Is Osteoarthritis a Vascular Disease?

Osteoarthritis (OA) is now considered as a multifaceted disease affecting various articular tissues, including cartilage, bone, synovium, and surrounding ligaments. The pathophysiology strongly implicates intricate chemical communication, primarily through cytokines, leading to the production of degradative enzymes in cartilage, inflammatory peptides in synovium, and structural changes in bone, resulting in characteristic clinical features such as joint deformities and loss of cartilage space seen on X-rays. Recent studies highlight the previously underestimated role of subchondral bone in OA, revealing its permeability to cytokines and raising questions about the influence of abnormal perfusion on OA pathophysiology, suggesting a vascular component in the disease's etiology. In essence, alterations in bone perfusion, including reduced venous outflow and intraosseous hypertension, play a crucial role in influencing the physicochemical environment of subchondral bone, impacting osteoblast cytokine expression and contributing to trabecular remodeling, changes in chondrocyte phenotype, and ultimately cartilage matrix degeneration in OA. Dynamic contrast (gadolinium) enhanced magnetic resonance imaging (DCE-MRI) was used to quantify perfusion kinetics in normal and osteoarthritic subchondral bone, demonstrating that decreased perfusion temporally precedes and spatially correlates with cartilage lesions in both young Dunkin-Hartley (D-H) guinea pigs and humans with osteoarthritis. Pharmacokinetic analysis of DCE-MRI generated data reveals decreased tracer clearance and outflow obstruction in the medial tibial plateau of osteoarthritic guinea pigs, coinciding with progressive cartilage degradation, loss of Safranin O staining, and increased expression of matrix metalloproteinases and interleukin-1. Positron emission tomographic (PET) scanning using 18F-Fluoride reveals a relationship among bone blood flow, cartilage lesions, and 18F-Fluoride influx rate in OA, highlighting the intricate relationships between decreased perfusion, altered bone metabolism, and the progression of osteoarthritis. These findings, supported by 18F-Fluoride PET data, suggest the presence of venous stasis associated with outflow obstruction, emphasizing the role of decreased subchondral bone perfusion in the pathophysiology of OA and its association with reduced osteoblast activity and advanced cartilage degeneration.

Management of Garden-I and II Femoral Neck Fractures: Perspectives on Primary Arthroplasty.

This review compares internal fixation versus arthroplasty in the treatment of nondisplaced femoral neck fractures (FNFs) calling attention to evolving areas of consensus that influence clinical decision-making. The Garden classification system, typically dichotomized into nondisplaced (types I and II) and displaced (types III and IV) fractures, has been used as a guide for surgical decision-making. Conventionally, treatment of nondisplaced FNF in the elderly has been with internal fixation, and treatment of a displaced FNF has been hemi-, or more recently total hip, arthroplasty. Studies over the last decade have raised concern over the appropriate treatment of nondisplaced FNFs due to high rates of reoperation of nondisplaced FNFs treated with internal fixation. Avascular necrosis (AVN), failure of internal fixation, secondary malunion, and pin/nail penetration through the femoral head have all been observed. Several studies have attributed fixation failure to a degree of femoral neck tilt ≥20°, either posteriorly or anteriorly as seen on the lateral X-ray. Because of these observations of fixation failures, the suggestion has been made that arthroplasty be used when the degree of posterior tilt exceeds a threshold of ≥20° tilt with the expectation of diminishing failure of fixation, decreasing the risk of reoperation and preserving function without increasing mortality rate. Frustrating additional analyses are uncertainties over the mechanisms of failure of internal fixation with ≥20° tilt and the persistently substantial 1-year mortality rate after FNF, which has not been influenced by fixation or replacement type. Due to the lack of consensus regarding the determination of the appropriate surgical intervention for nondisplaced FNFs, an improved algorithm for surgical decision-making for these fractures may prove useful.

Ochronotic Chondropathy: A Case Report.

