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1.  Heat and Radiofrequency Plasma Glow Discharge Pretreatment of a Titanium Alloy Promote Bone Formation and Osseointegration 
Journal of cellular biochemistry  2013;114(10):10.1002/jcb.24585.
Orthopedic and dental implants manifest increased failure rates when inserted into low density bone. We determined whether chemical pretreatments of a titanium alloy implant material stimulated new bone formation to increase osseointegration in vivo in trabecular bone using a rat model. Titanium alloy rods were untreated or pretreated with heat (600°C) or radiofrequency plasma glow discharge (RFGD). The rods were then coated with the extracellular matrix protein fibronectin (1 nM) or left uncoated and surgically implanted into the rat femoral medullary cavity. Animals were euthanized 3 or 6 weeks later, and femurs were removed for analysis. The number of trabeculae in contact with the implant surface, surface contact between trabeculae and the implant, and the length and area of bone attached to the implant were measured by histomorphometry. Implant shear strength was measured by a pull-out test. Both pretreatments and fibronectin enhanced the number of trabeculae bonding with the implant and trabeculae-to-implant surface contact, with greater effects of fibronectin observed with pretreated compared to untreated implants. RFGD pretreatment modestly increased implant shear strength, which was highly correlated (r2 = 0.87 – 0.99) with measures of trabecular bonding for untreated and RFGD-pretreated implants. In contrast, heat pretreatment increased shear strength 3 to 5-fold for both uncoated and fibronectin-coated implants at 3 and 6 weeks, suggesting a more rapid increase in implant-femur bonding compared to the other groups. In summary, our findings suggest that the heat and RFGD pretreatments can promote the osseointegration of a titanium alloy implant material.
PMCID: PMC3786157  PMID: 23649564
Dental implant; fibronectin; osteoblast; cell differentiation; bone mineralization; osseointegration
3.  Use of Imatinib in the Prevention of Heterotopic Ossification 
HSS Journal  2013;9(2):166-170.
Heterotopic ossification (HO) is a common complication following orthopedic and trauma surgery, which may have substantial negative effects on the postoperative outcome. Angiogenesis appears to play a critical role in heterotopic ossification. One of the involved signaling molecules is platelet-derived growth factor (PDGF) which may be inhibited by imatinib.
Our goal was to prevent HO by pharmacologically interfering with the molecular signaling pathways involved in the developmental process. We hypothesized that by administering a proven inhibitor of PDGF expression, heterotopic bone formation may be prevented.
The effect of imatinib on HO formation was studied in a murine model which reliably produces islets of HO within the soft tissue following Achilles tenotomy. The control group underwent Achilles tenotomy only. The imatinib group received imatinib mesylate. After trial completion, the limbs were harvested and scanned by micro-CT. Heterotopic bone volume was then identified and quantified.
The mean volume of heterotopic bone formed in the control group was 0.976mm3 compared to 0.221 mm3 in the imatinib group. The volume of HO in the treatment group was reduced by 85% compared to the control group.
The administration of imatinib was associated with a significantly reduced volume of HO. This may be due to the inhibitory effect of imatinib on the PDGF signaling pathway during development of HO.
Clinical Relevance
The successful reduction of HO formation following imatinib administration has led to further insight concerning the pathogenesis of HO which in the future may lead to new clinical approaches towards the prevention of HO.
Electronic supplementary material
The online version of this article (doi:10.1007/s11420-013-9335-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3757489  PMID: 24426864
heterotopic ossification; prevention; imatinib mesylate; murine; PDGF
4.  Low Vitamin D Status Does Not Adversely Affect Short-term Functional Outcome After Total Hip Arthroplasty 
The Journal of arthroplasty  2012;28(2):315-322.e2.
We prospectively measured functional performances (WOMAC, SF-36, 2-minute walk test and timed get-up-and-go test) of patients who underwent total hip arthroplasty (THA) and had serum vitamin D levels tested during the preoperative evaluation. Of 219 patients, 102 patients (46.6%) had low vitamin D levels (25-hydroxyvitamin D < 30 ng/mL). Low vitamin D status did not adversely affect short-term function at 6 weeks after THA. In addition, there was no association between serum vitamin D levels and the within-patient changes of scores of each outcome measurement. Since this 6-week period is generally adequate to correct vitamin D deficiency, orthopaedic surgeons can safely perform THA without delay. Nevertheless, because vitamin D deficiency impairs bone quality, patients with low vitamin D levels should be treated once identified.
