Alterations of bone material properties in adult patients with X-linked hypophosphatemia (XLH).

X-linked hypophosphatemia (XLH) caused by PHEX mutations results in elevated serum FGF23 levels, renal phosphate wasting and low 1,25-dihydroxyvitamin D. The glycophosphoprotein osteopontin, a potent inhibitor of mineralization normally degraded by PHEX, accumulates within the bone matrix. Conventional therapy consisting of supplementation with phosphate and vitamin D analogs is burdensome and the effects on bone material poorly characterized. We analyzed transiliac bone biopsies from four adult patients, two of them severely affected due to no diagnosis and no treatment until adulthood. We used light microscopy, qBEI and FTIRI to study histology, histomorphometry, bone mineralization density distribution, properties of the organic matrix and size of hypomineralized periosteocytic lesions. Non-treatment resulted in severe osteomalacia, twice the amount of mineralized trabecular volume, multiple osteon-like perforations, continuity of lamellae from mineralized to unmineralized areas and distinctive patches of woven bone. Periosteocytic lesions were larger than in treated patients. The latter had nearly normal osteoid thicknesses, although surface was still elevated. The median calcium content of the matrix was always within normal range, although the percentage of lowly mineralized bone areas was highly increased in non-treated patients, resulting in a marked heterogeneity in mineralization. Divalent collagen cross-links were evident independently of the mineral content of the matrix. Broad osteoid seams lacked measurable pyridinoline, a mature trivalent cross-link and exhibited considerable acidic lipid content, typically found in matrix vesicles. Based on our results, we propose a model that possibly integrates the relationship between the observed mineralization disturbances, FGF23 secretion and the known osteopontin accumulation in XLH.

Mortality after hip fracture in Austria 2008-2011.

Osteoporosis-related hip fractures represent a substantial cause of mortality and morbidity in industrialized countries like Austria. Identification of groups at high risk for mortality after hip fracture is crucial for health policy decisions. To determine in-hospital, long-term, and excess mortality after osteoporosis-related hip fracture in Austrian patients, we conducted a retrospective cohort analysis of pseudonymized invoice data from Austrian social insurance authorities covering roughly 98 % of the entire population. The data set included 31,668 subjects aged 50 years and above sustaining a hip fracture between July 2008 and December 2010 with follow-up until June 2011, and an age-, gender-, and regionally matched control population without hip fractures (56,320 subjects). Kaplan-Meier and Cox hazard regression analyses served to determine unadjusted and adjusted mortality rates: Unadjusted all-cause 1-year mortality amounted to 20.2 % (95 % CI: 19.7-20.7 %). Males had significantly higher long-term, in-hospital, and excess mortality rates than females, but younger males exhibited lower excess mortality than their female counterparts. Advanced age correlated with increased long-term and in-hospital mortality, but lower excess mortality. Excess mortality, particularly in males, was highest in the first 6 months after hip fracture, but remained statistically significantly elevated throughout the observation period of 3 years. Longer hospital stay per fracture was correlated with mortality reduction in older patients and in patients with more subsequent fractures. In conclusion, more efforts are needed to identify causes and effectively prevent excess mortality especially in male osteoporosis patients.

Microcracks and osteoclast resorption activity in vitro.

During bone remodeling osteoclasts resorb bone, thus removing material, e.g., damaged by microcracks, which arises as a result of physiological loading and could reduce bone strength. Such a process needs targeted bone resorption exactly at damaged sites. Osteocytic signaling plays a key role in this process, but it is not excluded that osteoclasts per se may possess toposensitivity to recognize and resorb damaged bone since it has been shown that resorption spaces are associated with microcracks. To address this question, we used an in vitro setup of a pure osteoclast culture and mineralized substrates with artificially introduced microcracks and microscratches. Histomorphometric analyses and statistical evaluation clearly showed that these defects had no effect on osteoclast resorption behavior. Osteoclasts did not resorb along microcracks, even when resorption started right beside these damages. Furthermore, quantification of resorption on three different mineralized substrates, cortical bone, bleached bone (bone after partial removal of the organic matrix), and dentin, revealed lowest resorption on bone, significantly higher resorption on bleached bone, and highest resorption on dentin. The difference between native and bleached bone may be interpreted as an inhibitory impact of the organic matrix. However, the collagen-based matrix could not be the responsible part as resorption was highest on dentin, which contains collagen. It seems that osteocytic proteins, stored in bone but not present in dentin, affect osteoclastic action. This demonstrates that osteoclasts per se do not possess a toposensitivity to remove microcracks but may be influenced by components of the organic bone matrix.

