Bone fragility has traditionally been associated with osteoporosis and reduced bone mineral density; however, contemporary evidence indicates that fracture risk is influenced by a broader spectrum of metabolic, nutritional, endocrine, inflammatory, and musculoskeletal factors. The objective of this review was to analyze the metabolic determinants associated with bone fragility beyond osteoporosis and to examine their influence on fracture risk and recovery outcomes. A structured narrative review of scientific literature published in major biomedical databases was conducted, focusing on diabetes mellitus, chronic kidney disease, vitamin D deficiency, malnutrition, osteosarcopenia, endocrine dysfunction, and chronic inflammation. The findings demonstrated that these conditions contribute significantly to alterations in bone quality, remodeling capacity, muscle performance, and tissue repair, thereby increasing susceptibility to fragility fractures independently of bone mineral density measurements. Diabetes mellitus and chronic kidney disease emerged as major determinants of skeletal fragility due to their effects on collagen integrity, mineral metabolism, vascular function, and bone turnover. Nutritional deficiencies and inadequate vitamin D status were consistently associated with impaired mineralization, increased fall risk, and delayed fracture healing. Furthermore, osteosarcopenia highlighted the close biological relationship between bone and muscle health and its contribution to fracture susceptibility and functional decline. The evidence supports a multidimensional understanding of skeletal fragility that incorporates metabolic health into fracture prevention and management strategies. Expanding fracture risk assessment beyond traditional osteoporosis models may improve early identification of vulnerable individuals and facilitate more comprehensive approaches to prevention, treatment, and rehabilitation.
Secondary osteoporosis is a major but frequently under-recognized contributor to skeletal fragility, particularly in men, premenopausal women, patients with fragility fractures at unexpectedly preserved bone mineral density, and individuals with rapid bone loss or inadequate response to standard therapy. Endocrine disorders are among the leading causes because they affect bone remodeling, mineral metabolism, sex steroid signaling, glucocorticoid pathways, insulin-like growth factor activity, and parathyroid hormone regulation. Management requires both correction of the underlying endocrine disorder and pharmacological treatment of skeletal fragility according to fracture risk. This review provides a clinically oriented and guideline-informed synthesis of endocrine-related secondary osteoporosis, with a focus on disease-specific skeletal phenotypes, diagnostic red flags, and targeted management strategies. Particular emphasis is placed on the concept of bone quality as a major determinant of fracture risk and on the limitations of conventional tools such as BMD and FRAX in this setting. We propose a practical clinical framework that integrates endocrine phenotype, vertebral imaging, trabecular bone score, and biochemical assessment into fracture-risk stratification and therapeutic decision-making. This approach supports a shift from a purely densitometric model toward a mechanism-based strategy, enabling improved identification of high- and very-high-risk patients and facilitating the appropriate use of anabolic and antiresorptive therapies.
I. Cincione, Robert A. Marcantonio, Marcellino Monda et al.· Frontiers in Endocrinology· 0 citations
Fragility fractures are a major clinical and public health challenge in aging societies. Current prevention strategies are commonly organized around skeletal risk assessment and osteoporosis management, yet fracture occurrence and post-fracture outcomes in older adults are also influenced by muscle dysfunction, frailty, fall propensity, physiological reserve, and rehabilitation capacity. This Perspective proposes a bone–muscle–function framework to complement existing osteoporosis-centered approaches to fragility fracture prevention. In this framework, bone represents skeletal strength and structural fragility, muscle represents sarcopenia-related impairment in strength and physical performance, and function represents frailty-related reserve, resilience, fall propensity, and recovery capacity. Osteosarcopenia provides the bone–muscle foundation, whereas the addition of function extends the framework to include broader vulnerability and recovery potential. Rather than simply adding frailty and sarcopenia to osteoporosis assessment, it organizes bone, muscle, and function into a staged framework for risk identification, recovery planning, and secondary prevention.
Shengzhu Lu, Chaodong Liu, Yinyao Gou et al.· Frontiers in Medicine· 0 citations
The prevalence of obesity, osteoporosis, and sarcopenia has increased dramatically over recent decades, contributing to frailty, disability, and reduced quality of life, particularly in aging populations. While excess body weight was traditionally considered protective for skeletal health due to increased mechanical loading, accumulating evidence indicates that adiposity, especially when centrally distributed and associated with metabolic dysfunction, may adversely affect bone quality and increase fracture risk despite normal or elevated bone mineral density. Bone, skeletal muscle, and adipose tissue are now recognized as components of an integrated biological system that communicates through endocrine, paracrine, and inflammatory pathways and shares common progenitor cells. Adipokines, myokines, and osteokines regulate tissue remodeling, energy metabolism, and insulin sensitivity, linking alterations in body composition to musculoskeletal and metabolic disorders. Aging amplifies these interactions through progressive muscle loss, visceral fat accumulation, hormonal changes, and chronic low-grade inflammation, giving rise to emerging clinical phenotypes like osteosarcopenic obesity. This review summarizes current clinical and biological evidence on the interactions among obesity, skeletal muscle, and bone, and discusses the implications of these relationships for integrated lifestyle-based interventions aimed at preserving musculoskeletal integrity and metabolic health across the lifespan. KEY WORDS: Excess adiposity, body composition, body mass index, bone mineral density, skeletal muscle, sarcopenia, osteosarcopenic obesity.
