[Osteoporosis-risk evaluation and case finding]. / Osteoporose ­ Risikoevaluation und "case finding".

Osteoporosis is one of the major diseases worldwide but is often underdiagnosed and undertreated. The most common reasons for underdiagnosis and undertreatment in ambulatory settings are demonstrated and potential solutions are discussed.

[Influence of frequently prescribed drugs on bone healing]. / Beeinflussung der Knochenheilung durch häufig verordnete Medikamente.

BACKGROUND: Bone healing after fractures is influenced by many different factors. Besides patient-related factors, such as age, gender and other comorbidities, other drugs taken also have a relevant impact on bone healing. OBJECTIVE: The aim of the study was to give an overview of the effects of frequently used drugs on fracture healing, with the exception of specific osteoporosis drugs and hormones. MATERIAL AND METHODS: This overview is based on a medline search with the search string of each pharmacological agent. RESULTS: Frequently used pharmacological substances were identified, for example corticosteroids, antihypertensive drugs, diuretics, antidepressive drugs, antiepileptics, statins, antibiotics, nonsteroidal anti-inflammatory drugs, anticoagulants and others. Except for antihypertensive drugs, thiazide diuretics and statins, which have osteoprotective effects and stimulate bone healing, all other drugs have negative effects on fracture healing in preclinical and animal studies. Clinical data are scarce. CONCLUSION: Data for the effects of the abovementioned pharmacological substances could be found mostly in preclinical studies. The effects of these agents on bone healing in humans has currently not been studied or published. Therefore, the use of these drugs should be discussed carefully in cases with a compromised fracture healing.

In vitro elution characteristics of gentamicin and vancomycin from synthetic bone graft substitutes.

OBJECTS: Beta tricalciumphosphate pellets loaded with individualized antibiotics may represent novel options in the treatment of osteomyelitis and infectious bone disease. Here, the in vitro antibiotic elution of vancomycin and gentamicin from the synthetic bone graft substitutes Cerasorb(®) and Cerasorb M(®) was tested. METHODS: Antibiotic elution and concentration of gentamcin and vancomycin were measured using photometrically-based measurement and homogeneous particle-enhanced turbidimetric inhibition immunoassays (PETINIA). RESULTS: Initially both materials showed a high release of the loaded antibiotics, with Cerasorb M(®) showing lower release levels for gentamicin and vancomycin than Cerasorb(®). Gentamicin concentrations of Cerasorb M granules and Cerasorb were below the minimum detectiontreshold until day four and six of the experiment respectively. The vancomycin release-level followed a similar pattern, although the vancomycin concentration eluted by Cerasorb M(®) granules stayed above the detection threshold during the experimental time. CONCLUSIONS: Cerasorb(®) and Cersorb M(®) may represent a new treatment option in osteomyelitis and infectious bone disease.

Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial.

Data on treatment of glucocorticoid-induced osteoporosis (GIO) in men are scarce. We performed a randomized, open-label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T-score ≤ -1.5 standard deviations. Subjects received 20 µg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1 -L3 ) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high-resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X-ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18-month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE-derived strength than risedronate.

How to store autologous bone graft perioperatively: an in vitro study.

INTRODUCTION: Autologous bone graft is the golden standard for bone grafting, but little is known about the influence of various preservation techniques used during surgery immediately following harvest on the osseous structures and graft vitality. Several studies focussed on the optimal treatment of the bone during harvest and implantation, but only few examined the intraoperative storage conditions on the back table. The aim of our study was to examine the influence of various intraoperative preservation techniques on human cancellous bone at different points to optimize the storage during surgery. MATERIALS AND METHODS: Cancellous bone was harvested during hip arthroplasty and stored for 2 and 4 h under dry conditions, inside a swab moistened with saline solution or in saline solution, 5% glucose solution or culture medium. After the storage period, the bone was cultured and examined 7 days after the first cells grew out in one of these groups. Following the identification of the cells as osteoblast-like cells, the cultures were analysed by fluorescence staining, cell count and the XTT-test. RESULTS: Fluorescence staining revealed no avital cells in all groups. Dry storage of the bone led to significantly lower cell metabolism after 2 h compared to saline solution and 5% glucose solution. The same was true after 4 h dry storage compared to the moistened swab, and glucose and culture medium. Cell count was significantly lower after 2 h of dry storage compared to saline solution and culture medium. CONCLUSIONS: Perioperative storage of cancellous bone under dry conditions should be avoided. The bone graft should be stored in saline or 5% glucose solution or a moistened swab.

