Matthias Krause

Micro-morphological properties of osteons reveal changes in cortical bone stability during aging, osteoporosis, and bisphosphonate treatment in women

SummaryWe analyzed morphological characteristics of osteons along with the geometrical indices of individual osteonal mechanical stability in young, healthy aged, untreated osteoporotic, and bisphosphonate-treated osteoporotic women. Our study revealed significant intergroup differences in osteonal morphology and osteocyte lacunae indicating different remodeling patterns with implications for fracture susceptibility.IntroductionBone remodeling is the key process in bone structural reorganization, and its alterations lead to changes in bone mechanical strength. Since osteons reflect different bone remodeling patterns, we hypothesize that the femoral cortices of females under miscellaneous age, disease and treatment conditions will display distinct osteonal morphology and osteocyte lacunar numbers along with different mechanical properties.MethodsThe specimens used in this study were collected at autopsy from 35 female donors (young group, nu2009=u20096, age 32u2009±u20098xa0years; aged group, nu2009=u200910, age 79u2009±u20099xa0years; osteoporosis group, nu2009=u200910, age 81u2009±u20099xa0years; and bisphosphonate group, nu2009=u20099, age 81u2009±u20097xa0years). Von Kossa-modified stained femoral proximal diaphyseal sections were evaluated for osteonal morphometric parameters and osteocyte lacunar data. Geometrical indices of osteonal cross-sections were calculated to assess the mechanical stability of individual osteons, in terms of their resistance to compression, bending, and buckling.ResultsThe morphological assessment of osteons and quantification of their osteocyte lacunae revealed significant differences between the young, aged, osteoporosis and bisphosphonate-treated groups. Calculated osteonal geometric indices provided estimates of the individual osteons’ resistance to compression, bending and buckling based on their size. In particular, the osteons in the bisphosphonate-treated group presented improved osteonal geometry along with increased numbers of osteocyte lacunae that had been formerly impaired due to aging and osteoporosis.ConclusionsThe data derived from osteons (as the basic structural units of the cortical bone) in different skeletal conditions can be employed to highlight structural factors contributing to the fracture susceptibility of various groups of individuals.

Multi-level characterization of human femoral cortices and their underlying osteocyte network reveal trends in quality of young, aged, osteoporotic and antiresorptive-treated bone

Characterization of bones hierarchical structure in aging, disease and treatment conditions is imperative to understand the architectural and compositional modifications to the material and its mechanical integrity. Here, cortical bone sections from 30 female proximal femurs - a frequent fracture site - were rigorously assessed to characterize the osteocyte lacunar network, osteon density and patterns of bone matrix mineralization by backscatter-electron imaging and Fourier-transform infrared spectroscopy in relation to mechanical properties obtained by reference-point indentation. We show that young, healthy bone revealed the highest resistance to mechanical loading (indentation) along with higher mineralization and preserved osteocyte-lacunar characteristics. In contrast, aging and osteoporosis significantly alter bone material properties, where impairment of the osteocyte-lacunar network was evident through accumulation of hypermineralized osteocyte lacunae with aging and even more in osteoporosis, highlighting increased osteocyte apoptosis and reduced mechanical competence. But antiresorptive treatment led to fewer mineralized lacunae and fewer but larger osteons signifying rejuvenated bone. In summary, multiple structural and compositional changes to the bone material were identified leading to decay or maintenance of bone quality in disease, health and treatment conditions. Clearly, antiresorptive treatment reflected favorable effects on the multifunctional osteocytic cells that are a prerequisite for bones structural, metabolic and mechanosensory integrity.

Healing Predictors of Stable Juvenile Osteochondritis Dissecans Knee Lesions After 6 and 12 Months of Nonoperative Treatment

