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Low bone mineral density (BMD) is common in patients with hemophilia (PWHs). The aim of the present study was to describe BMD and microarchitecture in PWHs in Northern Germany and to determine factors contributing to possible skeletal alterations. Demographic characteristics, BMD and microarchitecture, bone metabolism markers, and orthopaedic joint score (OJS) were assessed during routine check-ups. Areal BMD was assessed by dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine. Volumetric BMD and microarchitecture were quantified by high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Eighty male PWHs (median age, 33 years; range, 18–77) were retrospectively analyzed, of whom 67 (84.0%) and 13 (16.0%) had hemophilia A and B, respectively. Fifty-four (68.0%), six (7.0%), and 20 (25.0%) patients had severe, moderate, or mild hemophilia, and 35 (44.0%) were hepatitis C virus (HCV) positive. DXA analysis revealed low BMD (Z-score ≤ − 2.0) in 27.5% of PWHs, and higher bone turnover values were associated with lower BMD. Bone microarchitecture was dominated by cortical deficits at the radius and trabecular deficits at the tibia. Cortical deficits at the radius were influenced by lower body mass index, low-grade inflammation, and treatment regimen (higher cortical thickness on primary prophylaxis). Trabecular alterations at the tibia were mainly associated with OJS and HCV status. A positive effect of self-reported sportive activity on BMD could be shown. In conclusion, our findings demonstrate that the site-specific microarchitectural deficit observed in PWHs is primarily negatively influenced by poor joint status, inflammation, HCV infection, and high bone turnover.

ZUSAMMENFASSUNGDas Knochenmarködemsyndrom (KMÖS) ist eine durch pathologische Flüssigkeitsvermehrung im Knochenmark gekennzeichnete Erkrankung, die sich mittels MRT darstellen lässt. Das Spektrum potenziell verursachender Erkrankungen ist groß, wobei sich ätiologisch mechanische, metabolische, reaktive und ischämische KMÖS-Formen voneinander unterscheiden lassen. Zwar ist die Pathophysiologie des KMÖS noch unzureichend verstanden, doch wird ein lokal erhöhter Knochenumbau im Sinne einer aktivierten Knochenresorption angenommen, die zu einer erhöhten Vaskularisation mit konsekutiv vermehrter Flüssigkeitsansammlung führt. Ziel unserer Arbeit war es anhand der pathophysiologischen Überlegungen die möglichen verursachenden Erkrankungen differenzialdiagnostisch zu beleuchten und anhand derer einen diagnostischen Algorithmus zu präsentieren. Dabei zeigen wir, dass sich die verschiedenen KMÖS-Formen oft mittels typischer MRT-morphologischer sowie klinischer und laborchemischer Charakteristika unterscheiden lassen, sodass anhand der richtigen Diagnose gezielt therapeutische Maßnahmen getroffen werden können.

ZUSAMMENFASSUNGDie medikamentöse Therapie des primären Knochenmarködemsyndroms (KMÖS) stellt einen wesentlichen Bestandteil des Gesamttherapiekonzeptes des KMÖS dar, wobei eine frühe Detektion und eine zeitnahe Initiierung von therapeutischen Maßnahmen von entscheidender Bedeutung ist. Zunächst gilt es, neben dem Ausschluss von sekundären Ursachen, mögliche Störungen der Kalziumhomöostase zu untersuchen und ggf. auszugleichen, da von einem maßgeblichen Einfluss dieser Faktoren in der Pathogenese des primären KMÖS ausgegangen wird. So stellen Mangelzustände, wie ein Vitamin-D-Mangel, eine häufige Ursache einer solchen Störung der Kalziumhomöostase dar und können konsekutiv zu einer enteralen Kalziumaufnahmestörung sowie zu einer Mineralisationsstörung des Knochens führen. Da ein KMÖS häufig mit einem systemischen respektive lokalen High-Turnover-Knochenstoffwechsel einhergeht, ist die Steuerung des Knochenstoffwechsels im Rahmen der Therapie besonders wichtig. Im Falle eines High-Turnover-Knochenstoffwechsels oder anderer klinischer Faktoren, wie einer gelenknahen subchondralen Lokalisation des Knochenmarködems mit Risiko einer Infraktion, einer schnellen Progredienz, einem großen Volumen oder ausgeprägten, immobilisierenden Schmerzen, kann eine antiresorptive Therapie im Off-Label-Verfahren in die Behandlung integriert werden. So konnte für den Einsatz von intravenösen Bisphosphonaten, wie Ibandronat oder Zoledronat, als auch des subkutan zu injizierenden Denosumab eine klinisch relevante Effektivität festgestellt werden, wobei bei Letzterem der schnellste Wirkeintritt zu erwarten ist. Zoledronat scheint, allerdings auf Kosten einer höheren Anzahl potenziell unerwünschter Ereignisse, das effektivste Wirkprofil zu besitzen. Einen alternativen Therapieansatz stellt der Off-Label-Einsatz des Prostazyklin-Analogons Iloprost dar, welches gemäß der Studienlage eine probate Therapieoption in frühen Stadien des Knochenmarködems darstellt, allerdings unter stationärer Überwachung zu applizieren ist. Parallel zur medikamentösen Therapie ist die chirurgische Mitbehandlung mit regelmäßiger Evaluation zur Anbohrung (Core Decompression) als Teil des Gesamttherapiekonzeptes zu eruieren.

In patients with autoimmune hepatitis (AIH), osteoporosis represents a common extrahepatic complication, which we recently showed by an assessment of areal bone mineral density (aBMD) via dual-energy x-ray absorptiometry (DXA). However, it is well established that bone quality and fracture risk does not solely depend on aBMD, but also on bone microarchitecture. It is currently not known whether AIH patients exhibit a site-specific or compartment-specific deterioration in the skeletal microarchitecture. In order to assess potential geometric, volumetric, and microarchitectural changes, high-resolution peripheral quantitative computed tomography (HR-pQCT) measurements were performed at the distal radius and distal tibia in female patients with AIH (n = 51) and compared to age-matched female healthy controls (n = 32) as well as to female patients with AIH/primary biliary cholangitis (PBC) overlap syndrome (n = 25) and female patients with PBC alone (PBC, n = 36). DXA at the lumbar spine and hip, clinical characteristics, transient elastography (FibroScan) and laboratory analyses were also included in this analysis. AIH patients showed a predominant reduction of cortical thickness (Ct.Th) in the distal radius and tibia compared to healthy controls (p < .0001 and p = .003, respectively). In contrast, trabecular parameters such as bone volume fraction (BV/TV) did not differ significantly at the distal radius (p = .453) or tibia (p = .508). Linear regression models revealed significant negative associations between age and Ct.Th (95% confidence interval [CI], -14 to -5 μm/year, p < .0001), but not between liver stiffness, cumulative prednisolone dose (even after an adjustment for age), or disease duration with bone microarchitecture. The duration of high-dose prednisolone (≥7.5 mg) was negatively associated with trabecular thickness (Tb.Th) at the distal radius. No differences in bone microarchitecture parameters between AIH, AIH/PBC, and PBC could be detected. In conclusion, AIH patients showed a severe age-dependent deterioration of the cortical bone microarchitecture, which is most likely the major contribution to the observed increased fracture risk in these patients. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5′-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.