PMCID: PMC4037853  PMID: 22795877
5.  Plasma 25-Hydroxyvitamin D Levels in Operative Patella Fractures 
HSS Journal  2013;9(1):17-20.
Patella fractures have not traditionally been considered “fragility” fractures.
The purpose of this study was to examine the demographic patterns (age and gender distribution) and plasma 25-hydroxyvitamin D levels of a cohort of patients with operative patella fractures.
Patients and Methods
Medical records were reviewed on all consecutive patients presenting to our institution with operative patella fractures from 2003 to 2009. Seventy-eight operative patella fractures (25 male, 53 female) were identified with a mean age of 58 years (range, 22–89 years).
The majority of patients with patella fractures in this series were females over the age of 50 years who sustained low-energy falls from a standing height or less. Twenty-four patients (80%) had vitamin D insufficiency or deficiency at the time of injury. For 68 patients (87%), the patella fracture represented their first fracture. Patients with known osteoporosis risk factors did not have higher rates of vitamin D insufficiency/deficiency.
The age and gender distribution, as well as the prevalence of vitamin D insufficiency/deficiency, of operative patella fractures, suggest that these patients likely have abnormal vitamin D levels and should undergo a metabolic bone work-up.
PMCID: PMC3640726  PMID: 24426839
patella fracture; osteoporosis; vitamin D; fragility fracture; metabolic bone disease
6.  Bisphosphonate-associated Femur Fractures Have High Complication Rates with Operative Fixation 
Bisphosphonate-associated femur fractures have been well described but the preoperative patient factors, treatment modalities, and complications of treatment are unclear.
We asked whether a diagnosis of osteoporosis, the characteristic radiographic features of bisphosphonate-related femur fractures, and complication rates differed in patients with operatively treated femoral shaft fractures receiving bisphosphonates and in patients not receiving bisphosphonates.
We retrospectively reviewed 43 patients with bisphosphonate-associated femoral shaft fractures (including subtrochanteric) from 2002 to 2008 and 20 patients with similar fractures but not treated with bisphosphonates. Similar implants were used in both groups, but a greater number of adjuvants were used in the bisphosphonate cohort. We recorded preoperative osteoporosis and radiographic findings of the characteristic bisphosphonate femur fracture and early complications. The minimum followup was 5 months (mean, 29 months; range 5–60 months).
Preoperatively a greater percentage of patients treated with bisphosphonates had confirmed osteoporosis than those not treated with bisphosphonates (24% versus 5%, respectively), a greater percentage had a proximal fracture location (48% versus 40%, respectively), and their mean cortex to shaft diameter ratio was greater (24% versus 15%, respectively). The bisphosphonate cohort had a higher rate of intraoperative fractures (21% versus 0%) and postoperative plate failures (30% versus 0%).
Despite low rates of other risk factors and ample use of biologic adjuvants, patients treated with bisphosphonates having femur fractures have more complications.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3392377  PMID: 22669553
7.  A Single-Dose Conformal Delivery of Radiotherapy Following Osteoplasty  
HSS Journal  2011;8(2):169-174.
Multiple myeloma (MM) is a very radiosensitive tumor. Fractionated external beam radiation, which takes approximately 2 weeks of therapy, is typically used to irradiate myelomatous bone lesions with the goal of palliation. However, traditional radiotherapeutic techniques are not only lengthy but they also involve a considerable amount of healthy bone marrow in the treatment ports, which may undermine the total marrow reserve of a patient. Because of the limited survival time of patients with metastatic cancer, novel treatment concepts shortening the overall treatment time is desirable. We present an innovative approach of delivering targeted intra-operative radiotherapy to a solitary osteolytic metastasis in one application, while sparing healthy bone marrow from radiation toxicity and substantially reducing the overall treatment time. A 78-year-old Caucasian male with MM, previously treated with chemotherapy, who was off chemotherapy for 2 years due to bone marrow suppression, presented with a solitary recurrence at the left anterior superior iliac spine of the left iliac wing as diagnosed by PET-CT scan. This lesion was treated with a minimally invasive osteoplasty and intra-operative brachytherapy with to a dose of 8 Gy delivered to the surgical cavity only, followed by injection of the bone cement into the cavity. Three months after the procedure, the area of treatment demonstrated no uptake on a follow-up PET-CT scan. At 1.5 years after this procedure, 100% local control continues to persist in the treated area, as evidenced on nuclear imaging. To our knowledge, this is the first case of using focal intra-operative brachytherapy confined to the area of the pelvis in a patient treated for a solitary metastasis from MM. The purpose of the article is to present a novel approach as a more convenient and focal treatment of bony lesions of MM.
