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Context Many different inherited and acquired conditions can result in premature bone fragility/low bone mass disorders (LBMDs). Objective We aimed to elucidate the impact of genetic testing on differential diagnosis of adult LBMDs and at defining clinical criteria for predicting monogenic forms. Methods Four clinical centers broadly recruited a cohort of 394 unrelated adult women before menopause and men younger than 55 years with a bone mineral density (BMD) Z-score Results In total, 20.8% of the participants carried rare disease-causing variants (DCVs) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCVs in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and 4 X-linked disorders. A total of 9.7% of the participants harbored variants of unknown significance. A regression analysis revealed that the likelihood of detecting a DCV correlated with a positive family history of osteoporosis, peripheral fractures (> 2), and a high normal body mass index (BMI). In contrast, mutation frequencies did not correlate with age, prevalent vertebral fractures, BMD, or biochemical parameters. In individuals without monogenic disease-causing rare variants, common variants predisposing for low BMD (eg, in LRP5) were overrepresented. Conclusion The overlapping spectra of monogenic adult LBMD can be easily disentangled by genetic testing and the proposed clinical criteria can help to maximize the diagnostic yield.

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.

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.

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.

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.

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...

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.

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.

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.

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.

Although our understanding of the molecular mechanisms controlling osteoblast differentiation and function is steadily increasing, there are still many open questions, especially regarding the regulation of bone matrix mineralization. For instance, while there is hallmark evidence for the importance of the endopeptidase Phex, whose inactivation in Hyp mice or human patients causes X-linked hypophosphatemic rickets, it is still largely unknown how Phex controls bone mineralization since a physiological substrate for its endopeptidase activity has not been identified yet. Using a genome-wide expression analysis comparing primary calvarial osteoblasts, we have identified preproenkephalin (Penk) as a gene that is selectively expressed in mineralized cultures. Since a role of enkephalin in the regulation of bone remodeling has been suggested previously and since Leu-enkephalin is known to be cleaved by Phex, we analyzed whether Penk expression in osteoblasts is physiologically relevant. Through skeletal analysis of a Penk-deficient mouse model, we found that Penk expression is dispensable for bone development and remodeling since we could not detect any defect following nondecalcified bone histology and histomorphometry compared to wild-type littermates. When Penk was deleted in Phex-deficient Hyp mice, however, we observed a significant reduction of the osteoid enrichment at 24 weeks of age, whereas their disturbance of mineral homeostasis was not affected by the additional absence of the Penk gene. Taken together, our data provide the first in vivo analysis concerning the role of Penk in osteoblasts.

Fractures of the radial head are common; however, it remains to be determined whether the radial head has to be considered as a typical location for fractures associated with osteoporosis. To investigate whether the human radial head shows structural changes during aging, we analyzed 30 left and 30 right human radial heads taken from 30 individuals. The specimens taken from the left side were analyzed by peripheral quantitative computed tomography (pQCT) and micro-CT. The specimens taken from the right elbow joint were analyzed by radiography and histomorphometry. In these specimens pQCT revealed a significant decrease of total and cortical bone mineral density (BMD(to) BMD(co)) with aging, regardless of sex. Histomorphometry revealed a significant reduction of cortical thickness (Ct.Th), bone volume per tissue volume (BV/TV), and trabecular thickness (Tb.Th) in male and female specimens. In this context, mean BV/TV and mean trabecular number (Tb.N) values were significantly lower and, accordingly, mean trabecular separation (Tb.Sp) was significantly higher in female samples. The presented study demonstrates that the radial head is a skeletal site where different age- and sex-related changes of the bone structure become manifest. These microarchitectural changes might contribute to the pathogenesis of radial head fractures, especially in aged female patients where trabecular parameters (BMD(tr) and Tb.Sp) change significantly for the worse compared to male patients.