ZusammenfassungDie Hypophosphatasie (HPP) als Folge einer genetisch bedingt defizienten Aktivität der gewebeunspezifischen alkalischen Phosphatase (TNAP) ist geprägt durch ein ausgesprochen weites Spektrum möglicher Manifestationen, sowohl hinsichtlich der Art der Symptomatik als auch bzgl. des Schweregrades der assoziierten Einschränkungen. Eine adäquate Behandlung erfordert insofern immer auch eine multimodale Herangehensweise unter spezieller Berücksichtigung der individuellen Ausprägung der Erkrankung.Für Patienten, bei denen die Erkrankung im Kindesalter aufgetreten ist, steht in Europa zur Behandlung der Knochenmanifestation mit Asfotase alfa (Strensiq) eine Enzymersatztherapie zur Verfügung. Sowohl in den Zulassungsstudien als auch in der klinischen Anwendung zeigen sich bei schwer betroffenen Kindern prinzipiell sehr erfreuliche radiologische und funktionelle Verbesserungen und ein verbessertes Gesamtüberleben. Auch bei Erwachsenen mit zulassungsentsprechender Krankheitsausprägung zeigen erste Ergebnisse eine deutliche Verbesserung der krankheitsassoziierten Einschränkungen und funktionelle Verbesserungen. Inzwischen gibt es auch ermutigende Daten zur Sicherheit und Wirksamkeit von Asfotase alfa über mehrere Behandlungsjahre.Während die oftmals als stark belastend empfundenen entzündlichen Schmerzen häufig gut auf eine intermittierende, bedarfsangepasste Behandlung mit NSAR ansprechen, sind im Hinblick auf die muskuloskelettale Gesamtgesundheit nachhaltige, langfristig ausgerichtete supportive Maßnahmen mit spezifischen Trainingskonzepten und einer alters- und bedarfsgerechten orthopädietechnischen Versorgung zu empfehlen. Das Potenzial diätetischer Maßnahmen zur Beeinflussung des Phosphat- und Vitamin-B6-Stoffwechsels bedarf sicher noch weiterer Untersuchungen. Bezüglich spezifisch knochenwirksamer Strategien sind primär antiresorptive Substanzen nach aktueller Datenlage kritisch zu betrachten, wohingegen osteoanabole Konzepte grundsätzlich möglich erscheinen.Sinnvollerweise sollte die Gesamtheit aller therapeutischen Maßnahmen an einem Zentrum mit entsprechender Erfahrung koordiniert und überblickt werden, wobei ein Großteil der konkreten Maßnahmen im aktiven Austausch auch heimatnah umgesetzt werden kann.

Methotrexate (MTX) is one of the most commonly prescribed drugs for autoimmune rheumatic diseases. As there is no consensus on its negative effects on bone, the purpose of this investigation was to determine the clinical spectrum of patients with stress fractures due to long-term MTX treatment (i.e., MTX osteopathy). We have retrospectively analyzed data from 34 patients with MTX treatment, severe lower extremity pain and immobilization. MRI scans, bone turnover markers, bone mineral density (DXA) and bone microarchitecture (HR-pQCT) were evaluated. Stress fractures were also imaged with cone beam CT. While the time between clinical onset and diagnosis was prolonged (17.4 ± 8.6 months), the stress fractures had a pathognomonic appearance (i.e., band-/meander-shaped, along the growth plate) and were diagnosed in the distal tibia (53%), the calcaneus (53%), around the knee (62%) and at multiple sites (68%). Skeletal deterioration was expressed by osteoporosis (62%) along with dissociation of low bone formation and increased bone resorption. MTX treatment was discontinued in 27/34 patients, and a combined denosumab–teriparatide treatment initiated. Ten patients re-evaluated at follow-up (2.6 ± 1.5 years) had improved clinically in terms of successful remobilization. Taken together, our findings provide the first in-depth skeletal characterization of patients with pathognomonic stress fractures after long-term MTX treatment. Electronic supplementary material The online version of this article (10.1007/s00223-020-00765-5) contains supplementary material, which is available to authorized users.

Background Tissue-nonspecific alkaline phosphatase (TNSALP) encoded by the ALPL gene is of particular importance for bone mineralization. Mutation in the ALPL gene can lead to persistent low ALP activity resulting in the rare disease Hypophosphatasia (HPP) that is characterized by disturbed bone and dental mineralization. While severe forms are extremely rare with an estimated prevalence of 1/100.000, recent studies suggest that moderate form caused by heterozygous mutations are much more frequent with an estimated prevalence of 1/508. The purpose of this study was to estimate the prevalence of low AP levels in the population based on laboratory measurements. Methods In this study, the prevalence of low AP activity and elevated pyridoxal-5-phosphate (PLP) levels was analyzed in 6.918.126 measurements from 2011 to 2016 at a single laboratory in northern Germany. Only laboratory values of subjects older than 18 years of age were included. Only the first measurement was included, all repeated values were excluded. Results In total, 8.46% of the measurements of a total of 6.918.126 values showed a value Conclusion These data support the genetic estimation that the prevalence of moderate forms of HPP may be significantly higher than expected. Based on these data, we recommend automatically measurement of PLP in the case of low ALP activity and a notification to the ordering physician that HPP should be included in the differential diagnosis and further exploration is recommended.

Hereditary hemochromatosis (HHC) is characterized by excessive intestinal iron absorption resulting in a pathological increase of iron levels. Parenchyma damage may be a consequence of iron deposition in affected organs (e.g., liver, pancreas, gonads) as well as bones and joints, leading to osteoporosis with increased fracture risk and arthropathy. Up to date, it is not known whether HHC can also be considered as a risk factor for osteonecrosis. Likewise, the underlying skeletal changes are unknown regarding, e.g., microstructural properties of bone. We aimed to study the spectrum of skeletal complications in HHC and the possible underlying microarchitectural changes. Therefore, we retrospectively analyzed all patients with HHC (n = 10) presenting in our outpatient clinic for bone diseases. In addition to dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT) was performed and bone turnover markers, 25-OH-D3, ferritin and transferrin saturation were measured. Cortical volumetric bone mineral density (Ct.BMD) and cortical thickness (Ct.Th) were reduced, whereas trabecular microstructure (Tb.Th) and volumetric bone mineral density (Tb.BMD) were preserved compared to age- and gender-adjusted reference values from the literature. Interestingly, the occurrence of bone complications was age dependent; while younger patients presented with osteonecroses or transient bone marrow edema, patients older than 65 years presented with fractures. Our study provides first insights into altered bone microarchitecture in HHC and sheds new light on the occurrence of osteonecrosis. If available, HR-pQCT is a useful complement to fracture risk assessment and to determine microstructural deterioration and volumetric bone mineralization deficits.

Zusammenfassung Die Hypophosphatasie (HPP) ist eine erbliche metabolische Multisystemerkrankung, deren klinische Hauptcharakteristika Mineralisierungsstörungen von Knochen und Zähnen sowie Muskel- und Gelenkschmerzen sind. Die klinische Symptomatik ist vom Erkrankungsalter abhängig und gestaltet sich sowohl interindividuell als auch intrafamiliär sehr variabel. Es werden sechs Unterformen der HPP abgegrenzt, wobei die Übergänge fließend sind. Sie reichen von der schweren perinatalen Form, die früher aufgrund fehlender Skelettmineralisierung meist tödlich war, bis hin zur adulten Form mit typischen Symptomen wie Frakturheilungsstörungen oder Stressfrakturen. Unspezifische Symptome wie Muskelschmerzen und -schwäche, Migräne oder Depressionen können ebenfalls Teil der HPP sein. Während schwere Formen mit einer Prävalenz zwischen 1/100.000 und 1/300.000 selten sind, kommen milde Formen der HPP deutlich häufiger vor. Perinatale und frühkindliche Formen sind meist autosomal-rezessiv vererbt, hingegen werden später auftretende Formen autosomal-rezessiv oder -dominant vererbt. Ursache der HPP ist eine reduzierte oder fehlende Aktivität der gewebeunspezifischen alkalischen Phosphatase (AP), welche durch das ALPL-Gen kodiert wird. Laborchemisch lassen sich im Serum eine alters- und geschlechtsspezifisch erniedrigte AP-Aktivität und eine konsekutive Erhöhung der AP-Substrate, z. B. des Pyridoxal-5-Phosphats (PLP), feststellen. Seit der Erstbeschreibung der Erkrankung 1948 haben sich die Diagnostik und Therapie der HPP dramatisch verbessert. Vor 4 Jahren ist eine Enzymersatztherapie mit Asfotase alfa (Strensiq®) für schwer betroffene HPP-Patienten mit Beginn der Erkrankung vor dem 18. Lebensjahr zugelassen worden. Dieser Artikel gibt einen Überblick über das breite klinische Spektrum der HPP, pathophysiologische Hintergründe, die laborchemische und molekulargenetische Diagnostik sowie gegenwärtige Therapieoptionen und deren Behandlungsindikationen.

