Reduced Bone Turnover Markers Research Articles

P05 Osteoporosis in thalassemia; a case with multifactorial aetiology

Abstract Introduction Thalassemia patients are prone to osteoporosis due to multifactorial reasons, including anaemia, bone marrow expansion, iron overload and hypogonadism. Case description A 41-year-old British Asian male with beta thalassemia major was referred to rheumatology in 2018 for osteoporosis. In 2008, aged 27 years, whilst playing football, he developed a distal radial fracture and ulnar styloid process fracture and a DEXA scan had revealed low bone mineral density (BMD) for age. Subsequently, he was started on Ibandronic acid by his haematologist for a total of 10 years. After he was referred to rheumatology in 2018, bisphosphonates were discontinued as he had 5% improvement in BMD, a decade of bisphosphonates and no further fractures. Further assessment revealed multiple contributory factors for his osteoporosis. • Consistency low vitamin D – 9.6 nmol/L in 2009, average value of 20 • He was diagnosed with hypogonadism, poor compliance with IM testosterone injections • He had diabetes which was not optimally controlled • Evidence of iron overload with average serum ferritin of 2000 ug/L with deferasirox While these factors were optimised, it was decided to adopt a watch and wait policy with regards to specific osteoporosis treatment. Review in 2023 revealed serum testosterone level of 20.1 nmol/L (6.9-23.2) with better compliance with testosterone injections. Fructosamine levels were 310 (normal range 200-285) but it has reduced from a peak of 370. Serum ferritin levels have reduced to 776 down from a high of 5600. Normal vitamin D levels were maintained. The DEXA scan in 2023 revealed a spine T score of −2.4 which showed 10.2% increase in bone mineral density. DEXA scan in 2020 revealed T score of −3.1 in spine and −1.9 in hips. The P1NP level was 56 (19-69) which has reduced from 100 in 2021. Improvements in BMD and bone turnover markers were achieved through optimising contributory factors without any specific osteoporosis treatment. He will be monitored with periodic BMD and bone turnover markers. Discussion Anaemia and subsequent bone marrow expansion is a recognised cause for osteoporosis in thalassemia patients. While regular blood transfusions inhibit bone marrow expansion, ineffective erythropoiesis is not fully supressed. This patient received 3 units of blood every 4 weeks. Bone marrow expansion occurs mostly in trabecular bone resulting in low BMD is areas which generally have increased amount of trabecular bone such as the spine. Our patient had a lower BMD in the spine compared to the femoral neck. Iron overload directly disrupts bone formation and can result in endocrinopathies which contributes to osteoporosis. Hypogonadism is another well-recognised cause and is primarily results from iron deposition in pituitary and at times in the gonads. Hormonal replacement therapy reduces bone loss. Studies have shown that hypogonadic patients have more severe osteoporosis and predominant involvement of the femoral neck. Iron overload can cause diabetes mellitus and impaired growth hormone/ insulin growth factor-1 (IGF-1) axis which can contribute to osteoporosis. Our patient did have diabetes but had normal IGF-1 levels when checked previously. Deferoxamine which is one of iron chelating agents have been shown to reduce collagen synthesis and increases osteoblast apoptosis which might contribute to the development of osteoporosis. Vitamin D levels are well known to be low in patients with thalassemia compared to the general population. While there are no RCT’s to show that bisphosphonates reduce fracture risk, surrogate markers such as increased BMD and reduction in bone turnover markers are known to occur. Therefore, current guidance (Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK) recommends bisphosphonates to be considered in patients with a low BMD for age (Z-score < −2.0, T-score < −2.5 if post-menopausal or over 50), if there are fragility fractures or falling BMD despite adequate vitamin D levels, and hormone supplementation. Key learning points Learning point Important to assess for osteoporosis in thalassaemic patients. There are multiple factors contributing to the development of osteoporosis which needs to be addressed together with endocrinologist and haematologist. Bisphosphonates are recommended though further RCT evidence is required to support this

ODP101 In Men with Type 2 Diabetes Mellitus, Poor Glycemic Control is Associated with Diminished Circulating Osteoblast Progenitors