Entwicklungsgeschichtlich wird der Axis aus 4 Knochenkernen gebildet: 2 kraniale Knochenkerne, welche das Odontoid ausformen, werden von den Knochenkernen des Corpus axis durch die sog. subdentale Synchondrose getrennt. Wahrend der weiteren Entwicklung konnen Anteile der subdentalen Synchondrose – welche nach bisheriger Vorstellung vollstandig schliest – auch im adulten Axis persistieren. Im klinischen Alltag mussen Rudimente der subdentalen Synchondrose bisweilen von einer Fraktur der Densbasis (Typ II gemas Anderson und D’Alonzo) unterschieden werden. Um die Morphologie der subdentalen Synchondrose sowie des Axis zu charakterisieren, wurde der komplette Axis von 36 Patienten dreier Altersgruppen, welche den naturlichen Alterungsprozess des Skeletts reprasentieren, entnommen und untersucht. Zunachst wurde die Knochendichte (BMD) der Axispraparate mittels peripherer quantitativer Computertomographie (pQCT) bestimmt. Die morphologische Analyse an unentkalkten Praparaten zeigt eine Persistenz der subdentalen Synchondrose bei 87% aller Praparationen. Die histologische Charakterisierung der subdentalen Synchondrose weist auf eine uberwiegend knorpelige Matrix hin, in welcher einige nur schwach ausgepragte ossifizierte Bereiche eingegliedert sind. Histomorphometrisch konnte eine signifikante Verminderung der trabekularen Knochenmasse sowie der Kortikalisdicke im Bereich der Densbasis verglichen mit dem Dens und dem Corpus axis nachgewiesen werden. Zusammenfassend wird durch diese Untersuchung die strukturelle Besonderheit der subdentalen Synchondrose hervorgehoben. Neben den bekannten biomechanischen Eigenschaften weisen diese Daten darauf hin, dass die strukturelle Besonderheit der Densbasis des Axis zu einer erhohten Frakturneigung in dieser Region pradisponieren und zu einer verminderten Frakturheilungspotenz nach Typ-II-Frakturen gemas Anderson und D’Alonzo beitragen konnte.

Many neurodegenerative disorders present with sensory loss. In the group of hereditary sensory and autonomic neuropathies loss of nociception is one of the disease hallmarks. To determine underlying factors of sensory neurodegeneration we performed whole-exome sequencing in affected individuals with the disorder. In a family with sensory neuropathy with loss of pain perception and destruction of the pedal skeleton we report a missense mutation in a highly conserved amino acid residue of atlastin GTPase 3 (ATL3), an endoplasmic reticulum-shaping GTPase. The same mutation (p.Tyr192Cys) was identified in a second family with similar clinical outcome by screening a large cohort of 115 patients with hereditary sensory and autonomic neuropathies. Both families show an autosomal dominant pattern of inheritance and the mutation segregates with complete penetrance. ATL3 is a paralogue of ATL1, a membrane curvature-generating molecule that is involved in spastic paraplegia and hereditary sensory neuropathy. ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network. Mutant ATL3 p.Tyr192Cys fails to localize to branch points, but instead disrupts the structure of the tubular endoplasmic reticulum, suggesting that the mutation exerts a dominant-negative effect. Identification of ATL3 as novel disease-associated gene exemplifies that long-term sensory neuronal maintenance critically depends on the structural organisation of the endoplasmic reticulum. It emphasizes that alterations in membrane shaping-proteins are one of the major emerging pathways in axonal degeneration and suggests that this group of molecules should be considered in neuroprotective strategies. * Abbreviations : HSAN : hereditary sensory and autonomic neuropathies PDI : protein disulphide isomerase SPG : spastic paraplegia

