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Mini-abstract The aim of the current study was to examine the effects of light- to moderate intensity aerobic exercise on bone mineral density (BMD) in postmenopausal osteopenic women by using bone formation and resorption markers. In the current study, P1NP and CTX levels increased in both the exercise and the control group. Summary The aim of the current study was to examine the effects of light- to moderate-intensity aerobic exercise on bone mineral density (BMD) in postmenopausal osteopenic women by using rapidly responsive bone formation and resorption markers. Purpose In this prospective, randomized, controlled, single-blind clinical study, women aged 45–65 years with BMD T scores between − 1 and − 2.5 measured by double X-ray absorptiometry (DXA) were included after evaluation of exclusion criteria and the women were divided into 2 groups: aerobic exercise group and control group (exercise, n  = 25; control, n  = 25). At baseline and at the 12-week follow-up, the serum levels of bone formation and resorption biomarkers, including procollagen type 1 N-terminal propeptide (P1NP), cross-linked C-telopeptide of type I collagen (CTX), osteocalcin, oxidative markers such as malondialdehyde, nonbone-specific total alkaline phosphatase, 25(OH)D3, and parathyroid hormone (PTH), were examined in all patients. Results A statistically significant increase in P1NP and CTX levels was noted in both the exercise and control groups at the 12-week evaluation compared to baseline ( p  > 0.05). Although there was no significant change in osteocalcin levels in the control group ( p  > 0.05), a statistically significant increase was observed in the exercise group ( p  < 0.05). In the exercise group, no significant changes were observed in bone formation or resorption markers, including P1NP, CTX, osteocalcin, and total ALP, or in oxidative stress markers, such as malondialdehyde, compared to those in the control group ( p  > 0.05). Conclusion In conclusion, the current study revealed that regular walking exercise of light to moderate intensity significantly contributes to improvements in pain, walking speed, balance, lower extremity dynamic balance, and activities of daily living in postmenopausal women with osteopenia compared to inactive individuals. Trial registration Clinical Trial Number NCT06866561.

Summary This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. Introduction Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. Methods IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. Results This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. Conclusions This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.

In this randomized trial, women 65 years of age or older who had osteopenia received four infusions of zoledronate or normal saline at 18-month intervals. Zoledronate was associated with a significantly lower risk of fragility fractures than placebo.

In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.

Vitamin E is a strong anti-oxidative stress agent that affects the bone remodeling process. This study evaluates the effect of mixed-tocopherol supplements on bone remodeling in postmenopausal osteopenic women. A double-blinded, randomized, placebo-controlled trial study was designed to measure the effect of mixed-tocopherol on the bone turnover marker after 12 weeks of supplementation. All 52 osteopenic postmenopausal women were enrolled and allocated into two groups. The intervention group received mixed-tocopherol 400 IU/day, while the control group received placebo tablets. Fifty-two participants completed 12 weeks of follow-up. Under an intention-to-treat analysis, vitamin E produced a significant difference in the mean bone resorption marker (serum C-terminal telopeptide of type I collagen (CTX)) compared with the placebo group (−0.003 ± 0.09 and 0.121 ± 0.15, respectively (p < 0.001)). In the placebo group, the CTX had increased by 35.3% at 12 weeks of supplementation versus baseline (p < 0.001), while, in the vitamin E group, there was no significant change of bone resorption marker (p < 0.898). In conclusion, vitamin E (mixed-tocopherol) supplementation in postmenopausal osteopenic women may have a preventive effect on bone loss through anti-resorptive activity.

SummaryMeasurement of bone turnover markers is an alternative way to determine the effects of exercise on bone health. A 10-week group-based step aerobics exercise significantly improved functional fitness in postmenopausal women with low bone mass, and showed a positive trend in reducing resorption activity via bone turnover markers.IntroductionThe major goal of this study was to determine the effects of short-term group-based step aerobics (GBSA) exercise on the bone metabolism, bone mineral density (BMD), and functional fitness of postmenopausal women (PMW) with low bone mass.MethodsForty-eight PMW (aged 58.2 ± 3.5 years) with low bone mass (lumbar spine BMD T-score of −2.00 ± 0.67) were recruited and randomly assigned to an exercise group (EG) or to a control group (CG). Participants from the EG attended a progressive 10-week GBSA exercise at an intensity of 75–85 % of heart rate reserve, 90 min per session, and three sessions per week. Serum bone metabolic markers (C-terminal telopeptide of type 1 collagen [CTX] and osteocalcin), BMD, and functional fitness components were measured before and after the training program. Mixed-models repeated measures method was used to compare differences between the groups (α = 0.05).ResultsAfter the 10-week intervention period, there was no significant exercise program by time interaction for CTX; however, the percent change for CTX was significantly different between the groups (EG = −13.1 ± 24.4 % vs. CG = 11.0 ± 51.5 %, P < 0.05). While there was no significant change of osteocalcin in both groups. As expected, there was no significant change of BMD in both groups. In addition, the functional fitness components in the EG were significantly improved, as demonstrated by substantial enhancement in both lower- and upper-limb muscular strength and cardiovascular endurance (P < 0.05).ConclusionThe current short-term GBSA exercise benefited to bone metabolism and general health by significantly reduced bone resorption activity and improved functional fitness in PMW with low bone mass. This suggested GBSA could be adopted as a form of group-based exercise for senior community.

