Bone mineral density and fracture risk in adult patients with hypophosphatasia.

In adult hypophosphatasia (HPP) patients, elevated lumbar spine dual X-ray absorptiometry (DXA) values are associated with markers of disease severity and disease-specific fracture risk while femoral bone mineral density (BMD), being largely unaffected by the disease severity, may still be useful to monitor other causes of increased fracture risk due to low BMD. INTRODUCTION: Hypophosphatasia (HPP) is a rare inherited metabolic disorder due to deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP). Clinical manifestation in adult HPP patients is manifold including an increased risk for fractures, but data regarding clinical significance of DXA measurement and associations with fracture risk and disease severity is scarce. METHODS: Retrospective single-center analysis of DXA scans in patients with confirmed HPP (documented mutation, clinical symptoms, low alkaline phosphatase activity). Further data evaluation included disease-related fractures, laboratory results (alkaline phosphatase, pyridoxalphosphate, phosphoethanolamine), and medical history. RESULTS: Analysis included 110 patients (84 female, mean age of 46.2 years) of whom 37.3% (n = 41) were harboring two mutations. Average T-Score level at the lumbar spine was - 0.1 (SD 1.9), and mean total hip T-Score was - 1.07 (SD 0.15). Both lower ALP activity and higher substrate levels (pyridoxalphosphate and phosphoethanolamine) were significantly correlated with increased lumbar spine T-Score levels (p < 0.001) while BMD at the hip was not affected by indicators of disease severity. Increased lumbar spine BMD was significantly associated with an increased risk for HPP-related fractures, prevalent in 22 (20%) patients (p < 0.001) with 21 of them having biallelic mutations. CONCLUSION: BMD in adult HPP patients is not systematically reduced. Conversely, increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures while BMD at the hip appears unaffected by indicators of disease severity, suggesting suitability of this anatomic location for assessing and discerning disorders with increased fracture risk owing to reduced BMD like osteoporosis. TRIAL REGISTRATION NUMBER: German register for clinical studies (DRKS00014022) DATE OF REGISTRATION: 02/10/2018 - retrospectively registered.

Bilateral Looser zones or pseudofractures in the anteromedial tibia as a component of medial tibial stress syndrome in athletes.

PURPOSE: Medial 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. METHODS: Nine 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). RESULTS: In 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. CONCLUSION: In 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 EVIDENCE: III.

Fibrogenesis Imperfecta Ossium.

Fibrogenesis imperfecta ossium (FIO) is an extremely uncommon fatal bone disorder of poorly understood etiology. The pathogenesis of FIO is not well known. The fundamental skeletal defect appears to be an abnormality in organic matrix of bone characterized by defective mineralization of the abnormal collagen. FIO clinically manifests in middle-aged adults presenting with fracture and bone pain. Elevated serum alkaline phosphatase is the only and the most consistent biochemical abnormality. Although paraproteinemia is observed in one-third of cases, the pathogenic link to the disease process is unclear. Limited information on FIO and its close resemblance to many metabolic bone disorders leads to delayed or missed diagnoses and management. Prednisolone, bisphosphonates, melphalan and steroids have been tried previously with variable success. Recently, a trial of recombinant growth hormone therapy was found to be effective. Further research focused on the pathogenetic mechanisms of FIO is needed to identify and develop targeted therapeutic options.

A rat model of multicompartmental traumatic injury and hemorrhagic shock induces bone marrow dysfunction and profound anemia.

BACKGROUND: Severe trauma is associated with systemic inflammation and organ dysfunction. Preclinical rodent trauma models are the mainstay of postinjury research but have been criticized for not fully replicating severe human trauma. The aim of this study was to create a rat model of multicompartmental injury which recreates profound traumatic injury. METHODS: Male Sprague-Dawley rats were subjected to unilateral lung contusion and hemorrhagic shock (LCHS), multicompartmental polytrauma (PT) (unilateral lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofracture), or naïve controls. Weight, plasma toll-like receptor 4 (TLR4), hemoglobin, spleen to body weight ratio, bone marrow (BM) erythroid progenitor (CFU-GEMM, BFU-E, and CFU-E) growth, plasma granulocyte colony-stimulating factor (G-CSF) and right lung histologic injury were assessed on day 7, with significance defined as p values <0.05 (*). RESULTS: Polytrauma resulted in markedly more profound inhibition of weight gain compared to LCHS (p = 0.0002) along with elevated plasma TLR4 (p < 0.0001), lower hemoglobin (p < 0.0001), and enlarged spleen to body weight ratios (p = 0.004). Both LCHS and PT demonstrated suppression of CFU-E and BFU-E growth compared to naïve (p < 0.03, p < 0.01). Plasma G-CSF was elevated in PT compared to both naïve and LCHS (p < 0.0001, p = 0.02). LCHS and PT demonstrated significant histologic right lung injury with poor alveolar wall integrity and interstitial edema. CONCLUSIONS: Multicompartmental injury as described here establishes a reproducible model of multicompartmental injury with worsened anemia, splenic tissue enlargement, weight loss, and increased inflammatory activity compared to a less severe model. This may serve as a more effective model to recreate profound traumatic injury to replicate the human inflammatory response postinjury.

Tumour induced osteopenia due to phosphaturic mesenchymal sinonasal tumour presenting with delayed onset insufficiency fractures.