Background In Germany, vitamin D intake from food and synthesis in the skin is low, which leads to low 25(OH)D serum concentrations. In contrast to many other countries, general vitamin D food fortification is still prohibited in Germany, although the European Commission published a regulatory framework to harmonize addition of vitamins to foods. Thus the purpose of our study was to develop a vitamin D fortification model, taking into account all vitamin D sources with the goal to fulfill requirements of intake recommendations or preferable 25(OH)D serum concentrations. Finally, the aim was to assess the suitability of different carriers and associated risks. Methods We developed a mathematical bottom-up model of 25(OH)D serum concentrations based on data about vitamin D sources of the German population such as sunlight, food and supplements for all federal states taking seasonal and geographical variations into account. We used this model to calculate the optimal fortification levels of different vitamin D carriers in two approaches. First we calculated required fortification levels based on fixed intake recommendations from e.g. the IOM or the DGE and second based on achieving certain 25(OH)D serum concentrations. Results To lift 25(OH)D serum concentration in Germany to 75 nmol/L, e.g. 100 g bread has to be fortified with 11.3 μg during winter, resulting in a daily vitamin D intake of 23.7 μg. Bread seems to be a suitable carrier for base supply. However, overdose risk with a single fortified product is higher than the risk with several fortified carriers. Conclusions With the model in hand, it is possible to conceive vitamin D fortification strategies for different foodstuffs and model its impact on 25(OH)D serum concentrations.

Fractures of the talus in the elderly are rare and usually result from high-impact injuries, suggesting only minor age-related bone structure changes. However, total ankle replacement failures with age often result from talar subsidence, suggesting age-related bone loss in the talus. Despite a number of histological analyses of talar microarchitecture, the effects of age and sex on talar microarchitecture changes remain poorly defined.The aim of this study was to analyze changes or differences in the trabecular microarchitecture of the talus with regard to (1) age and (2) sex.Sixty human tali were harvested from 30 patients at autopsy of three different age groups (20-40, 41-60, 61-80 years). The specimens were analyzed by radiography, micro-CT, and histological analysis. Given that there was no difference between the left and right talus, static histomorphometric parameters were assessed in three regions of interest of the right talus only (body, neck, head; n = 30).The talar body, neck, and head were affected differently by age-related changes. The greatest loss of bone volume with age was seen in the talar body (estimate: -0.239; 95% confidence interval [CI], -0.365 to -0.114; p0.001). In the talar neck (estimate: -0.165; 95% CI, -0.307 to -0.023; p = 0.025), bone loss was only moderate and primarily was the result of reduction in trabecular thickness (estimate: -1.288; 95% CI, -2.449 to -0.127; p = 0.031) instead of number (estimate: -0.001; 95% CI, -0.005 to -0.003; p = 0.593). Bone structure changes were independent of sex.Age-related bone structure changes predominantly occur in the talar body, which poses a potential risk factor for total ankle replacement loosening. The moderate changes in the talar neck might explain the persistent low incidence of talar neck fractures with age.Our findings suggest that before total ankle replacement implantation, careful patient selection with dual-energy xray absorptiometry evaluation may be necessary to reduce the risk of talar implant subsidence.

Introduction The goal of this retrospective study was to evaluate the safety and efficacy of ibandronate for bone marrow oedema (BMO) syndrome and stress fracture cases, and to demonstrate an additional field of therapeutic importance—the high-performance athlete. Patients and methods This retrospective study included twenty-five high-performance athletes. Sixty per cent of the athletes were European soccer players and 40.0% other high-class international athletes (3 women and 22 men with an average age of 25.0 ± 4.2), with BMO of the lower trunk or extremity diagnosed by magnetic resonance imaging (MRI). The treatment regimen consisted of high-dose vitamin D supplementation and intravenous ibandronate therapy. Results The time between the onset of pain and proper diagnosis of BMO was 106.3 ± 104.1 days. Excellent pain reduction (pain at rest and under strain) and improved mobility was reported within the first two weeks after the first ibandronate administration by sixteen patients (64%). The time from first treatment until return to competition (RTC) was on average 102.6 ± 65.2 days in total. If the time from onset of pain until diagnosis was within 40 days, the RTC was significantly reduced (p ≤ 0.05) to almost 50% (63.8 ± 48.1 days) when compared to the athletes with later diagnosis (124.4 ± 63.2 days). Conclusions The here-applied therapy regimen of intravenous BPs application and vitamin D supplementation in BMO syndrome has a beneficial effect for high-performance athletes. An early diagnosis and rapid treatment start can reduce the RTC significantly. An optimal bone metabolism with sufficient daily calcium and vitamin D intake is crucial and should not only be strived for the professional but also for the recreational athlete.