Hypophosphatasia (HPP) is a hereditary musculoskeletal disorder characterized by low serum alkaline phosphatase (ALP) activity leading to poor bone mineralization. On a micro-morphological level, this may not only be reflected by an enrichment of osteoid but also a degradation of bone quality. Asfotase alfa is an enzyme replacement therapy that was recently demonstrated to improve bone mineralization as well as clinical status (e.g. growth, muscle strength and quality of life). However, the underlying changes of bone quality parameters on asfotase alfa treatment are currently not known. In the present study, we report a 24-year-old woman with genetically confirmed infantile-onset HPP and recurrent fractures. While the initiated asfotase alfa treatment was followed by rapid clinical improvements (i.e., disappearance of bone marrow edema, increase of muscle strength), the BMD assessed by DXA at the hip and spine increased moderately at two years follow-up. A detailed skeletal assessment using high-resolution peripheral quantitative computed tomography (HR-pQCT) and a high-resolution analysis of two consecutive iliac crest bone biopsies revealed only minor improvements of bone microarchitecture but a remarkable reduction of osteoid parameters. Furthermore, the high mineralization heterogeneity at baseline assessed by quantitative backscattered electron imaging (qBEI) decreased after 2 year of asfotase alfa treatment. Finally, we found an increase in mineral maturation reflected by higher mineral-to-matrix and carbonate-to-phosphate ratios using Fourier transform infrared spectroscopy (FTIR) imaging as well as increased local mechanical properties using reference point indentation (RPI). Taken together, our findings provide evidence for an improvement of bone quality indices beyond the mere reduction of osteoid indices and thereby contribute to the understanding of fracture risk reduction in HPP patients on asfotase alfa treatment.

Background & Aims Osteoporotic fractures are a major cause of morbidity and reduced quality of life in patients with primary sclerosing cholangitis (PSC), a progressive bile duct disease of unknown origin. Although it is generally assumed that this pathology is a consequence of impaired calcium homeostasis and malabsorption, the cellular and molecular causes of PSC-associated osteoporosis are unknown. Methods We determined bone mineral density by dual-X-ray absorptiometry and assessed bone microstructure by high-resolution peripheral quantitative computed tomography in patients with PSC. Laboratory markers of liver and bone metabolism were measured, and liver stiffness was assessed by FibroScan. We determined the frequency of Th17 cells by the ex vivo stimulation of peripheral blood mononuclear cells in a subgroup of 40 patients with PSC. To investigate the potential involvement of IL-17 in PSC-associated bone loss, we analyzed the skeletal phenotype of mice lacking Abcb4 and/or Il-17. Results Unlike in patients with primary biliary cholangitis, bone loss in patients with PSC was not associated with disease duration or liver fibrosis. However, we observed a significant negative correlation between the bone resorption biomarker deoxypyridinoline and bone mineral density in the PSC cohort, indicating increased bone resorption. Importantly, the frequency of Th17 cells in peripheral blood was positively correlated with the urinary deoxypyridinoline level and negatively correlated with bone mass. We observed that Abcb4-deficient mice displayed a low-bone-mass phenotype, which was corrected by an additional Il-17 deficiency or anti-IL-17 treatment, whereas the liver pathology was unaffected. Conclusions Our findings demonstrate that an increased frequency of Th17 cells is associated with bone resorption in PSC. Whether antibody-based IL-17 blockade is beneficial against bone loss in patients with PSC should be addressed in future studies. Lay summary Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by progressive bile duct destruction. One serious complication of PSC is reduced bone mass resulting in increased fracture risk. Herein, we demonstrate that Th17 cells mediate bone loss in PSC by inducing bone resorption, which suggests that antibody-based IL-17 blockade might be beneficial for the treatment of bone loss in affected patients.

This cross-sectional study examined the associations between c-terminal FGF23 levels, laboratory markers of bone metabolism and bone microarchitecture in 82 patients with osteoporosis. Higher FGF23 levels were associated with impaired trabecular but not cortical bone microarchitecture, and this was confirmed after adjusting for confounding variables such as age or BMI. Fibroblast growth factor 23 (FGF23) is an endocrine hormone-regulating phosphate and vitamin D metabolism. While its mode of action is well understood in diseases such as hereditary forms of rickets or tumor-induced osteomalacia, the interpretation of FGF23 levels in patients with osteoporosis with regard to bone microarchitecture is less clear. C-terminal FGF23 levels and bone turnover markers were assessed in 82 patients with osteoporosis (i.e., DXA T-score ≤ − 2.5 at the lumbar spine or total hip). Bone microarchitecture was measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and tibia. Data were analyzed in a cross-sectional design using correlation and regression models. We found a significant negative logarithmic correlation between FGF23 levels and trabecular but not cortical bone microarchitecture at both skeletal sites. Furthermore, using a multiple linear regression model, we confirmed FGF23 as a predictor for reduced trabecular parameters even when adjusting for confounding factors such as age, BMI, phosphate, bone-specific alkaline phosphatase, vitamin D3, and PTH. Taken together, high FGF23 levels are associated with impaired trabecular bone microarchitecture in osteoporosis patients, and this association seems to occur after adjustment of confounding variables including phosphate and vitamin D. Future longitudinal studies are now needed to validate our findings and investigate FGF23 in relation to fracture risk.

Hypophosphatasia (HPP) is a hereditary musculoskeletal disorder caused by inactivating variants in the ALPL gene and subsequently reduced serum tissue-nonspecific alkaline phosphatase (TNSALP) activity. This inborn error of metabolism results in decreased bone quality, accumulations of osteoid, and reduced bone mineralization. Increased incidence of fractures and prolonged bone healing are characteristic features for HPP. Available enzyme replacement therapy (asfotase alfa), was reported to recover bone mineralization and bone quality in adult HPP patients. Moreover, it was shown that asfotase alfa improved fracture healing of former nonunions in two adult HPP patients. We hypothesized that the nonunions are filled partially with osteoid, offering great potential to benefit from the treatment with asfotase alfa to promote bone healing. In the present study, we report three adult patients with pediatric-onset HPP and detected ALPL-mutations with prolonged bone healing after arthrodesis, tibial stress fracture, and osteotomy. After the initiation of asfotase alfa, immediately increased levels of alkaline phosphatase (ALP) and bone-specific ALP, as well as decreased levels of pyridoxal-5-phosphate (PLP), were detected in biochemical analysis. Importantly, even after up to 5 years of non-healing, a progredient consolidation was shown, assessed by a custom three-dimensional evaluation of repeated cone-beam computed tomography (CBCT) images, characterized by rapidly increasing levels of bone volume per tissue volume (BV/TV) within the volume of interest (i.e., the region of the non-healing bone). These radiographical findings were in line with the reported restoration of functional ability and pain-free full weight-bearing, as well as increased neuromuscular parameters (e.g., improved muscle strength). Taken together, our findings indicate that asfotase alfa improves the osseous consolidation of nonunions likely due to re-mineralization of osteoid tissue filling the former gap and improving the functional ability in adult HPP patients, characterized by increasing levels of BV/TV assessed via an innovative three-dimensional evaluation of CBCT images.

Reduced bone mineral density (BMD; ie, Z-score ≤-2.0) occurring at a young age (ie, premenopausal women and men

PurposeMedial tibial stress syndrome (MTSS) represents a common diagnosis in individuals exposed to repetitive high-stress loads affecting the lower limb, e.g., high-performance athletes. However, the diagnostic approach and therapeutic regimens are not well established.MethodsNine patients, diagnosed as MTSS, were analyzed by a comprehensive skeletal analysis including laboratory bone turnover parameters, dual-energy X-Ray absorptiometry (DXA), and high-resolution peripheral quantitative computed tomography (HR-pQCT).ResultsIn 4/9 patients, bilateral pseudofractures were detected in the mid-shaft tibia. These patients had significantly lower levels of 25-hydroxycholecalciferol compared to patients with MTSS but similar levels of bone turnover parameters. Interestingly, the skeletal assessment revealed significantly higher bone mineral density (BMD) Z-scores at the hip (1.3 ± 0.6 vs. − 0.7 ± 0.5,p = 0.013) in patients with pseudofractures and a trend towards higher bone microarchitecture parameters measured by HR-pQCT at the distal tibia. Vitamin D supplementation restored the calcium-homeostasis in all patients. Combined with weight-bearing as tolerated, pseudofractures healed in all patients and return to competition was achieved.ConclusionIn conclusion, deficient vitamin D levels may lead to pseudofractures due to localized deterioration of mineralization, representing a pivotal component of MTSS in athletes with increased repetitive mechanical loading of the lower limbs. Moreover, the manifestation of pseudofractures is not a consequence of an altered BMD nor microarchitecture but appears in patients with exercise-induced BMD increase in combination with reduced 25-OH-D levels. The screening of MTSS patients for pseudofractures is crucial for the initiation of an appropriate treatment such as vitamin D supplementation to prevent a prolonged course of healing or recurrence.Level of evidenceIII.

