Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their painpromoting effects. Finally, further examination of protein-sequestering antibodies and/or small *

Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.

Background: The time to diagnosis in stable slipped capital femoral epiphysis (SCFE) is often several months because of nebulous history, symptoms of knee/thigh pain, and Medicaid insurance. This study examined the impact of socioeconomic status and demographics on the time to diagnosis and SCFE severity in Indiana children. Methods: A retrospective review of all patients at a tertiary children’s hospital with SCFE from January 2010 through March 2021 was performed. Standard demographic data and type of insurance was collected. Neighborhood Atlas Mapping was used to determine the state decile of the area deprivation index (ADI), a measure of socioeconomic status using 17 variables related to income, employment, education, and housing. Statistical analyses consisted of standard univariate and bivariate analyses; logistic regression analysis was used to determine predictors of a mild SCFE. A P<0.05 was considered statistically significant. Results: There were 142 patients; 81 male and 61 female. The average age was 12.2±1.7 years, lateral epiphyseal shaft angle of 35±19 degrees, and symptom duration of 4.5±5.0 months. There was no correlation between ADI state deciles and lateral epiphyseal shaft angle (r 2=0.008) or symptom duration (r 2=0.019). Insurance status and race differed by ADI deciles. In the first decile (least disadvantaged), 44% had government insurance and 89% were White; in the 10th decile (most disadvantaged), 95% had government insurance and 38% were White. Predictors of a mild SCFE were female sex [odds ratio (OR): 3.2 [1.5, 7.0]; P=0.004], symptom duration <3 months [OR: 5.3 (2.4, 11.7); P=0.00004], and White race [OR: 2.4 (1.3, 6.2); P=0.01]. Insurance status and ADI were not significant. Conclusions: Contrary to other studies, neither insurance or socioeconomic status were associated with a delay in diagnosis or SCFE severity. The symptom duration in children with SCFE does not appear to be decreasing over the last several decades. Further investigation is required as to why. Level of Evidence: Level III—retrospective comparative study.

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