Endogenous ochronosis, also known as alkaptonuria, is a rare disease known for its bluish-black discoloration of the skin, sclerae, and pinnae, as well as urine that turns black upon standing. Though rarely fatal, joint degradation is a common sequela, and many patients require multiple large joint arthroplasties throughout their lifetime. Though many aspects of the pathophysiological mechanisms of the disease have been described, questions remain, such as how the initiation of ochronotic pigmentation is prompted and the specific circumstances that make some tissues more resistant to pigmentation-related damage than others. In this report, we present the case of an 83-year-old female previously diagnosed with alkaptonuria including high-quality arthroscopic images displaying the fraying of articular cartilage. We also offer a summary of the latest literature on the pathophysiological mechanisms of the disease, including cellular-level changes observed in ochronotic chondrocytes, biochemical and mechanical alterations to the cartilaginous extracellular matrix, and patterns of pigmentation and joint degradation observed in humans and mice models. With these, we present an overview of the mechanisms of ochronotic chondropathy and joint degradation as the processes are currently understood. While alkaptonuria itself is rare, it has been termed a "fundamental disease," implying that its study and greater understanding have the potential to lead to insights in skeletal biology in general, as well as more common pathologies such as osteoarthritis and their potential treatment mechanisms.

LRP5, Bone Mass Polymorphisms and Skeletal Disorders.

The formation and maintenance of the gross structure and microarchitecture of the human skeleton require the concerted functioning of a plethora of morphogenic signaling processes. Through recent discoveries in the field of genetics, numerous genotypic variants have been implicated in pathologic skeletal phenotypes and disorders arising from the disturbance of one or more of these processes. For example, total loss-of-function variants of LRP5 were found to be the cause of osteoporosis-pseudoglioma syndrome (OPPG). LRP5 encodes for the low-density lipoprotein receptor-related protein 5, a co-receptor in the canonical WNT-ß-catenin signaling pathway and a crucial protein involved in the formation and maintenance of homeostasis of the human skeleton. Beyond OPPG, other partial loss-of-function variants of LRP5 have been found to be associated with other low bone mass phenotypes and disorders, while LRP5 gain-of-function variants have been implicated in high bone mass phenotypes. This review introduces the roles that LRP5 plays in skeletal morphogenesis and discusses some of the structural consequences that result from abnormalities in LRP5. A greater understanding of how the LRP5 receptor functions in bone and other body tissues could provide insights into a variety of pathologies and their potential treatments, from osteoporosis and a variety of skeletal abnormalities to congenital disorders that can lead to lifelong disabilities.

The Effect of Surgical Duration on Complications and Patient Reported Outcomes in Total Hip Replacement as Evaluated Through Multi-Surgeon Pooled FORCE Registry Data from a Tertiary Care Referral Total Joint Center.

BACKGROUND: The relationship between operative times and patient outcomes in total hip arthroplasty (THA) has not been well defined. METHODS: From January 2016 to December 2019, data were prospectively collected for THA patients in the FORCE-TJR registry and hospital EMR of an academic total-joint center. RESULTS: 1,123 patients were included. Operative times ranged from 36 to 366 minutes, with a mean operative time of 111.26+/-31.37 minutes. Unadjusted GLM showed HOOS pain, ADL, and QoL scores differed across operative times, with patients who had operative times between 106 and 120 minutes having significantly lower pain, higher function, and better quality of life at 12 months, especially compared to patients with operative times < 90 minutes. Patients who had operative times between 106 and 120 minutes had significantly better VR-12 PCS and MCS at 12 months. Although statistically significant, differences were small and did not persist after controlling for within-surgeon effects, patient socio-demographics and baseline patient-reported outcomes, suggesting that patient characteristics or within-surgeon effects may play a more significant role in these patient-reported outcomes than operative time. CONCLUSION: This study showed that among THA patients, operative times were significantly associated with patient-reported outcomes at 12 months post-operatively, but is one of many surgeon and patient-related factors with effect on THA outcome.

Spontaneous Bone Marrow Edema: Perfusion Abnormalities and Treatment with Surgical Decompression.

Bone marrow edema (BME), also termed bone marrow lesions, is a syndrome characterized by bone pain and the appearance of high signal intensity on T2 fat-suppressed and short tau inversion recovery (STIR) MRI sequences. BME can be related to trauma or a variety of non-traumatic diseases, and current treatment modalities include non-steroidal anti-inflammatory drugs (NSAIDS), bisphosphonates, denosumab, extracorporeal shockwave therapy (ESWT), the vasoactive prostacyclin analogue iloprost, and surgical decompression. Spontaneous BME is a subset that has been observed with no apparent causative conditions. It is most likely caused by venous outflow obstruction and intraosseous hypertension. These are mechanistically related to impaired perfusion and ischemia in several models of BME and are related to bone remodeling. The association of perfusion abnormalities and bone pain provides the pathophysiological rationale for surgical decompression. We present a case of spontaneous BME and a second case of spontaneous migratory BME treated with surgical decompression and demonstrate resolution of pain and the high signal intensity on MRI. This report provides an integration of the clinical syndrome, MR imaging characteristics, circulatory pathophysiology, and treatment. It draws upon several studies to suggest that both the bone pain and the MRI characteristics are related to venous stasis, and when circulatory pathologies are relieved by decompression or fenestration, both the bone pain and the MRI signal abnormalities resolve.

