Ursula Föger-Samwald

Serum Levels of Sclerostin and Dickkopf-1: Effects of Age, Gender and Fracture Status

Background: Fragility fractures, especially hip fractures, are a very common complication of osteoporosis in elderly subjects. Sclerostin (SOST) and dickkopf-1 (DKK-1) are inhibitors of the canonical wnt signalling pathway and thus could be involved in the pathogenesis of age-related bone fragility. Objective: To investigate SOST and DKK-1 in a large group of geriatric patients with hip fractures and to relate the wnt inhibitors to age and gender. Methods: This was a cross-sectional study carried out in a department of acute geriatric care in a district hospital in Upper Austria and a hospital in Vienna, Austria. A total of 256 geriatric patients (172 women and 84 men) and 67 young control subjects were selected after exclusion. Medical history was obtained, a comprehensive geriatric assessment was performed and serum levels of SOST, DKK-1 and bone formation markers were analysed. Results: DKK-1 levels increased with age and in the presence of hip fractures. In contrast, SOST levels were lower in patients with hip fractures. When compared to women, men had higher SOST levels but lower DKK-1 levels. Conclusion: Serum levels of the inhibitors of the canonical wnt signalling pathway reflect different biological events and are useful for the study of bone fragility in geriatric patients.

Changes in Serum Levels of Myokines and Wnt-Antagonists after an Ultramarathon Race.

Background Regular physical activities have a positive effect on the muscular skeletal system but overstrenuous exercise may be different. Transiently suppressed bone formation and increased bone resorption after participation in a 246-km ultradistance race has been demonstrated. Purpose The aim of this study was to analyze effects of the Spartathlon race on novel musculoskeletal markers. Methods Venous blood samples were obtained before and immediately after the race from 19 participants of the Spartathlon. From 9 runners who were available 3 days after the start blood was drawn for a third time. Serum levels of myostatin, an inhibitor of myogenic differentiation, and its opponent follistatin as well as sclerostin and dickkopf-1, both of them inhibitors of the wnt signaling pathway, and markers of bone turnover were determined. Results Serum levels of myostatin were significantly higher after the race. Serum follistatin only showed a transient increase. Sclerostin levels did not significantly differ before and after the race, whereas dickkopf-1 levels were significantly decreased. At follow-up a decrement of sclerostin and dickkopf-1 levels was seen. Serum cathepsin K levels did not change. Conclusion The increase of serum levels of myostatin appears to reflect muscle catabolic processes induced by overstrenuous exercise. After the short-term uncoupling of bone turnover participation in an ultradistance race seems to initiate a long-term positive effect on bone indicated by the low-level inhibition of the Wnt/β-catenin signaling pathway.

Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture☆

Cathepsin S is a cysteine protease that controls adipocyte differentiation and has been implicated in vascular and metabolic complications of obesity. Considering the inverse relation of osteoblasts and adipocytes and their mutual precursor cell, we hypothesized that cathepsin S may also affect osteoblast differentiation and bone remodeling. Thus, the fat and bone phenotypes of young (3 months old) and aged (12 or 18 months old) cathepsin S knock-out (KO) and wild-type (WT) mice were determined. Cathepsin S KO mice had a normal body weight at both ages investigated, even though the amount of subscapular and gonadal fat pads was reduced by 20%. Further, cathepsin S deficiency impaired adipocyte formation (-38%, p<0.001), which was accompanied by a lower expression of adipocyte-related genes and a reduction in serum leptin, IL-6 and CCL2 (p<0.001). Micro-CT analysis revealed an unchanged trabecular bone volume fraction and density, while tissue mineral density was significantly lower in cathepsin S KO mice at both ages. Aged KO mice further had a lower cortical bone mass (-2.3%, p<0.05). At the microarchitectural level, cathepsin S KO mice had thinner trabeculae (-8.3%), but a better connected trabecular network (+24%). Serum levels of the bone formation marker type 1 procollagen amino-terminal-propeptide and osteocalcin were both 2-3-fold higher in cathepsin S KO mice as was the mineralized surface. Consistently, osteogenic differentiation was increased 2-fold along with an increased expression of osteoblast-specific genes. Interestingly, serum levels of C-terminal telopeptide of type I collagen were also higher (+43%) in cathepsin S KO mice as were histological osteoclast parameters and ex vivo osteoclast differentiation. Thus, cathepsin S deficiency alters the balance between adipocyte and osteoblast differentiation, increases bone turnover, and changes bone microarchitecture. Therefore, bone and fat metabolisms should be monitored when using cathepsin S inhibitors clinically.

