Skeletal characterization in a patient with Hajdu-Cheney syndrome undergoing total knee arthroplasty.

Hajdu-Cheney syndrome (HCS) is a rare genetic connective tissue disorder caused by gain-of-function mutations in the NOTCH2 gene. We report a 38-year-old male HCS patient with a history of multiple pathologic fractures, poor bone stock under intermittent antiresorptive therapy, and secondary osteoarthritis (OA) of the knee, in which we successfully performed total knee arthroplasty (TKA). Next to a detailed skeletal assessment including laboratory bone metabolism markers, dual energy X-ray absorptiometry (DXA), and high-resolution peripheral quantitative computed tomography (HR-pQCT), undecalcified histologic and histomorphometric analysis was performed on intraoperatively obtained tibial cut sections. This multiscale assessment revealed a severe, combined trabecular-cortical microarchitectural deterioration, increased bone turnover indices, and advanced cartilage degeneration, thus demonstrating the crucial role of Notch2 in skeletal and cartilage homeostasis, which is in line with the findings of previous mouse models.

High prevalence and undertreatment of osteoporosis in elderly patients undergoing total hip arthroplasty.

We detected a high prevalence of low bone mineral density assessed by DXA in 268 elderly patients with end-stage osteoarthritis scheduled for total hip arthroplasty (18% osteoporosis, 41% osteopenia). Therefore, and due to the identified concomitant undertreatment, routine DXA measurements should be considered in elderly patients prior to surgery. INTRODUCTION: Bone quality represents a decisive factor for osseointegration, durability, and complications of an implanted prosthesis. Although the risk of osteoporosis increases with age and the assessment of bone mineral density (BMD) prior to total hip arthroplasty (THA) is recommended in elderly patients, a systematic, unbiased analysis of such patients is not available in the literature. METHODS: In this retrospective study, we examined 268 elderly patients (age ≥70 years) who underwent dual-energy X-ray absorptiometry (DXA) within 3 months prior to primary THA. Demographics, medical history, radiographic OA grade, and stem fixation method (i.e., cemented or cementless) were obtained. RESULTS: In total, 153 (57%) cemented and 115 (43%) cementless stem fixations during THA were performed. Forty-nine patients (18%) were diagnosed with osteoporosis (T-score ≤-2.5), 110 patients (41%) with osteopenia (T-score ≤-1.0), and 109 patients (41%) with normal BMD (T-score >-1.0). Importantly, 36/49 patients (73%) with osteoporosis were not diagnosed before, resulting in a relevant undertreatment. Female sex and low body mass index (BMI) were the main factors negatively influencing the bone mineral density (BMD). CONCLUSIONS: Due to a high incidence of undiagnosed and untreated osteoporosis in elderly patients with potential effects on the success of osseointegration as well as other clinical outcomes, DXA measurements should be included in the clinical routine for these patients prior to THA.

Cartilage calcification is associated with histological degeneration of the knee joint: a highly prevalent, age-independent systemic process.

OBJECTIVES: To investigate if cartilage calcification (CC) is a systemic process, the purpose of this study was to determine the prevalence and the amount of meniscal/hyaline CC of the knee joint in the general population by high-resolution imaging (DCR) and to evaluate the association between CC with cartilage degeneration and age. METHODS: Cross-sectional DCR-study of 180 knee joints of 90 donors (42 female/48 male, mean age 62.3y). Histological hyaline (OARSI) and meniscal (Krenn) cartilage degeneration was determined of all knees. RESULTS: CC was observed in 100% of the donors (bilaterally in 98%), hyaline cartilage calcification (HCC) in 92% and meniscal calcification (MC) in 100%. CC was detected in more than three out of six distinct cartilage areas in 84.4% of all knees. The mean amount of CC correlated between both sides of donors, the different analyzed areas of the knee joint and between the various types of cartilage structures. There was more calcification in meniscal than in hyaline cartilage (factor 5.3) and in the medial than the lateral compartment (factor 1.2). HCC/MC were already detectable with only mild cartilage lesions and the amount correlated with histological cartilage degeneration, but not with age. CONCLUSIONS: The present study provides evidence that meniscal and hyaline CC occurs in a pattern that is compatible with CC being a systemically driven process and that meniscal fibrocartilage is more prone to calcification than hyaline cartilage. Furthermore, the age-independent association between the amount of CC and the grade of degeneration in both hyaline and meniscal cartilage, suggests that CC is an obligatory early event in initiating cartilage degeneration.

