Fracture is an under-recognized but common complication of diabetes mellitus, with an incidence approaching twofold in type 2 diabetes mellitus (T2DM) and up to sevenfold in type 1 diabetes mellitus (T1DM) compared with that in the general population. Both T1DM and T2DM induce chronic hyperglycaemia, leading to the accumulation of advanced glycosylation end products that affect osteoblast function, increased collagen crosslinking and a senescence phenotype promoting inflammation. Together with an increased incidence of microvascular disease and an increased risk of vitamin D deficiency, these factors reduce bone quality, thereby increasing bone fragility. In T1DM, reduced anabolic stimuli as well as the presence of autoimmune conditions might also contribute to reduced bone mass and increased fragility. Diabetes mellitus is the most common cause of kidney failure, and fracture risk is exacerbated when chronic kidney disease (CKD)-related mineral and bone disorders are superimposed on diabetic changes. Microvascular pathology, cortical thinning and trabecular deterioration are particularly prominent in patients with T1DM and CKD, who suffer more fragility fractures than do other patients with CKD. This Review explores the pathophysiology of bone fragility in patients with diabetes mellitus and CKD and discusses techniques to predict fracture and pharmacotherapy that might reduce fracture risk.

Osteoporosis is the most common skeletal disease worldwide, characterized by low bone mineral density, resulting in weaker bones, and an increased risk of fragility fractures. The maintenance of bone mass relies on the precise balance between bone synthesis and resorption. The close relationship between the immune and skeletal systems, called "osteoimmunology", was coined to identify these overlapping "scientific worlds", and its function resides in the evaluation of the mutual effects of the skeletal and immune systems at the molecular and cellular levels, in both physiological and pathological states. Lipids play an essential role in skeletal metabolism and bone health. Indeed, bone marrow and its skeletal components demand a dramatic amount of daily energy to control hematopoietic turnover, acquire and maintain bone mass, and actively being involved in whole-body metabolism. Statins, the main therapeutic agents in lowering plasma cholesterol levels, are able to promote osteoblastogenesis and inhibit osteoclastogenesis. This review is meant to provide an updated overview of the pathophysiology of bone remodelling cycle, focusing on the interplay between bone, immune system and lipids. Novel therapeutic strategies for the management of osteoporosis are also discussed.

Osteoporosis is a critical public health issue, particularly in the "older" (those aged over 75) and "oldest old" population (those aged 85 and above), who are at a heightened risk for fractures and related complications. This article reviews current osteoporosis treatments tailored for these age groups, emphasizing the balance between efficacy and safety, while considering cost/benefit aspects. We discuss pharmacological therapies available nowadays and their respective benefits and risks in the old population, based on the available literature on the subject. Special attention is given to specific features of this age category, like challenges of polypharmacy, physiological changes associated with age, comorbidities and patient adherence. This paper highlights the need for individualised treatment plans that consider the patient's overall health status, life expectancy and quality of life and the importance of continued innovation and personalized care in managing osteoporosis especially among the "older" population.

Osteoporosis, a common metabolic condition that affects the bones, increases the risk of fractures, thereby diminishing one's quality of life and, in severe cases, can even result in life-threatening conditions. Osteoporosis is becoming increasingly prevalent worldwide as the population ages. Previous research on osteoporosis has focused on skeletal cellular components such as osteoblasts and osteoclasts. The emerging field of "osteoimmunology" has recently been introduced through new research. The concept highlights the critical impact of bone-immune system interactions on osteoporosis progression. The pathogenesis of osteoporosis is significantly influenced by T cells, particularly cytotoxic and helper T cells, which modulate osteoclast differentiation and activity. A crucial aspect of understanding osteoporosis is how T lymphocytes interact with osteoclasts. However, the precise mechanisms underlying T cell-osteoclast crosstalk remain poorly understood. This review systematically examines T cell and osteoclast involvement in osteoimmunology, with a particular focus on their involvement in osteoporosis. It seeks to elucidate the immune mechanisms driving the progression of osteoporosis and identify key molecules involved in T cell-osteoclast interactions. This aims to discover novel molecular targets and intervention strategies to improve early diagnosis and management of osteoporosis. Furthermore, this article will explore the potential of intervening in T cell-osteoclast interactions using conventional therapies, traditional Chinese medicine, immunomodulatory agents, and nanomaterial-based treatments, providing new perspectives for future osteoporosis management.

Osteoporosis is a national health priority, and over six million Australians over the age of 50 years have poor bone health. Fragility fractures due to osteoporosis are associated with an increased morbidity and mortality risk and a high economic cost to the community. It is a chronic condition requiring long-term management. Despite notable advances in pharmacotherapy, large treatment gaps remain. Antiresorptive drugs have been the foundation of treatment; however, their efficacy wanes and rare adverse effects accumulate with prolonged use. Osteoanabolic drugs form new bone and can also restore deteriorated bone microarchitecture, in addition to increasing bone mineral density. Currently, antiresorptive drugs are used as first-line drugs for osteoporosis. However, recent studies have highlighted the superiority of anabolic drugs for fracture reduction over antiresorptives. Furthermore, for patients at very high risk or imminent risk of fracture, the use of sequential therapy with an osteoanabolic medication followed by an antiresorptive is superior to achieving optimal long-term bone health outcomes. This article will discuss the evidence supporting the anti-fracture benefits of osteoanabolic drugs, emphasising their benefits as first-line agents for osteoporosis. Challenges surrounding transitions between osteoanabolic and antiresorptive medications are also discussed, highlighting considerations for the optimal treatment sequence with a focus on recent updates to Australian prescribing recommendations and PBS requirements.

Wear-induced osteolysis is a leading cause of late failure in total hip arthroplasty (THA). Denosumab, a RANKL inhibitor, suppresses osteoclast activity and may slow osteolytic progression. This feasibility study aimed to assess the practicality of conducting a randomized, double-blind, placebo-controlled trial evaluating Denosumab's effect on periprosthetic osteolysis in asymptomatic THA patients.

Twelve patients were enrolled; ten completed follow-up. No significant difference in lesion volume change was observed between groups (Denosumab: +1.53 cm³; Placebo: +0.49 cm³). Secondary clinical outcomes also showed no notable differences. The trial protocol, recruitment, treatment, and follow-up were feasible, though slow enrollment limited statistical power. This study demonstrates the feasibility of a larger trial investigating Denosumab for osteolysis prevention.

Clinicaltrails.gov, NCT02299817. Registered 20 November 2014. https://www.

gov/study/NCT02299817?term=Denosumab%20for%20Treating%20Periprosthetic%20Osteolysis.%26;rank=1.

Osteoporosis is a chronic metabolic bone disease characterized by progressive bone loss and structural deterioration, increasing fracture risk and morbidity. As the global population ages, its incidence is rising, underscoring the urgent need for more effective prevention and treatment strategies.