Metabolic Bone Disorders Are Predictors for 2-year Adverse Outcomes in Patients Undergoing 2-3 Level Anterior Cervical Discectomy and Fusion for Cervical Radiculopathy or Myelopathy.

STUDY DESIGN: Retrospective cohort study utilizing the New York statewide planning and research cooperative system. STUDY OBJECTIVE: To investigate postoperative complications of patients with metabolic bone disorders (MBDs) who undergo 2-3 levels of anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: MBDs and cervical degenerative pathologies, including cervical radiculopathy (CR) and cervical myelopathy (CM), are prevalent in the aging population. Complications with ACDF procedures can lead to increased hospitalization times, more expensive overhead, and worse patient outcomes. METHOD: Patients with CM/CR who underwent an ACDF of 2-3 vertebrae from 2009 to 2011 with a minimum 2-year follow-up were identified. Patients diagnosed with 1 or more MBD at baseline were compared with a control cohort without any MBD diagnosis. Cohorts were compared for demographics, hospital-related parameters, and 2-year medical, surgical, and overall complications. Binary multivariate logistic regression was used to identify independent predictors. RESULTS: A total of 22,276 patients were identified (MBD: 214; no-MBD: 22,062). Among MBD patients, the majority had vitamin D deficiency (n = 194, 90.7%). MBD patients were older (53.0 vs 49.7 y, P < 0.001), and with higher Deyo index (1.0 vs 0.5, P < 0.001). MBD patients had higher rates of medical complications, including anemia (6.1% vs 2.3%), pneumonia (4.7% vs 2.1%), hematoma (3.3% vs 0.7%), infection (2.8% vs 0.9%), and sepsis (3.7% vs 0.9%), as well as overall medical complications (23.8% vs 9.6%) (all, P ≤0.033). MBD patients also experienced higher surgical complications, including implant-related (5.7% vs 1.9%), wound infection (4.2% vs 1.2%), and wound disruption (0.9% vs 0.2%), and overall surgical complications (9.8% vs 3.2%) (all, P ≤0.039). Regression analysis revealed that a baseline diagnosis of MBD was independently associated with an increased risk of 2-year surgical complications (odds ratio = 2.10, P < 0.001) and medical complications (odds ratio = 1.84, P = 0.001). CONCLUSIONS: MBD as a comorbidity was associated with an increased risk of 2-year postoperative complications after 2-3 level ACDF for CR or CM.

Osteoporosis, Fractures, and Blindness Due to a Missense Mutation in the LRP5 Receptor.

Familial exudative vitreoretinopathy (FEVR) is a genetic disorder whose presentation can include osteoporosis, multiple fractures, and incomplete retinal angiogenesis leading to retinal detachment and blindness if left untreated. Discussed herein are the cases of two pediatric siblings who presented to the orthopedic service with multiple fractures and, through interdisciplinary management, were diagnosed with FEVR and treated appropriately before permanent visual impairment. The skeletal manifestations of FEVR, which have not been explored in depth in prior literature, are described. One sibling presented to orthopedic services for evaluation of a closed distal radius fracture sustained while playing sports. A comprehensive history revealed he had suffered at least four appendicular fractures in his lifetime, and dual-energy x-ray absorptiometry (DEXA) scan revealed his bone density to be in the first percentile for his age. Concurrent evaluation of his younger sibling revealed a similar history of multiple fractures and low bone density. Referral to genetic services and ensuing whole-exome sequencing revealed a likely pathogenic variant in both siblings' LRP5 gene, the only known causative mutation for FEVR that leads to skeletal manifestations. While FEVR is well known in genetic and ophthalmologic settings, greater awareness of FEVR and other genetic disorders that predispose to fractures in pediatric populations is warranted in orthopedic settings. This will lead to reduced sequelae in pediatric patients with genetic disorders and improved interdisciplinary expertise. The story of these siblings illustrates that a high index of suspicion for genetic diseases is essential when treating children with osteoporosis and growth delays.