PMCID: PMC3715619  PMID: 23874259
multiple myeloma; radiotherapy; conformal radiation; brachytherapy
8.  Management Strategy for Symptomatic Bisphosphonate-Associated Incomplete Atypical Femoral Fractures 
HSS Journal  2012;8(2):103-110.
Long-term bisphosphonate use has often been associated with atypical femoral fractures. These fractures evolve from incomplete femoral fractures. A previous study demonstrated that the presence of a radiolucent line in an incomplete fracture can indicate a high risk of progression to complete fracture.
The aim of this study is to present a management strategy for symptomatic bisphosphonate-associated incomplete atypical femoral fractures. Specific study questions include the following: (1) Is there a difference in the prognosis of these fractures based on the presence or absence of a radiolucent fracture line? (2) Can treatment with teriparatide assist in clinical/radiographic healing of these incomplete fractures? (3) Is there a characteristic biochemical profile in these patients?
Patients and Methods
We retrospectively examined all femur radiographs ordered by the metabolic bone disease service at our hospital between July 1, 2006 and July 1, 2011 and identified 10 patients with a total of 14 incomplete fractures. Nine patients received bisphosphonates for a mean duration of 10 ± 5 years (range, 4–17). The mean follow-up since the time of diagnosis was 20 ± 11 months (range, 6–36 months).
Five fractures did not have a radiolucent fracture line and were treated conservatively with partial weight-bearing restrictions and pharmacologic therapy. All five of these fractures healed with conservative management. Nine fractures had a radiolucent fracture line, and only two of these were treated successfully with conservative management including teriparatide. Six of the eight patients with a radiolucent line elected for surgical prophylaxis after 3 months of conservative management, whereas one patient underwent surgical prophylaxis without a trial of conservative management. Regarding the biochemical profiles, bone turnover markers for our patient cohort were in the lower quartile.
Fractures without a radiolucent line appear to respond to conservative management and not require surgical prophylaxis. Teriparatide treatment may hold promise in promoting healing of these fractures.
PMCID: PMC3715620  PMID: 23874247
bisphosphonates; atypical femoral fractures; incomplete fractures; teriparatide; radiolucent fracture line
9.  A Fracture Does Not Adversely Affect Bone Mineral Density Responses after Teriparatide Treatment 
Fracture leads to local and systemic catabolic physiologic changes. As teriparatide is an agent used to treat osteoporosis in patients with fragility fractures, it is unclear whether teriparatide treatment alters bone mineral density (BMD) and bone markers when given to patients with fractures.
We asked whether BMD and bone marker responses would be blunted in patients with fractures placed on teriparatide after fracture compared with patients without fractures on teriparatide.
Patients and Methods
We retrospectively collected data from 141 patients treated with teriparatide for osteoporosis. Seventy-seven patients received teriparatide after fractures (fracture group), whereas 64 were treated for other indications (nonfracture group). We determined BMD at the lumbar spine and at the proximal femur before and 12 and 24 months posttreatment. Bone markers (urine N-telopeptide [urine NTX], bone-specific alkaline phosphatase [BALP]) were measured at baseline and 3, 12, and 24 months posttreatment.
Mean lumbar spine and hip BMDs at last followup increased from baseline with no differences between groups to approximately 9% and 4% at 24 months, respectively. Both bone markers increased from baseline in the nonfracture group, peaking at 12 months. For the fracture group, only urine NTX increased at 3 and 12 months posttreatment. Although the peak levels of both bone markers in the nonfracture group were greater, there was no difference between the two groups.
