Osteoporosis is a systemic disease that affects millions of people worldwide. It is estimated that 50% of women and approximately 20% of men more than 50 years of age will sustain a fragility fracture. The cause of nonunion in patients with osteoporosis is likely multifactorial, and includes age-related changes in fracture repair as well as challenges in achieving stable internal fixation. This article discusses fracture healing in patients with osteoporosis and the principles of fixation. Pharmacotherapy for the patient with osteoporosis is also discussed.
Key points
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The cause of nonunion in patients with osteoporosis is likely multifactorial, and includes age-related changes in fracture repair as well as challenges in achieving stable internal fixation.
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Age-related changes in signaling and mesenchymal cell function may delay the rate of fracture healing.
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Aged bone cells may have altered responses to the mechanical environment.
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Geriatric patients may use medications that alter fracture repair.
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Locking implants improve fixation in osteoporotic bone and are relevant in nonunion repair in patients with osteoporosis.
Osteoporosis is a systemic disease that affects millions of people worldwide. As life expectancy increases and the population ages, the number of people with osteoporosis is only expected to grow. It is estimated that 50% of women and approximately 20% of men more than 50 years of age will sustain a fragility fracture. As the absolute numbers of fragility fractures increase so too will the absolute numbers of complications including nonunion. Fractures due to osteoporosis often occur in the metaphysis of long bones; common sites include the proximal humerus, distal radius, proximal and distal femur, as well as the spine. The incidence of nonunion in patients with osteoporosis is not well reported in the literature, but failure of fixation for specific fractures is known. Although not all failures in fixation of osteoporotic fractures are due to nonunion, approximate rates can be inferred from these data until studies looking at exact incidences are performed. Failures of proximal humerus fractures treated with open reduction and internal fixation using a locked implant are reported to be up to 15%. Fixation failure of the distal femur is reported to be 25%. Parker and colleagues showed the incidence of proximal femur nonunion to be 19% in all comers, but the numbers increased as patients increased in age; the rate of nonunion in patients more than 70 years of age was 24.9%. This study did not look specifically at osteoporosis, but those elderly patients are at increased risk for osteopenia or osteoporosis. The same study showed that women are at higher risk of developing nonunion of the femoral neck than men.
The influence that osteoporosis or bone density has on the development of nonunion is debated in the literature. Bonnaire and colleagues recommended consideration of arthroplasty in patients with bone mineral density (BMD) less than 400 mg/cm 3 in displaced femoral neck fractures because the decreased BMD would not allow for stable fixation. Hedstrom in a small pilot study showed that those patients with osteoporosis and high levels of bone resorption markers Urinary deoxy-pyridinoline (U-DPD) and serum carboxy-terminaltelopeptide of type I collagen (s-ITCTP) on admission were at increased risk of developing nonunion of the femoral neck. Van Wunni and colleagues showed that BMD had no statistically significant effect on the development of nonunion in patients with fractures who were more than 50 years of age. Heetveld and colleagues found no difference in the rate of revision surgery after internal fixation of the proximal femur between patients with osteoporosis and those without. Animal studies have shown decreased callus formation and decreased bone density in osteoporosis models, but no clear link to nonunion. Age, gender, and accuracy of reduction have been shown to correlate with the risk of nonunion of the proximal femur in several studies.
Many features of osteoporotic bone lead to increased risk of fracture and make fixation of these fractures difficult. There is an increased cancellous to cortical bone ratio. Cross-linking between trabecular bone is decreased. Cortical bone is more porous and has decreased density, which affects the fixation of implants to the bone. Cellular factors contributing to delayed healing are decreased number of mesenchymal stem cells, decreased number of osteoblasts with increasing age, and impaired response of bone cells in osteoporotic bone cells.