This review synthesizes the latest evidence and guidelines from leading international societies, establishing a contemporary framework for osteoporosis pharmacotherapy. It emphasizes best practices and explores future directions in treatment optimization and fracture prevention.

To optimize outcomes, enhancing early detection, refining treatment strategies, and prioritizing patient-centered care are essential. Improving diagnosis through increased use of bone mineral density (BMD) assessments and identifying secondary causes are critical steps to addressing underdiagnosis, particularly in men. Pharmacotherapies play a vital role in management; while bisphosphonates serve as a cost-effective first-line treatment, denosumab and anabolic agents like Teriparatide and romosozumab are essential alternatives for high-risk patients. Future directions in osteoporosis management emphasize advancing treatment strategies through novel drug targets and innovative delivery systems, alongside personalized medicine approaches considering individual genetic and comorbidity profiles. Enhanced adherence strategies and further research into combination therapies and monitoring tools are crucial for improving prevention and treatment outcomes, ultimately reducing the fragility fracture burden worldwide.

Cystic fibrosis-related bone disease (CFBD) is a common endocrinopathy in people living with cystic fibrosis (CF) that is complex and multifactorial in origin. People with CF experience high rates of progressive bone density loss and increased fracture risk. Focus on prevention and treatment of CFBD is of increasing importance in a now aging CF population. This review will discuss current practices in CFBD, gaps in knowledge, and potential future studies with the goal of advancing the clinical care of patients with CFBD.

Realizing the potential of HIV prevention options requires understanding product tolerability across diverse groups vulnerable to HIV acquisition. Gender minority (GM) individuals are understudied in clinical trials.

HVTN 704/HIV Prevention Trials Network 085, a phase 2b randomized HIV prevention trial, enrolled MSM and transgender participants from Brazil, Peru, Switzerland, and the United States to receive an infusion every 8 weeks (10 total) of VRC01 30 mg/kg, VRC01 10 mg/kg, or placebo. Solicited adverse events (AEs) were recorded for 3 days after each infusion.

Gender was defined by self-report and sex assigned-at-birth. Multivariate mixed logistic models were used to estimate the association between gender (cisgender men [CM] vs. GM participants [transgender women, transgender men, or another gender]) and solicited AE frequency and severity.

GM participants reported more solicited AEs than CM among all participants (adjusted OR 1.59, 95% CI: 1.20 to 2.10, P = 0.001) and among placebo recipients (1.72, 1.05 to 2.81, P = 0.031). The severity of solicited AEs (occurrence of grade 2 and higher event) did not significantly differ overall (1.83, 0.79 to 4.20, P = 0.174) or among placebo recipients (3.05, 0.76 to 12.32, P = 0.112). Grade 2 events were reported after 1% and 2% of total infusions among CM and GM participants, respectively. Grade 3-4 events were rare overall (<0.1%). Completion of 10 infusions was high (78.6%) and slightly higher in CM (79.2%) than GM participants (73%).

This is the first report of associations between gender and solicited AEs after monoclonal antibody infusion. GM participants reported more events; severity was low. HIV prevention trials must engage and support GM individuals to best evaluate tolerability of novel agents.

Despite a high burden of osteoporosis and minimal trauma fractures worldwide, there is still a treatment gap in timely diagnosis and optimal treatment. There is also a lack of international consensus and guidelines on the management of bone fragility in premenopausal women. This review article provides an overview of the current understanding of factors impacting women's bone health across the adult lifespan, as well as dilemmas in the diagnosis, assessment and management of osteoporosis in premenopausal and postmenopausal women, premature ovarian insufficiency and bone health following breast cancer.

The objective of this retrospective, database study was to characterize the rate, magnitude and timeline of increases in parathyroid hormone (PTH) levels post-denosumab (DMAb) vs. zoledronic acid (ZA) injection in patients with osteoporosis and near normal baseline PTH. Included were osteoporotic females, ≥50 years, initiating treatment with 60 mg DMAb or 5 mg ZA. PTH levels within 6-months post-DMAb or 12-months post-ZA injection were extracted from the electronic database of a 4.5 million-member health maintenance organization. The indication for PTH measurements was unknown. Exclusion criteria were creatinine >2 mg/dL, vitamin D < 50 nmol/L or parathyroid hormone level > 1.5 × upper limit of normal (ULN). Among 3317 women, 1992 received DMAb and 1325 ZA. The DMAb group was older (73.3 ± 8.5 vs. 69.8 ± 8.6 years, p < 0.001) and more patients treated with DMAb compared with patients treated with ZA had prior non-vertebral fractures (7.7 % vs. 5.2 %, p < 0.01) and had previously been treated with osteoporosis medication (56.3 % vs. 50.3 %, p < 0.001). Among the patients, 14.9 % had at least one post-treatment PTH > 1.5 ULN. Of 7273 post-treatment PTH tests, 62.6 % were within normal limits, while 24.8 % were mildly elevated at 1.01-1.5 ULN. Two-months after both treatments, >1.5 ULN PTH levels peaked at ∼20 %. Elevated PTH was associated with eGFR < 60 mL/min/1.73 m2 and comorbidities. In conclusion, most PTH levels post-DMAb or ZA in osteoporotic patients with baseline PTH < 1.5 ULN, were within normal range. PTH increased to >1.5 ULN in 14.9 % of patients; peaking in the first 2-months post-treatment and declining thereafter. Elevated PTH may be related to anti-resorptive effects and is not medication specific. PTH measurements in the first few months post-DMAb and ZA therapy should be limited.

Discontinuation of denosumab can result in rebound bone loss and increased vertebral fracture risk. In residents of long-term care communities (LTCCs) with osteoporosis, there is limited data on managing the risks after discontinuation. We investigated the impact of a single dose of zoledronic acid on bone density and microarchitecture following two years of denosumab treatment. In an open-label, one-year extension study following a two-year double-blind, placebo-controlled, randomized clinical trial, 39 older adults aged 65 years and above, who were residents of LTCCs and participants in the PROUD (PReventing Osteoporosis Using Denosumab) trial, received a single 5 mg dose of zoledronic acid after completing four doses of denosumab 60 mg during the PROUD trial. We aim to evaluate the effects of a single 5 mg dose of zoledronic acid on bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius, as well as on the spine trabecular bone score (TBS), over a one-year period. Additionally, we surveyed patients for fractures. Our study included 27 women and 12 men, with a mean age of 81.5 years. Twelve months after the administration of zoledronic acid, the mean percent changes from the end of the denosumab trial showed no significant decline in any of the BMD sites in both women and men. In women, the mean percent changes were as follows: spine 0.97 (95% CI: -0.7 to 2.7, p = 0.242) and total hip -0.10 (95% CI: -2.3 to 2.1, p = 0.927). In men, the changes were -0.32 (95% CI: -3.7 to 3.1, p = 0.832) for the spine and 1.79 (95% CI: -0.7 to 4.3, p = 0.139) for the total hip. These findings indicate no evidence of rebound bone loss. In women, TBS significantly increased by 3.9% (95% CI: 0.8 to 5.8, p = 0.007), suggesting improved bone microarchitecture. In men, there was a trend toward improvement in TBS, with an increase of 3.3% (95% CI: -4.0 to 13.0, p = 0.054). There were no reported fragility fractures among participants during the post-denosumab period. In residents of LTCCs with osteoporosis receiving a single 5 mg dose of zoledronic acid following two years of denosumab, we found no evidence of a loss in BMD or TBS. Further, participants experienced enhanced bone microarchitecture.

