Osteosarcopenia in Chronic Kidney Disease: An Overlooked Syndrome?

Abstract

Background: Healthy ageing relies on maintaining physiological systems, particularly the musculoskeletal system (MKS). After 50, declines in bone density, muscle mass and strength increase the risk of osteoporosis and sarcopenia, leading to frailty, fractures and higher healthcare costs. Osteosarcopenia, combining osteoporosis and sarcopenia, is rising because of the ageing population. Chronic kidney disease (CKD) exacerbates this condition through disruptions in mineral metabolism, hormonal imbalances and inflammation, further compromising musculoskeletal health.

Aims: This review examines the pathophysiology of osteosarcopenia associated with CKD, focusing on the role of mineral and hormonal disturbances, chronic inflammation and endocrine dysfunction. It aims to increase clinical awareness and highlight the need for early diagnosis and intervention to mitigate the burden of osteosarcopenia on the quality of life and healthcare systems in ageing CKD populations.

Methods: A narrative review of the current literature was conducted, summarising evidence on the mechanisms underlying osteosarcopenia in CKD, including mineral metabolism alterations, inflammatory processes and hormonal imbalances.

Results: Osteosarcopenia is a recognised consequence of CKD, contributing to increased morbidity and mortality. The pathophysiology of osteosarcopenia in CKD is multifactorial, involving disruptions in mineral metabolism, inflammation, endocrine dysfunction and physical inactivity. CKD-mineral and bone disorder (CKD-MBD) leads to alterations in calcium, phosphate, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23) and vitamin D metabolism, resulting in impaired bone mineralisation and increased fracture risk. Simultaneously, CKD accelerates muscle wasting through systemic inflammation, anabolic resistance and metabolic derangements, increasing the risk of sarcopenia. Sarcopenic obesity, inflammaging and hormonal dysregulation further exacerbate bone muscle deterioration. Emerging evidence suggests that osteosarcopenia in CKD is a consequence of interconnected pathophysiological pathways rather than isolated conditions. Diagnosis remains challenging because of overlapping clinical features, necessitating integrated assessment tools. Targeted therapeutic strategies, including mineral metabolism correction, resistance exercise and anabolic interventions, are essential to mitigate osteosarcopenia's progression and improve patient outcomes in CKD.

Conclusions: Osteosarcopenia is a growing concern in ageing CKD populations. Early diagnostic strategies and targeted interventions are essential to mitigate the impact of osteosarcopenia on patient outcomes and reduce associated healthcare costs. Increased clinical awareness and research into effective therapies are crucial for improving the quality of life for individuals affected by CKD and osteosarcopenia.

Keywords: chronic kidney disease (CKD); mineral bone disorder (MBD); osteoporosis; osteosarcopenia; sarcopenia.

FIGURE 1

Schematic representations of PTH, vitamin D and FGF‐23 metabolism. Note: Schematic representations of PTH, vitamin D and FGF‐23 metabolism, illustrating their integrated roles in maintaining calcium‐phosphate homeostasis. The diagram details the mechanisms of PTH secretion in response to changes in serum calcium, its effects on bone resorption and renal phosphate excretion. It also highlights vitamin D metabolism, including its synthesis from precursors through sunlight and dietary sources, conversion to 25OH‐D in the liver and activation to 1,25OH‐D in the kidneys, emphasising its role in calcium absorption in the gut and feedback regulation of PTH. Additionally, the figure depicts FGF‐23 secretion by osteocytes in response to hyperphosphatemia, its interactions with the Klotho coreceptor and its suppression of calcitriol synthesis and renal phosphate reabsorption. These pathways collectively contribute to the dynamic regulation of mineral metabolism, with dysregulation contributing to the pathophysiology of CKD‐MBD. 1,25(OH)₂D, 1,25(OH) vitamin D; 25(OH)D, 25(OH) vitamin D; 7‐DHC, 7 dehydrocholesterol; Ca, calcium; CaSR, calcium sensing receptor; FGF‐23, fibroblast growth factor 23; P, phosphate; PTH, parathormone; PTH1r, parathormone 1 receptor; VDR, vitamin D receptor.

FIGURE 2

Cornerstones of inflammaging. Note: Inflammaging, a portmanteau of inflammation and ageing, describes the chronic, low‐grade inflammation prevalent in aged individuals. This figure illustrates the complex interplay of various cellular and molecular components contributing to inflammaging. Elevated levels of pro‐inflammatory cytokines, such as interleukin‐6 (IL‐6) and tumour necrosis factor‐alpha (TNF‐α), alongside activated immune cells like macrophages and T cells, signify the inflammatory milieu characteristic of inflammaging. This sustained inflammatory state is implicated in the pathogenesis of age‐related diseases, including cardiovascular disorders, neurodegenerative conditions and metabolic syndromes, ultimately influencing overall health span and longevity.

FIGURE 3

Main factors associated with osteosarcopenia development. Note: This figure depicts the multifactorial pathways leading to osteosarcopenia development in chronic kidney disease (CKD). Reduced renal function in CKD disrupts mineral and hormonal homeostasis, resulting in secondary hyperparathyroidism, elevated fibroblast growth factor 23 (FGF‐23) and decreased vitamin D synthesis. These disturbances contribute to bone loss, osteoporosis and increased fracture risk. Concurrently, CKD‐induced inflammation, metabolic acidosis and uremic toxins impair skeletal muscle integrity, promoting sarcopenia. The reciprocal relationship between bone and muscle further exacerbates the progression of osteosarcopenia, leading to frailty, disability and heightened mortality risk in CKD patients. GH, Growth hormone; IGF, Insuline growth factor; CKD, Chronic Kidney Disease; FFA, Free fatty acids.

FIGURE 4

Flowchart to diagnose osteosarcopenia. ASM, appendicular skeletal muscle mass; DXA, dual X‐ray absorptiometry; F, female; FRAX, Fracture Risk Assessment Tool; M, male; SARC‐F, strength, assistance with walking, rising from a chair, climbing stairs and falls; SPPB, short physical performance battery; STS5, 5 times sit‐to‐stand; TUG, timed up‐and‐go.