Perthes' or Perthes' resembling disease in 13-month-old boy.

Onset of Perthes' disease is reported frequently from the age of 2 years. Latest publications showed cases with onset of this disease in infancy at ages of 17 and 18 months. We report the case of a 13-month-old boy, who presented with left-sided limping. Radiological examination showed reduced height and fragmentation of the femoral head. Magnetic resonance imaging showed the typical signs of an avascular necrosis. Follow-up was done after 3, 7 and 15 months. Plain radiography showed the femoral head in a state of reparation. This is the youngest documented case of Legg-Calvé-Perthes' disease and is discussed under consideration of the current literature.

Lack of effect on bone healing of injectable BMP-2 augmented hyaluronic acid.

INTRODUCTION: Autologous bone graft is the gold standard for the filling of large osseous defects. Because of its limited supply and complications such as pain, bleeding or infection, the development of alternative bone substitutes has been the subject of several studies. In clinical practice, the most commonly used bone substitutes are calcium phosphates like hydroxyapatite or tricalcium phosphate. With the aim to improve the osseointegration of these materials, growth factors such as bone morphogenetic protein-2 (BMP-2) have been added. Preferably, an injectable bone substitute should be made available. Hyaluronic acid is a component of the extracellular matrix of many tissues, including bone. We examined the bone regenerative effect of commercially available, injectable hyaluronic acid (Hyalart) with and without addition of bone morphogenetic protein-2 (BMP-2). MATERIALS AND METHODS: Trepanation defects of 9.4 mm diameter in the intercondylar groove of sheep femora were filled with pure and augmented (200 microg BMP-2) hyaluronic acid. As controls, empty defects and defects treated with autologous bone graft harvested from the contralateral side were used. After 3 months, the defects were analysed by fluorescence microscopy after intravital fluorescence staining, contact microradiography, histology and histomorphometry. RESULTS: Treatment of the defects with loaded and unloaded hyaluronic acid resulted in a significant lack of bone formation inside the defects. Untreated defects showed an amount of 5.1% newly formed bone, and defects treated with autologous bone graft revealed a bone content of 20%. The difference between both groups was statistically significant (P < 0.05). Furthermore, there was neither a remarkable effect in the periphery of the defects nor ectopic bone formation. CONCLUSION: The application of the used injectable hyaluronic acid (Hyalart) with and without BMP-2 is not advantageous as sole bone substitute for the filling of osseous defects.

BMP-2 incorporated in a tricalcium phosphate bone substitute enhances bone remodeling in sheep.

Bone morphogenetic protein-2 (BMP-2) is a well-known osteoinductive protein, which requires a carrier for local application. As an alternative to the previously described carriers, an in situ hardening, resorbable, and osteoconductive beta-tricalcium phosphate cement (TCP) is tested. Trepanation defects in the bovine distal femoral epiphysis are filled with a composite consisting of TCP and 200 microg rhBMP-2 per cm3 TCP, autologous bone graft, pure TCP, or left empty. A radiological follow-up is performed after 7 weeks and 3 months. The sheep are euthanized and bone samples are analyzed by microradiography, histology, and histomorphometry. Microradiography and histology show similar results for pure TCP and the composite. The defects are filled with trabecular bone and newly formed bone is in close contact with the remaining TCP-particles. The majority of the cement is resorbed, in the composite group the amount of remaining cement particles is reduced. Defects treated with autologous bone graft are filled completely, while untreated defects shows only a small amount of bone originating from the rim of the defect. Histomorphometry of the defects treated with pure TCP shows a significantly increased bone content in comparison to defects treated with the composite or autologous bone graft. Analysis of the remaining cement particles shows significantly less cement in the TCP/rhBMP-2 group in comparison to pure TCP. The sum of bone and cement content in the rhBMP-2 group shows amounts comparable to the calcified structures found following autologous bone grafting. The addition of rhBMP-2 to the TCP leads to faster remodeling of the defect comparable to autologous bone graft, while defects treated with pure TCP are not completely remodeled.

