Fracture Healing in the Setting of Endocrine Diseases, Aging, and Cellular Senescence
Open accessAbstract
More than 2.1 million age-related fractures occur in the United States annually, resulting in an immense socioeconomic burden. Importantly, the age-related deterioration of bone structure is associated with impaired bone healing. Fracture healing is a dynamic process which can be divided into four stages. While the initial hematoma generates an inflammatory environment in which mesenchymal stem cells and macrophages orchestrate the framework for repair, angiogenesis and cartilage formation mark the second healing period. In the central region, endochondral ossification favors soft callus development while next to the fractured bony ends, intramembranous ossification directly forms woven bone. The third stage is characterized by removal and calcification of the endochondral cartilage. Finally, the chronic remodeling phase concludes the healing process. Impaired fracture healing due to aging is related to detrimental changes at the cellular level. Macrophages, osteocytes, and chondrocytes express markers of senescence, leading to reduced self-renewal and proliferative capacity. A prolonged phase of “inflammaging” results in an extended remodeling phase, characterized by a senescent microenvironment and deteriorating healing capacity. Although there is evidence that in the setting of injury, at least in some tissues, senescent cells may play a beneficial role in facilitating tissue repair, recent data demonstrate that clearing senescent cells enhances fracture repair. In this review, we summarize the physiological as well as pathological processes during fracture healing in endocrine disease and aging in order to establish a broad understanding of the biomechanical as well as molecular mechanisms involved in bone repair.
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Dysregulated inflammation, as seen in advanced age, diabetes, obesity, and autoimmune disease, is often associated with non-union, delayed healing, and other complications.
“Dysregulated inflammation, as seen in cases of advanced age, diabetes, obesity, and autoimmune disease, is often associated with non-union, delayed healing, and other complications [1–3].”
From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [3]
The indexed copy (section labeled Abstract; page unavailable) links age-related inflammation to delayed bone healing and reports higher nonunion rates with obesity and type 2 diabetes, while describing a chronic inflammatory state as a possible confounder. It does not establish the claimed association for autoimmune disease, and it says the evidence that older age increases nonunion risk is inconsistent. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPro-inflammatory cytokines such as IL-1β, IL-6, IFNγ, TNFα, and C-reactive protein (CRP) are more highly expressed in aged patients and associated with an increased risk for fracture.
“In general, this work in addition to that of others indicates pro-inflammatory cytokines such as IL-1β, IL-6, IFNγ, TNFα, and C-reactive protein (CRP) are more highly expressed in aged patients and associated with an increased risk for fracture [3, 51•, 82, 90, 91].”
From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [3]
The discussion of age-related fracture repair (page unavailable in our copy) describes a more intense inflammatory response in aged female mice that delays bone healing, and the Vascular Supply passage reports prolonged TNFα expression in older animals. It does not establish that the full list of markers, including CRP, is more highly expressed in aged patients or associated with an increased risk of sustaining a fracture; its evidence concerns healing after fracture. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn aged mice, lowering the level of M1 macrophages led to improved fracture healing.
“In studies using aged mice, lowering the level of M1 macrophages led to improved fracture healing [3, 87].”
From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [3]
The macrophage discussion (indexed as Abstract; no page available) says that blocking macrophage recruitment to fracture sites enhanced healing in elderly mice. It does not say that M1 macrophages specifically were reduced; it describes the blockade as affecting macrophages generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPlatelets secrete PDGF, VEGF, TGFβ, and IGF-1 to promote mesenchymal progenitor cell proliferation and differentiation.
“Platelets secrete PDGF, VEGF, TGFβ, and IGF-1 to promote mesenchymal progenitor cell proliferation and differentiation [3, 37].”
From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [3]
B cells express IL-10 to limit proinflammatory signaling and to reduce the early inflammatory response.
“B cells are prolific cytokine producers in the fracture callus; they express IL-10 to limit proinflammatory signaling and to reduce the early inflammatory response [3].”
From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [3]
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3D-printed polymeric biomaterials in bone tissue engineering
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- Authors
- Saul, D., & Khosla, S.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Khosla, Sundeep
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2022-02-19
- Volume
- 43
- Issue
- 6
- Pages
- 984-1002
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- PMC
- PMC9695115
- OpenAlex
- W4213167559
- Cited by
- 185
- References
- 249
- Citations by year
- 2026: 55 · 2025: 65 · 2024: 47 · 2023: 16 · 2022: 2
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Endocrine Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG062413, AG065868)
- German Research Foundation (413501650)
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Epidemiology › Bone fractures and treatments
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- fracture healing, endocrine disorders, aging, cellular senescence, inflammaging, endochondral ossification, intramembranous ossification, mesenchymal stem cells, macrophages, osteocytes, chondrocytes, senolytics, bone remodeling, hematoma, angiogenesis, chondrogenesis
- MeSH terms
- Aging, Bony Callus, Endocrine System Diseases, Humans, Osteogenesis, Cellular Senescence, Fracture Healing, Fractures, Bone
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