Can We Predict Imbalance in Patients? Analysis of the CDC National Health and Nutrition Examination Survey.

Understanding global body balance can optimize the postoperative course for patients undergoing spinal or lower limb surgical realignment. This observational cohort study aimed to characterize patients with reported imbalance and identify predictors. The CDC establishes a representative sample annually via the NHANES. All participants who said "yes" (Imbalanced) or "no" (Balanced) to the following question were identified from 1999-2004: "During the past 12 months, have you had dizziness, difficulty with balance or difficulty with falling?" Univariate analyses compared Imbalanced versus Balanced subjects and binary logistic regression modeling predicted for Imbalance. Of 9964 patients, imbalanced (26.5%) were older (65.4 vs. 60.6 years), with more females (60% vs. 48%). Imbalanced subjects reported higher rates of comorbidities, including osteoporosis (14.4% vs. 6.6%), arthritis (51.6% vs. 31.9%), and low back pain (54.4% vs 32.7%). Imbalanced patients had more difficulty with activities, including climbing 10 steps (43.8% vs. 21%) and stooping/crouching/kneeling (74.3% vs. 44.7%), and they needed greater time to walk 20 feet (9.5 vs. 7.1 s). Imbalanced subjects had significantly lower caloric and dietary intake. Regression revealed that difficulties using fingers to grasp small objects (OR: 1.73), female gender (OR: 1.43), difficulties with prolonged standing (OR: 1.29), difficulties stooping/crouching/kneeling (OR: 1.28), and increased time to walk 20 feet (OR: 1.06) were independent predictors of Imbalance (all p < 0.05). Imbalanced patients were found to have identifiable comorbidities and were detectable using simple functional assessments. Structured tests that assess dynamic functional status may be useful for preoperative optimization and risk-stratification for patients undergoing spinal or lower limb surgical realignment.

Stimulation of Chondrogenesis in a Developmental Model of Endochondral Bone Formation by Pulsed Electromagnetic Fields.

Notable characteristics of the skeleton are its responsiveness to physical stimuli and its ability to remodel secondary to changing biophysical environments and thereby fulfill its physiological roles of stability and movement. Bone and cartilage cells have many mechanisms to sense physical cues and activate a variety of genes to synthesize structural molecules to remodel their extracellular matrix and soluble molecules for paracrine signaling. This review describes the response of a developmental model of endochondral bone formation which is translationally relevant to embryogenesis, growth, and repair to an externally applied pulsed electromagnetic field (PEMF). The use of a PEMF allows for the exploration of morphogenesis in the absence of distracting stimuli such as mechanical load and fluid flow. The response of the system is described in terms of the cell differentiation and extracellular matrix synthesis in chondrogenesis. Emphasis is placed upon dosimetry of the applied physical stimulus and some of the mechanisms of tissue response through a developmental process of maturation. PEMFs are used clinically for bone repair and have other potential clinical applications. These features of tissue response and signal dosimetry can be extrapolated to the design of clinically optimal stimulation.

Rehabilitation for Total Knee Arthroplasty: A Systematic Review.

ABSTRACT: We sought to determine the comparative benefit and harm of rehabilitation interventions for patients who have undergone elective, unilateral total knee arthroplasty for the treatment of primary osteoarthritis. We searched PubMed, Embase, The Cochrane Register of Clinical Trials, CINAHL, PsycINFO, Scopus, and ClinicalTrials.gov from January 1, 2005, through May 3, 2021. We included randomized controlled trials and adequately adjusted nonrandomized comparative studies of rehabilitation programs reporting performance-based, patient-reported, or healthcare utilization outcomes. Three researchers extracted study data and assessed risk of bias, verified by an independent researcher. The team assessed strength of evidence. Evidence from 53 studies randomized controlled trials suggests that various rehabilitation programs after total knee arthroplasty may lead to comparable improvements in pain, range of motion, and activities of daily living. Rehabilitation in the acute phase may lead to increased strength but result in similar strength when delivered in the postacute phase. No studies reported evidence of risk of harms due to rehabilitation delivered in the acute period after total knee arthroplasty; risk of harms among various postacute rehabilitation programs seems comparable. All findings were of low strength of evidence. Evaluation of rehabilitation after total knee arthroplasty needs a systematic overhaul to sufficiently guide future practice or research including the use of standardized intervention components and core outcomes.