A bFGF/TCP-composite inhibits bone formation in a sheep model.

Basic fibroblast growth factor is a well known osteostimulative protein. The effects of basic fibroblast growth factor are dose-dependent and, when used with a carrier, influenced by the release kinetics. Aim of our study was to determine the effects of a composite of basic fibroblast growth factor and a newly developed, in situ setting tricalcium phosphate (TCP) cement. A trepanation defect in the distal femoral epiphysis of Merino-Mix sheep with a diameter of 9.4 mm and 10 mm depth was filled with the in situ setting TCP cement combined with 0 or 200 microg of bFGF/cm(3) TCP, autologous bone graft or left empty. The sheep were euthanized after 3 months. The defect and the periimplant area were examined by microradiography, histology, and histomorphometry. The data was analyzed with the help of the Wilcoxon and Kruskal-Wallis tests. Defects filled with TCP with or without bFGF showed a close bone-cement contact. The histomorphometric analysis revealed that the addition of bFGF inhibited the ingrowth of bone significantly, while the resorption of the cement was not influenced. In conclusion, the clinical application of this bFGF/TCP-composite does not seem promising. The reason for the inhibition of new bone formation will be discussed, but requires further investigation.

Ingrowth of osteochondral grafts under the influence of growth factors: 6-month results of an animal study.

INTRODUCTION: In the age of growth factors and gene therapy, the induction of cartilage healing remains an unsolved problem. Even in autologous grafting, one of the preferred methods of treatment for focal osteochondral lesions, chondral integration remains difficult. This study aims to define a possible positive influence of growth factor augmentation on the ingrowth of these transplants. MATERIALS AND METHODS: In an ovine model, questions regarding the healing of osteochondral transplants under the influence of two different growth factors were to be addressed. Two osteochondral autologous transplantations (OAT), one in the weight-bearing surface of each femoral condyle, were performed on the ovine knee using the standard operative protocol. One of the grafts was bathed in augmented PBS containing 50 microg bFGF or bone morphogenetic protein (BMP)-2 directly prior to implantation, while the other condyle served as the control. Two groups, consisting of eight sheep each, were evaluated for each growth factor after 6 months. RESULTS: During the evaluation of all the specimens, neither osteophytes nor synovial changes were observed. The mechanical consistency of the cartilaginous tissue began to reach a level equivalent to the surrounding tissue at 6 months, independent of the use of growth factor. Macroscopically, the superficial border of the transplanted osteochondral plug could easily be outlined in all groups, while the cartilage interface of the bFGF specimens was determined to be less demarcated than the BMP augmented plugs or the controls. Radiographically, a solid osteointegration of the graft could be documented at 6 months in the native and augmented groups. In contrast, integration of the chondral surface of the OAT was not seen macro- or microscopically in any specimen, even though cartilage surfaces remained viable. A firm physical interdigitation of the reconstructed joint surface could not be demonstrated in either of the two augmented groups or the control population. The augmentation with bFGF and BMP-2 stimulated the osseous ingrowth and seems to expedite the remodelling process, but was not able to improve chondral healing. CONCLUSION: The lack of integration of the cartilaginous portion of the transplanted plugs into the reconstructed joint surface, even following the augmentation with bFGF and BMP-2, does not bode well for the long-term survival of the joint itself.

Efficacy and safety of a novel moldable, resorbable, and degradable sealant of bone surfaces for hemostasis after bone graft harvesting from the iliac crest.