Background The aetiology and pathogenesis of primary bone marrow oedema syndrome (BMES) remain unclear. This retrospective cross-sectional study in a large cohort of patients with BMES was performed to characterise the overall skeletal status and turnover in patients with BMES, with the aim of identifying risk factors for this disease. Methods Patients who were diagnosed with BMES on the basis of clinical and radiological (magnetic resonance imaging) findings in our outpatient clinic were identified retrospectively. Patient history, co-existing metabolic disorders, bone metabolism parameters (serum calcium, phosphate, 25-OH-D3, bone-specific alkaline phosphatase, parathyroid hormone, and osteocalcin, and urinary deoxypyridinoline) and bone mineral density (as measured by dual-energy X-ray absorptiometry) were extracted from the medical records. Patients with secondary causes for BMES were excluded from the study. Results Of the 171 patients, 65 were identified without secondary cause for BMES. Of the 65 patients, 61.5% were female. The mean age was 49.5 ± 16.7 years, and age-related BMES prevalence showed two peaks, one in adolescence (11–20 years) and one at an older age (51–70 years). BMES predominantly affected the weight-bearing joints, namely, the ankle/foot (55.1%), knee (22.4%) and proximal femur (16.3%). Thyroid disorders and secondary hyperparathyroidism were highly prevalent (21.5 and 21.4%, respectively). On average, the cohort had elevated deoxypyridinoline levels and low 25-OH-D3 levels (19.0 ± 7.5 μg/l in patients without vitamin D supplementation). Osteopenia and osteoporosis were diagnosed in 47.4 and 17.5% of patients, respectively. Conclusions BMES is associated with high bone turnover. Patients who are diagnosed with BMES should be screened carefully for bone metabolism disorders and their potential risk factors. Electronic supplementary material The online version of this article (10.1186/s12891-018-2379-x) contains supplementary material, which is available to authorized users.

Primary biliary cholangitis (PBC) is known to be a major risk factor for osteoporosis reflected by a reduction of bone mineral density (BMD). However, both the extent of the macro- and microstructural alterations of bone as well as the causative factors are unknown. We have retrospectively analyzed a total of 96 patients with PBC and 53 healthy controls matched for age, sex, and body mass index. In addition to dual-energy X-ray absorptiometry (DXA) measurements at the lumbar spine and hip, high-resolution peripheral quantitative computed tomography (HR-pQCT) was used to assess the geometric, volumetric, and microstructural changes of bone at the distal radius and tibia. Furthermore, serum analyses and measures of disease duration and stage including transient elastography were performed. Total, cortical, and trabecular volumetric BMD as well as geometric parameters were significantly reduced in PBC patients. Microstructural analysis revealed a significantly lower cortical thickness (p < 0.001) and bone volume per tissue volume (p < 0.001) in the radius and tibia but unchanged trabecular number in patients with PBC (radius: p = 0.42; tibia: p = 0.12). Multivariate regression models pointed out that disease duration and stage are the primary factors that are independently associated with bone loss in PBC. A subgroup analysis of patients with additional autoimmune hepatitis (AIH) revealed no significant changes in bone structure compared with PBC only. Taken together, PBC patients demonstrate severe alterations in bone microstructure that are positively associated with disease duration and stage. By applying HR-pQCT in the distal radius and tibia, a combined bone loss syndrome expressed by a predominant decrease in BMD and cortical thickness could be detected. © 2018 American Society for Bone and Mineral Research.

In this study, we report on clinical, radiographic and biochemical characteristics of 38 patients with adult hypophosphatasia. High-resolution peripheral quantitative computed tomography showed alterations of bone microstructure in a subgroup of 14 patients. Pyridoxal-5-phosphate levels correlated with the occurrence of fractures and the number of symptoms. Hypophosphatasia (HPP) is a rare disorder with a wide range of clinical manifestations. A reduced enzymatic activity of alkaline phosphatase (ALP) is the key marker of the disease, causing an accumulation of ALP substrates such as pyridoxal-5-phosphate (PLP). The purpose of this retrospective study was to further characterize adult onset HPP. We assessed clinical, radiographic and laboratory characteristics of 38 adult patients with HPP. Diagnosis of HPP was established by the combination of low-serum ALP, raised PLP levels and typical symptoms and was genetically confirmed in 32 patients. Dual-energy X-ray absorptiometry (DXA) and laboratory data were available in most patients. High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed in 14 patients. Clinical characteristics included a wide spectrum of symptoms. A history of fracture was present in 15 patients (39%). Twenty-one patients (55%) complained about recurring headaches, 23 patients (61%) had recurring muscle pain, 4 patients (11%) suffered from severe muscle weakness and 18 patients (47%) showed dental abnormalities. Z-scores assessed by DXA were only slightly reduced in most adult HPP patients. HR-pQCT of 14 patients showed microstructural changes of trabecular and cortical bone compared to reference values of healthy subjects. The occurrence of fractures and multiple symptoms (>2 typical HPP symptoms) were associated with significantly elevated levels of PLP. Adult HPP presents with a wide range of clinical symptoms and is not associated with low bone mass in general. PLP seems to be a good marker for disease severity in adult patients as its level is correlated with the occurrence of fractures and number of symptoms.

A boy aged 9 years and 4 months developed a recurrent right-sided limp. His father, a radiologist, prompted a contrast magnetic resonance imaging (MRI) after 6 weeks and diagnosed early Perthes’ di...

Hypothalamic-pituitary disconnection (HPD) leads to low bone turnover followed by bone loss and reduced biomechanical properties in sheep. To investigate the role of peripheral hormones in this centrally induced systemic bone loss model, we planned a hormone replacement experiment. Therefore, estrogen (OHE), thyroxin (OHT) or a combination of both (OHTE) was substituted in ovariectomized HPD sheep, as both hormones are decreased in HPD sheep and are known to have a significant but yet not fully understood impact on bone metabolism. Bone turnover and structural parameters were analyzed in comparison to different control groups - untreated sheep (C), ovariectomized (O) and ovariectomized+HPD sheep (OH). We performed histomorphometric and HR-pQCT analyses nine months after the HPD procedure, as well as biomechanical testing of all ewes studied. In HPD sheep (OH) the low bone turnover led to a significant bone loss. Treatment with thyroxin alone (OHT) mainly increased bone resorption, leading to a further reduction in bone volume. In contrast, the treatment with estrogen alone (OHE) and the combined treatment with estrogen and thyroxin (OHTE) prevented HPD-induced bone loss completely. In conclusion, peripheral hormone substitution was able to prevent HPD-induced low-turnover osteoporosis in sheep. But only the treatment with estrogen alone or in combination with thyroxin was able to completely preserve bone mass and structure. These findings demonstrate the importance of peripheral hormones for a balanced bone remodeling and a physiological bone turnover.

Einleitung Vitamin D spielt eine Rolle in der Kalziumhomoostase und beeinflusst die Expression von uber 900 Genen mit Folgen fur die muskuloskelettale Gesundheit und Funktion. Daruber hinaus konnten durch Nachweis des Vitamin D-Rezeptors (VDR) in vielen Geweben des Organismus weitere Effekte von Vitamin D beobachtet werden. Material und Methoden Im Rahmen der vorliegenden Arbeit wurde die Literatur im Hinblick auf die Bedeutung von Vitamin D fur die muskuloskelettale Gesundheit und die maximale sportliche Leistungsfahigkeit untersucht. Ergebnisse und Diskussion Die hohe Pravalenz fur einen Vitamin D-Mangel, die bereits aus der Allgemeinbevolkerung bekannt ist, konnte fur Athleten unterschiedlicher Sportarten bestatigt werden. Somit ergibt sich eine Relevanz fur den Leistungssport. Hierfur sind u. a. die geografische Lage, das vorherrschende Klima, die Tages- und Jahreszeit sowie die Sportart (Indoor/Outdoor) verantwortlich. Es konnten Zusammenhange zwischen verschiedenen Serumkonzentrationen von 25-OH-D3 und unterschiedlichen Aspekten des Leistungssports beobachtet werden. So gewahrleistet eine Serumkonzentration oberhalb von 30 ng/ml eine regelrechte Mineralisation der Knochenmatrix und tragt entscheidend zur Knochengesundheit bei. Auch konnte in diesem Bereich ein positiver Zusammenhang mit einer beschleunigten Regeneration der muskularen Kraft gezeigt werden. Hohere Werte, oberhalb von 40 ng/ml, hatten einen protektiven Effekt bei der Genese von Stressfrakturen. Hinsichtlich der Leistungsfahigkeit vermuten Forscher Werte von ≥ 50 ng/ml als Voraussetzung fur die Entwicklung der maximalen korperlichen Leistung. Wahrend der Nutzen von hoheren Serumkonzentrationen umstritten ist, zeigen sich deutliche Defizite der Mineralisation (Rachitis, Osteomalazie) und muskularen Funktion (Reversible Myopathie) bei Unterschreiten einer Konzentration 30 ng/ml. Schlussfolgerung Sportmedizinische Untersuchungen sollten die laborchemische Bestimmung von 25-OH-D3, Kalzium, Kreatinin und Parathormon enthalten und somit die Vitamin D-abhangige Kalziumhomoostase adressieren. Im Falle eines Mangelzustandes kann durch Optimierung der Lebensweise und ggf. orale Substitution von Cholecalciferol eine Normalisierung auf ≥ 30 ng/ml herbeigefuhrt werden. Eine solche Konzentration zeigt einen protektiven und leistungssteigernden Effekt. Sie ist wichtig fur die Wiederherstellung und Erhaltung der muskuloskelettalen Gesundheit und Leistungsfahigkeit.