Osteoporosis requires life-long management. This involves the use of different drugs in various sequences followed by long-term maintenance therapy. This review highlights the important transitions among osteoporosis therapies and outlines a strategy of intermittent bisphosphonate therapy for long-term maintenance.

Over the past few years, the effects and limitations of long-term treatment with bisphosphonates and denosumab have become apparent as have several key factors in the sequential use of anti-remodeling drugs and osteoanabolic agents. Strategies for transitions from estrogen, bisphosphonates, denosumab and the bone-forming drugs will be discussed, based on extant evidence, clinical experience and expert opinion. By appropriate selection of both the initial and subsequent drugs for the prevention and treatment of osteoporosis, therapeutic benefits can be optimized and safety issues minimized. Developing a strategy for long-term maintenance of the benefits of the initial therapies can provide a life plan for managing patients with osteoporosis.

Background: Denosumab, a receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor, demonstrates therapeutic effects beyond traditional osteoporosis management through the RANK/RANKL/osteoprotegerin pathway. Methods: This narrative review analyzed 37 studies (2018-2024) examining denosumab's broader physiological effects and clinical applications. Results: Long-term safety data spanning 10 years showed sustained fracture prevention efficacy with a favorable benefit/risk profile. Compared to bisphosphonates, denosumab demonstrated superior outcomes in bone mineral density improvement and fracture risk reduction, particularly in elderly and frail populations. It enhanced muscular function by improving appendicular lean mass and grip strength while reducing fall risk. The drug showed potential cardiovascular benefits through its effects on cardiac and smooth muscle function. Notably, denosumab use was associated with reduced Type II diabetes mellitus risk through improved glucose metabolism. Additionally, it demonstrated promise in osteoarthritis treatment by suppressing osteoclast activity and chondrocyte apoptosis. While there are multisystem benefits, vigilance is required regarding adverse events, including hypocalcemia, infection risk, cutaneous reactions, and osteonecrosis of the jaw. Conclusions: Denosumab exhibits potential benefits in bone and systemic metabolism. Further research is needed to fully understand its therapeutic potential beyond osteoporosis and optimize clinical applications across different populations.

Rebound bone loss following denosumab discontinuation is an important barrier in the effective long-term treatment of skeletal disorders. This is driven by increased osteoclastic bone resorption following the offset of RANKL inhibition, and sequential osteoclast-directed therapy has been utilized to mitigate this. However, current sequential treatment strategies intervene following the offset of RANKL inhibition and this approach fails to consistently prevent bone loss. Our previous work, using a mouse model of denosumab discontinuation, has shown that the processes that drive the rebound phenomenon occur earlier than when bone loss is detected, namely a rise and overshoot in serum tartrate-resistant acid phosphatase (TRAP). We identified that these changes in serum TRAP may provide an earlier window of opportunity to intervene with sequential therapy following RANKL inhibition withdrawal. Here, we show that early treatment with zoledronate (10 mg/kg, 3 wk following the last dose of OPG:Fc), preceding the rise and overshoot in serum TRAP, effectively mitigates rebound bone density loss through preventing the overshoot in serum TRAP. Further, we show that multiple doses of zoledronate (early treatment and during anticipated BMD loss) is superior in consolidating bone density gains made with RANKL inhibition and preventing rebound BMD loss as measured by DXA. Importantly, we demonstrate the efficacy of early and multi-dose zoledronate strategy in preventing bone loss in both growing and skeletally mature mice. MicroCT analysis showed improved trabecular bone structure in both the femur and lumbar vertebrae with zoledronate treatment compared with control. These increases in bone mass translated to increased fracture resistance in skeletally mature mice. This work provides a novel approach of early and multi-dose sequential treatment strategy following withdrawal of RANKL inhibition, contributing valuable insight into the clinical management of patients who discontinue denosumab therapy.

Upon denosumab discontinuation, an observed overshoot phenomenon in bone turnover may occur, potentially leading to a reduction in bone mineral density and the occurrence of vertebral fractures. Several theories have been proposed to explain this phenomenon, one of which is that osteoclast precursors might be accumulating during treatment. Our aim was to study the effects of denosumab on osteoclast precursors in postmenopausal women. This cross-sectional observational study included 30 postmenopausal women with osteopenia or osteoporosis, divided into 2 groups: 15 treated with denosumab (mean duration 4 years, range 6 months-9 years) and 15 treatment-naïve controls. Peripheral blood mononuclear cells were isolated from whole blood and were stained for CD14, MCSFR, CD11b, and TNFRII. Osteoclast precursors (CD14+/MCSFR+, CD14+/CD11b + OR CD14+/TNFRII+) were identified with fluorescent activated cell sorting. The proportion of osteoclasts was determined by calculating their percentage of the total cell population in each whole blood sample. To confirm the expected suppression of bone turnover in the subjects treated with denosumab, we measured serum PINP, CTX, and TRACP5b. Denosumab-treated patients exhibited a significantly higher count of CD14+/CD11b + osteoclast precursors compared with controls (median 4% vs 0.75%, p=.011). There was no correlation with the duration of treatment. Bone turnover markers were significantly lower in the group treated with denosumab than controls. Our findings indicate an increase in osteoclast precursors, which could explain the overshoot phenomenon observed after discontinuing denosumab.

The present systematic review investigates whether different doses of vitamin D and calcium supplementation in women with postmenopausal osteoporosis undergoing antiresorptive therapy have an association with BMD (spine, hip, femur neck), serum markers of osteoporosis (bone-ALP, NTX, CTX), the rate of pathological vertebral and non-vertebral fractures, adverse events, and mortality. This systematic review was conducted according to the PRISMA 2020 guidelines. PubMed, Google Scholar, Embase, and Scopus databases were accessed in September 2024. All randomised clinical trials (RCTs) comparing two or more treatments for postmenopausal osteoporosis supplemented with vitamin D and/or calcium were accessed. Only studies that indicated daily vitamin D and/or calcium supplementation doses were accessed. Data from 37 RCTs (43,397 patients) were retrieved. Patients received a mean of 833.6 ± 224.0 mg and 92.8 ± 228.7 UI of calcium and vitamin D supplementation, respectively. The mean length of the follow-up was 25.8 ± 13.3 months. The mean age of the patients was 66.4 ± 5.6 years, and the mean BMI was 25.2 ± 1.6 kg/m2. There was evidence of a statistically significant negative association between daily vitamin D supplementation and gastrointestinal adverse events (r = - 0.5; P = 0.02) and mortality (r = - 0.7; P = 0.03). No additional statistically significant associations were evidenced. In postmenopausal women who undergo antiresorptive treatment for osteoporosis, vitamin D was associated with a lower frequency of gastrointestinal adverse events and mortality. Calcium supplementation did not evidence an association with any of the endpoints of interest.Level of evidence Level I, systematic review of RCTs.