Molecular evidence of osteoblast dysfunction in elderly men with osteoporotic hip fractures

Osteoporosis is extremely frequent in post-menopausal women; nevertheless, osteoporosis in men is also a severe and frequently occurring but often underestimated disease. Increasing evidence links bone loss in male idiopathic osteoporosis and age related osteoporosis to osteoblast dysfunction rather than increased osteoclast activity as seen in postmenopausal osteoporosis. The aim of this study was to investigate gene expression of osteoblast related genes and of bone architecture in bone samples derived from elderly osteoporotic men with hip fractures (OP) in comparison to bone samples from age matched men with osteoarthritis of the hip (OA). Femoral heads and adjacent neck tissue were collected from 12 men with low-trauma hip fractures and consecutive surgical hip replacement. Bone samples of age matched patients undergoing hip replacement due to osteoarthritis served as controls. One half of the bone samples was subjected to RNA extraction, reverse transcription, and real-time polymerase chain reactions. The second half of the bone samples was analyzed by static histomorphometry. From each half samples from four different regions, the central and subcortical region of the femoral head and neck, were analyzed. OP patients displayed a significantly decreased RUNX2, Osterix and SOST expression compared to OA patients. Major microstructural changes in OP bone were seen in the subcortical region of the neck and were characterized by a significant decrease of bone volume, and a significant increase of trabecular separation. In conclusion, decreased local gene expression of RUNX2 and Osterix in men with hip fractures strongly supports the concept of osteoblast dysfunction in male osteoporosis. Major microstructural changes in the trabecular structure associated with osteoporotic hip fractures in men are localized in the subcortical region of the femoral neck.

Molecular mechanisms of osteoporotic hip fractures in elderly women

A common manifestation of age-related bone loss and resultant osteoporosis are fractures of the hip. Age-related osteoporosis is thought to be determined by a number of intrinsic factors including genetics, hormonal changes, changes in levels of oxidative stress, or an inflammatory status associated with the aging process. The aim of this study was to investigate gene expression and bone architecture in bone samples derived from elderly osteoporotic women with hip fractures (OP) in comparison to bone samples from age matched women with osteoarthritis of the hip (OA). Femoral heads and adjacent neck tissue were collected from 10 women with low-trauma hip fractures (mean age 83±6) and consecutive surgical hip replacement. Ten bone samples from patients undergoing hip replacement due to osteoarthritis (mean age 80±5) served as controls. One half of each bone sample was subjected to gene expression analysis. The second half of each bone sample was analyzed by microcomputed tomography. From each half, samples from four different regions, the central and subcortical region of the femoral head and neck, were analyzed. We could show a significantly decreased expression of the osteoblast related genes RUNX2, Osterix, Sclerostin, WNT10B, and Osteocalcin, a significantly increased ratio of RANKL to Osteoprotegerin, and a significantly increased expression of the enzymes superoxide dismutase 2 (SOD2) and glutathione peroxidase GPX3, and of the inflammatory cytokine IL6 in bone samples from hip fracture patients compared to controls. Major microstructural changes in OP bone were seen in the neck and were characterized by a significant decrease of bone volume, trabecular number, and connectivity density and a significant increase of trabecular separation. In conclusion, our data give evidence for a decreased expression of osteoblast related genes and increased expression of osteoclast related genes. Furthermore, increased expression of SOD2 and GPX3 suggest increased antioxidative activity in bone samples from elderly osteoporotic women with hip fractures.