[Calcium supplementation uncovering lactose intolerance - a case report]. / Abdominalschmerzen und Diarrhoe durch Kalziumsubstitution - Fallbericht einer Patientin mit Laktoseintoleranz.

A 44 yr-old female with osteoporosis had no relevant gastrointestinal symptoms and did not avoid any specific food. However, after prescription of a lactose-rich calcium supplementation, clinical symptoms suspicious for lactose intolerance occurred, which were thereafter confirmed by a lactose tolerance test. Lactose intolerance may present with only slight or subtle symptoms. Drugs containing lactose may induce or increase gastrointestinal symptoms in patients with lactose intolerance. In case of gastrointestinal symptoms occurring after the initiation of drugs containing lactose, the possibility of lactose intolerance should be considered and tested by lactose tolerance test or genetic testing for the LCT (-13910) polymorphism. Due to the prevalence of about 15-25% lactose intolerance in the Austrian population, lactose free drugs should be prescribed as widely as possible.

Biomarkers of bone turnover in diagnosis and therapy of osteoporosis: a consensus advice from an Austrian working group.

AIM: Reasonable application of laboratory parameters in prevention, diagnosis, treatment and therapy monitoring of osteoporosis. TARGET GROUPS: Physicians from different specialist disciplines (general medicine, geriatrics, gynaecology, urology, internal medicine-especially endocrinology and metabolism, nephrology, laboratory medicine, rheumatology, nuclear medicine, orthopaedics, paediatrics, rehabilitation and physical medicine, radiology, social medicine, transplantation medicine, accident surgery), moreover social insurances, hospitals and self-help groups. BACKGROUND: Evaluation of aetiology of bone disorders, widening of the therapeutic spectrum for diseases of bone and knowledge on biochemical markers of bone turnover. Improvements in judging the success of therapy and in monitoring the compliance of patients. Research perspectives. BASES: Scientific literature and guidelines, consensus meetings. RÉSUMÉ: Basic and specialized laboratory investigations are important in differentiation between primary and secondary osteoporosis for an adequate therapy. Biochemical markers of bone turnover are an additional aid in evaluation of individual fracture risk. These markers identify responders to bone therapy faster than surveillance of bone mineral density, which helps to improve patient's compliance too. Characteristics, preanalytic precautions and applications are presented for selected markers of bone resorption and formation and for parameters regulating bone metabolism.

Fragility fractures in men with idiopathic osteoporosis are associated with undermineralization of the bone matrix without evidence of increased bone turnover.

The pathogenesis of primary osteoporosis in younger individuals is still elusive. An important determinant of the biomechanical competence of bone is its material quality. In this retrospective study we evaluated bone material quality based on quantitative backscattered electron imaging to assess bone mineralization density distribution (BMDD) in bone biopsies of 25 male patients (aged 18-61 years) who sustained fragility fractures but were otherwise healthy. BMDD of cancellous bone was compared with previously established adult reference data. Complementary information was obtained by bone histomorphometry. The histomorphometric results showed a paucity of osteoblasts and osteoclasts on the bone surface in the majority of patients. BMDD revealed a significant shift to lower mineralization densities for cancellous bone values: CaMean (weighted mean Ca content, -5.9%), CaPeak (mode of the BMDD, -5.6%), and CaHigh (portion of fully mineralized bone, -76.8%) were decreased compared to normative reference; CaWidth (heterogeneity in mineralization, +18.5%) and CaLow (portion of low mineralized bone, +68.8; all P < 0.001) were significantly increased. The shift toward lower mineral content in the bone matrix in combination with reduced indices of bone formation and bone resorption suggests an inherent mineralization defect leading to undermineralized bone matrix, which might contribute to the susceptibility to fragility fractures of the patients. The alteration in bone material might be related to osteoblastic dysfunction and seems fundamentally different from that in high bone turnover osteoporosis with a negative bone balance.

Screening and Confirmatory Testing for SARS-CoV-2 Antibodies: Comparison of Health and Non-Health Workers in a Nationwide Healthcare Organization in Central Europe.

Despite being located close to the European epicenter of the COVID-19 pandemic in Italy, Austria has managed to control the first wave. In Austria, the largest health insurance fund covers 7 million people and has 12,000 employees, including 3700 healthcare workers (HCW). For patient and staff safety, transmission control measures were implemented and mass testing of employees for SARS-CoV-2 antibodies was conducted. An IgG SARS-CoV-2 rapid test on fingerstick blood was used as a screening test (ST), followed by serologic studies with 3 different immunoassays and confirmatory testing by a neutralization test (NT). Among 7858 employees, 144 had a positive ST and 88 were confirmed by a NT (1.12%, CI: 0.9-1.38%). The positive predictive value (PPV) of the ST was 69.3% (CI: 60.5-77.2). Interestingly, 40% of the NT positive serum samples were tested negative in all 3 immunoassays. Of the total sample, 2242 HCW (28.5%) were identified. Unexpectedly, there was no difference in the prevalence of NT positives in HCW compared to non-HCW (23/2242 vs. 65/5301, p = 0.53). SARS-CoV-2 antibody prevalence was not increased among HCW. Although HCW are at potentially increased risk for SARS-CoV-2 infection, transmission control measures in healthcare facilities appear sufficient to limit transmission of infection.

NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for postoperative pain control. However, concerns regarding the potential deleterious effects of NSAIDs on bone healing have compelled many physicians to avoid NSAIDs in patients with healing fractures, osteotomies, and fusions. We systematically reviewed and analyzed the best clinical evidence regarding the effects of NSAID exposure on bone healing. Medline, Embase, and Cochrane electronic databases were searched for prospective and retrospective clinical studies of fracture, osteotomy, and fusion studies of patients with NSAID exposure and nonunion as an outcome. Study quality was assessed using the Newcastle-Ottawa Scale. Data on study design, patient characteristics, and risk estimates were extracted. Pooled effect estimates were calculated. Subanalyses were performed by bone type and by NSAID dose, duration, and route of administration. In the initial analysis of 11 cohort and case-control studies, the pooled odds ratio for nonunion with NSAID exposure was 3.0 (95% confidence interval 1.6-5.6). A significant association between lower-quality studies and higher reported odds ratios for nonunion was observed. When only higher-quality studies were considered, seven spine fusion studies were analyzed, and no statistically significant association between NSAID exposure and nonunion was identified (odds ratio = 2.2, 95% confidence interval 0.8-6.3). There was no increased risk of nonunion with NSAID exposure when only the highest-quality studies were assessed. Randomized controlled trials assessing NSAID exposure in fracture, fusion, and osteotomy populations are warranted to confirm or refute the findings of this meta-analysis of observational studies.

Treatment of osteoporosis with parathyroid hormone and teriparatide.

Nowadays osteoporosis treatment is based primarily on therapy with antiresorptive agents, like the bisphosphonates. Parathyroid hormone (Preotact) and human recombinant parathyroid hormone peptide 1-34 (Teriparatide) are relatively new for the treatment of osteoporosis and belong to the group of anabolic agents. Both agents demonstrated an increase in bone mineral density and a significant reduction in vertebral fractures in postmenopausal women with osteoporosis when given for 18-24 months. Data on nonvertebral fractures are, however, not clear-cut, and so far only bisphosphonates and strontium ranelate have been demonstrated to reduce all types of fractures and therefore remain the front-line option for treatment of osteoporosis. As the safety, tolerability, and cost of the therapy also influence the choice of therapy, Preotact and Teriparatide might be useful additions to the armamentarium for (second-line) treatment of osteoporosis.

Higher dose but not low dose proton pump inhibitors are associated with increased risk of subsequent hip fractures after first hip fracture: A nationwide observational cohort study.

AIM: To examine the association of proton pump inhibitor (PPI) use with subsequent hip fracture incidence in hip fracture patients, accounting for gender, age, PPI doses, PPI initiation before or after first fracture, and year from first fracture in which the first subsequent fracture occurred. METHODS: Data from 31,668 Austrian patients ≥50 years with the first hip fracture between July 2008 and December 2010 were analyzed retrospectively. After exclusion of patients on anti-osteoporotic medication, incidence of subsequent hip fractures was compared between users and non-users of PPIs using regression models. RESULTS: In general, use of PPIs among hip fracture patients was associated with increased risk for subsequent hip fracture (OR 1.58, 95%-CI 1.25-2.00), in particular in men, in the age group of 70-84 years, and when PPIs were initiated before the first fracture. Low PPI doses of ≤90 cumulative DDDs and ≤0.25 DDDs/day, however, were not linked to elevated subsequent fracture risk, especially among female patients. Subsequent hip fracture incidence was elevated within the first year after first fracture in female and male PPI users (OR 1.75, 95%-CI 1.28-2.38) and dropped in women but not in men in the second year. CONCLUSIONS: Low-dose PPI use is not associated with increased risk of subsequent hip fractures, especially in women. Patients thus get most benefit of short-term PPI use after a hip fracture that has previously been linked to lowered mortality if low doses are not exceeded. Varying risk profiles for the time of subsequent hip fracture could have implications for risk group-specific follow-up care.

Novel PHEX mutation associated with hypophosphatemic rickets.