Bone metabolism is highly regulated, and microRNAs (miRs) can contribute to this process. Among them, miR-125b is well known to enhance osteoporosis and reduce osteogenic differentiation of human mesenchymal stem cells (hMSCs). In this work, we aim to evaluate and understand how miR-125b modulates mineralization of hMSCs in two different in vitro models. Cells were cultured in dexamethasone or calcium medium and transfected with miR-125b mimic. Exposure to dexamethasone or calcium medium increased the mineralization of hMSCs and was associated with decreased miR-125b expression. Transfection of miR-125b mimic in dexamethasone-treated cells increased mineralization, while it decreased it in calcium-treated cells. Levels of osteogenic markers presented the same difference. We identified STAT3, p53, and RUNX2 as direct targets of miR-125b in hMSCs. While these targets remained identical in both treatments, their modulation after transfection was different. We showed that miR-125b mimicking differentially modulated the expression of the miR-199a/214 cluster, probably via STAT3/miR-199a/214 and p53/miR-214 pathways. In conclusion, miR-125b affinity for targets implicated in bone remodeling changed depending on the in vitro models used to induce mineralization and led to opposite physiological effects. This work shows the complexity of drugs such as dexamethasone and opens the door for new in vitro models of mineralization.

Denosumab produces a continuous increase in bone mineral density over ten years, associated with a low risk of vertebral and non-vertebral fractures. Denosumab is well tolerated and easy to manage in daily clinical practice. For all these reasons, this treatment has a huge success. On the other hand, discontinuation of treatment is associated with a severe rebound effect including a sharp increase in bone turnover markers, loss of the bone density gained and a risk of nearly 20% of multiple vertebral fractures in postmenopausal women. High doses of potent bisphosphonates are needed to maintain bone turnover markers in the low range of premenopausal women, to mitigate this rebound effect. Prolonged treatment with denosumab is associated with a greater rebound effect and increases the risk of an early rebound effect. The occurrence of rare side effects such as osteonecrosis of the jaw or atypical femoral fracture, as well as the onset of severe renal failure, leave clinicians at a therapeutic impasse. Continuing denosumab or switching to bisphosphonates remains suboptimal and, currently, no evidence clarifies the optimal treatment approach for these patients. The aim of this review is to give a very practical clinical approach to the use of denosumab (duration of treatment), and to the management of rebound effect and possible adverse effects.

Rebound vertebral fractures (VFs) after denosumab (Dmab) withdrawal have been documented, highlighting the need for further research into this phenomenon and the importance of a well-planned strategy for discontinuing Dmab.

From the TriNetX US network, we enrolled osteoporosis patients aged 50 years or older who had withdrawn from at least 2 doses of Dmab and compared them with a matched cohort who had received at least 1 dose of zoledronate (ZOL) before discontinuation. We analyzed hazard ratios (HRs) with 95% confidence intervals (CIs) and conducted Kaplan-Meier analyses, along with subgroup analyses, drug discontinuation modification, and sensitivity analyses.

After matching propensity scores (n = 10 422) between the 2 cohorts (Dmab: 11 104 and ZOL: 15 976), we found that the risks of VFs (HR = 1.479, 95% CI = 1.222-1.789) and its subcategories-thoracic (1.309, 1.023-1.674), lumbar (1.865, 1.425-2.440), and collapsed fractures (1.928, 1.462-2.542)-as well as all-cause mortality (1.588, 1.475-1.710), were significantly higher in the Dmab group compared with the ZOL group. Stratified analyses showed increased VF risks in Dmab patients who were female, aged 50-64, 65 years or older, and white, regardless of fracture history compared with those using ZOL.

After adjusting for drug discontinuation, Dmab showed an increased risk of VFs within the first 2 years, contributing to an elevated overall mortality risk. Sensitivity analyses revealed consistent results across different regions.

Denosumab is approved for treating hypercalcemia of malignancy, but data on its efficacy for hypercalcemia related to primary hyperparathyroidism (PHPT) are limited.

To compare the efficacy and safety of denosumab with zoledronic acid in PHPT-related hypercalcemia.

We retrospectively collected data from 29 PHPT patients with moderate/severe hypercalcemia (corrected serum calcium [CSC] ≥ 3.0 mmol/L) treated with denosumab (60 or 120 mg; Dmab group) and CSC-matched 29 PHPT patients treated with zoledronic acid (4 mg; ZA group). The primary efficacy outcome was the change of CSC (ΔCa), while secondary outcomes included the response proportion, time to response, and duration of response. Safety data were also collected.

Both groups showed significant reductions in CSC levels (Dmab: 3.37±0.37mmol/L to 2.64±0.33mmol/L, p＜0.01; ZA: 3.41±0.32mmol/L to 2.57±0.23mmol/L, p＜0.01), with similar ΔCa. In the Dmab group, 82.8% (24/29) responded with CSC levels below 3.0 mmol/L, and 72.4% (21/29) achieved complete response (CR, serum CSC less than 2.7mmol/L), comparable to the ZA group. The time to CR was shorter for ZA (3.0 vs. 7.0 days, p<0.01), while Dmab had a longer duration of response (19.0 vs. 13.0 days, p=0.02). Hypocalcemia occurred in 6.9% (2/29, both with Chronic Kidney Disease stage 3b) of Dmab patients, while none in the ZA group.

A single 60 mg dose of denosumab effectively reduces serum calcium levels in PHPT patients with moderate/severe hypercalcemia, at least maintaining efficacy for a median of nearly 3 weeks without serious adverse events.

Most subjects in osteoporosis clinical trials were women with postmenopausal osteoporosis and while bridging studies (BMD endpoint) provide an expectation that osteoporosis medications will reduce fracture risk in men. This real-world study shows direct evidence of fracture risk reduction among men with osteoporosis (36% of hip fracture reduction with denosumab).

Direct evidence for fracture risk reduction of medications used among men with osteoporosis is very limited. This study aims to evaluate the real-world effectiveness of denosumab in reducing fracture risk.

This study included 13,797 men aged ≥ 50 years with osteoporosis who had initiated denosumab in Taiwan. Taiwan's National Health Insurance Research Database includes all Taiwan residents' complete health claim data. We compared incidence rates of clinical fractures between patients on denosumab 60 mg subcutaneously every 6 months (on-treatment) and patients ending therapy after one administration (off-treatment). Propensity score (PS) analysis, adjusting for measured differences at baseline covariates, was used to estimate the adjusted hazard ratio using a Cox proportion hazards model.