Bone Effects of Binge Alcohol Drinking Using Prepubescent Pigs as a Model

Background Although chronic alcohol consumption in adults is an established risk factor for osteoporotic fractures, there is a huge gap in our knowledge about bone effects of binge drinking in adolescents. The aim of this pilot study was therefore to assess skeletal effects of binge alcohol drinking using prepubescent pigs as a large animal model. Methods Piglets aged 2 months were offered alcohol orally as a mixture of hard liquor and apple juice. Those with the highest propensity to drink alcohol were included in the experiment and received 1.4 g alcohol/kg bodyweight 2 times per week for 2 months (alcohol group); control piglets received apple juice in an identical manner. At the age of 4 months, the animals were euthanized; trabecular and cortical bone samples from the femur, the tibia, the humerus, and the fourth vertebral body harvested during necropsy were assessed by microcomputed tomography and dynamic histomorphometry. In addition, blood chemistry and blood alcohol determinations were performed. Results Blood alcohol levels assessed 1 hour after alcohol administration were 0.99‰ ± 0.15, 1.12‰ ± 0.2, and 1.14‰ ± 0.18 at the ages of 2, 3, and 4 months, respectively. In the alcohol group, serum calcium and phosphate levels were decreased. In the femur, trabecular number and connectivity density were lower in the alcohol than in the control group, and in the humerus and the fourth vertebral bodies, an opposite pattern was seen for trabecular number and connectivity density, respectively. Cortical density was higher in the humerus and trabecular density higher in the tibia of the alcohol group compared to the control group. Cortical porosity was lower in the humerus of the alcohol group. No significant differences were seen for trabecular thickness, trabecular separation, bone volume fraction, and static and dynamic histomorphometric parameters. Conclusions In this pilot study, we have assessed skeletal effects of binge alcohol drinking by using prepubescent pigs as a promising large animal model. Binge drinking has bone effects that are site‐specific. However, these data have to be verified in a larger study population.

Comparing Two Major Bone Pathologies in Humans and Companion Animals: Osteoporosis and Hyperparathyroidism

Metabolic/endocrinological diseases of bone are a major topic in human medicine, but are not that frequent in veterinary medicine. We will focus on two major bone diseases of human medicine, namely, osteoporosis and hyperparathyroidism, and compare their expression and pathophysiology in companion animals. In humans, postmenopausal osteoporosis is the most frequent and economically most important bone disease, but interestingly has no direct equivalent in veterinary medicine. This is also due to the fact that osteoporosis is not only a matter of low bone mineral density but also of altered bone (micro)structure. Also, hypoestrogenism does not seem to be of that clinical importance in our domestic mammals. On the other hand, hyperparathyroidism, which is frequently diagnosed in humans as well, resembles a clinical problem also the veterinarian has to deal with.

Pathophysiology of Bone Fragility

Fragility fractures are defined as fractures that occur as a result of a minimal trauma, such as a fall from standing height or less, or in the absence of an obvious trauma. When getting older, the probability to sustain a fragility fracture increases. This age-related increase is even more pronounced in women due to the sudden drop in sex steroid secretion during menopausal transition. In the first part of this chapter, you will learn how different bone-related properties including bone mass, bone microarchitecture and macroarchitecture, bone material properties, and bone metabolism contribute to bone fragility. The most prominent and most frequent disease associated with bone fragility is osteoporosis. However, also patients with various other diseases including Paget’s disease, primary hyperparathyroidism, rickets, osteomalacia, and chronic kidney disease-mineral bone disorder (CKD-MBD) do have an increased risk to sustain fragility fractures. In the second and third part of this chapter, you will learn about the pathophysiological mechanisms leading to bone fragility in these diseases.

Bone Turnover Markers

Bone is a very active tissue that is constantly remodeled in order to adapt to mechanic or metabolic requirements. Since disturbances in bone remodeling may result in relevant skeletal diseases, there is great interest in tools to assess bone remodeling for scientific and clinical applications. Bone turnover markers (BTMs) are among these tools; this chapter presents established markers of bone resorption and bone formation and also selected novel markers. For each marker the biochemical background will be described; in addition you will learn about non-pathological and pathological conditions that lead to alterations of the levels of BTMs. Finally, strengths and weaknesses of the BTMs – especially with regard to their potential clinical applications – will be discussed.