Highlights • A series of patients with intra-articular osteoid osteoma (OO) is demonstrated. • Extensive and persistent bone marrow edema syndrome masked the correct diagnosis. • No consistent patterns of impaired bone mineral status could be confirmed in these patients. • Nidus specimens displayed significantly higher mineralization heterogeneity determined by qBEI., Osteoid osteoma (OO) is a benign bone tumor producing non-mineralized bone matrix (i.e., osteoid). While peritumoral edema is commonly found in OO, extensive bone marrow edema has been reported less frequently. Furthermore, the micro-morphological characteristics of the nidus and its central calcification remain unclear. In this study, a consecutive series of four patients suffering from extensive bone marrow edema triggered by intra-articular osteoid osteoma underwent clinical examination, magnetic resonance imaging (MRI) and computed tomography (CT) as well as dual-energy X-ray absorptiometry (DXA) and laboratory bone turnover analyses. The obtained resection specimens were processed by undecalcified histology and were subsequently analyzed by light microscopy and quantitative backscattered electron imaging (qBEI). We report an entity of intra-articular osteoid osteoma in the knee and foot, in which an extensive and persistent bone marrow edema syndrome masked the correct diagnosis. While metabolic bone diseases were excluded in all cases, the reassessment of the patients’ clinical history including pain characteristics (nocturnal, aspirin sensitivity) led us to perform additional CT, where the tumor was diagnosed. The micro-morphological analysis of the OO biopsies revealed that the nidus was surrounded by hyperosteoidosis, while central mineralization was detected in all cases. This mineralized area showed a significantly higher mineralization heterogeneity than the surrounding trabecular bone and more disorganized collagen fibers detected by qBEI and polarized light microscopy, respectively. Taken together, our results indicate that osteoid osteoma should be considered when persistent and extensive, peri-articular bone marrow edema is diagnosed. The central calcification that is found inside the nidus in conventional imaging was mirrored by bone matrix with a heterogeneous mineralization pattern.

Pregnancy and lactation-associated osteoporosis (PLO) is a rare skeletal disorder characterized by early-onset osteoporosis typically manifestating with vertebral compression fractures or transient osteoporosis of the hip. We hypothesized that genetic variants may play a role in the development of PLO. This study aimed to analyze the presence of genetic variants and a potential association with the clinical presentation in PLO. 42 women with PLO were included from 2013 to 2019 in a multicenter study in Germany. All cases underwent comprehensive genetic analysis based on a custom-designed gene panel including genes relevant for skeletal disorders. The skeletal status was assessed using dual-energy X-ray absorptiometry (DXA). Subgroups were further analyzed by serum bone turnover markers (n = 31) and high-resolution peripheral computed tomography (HR-pQCT; n = 23). We detected relevant genetic variants in 21 women (50%), with LRP5, WNT1 and COL1A1/A2 being the most commonly involved genes. The mean number of vertebral compression fractures was 3.3 ± 3.4 per case with a significantly higher occurrence in the subgroup with genetic variants (4.8 ± 3.7 vs. 1.8 ± 2.3, p = 0.02). Among the total cohort, DXA Z-scores were significantly lower at the lumbar spine compared to the femoral neck (p = 0.002). HR-pQCT revealed a pronounced reduction of trabecular and cortical thickness, while trabecular number was within the reference range. Eighteen women (43%) received a bone-specific therapy (primarily teriparatide). Overall, a steep increase in bone mass (+37.7%) was observed after 3 years. In conclusion, pregnancy and lactation represent skeletal risk factors, which may unmask hereditary bone disorders leading to PLO. These cases were affected more severely. Nevertheless, a timely diagnosis and adequate treatment can ensure a substantial recovery potential even without specific therapy. Patients with genetically induced low bone turnover (e.g.; LRP5, WNT1) may especially benefit from osteo-anabolic medication.

In the course of complex regional pain syndrome (CRPS), local osteopenia in the subchondral/subcortical areas of the affected limb represents a central manifestation. Mechanistic aspects of CRPS-associated pathologies remain unclear, and knowledge about bone morphology in CRPS-affected areas is rare. The aim of this study was to assess trabecular and cortical bone microstructure in patients with CRPS of the distal tibiae. We retrospectively analysed 14 women diagnosed with unilateral CRPS type I of the lower limb whose affected and unaffected distal tibiae were examined by high-resolution peripheral quantitative computed tomography (HR-pQCT). Laboratory tests included serum levels of calcium, phosphate, 25-hydroxyvitamin D, bone alkaline phosphatase, parathyroid hormone, osteocalcin and urinary levels of deoxypyridinoline (DPD). Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and both proximal femurs. Average urinary DPD levels, a biochemical marker of bone resorption, were elevated in the examined patient cohort (7.1 ± 1.9 nmol/mmol, reference 3.0–7.0 nmol/mmol). According to HR-pQCT, CRPS-affected distal tibiae showed significantly lower values of cortical BMD and cortical thickness compared to the unaffected contralateral side. Also, bone volume relative to total volume was significantly lower. Trabecular number and trabecular thickness tended to be lower in the affected tibiae. CRPS is associated with significant alterations in bone microstructure of the affected tibiae. Increased bone resorption seems to play a crucial role within a multifactorial process of CRPS-mediated bone atrophy. HR-pQCT could possibly serve as a diagnostic tool in specific CRPS therapy.

Background Impaired bone quality is associated with poor outcome of spinal surgery. The aim of the study was to assess the bone mineral status of patients scheduled to undergo spinal surgery and to report frequencies of bone mineral disorders. Methods We retrospectively analyzed the bone mineral status of 144 patients requiring spinal surgery including bone mineral density by dual-energy X-ray absorptiometry (DXA) as well as laboratory data with serum levels of 25-hydroxyvitamin D (25-OH-D), parathyroid hormone, calcium, bone specific alkaline phosphate, osteocalcin, and gastrin. High-resolution peripheral quantitative computed tomography (HR-pQCT) was additionally performed in a subgroup of 67 patients with T-Score below − 1.5 or history of vertebral fracture. Results Among 144 patients, 126 patients (87.5%) were older than 60 years. Mean age was 70.1 years. 42 patients (29.1%) had suffered from a vertebral compression fracture. 12 previously undiagnosed vertebral deformities were detected in 12 patients by vertebral fracture assessment (VFA). Osteoporosis was present in 39 patients (27.1%) and osteopenia in 63 patients (43.8%). Only 16 patients (11.1%) had received anti-osteoporotic therapy, while 54 patients (37.5%) had an indication for specific anti-osteoporotic therapy but had not received it yet. The majority of patients had inadequate vitamin D status (73.6%) and 34.7% of patients showed secondary hyperparathyroidism as a sign for a significant disturbed calcium homeostasis. In a subgroup of 67 patients, severe vertebral deformities were associated with stronger deficits in bone microarchitecture at the distal radius compared to the distal tibia. Conclusions This study shows that bone metabolism disorders are highly prevalent in elderly patients scheduled for spinal surgery. Vertebral deformities are associated with a predominant deterioration of bone microstructure at the distal radius. As impaired bone quality can compromise surgical outcome, we strongly recommend an evaluation of bone mineral status prior to operation and anti-osteoporotic therapy if necessary.