Age-related changes of micro-morphological subchondral bone properties in the healthy femoral head.

OBJECTIVE: Alterations in the subchondral bone (SCB) are likely to play a decisive role in the development of osteoarthritis (OA). Since aging represents a major risk factor for OA, the aim of the current study was to assess the microstructural changes of the subchondral bone in the femoral head during aging. DESIGN: Femoral heads and matched iliac crest biopsies of 80 individuals (age 21-99 years) were collected post-mortem. The bone microstructure of the subchondral trabecular bone as well as the cartilage thickness (Cg.Th) and subchondral bone plate thickness (SCB.Th) were quantified using histomorphometry. The different subregions of the SCB were also imaged by quantitative backscattered electron imaging (qBEI) in 31 aged cases to assess the bone mineral density distribution (BMDD). RESULTS: The detected linear decline of bone volume per tissue volume (BV/TV) in the femoral head with aging (Slope, 95% CI: -0.208 to -0.109 %/yr.) was primarily due to a decrease in trabecular thickness (Tb.Th, Slope, 95% CI: -0.774 to -0.343 µm/yr). While SCB.Th declined with aging (Slope, 95% CI: -1.941 to -0.034 µm/yr), no changes in Cg.Th were detected (Slope, 95% CI: -0.001 to 0.005 mm/yr). The matrix mineralization of the subchondral bone was lower compared to the trabecular bone and also decreased with aging. CONCLUSIONS: Regular changes of the SCB during aging primarily involve a reduction of Tb.Th, SCB.Th and matrix mineralization. Our findings facilitate future interpretations of early and late OA specimens to decipher the role of the SCB in OA pathogenesis.

[Indications and contraindications for radiosynoviorthesis]. / Indikationen und Kontraindikationen zur Radiosynoviorthese.

BACKGROUND: Radiosynoviorthesis (RSO) provides a simple method for the treatment of patients with chronic synovitis and has only few side effects. OBJECTIVES: Evidence-based indications and contraindications for performing RSO based on the current literature are presented. MATERIAL AND METHODS: Published information on the indications and contraindications for performing RSO in chronic synovitis were analyzed and summarized. RESULTS: According to the guideline recommendations of the German Society of Rheumatology indications for RSO are given in patients with rheumatoid arthritis, seronegative spondyloarthropathy, crystal arthropathy, villonodular synovitis and hemophilia with recurrent joint bleeding. Osteoarthritis with documented reactive synovitis is also regarded as an indication in the guidelines of the nuclear medicine societies. The European League Against Rheumatism (EULAR) and the German Society of Rheumatology (DGRh) have given no recommendations for using RSO in osteoarthritis. Given the correct indications RSO shows high success rates. CONCLUSION: The effects of RSO with the named secondary side effects last on average for 5 years. Crucial for the success of RSO are the correct indications, the correct timing and combination with other therapeutic procedures, such as surgical synovectomy.

High fluoride and low calcium levels in drinking water is associated with low bone mass, reduced bone quality and fragility fractures in sheep.