STUDY DESIGN: A prospective, controlled, open, randomized multicenter study. OBJECTIVE: The study's objective was to demonstrate equivalence of a novel, moldable, resorbable, and degradable synthetic polymer (Bone Seal) compared with a collagen fleece (Lyostypt) in efficacy and safety for topical hemostasis after iliac crest bone graft harvesting. SUMMARY OF BACKGROUND DATA: Harvesting cortico-cancellous bone from the iliac crest is a well established procedure in orthopedic and particularly in spine surgery. It is associated with significant morbidity at the donor site where hematoma formation may cause impaired wound healing and infections in up to 10% of cases. METHODS: A total of 112 patients were included in the safety analysis. Safety was determined by a compound wound healing score and the incidence of adverse clinical effects. One hundred and eight patients were studied for equivalence in efficacy using a compound bleeding score. The handling properties and the application to the bone surface of either device were measured with two additional compound scores. RESULTS: The mean bleeding scores in the final analysis was 4.5 +/- 1.3 for the Bone Seal group and 4.2 +/- 1.3 for the collagen fleece group. Bone Seal was better applicable to the bleeding bone surfaces than the collagen fleece, even though its handling was more complicated. Wound healing and the incidences of adverse clinical events were comparable in either study group. CONCLUSIONS: Bone Seal is an effective and safe hemostatic material for sealing bleeding bone surfaces after iliac crest bone graft harvesting. By virtue of its hemostatic efficacy, Bone Seal is preventive for wound healing disorders.

Bioactivation of inert alumina ceramics by hydroxylation.

Alumina ceramics (Al(2)O(3)) are frequently used for medical implants and prostheses because of the excellent biocompatibility, and the high mechanical reliability of the material. Inauspiciously alumina is not suitable for implant components with bone contact, because the material is bioinert and thereby no bony ongrowth, and subsequently loosening of the implant occurs. Here, we present a new method to bioactivate the surface of the material. Specimens made of high purity alumina were treated in sodium hydroxide. Cell culture tests with osteoblast-like cells as well as spectroscopical and mechanical tests were performed. Aluminium hydroxide groups were detected on the surface of the treated specimens. Enhanced cell adhesion, proliferation and secretion of osteocalcin were determined after hydroxylation. The bioactivating treatment had no deteriorating effect on the short- and long-term strength behaviour. Our results indicate that the described surface technique could be used to develop a new class of osseointegrative high-strength ceramic implants.

Evaluation of a resorbable, in situ setting bone substitute in a sheep model.

The gold standard for bone substitution is the autologous bone graft, but because of its limited supply and the associated morbidity, the search for synthetic alternatives is necessary. A new in situ setting tricalcium phosphate cement was implanted in a trepanation defect (9.4 mm diameter, 10 mm depth) in the distal femoral epiphysis of sheep. Empty cavities and autologous bone graft were used as controls. Histologic and histomorphometric examinations were carried out after 12 weeks. Nearly 90% of the implanted cement was resorbed and replaced by ingrown bone with close contact between surrounding bone, new bone, and remaining cement particles. The amount of bone in the defect area was significantly higher in defects filled with cement relative to defects filled with autologous bone graft (mean 27 vs. 21%, 95% confidence intervals 23 to 31 and 18 to 23, p = 0.026). In conclusion, this new in situ setting cement is bioactive, resorbable, and osteoconductive. It will be useful as an alternative to autologous bone graft to fill stable defects.

Osteonecrosis 15 years after femoral neck fracture and long-term low-dose inhaled corticosteroid therapy.

Posttraumatic avascular necrosis of the femoral head typically occurs immediately or within a few years after a femoral neck injury, and non-traumatic avascular necrosis is often related to systemic glucocorticoid therapy. We report an unusual case in which avascular necrosis of the femoral head occurred 15 years after a transcervical femoral fracture in a woman with a 20-year history of daily inhaled glucocorticoid therapy for chronic bronchitis. She had not taken glucocorticoids by any other route and had no other risk factors for osteonecrosis. To our knowledge, this is the first report of osteonecrosis associated with inhaled glucocorticoid therapy in a patient with a local cause of diminished vascular reserve. Inhaled glucocorticoid therapy should be added to the list of risk factors for osteonecrosis.

