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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.

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.

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.

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

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.

To the Editor, We would like to thank you for the opportunity to comment on the letter to the editor from Drs. Padulo and Ardigo regarding our article entitled "Influence of non-traumatic thoracic and lumbar vertebral fractures (VFs) on sagittal spine alignment assessed by radiation-free spinometry" recently published [1]. In this study, we introduced a radiation-free spinometry as a new method to "raise suspicion of new VFs radiation-free and indicate proper diagnostics, such as radiographs,MRI, or CT." Drs. Padulo and Ardigo question (1) the validity of radiationfree spinometry to assess spine parameters and (2) that spinometry showed better predictive accuracy than historical height loss (HHL) to predict vertebral fractures. Regarding the specific comments, we would like to reply as follows: (1) By questioning the validity of radiation-free spinometry compared to conventional x-rays, Drs. Padulo and Ardigo argue that our data should be viewed with caution. They implicate that radiation-free spinometry is not a sufficiently accurate device to be used in patient care. This is hard to understand, as the primary aim of our study was not to validate radiation-free spinometry but "to investigate the accuracy of spinometry to predict VFs by measuring [thoracic kyphosis] and [lumbar lordosis] based on different fracture locations and fracture grades." No data concerning the correct assessment of thoracic kyphosis or lumbar lordosis by radiation-free spinometry were presented in the study. The letter’s authors support their claim by reporting a low accuracy of the assessment of the Cobb angle and differences of 44 % between radiation-free spinometry and conventional radiographs analyzed by the Raimondi method by interpreting data from another study group [8]. In fact, compared to radiographs, Hackenberg et al. [2, 3] and Drerup and Hierholzer [4] performed validation studies based on a best-fit superimposition and differences between the lateral deviation and rotation curves of radiation-free spinometry and digitized x-rays [5, 6]. This approach takes local measurement shortcomings into account acknowledging that isolated segmental radiographic parameters might be erroneous. Given that the tilt of the single vertebrae cannot exactly be assessed it is widely accepted that the accuracy of the Cobb angle assessed by radiation-free spinometry is limited and not automatically given [2–4]. Although a comparison of radiation-free spinometry with, e.g., radiographs using Bland-Altman plots would be an adequate approach for its validation, we again want to emphasize that this was not the aim of our previous study. From our point of view, the letter’s authors rather miss the opportunity to present data or even Bland-Altman analyses of their own [7, 8]. In fact, due to the previously reported excellent interand intratester reliability of the assessment of thoracic kyphosis (intertester Cronbach’s α=0.979; intratester Cronbach’s α=0.920) and lumbar lordosis (intertester Cronbach’s α=0.992; intratester Cronbach’s α=0.955) with radiation-free spinometry, we feel confident in our results and conclusions [9]. Second, their claim that patients "deserve [...] reduced exposure to ionizing radiation" questioning overall application of radiation-free spinometry in patient care should be viewed with caution. We suggested that the combined assessment of thoracic kyphosis and lumbar lordosis by radiation-free spinometry could help raise suspicion for VFs und The letter referred to here can be found at DOI 10.1007/s00198-0142621-9.