During follow-up, 248 hip fracture events occurred. The crude incidence rates of hip fracture were 1.13 events and 1.73 events per 100 person-years in on-treatment and off-treatment cohorts, respectively. After PS inverse probability of treatment weighting, the cohorts achieved balance in all 59 covariates. The hip fracture event rate was lower in on-treatment cohort versus off-treatment cohort by 36% (hazard ratio, 0.64 [95% CI 0.50-0.83]). A similar magnitude of risk reduction was observed in clinical vertebral and nonvertebral fractures. A series of sensitivity analysis, including a validation analysis using a-million individual health records, demonstrated that unmeasured confounders were not suggested to impact study result interpretation.

In this large, real-world study evaluating denosumab treatment among men with osteoporosis, the observed fracture risk reductions were consistent with the available risk reductions demonstrated in clinical trials among women with postmenopausal osteoporosis.

Osteoporosis is a prevalent metabolic bone disease. Osteoporotic fractures can lead to severe functional impairment and increased mortality. Long noncoding RNA H19 has emerged as a pivotal player in bone remodeling, serving both as a biomarker and a regulator. While previous research has elucidated H19's role in promoting osteogenic differentiation through diverse mechanisms, its involvement in osteoclast differentiation remains largely unknown.

In this study, we used lentiviral vectors to stably overexpress or knockdown H19 in RAW264.7 cell lines. Quantitative reverse polymerase chain reaction, Western blot, tartrate resistant acid phosphatase staining and bone resorption assay were performed to assess the level of osteoclast differentiation and bone resorption capacity. And fluorescence in situ hybridization, dual-luciferase reporter and RNA immunoprecipitation were used to explore the specific mechanism of H19 regulating osteoclast differentiation in vitro. Then, ovariectomized osteoporosis models in wild type mice and H19 knockout mice were conducted. And micro-CT analysis, HE staining, and immunohistochemistry were performed to verify the mechanism of H19 regulating osteoclast differentiation in vivo. Bone marrow derived monocytes and bone mesenchymal stem cells were extracted from mice and assayed for osteoclastic and osteogenic-related assays, respectively.

In vitro, H19 promoted osteoclast differentiation and bone resorption of RAW264.7 cells, while miR-29c-3p inhibited them. Both H19 and cathepsin K were the target genes of miR-29c-3p. In vivo, H19 knockout mice have increased femur bone mineral density, decreased osteoclast formation, and reduced cathepsin K expression. MiR-29c-3p agomir could increase bone mineral density in osteoporotic mice on the premise of H19 knockout.

H19 upregulates cathepsin K expression through sponging miR-29c-3p, which promoting osteoclast differentiation and enhancing bone resorption. This underscores the potential of H19 and miR-29c-3p as promising biomarkers for osteoporosis.

This study evaluated the efficacy, safety, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of SB16 versus reference denosumab (DEN) up to 18 months in postmenopausal osteoporosis (PMO) patients, and assessed outcomes after switching from DEN to SB16 compared to those who continued with DEN or SB16.

457 PMO patients were initially randomized, with 407 re-randomized at Month 12 to either continue DEN (DEN+DEN), switch to SB16 (DEN+SB16), or continue SB16 (SB16 + SB16) through Month 18. Efficacy was assessed by the percent change from baseline in bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck. Safety, PD, PK, and immunogenicity were evaluated throughout the study period.

Mean percent changes from baseline in lumbar spine, total hip, and femoral neck BMD at Month 18 were comparable across treatment groups, indicating comparable efficacy between SB16 and DEN. The mean percent change in lumbar spine BMD was 6.8 % (SB16 + SB16), 6.2 % (DEN+SB16), and 6.8 % (DEN+DEN). Total hip BMD increased by 4.4 %, 3.5 %, and 4.0 %, and femoral neck BMD by 3.4 %, 3.1 %, and 2.7 % for SB16 + SB16, DEN+SB16, and DEN+DEN, respectively. Safety profiles were similar among groups, with no new safety concerns identified after switching. Only one patient in the DEN+SB16 group developed non-neutralizing anti-drug antibodies by Month 18, indicating a low immunogenicity risk for SB16.

Switching from DEN to SB16 demonstrated comparable efficacy, safety, PD, PK, and immunogenicity in PMO patients relative to those who continued DEN. SB16 was well tolerated over 18 months, demonstrating comparable outcomes to DEN.

In patients receiving long-term treatment with denosumab, denosumab discontinuation via sequential treatment with zoledronate, resulted in a minor decrease in bone mass density (BMD) of 0-2.5% within the first year and stabile BMD in the second year, thus showing that repeated treatments with zoledronate limit the loss of BMD, when discontinuing denosumab.

Discontinuing denosumab (DMAb) rapidly decreases bone mineral density (BMD) and increases the risk of multiple vertebral fractures. We wanted to examine if the recommendation stated in the ECTS position paper on DMAb discontinuation can prevent the bone loss in a clinical setting.

We conducted a retrospective cohort study based on medical records of patients referred for DMAb discontinuation. We administered zoledronate (ZOL) 6 months after the last DMAb injection and 3, 6, 12, and 24 months thereafter if p-C-terminal collagen crosslinks (CTX) increased above 0.5 μg/l or BMD decreased (≥ 5% at the hip, ≥ 3% at the spine) at months 12 and 24.

We included 66 women and men discontinuing DMAb after a mean treatment duration of 6.7 ± 2.7 (mean ± SD) years. BMD decreased 12 months after the initial ZOL treatment by 2.5 ± 4.2% and 1.9 ± 2.5% at the LS and TH, respectively (n = 44) (p ≤ 0.001 for all). There was no significant change in FNBMD (0.0 ± 5.1) (p > 0.05). No significant change in BMD was seen from month 12 to month 24 at any site (p > 0.05 for all). Thirty percent and twenty-two percent of patients experienced flu-like symptoms after the first and second ZOL infusion. No fractures occurred during the study period.

Adhering to the recommendation in the ECTS position statement, a mean of 3 infusions of ZOL limited the bone loss 12 and 24 months after DMAb discontinuation, thereby preserving most of the BMD gained during DMAb treatment. The frequent occurrence of flu-like symptoms after ZOL proves to be a challenge, showing that routine prophylaxis against acute phase responses should be considered in patients treated with ZOL after discontinuing DMAb.

This is the executive summary of a work by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) (Nicholas Fuggle et al. in Drugs, 2024).

