and parity. It is recommended that the age range 35–45 years should be used when establishing biochemical BTMs reference intervals in Saudi Arabian pre-menopausal women.     

The Effect of High-Dose Vitamin D Supplementation on Calciotropic Hormones and Bone Mineral Density in Obese Subjects with Low Levels of Circulating 25-Hydroxyvitamin D: Results from a Randomized Controlled Study

Low levels of 25-hydroxyvitamin D (25OHD) are associated with increased bone turnover and risk of fractures. Plasma 25OHD is inversely related to body mass index, and vitamin D deficiency is common in obesity. We aimed to determine whether vitamin D supplementation affects bone turnover and bone mineral density (BMD) in obese subjects. Fifty-two healthy obese men and women aged 18–50 years with plasma 25OHD levels below 50 nmol/L were randomized to 7,000 IU of cholecalciferol daily or placebo for 26 weeks. We measured plasma levels of 25OHD, parathyroid hormone (PTH), and markers of bone turnover, as well as BMD at the hip, spine, forearm, and whole body. Compared with placebo, treatment with cholecalciferol increased mean plasma 25OHD from 35 to 110 nmol/L (p < 0.00001) and significantly decreased PTH (p < 0.05). BMD increased significantly at the forearm by 1.6 ± 0.7 % (p = 0.03). The bone resorption marker C-terminal telopetide of type 1 collagen (CTX) decreased borderline significantly in the cholecalciferol group compared with the placebo group (p = 0.07). Changes in plasma 25OHD correlated inversely with changes in plasma levels of bone-specific alkaline phosphatase (r = ?0.38, p = 0.01) and CTX (r = ?0.33, p = 0.03). Changes in CTX correlated inversely with changes in spine BMD (r = ?0.45, p = 0.04). Increasing circulating 25OHD levels by cholecalciferol treatment is of importance to bone health in young obese subjects as increased levels of 25OHD are associated with a decrease in both PTH and bone turnover and with an increase in BMD at the forearm.     

Biochemical bone turnover markers are useful tools to assess changes in bone metabolism in marmosets

This study was designed to investigate whether biochemical markers of bone resorption and formation could be determined in the serum and urine of marmosets (Callithrix jacchus), using standard laboratory chemistry methods and commercially available human kits. Consequently, the findings from this study will indicate whether the techniques and kits could serve as appropriate tools for assessing changes in bone turnover in this species. Two groups of animals (n = 12/group), consisting of a comparable number of young and old male and female marmosets, were given either isotonic saline or a single dose of the bisphosphonate ibandronate (0.1mg/kg) s.c. in order to suppress bone turnover. Blood and urine were collected at baseline and 5 days after administration. Samples were analyzed for urinary (u) and serum (s) markers of bone formation (serum osteocalcin [sOC], serum N-terminal crosslinks of human pro-collagen type I [sP1NP]) and bone resorption (urinary pyridinoline [uPYD], urinary deoxypyridinoline [uDPD], serum C-terminal crosslinks of human collagen type I (C-telopeptide) [sCTX]), intact serum parathyroid hormone (iPTH) and urinary calcium and creatinine. Levels of all the markers of bone resorption and formation decreased during the study period. As expected, the bone formation markers decreased slightly less relative to the resorption markers. The most sensitive markers were sCTX (–33%; P 0.001) for bone resorption, and sP1NP (–3%; P 0.05) for bone formation. Serum PTH levels increased by 8% (P 0.05), demonstrating a physiological reaction to prevent changes in serum calcium. Although not all variables reached statistical significance within the tested interval, the applied methods and kits were considered suitable for evaluating bone turnover changes in marmosets. Thus, these methods and kits can be utilized not only during the course of pharmacological investigations but also as additional tools to assess the overall bone health of this species.     

Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized,Double‐Blind,Phase 2, Parallel Group Study

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T‐score ≤–2.0 and ≥–3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open‐label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker β‐CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and β‐CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.     

Low bone turnover and low bone density in a cohort of adults with Down syndrome

Summary

Increased incidence of osteoporosis in Down syndrome has been reported, but etiology is not established. We report low bone turnover markers and bone mineral density (BMD) in a cohort of people with Down syndrome without consistent clinical risk factors. Our results should guide future studies and treatments for this common problem.

Introduction

To better understand the etiology for osteoporosis in Down syndrome (DS), we measured bone density by dual-energy X-ray absorptiometry (DXA) and circulating biochemical markers of bone formation and resorption in a cohort of 30 community-dwelling DS adults.

Methods

Seventeen males and 13 females followed in the University of Arkansas Down Syndrome Clinic were evaluated by DXA to estimate BMD and underwent phlebotomy to measure serum procollagen type-1 intact N-terminal propeptide (P1NP) to evaluate bone formation, and serum C-terminal peptide of type-I collagen (CTx) to evaluate bone resorption.

Results

Seven of 13 DS females and 12 of 17 DS males had low bone mass at one of measured sites (z?≤??2.0). When data were grouped by age, males had apparent osteopenia earlier than females. The mean P1NP in the normal group was 19.2?±?5.2 ng/ml vs. 2.2?±?0.9 ng/ml in the DS group (P?=?0.002). Serum CTx levels in the normal group were 0.4?±?0.1 ng/ml vs. 0.3?±?0.1 ng/ml (P?=?0.369).

Conclusions

Low BMD in adults with DS is correlated with a significant decrease in bone formation markers, compared to controls without DS, and is independent of gender. These data suggest that diminished osteoblastic bone formation and inadequate accrual of bone mass, with no significant differences in bone resorption, are responsible for the low bone mass in DS. These observations question the use of antiresorptive therapy in this population and focus attention on increasing bone mass by other interventions.