Due to inconsistent findings, the influence of vitamin D on postural body sway (PBS) is currently under debate. This study evaluated the impact of vitamin D on PBS with regards to different foot positions and eye opening states in community-dwelling older individuals.In a cross-sectional study, we assessed PBS in 342 older individuals (264 females [average age (± SD): 68.3 ± 9.0 years], 78 males [65.7 ± 9.6 years]). A detailed medical history and vitamin D level were obtained for each individual. Fall risk was evaluated using the New York-Presbyterian Fall Risk Assessment Tool (NY PFRA). PBS parameters (area, distance, velocity, frequency) were evaluated on a pressure plate with feet in closed stance (CS) or hip-width stance (HWS), open eyes and closed eyes. Statistical analysis included logarithmic mixed models for repeated measures with the MIXED model procedure to test the influence of vitamin D (categorized in10 μg/l, 10-20 μg/l, 21-30 μg/l,30 μg/l), foot position, eye opening state, age, sex and frequency of physical activity on PBS.Vitamin D was not an independent risk factor for falls experienced in the last 12 months. Nonetheless, PBS was higher in patients with vitamin D deficiency (10 μg/l) in HWS (A/P p=0.028 and area p=0.037). Additionally, vitamin D deficiency intensified the deleterious effects of male sex (distance p=0.002) and absence of vision (area p0.001) on PBS.Independent risk factors for increased PBS like male sex and absence of vision are additionally compromised by vitamin D deficiency.

Indolent systemic mastocytosis (ISM) can trigger bone loss. However, the clinical relevance of different mast cell infiltration patterns for bone remains to be clarified. Here, we report increased bone turnover in individuals with ISM, and its extent is rather related to the type of mast cell distribution within the bone marrow than to the presence or absence of cutaneous manifestations.It is well established that ISM can trigger osteopenia or osteoporosis. However, neither the clinical relevance of the infiltration pattern of mast cells within the bone marrow nor the impact of the presence or absence of cutaneous mast cell infiltration has been elucidated.We retrospectively analysed 300 cases with histologically proven ISM of the bone marrow and performed quantitative histomorphometry for a subgroup of 159 patients that did not receive any treatment before the biopsies were taken. Most importantly, since 66 % of the patients displayed ISM without the characteristic skin lesions, we were able to compare ISM with or without cutaneous manifestation.We found that both forms of ISM were not only characterized by a decreased trabecular bone mass but also by an increased number of osteoclasts and osteoblasts. Interestingly, when we analysed these data in relation to mast cell distribution, we found that the bone cell numbers in cases with mast cell granulomas were significantly increased compared to cases with diffuse mast cell distribution. Moreover, evidence of increased bone turnover was also found in 16 patients displaying osteosclerosis.Based on the largest cohort of bone biopsies from patients with ISM analysed so far, we could demonstrate high bone turnover, more specifically increased osteoblast and osteoclast numbers and surface indices, as a cause of the skeletal changes. Moreover, the severity of the bone disease is presumably rather dependent on the amount of mast cells and their distribution within the bone marrow irrespective of the presence or absence of cutaneous involvement.

A remarkable property of bone remodeling is that osteoblasts form bone matrix exactly where and when osteoclasts have removed it. The bone remodeling compartment (BRC) canopies that cover bone surfaces undergoing remodeling, were proposed to be critical players in this mechanism. Here, we provide support to this hypothesis by analyzing the changes in prevalence of BRC canopies during the progress of the remodeling cycle in a cohort of healthy individuals and in patients with endogenous Cushing's syndrome (CS), and by relating these changes in prevalence with the extent of bone forming surfaces. Both cohorts showed almost 100% canopy coverage above resorbing osteoclasts, and only about 76% above bone forming surfaces. This indicates that BRC canopies are invariably associated with the early stage of the remodeling cycle, but may disappear later. Interestingly, in control and two thirds of the CS patients, a significant decline in canopy coverage occurred only once bone formation was initiated, but in the remaining third of the CS patients the prevalence of canopies already decreased prior to bone formation. This canopy loss prior to initiation of bone formation coincided with significantly less bone forming surface compared to what did canopy loss at a later stage. These observations support a model where bone restitution is compromised in the absence of BRC canopies, and apparently does not start when the BRC canopy is lost prior to initiation of the bone formation step. This model is discussed in the context of possible biological roles of BRC canopies. It suggests that BRC canopies could be privileged targets for treating patients suffering from a negative bone formation-resorption balance. © 2011 American Society for Bone and Mineral Research.