Abstract Background An emerging field of research concerns the deleterious effects of type 2 diabetes mellitus (T2DM) on bone. Our group has previously reported a hemoglobin A1c (A1c) threshold of 7% where bone impairment occurs as reflected by reduction in bone turnover markers and deterioration in bone microarchitecture and strength. However, whether poor glycemic control is also associated with underlying derangements in cellular flux remains unclear. Methods Analysis of the baseline data from 42 consecutive men aged 35-65 enrolled in a clinical trial (NCT03887936) at the Michael E DeBakey VA Medical Center, Houston, TX, who were able to provide the outcomes of interest. Inclusion criteria were average fasting morning testosterone from 2 measurements of <300 ng/dl, T2DM and BMI<35 kg/m2. The following variables were assessed: A1c by high performance liquid chromatography; testosterone and estradiol by LC/MS; bone turnover markers and sex hormone binding globulin by ELISA; quantification of osteoblast (OB) progenitors and osteoclast (OC) precursors by flow cytometry; areal bone mineral density (aBMD) and body composition by DXA; and bone microarchitecture and strength by high resolution peripheral quantitative computerized tomography. Results Participants with poorly controlled T2DM (A1c>7%) had significantly lower percent of OB progenitors in circulation than those with A1c≤7% (1.12 ± 0. 079% v 1.47 ± 0.11% of non-B non-T non-NK cells, p=0. 02) when controlling for age, duration of T2DM, free testosterone, and 25-hydroxyvitamin D levels. Higher levels of free testosterone were associated with smaller percentage of OB progenitors (r = -0.31, p = 0. 05). Although the percent of OC precursors in circulation (cells that were dual CD14CD11b+, CD14MCSFR+, or CD14CD120b+) was not significantly related to A1c, it was positively associated with percent of OB progenitors in peripheral blood (r = 0.34, p = 0. 03; r = 0.35, p = 0. 02; r = 0.39, p = 0. 01) respectively. There was a significant positive association between OB progenitors and visceral adipose tissue (VAT) volume (r=0.41, p=0. 009). Although there was no association between osteoblast progenitors and osteocalcin levels (product of mature OBs), osteocalcin negatively correlated with VAT (r=-0.47, p=0. 002). There was no association between OB progenitors and OC precursors with aBMD or bone microarchitecture parameters. Conclusions Poor glycemic control is associated with fewer circulating OB progenitors, as was higher free testosterone levels while the converse was true for VAT. It is possible that the former harms cell viability, while the latter two affect differentiation of OB progenitors into mature OB's; with testosterone promoting, and visceral adipose tissue (via unknown mediators) retarding maturation as suggested by the negative association between osteocalcin and VAT. The positive association between OB progenitors with circulating OC precursors is consistent with the physiologic crosstalk between OB and OC which appears to be preserved in patients with T2D. Presentation: No date and time listed

Yak (Bos grunniens) milk improves bone mass and microarchitecture in mice with osteoporosis.

The effect of milk on bone health is controversial. In this study, the effects of yak milk in mice with retinoic acid-induced osteoporosis (OP) were evaluated. Yak milk was provided to OP mice as a nutrition supplement for 6 wk. The results showed that yak milk significantly reduced bone turnover markers (tartrate acid phosphatase and alkaline phosphatase). The yak milk treatment was also associated with remarkably increased bone mineral density, bone volume, trabecular thickness, and trabecular number, as well as improved biomechanical properties (maximum load and stress) of the tibia. Furthermore, yak milk mitigated the deterioration of the network and thickness of trabecular bone in treated OP mice compared with the OP model group. The results indicated that yak milk could improve bone mass and microarchitecture through the inhibition of bone resorption in OP mice.

Efficacy of Denosumab for Osteoporosis in Patients with Rheumatic Diseases.

Objective Denosumab, an anti-RANKL monoclonal antibody, was reported to improve bone mineral density (BMD) and reduce fracture risk, offering favorable efficacy against postmenopausal osteoporosis. However, some patients have experienced a reduced BMD despite denosumab therapy. Methods We performed an observational study to clarify the clinical efficacy of denosumab for osteoporosis in rheumatic disease patients. Serum levels of bone turnover markers and lumber BMD in 100 rheumatic disease patients were examined at baseline and 6 and 12 months after denosumab therapy. The independent influence of changes in the BMD was examined by multiple regression analyses adjusted for patient characteristics and bone turnover markers. Results As bone resorption markers, serum levels of N-telopeptide crosslinked of type I collagen (NTx) and tartrate-resistant acid phosphatase isoform 5b were statistically decreased after 12 months. As bone formation markers, serum levels of osteocalcin, procollagen type I N-terminal peptide, and bone alkaline phosphatase were significantly decreased after 12 months. The mean BMD was significantly increased after 12 months. However, in 10 patients, the BMD decreased. A multivariate analysis of factors related to BMD changes highlighted a young age, low prednisolone dosage, and reduction in NTx. Conclusions Denosumab increases the BMD to combat osteoporosis in rheumatic disease patients, and potential predictors of a better response to denosumab include a young age, reduction in bone turnover markers, and low-dose glucocorticoid use.

The Rationale for Using Neridronate in Musculoskeletal Disorders: From Metabolic Bone Diseases to Musculoskeletal Pain.

Neridronate or ((6-amino-1-hydroxy-1-phosphonohexyl) phosphonic acid) is an amino-bisphosphonate (BP) synthetized in Italy in 1986. Bisphosphonates are molecules with a P-C-P bond in their structure that allows strong and selectively binding to hydroxyapatite (HAP) as well as osteoclasts inhibition through different mechanisms of action. Neridronate was initially used to treat Paget disease of the bone, demonstrating effectiveness in reducing bone turnover markers as well as pain. The interesting molecular properties of neridronate foster its wide use in several other conditions, such as osteogenesis imperfecta, and osteoporosis. Thanks to the unique safety and efficacy profile, neridronate has been used in secondary osteoporosis due to genetic, rheumatic, and oncological diseases, including in pediatric patients. In the last decade, this drug has also been studied in chronic musculoskeletal pain conditions, such as algodystrophy, demonstrating effectiveness in improving extraskeletal outcomes. This review highlights historical and clinical insights about the use of neridronate for metabolic bone disorders and musculoskeletal pain conditions.