UNLABELLED: Chronic environmental fluoride exposure under calcium stress causes fragility fractures due to osteoporosis and bone quality deterioration, at least in sheep. Proof of skeletal fluorosis, presenting without increased bone density, calls for a review of fracture incidence in areas with fluoridated groundwater, including an analysis of patients with low bone mass. INTRODUCTION: Understanding the skeletal effects of environmental fluoride exposure especially under calcium stress remains an unmet need of critical importance. Therefore, we studied the skeletal phenotype of sheep chronically exposed to highly fluoridated water in the Kalahari Desert, where livestock is known to present with fragility fractures. METHODS: Dorper ewes from two flocks in Namibia were studied. Chemical analyses of water, blood and urine were executed for both cohorts. Skeletal phenotyping comprised micro-computer tomography (µCT), histological, histomorphometric, biomechanical, quantitative backscattered electron imaging (qBEI) and energy-dispersive X-ray (EDX) analysis. Analysis was performed in direct comparison with undecalcified human iliac crest bone biopsies of patients with fluoride-induced osteopathy. RESULTS: The fluoride content of water, blood and urine was significantly elevated in the Kalahari group compared to the control. Surprisingly, a significant decrease in both cortical and trabecular bones was found in sheep chronically exposed to fluoride. Furthermore, osteoid parameters and the degree and heterogeneity of mineralization were increased. The latter findings are reminiscent of those found in osteoporotic patients with treatment-induced fluorosis. Mechanical testing revealed a significant decrease in the bending strength, concurrent with the clinical observation of fragility fractures in sheep within an area of environmental fluoride exposure. CONCLUSIONS: Our data suggest that fluoride exposure with concomitant calcium deficit (i) may aggravate bone loss via reductions in mineralized trabecular and cortical bone mass and (ii) can cause fragility fractures and (iii) that the prevalence of skeletal fluorosis especially due to groundwater exposure should be reviewed in many areas of the world as low bone mass alone does not exclude fluorosis.

[Dupuytren's contracture associated with silicone wear reaction in late failure of lunate bone spacer prosthesis]. / Silikonabriebassoziierte Dupuytren-Kontraktur bei Spätversagen einer Lunatumspacerprothese.

The pathophysiological mechanisms of palmar fibromatosis (Dupuytren's contracture) are still not yet fully understood. In the vast majority of cases, however, reactive changes and reparative processes of tendon tissue can easily be ruled out by clinical and histopathological investigations. This article presents the case of a 62-year-old male patient suffering from palmar fibromatosis associated with a failed silicon spacer of the lunate bone 30 years after index surgery. Although silicon wear particles were observed in distal locations, proximal tendon tissues showed changes consistent with a degenerative palmar fibromatosis in the absence of a pathological wear reaction. The findings are discussed in the light of the current literature on Dupuytren's contracture.

[Hemiarthroplasty for geriatric femoral neck fractures]. / Hemiprothese bei geriatrischer Schenkelhalsfraktur.

OBJECTIVE: Restoration of pain-free joint function by implantation of a bipolar hemiarthroplasty via anterolateral approach. INDICATIONS: Elderly multimorbid patients >70 years, age >80 years, low functional demand. CONTRAINDICATIONS: Infection. Relative contraindications: dysplastic hip joint. SURGICAL TECHNIQUE: Supine position. Anterolateral approach. Incision of the iliotibial tract and entering the interval between tensor fasciae latae muscle/gluteus medius muscle. Capsulotomy. Femoral neck osteotomy. Removal of the femoral head and determination of the size of the bipolar prosthetic head. Inspection of the acetabulum. Adduction, external rotation ("figure 4" position) of the leg. Medullary preparation of the femur with rasps up to the correct level and size of the planed stem. Ensure the correct rotation of anteversion (10-15°). Trial reduction and examination of hip stability. Verification with image intensifier. Cement restrictor, jet lavage, drying the medullary canal, injection of bone cement and insertion of the prosthetic stem. Assembly/attachment of the definitive bipolar head to the stem. Reduction of the joint. Wound closure. POSTOPERATIVE MANAGEMENT: Early mobilization and full weight bearing. Limitation of hip flexion >90°, rotation and adduction for 6 weeks. Venous thromboembolism prophylaxis. Osteoporosis evaluation and management. Clinical-radiological control (after 6 weeks, 1/3/5 years). RESULTS: The implantation of a cemented hemiarthroplasty using the anterolateral approach is a muscle-sparing and dislocation-safe surgical procedure with a low risk of revision, which enables early patient mobilization and a good hip joint function.