Fracture healing in patients with osteoporosis
Age-related changes in fracture healing are important considerations in the management of nonunion. Evaluation of the cause of nonunion is uniform across patient populations and includes a thoughtful analysis of the relevant contribution of biomechanical and biological factors. Fracture healing is a complex cascade, which creates significant difficulty in understanding the exact deficiencies or sites of failure in the healing sequence, but stepwise analysis can be helpful in choosing repair techniques.
Changes in Remodeling Potential
In many ways, osteoporosis represents imbalance in bone formation versus bone remodeling. This alteration is potentially problematic for fracture repair as well because efficient fracture healing requires not only new bone formation but also remodeling of callus for appropriate strength. The cell populations involved with remodeling and fracture healing, including osteoblasts and osteoclasts, are subject to cumulative effects of aging that can potentially impair their function. Both glycation and oxidative damage are common in aging tissues ; in the setting of cell function, it is likely that these aging processes impair the cell population critical for bone repair.
Local and Systemic Signaling
Age-related changes in the expression of many signaling molecules have been implicated in the process of normal fracture healing, including insulinlike growth factor (IGF) and parathyroid hormone (PTH). Although both IGF and PTH have been demonstrated to increase expression with age, there is no correlation with an improved rate and quality of fracture healing. This finding demonstrates some of the major challenges in understanding the redundant and complicated signaling pathways associated with normal fracture repair. Small animal studies show interesting trends. Fractures in old rats are known to heal slowly. In rat defect models, a combination of transforming growth factor β (TGF-β) and IGF-1 together induce healing in critical defect models. Noncritical defect models in aged rats show a similar response to exogenous treatments. Growth hormone applications to healing fractures in old rats can improve bone quality but do not improve the rate of fracture healing to normal levels.
Mesenchymal Stem Cells
Studies on human bone marrow cells indicate that, in a normal host, mesenchymal stem cells can form bone equally well whether from a young or old donor. Clinically, it is observed that bone marrow changes with age and becomes fatty; this evidence is accumulating for several tissues, showing that, with age, marrow stem cells tend to form adipocytes and other cell types. This may become a critical limitation in the application of autologous mesenchymal stem cell harvesting techniques for elderly patients.
Mesenchymal stem cells are rare in adult marrow, and an age-related decrease in numbers has been reported. Although the discreet population of cells that are intricately involved in fracture repair remains elusive, these marrow precursors have been studied extensively in bone models and there is a threshold number of cells required for successful union in both defect and nondefect models (Tseng and Lee, submitted for publication, 2013).
Stem cell senescence related to telomeric shortening has also been studied. Telomerase transfection prolongs the life span of mesenchymal stem cells and enhances osteogenic differentiation and bone formation in mouse models. Age-related senescence of stem cells, which are important for fracture healing, may limit the usefulness of autologous cancellous bone graft harvesting.
Periosteum
Periosteum contains undifferentiated mesenchymal stem cells that possess the potential for chondrogenesis and involvement with the process of normal fracture repair. With aging, the chondrogenic potential of periosteum declines. Periosteum-derived cells from elderly rats respond less well to 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and TGF-β than cells from nonelderly donors. Similar findings have been reported in human cells. These studies correlate with the clinical findings of decreased periosteum and periosteal-mediated healing responses in elderly patients.
Mechanobiology
Many of the molecular events in fracture healing are influenced by the mechanical environment, which is sensed by local cells, probably osteoblasts and osteocytes. Bone cells in aged or osteoporotic bone may have altered responsiveness to mechanical stimuli; this has been studied via loading of normal and aged osteoblasts. Differential proliferative potential was seen in osteoblastic cells exposed to cyclic strain from both osteoporotic and normal donors. These findings are a concern because unique fixation algorithms may be required in elderly patients.
Summary
Fracture repair in patients with osteoporosis is likely a unique process. The differences in signaling response, cell populations, and their responsiveness to normal stimuli requires optimization of the biological milieu for successful treatment of nonunion. Approaches used in younger, more optimal hosts may be inadequate in these patients.