The effect of basic fibroblast growth factor on bone regeneration when released from a novel in situ setting tricalcium phosphate cement.

The osteostimulative effect of the basic fibroblast growth factor is well known, but it is dose dependent, and release kinetic depends on interactions with the used carrier. The aim of our study was to determine the osteostimulative effect of a composite, consisting of an in situ setting tricalcium phosphate cement and basic fibroblast growth factor. A trepanation defect of 1.5 mm in the femur diaphysis of Sprague-Dawley rats was filled with the in situ setting TCP cement combined with 0, 0.25, 2.5, or 25 microg rh bFGF, an autologous bone graft or left empty. The rats were euthanized after 1 and 3 weeks and examined by radiography, histology, histomorphometry, and bending test. The data were analyzed by the Wilcoxon and Kruskal-Wallis test. All TCP groups with or without bFGF showed a good bony ingrowth with a close bone-cement contact. Osseous ingrowth was not influenced by the addition of the different doses of bFGF as shown by histomorphometry. Also, mechanical strength was not affected. In conclusion, the combination of this in situ setting cement with bFGF is not useful for clinical application. The reason of these negative results remains unclear: the osteostimulative effect of bFGF is well known, and the TCP-cement was used as a carrier for rhBMP-2 successfully. These negative results may be due to a too slow or too fast release of bFGF from the cement.

Stimulation of bone formation with an in situ setting tricalcium phosphate/rhBMP-2 composite in rats.

The aim of the study was to determine bone-regenerative effects of an in situ setting tricalcium phosphate (TCP) cement combined with rhBMP-2 and to compare it with autologous bone graft. A trepanation defect of 1.5 mm in the femur diaphysis of Sprague-Dawley rats was filled with an in situ setting TCP cement combined with 0, 0.25, 2.5, or 25 microg of rhBMP-2, an autologous bone graft, or left empty. The rats were euthanized after 1 and 3 weeks and examined by radiography, histology, histomorphometry, and bending tests. All TCP groups with or without BMP-2 showed a good bony ingrowth with a close bone-cement contact. Histomorphometric analysis showed no increase of new bone formation in the defect, but a dose-dependent increase in callus formation with a maximum at 25 microg of rhBMP-2. As shown with intravital fluorochrome staining, new bone formation started earlier using rhBMP-2. Bone strength, measured in a three-point bending test and expressed in percentage of the contralateral healthy femur, was 75% for TCP + 25 microg rhBMP-2, 44% for TCP + 2.5 microg rhBMP-2, and 34% for autologous bone graft. TCP particles were detectable in all groups after 3 weeks. Callus formation and bending strength of the TCP + 25 microg rhBMP-2 group was superior to autologous bone graft. So TCP/rhBMP-2 composites may prove to be an effective substitute for autologous bone grafts.

Healing of osteochondral grafts in an ovine model under the influence of bFGF.

PURPOSE: The well-recognized limitations in cartilage healing have lead to the development of a number of resurfacing techniques for defects of joint surfaces. Autologous grafting has developed into 1 of the preferred methods of treatment for focal osteochondral lesions, although basic research on this topic remains sparse. TYPE OF STUDY: In an animal study, questions regarding the healing of osteochondral transplants under the influence of basic fibroblast growth factor (bFGF) were addressed. METHODS: Two osteochondral autologous transplantations (OAT), 1 in the weight-bearing surface of each femoral condyle, were performed on the ovine knee using a standard operative protocol. One of the grafts was bathed in phosphate buffered sulfate (PBS) containing 50 microgram of recombinant human bFGF (rh-bFGF) directly before implantation. Two groups consisting of 10 sheep each were evaluated after 3 and 6 months, respectively. RESULTS: During the evaluation of the specimens, neither osteophytes nor synovial changes were observed. Macroscopically, the superficial border of the transplanted osteochondral plug could easily be outlined at both time periods, even though the cartilage interface of the rh-bFGF specimens was less demarcated. Radiographically, a solid osteointegration of the graft could already be documented at 3 months in the control group. In contrast, integration of the chondral surface of the OAT was not seen macroscopically or microscopically at any point. A firm physical interdigitation of the reconstructed joint surface could not be demonstrated in either of the 2 groups. The augmentation with rh-bFGF stimulated the osseous ingrowth, but was not able to improve chondral healing. CONCLUSIONS: The lack of integration of the cartilaginous portion of the transplanted plugs into the reconstructed joint surface, even following augmentation with bFGF, leads to questions regarding the long-term survival of the joint itself.