Prehabilitation for Total Knee or Total Hip Arthroplasty: A Systematic Review.

ABSTRACT: We sought to systematically review the evidence on the benefits and harms of prehabilitation interventions for patients who are scheduled to undergo elective, unilateral total knee arthroplasty or total hip arthroplasty surgery for the treatment of primary osteoarthritis. We searched PubMed, Embase, The Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, Scopus, and ClinicalTrials.gov from January 1, 2005, through May 3, 2021. We selected for inclusion randomized controlled trials and adequately adjusted nonrandomized comparative studies of prehabilitation programs reporting performance-based, patient-reported, or healthcare utilization outcomes. Three researchers extracted study data and assessed risk of bias, verified by an independent researcher. Experts in rehabilitation content and complex interventions independently coded rehabilitation interventions. The team assessed strength of evidence. While large heterogeneity across evaluated prehabilitation programs limited strong conclusions, evidence from 13 total knee arthroplasty randomized controlled trials suggest that prehabilitation may result in increased strength and reduced length of stay and may not lead to increased harms but may be comparable in terms of pain, range of motion, and activities of daily living (all low strength of evidence). There was no evidence or insufficient evidence for all other outcomes after total knee arthroplasty. Although there were six total hip arthroplasty randomized controlled trials, there was no evidence or insufficient evidence for all total hip arthroplasty outcomes.

Rehabilitation for Total Hip Arthroplasty: A Systematic Review.

ABSTRACT: We sought to determine the comparative benefits and harms of rehabilitation interventions for patients who have undergone elective, unilateral THA surgery for the treatment of primary osteoarthritis. We searched PubMed, Embase, The Cochrane Register of Clinical Trials, CINAHL, PsycINFO, Scopus, and ClinicalTrials.gov from January 1, 2005, through May 3, 2021. We included randomized controlled trials and adequately adjusted nonrandomized comparative studies of rehabilitation programs reporting performance-based, patient-reported, or healthcare utilization outcomes. Three researchers extracted study data and assessed risk of bias, verified by an independent researcher. Experts in rehabilitation content and complex interventions independently coded rehabilitation interventions. The team assessed strength of evidence. Large heterogeneity across evaluated rehabilitation programs limited conclusions. Evidence from 15 studies suggests that diverse rehabilitation programs may not differ in terms of risk of harm or outcomes of pain, strength, activities of daily living, or quality of life (all low strength of evidence). Evidence is insufficient for other outcomes. In conclusion, no differences in outcomes were found between different rehabilitation programs after THA. Further evidence is needed to inform decisions on what attributes of rehabilitation programs are most effective for various outcomes.

The Roles of a Fracture Liaison Service.

The roles of a fracture liaison service (FLS) are extensive and include, but are not limited to: 1) providing a standardized framework for the evaluation and management of low-energy fractures, also known as fragility fractures; 2) improving patient outcomes through the recognition of fragility fractures as signal events requiring further diagnostic explanation; and 3) lowering direct and indirect healthcare expenditures. One of the central tenets of the FLS is its recognition of fragility fractures as warning signs of underlying pathology, often osteoporosis or other metabolic bone diseases. This understanding, combined with the application of a multidisciplinary management team specialized in diagnosing and treating such pathologies, allows for better short- and long-term management of patients and concordant improvement in outcomes. This article should be viewed as a thematic introduction to the FLS, with others in this volume each illustrating specific examples of how FLS paradigms facilitate the roles described herein.

Osteoporosis and Fragility Fractures.

Osteoporosis and fragility fractures (FFs) are closely intertwined as the former is a common predisposing factor to the latter. This causal relationship is due to low bone density of osteoporosis and compromised bone microarchitecture, leading to structural failure, decreased ability to withstand applied stresses, and increased propensity to fracture. Osteoporosis can be idiopathic or due to a variety of secondary causes, and numerous treatment strategies are available. FFs are common injuries among the elderly and are caused by factors both intrinsic and extrinsic to the patient. The clinical and economic significances of osteoporosis and FFs are substantial, with considerable associated morbidity and mortality, and billions spent on healthcare expenditures in the US annually. Osteoporosis and FFs are two of the most important topics related to fracture liaison services (FLSs), and their understanding is integral to appreciating the benefits an FLS can provide for patients and providers.

