Osteoporosis in men is under-recognized and under-treated despite a substantial disease burden and poorer fracture-related outcomes than in women. Secondary osteoporosis is highly prevalent in men, making the identification and management of underlying causes essential. Bone mineral density (BMD) and fracture risk are influenced by sex-specific patterns of skeletal growth and age-related bone loss, with men typically exhibiting greater cortical thickness, larger bone size, and trabecular thinning rather than loss of trabecular number. Although randomized controlled trials in men are fewer than in postmenopausal women, bisphosphonates, denosumab, teriparatide, abaloparatide, and romosozumab have all been shown to significantly increase BMD. Fracture outcome data remain limited; however, reductions in vertebral fracture risk have been demonstrated for zoledronate, alendronate, risedronate, denosumab, and teriparatide. Treatment should be individualized according to fracture risk, comorbidities, and patient preferences. In men at very high fracture risk, osteoanabolic therapy should be considered as first-line treatment, followed by antiresorptive therapy to consolidate and maintain BMD gains. Goal-directed (treat-to-target) management, including long-term maintenance therapy, and careful discontinuation strategies, particularly following denosumab, is essential for optimizing long-term skeletal health. This narrative review and position statement by The ECTS Clinical Action Group provides an updated overview of current and emerging treatment options and offers practical, evidence-based recommendations for the long-term management of osteoporosis in men.

Muscle and bone are closely related during growth and development. We sought to identify determinants of the muscle-bone relationship using peripheral quantitative computed tomography (pQCT) at the distal lower extremity and jumping mechanography among Canadian children. Data were obtained from the Canadian Health Measures Survey (CHMS), a national, cross-sectional, population-based study. 3,225 participants (aged 6 to 19.9 years) were included. Calf muscle cross-sectional area (CSA; 66% site) z-score was used as a surrogate measure of muscle strength, bone mineral content (BMC) z-score of the tibia shaft cross-section (38% site) was used as a surrogate measure of bone strength. Maximum jumping power (Pmax) z-score from the single two-legged jump test was assessed as a mediator between muscle CSA and BMC z-scores using path analysis. Peripheral QCT and Pmax z-scores were calculated using CHMS data. Height, weight, and body mass index (BMI) z-scores were calculated using Centers for Disease Control reference data. We found a strong positive association between muscle CSA z-score and tibia BMC z-score (β = 0.64, 95% confidence interval [CI]: 0.62 to 0.67). Calf subcutaneous fat CSA (β = -0.04, 95% CI: -0.07 to -0.01) and muscle density (β = 0.08, 95% CI: 0.03 to 0.13) z-scores were weak determinants, and weight (β = 0.10, 95% CI: 0.05 to 0.15) and BMI (β = 0.14, 95% CI: 0.07 to 0.21) z-scores were strong determinants of the association between muscle CSA z-score and BMC z-score. Self-reported moderate-to-vigorous physical activity and serum total calcium, 25-hydroxy-vitamin D3, and parathyroid hormone were not determinants. Pmax z-score was a partial mediator of the association between muscle CSA and BMC z-scores. In conclusion, we found that the effect of muscle size on bone mass was in part mediated by muscle power. Subcutaneous fat, muscle density, weight, and BMI were determinants of the muscle-bone relationship.

Bone fragility is increasingly recognized as a complication of metabolic dysfunction, but endocrine mechanisms linking hepatic stress to impaired bone formation remain incompletely defined. We tested whether selenoprotein P, a hepatokine elevated in metabolic disease, suppresses osteoblast function and skeletal integrity. In mice fed a high-fat, high-sucrose diet, whole-body Selenop deficiency preserved trabecular bone mass, bone formation, bone stiffness, and cortical bone defect repair. Hepatocyte-specific Selenop deficiency also preserved trabecular bone mass. Histomorphometry showed that selenoprotein P primarily suppressed osteoblast activation without materially altering osteoclast indices. In calvaria-derived osteoblast cultures, purified human plasma-derived selenoprotein P inhibited IGF-1-induced phosphorylation of IGF-1 receptor, IRS-1, PI3K, PDK1, and Akt, reduced alkaline phosphatase activity, matrix mineralization, and osteogenic gene expression, and blunted receptor-proximal ROS generation. LRP1 was the predominant candidate receptor during osteogenic differentiation. Osteoblast cultures derived from Osx-Cre/+ Lrp1fl/fl mice showed reduced cell-associated human selenoprotein P, and the inhibitory effects of selenoprotein P on IGF-1 signaling and osteoblast maturation were absent in these cultures. In vivo, pharmacologic blockade of IGF-1 receptor signaling eliminated the skeletal protection conferred by Selenop deficiency, supporting a requirement for intact IGF-1 receptor signaling in this pathway. In a cross-sectional analysis of a general population cohort, serum selenoprotein P was not significantly associated with OSI across the full cohort, whereas exploratory analyses in the highest quintile suggested an inverse association between high circulating selenoprotein P and bone mass. Together, these findings identify hepatic selenoprotein P as a negative regulator of bone formation and define a hepato-osteogenic reductive stress axis that links metabolic stress to impaired skeletal integrity.