INTRODUCTION The improvement and acceleration of fracture healing has been a component of medical practice since fractures have been treated. The aim is not only to fulfill the basic principles of fracture healing, such as reduction, retention, soft tissue coverage and infection prevention but also to reduce negative influences on fracture healing and promote positive factors. Nicotine, alcohol, diabetes and malnutrition can negatively affect fracture healing and should be appropriately controlled during fracture treatment; however, it is far more difficult to develop medicinal treatment strategies that lead to improvement and acceleration of fracture healing. AIM This article provides an overview of pharmacological factors influencing fracture healing. In addition, substances frequently used in clinical practice will be evaluated in terms of the effects on fracture healing processes. MATERIAL AND METHODS An extensive literature search was conducted in PubMed based on thematic keywords. The selection of studies and scientific publications focused mainly on results from clinical trials in order to provide practically relevant information. RESULTS In this context, preclinical studies have identified several drugs that lead to the acceleration of fracture healing; however, only a very limited number of clinical trials have confirmed this positive effect. Most of these studies dealt with drugs developed for the treatment of osteoporosis, as osteoporotic fractures are common and a positive or negative influence of such drugs are of particular interest in this field. In the field of osteoporosis medication a certain degree of positive effect of parathyroid hormone 1-34 (PTH) on fracture healing has been shown in clinical trials. For other osteoporosis medications no negative influence on fracture healing in clinical settings has been reported; however, there seems to be a positive effect in terms of better implant fixation for patients receiving oral bisphosphonate therapy. DISCUSSION Systemic medication to improve fracture healing will not be part of the clinical routine in the foreseeable future as the available data for already approved drugs and drugs under development do not currently justify routine administration. However, the currently known data should encourage the potential of known medications to be completely exhausted in fracture healing studies as well as novel therapy options in the sense of positive effects on fracture healing in order to improve patient care.

ObjectiveThe study evaluates the economic benefit of population-wide vitamin D and Ca food fortification in Germany.DesignBased on a spreadsheet model, we compared the cost of a population-wide vitamin D and Ca food-fortification programme with the potential cost savings from prevented fractures in the German female population aged 65 years and older.SettingThe annual burden of disease and the intervention cost were assessed for two scenarios: (i) no food fortification; and (ii) voluntary food fortification with 20 µg (800 IU) of cholecalciferol (vitamin D3) and 200 mg of Ca. The analysis considered six types of fractures: hip, clinical vertebral, humerus, wrist, other femur and pelvis.SubjectsSubgroups of the German population defined by age and sex.ResultsThe implementation of a vitamin D and Ca food-fortification programme in Germany would lead to annual net cost savings of €315 million and prevention of 36 705 fractures in the target population.ConclusionsVitamin D and Ca food fortification is an economically beneficial preventive health strategy that has the potential to reduce the future health burden of osteoporotic fractures in Germany. The implementation of a vitamin D and Ca food-fortification programme should be a high priority for German health policy makers because it offers substantial cost-saving potential for the German health and social care systems.

Vitamin D deficiency is prevalent in many countries, including Germany. Some countries have introduced vitamin D food fortification to address the problem, but such fortification is generally prohibited in Germany. While recent changes in legislation have opened the window to a population-wide introduction of vitamin D food fortification, before it can be implemented in Germany, the strategy must be adapted to the German scenario. This requires gathering detailed insights about German consumers’ perceptions of vitamin D-fortified food and the impact of vitamin D knowledge and health awareness on consumers’ acceptance. We gather information on these issues and identify consumers’ preferred sources of nutritional information. The study shows a high level of acceptance of vitamin D-fortified food among the German population, which indicates good prospects for successful implementation of a vitamin D food fortification program in Germany. Moreover, the study shows that consumers’ health awareness is an essential determinant of their acceptance of vitamin D-fortified food, so informing consumers about the health effects associated with vitamin D could be a viable way to raise their awareness and ensure their acceptance of vitamin D-fortified products. The study also shows that physicians, health insurance companies, and the internet/television are consumers’ preferred sources of nutritional information and should be the central communication channels for an information campaign. These insights will be valuable in developing and implementing an effective vitamin D food fortification program that is suitable for the German scenario.

Pregnancy was found to be a skeletal risk factor promoting the initial onset of previously unrecognized monogenic bone disorders, thus explaining a proportion of cases with pregnancy-associated osteoporosis. Therapeutic measures should focus in particular on the normalization of the disturbed calcium homeostasis in order to enable the partial skeletal recovery. Pregnancy-associated osteoporosis (PAO) is a rare skeletal condition, which is characterized by a reduction in bone mineral density (BMD) in the course of pregnancy and lactation. Typical symptoms include vertebral compression fractures and transient osteoporosis of the hip. Since the etiology is not well understood, this prospective study was conducted in order to elucidate the relevance of pathogenic gene variants for the development of PAO. Seven consecutive cases with the diagnosis of PAO underwent a skeletal assessment (blood tests, DXA, HR-pQCT) and a comprehensive genetic analysis using a custom-designed gene panel. All cases showed a reduced BMD (DXA T-score, lumbar spine − 3.2 ± 1.0; left femur − 2.2 ± 0.5; right femur − 1.9 ± 0.5), while the spine was affected more severely (p

Background & Aims Osteoporosis is a feared complication of autoimmune hepatitis (AIH), but bone disease has not been well studied in these patients. We aimed to identify specific risk factors for osteoporosis in patients with AIH and to develop a scoring system that could be used to identify patients with increased risk of osteoporosis. Methods We performed a retrospective cross-sectional study of 211 patients (mean age, 56.8 years; 79.1% women) in Germany with a diagnosis of AIH from 2012 through 2017 and an indication for assessment of bone mineral status. The patients underwent bone mineral density measurements by dual energy X-ray absorptiometry. A subgroup of 99 patients underwent a second measurement. We used logistic regression to identify patient and clinical factors associated with the presence of osteoporosis. We developed a weighted sum score for estimating risk of osteoporosis and tested it in development (n = 141) and validation (n = 70) sets of patients. Results According to dual energy X-ray absorptiometry measurements, 15.6% of patients had osteoporosis 42.9% were in the range for osteopenia. The prevalence of osteoporosis in patients 50 years or older was 19.2%. Univariate and logistic regression analyses showed that age older than 54 years, duration of glucocorticoid use >90 months, body mass index 8 kPA increased risk of osteoporosis 13.8-fold, 6.2-fold, 5.9-fold, and 3.0-fold, respectively. Based on these factors, we developed an index that identified patients at low-, moderate-, and high-risk of osteoporosis with an area under the curve of 0.811. Of the patients with a second osteodensitometry measurement, the rate of bone loss progression ranged from 2.7% after 1 year to 8.4% after 7 years (mean bone loss, 1.2% per year). Conclusions Almost 20% of patients with AIH older than 50 years have osteoporosis. Older age, duration of corticosteroid use, low body mass index, and liver fibrosis are independent risk factors for bone loss.

We 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.Gastrectomy 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.Undecalcified 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.Biopsies from gastrectomized individuals showed significantly increased osteoid, osteoclast, and osteoblast indices and fibroosteoclasia (p0.05) 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 6 months (p0.05). Calcium gluconate was superior to calcium carbonate in maintaining calcium metabolism in a mouse model of achlorhydria.Gastrectomy 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.

After introducing radiation-free spinometry as a diagnostic tool to predict prevalent vertebral fractures, its validity and comparison with established tools such as historical height loss (HHL) was missing. This study shows that radiation-free spinometry is valid and its application adds predictive power to the ability of HHL to assess presence of vertebral fractures. Recently, radiation-free spinometry was introduced to identify patients with vertebral fractures (VFs). The goals of this study were to validate previous findings and to test the predictive accuracy of radiation-free spinometry compared to the assessment of historical height loss (HHL). We analyzed 304 patients [258 (85 %) females (age range, 42–90 years) and 46 males (50–84 years)], including 108 patients with VFs. We performed receiver operator characteristic and net reclassification improvement (NRI) analyses to quantify the predictive power and the added predictive ability of radiation-free spinometry and HHL for VFs. The estimated odds ratios in the thoracic and the lumbar spine showed no significant differences compared to the previously published, except for the effect of thoracic kyphosis in region “Th12 + L4-5.” Radiation-free spinometry and HHL were both moderately accurate to raise suspicion for VFs. According to the NRI, which is defined as the net sum of the predicted risk increase in individuals who have VFs and the predicted net risk decrease for those who have not, we found significant improvements in all regions of interest when HHL and radiation-free spinometry were used in combination (area under the curve (AUC) 0.729–0.788). Our results based on a new data set suggest validity of the prognostic score published previously. In addition, although our findings did not confirm our initial hypothesis that radiation-free spinometry alone performs superior to the assessment of HHL to predict VFs, we showed that radiation-free spinometry still adds predictive power to the ability of HHL to discriminate patients with VFs.