Fracture healing in patients with osteoporosis
Age-related changes in fracture healing are important considerations in the management of nonunion. Evaluation of the cause of nonunion is uniform across patient populations and includes a thoughtful analysis of the relevant contribution of biomechanical and biological factors. Fracture healing is a complex cascade, which creates significant difficulty in understanding the exact deficiencies or sites of failure in the healing sequence, but stepwise analysis can be helpful in choosing repair techniques.
Changes in Remodeling Potential
In many ways, osteoporosis represents imbalance in bone formation versus bone remodeling. This alteration is potentially problematic for fracture repair as well because efficient fracture healing requires not only new bone formation but also remodeling of callus for appropriate strength. The cell populations involved with remodeling and fracture healing, including osteoblasts and osteoclasts, are subject to cumulative effects of aging that can potentially impair their function. Both glycation and oxidative damage are common in aging tissues ; in the setting of cell function, it is likely that these aging processes impair the cell population critical for bone repair.
Local and Systemic Signaling
Age-related changes in the expression of many signaling molecules have been implicated in the process of normal fracture healing, including insulinlike growth factor (IGF) and parathyroid hormone (PTH). Although both IGF and PTH have been demonstrated to increase expression with age, there is no correlation with an improved rate and quality of fracture healing. This finding demonstrates some of the major challenges in understanding the redundant and complicated signaling pathways associated with normal fracture repair. Small animal studies show interesting trends. Fractures in old rats are known to heal slowly. In rat defect models, a combination of transforming growth factor β (TGF-β) and IGF-1 together induce healing in critical defect models. Noncritical defect models in aged rats show a similar response to exogenous treatments. Growth hormone applications to healing fractures in old rats can improve bone quality but do not improve the rate of fracture healing to normal levels.
Mesenchymal Stem Cells
Studies on human bone marrow cells indicate that, in a normal host, mesenchymal stem cells can form bone equally well whether from a young or old donor. Clinically, it is observed that bone marrow changes with age and becomes fatty; this evidence is accumulating for several tissues, showing that, with age, marrow stem cells tend to form adipocytes and other cell types. This may become a critical limitation in the application of autologous mesenchymal stem cell harvesting techniques for elderly patients.
Mesenchymal stem cells are rare in adult marrow, and an age-related decrease in numbers has been reported. Although the discreet population of cells that are intricately involved in fracture repair remains elusive, these marrow precursors have been studied extensively in bone models and there is a threshold number of cells required for successful union in both defect and nondefect models (Tseng and Lee, submitted for publication, 2013).
Stem cell senescence related to telomeric shortening has also been studied. Telomerase transfection prolongs the life span of mesenchymal stem cells and enhances osteogenic differentiation and bone formation in mouse models. Age-related senescence of stem cells, which are important for fracture healing, may limit the usefulness of autologous cancellous bone graft harvesting.
Periosteum
Periosteum contains undifferentiated mesenchymal stem cells that possess the potential for chondrogenesis and involvement with the process of normal fracture repair. With aging, the chondrogenic potential of periosteum declines. Periosteum-derived cells from elderly rats respond less well to 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and TGF-β than cells from nonelderly donors. Similar findings have been reported in human cells. These studies correlate with the clinical findings of decreased periosteum and periosteal-mediated healing responses in elderly patients.
Mechanobiology
Many of the molecular events in fracture healing are influenced by the mechanical environment, which is sensed by local cells, probably osteoblasts and osteocytes. Bone cells in aged or osteoporotic bone may have altered responsiveness to mechanical stimuli; this has been studied via loading of normal and aged osteoblasts. Differential proliferative potential was seen in osteoblastic cells exposed to cyclic strain from both osteoporotic and normal donors. These findings are a concern because unique fixation algorithms may be required in elderly patients.
Summary
Fracture repair in patients with osteoporosis is likely a unique process. The differences in signaling response, cell populations, and their responsiveness to normal stimuli requires optimization of the biological milieu for successful treatment of nonunion. Approaches used in younger, more optimal hosts may be inadequate in these patients.
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