The effect of Cissus quadrangularis L. on delaying bone loss in postmenopausal women with osteopenia: A randomized placebo-controlled trial

BackgroundOsteopenia refers to bone density that is not normal but also not as low as that noted in osteoporosis. Osteopenia leads to osteoporosis and increases the risk of fractures. Current research is focused on agents that will prevent or slow the progression of bone loss. On the basis of published evidence, Cissus quadrangularis (CQ) might potentially provide a novel natural treatment for osteopenia. PurposeTo determine the effect of 24 weeks of consecutive treatment with CQ on delaying bone loss and safety in postmenopausal women (PMW) with osteopenia. MethodsThis study is a randomized, placebo-controlled trial. Here, 134 enrolled PMW with osteopenia (> 40 years and having no period for 1–10 years) received CQ at 1.2 (CQ1.2) or 1.6 g/day (CQ1.6) or placebo. The %change in bone mineral density (BMD) at the lumbar spine (L1–L4), femoral neck, and total hip served as the primary outcome. The %change in bone turnover markers (BTMs), including C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 amino-terminal propeptide (P1NP), was the secondary outcome. These outcomes were compared between the CQ vs. placebo group at weeks 12 and 24. The least significant change (LSC) was used to monitor clinical changes. The adverse events (AE) were monitored. ResultsA total of 108 participants completed this study. The %BMD changes in the CQ-treated groups did not differ at any site after 24 weeks compared to the placebo. Statistically significant differences were detected in CQ1.6 at the lumbar spine (0.011 ± 0.025 g/cm2, p = 0.008) and CQ1.2 at the femoral neck (–0.015 ± 0.036 g/cm2, p = 0.024) compared to baseline, but these changes did not exceed the LSC. Reduced bone remodeling activity was detected in both CQ-treated groups. Compared to the placebo, the %P1NP change was significantly reduced in CQ1.6 (–2.46 ± 26.05%; p < 0.01) at week 12 and in CQ1.2 (–3.36 ± 29.47%; p < 0.01) and CQ1.6 (–9.95 ± 22.22%; p < 0.01) at week 24. These results correlated with the within-group comparison, which showed a continuously significant increase in both BTMs in the placebo group. However, a stable CTX and a significant reduction in P1NP (p < 0.05) were detected in both CQ-treated groups. This reduction exceeded the LSC of P1NP. The incidence of adverse events did not differ among the three groups. ConclusionThis is the first clinical report that showed a promising effect on delaying bone loss of orally administration of CQ for 24 weeks, as indicated by a slower bone remodeling process via a reduction in BTMs. However, no change in BMD was observed.

Abstract 41: Effect of zoledronic acid on bone mineral density in Indian postmenopausal osteoporotic women with and without diabetes – A prospective cohort study

Background and Aims: A significant number of postmenopausal women have both diabetes and osteoporosis in our country. The objectives of the study were to study the effect of intravenous (IV) zolendronic acid (ZA) on change in bone mineral density (BMD) at lumbar spine (LS), total hip (TH), femoral neck (FN) and distal forearm (FA) and the changes in bone turnover markers (BTMs) in postmenopausal osteoporotic women with and without diabetes after 12 months of treatment.Results: A total of 80 patients with postmenopausal osteoporosis were included-diabetes (n=40) and non-diabetes (n=40). Patients with diabetes were older and had lower BTMs levels compared to non-diabetic patients. At baseline, BMD at all four areas were similar in both the groups. Mean increase in LS-BMD at 12-months in diabetes and non-diabetes group was 3.6 ± 4.7% and 6.2 ± 4.7 % respectively (P=0.02). There was no difference in the percent change in the TH, FN and FA BMD between the groups at 12 months. There was a significant reduction in BTMs from the baseline in both the groups after 12 months of follow-up. Acute phase reactions were seen in 75% of patients with pyrexia being more common in non-diabetes group.Conclusion: The gain in the LS-BMD was significantly lower in the diabetes group as compared to the non-diabetes group at 12 months following a single IV infusion of 4 mg ZA.