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia and low calcitriol levels as well as clinical symptoms like diffuse bone and muscle pain, fatigue fractures or increased fracture risk. Conventional imaging methods, however, often fail to detect the small tumors. Lately, tumor localization clearly improved by somatostatin-receptor (SSTR) imaging, such as octreotide scintigraphy or octreotide SPECT/CT. However, recent studies revealed that still a large number of tumors remained undetected by octreotide imaging. Hence, studies focused on different SSTR imaging methods such as 68Ga DOTA-NOC, 68Ga DOTA-TOC and 68Ga DOTA-TATE PET/CT with promising first results. Studies comparing different SSTR imaging methods for tumor localization in TIO are rare and thus little is known about diagnostic alternatives once a particular method failed to detect a tumor in patients with TIO. Here, we report the data of 5 consecutive patients suffering from TIO, who underwent both 111Indium-octreotide scintigraphy (111In-OCT) SPECT/CT as well as 68Ga DOTA-TATE PET/CT for tumor detection. While 111In-OCT SPECT/CT allowed tumor detection in only 1 of 5 patients, 68Ga DOTA-TATE PET/CT was able to localize the tumor in all patients. Afterwards, anatomical imaging of the region of interest was performed with CT and MRI. Thus, successful surgical resection of the tumor was achieved in all patients. Serum phosphate levels returned to normal and all patients reported relief of symptoms within weeks. Moreover, an iliac crest biopsy was obtained from every patient and revealed marked osteomalacia in all cases. Follow-up DXA revealed an increase in BMD of up to 34.5% 1-year postoperative, indicating remineralization. No recurrence was observed. In conclusion our data indicates that 68Ga DOTA-TATE PET/CT is an effective and promising diagnostic tool in the diagnosis of TIO, even in patients in whom 111In-OCT prior failed to detect a tumor.

Osteopetrosis is an inherited disorder of impaired bone resorption, with the most commonly affected genes being CLCN7 and TCIRG1, encoding the Cl(-) /H(+) exchanger CLC-7 and the a3 subunit of the vacuolar H(+) -ATPase, respectively. We and others have previously shown that the disease is frequently accompanied by osteomalacia, and that this additional pathology is also found in Tcirg1-deficient oc/oc mice. The remaining question was whether osteoid enrichment is specifically associated with TCIRG1 inactivation, or whether CLCN7 mutations would also cause skeletal mineralization defects. Here we describe a complete osteologic assessment of one family carrying a novel mutation in CLCN7 (D145G), which impairs the activation and relaxation kinetics of the CLC-7 ion transporter. The two siblings carrying the mutation in the homozygous state displayed high bone mass, increased serum levels of bone formation markers, but no impairment of calcium homeostasis when compared to the other family members. Most importantly, however, undecalcified processing of an iliac crest biopsy from one of the affected children clearly demonstrated a pathological increase of trabecular bone mass, but no signs of osteomalacia. Given the potential relevance of these findings we additionally performed undecalcified histology of iliac crest biopsies from seven additional cases with osteopetrosis caused by a mutation in TNFRSF11A (n=1), CLCN7 (n=3), or TCIRG1 (n=3). Here we observed that all cases with TCIRG1-dependent osteopetrosis displayed severe osteoid accumulation and decreased calcium content within the mineralized matrix. In contrast, there was no detectable bone mineralization defect in the cases with TNFRSF11A-dependent or CLCN7-dependent osteopetrosis. Taken together, our analysis demonstrates that CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization, and that there is a need to modify the current classification of osteopetrosis.

X-linked hypophosphatemic rickets (XLH) is a genetic disorder caused by mutational inactivation of the PHEX gene, encoding a transmembrane endopeptidase expressed in osteoblasts. Since several experiments involving Phex-deficient Hyp mice have demonstrated that an increased expression of Fgf23 in osteoblasts is causative for the renal phosphate loss characteristic of XLH, we performed genome-wide expression analysis to compare differentiated osteoblasts from wildtype and Hyp mice. Here we did not only observe the expected increase of Fgf23 expression in the latter ones, but also a differential expression of genes that are either induced by or involved in retinoic acid signaling, which led us to analyze whether dietary retinol deprivation would influence the phenotype of Hyp mice. Unexpectedly, feeding a retinol-free diet resulted in a partial rescue of the growth plate and bone mineralization defects in 6 weeks old Hyp mice. When we fed the same diet for 24 weeks the amount of non-mineralized bone matrix (osteoid) was reduced by more than 70%, although phosphate homeostasis was unaffected. In contrast, a dietary normalization of serum phosphate levels in Hyp mice reduced the osteoid amount by less than 30%, thereby demonstrating a previously unknown impact of retinol on the cell-autonomous mineralization defect of Phex-deficient osteoblasts.

Hypothalamo-pituitary disconnection (HPD) leads to low bone turnover and osteoporosis in sheep. To determine the sustainability of bone loss and its biomechanical relevance, we studied HPD-sheep 24 months after surgery (HPD + OVX-24) in comparison to untreated control (Control), ovariectomized sheep (OVX), and sheep 12 months after HPD (HPD + OVX-12). We performed histomorphometric, HR-pQCT, and qBEI analyses, as well as biomechanical testing of all ewes studied. Twenty-four months after HPD, histomorphometric analyses of the iliac crest showed a significant reduction of BV/TV by 60% in comparison to Control. Cortical thickness of the femora measured by HR-pQCT did not change between 12 and 24 months after HPD but remained decreased by 30%. These structural changes were caused by a persisting depression of osteoblast and osteoclast cellular activity. Biomechanical testing of the femora showed a significant reduction of bending strength, whereas calcium content and distribution was found to be unchanged. In conclusion, HPD surgery leads to a persisting low turnover status with negative turnover balance in sheep followed by dramatic cortical and trabecular bone loss with consequent biomechanical impairment. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1067–1074, 2013

Background The use of beta-tricalciumphospate (s-TCP, Cerasorb®) ceramics as an alternative for autologous bone-grafting has been outlined previously, however with no study focusing on both clinical and histological outcomes of s-TCP application in patients with multi-fragment tibial plateau fractures. The aim of this study was to analyze the long-term results of s-TCP in patients with tibial plateau fractures. Methods 52 patients were included in this study. All patients underwent open surgery with s-TCP block or granulate application. After a mean follow-up of 36 months (14–64 months), the patients were reviewed. Radiography and computed-tomography were performed, while the Rasmussen score was obtained for clinical outcome. Furthermore, seven patients underwent biopsy during hardware removal, which was subsequently analyzed by histology and backscattered electron microscopy (BSEM). Results An excellent reduction with two millimeters or less of residual incongruity was achieved in 83% of the patients. At follow-up, no further changes occurred and no nonunions were observed. Functional outcome was good to excellent in 82%. Four patients underwent revision surgery due to reasons unrelated to the bone substitute material. Histologic analyses indicated that new bone was built around the s-TCP-grafts, however a complete resorption of s-TCP was not observed. Discussion s-TCP combined with internal fixation represents an effective and safe treatment of tibial plateau depression fractures with good functional recovery. While its osteoconductivity seems to be successful, the biological degradation and replacement of s-TCP is less pronounced in humans than previous animal studies have indicated.

The hormone leptin is a critical regulator of adipogenesis and energy metabolism. Similarly, leptin-deficient ob/ob mice display various metabolic abnormalities, including not only obesity and insulin resistance, but also hypogonadism and high bone mass. By genome-wide expression analysis using hypothalamus RNA from wild-type and ob/ob mice, we observed the increased expression of the gene for transthyretin (Ttr) in the latter, as confirmed by quantitative real-time-polymerase chain reaction. Because Ttr encodes a carrier protein for retinol transport, and because we further found increased retinol levels in the serum of ob/ob mice, we investigated whether the additional absence of Ttr would influence the ob/ob phenotype. It was found that Ttr-deficient ob/ob mice were indistinguishable from ob/ob littermates in terms of body weight, as well as serum glucose, insulin and cholesterol levels. Although all of these parameters were identical to wild-type controls in Ttr-deficient mice, we found that the sole deletion of Ttr caused a significant increase of trabecular bone mass, bone marrow adiposity and mean adipocyte area in white adipose tissue. Interestingly, all these latter parameters were highest in Ttr-deficient ob/ob mice, and only in these mice did we observe a full penetrance of liver steatosis at 24 weeks of age. Taken together, our data demonstrate that the increased expression of Ttr in ob/ob mice does not cause (but rather attenuates) their phenotypic abnormalities.