Osteomalacia and Renal Osteodystrophy.

Osteomalacia is defined by the undermineralization of newly formed bone due to a lack of available calcium, phosphorus, or vitamin D. Causative factors of osteomalacia include nutritional deficiency, diminished absorptive capabilities (often due to gastrointestinal disorders), and renal insufficiency. Renal osteodystrophy is a specific form of metabolic bone disease defined by the presence of osteomalacia and associated hyperparathyroidism secondary to a malfunction in, or absence of, renal parenchyma. This reduces the conversion of vitamin D to its active form, thus leading to a cascade of effects that negatively impact the stability of the skeleton. Osteomalacia occurs across a spectrum of severity and can produce severe consequences for specific populations, including patients with dietary, nutritional, and absorptive deficiencies. Renal osteodystrophy affects patients with chronic kidney disease, those undergoing dialysis, and renal transplant patients. Special considerations must be taken into account when assessing the bone health of patients fitting these criteria.

Monoclonal Gammopathies in a Fracture Liaison Service.

Monoclonal gammopathies are a spectrum of disorders characterized by the overproduction of plasma B-cells and immunoglobulin. Monoclonal gammopathy of uncertain significance (MGUS), a pre-malignant form of multiple myeloma, is defined by relatively low bone marrow concentration of clonal plasma cells and asymptomatic clinical presentation. New evidence, however, points to an association of MGUS with osteoporosis, microarchitectural bone deficiency, and fractures, and it has been suggested that it be renamed "Monoclonal Gammopathy of Skeletal Significance." The prevalence of MGUS in the general geriatric population is estimated to be 3-8%, while the prevalence in geriatric vertebral fracture patients is 15%, and the prevalence in all fracture patients within the Rhode Island Fracture Liaison Service is 10%. Therefore, MGUS and other monoclonal gammopathies should be suspected in all patients diagnosed with osteoporosis or an osteoporotic fracture, and patients diagnosed with monoclonal gammopathies should be evaluated for osteoporosis and fracture risk and treated appropriately.

Hyperparathyroidism in a Fracture Population.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder that results in excess parathyroid hormone (PTH) secretion and hypercalcemia. PHPT is usually caused by an adenoma and its presentation is often asymptomatic, though it can negatively impact the skeleton via osteoporosis mostly affecting cortical bone and fracture. The diagnosis of PHPT is made by clinical presentation and biochemical and hormonal assessment. Surgical treatment guided by ultrasound sonography and/or 99mTc-sestamibi scintigraphy is generally curative. Normocalcemic hyperparathyroidism (NPHPT) is a variant of hyperparathyroidism defined by normal serum calcium and persistently elevated serum PTH levels. Limited data exist on NPHPT's effects on the skeleton, though current evidence suggests a positive correlation between the disorder and the presence of osteoporotic fractures. Taken together, patients affected by the various manifestations of hyperparathyroidism and their associated homeostatic disturbances represent a not insignificant portion of fracture patients seen in a fracture liaison service.

Biophysical Modulation of Mesenchymal Stem Cell Differentiation in the Context of Skeletal Repair.

A prominent feature of the skeleton is its ability to remodel in response to biophysical stimuli and to repair under varied biophysical conditions. This allows the skeleton considerable adaptation to meet its physiological roles of stability and movement. Skeletal cells and their mesenchymal precursors exist in a native environment rich with biophysical signals, and they sense and respond to those signals to meet organismal demands of the skeleton. While mechanical strain is the most recognized of the skeletal biophysical stimuli, signaling phenomena also include fluid flow, hydrostatic pressure, shear stress, and ion-movement-related electrokinetic phenomena including, prominently, streaming potentials. Because of the complex interactions of these electromechanical signals, it is difficult to isolate the significance of each. The application of external electrical and electromagnetic fields allows an exploration of the effects of these stimuli on cell differentiation and extra-cellular matrix formation in the absence of mechanical strain. This review takes a distinctly translational approach to mechanistic and preclinical studies of differentiation and skeletal lineage commitment of mesenchymal cells under biophysical stimulation. In vitro studies facilitate the examination of isolated cellular responses while in vivo studies permit the observation of cell differentiation and extracellular matrix synthesis.