Fracture does not have a negative effect on the BMD and bone marker responses to teriparatide treatment. Clinicians should anticipate comparable BMD responses when treating patients with teriparatide for osteoporotic fractures and for other indications.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3270178  PMID: 21863393
10.  Need to Knowledge (NtK) Model: an evidence-based framework for generating technological innovations with socio-economic impacts 
Traditional government policies suggest that upstream investment in scientific research is necessary and sufficient to generate technological innovations. The expected downstream beneficial socio-economic impacts are presumed to occur through non-government market mechanisms. However, there is little quantitative evidence for such a direct and formulaic relationship between public investment at the input end and marketplace benefits at the impact end. Instead, the literature demonstrates that the technological innovation process involves a complex interaction between multiple sectors, methods, and stakeholders.
The authors theorize that accomplishing the full process of technological innovation in a deliberate and systematic manner requires an operational-level model encompassing three underlying methods, each designed to generate knowledge outputs in different states: scientific research generates conceptual discoveries; engineering development generates prototype inventions; and industrial production generates commercial innovations. Given the critical roles of engineering and business, the entire innovation process should continuously consider the practical requirements and constraints of the commercial marketplace.
The Need to Knowledge (NtK) Model encompasses the activities required to successfully generate innovations, along with associated strategies for effectively communicating knowledge outputs in all three states to the various stakeholders involved. It is intentionally grounded in evidence drawn from academic analysis to facilitate objective and quantitative scrutiny, and industry best practices to enable practical application.
The Need to Knowledge (NtK) Model offers a practical, market-oriented approach that avoids the gaps, constraints and inefficiencies inherent in undirected activities and disconnected sectors. The NtK Model is a means to realizing increased returns on public investments in those science and technology programs expressly intended to generate beneficial socio-economic impacts.
PMCID: PMC3598477  PMID: 23414369
Knowledge translation; Technology transfer; Commercial transaction; Evidence-based; Technology-based; Scientific research; Engineering development; Industrial production; States of knowledge; Innovation
11.  The Effect of Long-term Alendronate Treatment on Cortical Thickness of the Proximal Femur 
One of the radiographic hallmarks in patients with atypical femoral insufficiency fractures after prolonged bisphosphonate treatment is generalized cortical hypertrophy. Whether cortical thickening in the proximal femur is caused by long-term alendronate therapy, however, remains unknown.
We asked whether long-term alendronate use of 5 years or more results in progressive thickening of the subtrochanteric femoral cortices.
Patients and Methods
We retrospectively evaluated changes in cortical thickness and cortical thickness ratio (ratio of cortical to femoral shaft diameter) at the subtrochanteric region of the proximal femur in baseline and latest hip dual-energy xray absorptiometry (DXA) scans of 131 patients. The mean followup was 7.3 years. Patients were divided into two groups: control (no history of alendronate, 45 patients) and alendronate (history of alendronate ≥ 5 years, 86 patients). We determined cortical thickness and cortical thickness ratio at 3.5 and 4.0 cm below the tip of the greater trochanter, representing the subtrochanteric region.
After a minimum of 5 years followup, mean cortical thickness decreased approximately 3% in the alendronate and control groups. The cortical thickness at the subtrochanteric femoral region changed less than 1 mm in greater than 90% of the patients with long-term alendronate treatment. We observed no differences in mean changes of cortical thickness and percent changes of cortical thickness between the two groups.
Long-term alendronate treatment did not appear to cause thickened femoral cortices within the detection limits of our method. This finding contrasts with the notion that long-term alendronate treatment leads to generalized cortical thickening.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3237985  PMID: 21773861
13.  Diseases Affecting Bone Quality: Beyond Osteoporosis 
Bone quantity, quality, and turnover contribute to whole bone strength. Although bone mineral density, or bone quantity, is associated with increased fracture risk, less is known about bone quality. Various conditions, including disorders of mineral homeostasis, disorders in bone remodeling, collagen disorders, and drugs, affect bone quality.
The objectives of this review are to (1) identify the conditions and diseases that could adversely affect bone quality besides osteoporosis, and (2) evaluate how these conditions influence bone quality.
We searched PubMed using the keywords “causes” combined with “secondary osteoporosis” or “fragility fracture.” After identifying 20 disorders/conditions, we subsequently searched each condition to evaluate its effect on bone quality.
Many disorders or conditions have an effect on bone metabolism, leading to fragility fractures. These disorders include abnormalities that disrupt mineral homeostasis, lead to an alteration of the mineralization process, and ultimately reduce bone strength. The balance between bone formation and resorption is also essential to prevent microdamage accumulation and maintain proper material and structural integrity of the bone. As a result, diseases that alter the bone turnover process lead to a reduction of bone strength. Because Type I collagen is the most abundant protein found in bone, defects in Type I collagen can result in alterations of material property, ultimately leading to fragility fractures. Additionally, some medications can adversely affect bone.