Up-to-date knowledge about vitamin D supply and serum concentration in Germany is not sufficient. Our purpose was to compare a novel holistic bottom-up modeling of 25(OH)D concentrations with vitamin D sources such as sunlight, food and supplements for all federal states taking seasonal and geographical variations into account. The second purpose was to update and detail vitamin D supply through food in Germany. To confirm the model of 25(OH)D concentrations, we used the population (1,763 men and 2,267 women, 18–79 years) participated in the representative German National Health Interview and Examination Survey 1998 and the integrated German Nutrition Survey. The maximum model value is 67.5 nmol/L in July and minimum model value is 29.3 nmol/L in January, while the average model value is 45.0 nmol/L. Men have a mean daily intake of 137 IU (3.42 μg) and women of 112 IU (2.79 μg). Correlation between model and actual data is 0.77 (p = 0.003). A comparison of the model data with population-based values showed good agreement. None of the vitamin D sources can provide the German population with enough vitamin D.

The purpose of this study was to investigate specific risk factors, common fracture locations and possible sex-specific differences in elderly patients with stress fractures. This analysis enrolled 105 patients (83 women, 22 men) with stress fractures. For the analysis of possible risk factors related to increasing age, data from 82 patients (67 women, 15 men) aged 40 years and older (mean age of 57.4 ± 11.0 years) were compared with that from a younger control group [23 patients (16 women, seven men), mean age 28.4 ± 6.7 years]. Bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry bone densitometry (DXA) and blood samples were taken. A total of 211 stress fractures were found. Of these, 177 were found in the study group, of which 90.4 % were located in the lower limb. Lumbar and femoral BMD was significantly lower in elderly patients; however, the BMD of most patients was within the osteopenic or normal range. Within the study group, a total of 83.8 % had a vitamin D insufficiency (

Due to missing indications for specific diagnostics, the majority of non-symptomatic vertebral fractures are not diagnosed. This study shows the ability of radiation-free spinometry to assess sagittal spine parameters to raise suspicion for new non-traumatic thoracic and lumbar vertebral fractures and indicate specific diagnostics. The primary aim of this study was to investigate the accuracy of radiation-free spinometry to predict new non-traumatic vertebral fractures (VF) by the assessment of thoracic kyphosis (TK), lumbar lordosis (LL), and trunk inclination. Three hundred sixty-one patients (278 females and 83 males; age, 67.0 ± 8.6 years) were enrolled. In 86 women and 24 men, at least one non-traumatic VF was confirmed by radiography, MRI, and/or CT. Spinometry (video rasterstereography) was used to assess TK, LL, and trunk inclination. Receiver operating characteristic (ROC) and multivariate logistic regression analyses were performed to test the influence of age, sex, number, location, and grade of fractures on sagittal spine alignment. TK, LL, and trunk inclination were associated with advancing age (p

Paget’s disease of bone (PDB) is the second most frequent metabolic bone disease with the spine being a common site of manifestation. Still, neither the disease’s etiology nor reasons for its manifestation at preferred skeletal sites are understood. The aim of the current study was therefore to perform a histologic and histomorphometric analysis of PBD biopsies of the spine to achieve a more detailed understanding concerning PDB activity and characteristics. Out of 754 cases with histologically proven PDB, 101 cases were identified to have involvement of the spine. A total of 29 individual vertebral body biopsies were available for histologic and histomorphometric analysis and were compared to age- and sex-matched spinal bone specimens obtained from skeletal-intact individuals at autopsy. Histomorphometric results were correlated with vertebral body height, disease location and iliac crest biopsies. In the majority of patients, PDB was located in the lumbar spine (62.2%). The cervical spine was affected in 8.2% of all cases with involvement of the second vertebral body (C2) in every other case. In comparison to age-matched individuals, histomorphometric analysis of vertebral body biopsies revealed a significant increase both in trabecular bone volume as well as osteoid parameters. In comparison to histomorphometric data obtained for extra-spinal skeletal locations affected by PDB (iliac crest), no differences in bone micro-architecture or disease activity were observed. Disease activity in terms of osteoblast and osteoclast number does not appear to be significantly associated with disease location when spinal and iliac bone biopsies are compared. However, a positive correlation between vertebral body height and density in skeletal-intact individuals and disease incidence was observed leading to the conclusion that vertebral body height and possibly at least the spine bone volume together with bone density might play an important role in the incidence of PDB.

Vitamin D is critical for musculoskeletal health and has been implicated in the risk of extraskeletal diseases, including cancer, cardiovascular diseases, and autoimmune diseases, as well as overall mortality. Although numerous studies deal and have dealt with vitamin D deficiency and its consequences, experts cannot agree on the right 25-hydroxyvitamin D levels. This survey aims to shed light on the ongoing vitamin D controversy from different angles.We discuss the minimum threshold for the 25-hydroxyvitamin D level to guarantee optimal health, why vitamin is D critical to musculoskeletal and extraskeletal functions, and new evidence for the success of prevention measures such as food fortification.We searched PubMed, Google Scholar, and reference lists of articles using several keywords. The most recent search was in February 2011.While the use of parathyroid hormone as a surrogate measure did not lead to a consensus concerning the required 25-hydroxyvitamin D serum level, the combined analysis of bone mineralization and vitamin D status has established minimum levels of more than 75 nmol/L (30 ng/mL) to guarantee at least skeletal health. An effective measure to approach this status is food fortification, which has been demonstrated by countries such as Canada, the United States, and Finland.Given the health economic implications of failure to maintain a balanced vitamin D status, action is recommended to integrate current scientific knowledge on vitamin D into physicians' treatment of patients and governmental policies on food fortification.

Histomorphometry and quantitative backscattered electron microscopy of iliac crest biopsies from patients with adult hypophosphatasia not only confirmed the expected enrichment of non-mineralized osteoid, but also demonstrated an altered trabecular microarchitecture, an increased number of osteoblasts, and an impaired calcium distribution within the mineralized bone matrix. Adult hypophosphatasia is an inherited disorder of bone metabolism caused by inactivating mutations of the ALPL gene, encoding tissue non-specific alkaline phosphatase. While it is commonly accepted that the increased fracture risk of the patients is the consequence of osteomalacia, there are only few studies describing a complete histomorphometric analysis of bone biopsies from affected individuals. Therefore, we analyzed iliac crest biopsies from eight patients and set them in direct comparison to biopsies from healthy donors or from individuals with other types of osteomalacia. Histomorphometric analysis was performed on non-decalcified sections stained either after von Kossa/van Gieson or with toluidine blue. Bone mineral density distribution was quantified by backscattered electron microscopy. Besides the well-documented enrichment of non-mineralized bone matrix in individuals suffering from adult hypophosphatasia, our histomorphometric analysis revealed alterations of the trabecular microarchitecture and an increased number of osteoblasts compared to healthy controls or to individuals with other types of osteomalacia. Moreover, the analysis of the mineralized bone matrix revealed significantly decreased calcium content in patients with adult hypophosphatasia. Taken together, our data show that adult hypophosphatasia does not solely result in an enrichment of osteoid, but also in a considerable degradation of bone quality, which might contribute to the increased fracture risk of the affected individuals.

Background: The distal radius is the most frequent fracture localization in humans. Although younger patients receive a distal radius fracture after an adequate trauma, elderly patients suffer fractures through low-energy mechanisms. Low-energy fractures are hallmarks of osteoporosis. Osteoporotic changes of the distal radius are well described by DXA and peripheral quantitative computed tomography measurements. However, to date, the effects of aging on the microarchitecture of the distal radius have not been investigated. Methods: To investigate whether the microarchitecture of the human distal radius shows osteoporotic changes in bone mass and structure during aging, we dissected out 60 complete human distal radii from 30 age- and gender-matched patients at autopsy. Each of the three different age groups (group I: 20-40 years, group II: 41-60 years, group III: 61—80 years) was represented by 10 autopsy cases and 20 specimens (double-sided extraction), respectively. The specimens were analyzed by peripheral quantitative computed tomography, contact-radiography, and histomorphometry. Results: We observed a significant age-related decrease in bone mass, bone mineral density and an increase in typical osteoporotic changes of the bone microarchitecture in female distal radius specimens. Comparable observations of age-related changes have not been made in male specimens. Conclusions: The distal radius is a location of osteoporosis-specific bone changes. Our data provide evidence for the occurrence of typical osteoporotic changes, especially postmenopausal osteoporotic changes, in the distal radius during aging.