Acute Phase Reactions After Intravenous Infusion of Zoledronic Acid in Japanese Patients with Osteoporosis: Sub-analyses of the Phase III ZONE Study

In a clinical trial involving Japanese patients with osteoporosis, post hoc analyses were performed to evaluate the incidence of acute phase reactions (APRs) after infusion of zoledronic acid (ZOL). The results highlighted differences in baseline factors between patients with vs without APRs. Changes in efficacy indicators such as bone turnover markers (BTMs) also showed significant differences. We, therefore, investigated the factors involved in the development of APRs in Japanese patients treated with a once-yearly intravenous infusion of ZOL 5 mg for 2 years by assessing the relation between APRs and efficacy. APRs reported in patients with primary osteoporosis from the ZONE study were analyzed post hoc. Baseline factors were compared in patients with vs without APRs, and changes in BTMs and bone mineral density (BMD) were also investigated. In the ZOL group, 51.2% (169/330) of patients developed APRs after the first infusion and 12.3% (33/268) after the second infusion. Comparison of baseline factors showed that patients without APRs in the ZOL group had a significantly higher neutrophil/lymphocyte ratio, lower serum levels of procollagen type I N-terminal propeptide, older age, and higher likelihood of prior bisphosphonate use vs patients with APRs. Patients with APRs showed significantly higher increases in total hip BMD at 6 and 12 months and larger reductions in BTMs vs patients without APRs. Patient profiles differed significantly between patients with vs without APRs, with APRs after the first infusion of ZOL being related to increases in total hip BMD and suppression of BTMs.This study is registered with ClinicalTrials.gov (identifier: NCT01522521; January 31, 2012).

Effectiveness of bazedoxifene in preventing glucocorticoid-induced bone loss in rheumatoid arthritis patients

ObjectiveTo evaluate the effectiveness of bazedoxifene in preventing bone loss in patients with rheumatoid arthritis (RA) receiving low-dose glucocorticoids (GCs).MethodsIn this randomized, controlled, open-label study, we assigned postmenopausal women with osteopenia who had been receiving low-dose GCs for RA to two groups: a group receiving bazedoxifene (20 mg/day) with elemental calcium 1200 mg and vitamin D 800 IU daily (bazedoxifene group) and a group receiving the same doses of calcium and vitamin D only (control group). As primary outcome, bone mineral density (BMD) change in the lumbar spine (L-spine) from baseline to 48 weeks was assessed. Changes in BMD in the femur, trabecular bone score, bone turnover markers, and development of fracture were assessed as secondary outcomes. For intention-to-treat analysis, 20 completed data sets were created by applying multiple imputations by chained equations.ResultsA total of 114 patients (57 patients in each group) were recruited. A significant increase in L-spine BMD (0.015 g/cm2, P = 0.007) was observed in the bazedoxifene group, and the increase was significantly higher than in the control group (0.013, 95% CI 0.0003–0.026, P = 0.047). Reductions in bone turnover markers in the bazedoxifene group were significantly greater than in the control group. Only one fracture was observed in the bazedoxifene group, while four fractures developed in the control group.ConclusionIn postmenopausal patients with RA receiving low-dose GCs, bazedoxifene improved BMD and reduced bone turnover markers. However, the change in BMD did not exceed the least significant change.Trial registrationClinicalTrials.gov, NCT02602704.

Retraction Note: Comparison of the effect of alendronate on lumbar bone mineral density and bone turnover in men and postmenopausal women with osteoporosis.

The purpose of the present study was to compare the effect of alendronate treatment on lumbar bone mineral density (BMD) and bone turnover in men and postmenopausal women with osteoporosis. Sixty men with primary or secondary osteoporosis and 318 women with postmenopausal osteoporosis were treated with alendronate. The primary end points were lumbar BMD and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) and serum alkaline phosphatase (ALP) levels. The secondary end point was the incidence of vertebral and nonvertebral fractures. Forty-seven (78.3%) men and 254 (79.9%) women who could complete the 12-month trial were analyzed. The mean ages of men and postmenopausal women were 69.1 and 70.4 years, respectively. Both men and postmenopausal women showed higher levels of urinary NTX as compared with normal range of premenopausal women. Alendronate treatment decreased urinary NTX level by 39.2% in men and 45.4% in postmenopausal women at 3 months and serum ALP level by 17.8 and 21.0%, respectively, at 12 months. Following reduction in bone turnover markers, lumbar BMD increased 5.8 and 7.6% in men and postmenopausal women, respectively, at 12 months. Reduction in urinary NTX level and increase in lumbar BMD were smaller in men than in postmenopausal women. The incidence of vertebral and nonvertebral fractures was 10.6 and 8.5%, respectively, in men and 8.3 and 7.5%, respectively, in postmenopausal women, with no significant difference in these incidences between them. These results suggested that alendronate treatment effectively increased lumbar BMD from baseline in men with primary or secondary osteoporosis following reduction in bone turnover, although its efficacy did not appear to be greater than in postmenopausal women with osteoporosis.

Bone Mineral Density and Bone Turnover 10 Years After a Single 5 mg Dose or Two 5-Yearly Lower Doses of Zoledronate in Osteopenic Older Women: An Open-Label Extension of a Randomized Controlled Trial.