Secondary confounders of osteoporotic hip fractures in patients admitted to a geriatric acute care department.

BackgroundWith respect to the pathogenesis of osteoporosis, primary and secondary forms of the disease can be distinguished. It has been recognized that the incidence of primary and secondary osteoporosis differs in women and men.ObjectiveThe aim of the present study was to assess the incidence and gender distribution of factors contributing to osteoporosis in older hip fracture patients.MethodsIn this cross-sectional study 404 patients with hip fractures and controls referred to an acute geriatric care department over a period of 15 months were included. The medical history was recorded and blood samples were analyzed for routine laboratory parameters.ResultsA total of 249 patients with hip fractures and 155 matched controls were studied. The Tinetti test and the Barthel index were found to show highly significant differences in both groups mainly because of the postoperative state of patients with fractures. Vitamin D deficiency was found in 94.1 % of male fracture patients and 94.6 % of female fracture patients. On average 2.4 secondary contributors of osteoporosis were present in male fracture patients versus 2.9 in male controls and 2.3 in female fracture patients versus 2.3 in female controls. For most parameters no significant gender differences of possible secondary contributors to osteoporosis were found. Secondary osteoporosis was diagnosed in all male fracture patients and in 56.2 % of all female fracture patients.ConclusionBased on the findings of this study it is recommended that hip fracture patients should be assessed for secondary contributors of osteoporosis. Although the overall distribution of secondary contributors was similar in women and men, the prevalence of secondary osteoporosis was higher in men.ZusammenfassungHintergrundIm Hinblick auf die Pathogenese lassen sich primäre und sekundäre Formen der Erkrankung unterscheiden. Die Inzidenz der primären und der sekundären Osteoporose ist bei Frauen und Männern verschieden.ZielZiel der vorgestellten Studie war die Analyse der Inzidenz und der Geschlechtsverteilung der Faktoren, die zu Osteoporose bei älteren Patienten mit Hüftfrakturen beitragen.MethodenIn die Querschnittsstudie wurden innerhalb von 15 Monaten 404 Patienten insgesamt eingeschlossen, sowohl Patienten mit Hüftfrakturen als auch Patienten, die aus anderen Gründen auf eine Station der geriatrischen Akutversorgung aufgenommen worden waren. Die medizinische Anamnese wurde erhoben, und Routine-Laborparameter wurden in Blutproben bestimmt.ErgebnisseInsgesamt 249 Patienten mit Hüftfrakturen und 155 gematchte Kontrollpatienten wurden untersucht. Die Scores im Tinetti-Test und im Barthel-Index waren hoch signifikant unterschiedlich in den beiden Gruppen, vor allem bedingt durch den postoperativen Zustand der Patienten mit Frakturen. Ein Vitamin-D-Mangel bestand bei 94,1% der männlichen und 94,6% der weiblichen Patienten mit Frakturen. Durchschnittlich lagen bei den männlichen Frakturpatienten 2,4 Sekundärfaktoren für eine Osteoporose vor (vs. 2,9 bei den männlichen Kontrollpatienten) und 2,3 bei den weiblichen Frakturpatienten (vs. 2,3 bei den weiblichen Kontrollpatienten). Für die meisten Parameter zeigten sich keine signifikanten Geschlechtsunterschiede möglicher sekundärer Faktoren für die Entwicklung einer Osteoporose. Die Diagnose sekundäre Osteoporose wurde bei allen männlichen und bei 56,2% der weiblichen Patienten gestellt.SchlussfolgerungAuf der Basis der Ergebnisse dieser Studie wird empfohlen, dass Patienten mit Hüftfrakturen auf Faktoren untersucht werden, die zu einer sekundären Osteoporose beitragen. Zwar erwies sich die Verteilung dieser Faktoren als insgesamt ähnlich bei Männern und Frauen, doch die Prävalenz der sekundären Osteoporose war bei Männern höher.