Osteoporosis represents a major healthcare concern. The development of novel treatments presents challenges due to the limited cost-effectiveness of clinical trials and ethical concerns associated with placebo-controlled trials. Computational models for the design and assessment of biomedical products (In Silico Trials) are emerging as a promising alternative. In this study, a novel In Silico Trial technology (BoneStrength) was applied to replicate the placebo arms of two concluded clinical trials and its accuracy in predicting hip fracture incidence was evaluated. Two virtual cohorts (N = 1238 and 1226, respectively) were generated by sampling a statistical anatomy atlas based on CT scans of proximal femurs. Baseline characteristics were equivalent to those reported for the clinical cohorts. Fall events were sampled from a Poisson distribution. A multiscale stochastic model was implemented to estimate the impact force associated to each fall. Finite Element models were used to predict femur strength. Fracture incidence in 3 years follow-up was computed with a Markov chain approach; a patient was considered fractured if the impact force associated with a fall exceeded femur strength. Ten realizations of the stochastic process were run to reach convergence. Each realization required approximately 2500 FE simulations, solved using High-Performance Computing infrastructures. Predicted number of fractures was 12 ± 2 and 18 ± 4 for the two cohorts, respectively. The predicted incidence range consistently included the reported clinical data, although on average fracture incidence was overestimated. These findings highlight the potential of BoneStrength for future applications in drug development and assessment.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious, debilitating condition of the jaw bones. Dental extraction is the most significant independent risk factor for MRONJ. This interim study aimed to evaluate the demographics, medical data and outcomes of patients at risk for MRONJ who underwent dental extractions in a dedicated MRONJ clinic following a risk reduction protocol at a large public dental clinic in New South Wales Health.

A retrospective study analysed demographic and clinical data of patients at risk for MRONJ who underwent dental extractions between March 2020 and April 2024.

Data from 329 at-risk patients who underwent 836 dental extractions were included. Most patients were women (75.1%) with a median age of 74 years (IQR 67-80). The primary indication for medications was osteoporosis (85.4%), with Denosumab being the most frequently prescribed (66.9%). Eighteen patients (5.5%) developed MRONJ at 8 weeks of follow-up. Patients categorized as high-risk had a higher incidence of MRONJ (72.2%) compared to the low-risk group (22.2%).

This study is the first retrospective audit carried out after implementing preventive protocols in this dedicated MRONJ clinic. The higher incidence of MRONJ in patients classified as 'high risk' underscores the importance of considering individual risk factors in their treatment.

Osteoporosis treatments reduce fracture risk but cannot fully eliminate it, and the concept of treatment failure (TF) or inadequate clinical response (ICR) remains debated.

The TAILOR study aims to assess the prevalence of ICR and TF in osteoporotic women undergoing active drug treatment for postmenopausal osteoporosis.

TAILOR is a retrospective study conducted in an Italian outpatient service. We included 415 patients with at least 12 months of treatment and up to 10 years, examining clinical characteristics predicting TF and ICR. TF was defined as the occurrence of two fragility fractures while on treatment or one fracture plus lack of variation BMD and ICR as the occurrence of a new osteoporotic fracture in treated patients according to previous literature.

Seventy-two patients experienced fractures during the follow-up, of those, 26 (36%) were classified as TF. The clinical characteristics of patients with fractures were similar to those without, except for a longer postmenopausal period and lower lumbar spine bone mineral density (BMD). Postmenopausal period was significantly longer in TF compared to ICR patients. However, no significant differences were found in baseline fractures, prescribed treatments, or fracture-free survival curves with age, postmenopausal period, BMD, and previous treatments. The clinical follow-up was longer in ICR and TF patients.

TAILOR shows a higher prevalence of ICR and TF (17.3%) compared to randomized controlled trials and real-world data, with 36% of fractures during follow-up classified as TF. Clinician decisions often led to changes in antiosteoporosis treatment, particularly in TF cases, though TF diagnosis was rarely cited explicitly in medical records.

TAILOR emphasizes that common clinical factors do not reliably predict ICR and TF. The findings highlight the complexity of determining an algorithm for the best treatment approach to prevent TF and ICR.

The aim of this study is to evaluate the bone scintigraphy (BS) and positron emission tomography (PET) in the early diagnosis of medication-related osteonecrosis of the jaws (MRONJ) and their possible use in the identification of patients at risk for MRONJ.

Thirty-one patients treated with ONJ-related drugs and who had undergone BS or PET for the evaluation of bone lesions were included in the study. The jaws of each patient were divided into four areas. For each area, the presence of pathological tracer uptake was evaluated and related to the eventual MRONJ development. Sensitivity, specificity, and predictive values of both techniques were determined. The latency from the finding of pathological tracer uptake in BS or PET to the clinical diagnosis of MRONJ and the odds ratio were also calculated.

Sensitivity and specificity of BS for MRONJ prediction were, respectively, 83.3 and 87.5%. Positive and negative predictive values were, respectively, 73.2 and 92.8%. The odds ratio was 35. Sensitivity of PET was 33.3%, specificity was 94.9%, and positive and negative predictive values were 70.0 and 80.0%, respectively. The odds ratio was 9.333. All values were statistically significant.

BS and PET may be accurate techniques for an early prediction of MRONJ.

Osteoporotic fractures are associated with psychological distress, subsequent fractures, loss of independence, reduced ability to perform activities of daily living, and death.

The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the evidence on the benefits and harms of screening for osteoporosis to prevent fractures in adults 40 years or older with no known diagnosis of osteoporosis or history of fragility fracture.

Adults 40 years or older without known osteoporosis or history of fragility fractures.

The USPSTF concludes with moderate certainty that screening for osteoporosis to prevent osteoporotic fractures in women 65 years or older has moderate net benefit. The USPSTF concludes with moderate certainty that screening for osteoporosis to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk has moderate net benefit. The USPSTF concludes that the evidence is insufficient and the balance of benefits and harms for screening for osteoporosis to prevent osteoporotic fractures in men cannot be determined.

The USPSTF recommends screening for osteoporosis to prevent osteoporotic fractures in women 65 years or older. (B recommendation) The USPSTF recommends screening for osteoporosis to prevent osteoporotic fractures in postmenopausal women younger than 65 years who are at increased risk for an osteoporotic fracture as estimated by clinical risk assessment. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement).

Fragility fractures result in significant morbidity.

To review evidence on osteoporosis screening to inform the US Preventive Services Task Force.

PubMed, Embase, Cochrane Library, and trial registries through January 9, 2024; references, experts, and literature surveillance through July 31, 2024.

Randomized clinical trials (RCTs) and systematic reviews of screening; pharmacotherapy studies for primary osteoporosis; predictive and diagnostic accuracy studies.

Two reviewers assessed titles/abstracts, full-text articles, study quality, and extracted data; when at least 2 similar studies were available, meta-analyses were conducted.

Hip, clinical vertebral, major osteoporotic, and total fractures; mortality; harms; accuracy.