Recognizing these conditions and diseases and understanding their etiology and pathogenesis is crucial for patient care and maintaining overall bone health.
PMCID: PMC3126973  PMID: 21107923
14.  Sex and Gender Considerations in Male Patients With Osteoporosis 
Osteoporosis remains underrecognized and undertreated in both men and women, but men who sustain fragility fractures experience greater morbidity and mortality. While men exhibit advanced comorbidity at the time of hip fracture presentation, there are distinct sex- and gender-specific factors related to the pathophysiology and treatment of osteoporosis that further influence morbidity and mortality.
With a selective review of the literature, we evaluated sex- and gender-based differences contributing to increased morbidity and mortality in men with osteoporosis.
Where are we now?
Sex-specific differences in bone biology and morphology may affect the pathophysiology of osteoporosis, choice of pharmacotherapy, and surgical implant selection. Additionally, estrogen metabolism may play a key role in both fracture prevention and healing. Gender-based differences in recommendations for screening and prevention between men and women may influence the severity at which osteoporosis is recognized. Primary, secondary, and tertiary prevention efforts in men lag behind those of women. This may be due to a lack of consensus regarding screening guidelines for osteoporosis in men but may be attributed to lack of awareness in the physician and patient about osteoporosis and its potentially debilitating consequences.
Where do we need to go?
These disparities are a call to action for healthcare providers to raise awareness for early prevention and treatment of this potentially debilitating disease, particularly in men.
How do we get there?
Continued prospective research on the differences between men and women diagnosed with osteoporosis is needed, as well as sex-specific stratification of data in all studies on osteoporosis.
PMCID: PMC3111783  PMID: 21400003
15.  Does a Multidisciplinary Team Decrease Complications in Male Patients With Hip Fractures? 
Men with hip fractures are more likely to experience postoperative complications than women. The Medical Orthopaedic Trauma Service program at New York Presbyterian Hospital utilizes a multidisciplinary team approach to care for patients with hip fractures. The service is comanaged by an attending hospitalist and orthopaedic surgeon, with daily walking rounds attended by the hospitalist, orthopaedic resident, physical therapist, social worker, and a dedicated Medical Orthopaedic Trauma Service physician assistant.
We asked whether a multidisciplinary service for patients with hip fracture decreases (1) the incidence of inpatient complications in men, (2) the length of hospitalization, and (3) 90-day and 1-year mortality.
Patients and Methods
We retrospectively reviewed the charts of 74 men who had surgery for a nonperiprosthetic femoral neck, intertrochanteric, or subtrochanteric fracture for two 7-month periods before and after implementation of the Medical Orthopaedic Trauma Service. Age, ethnicity, comorbidity status, time to surgery, and postoperative complication data were collected. Regression modeling was used to evaluate the likelihood of postoperative complications, length of hospitalization, and 90-day and 1-year mortality while controlling for age, Charlson Comorbidity Index score, fracture type, and time from admission to surgery.
We observed a decrease in the likelihood of experiencing at least one inpatient complication in male patients after implementation of the Medical Orthopaedic Trauma Service (odds ratio = 0.264). There was no difference in length of hospitalization, 90-day mortality, or 1-year mortality.
Multidisciplinary collaboration for patients with hip fractures can decrease the likelihood of experiencing inpatient complications in male patients.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3111804  PMID: 21350887
16.  Modeling technology innovation: How science, engineering, and industry methods can combine to generate beneficial socioeconomic impacts 
Government-sponsored science, technology, and innovation (STI) programs support the socioeconomic aspects of public policies, in addition to expanding the knowledge base. For example, beneficial healthcare services and devices are expected to result from investments in research and development (R&D) programs, which assume a causal link to commercial innovation. Such programs are increasingly held accountable for evidence of impact—that is, innovative goods and services resulting from R&D activity. However, the absence of comprehensive models and metrics skews evidence gathering toward bibliometrics about research outputs (published discoveries), with less focus on transfer metrics about development outputs (patented prototypes) and almost none on econometrics related to production outputs (commercial innovations). This disparity is particularly problematic for the expressed intent of such programs, as most measurable socioeconomic benefits result from the last category of outputs.