Background: Nonoperative treatment of stable juvenile osteochondritis dissecans (JOCD) lesions of the knee fails in up to 50% of cases. Healing predictors are needed to identify potential failures and thus determine treatment options. Purpose: A predictive model for healing potential after 6 and 12 months of nonoperative treatment of stable JOCD lesions based on sensitive magnetic resonance imagining (MRI) follow-up measurements was developed. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: A retrospective cross-sectional study was conducted to analyze 62 white patients (76 stable JOCD lesions) who were initially treated by restriction of activity until they were free of pain. The primary end point was healing investigated on MRI with follow-up measurements after 6 and 12 months of nonoperative treatment. Multivariate logistic regression was used to determine the influence of age, sex, JOCD lesion size, clinical symptoms, and the occurrence of cystlike lesions (CLLs) on healing potential. Additionally, optimal prognostic cutoffs were defined to differentiate failures from nonfailures. Results: After 6 months of nonoperative treatment, 51 (67%) of 76 stable JOCD lesions showed no progression toward healing or showed signs of instability. Normalized lesion width and area and CLL occurrence differed significantly between failures and nonfailures (P < .05). A multivariate logistic regression best-predictors model that included age, CLL size, and normalized lesion width best predicted healing after 6 months and resulted in an area under the curve (AUC) of 0.779 (P < .001). A cutoff at 48% healing probability, as predicted by a nomogram based on age, normalized lesion width, and CLL size, differentiated failures from nonfailures (sensitivity, 60.0%; specificity, 83.7%). After 12 months, 37 lesions (49%) had progressed toward healing, and the sole observation of CLL size had the highest predictive validity (AUC, 0.766). The optimal cutoff was a healing probability of 61% (lesion size, 1.3 mm; sensitivity, 70.3%; specificity, 74.1%). Conclusion: A 6-month period of nonoperative treatment with or without casting might be appropriate if the healing potential is >48%. A 12-month period of nonoperative treatment may be successful if the CLL is <1.3 mm in length as assessed on MRI.

Morphologic Analysis of Periprosthetic Fractures After Hip Resurfacing Arthroplasty

BACKGROUNDnPeriprosthetic fractures have long been recognized as one of the major complications of hip resurfacing arthroplasty. The objective of this study was to develop a systematic and morphologic classification of the fracture mode based on pathogenesis.nnnMETHODSnOne hundred and seven retrieved specimens consisting of the femoral remnant and the femoral component of a total hip resurfacing arthroplasty that had failed as a result of a periprosthetic fracture were analyzed with regard to the morphologic failure mode. The location of the fracture line was used to differentiate the fractures. The fractures were also classified histopathologically as acute biomechanical, acute postnecrotic, or chronic biomechanical.nnnRESULTSnFifty-nine percent (sixty-three) of the fractures occurred within the bone inside the femoral component. Fifty-one percent (fifty-five) of the fractures were classified morphologically as acute postnecrotic; 40% (forty-three), as chronic biomechanical; and 8% (nine), as acute biomechanical. Acute biomechanical fractures were found exclusively in the femoral neck and occurred earlier (mean time [and standard deviation] between implantation and revision, 41 +/- 57 days) than acute postnecrotic fractures (mean time between implantation and revision, 149 +/- 168 days; p = 0.002) or chronic biomechanical fractures (mean time between implantation and revision, 179 +/- 165 days; p = 0.001). The latter two fracture types both occurred predominantly in the bone inside the femoral component.nnnCONCLUSIONSnThree distinct fracture modes were characterized morphologically. Osteonecrosis was the most frequent cause of fracture-related failures. We suggest that an intraoperative mechanical injury of the femoral neck such as notching and/or malpositioning of the femoral component might lead to changes in the loading pattern or in the resistance to fracture of the femoral neck and may result in both acute and chronic biomechanical femoral neck fractures. These findings may serve as feedback information for the surgeon and possibly influence future therapeutic strategies.

Spontaneous osteonecrosis of the knee (SONK)

PurposeSpontaneous osteonecrosis of the knee (SONK/Morbus Ahlback) mainly affects the medial condyle of elderly women. It is assumed that localized vascular insufficiency leads to necrosis of the subchondral bone with subsequent disruption of the nutrition supply to the cartilage above. The aetiology remains unclear in detail. Operative treatment procedures compete against non-operative strategies, whereas the outcome is unpredictable in many cases.MethodA consecutive case series of five patients suffering from SONK was analysed. All patients underwent a clinical examination, magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry scan, as well as laboratory analyses and visual analogue scale (VAS) evaluation. Our treatment regime is based on high-dose vitamin D administered orally and intravenous application of 3xa0mg ibandronate two times within 8xa0weeks. Another 8xa0weeks later, all patients were followed up including a follow-up MRI.ResultsWithin 4xa0weeks, all patients were free of symptoms. The MRI follow-up showed remission of the bone marrow oedema in every case studied. VAS decreased significantly from 7.4xa0±xa01.0 pre-interventional to 0.8xa0±xa01.0 post-interventional. No allergic reactions or other side effects were documented.ConclusionWe showed that our treatment regime not only eliminated the pathological findings in the MRI of all cases studied, but also decreased the pain level and functional limitations within a short-time period.Level of evidenceIV.

Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II

Mucolipidosis type II (MLII) is a severe multi‐systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock‐in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro‐osteoclastogenic cytokine interleukin‐6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature.

Intra-articular tibial plateau fracture characteristics according to the “Ten segment classification”

BACKGROUNDnCurrently existing classifications of tibial plateau fractures do not help to guide surgical strategy. Recently, a segment-based mapping of the tibial plateau has been introduced in order to address fractures with a fracture-specific surgical approach. The goal of the present study was to analyze incidence and fracture specifics according to a new 10-segment classification of the tibial plateau.nnnMETHODSnA total of 242 patients with 246 affected knees were included (124 females, 118 males, mean age 51.9±16.1years). Fractures were classified according to the OTA/AO classification. Fracture pattern was analyzed with respect to a 10-segment classification based on CT imaging of the proximal tibial plateau 3cm below the articular surface.nnnRESULTSn161 Patients suffered an OTA/AO type 41-B and 85 patients an OTA/AO type 41-C tibial plateau fracture. Females had an almost seven times higher risk to suffer a fracture due to low-energy trauma (OR 6.91, 95% CI (3.52, 13.54), p<0.001) than males. In 34% of the patients with affection of the medial tibial plateau, a fracture comminution, primarily due to low-energy trauma (p<0.001), was observed. In type B fractures, the postero-latero-lateral (65.2%), the antero-latero-lateral (64.6%) and the antero-latero-central (60.9%) segment were most frequently affected. Every second type C fracture showed an unique fracture line and zone of comminution. The tibial spine was typically involved (89.4%). A typical fracture pattern of high-energy trauma demonstrated a zone of comminution of the lateral plateau and a split fracture in the medial plateau. The most frequently affected segments were the postero-latero-central (85.9%), postero-central (84.7%), and antero-latero-central (78.8%) segment.nnnCONCLUSIONnPosterior segments were the most frequently affected in OTA/AO type B and C fractures. Acknowledging the restricted visibility of posterior segments, whose reduction and fixation is crucial for long-term success, our findings implicate the use of posterior approaches more often in the treatment of tibial plateau fractures. Also, low-energy trauma was identified as an important cause for tibial plateau fractures.

Calcium gluconate supplementation is effective to balance calcium homeostasis in patients with gastrectomy

SummaryWe demonstrate histological evidence for hyperparathyroidism in patients with gastrectomy. This is, at least in part, explained by impaired calcium absorption, resulting in mineralization defects and secondary hyperparathyroidism. Additionally, we demonstrate improved bone mineralization in patients with gastrectomy after gluconate therapy and showed the effectiveness of calcium gluconate over carbonate to balance impaired calcium hemostasis in mice.IntroductionGastrectomy and hypochlorhydria due to long-term proton pump inhibitor therapy are associated with increased fracture risk because of intestinal calcium malabsorption. Hence, our objectives were to histologically investigate bone metabolism in patients with gastrectomy and to analyze the impact of calcium gluconate supplementation on skeletal integrity in the setting of impaired gastric acidification.MethodsUndecalcified bone biopsies of 26 gastrectomized individuals were histologically analyzed. In the clinical setting, we retrospectively identified 5 gastrectomized patients with sufficient vitamin D level, who were additionally supplemented with calcium gluconate and had a real bone mineral density (aBMD) follow-up assessments. A mouse model of achlorhydria (ATP4b−/−) was used to compare the effect of calcium gluconate and calcium carbonate supplementation on bone metabolism.ResultsBiopsies from gastrectomized individuals showed significantly increased osteoid, osteoclast, and osteoblast indices and fibroosteoclasia (pu2009<u20090.05) as well as impaired calcium distribution in mineralized bone matrix compared to healthy controls. Five gastrectomized patients with sufficient vitamin D level demonstrated a significant increase in aBMD after a treatment with calcium gluconate alone for at least 6xa0months (pu2009<u20090.05). Calcium gluconate was superior to calcium carbonate in maintaining calcium metabolism in a mouse model of achlorhydria.ConclusionGastrectomy is associated with severe osteomalacia, marrow fibrosis, and impaired calcium distribution within the mineralized matrix. We show that calcium gluconate supplementation can increase bone mineral density in gastrectomized individuals and performs superior to calcium carbonate in restoring calcium/skeletal homoeostasis in a mouse model of achlorhydria.