BACKGROUND: X-linked hypophosphatemia (XLH) is the most prevalent heritable form of rickets. It is a dominantly inherited disorder, characterized by renal phosphate wasting, abnormal vitamin D and PTH metabolism, and defective bone mineralization. Inactivating mutations in the gene encoding PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) have been found to be associated with XLH. METHODS: We report about a 54-year-old male patient who exhibited the typical features of XLH, and in whom mutational analysis using PCR and sequencing was performed. Additionally, extensive laboratory and radiological investigations were carried out. RESULTS: A 1-bp deletion in exon 2 of the PHEX gene was detected (177delC), which, to the best of our knowledge, has not been reported yet. This deletion results in a premature stop codon (C59X), suggesting a truncation of the PHEX protein. Furthermore, elevated FGF23 and PTH levels as well as an increased axial bone mineral density score were measured. CONCLUSIONS: We present a male patient with XLH, who harbors a novel mutation in the PHEX gene, which might be the cause for his disease. Our data support previous findings and therefore contribute to the decipherment of the pathogenetic pathways of XLH.

Hip fracture incidence 2003-2013 and projected cases until 2050 in Austria: a population-based study.

OBJECTIVES: Elevated hip fracture incidence is a major public health problem looming to aggravate in industrialized countries due to demographic developments. We report hip fracture incidence and expected future cases from Vorarlberg, the westernmost province of Austria, results potentially representative of Central European populations. METHODS: Crude and standardized hip fracture incidence rates in Vorarlberg 2003-2013 are reported. Based on the age-specific incidence in 2013 or trends 2003-2013, we predict hip fractures till 2050. RESULTS: Female age-standardized hip fracture incidence decreased 2005-2013, whereas for men, the trend was rather unclear. Uncorrected forecasts indicate that by 2050, female and male cases will each have more than doubled from 2015 in all demographic core scenarios. Corrected by incidence trends before 2013, cases are expected to drop among women but rise among men. CONCLUSIONS: We anticipate rising hip fracture numbers in Vorarlberg within the next decades, unless prevention programs that presumably account for decreasing incidence rates, particularly among women since 2005, take further effect to counteract the predicted steady increase due to demographic changes. Concomitantly, augmented endeavors to target the male population by these programs are needed.

Low bone mineral density and fragility fractures in permanent vegetative state patients.

Disuse of the musculoskeletal system causes bone loss. Whether patients in vegetative state, a dramatic example of immobilization after severe brain injury, suffer from bone loss and fractures is currently unknown. Serum markers of bone turnover, bone mineral density (BMD) measurements, and clinical data were cross-sectionally analyzed in 30 consecutive vegetative state patients of a dedicated apallic care unit between 2003 and 2007 and compared with age- and sex-matched healthy individuals. Vegetative state patients showed low calcium levels and vitamin D deficiency compared with healthy controls. Serum bone turnover markers revealed high turnover as evidenced by markedly elevated carboxy-terminal telopeptide of type I collagen (ß-crosslaps) and increased levels of alkaline phosphatase. BMD measured by dual-energy X-ray absorptiometry (DXA) scanning showed strongly decreased T- and Z-scores for hip and spine. Over a period of 5 years, 8 fragility fractures occurred at peripheral sites in 6 of 30 patients (n = 3 femur, n = 2 tibia, n = 2 fibula, n = 1 humerus). In conclusion, high bone turnover and low BMD is highly prevalent in vegetative state patients, translating into a clinically relevant problem as shown by fragility fractures in 20% of patients over a time period of 5 years. .

Cardiometabolic phenotyping of patients with familial hypocalcuric hypercalcemia.