Intravenous zoledronate reduces fracture risk (5 mg at 18-month intervals) and prevents bone loss (doses of 1 to 5 mg for 3 to >5 years), but the duration of action of a single 5 mg dose and the effects of lower doses beyond 5 years are unknown. We report the second open-label extension (years 5 to 10) of a 2-year randomized, multidose, placebo-controlled, double-blinded trial. A total of 116 older women who completed 5 years of participation either continued observation without further treatment (zoledronate 5 mg and placebo at baseline) or received repeat doses of 1 or 2.5 mg zoledronate (zoledronate 1 mg and zoledronate 2.5 mg at baseline, respectively). Outcomes were spine, hip, and total body bone mineral density (BMD) and serum markers of bone turnover. After a single 5 mg dose of zoledronate, mean BMD at the lumbar spine and total hip was maintained at or above baseline levels for 9 and 10 years, respectively. The mean level of the bone resorption marker β-C-terminal telopeptide of type I collagen (β-CTX) was at least 25% lower than that in the placebo group for 9 years. In women administered 5-yearly doses of 2.5 mg zoledronate, mean BMD at the total hip and lumbar spine was maintained at or above baseline levels for 9 and 10 years, respectively. Redosing with 1 or 2.5 mg zoledronate at 5 years reduced bone turnover markers for 3 to 4 years. BMD increased for 3 to 4 years after redosing with 1 mg zoledronate. In the group given 5-yearly 2.5 mg zoledronate, β-CTX was at least 20% lower than that in the placebo group for 10 years. Both a single baseline 5 mg dose of zoledronate and 5-yearly doses of 1 and 2.5 mg zoledronate prevented bone loss at hip and spine for 8 to 10 years in older postmenopausal women. Clinical trials to evaluate the effects on fracture risk of these very infrequent and lower doses of zoledronate are justified. © 2021 American Society for Bone and Mineral Research (ASBMR).

P0874THE IMPACT OF CHRONIC EXPOSURE TO INDOXYL SULFATE ON BONE TURNOVER MARKERS, PTH, VITAMIN D3, AND BIOMECHANICAL AND DENSITOMETRIC PROPERTIES OF BONES IN RAT MODEL

Abstract Background and Aims Chronic kidney disease (CKD) is a crucial risk factor for biochemical and bone disturbances, as well as non-skeletal calcifications known as Chronic Kidney Disease – Mineral and Bone Disorders (CKD-MBD). Etiopathogenesis of CKD-MBD still remains unknown and arouses much controversy. Indoxyl sulfate (IS) is one of the most potent protein-bound uremic toxin that accumulates during CKD, and exerts aggressive and multidirectional effect on the body. In vitro studies indicate that IS modulates the differentiation and activation of osteoblasts and osteoclasts, however IS impact on bone and mineral disorders still remains unclear. The purpose of the study was to assess IS effect on bone turnover markers, parathyroid hormone (PTH), vitamin D3, and densitometric and biomechanical properties of bones in rat model. Method Male Wistar rats weighting 180 – 210 g (n=48) were divided into three groups – control group that received pure water and two experimental groups. Experimental groups were exposed to IS in the doses of 100 or 200 mg/kg of b.w. (200 IS) in the drinking water during 4 weeks. At the end of experiment, rats were anesthetized and samples of blood, as well as tibiae, femurs and lumbar spines were collected. Next, the IS bone (cortical and trabecular), plasma and urine levels were determined by high-performance liquid chromatography (HPLC). We also assessed IS influence on bone turnover markers (alkaline phosphatase – ALP, and tartrate-resistant acid phosphatase - TRAP), and level of vitamin D3, and PTH. Furthermore, we evaluated densitometric parameters of tibiae, femurs and lumbar spines using Horizon QDR Series X-ray Bone Densitometer, and performed biomechanical parameters analysis of the cortical bone of the femoral diaphysis using three-point bending test, and the mixed cortico-trabecular structure of the proximal femur by the bending test of the femoral neck. Results Chronic exposure to IS led to statistically significant increase in plasma, urine, cortical and trabecular bone IS concentrations. We observed reduction in bone turnover markers – bone formation marker ALP in trabecular and cortical bone, and bone resorption marker TRAP in cortical bone. Moreover, the highest dose of IS increased PTH. None of tested IS doses affected vitamin D3. From data obtained due to biomechanical tests, the highest dose of IS decreased the main indicators of bone strength: yield load (Fy) and displacement at yield [dl(Fy)] of femoral diaphysis and femoral neck, and ultimate load (Fu) and displacement at ultimate [dl(Fu)] of femoral diaphysis. Furthermore, we observed the decrease in elasticity of femoral diaphysis (increased Young’s modulus of elasticity E). Additionally, densitometric measurements revealed reduction only in the bone mineral density (BMD) and BMD of diaphyseal area (BMD R2) of tibiae, BMD R2 of femurs in 200 IS group, as well as BMD and BMD R2 of tibiae in 100 IS group. Conclusion Obtained data confirm that IS affects bones. We observed reduced bone metabolism and strength after exposure to IS. On the basis of the results, we concluded that IS can be one of crucial uremic factors responsible for increased risk of fracture during CKD.