Identification of molecular markers for articular cartilage.

OBJECTIVE: The aim of the current study was to identify molecular markers for articular cartilage (AC) that can be used as tools for the quality control of tissue engineered (TE) cartilage. DESIGN: A genome-wide expression analysis was performed using RNA isolated from articular and growth plate (GP) cartilage, both extracted from the knee joints of 6 weeks old minipigs. After confirming the specific expression for selected genes by RT-PCR, these were used as molecular markers for the quality control of TE cartilage. RESULTS: Albeit several known chondrocyte markers were expressed to a similar extent in articular and GP cartilage, our genome-wide expression analysis led us to identify genes being selectively expressed in either GP or articular chondrocytes. These findings led us to perform a RT-PCR expression analysis for the corresponding genes to demonstrate the absence of GP-specific markers in TE cartilage, while common or AC markers were expressed. CONCLUSIONS: Taken together, these results provide important novel insights into chondrocyte biology in general and AC in particular. In addition, it is reasonable to speculate, that some of the identified genes play distinct roles in the regulation of articular chondrocyte differentiation and/or function, thereby raising the possibility that they may serve as targets for non-operative therapies of osteoarthritis (OA).

High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1.

UNLABELLED: Although it is known that neurofibromatosis 1 (NF1) patients suffer from vitamin D deficiency and display decreased bone mineral density (BMD), a systematic clinical and histomorphometrical analysis is absent. Our data demonstrate that NF1 patients display high bone turnover and accumulation of osteoid and that supplementation of vitamin D has a beneficial effect on their BMD. INTRODUCTION: Neurofibromatosis 1 results in a wide range of clinical manifestations, including decreased BMD. Although it has been reported that NF1 patients have decreased vitamin D serum levels, the manifestation of the disease at the bone tissue level has rarely been analyzed. METHODS: Thus, we performed a clinical evaluation of 14 NF1 patients in comparison to age- and sex-matched control individuals. The analysis included dual X-ray absorptiometry osteodensitometry, laboratory parameters, histomorphometric and quantitative backscattered electron imaging (qBEI) analyses of undecalcified bone biopsies. RESULTS: NF1 patients display significantly lower 25-(OH)-cholecalciferol serum levels and decreased BMD compared to control individuals. Histomorphometric analysis did not only reveal a reduced trabecular bone volume in biopsies from NF1 patients, but also a significantly increased osteoid volume and increased numbers of osteoblasts and osteoclasts. Moreover, qBEI analysis revealed a significant decrease of the calcium content in biopsies from NF1 patients. To address the question whether a normalization of calcium homeostasis improves BMD in NF1 patients, we treated four patients with cholecalciferol for 1 year, which resulted in a significant increase of BMD. CONCLUSION: Taken together, our data provide the first complete histomorphometric analysis from NF1 patients. Moreover, they suggest that low vitamin D levels significantly contribute to the skeletal defects associated with the disease.

[Revision surgery in acute periprosthetic knee joint infections]. / Revisionseingriffe bei akuten periprothetischen Kniegelenkendoprothesen-Infektionen.