The identification of pathogenic PLS3 variants in individuals with X-linked osteoporosis (XLO) has demonstrated the importance of the actin-bundling protein plastin-3 for skeletal integrity. We and others have previously reported that Pls3-deficient mice display a skeletal phenotype that unexpectedly affects only the cortical bone compartment. To better characterize the impact of PLS3 inactivation on bone (micro-)architectural parameters in humans, we retrospectively analyzed skeletal parameters obtained from male XLO patients and compared them to corresponding data from male individuals with genetically diagnosed osteogenesis imperfecta type I (OI-I). We observed no major differences between XLO and OI-I patients in baseline characteristics, laboratory parameters, or bone mineral density measurements by dual-energy X-ray absorptiometry (DXA). However, there was a significant difference between the two groups observed by high resolution peripheral quantitative computed tomography (HRpQCT). More specifically, XLO patients displayed significantly reduced cortical bone parameters, compared to both normal reference ranges and OI-I, especially at the distal radius. We also analyzed female heterozygous carriers of (likely) pathogenic PLS3 alleles, who were less affected compared to male XLO patients. However, two of them displayed osteoporotic fractures at a postmenopausal age, thus treatment with romosozumab, a monoclonal antibody targeting sclerostin, was initiated and appeared to be effective. Since another sclerostin-neutralizing antibody is currently studied for the treatment of OI patients, we crossed Pls3-deficient mice with mice carrying a high bone mass allele of Lrp5 (Lrp5A213V), which serves as a molecular mimic of anti-sclerostin therapy. We found that the presence of the Lrp5A213V allele led to significantly increased cortical and trabecular bone mass not only in wildtype but also in Pls3-deficient mice. Taken together, our data raise the hypothesis that PLS3 inactivation predominantly affects cortical bone parameters in mice and humans and that anti-sclerostin therapy could be effective for the treatment of XLO.

X-linked hypophosphatemia (XLH) is a progressive disease in which excess FGF23 causes renal phosphate wasting, leading to hypophosphatemia. Consequences in adults include osteomalacia, fractures, pseudofractures, joint dysfunction, pain, and impaired mobility. Treatments for XLH are the anti-FGF23 antibody burosumab and active forms of vitamin D alone or in combination with oral phosphate (Pi/D). Randomized studies comparing burosumab with Pi/D in adults with XLH are lacking. We present a 3-yr follow-up analysis evaluating real-world effectiveness of burosumab versus Pi/D based on biochemistry and standardized symptom assessments (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) using data from the XLH Disease Monitoring Program (DMP; NCT03651505), a prospective, Americas-based study. Adults with XLH initiated burosumab between baseline and the year 1 visit (N = 54) or reported being on Pi/D therapy at enrollment (N = 55) were included. After adjusting for baseline differences using inverse probability of treatment weighting, the data showed a significantly higher mean (SD) change from baseline in serum phosphate with burosumab versus Pi/D (year 1: 0.8 [0.8] vs 0.1 [0.7] mg/dL; year 3: 0.6 [0.8] vs 0.1 [0.7] mg/dL, both p < .001). A higher proportion of burosumab versus Pi/D participants achieved serum phosphate levels above the lower limit of normal (2.5 mg/dL; year 1: 70.5% vs 18.8%; year 3: 60.8% vs 25.0%, both p < .001). At year 1, changes from baseline in WOMAC pain (-6.3 [27.7] vs 2.1 [22.4], p = .055), physical function (-6.4 [19.1] vs 0.1 [29.0], p = .122), and stiffness (-11.1 [32.1] vs -2.3 [33.7], p = .073) were not statistically significant between cohorts, but were significant at year 3 (pain: -9.8 [22.6] vs 3.3 [24.1], p < .001; physical function: -10.0 [25.7] vs 3.3 [24.7], p = .001; stiffness: -15.2 [29.5] vs -3.7 [31.4], p = .016). In this real-world analysis of adults with XLH over a 3-yr follow-up, burosumab treatment was associated with improved serum phosphate and patient-reported outcomes versus Pi/D.