Bone Features of Unaffected Skeletal Sites in Melorheostosis: A Case Report

Background: Melorheostosis is a rare sporadic sclerosing bone dysplasia, which commonly affects appendicular skeleton with bone hyperostosis and soft tissues sclerosis; fragility fractures are rare in melorheostotic patients. We investigated bone features at unaffected sites in a postmenopausal woman with melorheostosis of the right lower limb and with a fracture of the melorheostosis-free T11 vertebral. Methodology: Melorheostotic lesions were evaluated by plain radiography, magnetic resonance of the right lower limb, and whole-body bone scintigraphy. Dual X-ray absorptiometry, trabecular bone score, and quantitative computed tomography were performed to investigate unaffected bone sites. Biochemical assessment of bone metabolism was obtained. Results: Dual X-ray absorptiometry was indicative of normal mineralization at femoral sites and osteopenia at lumbar spine (T-score −1.1), which was confirmed by spinal quantitative computed tomography (volumetric bone mineral density 89 mg/cm3). Trabecular bone score suggested only mildly altered bone microarchitecture (1.304, normal values >1.350). Bone markers were consistent with high bone turnover. Causes of secondary osteoporosis or alterations in bone metabolism were excluded. Zoledronic acid induced a reduction in bone turnover markers after 6 months without significant changes in clinical features. Conclusions: Fragility fractures at apparently unaffected sites may occur in adults with melorheostosis, in absence of significant demineralization diagnosed by dual X-ray absorptiometry, trabecular bone score, and quantitative computed tomography, which may underestimate the fracture risk in this set of patients. Treatment with zoledronate could be considered also to prevent fragility fractures.

Effects of the Intravenous Calcimimetic Etelcalcetide on Bone Turnover and Serum Fibroblast Growth Factor 23: Post Hoc Analysis of an Open-label Study

PurposeSecondary hyperparathyroidism (SHPT) is a serious complication that increases the risk of bone disorders in patients with chronic kidney disease (CKD) undergoing hemodialysis. Etelcalcetide is the first injectable calcimimetic approved for treatment of SHPT, which reduces bone turnover markers and suppresses intact fibroblast growth factor 23 (iFGF-23). This study aimed to explore the associations between etelcalcetide-induced changes in circulating factors and serum iFGF-23 levels. MethodsThis study was a post hoc analysis of data from a previous multicenter, open-label study of etelcalcetide administered to 191 Japanese patients with SHPT undergoing hemodialysis for 52 weeks. Correlations were analyzed between changes from baseline in serum iFGF-23 and serum intact parathyroid hormone (iPTH), corrected calcium, phosphate, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase-5b (TRACP-5b), and 1α,25-dihydroxyvitamin D (1,25[OH]2D) levels at 1, 2, 3, 6, and 12 months. Akaike's Information Criterion (AIC) was calculated using serum iPTH, corrected calcium, phosphate, BAP, TRACP-5b, and 1,25(OH)2D levels as potential predictor variables at each time point. Four models with the smallest AIC at the 3-month time point were chosen as the fitted models to predict changes in iFGF-23 levels, and stepwise multivariate analysis was performed to determine the predictor variables with the greatest contribution to the change in iFGF-23 levels by calculating the partial coefficients of determination. FindingsThe etelcalcetide-induced reduction in iFGF-23 was positively correlated with serum levels of corrected calcium and phosphate and negatively with BAP. By calculating the AIC, corrected calcium, phosphate, iPTH, BAP, and TRACP-5b were suggested to be predictors of iFGF-23 levels. Stepwise multivariate analysis found that phosphate, corrected calcium, BAP, and TRACP-5b correlated with iFGF-23, in order from strongest to weakest. ImplicationsThese results suggest that etelcalcetide effectively lowered iFGF-23 and that this reduction may occur via improvements in phosphate, corrected calcium, BAP, and TRACP-5b. Etelcalcetide is thus a promising calcimimetic for decreasing iFGF-23 and improving bone turnover in patients with CKD undergoing hemodialysis with severe SHPT, in addition to decreasing PTH itself. JapicCTI identifier: 142,665.

Effect of isolated vitamin D supplementation on bone turnover markers in younger postmenopausal women: a randomized, double-blind, placebo-controlled trial.