OBJECTIVE: Reduction of pathogens in the knee joint by removal of infected periprosthetic soft tissue, irrigation and modular implant exchange of the total knee arthroplasty (TKA) to eliminate the infection and long-term preservation of the TKA. INDICATIONS: Early infection of TKA (<4 weeks postoperatively); acute hematogenous TKA infection (symptom duration <3 weeks). CONTRAINDICATIONS: Delayed (>4 weeks postoperatively) or chronic TKA infection; TKA loosening; difficult-to-treat pathogens; critical soft tissue with draining sinus tract. SURGICAL TECHNIQUE: Excision of the wound or old surgical scar (= primary approach to the knee joint). Preparation of subcutaneous tissue. Opening the joint capsule. Removal of the old suture in tissue layers. Five tissue samples taken for microbiological and 1 tissue sample for histopathological examination using an unused instrument from the knee joint. Debridement of the upper recesses with complete synovectomy. Partial resection of Hoffa's fat body. Eversion of the patella. Resection of peripatellar soft tissue and infection membranes from the medial and lateral part of the capsule. Removal of the polyethylene inlay. Débridement of the posterior joint capsule with protection of vessels and nerve. Systematic removal of avital and infected periprosthetic tissue. Checking for correct fit of the femoral and tibial part of TKA. Antiseptic rinsing of the joint cavity with mechanical cleaning of the TKA. Extensive irrigation of the joint cavity by jet lavage (3-5 l saline solution). Glove change of the surgical team and new operation coverage. Inserting new polyethylene. Layerwise wound closure. POSTOPERATIVE MANAGEMENT: Removal of redon drain on postoperative day 2. Physiotherapy and CPM. Removal of cutaneous suture about 2 weeks postoperatively. Antibiotic treatment for 12 weeks postoperatively (2 weeks intravenous, 10 weeks per oral). Checking of inflammatory markers. RESULTS: Using correct indications and therapy, up to 90% of patients with acute periprosthetic TKA infection can be successfully treated with infection elimination and TKA preservation.

[Subdental synchondrosis. Computed tomographic and histologic investigation on morphological aspects of fracture at the base of the dens in 36 human axis specimens]. / Die subdentale Synchondrose. Eine computertomographische und histologische Untersuchung zu morphologischen Aspekten der Densbasisfraktur an 36 humanen Axispräparaten.

BACKGROUND: During development of the axis, four different ossification centers are formed. The two cranial ossification centers are demarcated from the ossification center of the vertebral corpus by a subdental synchondrosis. During further development the subdental synchondrosis--which is thought to close spontaneously--might not close completely, which leads to the necessity for differentiating synchondrotic remnants from a fracture at the base of the dens (type II according to Anderson and D'Alonzo). RESULTS: To characterize the architecture of the axis with particular attention to the subdental synchondrosis, the axis was harvested from 36 age- and gender-matched patients covering the human aging process from adolescence to senescence. In all specimens bone mineral density (BMD) was measured by peripheral quantitative computed tomography (pQCT). Morphological analysis after undecalcified processing of all specimens revealed a persistency of the subdental synchondrosis in 87% of all patients. Histological characterization of the subdental synchondrosis showed a cartilaginous structure interspersed with focal mineralization. Furthermore, static histomorphometric analysis revealed that trabecular bone volume and cortical thickness were significantly reduced within the base of the axis as compared to the dens and the corpus, respectively. CONCLUSION: Taken together, these results provide evidence that the base of the axis is a structurally distinct region. Besides well-recognized biomechanical aspects, these results suggest that the structure of the base of the axis might contribute to the occurrence of fractures of the axis and offer an additional explanation for the observation of nonunion after type II dens fractures.

[Pathophysiology and pathomorphology of osteoporosis]. / Pathophysiologie und Pathomorphologie der Osteoporose.

Osteoporosis is a disease that leads to fragility fractures due to loss of bone mass and bone microstructure. This review presents an update on the fundamental pathophysiologic and pathomorphologic mechanisms of bone loss situations. Pathomorphologic characteristics such as perforations and microcallus formations are explained. The physiologic relevance of the remodeling process as well as its control by local-paracrine, systemic-endocrine and central-neural signaling pathways is discussed. Furthermore the role of hormones such as estrogen, FSH and leptin, of transcription-factors such as Runx2 and osterix and as well as that of the wnt signaling pathway for bone cell differentiation and function is presented. On the basis of current knowledge osteoporosis can be diagnosed, treated and fractures can be prevented. However, it is likely that new and even more effective diagnostic and therapeutic strategies will emerge as our understanding of the remodeling process that controls osteoblast and osteoclast function increases.

Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass.

Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.