This paper proposes a conceptual framework integrating all three knowledge-generating methods into a logic model, useful for planning, obtaining, and measuring the intended beneficial impacts through the implementation of knowledge in practice. Additionally, the integration of the Context-Input-Process-Product (CIPP) model of evaluation proactively builds relevance into STI policies and programs while sustaining rigor.
The resulting logic model framework explicitly traces the progress of knowledge from inputs, following it through the three knowledge-generating processes and their respective knowledge outputs (discovery, invention, innovation), as it generates the intended socio-beneficial impacts. It is a hybrid model for generating technology-based innovations, where best practices in new product development merge with a widely accepted knowledge-translation approach. Given the emphasis on evidence-based practice in the medical and health fields and “bench to bedside” expectations for knowledge transfer, sponsors and grantees alike should find the model useful for planning, implementing, and evaluating innovation processes.
High-cost/high-risk industries like healthcare require the market deployment of technology-based innovations to improve domestic society in a global economy. An appropriate balance of relevance and rigor in research, development, and production is crucial to optimize the return on public investment in such programs. The technology-innovation process needs a comprehensive operational model to effectively allocate public funds and thereby deliberately and systematically accomplish socioeconomic benefits.
PMCID: PMC3466157  PMID: 22591638
17.  Engaging national organizations for knowledge translation: Comparative case studies in knowledge value mapping 
Government sponsors of research and development, along with their funded investigators, are increasingly tasked with demonstrating evidence of knowledge use by nontraditional audiences. This requires efforts to translate their findings for effective communication. For technology-related knowledge, these audiences include clinicians, consumers, manufacturers, public policy agencies, and knowledge brokers. One potentially efficient approach is to communicate research findings through relevant national organizations. However, this requires an understanding of how such organizations view and treat research knowledge, which can be determined through knowledge-value mapping. Do knowledge values differ between national organizations representing different audiences? Can a deeper understanding of knowledge values help sponsors, investigators, and organizations better communicate research findings to stakeholders?
A series of comparative case studies on knowledge-value mapping were derived through interviews with spokespersons for six national organizations. The semi-structured interviews followed a 10-item questionnaire to characterize different ways in which each organization engages with research-based knowledge. Each participating organization represents a particular stakeholder group, while all share a common interest in the research subject matter.
Each national organization considers the value of the research knowledge in the context of their organization's mission and the interests of their members. All are interested in collaborating with researchers to share relevant findings, while they vary along the following dimensions of knowledge engagement: create, identify, translate, adapt, communicate, use, promote, absorptive capacity, and recommendations for facilitation.
The principles of knowledge translation suggest that investigators can increase use by tailoring the format and context of their findings to the absorptive capacity of nonscholars. Greater absorption should result in higher levels of knowledge awareness, interest, and use, which can then be documented. National organizations and their members, in turn, can strive to optimize their absorptive capacities regarding the state of the sciences. This combination will ensure the highest possible return on public investment in research activities. This knowledge-value mapping study concludes that national organizations are appropriate channels for communicating research findings and for meeting statutory requirements and general expectations for generating and documenting knowledge use.
PMCID: PMC3180429  PMID: 21910866
18.  Nitric oxide modulates recombinant human bone morphogenetic protein-2-induced corticocancellous autograft incorporation: a study in rat intertransverse fusion 
European Spine Journal  2010;19(6):931-939.