The purpose of this study is to evaluate the effect of VD supplementation alone on bone turnover markers in younger postmenopausal women. In this double-blind, placebo-controlled trial, 160 women were randomized into the VD group (supplementation with 1000IU of vitamin D3/day, orally; n = 80) or placebo group (n = 80). Women aged 50-65years with amenorrhea ≥ 12months and normal bone mineral density were included. The intervention lasted 9months, and the participants were assessed at the beginning and end of treatment. Serum levels of total calcium, parathormone (PTH), alkaline phosphatase (AP), and 24-h urine calcium were determined. Serum C-terminal telopeptide of type I collagen (s-CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured by immunoassay as markers of bone resorption and formation, respectively. Plasma 25-hydroxyvitamin-D [25(OH)D] concentrations were measured by HPLC. Intention-to-treat analysis was performed using ANOVA, Student's t test, Tukey's test, and gamma distribution. Over the period of 9months, 25(OH)D concentrations increased from 15.0 ± 7.5 to 27.5 ± 10.4ng/mL (+ 45.4%) in the VD group and decreased from 16.9 ± 6.7 to 13.8 ± 6.0ng/mL (- 18.5%) in the placebo group (p< 0.001). There was a decrease (- 21.3%) of PTH levels in the VD group with a significant difference between groups at the end of the study (p< 0.001). No significant differences were observed in the other laboratory parameters (total calcium, AP, and calciuria) in either group (p> 0.05). A comparison of bone turnover markers showed a significant reduction in of s-CTX (- 24.2%, p< .0001) and P1NP (- 13.4%, p= 0.003) levels in the VD group. No significant variations in bone turnover markers were observed in the placebo group (s-CTX, - 6.9%, p= 0.092 and P1NP, - 0.6%, p= 0.918). In younger postmenopausal women with VD deficiency, isolated supplementation with 1000IU of vitamin D3 for 9months is associated with a reduction in bone turnover markers. However, any between-group differences was not observed in bone turnover markers.

A study on OPG/RANK/RANKL axis in osteoporotic bile duct-ligated rats and the involvement of nitrergic and opioidergic systems.

Chronic liver disease (CLD) affects millions of people and its impact on bone loss has become a subject of interest. Nitric oxide and endogenous opioids are suggested to increase during cholestasis/cirrhosis and may impact bone resorption by different mechanisms. The receptor activator of nuclear factor-κB (RANK)/RANK-ligand (RANKL)/osteoprotegerin (OPG) signaling pathway regulates bone resorption, but its role in metabolic bone disease subsequent to CLD is unknown. We aimed to investigate the involvement of nitrergic and opioidergic systems in bone loss relative to the RANK/RANKL/OPG pathway, in bile duct-ligated (BDL) rats. Eighty BDL/sham-operated (SO) rats received injections of 3 mg/kg/day Nω-Nitro-L-arginine methyl ester ± naltrexone (10 mg/kg/day) or saline for 28 days. Plasma bone turnover markers, OPG, RANK, and RANKL along with mRNA expression levels of the latter three were assessed. Plasma bone turnover markers and OPG level increased, but RANKL decreased in the BDL group compared with their SO controls (both: P ≤ 0.05). Administration of naltrexone reduced bone turnover markers and OPG level while increased RANKL content in comparison to BDL rats (P ≤ 0.05). As compared to untreated BDL rats, nitric oxide inhibition showed no effect on bone turnover marker i.e. OPG, RANK, and RANKL levels. BDL significantly increased RANK mRNA, but had no significant effect on RANKL and OPG mRNA expression. The lack of association between plasma levels and quantitative gene expression of RANKL and OPG suggests an indirect function of these markers in BDL rats. Considering that opioid receptor blockage by naltrexone in BDL animals caused a significant decrease in OPG and an increase in RANKL plasma contents, it could be postulated that the opioidergic system may have a regulatory effect on these bone markers.

Improvement of bone turnover markers and bone mineral density following treatment of primary aldosteronism.

Recent studies showed association between hyperaldosteronism and low bone density among patients with primary aldosteronism (PA) due to secondary hyperparathyroidism. Our objective is to assess bone turnover markers (BTM) and bone mineral density (BMD) of PA patients compared to essential hypertension. This was an open-label, prospective, case-controlled study, conducted over 12 months. Fifty-two consecutive patients referred for secondary hypertension were screened. Eighteen patients with confirmed PA (diagnosis based on the Endocrine Society clinical guideline) and seventeen matched controls with essential hypertension were recruited. BTM (CTX and P1NP), BMD, intact parathyroid hormone (iPTH), and bone profile were assessed at baseline and three months following treatment among the PA patients. Calcium intake was assessed using a validated questionnaire. Primary outcomes were the changes of bone markers and BMD following treatment of PA, and their relation to other parameters. PA patients had significantly lower serum calcium and higher iPTH despite comparable vitamin D levels with control group. Both BTM were significantly higher among the PA group. BMD of lumbar spine, neck of femur and distal radius did not differ between groups. Three months following treatment, there were significant: 1) reduction in BTM; 2) improvement in the lumbar spine BMD; 3) reduction in iPTH level; and 4) increment of serum 25-OH vitamin D level. Our findings support that bone loss and potential fracture risk among PA patients are likely a result of aldosterone-mediated secondary hyperparathyroidism. Patients with early PA may already exhibit increased bone turnover despite no significant changes in BMD.

Effect of conjugated estrogens/bazedoxifene on postmenopausal bone loss: pooled analysis of two randomized trials.