Spontaneous osteonecrosis of the knee (SONK/Morbus Ahlback) mainly affects the medial condyle of elderly women. It is assumed that localized vascular insufficiency leads to necrosis of the subchondral bone with subsequent disruption of the nutrition supply to the cartilage above. The aetiology remains unclear in detail. Operative treatment procedures compete against non-operative strategies, whereas the outcome is unpredictable in many cases.A consecutive case series of five patients suffering from SONK was analysed. All patients underwent a clinical examination, magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry scan, as well as laboratory analyses and visual analogue scale (VAS) evaluation. Our treatment regime is based on high-dose vitamin D administered orally and intravenous application of 3 mg ibandronate two times within 8 weeks. Another 8 weeks later, all patients were followed up including a follow-up MRI.Within 4 weeks, all patients were free of symptoms. The MRI follow-up showed remission of the bone marrow oedema in every case studied. VAS decreased significantly from 7.4 ± 1.0 pre-interventional to 0.8 ± 1.0 post-interventional. No allergic reactions or other side effects were documented.We showed that our treatment regime not only eliminated the pathological findings in the MRI of all cases studied, but also decreased the pain level and functional limitations within a short-time period.IV.

Fractures of the humeral head are frequent and will further increase due to demographic changes. Prior to operative fracture treatment, the regional differences of bone quality, especially of elderly people, have to be carefully considered to assure stable implant fixation. However, conclusive data concerning the variation of histomorphometric parameters are still lacking. Consequently, the purpose of this study was to analyze the age- and sex-related changes in bone microarchitecture. For that reason, 60 proximal humeri were harvested from patients at autopsy. Twelve regions of interest (ROI) were defined for each centered coronar humeral head slice and the specimens were subjected to radiographic, histological, and histomorphometric analyses. We could demonstrate that in contrast to men, women over 60 years of age had a significant age-related decrease in bone mass. The most prominent decrease was observed in the region of the greater tuberosity, which represents an osteoporotic fracture site. The most superior and medially located part of the centered coronar humeral head slice showed, independent from age and sex, the highest bone mass and can therefore be considered as the best location for subchondral screw placement. Taken together, our study revealed distinct sex-related changes of the humeral head bone microarchitecture with aging, which should be considered in implant positioning.

Several studies have evaluated quantitative anatomic data for direct lateral mass screw fixation. To analyze anatomic landmarks and safe zones for optimal screw placement through the posterior arc of the human atlas, morphometric parameters of 41 adult native human atlas specimens were quantitatively measured. Internal dimensions of the atlas (lateral mass, maximum and minimum intraosseous screw length), minimum height and width of the posterior arc and optimal screw insertion angles were defined on pQCT scans. By this, an optimal posterior screw insertion point (OIP) and a preferable screw direction (PSD) through the posterior arch into the lateral mass of C1 were defined. External dimensions (transverse and sagittal diameter) as well as the width of the mid-portion of C1 lateral mass were significantly higher in male specimens. The mean height of the posterior arch at the vertebral artery groove was 4.1 +/- 0.8 mm in female and 4.6 +/- 0.9 mm in male specimens. The optimal screw insertion point was located 21.6 +/- 1.7 mm in female and 23.6 +/- 2.3 mm in male lateral from the posterior tubercle of C1 (P0.01). The preferable screw direction was a mean medial inclination of 7.9 +/- 1.9 degrees in female and 7.3 +/- 2.7 degrees in male specimens and a mean rostral direction of 2.4 +/- 1.8 degrees in female and 3.1 +/- 1.7 degrees in male specimens. In conclusion, the presented study provides information for the use and design of upper cervical spine instrumentation techniques, such as screw placement to C1 via the posterior arch. The characterization of working areas and safe zones (OIP, PSD) might contribute to a minimization of screw malposition in this highly demanding instrumentation technique.