Three RCTs and 3 systematic reviews reported benefits of screening in older, higher-risk women. Two RCTs used 2-stage screening: Fracture Risk Assessment Tool estimate with bone mineral density (BMD) testing if risk threshold exceeded. One RCT used BMD plus additional tests. Screening was associated with reduced hip (pooled relative risk [RR], 0.83 [95% CI, 0.73-0.93]; 3 RCTs; 42 009 participants) and major osteoporotic fracture (pooled RR, 0.94 [95% CI, 0.88-0.99]; 3 RCTs; 42 009 participants) compared with usual care. Corresponding absolute risk differences were 5 to 6 fewer fractures per 1000 participants screened. The discriminative accuracy of risk assessment instruments to predict fracture or identify osteoporosis varied by instrument and fracture type; most had an area under the curve between 0.60 and 0.80 to predict major osteoporotic fracture, hip fracture, or both. Calibration outcomes were limited. Compared with placebo, bisphosphonates (pooled RR, 0.67 [95% CI, 0.45-1.00]; 6 RCTs; 12 055 participants) and denosumab (RR, 0.60 [95% CI, 0.37-0.97] from the largest RCT [7808 participants]) were associated with reduced hip fractures. Compared with placebo, no statistically significant associations were observed for adverse events.

Screening in higher-risk women 65 years or older was associated with a small absolute risk reduction in hip and major fractures compared with usual care. No evidence evaluated screening with BMD alone or screening in men or younger women. Risk assessment instruments, BMD alone, or both have poor to modest discrimination for predicting fracture. Osteoporosis treatment with bisphosphonates or denosumab over several years was associated with fracture reductions and no meaningful increase in adverse events.

Osteoporosis is defined as a condition of increased risk of fracture due to decreased bone strength. In developed countries, the number of patients with osteoporosis and fragility fractures has been increasing in recent years due to the growing elderly population, posing a social challenge not only to fracture patients and their families but also to the social healthcare economy. Osteoporosis can be divided into two categories: primary osteoporosis caused by aging or menopause and secondary osteoporosis caused by metabolic or inflammatory diseases or drugs such as glucocorticoids. The majority of patients have primary osteoporosis, and the pathogenesis of postmenopausal osteoporosis and factors associated with fragility fractures in the elderly have been elucidated. On the other hand, rheumatoid arthritis (RA) is one of the causes of secondary osteoporosis. RA is a chronic inflammatory disease characterized by joint swelling and destruction. Most often, treatment focuses on suppressing these symptoms. However, physicians should be aware of the risk of osteoporosis in RA patients, because (1) RA is a chronic inflammatory disease, which itself can be a risk factor for osteoporosis; (2) glucocorticoids, which are sometimes administered to treat RA, can be a risk factor for osteoporosis; and (3) patients with RA are becoming older, and aging is an osteoporosis risk factor. A comprehensive understanding of the pathogenesis of osteoporosis and its fragility fractures requires elucidating the mechanisms underlying osteoclast activation, which drives their development. Furthermore, identifying the factors associated with fragility fractures is essential. This review summarizes the pathogenesis of osteoporosis, the factors associated with fragility fractures, and the associations between RA and osteoporosis development.

Osteonecrosis of the jaw (ONJ) is a severe disease leading to decreased quality of life, but risk factors for ONJ in chronic kidney disease (CKD) patients remain unclear. We conducted a nested case-control study using a large Japanese administrative database to investigate. CKD patients were identified based on estimated glomerular filtration rate (eGFR) measurements, and ONJ cases were identified using ICD-10 codes and diagnostic terms. Controls were matched 1:4 by age and sex. Among 597 026 CKD patients, 75 ONJ cases were identified during a median follow-up of 2.9 yr (incidence rate: 3.27 per 100 000 patient-years). A total of 375 patients (250 males, 66.7%) with a median age of 72 yr (interquartile range (IQR), 64-78) were included after matching controls. The use of bisphosphonates and denosumab for tumor-related disorders in the case group was significantly higher compared to the control group. There was no significant association between kidney functions and the ONJ risk. Multivariate analysis revealed that anti-resorptive drugs for tumor-related disorders [odds ratio (OR): 74.74, 95% confidence interval (CI): 8.81-634.39, p<.001] and oral corticosteroids (OR: 13.23, 95% CI: 3.34-52.33, p<.001) were significantly associated with increased ONJ risk, while anti-resorptive drugs for osteoporosis and injectable corticosteroid use were not. Other relevant factors such as diabetes, liver disease, anabolic drugs, and radiation therapy did not have a significant association with ONJ risk. When stratified by indications for bisphosphonate use (known to be eliminated by renal excretion), bisphosphonate use for tumor-related disorders showed a significant association with ONJ risk (OR: 27.80, 95% CI: 2.47-313.29, p<.01), while bisphosphonates use for osteoporosis did not (OR: 0.74, 95% CI: 0.19-2.92, p=.67). These findings suggest that anti-resorptive drugs for tumor-related disorders and oral corticosteroids are associated with ONJ risk in CKD patients. Heightened surveillance may be necessary for CKD patients receiving these treatments to prevent or detect ONJ early.

Romosozumab following anti-resorptive can be an effective sequential treatment strategy to improve bone strength. However, whether the transition to romosozumab after denosumab is associated with greater improvement in bone mineral density (BMD) and trabecular bone score (TBS) compared with denosumab continuation remains unclear. In this propensity score-matched cohort study, we analyzed data from postmenopausal women who initiated denosumab between 2017 and 2020. Individuals who were transited to 12 mo of romosozumab after denosumab were 1:1 matched to those who continued an additional 12 mo of denosumab (n = 86 for each group; denosumab-romosozumab [DR] and denosumab-denosumab [DD]). Mean BMD gain by denosumab treatment in matched DR and DD groups from denosumab initiation to transition (median 4 times [range 2-8]) was +4.8% and +2.0% in the lumbar spine (LS) and total hip, respectively. DR group showed greater LS BMD gain compared with the DD group (+6.8 vs +3.3% point, p<.001) for 12 mo post-transition independent of the duration of prior denosumab treatment, yielding greater overall LS BMD gain in DR compared with DD (+11.6% vs +8.0%, p<.001). DD group showed continued improvement of hip BMD, whereas hip BMD was maintained but not improved in the DR group. DR group was associated with greater TBS improvement than the DD group (2.9% vs 1.0%, p = .042). One month after the transition to romosozumab from denosumab, P1NP immediately increased above the level of denosumab initiation with relatively suppressed CTx, creating a transient anabolic window. For 12 mo follow-up, 1 incident morphometric vertebral fracture and 1 patella fracture were observed in DD, whereas 1 ankle fracture was observed in the DR group. Romosozumab following denosumab improved LS BMD and TBS greater than denosumab continuation in postmenopausal women.

The implementation of an in-hospital fracture liaison service facilitated prompt initiation of anti-osteoporosis treatment following a hip fracture (HF), increasing follow-up and treatment rates. This led to a 48% reduction in the risk of subsequent HF and a 29% decrease in mortality rates.

To demonstrate the impact of an institutional fracture liaison service (FLS) which allowed in-hospital anti-osteoporosis treatment following hip fracture (HF) on subsequent HF and mortality rate.