Polysegmental spondylodiscitis and concomitant aortic aneurysm rupture: case report with 3-year follow-up period.

STUDY DESIGN: A case report describing a patient with spondylodiscitis of the thoracic and lumbar spine complicated by rupture of an abdominal aortic aneurysm and aggravation of neurologic symptoms is presented. OBJECTIVE: To present a cardiovascular complication worsening the clinical condition during conservative spondylodiscitis therapy, and to describe a minimally invasive treatment regimen for both spondylodiscitis and aortic aneurysm rupture in multimorbid patients at high risk for complications or refusal of surgery. SUMMARY OF BACKGROUND DATA: Few articles describe minimally invasive treatment of spondylodiscitis. Some available reports describe neurologic symptoms resulting from spinal cord ischemia in aortic aneurysm rupture. No data were found describing simultaneous therapy for spondylodiscitis and rupture of aortic aneurysm. METHODS: Therapy consisted of CT-guided percutaneous drainage of the spondylodiscitis and parenteral antibiotic treatment combined with immobilization and minimally invasive endoluminal exclusion of the aortic aneurysm with a bifurcated stent graft. RESULTS: Effective therapy for polysegmental spondylodiscitis on the one hand and contained rupture of aortic aneurysm on the other are presented. The successful clinical outcome after conservative orthopedic therapy and vascular intervention has been followed for 3 years. CONCLUSIONS: In older patients, spondylodiscitis may be complicated by other underlying diseases. Pain and neurologic symptoms may occur secondarily to concomitant illnesses instead of being caused by the inflammation itself. Minimally invasive therapy is shown to be an effective alternative to surgery in older and multimorbid patients with spondylodiscitis and contained aortic aneurysm rupture.

Correlation of bone and cartilage markers in the synovial fluid with the degree of osteoarthritis.

In recent years, many biochemical markers were tested with the aim of developing a tool for the early detection and monitoring of osteoarthritis (OA). Apart from chondral markers, we also evaluated osseous markers from the synovial fluid to obtain more comprehensive information, and we compared the levels in relation to the severity of OA. In this prospective, cross-sectional study, synovial fluid samples were obtained from 73 patients with OA of the knee joint prior to operation and after the joint was flushed with 50 ml of normal saline. All patients underwent surgery and were classified in accordance with the Outerbridge and the Noyes classification. The measured biochemical markers included pyridinoline (PD), deoxypyridinoline (DPD), N-telopeptide (NTx), carboxyterminal propeptide of collagen-1 (PICP), matrix metalloproteinases (MMP-1 and MMP-3), and tissue inhibitor of MMPs (TIMP-1). The marker levels were normalized against the total protein content and were compared with the Outerbridge and the Noyes classification. For the majority of markers, the correlation coefficient was below r=0.3, with large 95% confidence intervals. The highest correlation coefficients were obtained from DPD and TIMP-1. In relation to the Outerbridge classification, DPD revealed high values only in stage IV. The overall results indicate that the majority of the tested markers are unspecific with regard to the different stages of OA. The two markers with the highest correlation coefficients showed no major sensitivity to detect OA at an initial stage. However, they might give additional information to clinical and radiological findings with regard to the severity of the disease.