A novel rat model was used to investigate the effect of nitric oxide synthase inhibition in posterior spinal fusion augmented with recombinant human bone morphogenetic protein-2. Nitric oxide (NO) has important physiological functions including the modulation of fracture healing. Recombinant human BMP-2 (rhBMP-2) enhances spinal fusion. It is not known whether nitric oxide has a role in rhBMP-2 enhanced spinal fusion and remodeling. A novel rat intertransverse fusion model was created using a defined volume of bone graft along with a collagen sponge carrier, which was compacted and delivered using a custom jig. The control groups consisted of a sham group (S, n = 20), an autograft + carrier group (A, n = 28) and a group consisting of 43 μg of rhBMP-2 mixed with autograft + carrier (AB, n = 28). Two experimental groups received a nitric oxide synthase (NOS) inhibitor, NG-nitro l-arginine methyl ester, in a dose of 1 mg/ml ad lib in the drinking water (AL, n = 28) and one of these experimental groups had rhBMP-2 added to the graft mixture at the time of surgery (ALB, n = 28). Rats were killed at 22 and 44 days, spinal columns subjected to radiology, biomechanics and histology. On a radiographic score (0–4) indicating progressive maturation of bone fusion mass, no difference was found between the A and AL groups, however, there was a significant enhancement of fusion when rhBMP-2 was added when compared to the A group (P < 0.001). However, on day 44, the ALB group showed significantly less fusion progression when compared to the AB group (P < 0.01). There was a 25% (P < 0.05) more fusion-mass-area in day 44 of ALB group when compared to day 44 of the AB group indicating that NOS inhibition delayed the remodeling of the fusion mass. Biomechanically, the rhBMP-2 groups were stiffer at all time points compared to the NOS inhibited groups. Decalcified histology demonstrated that there was a delay in graft incorporation whenever NOS was inhibited (AL and ALB groups) as assessed by a 5 point histological maturation score. In a novel model of rat intertransverse process fusion, nitric oxide synthase modulates rhBMP-2 induced corticocancellous autograft incorporation.
PMCID: PMC2899991  PMID: 20063019
Spinal fusion; rhBMP-2; Nitric oxide; Nitric oxide synthase
19.  Local Soft Tissue Compression Enhances Fracture Healing in a Rabbit Fibula 
HSS Journal  2009;6(1):43-48.
Local soft tissue compression of fractures enhances fracture healing. The mechanism remains uncertain. Past studies have focused on intermittent soft tissue compression. We report a preliminary study assessing the relationship between constant soft tissue compression and enhanced fracture healing in an osteotomy model designed to minimize confounding variables. Fibulae of nine New Zealand white rabbits were bilaterally osteotomized, openly stabilized, and fitted with spandex stockinets. Soft tissue at the osteotomy site was unilaterally compressed using a deforming element (load = 26 mmHg). The contralateral side was saved as the control and was not compressed. Osteotomies were monitored with weekly radiographs. All fibulae in both groups were healed 6 weeks postoperatively. Micro-CT analysis of bone mineral density (BMD) and bone volume (BV) was then performed on both the experimental and control sides. Radiographic measurement of transverse callus-to-shaft ratios (TCSR) was compared. BMD of the experimental callus was greater than the noncompressed controls. BV and TCSR were not different between controls and experimental osteotomies. Constant local soft tissue compression produced significant increases in BMD, but not in BV or transverse callus size, indicating significant measurable increases in callus composition without significant change in gross dimensions. Our experimental design minimizes confounding factors, such as micromotion, immobilization, and altered venous flow, suggesting that these are not the primary mechanisms for fracture healing enhancement. Further studies with more animals and study groups are necessary to confirm efficacy and identify optimal compression pressures and schedules.
PMCID: PMC2821484  PMID: 19911234
soft tissue compression; fracture healing; osteotomy; bone mineral density (BMD); bone volume (BV); micro-CT
20.  Vascular Endothelial Growth Factor: An Essential Component of Angiogenesis and Fracture Healing 
HSS Journal  2009;6(1):85-94.
Fractures require adequate stability and blood supply to heal. The vascular supply to long bones is compromised in a fracture, and the ability to heal hinges on the ability of new blood vessels to proliferate from surrounding vessels in a process known as angiogenesis. This process is largely driven by the growth factor, vascular endothelial growth factor (VEGF), whose levels are increased locally and systemically during fracture healing. VEGF is involved in many steps throughout the fracture healing cascade, from initially being concentrated in fracture hematoma, to the promotion of bone turnover during the final remodeling phase. This article reviews the current literature surrounding the role of VEGF and other growth factors in reestablishing vascular supply to fractured bone, as well as medications and surgical techniques that may inhibit this process.