Key Points Phylogenetic analysis indicates that the bone morphogenetic protein (BMP) pathway is ancient and highly conserved across the animal kingdom Gene duplication and divergence has created a diverse matrix of BMP ligand–receptor pairs that achieve sophisticated control of signalling through variable activity profiles and functional redundancy Members of the BMP superfamily affect almost all aspects of bone, cartilage and joint biology Altered BMP signalling is a major underlying cause of human skeletal disorders Modulation of BMP signalling is emerging as a promising therapeutic strategy for improving bone mass and bone quality, ameliorating diseases of skeletal overgrowth and repairing damage to bones and joints Bone morphogenetic proteins (BMPs) have been implicated in almost all aspects of bone, cartilage and joint biology. Here, Valerie Salazar and colleagues discuss BMP superfamily signalling in the context of skeletal development and joint morphogenesis, and summarize the status of the BMP pathway as a therapeutic target for treating skeletal trauma and disease. Since the identification in 1988 of bone morphogenetic protein 2 (BMP2) as a potent inducer of bone and cartilage formation, BMP superfamily signalling has become one of the most heavily investigated topics in vertebrate skeletal biology. Whereas a large part of this research has focused on the roles of BMP2, BMP4 and BMP7 in the formation and repair of endochondral bone, a large number of BMP superfamily molecules have now been implicated in almost all aspects of bone, cartilage and joint biology. As modulating BMP signalling is currently a major therapeutic target, our rapidly expanding knowledge of how BMP superfamily signalling affects most tissue types of the skeletal system creates enormous potential to translate basic research findings into successful clinical therapies that improve bone mass or quality, ameliorate diseases of skeletal overgrowth, and repair damage to bone and joints. This Review examines the genetic evidence implicating BMP superfamily signalling in vertebrate bone and joint development, discusses a selection of human skeletal disorders associated with altered BMP signalling and summarizes the status of modulating the BMP pathway as a therapeutic target for skeletal trauma and disease.

Multiple myeloma (MM) causes lytic bone lesions due to increased bone resorption and concomitant marked suppression of bone formation. Sclerostin (Scl), an osteocyte-derived inhibitor of Wnt/β-catenin signaling, is elevated in MM patient sera and increased in osteocytes in MM-bearing mice. We show here that genetic deletion of Sost , the gene encoding Scl, prevented MM-induced bone disease in an immune-deficient mouse model of early MM, and that administration of anti-Scl antibody (Scl-Ab) increased bone mass and decreases osteolysis in immune-competent mice with established MM. Sost /Scl inhibition increased osteoblast numbers, stimulated new bone formation and decreased osteoclast number in MM-colonized bone. Further, Sost /Scl inhibition did not affect tumor growth in vivo or anti-myeloma drug efficacy in vitro . These results identify the osteocyte as a major contributor to the deleterious effects of MM in bone and osteocyte-derived Scl as a promising target for the treatment of established MM-induced bone disease. Further, Scl did not interfere with efficacy of chemotherapy for MM, suggesting that combined treatment with anti-myeloma drugs and Scl-Ab should effectively control MM growth and bone disease, providing new avenues to effectively control MM and bone disease in patients with active MM.

Purpose The phase III DATA study compared 6 and 3 years of adjuvant anastrozole following 2–3 years of tamoxifen in postmenopausal breast cancer patients. This pre-planned side-study assessed the relationship between a reduced bone mineral density (BMD) and distant recurrence-free survival (DRFS), and evaluated the effect of bisphosphonates on DRFS. Methods We selected all patients with a BMD measurement within 3 years after randomisation (landmark) without any DRFS events. Kaplan–Meier methods and Cox proportional hazards models were used for analyses. Results Of 1860 eligible patients, 1142 had a DEXA scan before the landmark. The BMD was normal in 436 (38.2%) and showed osteopenia in 565 (49.5%) and osteoporosis in 141 (12.3%) patients. After a median follow-up of 5.0 years from the landmark, neither osteopenia nor osteoporosis (compared with normal BMD) were associated with DRFS in both the 6-year [osteopenia HR 0.82 (95% CI 0.45–1.49), osteoporosis HR 1.10 (95% CI 0.26–4.67)] and the 3-year arm [osteopenia HR 0.75 (95% CI 0.40–1.42), osteoporosis HR 1.86 (95% CI 0.43–8.01)]. Moreover, bisphosphonate use did not impact DRFS. Conclusion No association was observed between a reduced BMD and DRFS. Neither did we observe an impact of bisphosphonates on DRFS.