CONTEXT: Heterozygous inactivating mutations of the calcium-sensing receptor (CaSR) gene cause alterations in calcium metabolism [familial hypocalciuric hypercalcemia (FHH)]. In addition, calcium-sensing receptor is expressed in the myocardium and endocrine cells including pancreatic islets, enteroendocrine cells, and adipose tissue. OBJECTIVE: To discern whether FHH is associated with cardiometabolic alterations of clinical significance, endocrine responses to systemic calcium stimulation and oral glucose tolerance tests were performed. Ectopic lipid deposition and heart function were assessed using magnetic resonance spectroscopy/imaging. PARTICIPANTS: Eight FHH patients and nine controls matched for anthropometric characteristics (age 45 ± 18 y; body mass index 29 ± 4 vs 29 ± 6 kg/m(2)) were studied to determine cardiac function, ectopic and visceral lipid content, and insulin sensitivity and secretion. RESULTS: Insulin sensitivity (clamp-like index: 4.5 ± 0.6 vs 4.3 ± 0.4 mg/kg · min), basal (insulin secretion rate: 266 ± 33 vs 218 ± 25 pmol/min), and glucose-stimulated ß-cell function (adaptation index: 180.2 ± 12.2 vs 176.2 ± 17.4) as well as calcium-stimulated insulin secretion were comparable between FHH and controls, respectively. Ectopic lipid content in liver [3.75% (1.4%; 34%) vs 4.18% (0.9%; 28%)], soleus muscle (1.07% ± 0.38% vs 1.02% ± 0.56 %), and myocardium (0.39% ± 0.3% vs 0.32% ± 0.1 %), visceral and sc adipose tissue distribution (0.51 ± 0.16 vs 0.47 ± 0.17) as well as heart function (ejection fraction: 71.5% ± 8% vs 72.8% ± 8 %; E to A ratio: 1.4% ± 0.6% vs 1.3% ± 0.7%) were not different between the groups. CONCLUSION: Despite comprehensive cardiometabolic phenotyping, no alterations in myocardial function, lipid distribution, or glucose metabolism were observed in FHH. Thus, FHH might reflect a laboratory finding without any relevant cardiometabolic alterations.

Musculo-skeletal abnormalities in patients with Marfan syndrome.

BACKGROUND: A leptosomic body type is tall and thin with long hands. Marfanoid features may be familial in nature or pathological, as occurs in congenital contractual arachnodactyly (Beal's syndrome) and Shprintzen-Goldberg syndrome mimicking some of the changes of Marfan syndrome, although not accompanied by luxation of lens and dissecting aneurysm of aorta. METHODS: In this article we collected eight patients who were consistent with the diagnosis of Marfan syndrome via phenotypic and genotypic characterization. RESULTS: Our patients manifested a constellation of variable presentations of musculo-skeletal abnormalities ranging from developmental dysplasia of the hip, protrusio acetabuli, leg length inequality, patellar instability, scoliosis, to early onset osteoarthritis. Each abnormality has been treated accordingly. CONCLUSION: This is the first paper which includes the diagnosis and the management of the associated musculo-skeletal abnormalities in patients with Marfan syndrome, stressing that patients with Marfan syndrome are exhibiting great variability in the natural history and the severity of musculo-skeletal abnormalities.

Reduced basal ATP synthetic flux of skeletal muscle in patients with previous acromegaly.

BACKGROUND: Impaired mitochondrial function and ectopic lipid deposition in skeletal muscle and liver have been linked to decreased insulin sensitivity. As growth hormone (GH) excess can reduce insulin sensitivity, we examined the impact of previous acromegaly (AM) on glucose metabolism, lipid storage and muscular ATP turnover. PARTICIPANTS AND METHODS: Seven AM (4f/3 m, age: 46+/-4 years, BMI: 28+/-1 kg/m(2)) and healthy volunteers (CON: 3f/4 m, 43+/-4 years, 26+/-2 kg/m(2)) matched for age and body mass underwent oral glucose testing for assessment of insulin sensitivity (OGIS) and ss-cell function (adaptation index, ADAP). Whole body oxidative capacity was measured with indirect calorimetry and spiroergometry. Unidirectional ATP synthetic flux (fATP) was assessed from (31)P magnetic resonance spectroscopy (MRS) of calf muscle. Lipid contents of tibialis anterior (IMCLt) and soleus muscles (IMCLs) and liver (HCL) were measured with (1)H MRS. RESULTS: Despite comparable GH, insulin-like growth factor-1 (IGF-I) and insulin sensitivity, AM had approximately 85% lower ADAP (p<0.01) and approximately 21% reduced VO(2)max (p<0.05). fATP was similarly approximately 25% lower in AM (p<0.05) and related positively to ADAP (r = 0.744, p<0.01), but negatively to BMI (r = -0.582, p<0.05). AM had approximately 3 fold higher HCL (p<0.05) while IMCLt and IMCLs did not differ between the groups. CONCLUSIONS: Humans with a history of acromegaly exhibit reduced insulin secretion, muscular ATP synthesis and oxidative capacity but elevated liver fat content. This suggests that alterations in ss-cell function and myocellular ATP production may persist despite normalization of GH secretion after successful treatment of acromegaly.

Vertebral hyperostosis, ankylosed vertebral fracture and atlantoaxial rotatory subluxation in an elderly patient with a history of infantile idiopathic scoliosis; a case report.

This is a case report of a 48-year-old-woman with scoliosis since early childhood. Recent radiographic spinal assessment revealed the presence of distinctive spinal abnormalities. To the best of our knowledge this is the first clinical report describing a constellation of unusual changes in an elderly woman with a history of infantile idiopathic scoliosis.