Conjugated estrogens/bazedoxifene reduces vasomotor symptoms and prevents postmenopausal bone loss without stimulating the breast and endometrium. We analyzed changes in bone mineral density (BMD) and bone markers using pooled data from two phase-3 trials. Selective Estrogens, Menopause, and Response to Therapy (SMART)-1 and SMART-5 were randomized, double-blind, placebo- and active-controlled studies conducted in postmenopausal nonhysterectomized women. BMD and turnover marker data were pooled for women given conjugated estrogens (0.45 or 0.625 mg) plus bazedoxifene 20 mg or placebo over 12 months. Sensitivity analyses were conducted using baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, race, and geographic region. There were 1,172 women, mean age 54.9 years, mean 6.21 years since menopause, mean lumbar spine, and total hip T scores -1.05 and -0.58; 58.8% had a Fracture Risk Assessment Tool score less than 5% indicating low fracture risk. At 12 months, adjusted differences (vs placebo) in BMD change in the groups taking conjugated estrogens 0.45 or 0.625 mg plus bazedoxifene 20 mg were 2.3% and 2.4% for lumbar spine, 1.4% and 1.5% for total hip, and 1.1% and 1.5% for femoral neck (all P < 0.001 vs placebo). These increases were unrelated to baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, or geographic region. Both doses reduced bone turnover markers (P < 0.001). Conjugated estrogens/bazedoxifene significantly improved BMD and turnover in a large population of younger postmenopausal women at low fracture risk and is a promising therapy for preventing postmenopausal bone loss.

IL-1 drives breast cancer growth and bone metastasisin vivo

BackgroundWe have recently identified interleukin 1B (IL-1B) as a potential biomarker for predicting breast cancer patients at increased risk for developing bone metastasis. In mouse models, IL-1B and its receptor (IL-1R1) are upregulated in breast cancer cells that metastasise to bone compared with cells that do not. We have now investigated the functional role of IL-1 by blocking IL-1R signalling with the clinically licensed antagonist, anakinra.Methodology6-week old female BALB/c mice received a subcutaneous or intra-venous injection of MDA-MB-231-IV or MCF7 cells. Anakinra (1mg/kg/day) or placebo was administered 3 days before (preventative) or 7 days later (treatment). Tumour volume, apoptosis (TUNEL, Caspase 3), proliferation (Ki67) and angiogenesis (CD34, VEGF and endothelin) were analysed. Effects on bone were measured by uCT, and TRAP, P1NP, IL-1B, TNF alpha and IL-6 ELISA.ResultsAnakinra significantly reduced growth of MDA-MB-231-IV tumours in bone from 6.50+/3.00mm2 (placebo) to 2.56+/−1.07mm2 (treatment) and 0.63+/−0.18mm2 (preventative). Anakinra also reduced the number of mice that developed bone metastasis from 90% (placebo) to 40% (treatment) and 10% (preventative). Anti-tumour effects were not confined to bone, subcutaneous tumour volumes reduced from 656.68mm3 (placebo) to 160.47mm3 (treatment) and 31.08mm3 (preventative). Anakinra did not increase tumour cell apoptosis but reduced proliferation and angiogenesis in addition to exerting significant effects on the tumour environment reducing bone turnover markers, IL-1B and TNF alpha.ConclusionsOur novel data demonstrate a functional role of IL-1 signalling in breast tumour progression and metastasis, supporting that anakinra could be repurposed for the treatment of breast cancer bone metastasis.

Soy Reduces Bone Turnover Markers in Women During Early Menopause: A Randomized Controlled Trial.

Menopausal estrogen loss leads to an increased bone loss. Soy isoflavones can act as selective estrogen receptor modulators, their role in bone turnover is unclear. The primary outcome was assessing changes in plasma bone turnover markers. The secondary outcomes were assessing changes in cardiovascular risk markers including insulin resistance, blood pressure, and lipid profile. We performed a double-blind randomized parallel study in which 200 women within 2 years after the onset of their menopause were randomized to 15 g soy protein with 66 mg isoflavone (SPI) or 15 g soy protein alone (SP), daily for 6 months. There was a significant reduction in type I collagen crosslinked beta C-telopeptide (βCTX) (bone-resorption marker) with SPI supplementation (0.40 ± 0.17 versus 0.15 ± 0.09 μg/L; p < 0.01) compared to SP supplementation (0.35 ± 0.12 versus 0.35 ± 0.13 μg/L; p = 0.92) after 6 months. There was also a significant reduction in type I procollagen-N-propeptide (P1NP) (bone formation marker) with SPI supplementation (50.5 ± 25.0 versus 34.3 ± 17.6 μg/L; p < 0.01), more marked between 3 and 6 months. Following SPI there was a significant reduction in fasting glucose, fasting insulin, insulin resistance, and systolic blood pressure whereas no significant changes in these parameters was observed with SP. There were no significant changes in fasting lipid profile and diastolic blood pressure with either preparation. There was a significant increase in TSH and reduction in free thyroxine (p < 0.01) with SPI supplementation though free tri-iodothyronine was unchanged. In conclusion, soy protein with isoflavones may confer a beneficial effect on bone health, analogous to the mode of action of antiresorptive agents, albeit to a less magnitude. There was a significant improvement of cardiovascular risk markers, but a significant increase in TSH and reduction in free thyroxine after SPI supplementation indicating a detrimental effect on thyroid function. © 2016 American Society for Bone and Mineral Research.