We retrospectively evaluated patients aged 65 years and older, admitted with an osteoporotic HF, who were transferred following surgery for rehabilitation in the geriatrics department in two time periods: before and after the implementation of an institutional FLS ("geriatric-pre-FLS" and "geriatric-FLS" cohorts, respectively). Data were captured from electronic records and the two cohorts were compared following an assessment of baseline characteristics, follow-up, and anti-osteoporosis treatment initiation. A multivariable Cox regression model evaluated differences between the cohorts regarding subsequent HF and mortality rates.

Three hundred and eighteen and 448 patients comprised the geriatric-pre-FLS (07/2008-06/2014) and the geriatric-FLS (03/2016-03/2020) cohorts, respectively. Baseline characteristics were comparable between the cohorts (median age 81 vs. 82, p = 0.08 and female sex 73% vs. 70%, p = 0.48, respectively). Rates of endocrine consultation (3.5% vs. 99%%, p < 0.001), DXA-BMD testing (7.5% vs. 34%, p < 0.001), and parenteral anti-osteoporosis treatment (4% vs. 76.6%, p < 0.001) were all higher in the geriatric-FLS cohort. The implementation of the FLS led to a 48% reduction in subsequent HF risk (HR 0.52; 95% CI 0.37-0.74, p < 0.001) and a 29% decrease in mortality rate (HR 0.71; 95% CI 0.54-0.92, p = 0.011).

The implementation of an in-hospital FLS facilitated prompt initiation of anti-osteoporosis treatment following a HF, increased follow-up and treatment rates, and resulted in a 48% reduction in subsequent HF risk and a 29% reduction in mortality rates.

In long-term care (LTC), the incidence of hip or vertebral fractures are eight times that in the community. Despite the wide availability of osteoporosis therapy, LTC residents are omitted from pivotal trials and not treated. Denosumab is a relatively new, monoclonal antibody therapy for osteoporosis treatment. Via a randomized trial, we sought to determine the safety and efficacy of denosumab in LTC residents.

We conducted a 2-year, double-blind, placebo-controlled, randomized clinical trial in 201 osteoporotic men and women aged ≥ 65 years, living in LTC communities. Participants with multimorbidity, dysmobility, and cognitive impairment were not excluded. The intervention was denosumab 60 mg subcutaneous every 6 months or placebo. Our primary outcome measures were hip and spine bone mineral density (BMD) improvement at 24 months. Secondary outcomes included BMD at other skeletal sites, function, and safety.

We included 123 women and 78 men with a mean ± standard error age of 81.5 ± 0.6. Overall, 83% and 71% completed 12 and 24 months, respectively. Compared with placebo, the women receiving denosumab had a greater 24-month percent increase in spine (7.41 ± 0.93 vs. 2.15 + 0.56; p = 0.014), and total hip BMD (4.62 ± 0.62 vs. -0.19 ± 0.79; p = 0.007); and men in spine (7.91 ± 0.96 vs. 1.12 ± 1.13; p = 0.002) and total hip (3.74 ± 0.55 vs. 0.48 ± 0.74; p = 0.018). There were no significant differences in safety metrics.

Denosumab was a safe and effective therapy for improving BMD in osteoporotic older men and women with multiple comorbidities in LTC.

Renal osteodystrophy is commonly seen in patients with chronic kidney disease (CKD) due to disrupted mineral homeostasis. Given the impaired renal function in these patients, common antiresorptive agents, including bisphosphonates, must be used with caution or even contraindicated. Therefore, an alternative therapy without renal burden to combat renal osteodystrophy is urgently needed. Here, we report that clinically relevant aerobic exercise significantly prevents high-turnover renal osteodystrophy in CKD mice and patients with CKD without compromising renal function. Mechanistically, 4-week aerobic exercise in CKD mice increased expression of skeletal muscle PPARγ coactivator-1α (PGC-1α) and circulating irisin. Both exercise and irisin administration significantly activated osteoblasts, but not osteoclasts, via integrin αvβ5, thereby conferring bone quality benefits. Removal of irisin-influenced thermogenic adipose tissues or genetic ablation of uncoupling protein 1 did not alter the irisin-conferred antiosteodystrophy effect. Importantly, in a pilot clinical study, 12-week aerobic exercise in patients with high-grade CKD significantly increased circulating irisin and prevented osteodystrophy progression, without detectable renal burden. The combination of irisin and current antiresorptive agents effectively rescued renal osteodystrophy in mice. Our work provides mechanistic insights into the role of exercise and irisin in renal osteodystrophy, and it highlights a clinically relevant, low-cost, kidney-friendly therapy for patients with this devastating disease.

The formation of functional bone requires a delicate interplay between osteogenesis and osteolysis. Disturbances in this subtle balance result in an increased risk for fractures. Besides its mechanical function, bone tissue represents a key player in the regulation of calcium homeostasis. Impaired bone formation results in bone fragility, which is especially pronounced in osteogenesis imperfecta (OI). This rare genetic disorder is characterized by frequent fractures as well as extraskeletal manifestations. The current classification of OI includes 23 distinct types. In recent years, several new mutations in different genes have been identified, although the exact pathomechanisms leading to the clinical presentation of OI often remain unclear. While bisphosphonates are still the standard of care, novel therapeutic approaches are emerging. Especially, targeted antibody therapies, originally developed for osteoporosis, are increasingly being investigated in children with OI and represent a promising approach to alleviate the consequences of impaired osteogenesis and improve quality of life in OI patients. This review aims to provide insight into the pathophysiology of OI and the consequences of distinct disease-causing mutations affecting the regulation of bone homeostasis. In this context, we describe the four most recently identified OI-causing genes and provide an update on current approaches for diagnosis and treatment.

Rheumatoid arthritis (RA) and prolonged high-dose glucocorticoid (GC) treatment are established risk factors for osteoporosis.

In this study, we aimed to evaluate the therapeutic efficacy of denosumab according to the GC dose considered to increase the risk of glucocorticoid-induced osteoporosis (GIOP) in patients with RA.

A retrospective analysis of collected data on RA patients with osteoporosis starting denosumab.

We included 418 patients with RA who were started on denosumab therapy and categorized them into those with and without GC intake ⩾2.5 mg/day for >3 months. The T-score and areal bone mineral density (aBMD) at the lumbar spine, total hip, and femur neck, as well as serum bone turnover markers, were measured at baseline and 12 months. We performed between-group and within-group comparisons of the BMD values at baseline and at 12 months.

Denosumab significantly increased the T-scores and aBMD at the lumbar spine, total hip, and femur neck after 12 months, regardless of GC intake. However, apart from the T-score at the lumbar spine, the other parameters did not show significant between-group differences. Similarly, in patients with anti-cyclic citrullinated peptide (CCP) antibody positivity or those treated with biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs), although there were significant increases in the T-score and areal BMD at all sites in both groups, there were no significant between-group differences.

Our findings suggest that the GC dose considered to increase the risk of GIOP did not significantly attenuate the therapeutic efficacy of denosumab in RA patients, including those positive for anti-CCP antibodies and users of biologic or targeted synthetic DMARDs.