Hypophosphatasia is a rare inherited disorder characterized by defective skeletal mineralization and low alkaline phosphatase activities in the serum. The genetic cause of hypophosphatasia is believed related to inactivating mutations in the TNSALP gene, encoding tissue-nonspecific alkaline phosphatase. Another rare inheritable disease, Saethre-Chotzen syndrome, leads to premature fusion of the cranial sutures caused by heterozygous mutations of the human TWIST1 gene. Because the two disorders apparently are not genetically related (only reported individually) yet both involve defective skeletal formation, we believe it is important to report our findings on a patient harboring mutations of TNSALP and TWIST1.

Our understanding of the developmental biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics, but we still know very little, in molecular and genetic terms, about skeletal physiology. Thus, among the many questions that are largely unexplained are the following: why is osteoporosis mainly a women's disease? How is bone mass maintained nearly constant between the end of puberty and the arrest of gonadal functions? Molecular genetics has emerged as a powerful tool to study previously unexplored aspects of the physiology of the skeleton. Among mammals, mice are the most promising animals for this experimental work. The input that transgenic animals can offer to our field depends on our means of phenotypic characterization of the mouse skeleton. In fact, full appreciation of the skeletal characteristics of a given mouse model requires the application of standardized protocols for noninvasive imaging, histology, histomorphometry, biomechanics, and individually adapted in vitro and in vivo analysis. Over the past years we have established a mouse archive that consists of 14,839 cases from more than 120 different mouse models that we have phenotypically characterized in Hamburg. Today, this is one of the biggest databases on the mouse skeleton. This review focuses on one aspect of skeletal physiology, namely skeletal aging, and demonstrates that mouse models can be a valuable tool to gain insights in certain facets of skeletal physiology that have been unexplored previously.

Background The aim of this large collective and meticulous study of primary bone tumours and tumourous lesions of the hand was to enhance the knowledge about findings of traumatological radiographs and improve differential diagnosis. Methods This retrospective study reviewed data collected from 1976 until 2006 in our Bone Tumour Registry. The following data was documented: age, sex, radiological investigations, tumour location, histopathological features including type and dignity of the tumour, and diagnosis. Results The retrospective analysis yielded 631 patients with a mean age of 35.9 ± 19.2 years. The majority of primary hand tumours were found in the phalanges (69.7%) followed by 24.7% in metacarpals and 5.6% in the carpals. Only 10.6% of all cases were malignant. The major lesion type was cartilage derived at 69.1%, followed by bone cysts 11.3% and osteogenic tumours 8.7%. The dominant tissue type found in phalanges and metacarpals was of cartilage origin. Osteogenic tumours were predominant in carpal bones. Enchondroma was the most commonly detected tumour in the hand (47.1%). Conclusions All primary skeletal tumours can be found in the hand and are most often of cartilage origin followed by bone cysts and osteogenic tumours. This study furthermore raises awareness about uncommon or rare tumours and helps clinicians to establish proper differential diagnosis, as the majority of detected tumours of the hand are asymptomatic and accidental findings on radiographs.

Summary Research in the last decade has revealed that bone is not only a target tissue for numerous circulating hormones but functions as an endocrine organ itself. As a recent study demonstrated a stimulatory effect of the osteoblast-derived hormone osteocalcin (OCN) on testosterone production in mice, we investigated whether such an association can be replicated in humans. We used data from 1338 men (25–86 years) in the population-based epidemiological Study of Health in Pomerania and from 110 male outpatients with bone disorders (18–85 years) for the study. We analysed cross-sectional associations between OCN and total testosterone serum concentrations (TT), as well as associations between further markers of bone turnover [bone-specific alkaline phosphatase (BAP), serum C-terminal telopeptides of Type I collagen (CTX), urinary deoxypyridinoline] and TT using ordinary least square (OLS) regression models. Multivariable OLS models revealed a positive association between OCN and TT in the population-based (β coefficients for a one standard deviation increase, 0.590; standard error (SE), 0.175; p-value