Chronic liver disease frequently leads to debilitating bone fractures, yet the mechanistic link between liver injury and skeletal fragility remains elusive. This study aimed to investigate a liver-bone axis where dysregulated iron flux, mediated by hepatocyte ferroportin (FPN), drives osteoporosis during the progression of cirrhosis. We utilized a mouse model of progressive liver disease and generated hepatocyte-specific FPN deletion mice to examine systemic iron homeostasis. Bone quality and microarchitecture were evaluated via micro-computed tomography and histological analysis. To assess fracture risk and mechanical integrity, we employed engineering-based finite element simulations and physical mechanical testing. Our data reveal a critical window during liver fibrosis where compensatory mechanisms counteract iron toxicity. However, upon progression to cirrhosis, this homeostatic balance collapses, leading to massive toxic iron accumulation in the skeleton. This creates a pro-inflammatory environment that suppresses bone formation and accelerates resorption. Biomechanical simulations and testing demonstrate that combined deficits in bone material properties and architecture create distinct stress concentration zones, markedly reducing load-bearing capacity. Strikingly, hepatocyte-specific deletion of FPN attenuated liver fibrosis and restored systemic iron balance, thereby preserving bone microarchitecture and mechanical performance. Hepatocyte FPN-regulated iron homeostasis is a central mediator of the liver-bone axis. Cirrhosis-induced iron overload is a major contributor to skeletal mechanical failure, identifying FPN as a key regulator of bone health in chronic liver disease.

The Fracture Risk Assessment Tool estimates 10-year fracture probability, but its performance may vary across populations. We respond to correspondence concerning our Women's Health Initiative analysis by clarifying prior findings and addressing questions about age structure, differential follow-up, construction of clinical inputs, polygenic-score portability, comparator choice, and model performance. Observed fracture probability was estimated using cumulative incidence with death as a competing event. Additional age-stratified analyses showed a similar qualitative pattern of overestimation in Black and Hispanic/Latina women. Using the medium polygenic-score group as the reference, associations with major osteoporotic fracture remained directionally consistent; inverse probability of censoring-weighted estimates were similar for major osteoporotic fracture but less stable for hip fracture. Adding the polygenic score produced only modest gains in time-dependent discrimination. We acknowledge that informative censoring that differs across racial and ethnic groups, sparse subgroup events, multiple comparisons, and limited cross-ancestry portability remain important limitations. These considerations support cautious interpretation and further validation of fracture-risk tools in diverse populations.

The human skull, whose 22 separate bones make up the cranial vault, facial bones and jaw, is arguably the most complex skeletal structure in the body. In addition to protecting the brain, it provides structures necessary for mastication and audition and serves as the underlying scaffold for the face to define our unique identities. Proper development and growth of the skull requires initial incorporation of positional information to cranial neural crest cells (CNCC) and paraxial mesoderm to define the location of each bone followed by the coordination of postnatal cranial growth with the underlying expansion of the brain, a process that is mediated by two specific growth centers, cranial sutures and cranial base synchondroses. This Perspective will provide an overview of general principles governing craniofacial development, growth, and regeneration with emphasis on the unique functions of neural crest cells, cranial sutures, cranial base synchondroses and associated stem cells. In addition, examples will be included of how defects in skull development can explain specific craniofacial disorders as well as future directions for cranial bone regeneration and correction of craniofacial anomalies that are informed by recent discoveries in this field.

Bone remodeling is regulated by circadian rhythm, yet the molecular mechanisms linking circadian clock components to osteoclast function remain largely undefined. We previously showed that osteoclast-specific deletion of Per1, a core circadian regulator, increased osteoclastogenesis and reduced bone mass in male mice, whereas deletion of Per2 had little effect. Here, we investigated Per1;Per2 conditional double-knockout (dKO) mice and unexpectedly found the opposite phenotype. In contrast to Per1 deficiency, dKO suppressed osteoclastogenesis and increased bone mass specifically in male mice, revealing previously unrecognized functional interactions between PER1 and PER2 in osteoclasts. Transcriptomic analyses showed that dKO osteoclasts preferentially downregulated innate immunity genes, including both positive and negative regulators of osteoclastogenesis. Chromatin immunoprecipitation and reporter assays further identified innate immunity genes as downstream targets of PER-dependent circadian regulation. These findings indicate that PER1 and PER2 regulate osteoclastogenesis through coordinated control of a network of immune genes with opposing effects on osteoclast differentiation, rather than acting as simple promoters or inhibitors of bone resorption. More broadly, this study establishes innate immunity as a mechanistic interface between the circadian clock and osteoclast function, providing a framework for understanding how circadian disruption influences bone remodeling and inflammatory bone diseases.