Intraosseous lymphocytic infiltrates after hip resurfacing arthroplasty : a histopathological study on 181 retrieved femoral remnants.

To identify a possible role of lymphocytic infiltrates in failure mechanism of the metal-on-metal hip resurfacing arthroplasty, the extent of lymphocytic infiltration was compared with reasons for prosthesis failure in a series of retrieval specimens. One hundred eighty-one femoral head and neck remnants were subjected to thorough analysis of histological findings and clinical data. Lymphocytic infiltrates were considered weak to moderate in 52 (28.7%) and excessive in ten (5.5%) cases. Six cases with excessive lymphocytic infiltrates belonged to the group of 33 (18.2%) revisions without obvious cause (periprosthetic fracture, component loosening, and infection) for prosthesis failure. Excessive lymphocytic infiltrates were strongly linked to the presence of proliferative desquamative synovitis (pu2009<u20090.0001). Both the excessive lymphocytic infiltrates and proliferative desquamative synovitis were associated with female gender (pu2009<u20090.05). We hypothesize that a specific cause of groin pain might be related to excessive intraosseous lymphocytic infiltrates and explained possibly by the hypersensitivity reaction of the delayed type after the hip resurfacing arthroplasty. Proliferative desquamative synovitis might constitute another morphologic feature associated with the delayed type hypersensitivity reaction.

Accuracy of trabecular structure by HR-pQCT compared to gold standard μCT in the radius and tibia of patients with osteoporosis and long-term bisphosphonate therapy

SummaryDespite an increasing use of high-resolution peripheral quantitative computed tomography (HR-pQCT) to evaluate bone morphology in vivo, there are reservations about its applicability in patients with osteoporosis and antiresorptive therapy. This study shows that HR-pQCT provides acceptable in vivo accuracy for bone volume fraction (BV/TV) in patients with osteoporosis and bisphosphonate (BP) treatment.IntroductionThe primary aim was to analyze agreement of trabecular structure between HR-pQCT and gold standard microtomography (μCT) in patients with osteoporosis and long-term BP therapy.MethodsIn the BioAsset study, we analyzed cadaver radii and tibiae of 34 postmenopausal females (81.1u2009±u20097.1xa0years) with osteoporosis (no BP nu2009=u200922, 1–5xa0years BP nu2009=u20095, >5xa0years BP nu2009=u20097). Two HR-pQCT protocols (patient-mode and μCT-mode) were compared with gold standard μCT after image registration. Undecalcified histological sections were obtained to quantify nonmineralized bone matrix. Bland-Altman plots illustrated methodological agreement. Multiple regression analysis was used to test for variables associated with method agreement.ResultsIn the radius and tibia, patient-mode HR-pQCT derived indices including bone volume fraction, trabecular number, and trabecular separation correlated well with gold standard μCT (R2u2009=u20090.78u2009−u20090.88) except for trabecular thickness (R2u2009=u20090.11). Bland-Altman plots illustrated adequate agreement for bone volume fraction. Lower agreement of trabecular number and trabecular separation improved with decreasing structural impairment at the tibia only. Trabecular thickness was not appropriately assessed with HR-pQCT at both skeletal sites. Higher agreement for bone volume fraction was associated with increasing tissue mineral density in the tibia.ConclusionsHR-pQCT provides acceptable in vivo accuracy for BV/TV in patients with osteoporosis and BP treatment. Higher TMD was associated with higher BV/TV accuracy in vivo. Overall, methodological agreement got less accurate with increasing structural impairment in the tibia.