Olivia Di Vincenzo, Ludovica Cardinali, Marianna Minnetti et al.· International Journal of Bon...· 0 citations
The relationship between obesity and bone health is increasingly recognized as complex and paradoxical. Despite higher bone mineral density (BMD) in individuals with obesity, fracture risk is not uniformly reduced. Instead, fractures tend to occur more frequently at peripheral sites such as the ankle, humerus, and tibia, indicating a mismatch between BMD and true bone strength. In the early stages of weight gain, mechanical loading and adipose-derived hormonal factors may promote bone formation. However, these effects are progressively counterbalanced by chronic inflammation, oxidative stress, and marrow adiposity, which impair bone quality and compromise microarchitecture. Conventional dual-energy X-ray absorptiometry (DXA), while central to clinical assessment, cannot capture these changes and may overestimate skeletal strength in the presence of excess soft tissue. Emerging tools such as trabecular bone score and high-resolution peripheral quantitative computed tomography provide additional insights into bone quality, including microarchitecture and cortical porosity, particularly in individuals with type 2 diabetes. Obesity is also associated with vitamin D deficiency, impaired muscle function, and sarcopenic phenotypes, further increasing fracture risk. Bariatric surgery introduces additional challenges by accelerating bone turnover and loss. This review highlights the need to move beyond BMD alone and adopt comprehensive, individualized approaches to fracture risk assessment and management in obesity.
Riad Sulimani· Frontiers in Endocrinology· 0 citations
Osteoporosis is defined as a systemic skeletal disorder characterized by decreased bone mineral density (BMD) and deterioration of bone microarchitecture, leading to increased fracture risk. Among the causes of secondary osteoporosis, chronic kidney disease (CKD) plays a crucial role, as the kidneys are central regulators of endocrine mineral metabolism, including calcium, phosphate, vitamin D, and parathyroid hormone, as well as Klotho-FGF23 axis. These disturbances contribute to the deterioration of BMD and bone quality. Collectively, these factors highlight the need to recognize and further define CKD-associated osteoporosis as a distinct clinical entity. While not routinely required, bone biopsy continues to play an important role in selected complex cases where diagnostic uncertainty persists. Among the available markers, bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b are not significantly affected by renal clearance and are therefore considered reliable indicators of bone metabolism in CKD. Additionally, intact N-terminal telopeptide of type I collagen may also be applied in this clinical setting. Presents of calcification in CKD require the new approaches for BMD assessment in kidney impairment. Results indicate that radiofrequency echographic multispectrometry provides BMD and fracture risk assessment comparable to DXA in patients on peritoneal dialysis, while also highlighting the impact of vascular calcifications on the diagnostic accuracy of lumbar spine DXA measurements. Patients with CKD typically have impaired bone microarchitecture, as evidenced by lower trabecular bone score. A comprehensive and collaborative approach is essential to improve diagnostic accuracy and to develop more precise and effective therapeutic strategies for this patient population.
O. Nishkumay, O. Iaremenko, V.E. Kondratiuk et al.· International Journal of End...· 0 citations
Chronic kidney disease-mineral and bone disorder is a major contributor to skeletal fragility in patients with chronic kidney disease and after kidney transplantation. Alterations in mineral metabolism begin early during CKD and persist through later stages, leading to a markedly increased fracture risk that may precede renal failure. Bone fragility in CKD arises from the interplay of primary osteoporosis, secondary causes, and CKD-specific disturbances in bone turnover and mineralisation. CKD related bone disease and post-transplant bone loss are characterised not only by reduced bone mineral density but also by impaired bone quality, driven by abnormalities in trabecular and cortical microarchitecture, collagen properties, and mineral composition. Immunosuppressive therapy further exacerbates skeletal vulnerability after kidney transplantation. Recent guidelines have therefore adopted the term CKD-associated osteoporosis to emphasise the need for integrated diagnostic and therapeutic approaches. Diagnosis remains challenging because BMD alone fails to capture alterations in bone turnover and mineralisation that critically influence fracture risk and treatment response. Although bone biopsy remains the reference standard, limited availability has led to increased reliance on bone turnover markers, particularly those not cleared by the kidneys. Combined assessment of parathyroid hormone and BTMs improves discrimination of turnover states and supports individualised clinical decision-making. A pragmatic approach could be based on an integrated evaluation of CKD-MBD parameters, BTM trends, and baseline and follow-up imaging. Therapeutic management becomes increasingly complex in advanced CKD, where fracture risk is high, and evidence for osteoporosis treatments is limited. Antiresorptive, osteoanabolic, and dual-action agents have distinct effects on bone modelling and remodelling, with important implications for efficacy and safety. Despite progress, no consensus exists on optimal treatment strategies. Emerging sequential and combination therapies remain insufficiently studied in advanced CKD and transplant populations, underscoring the need for robust clinical evidence.
Giuseppe Cianciolo, Antonio Bellasi, Sandro Giannini et al.· Kidney360· 0 citations