PMCID: PMC2821499  PMID: 19763695
VEGF; growth factor; fracture; angiogenesis; non-union; blood supply; vascular endothelial growth factor; fracture healing
21.  Role of Parathyroid Hormone in the Mechanosensitivity of Fracture Healing 
The mechanical environment at a fracture site can influence the course of healing. Intermittent parathyroid hormone (PTH) has been shown to accelerate fracture healing. Intact bone models show that mechanical loading and PTH have a synergistic beneficial effect on osteogenesis. We hypothesized that PTH and mechanical loading would have a similar synergistic effect on fracture healing. Eighty mice underwent surgical osteotomy and intramedullary nailing of the tibia. The mice were divided into four groups: one underwent daily loading, one received daily subcutaneous PTH injections (30 µg/kg/day), one received both loading and PTH, and a control group received sham loading and vehicle injection. Daily loading was applied to the ends of the tibia with an external loading device for 2 weeks. Fracture healing was assessed by microcomputed tomography, histology, and biomechanical testing. The group with both loading and PTH had increased osteoblast and osteoclast activity and was the only group with a significantly larger callus mineral density and bone volume fraction. The PTH only group had significantly more osteoid in the callus compared to the control group, indicating enhanced early osteoblast activity. This group also had a significantly higher bone mineral content and total bone volume compared to controls. The group that received loading as the only intervention had significantly greater osteoclast activity versus controls. The contribution of loading and PTH administration to the fracture healing cascade indicates a synergistic effect. This finding may be of potential clinical utility when weight bearing is utilized to stimulate lower extremity fracture healing.
PMCID: PMC2948234  PMID: 17568439
parathyroid hormone; fracture healing; mouse tibia; in vivo mechanical loading; microcomputed tomography; mechanosensitivity
22.  Recent Advances Toward the Clinical Application of PTH (1-34) in Fracture Healing 
HSS Journal  2009;5(2):149-153.
PTH 1-34, an active form of parathyroid hormone, has been shown to enhance osteoblastic bone formation when administered as a daily subcutaneous injection. The effect of the intermittent administration of PTH (1-34) is an uncoupling of bone turnover with an increase in bone mass and density and decrease in risk of vertebral and nonvertebral fractures. While PTH (1-34) has been used clinically to increase bone mass and reduce fracture risk in postmenopausal women with osteoporosis, there is increasing evidence that PTH (1-34) may promote fracture healing. Animal studies have demonstrated accelerated callus formation with enhanced remodeling and biomechanical properties of the healing fracture. Given these effects, PTH (1-34) will likely be used clinically to enhance fracture union in poor healing situations such as osteoporosis and recalcitrant nonunions.
PMCID: PMC2744747  PMID: 19290582
24.  Bone Disease in Thalassemia: A Frequent and Still Unresolved Problem 
Adults with β thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, ≥6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1–75 yr), were studied. Spine and femur BMD Z-scores < −2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.
PMCID: PMC3276604  PMID: 18505376
DXA; BMD; fractures; vertebral morphometry; thalassemia
25.  Translating three states of knowledge--discovery, invention, and innovation 
Knowledge Translation (KT) has historically focused on the proper use of knowledge in healthcare delivery. A knowledge base has been created through empirical research and resides in scholarly literature. Some knowledge is amenable to direct application by stakeholders who are engaged during or after the research process, as shown by the Knowledge to Action (KTA) model. Other knowledge requires multiple transformations before achieving utility for end users. For example, conceptual knowledge generated through science or engineering may become embodied as a technology-based invention through development methods. The invention may then be integrated within an innovative device or service through production methods. To what extent is KT relevant to these transformations? How might the KTA model accommodate these additional development and production activities while preserving the KT concepts?
Stakeholders adopt and use knowledge that has perceived utility, such as a solution to a problem. Achieving a technology-based solution involves three methods that generate knowledge in three states, analogous to the three classic states of matter. Research activity generates discoveries that are intangible and highly malleable like a gas; development activity transforms discoveries into inventions that are moderately tangible yet still malleable like a liquid; and production activity transforms inventions into innovations that are tangible and immutable like a solid. The paper demonstrates how the KTA model can accommodate all three types of activity and address all three states of knowledge. Linking the three activities in one model also illustrates the importance of engaging the relevant stakeholders prior to initiating any knowledge-related activities.
Science and engineering focused on technology-based devices or services change the state of knowledge through three successive activities. Achieving knowledge implementation requires methods that accommodate these three activities and knowledge states. Accomplishing beneficial societal impacts from technology-based knowledge involves the successful progression through all three activities, and the effective communication of each successive knowledge state to the relevant stakeholders. The KTA model appears suitable for structuring and linking these processes.
PMCID: PMC2827367  PMID: 20205873

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