We present a case of a 48-year-old female who presented with epistaxis. Magnetic resonance imaging (MRI) revealed a mass within the left nasal cavity which was revealed to be a phosphaturic mesenchymal sinonasal tumour. The patient defaulted treatment at this stage and later re-presented with pelvic and groin pain for which plain radiographs and computed tomography (CT) scan demonstrated diffuse osteopenia and multiple pelvic fractures of varying ages. MRI of the pelvis and both thighs revealed abnormal marrow signal of the bones and confirmed the presence of pelvic fractures. Multiple pseudo-fractures were seen at both femurs and scapula. The radiological findings along with abnormal biochemical markers were attributed to the paraneoplastic entity of tumour induced osteomalacia, in the context of unresected phosphaturic mesenchymal tumour. The tumour was resected, and patient showed complete reversal of the associated biochemical abnormalities. This case exemplifies that with early identification and complete resection of the causative tumour, the prognosis is excellent.

Impact of muscular symptoms and/or pain on disease characteristics, disability, and quality of life in adult patients with hypophosphatasia: A cross-sectional analysis from the Global HPP Registry.

Introduction: Hypophosphatasia (HPP) manifests in adults as fractures/pseudofractures, pain, muscle weakness, and other functional impairments. Better phenotypic disease characterization is needed to help recognize disability and treat patients with HPP. Methods: Baseline/pretreatment demographic, clinical characteristic, and patient-reported disability/health-related quality-of-life (HRQoL) data from adults (≥18 y) in the Global HPP Registry (NCT02306720) were stratified by presence of overt skeletal manifestations (skeletal group) versus muscular/pain manifestations without skeletal manifestations (muscular/pain group) and summarized descriptively. Disability was measured using the Health Assessment Questionnaire-Disability Index (HAQ-DI), and HRQoL using the 36-item Short Form Health Survey (SF-36v2). Results: Of 468 adults, 300 were classified into the skeletal group and 73 into the muscular/pain group. The skeletal group had a higher median age at baseline (50.1 vs 44.4 y; P=0.047) but a lower median age at first HPP manifestation (12.3 vs 22.1 y; P=0.0473), with more signs and symptoms (median, 4 vs 3; P<0.0001) and involved body systems (median, 3 vs 2; P<0.0001) than the muscular/pain group. More patients in the skeletal group required any use of mobility aids (22.6% vs 3.5%, respectively; P=0.001). Six-Minute Walk test distances walked were similar between groups. SF-36v2 and HAQ-DI scores were similar between groups for physical component summary (n=238; mean [SD]: 40.2 [11.0] vs 43.6 [11.2]; P=0.056), mental component summary (n=238; mean [SD]: 43.6 [11.3] vs 43.8 [11.8]; P=0.902), and HAQ-DI (n=239; median [minimum, maximum]: 0.4 [0.0, 2.7] vs 0.3 [0.0, 2.1]; P=0.22). Conclusion: Adults with HPP experience similar QoL impairment regardless of skeletal involvement. Registration: https://clinicaltrials.gov/ct2/show/NCT02306720 and https://www.encepp.eu/encepp/viewResource.htm?id=47907, identifier NCT02306720; EUPAS13514.

Radiological evaluation of pseudofracture after the administration of asfotase alfa in an adult with benign prenatal hypophosphatasia: A case report.

Hypophosphatasia (HPP) is a congenital disorder with decreased activity of tissue-nonspecific alkaline phosphatase. Asfotase alfa is the only treatment approved for HPP and improves the impairment of bone mineralization. Although several previous studies have reported the efficacy of asfotase alfa to treat fractures and pseudofractures in patients with HPP, there are only a few reports with a detailed description of the healing process. In this case report, we present an 18-year-old female patient with benign prenatal HPP who received asfotase alfa to treat her pseudofracture. At the age of 17, a pseudofracture developed in her left tibia after repetitive gymnastic exercise for months. Following observation over a year, she was referred to our department. X-ray images indicated a narrow radiolucent band in the mid-diaphysis of her left tibia, and bone scintigraphy showed nuclide accumulation in the same region. Replacement therapy with asfotase alfa was started, resulting in pain relief in two months, and the disappearance of nuclide accumulation on bone scintigraphy and union of the pseudofracture on X-ray after two years. This is the first case report describing the detailed pseudofracture healing process in a patient with benign prenatal HPP initiating asfotase alfa.

Lower Limb Deformity and Gait Deviations Among Adolescents and Adults With X-Linked Hypophosphatemia.

Background: X-linked hypophosphatemia (XLH) is a rare genetic disorder characterized by lower limb deformity, gait and joint problems, and pain. Hence, quality of life is substantially impaired. This study aimed to assess lower limb deformity, specific radiographic changes, and gait deviations among adolescents and adults with XLH. Design: Data on laboratory examination and gait analysis results were analyzed retrospectively. Deformities, osteoarthritis, pseudofractures, and enthesopathies on lower limb radiographs were investigated. Gait analysis findings were compared between the XLH group and the control group comprising healthy adults. Patients and Controls: Radiographic outcomes were assessed retrospectively in 43 patients with XLH (28 female, 15 male). Gait analysis data was available in 29 patients with confirmed XLH and compared to a healthy reference cohort (n=76). Results: Patients with XLH had a lower gait quality compared to healthy controls (Gait deviation index GDI 65.9% +/- 16.2). About 48.3% of the study population presented with a greater lateral trunk lean, commonly referred to as waddling gait. A higher BMI and mechanical axis deviation of the lower limbs were associated with lower gait scores and greater lateral trunk lean. Patients with radiologic signs of enthesopathies had a lower GDI. Conclusions: This study showed for the first time that lower limb deformity, BMI, and typical features of XLH such as enthesopathies negatively affected gait quality among adolescents and adults with XLH.

Brown Tumor as an Index Presentation of Severe Vitamin D Deficiency in a Teenage Girl.

Brown tumor is a non-neoplastic fibro-cystic expansile bone lesion caused by parathyroid hormone excess. It has been commonly described in patients with primary hyperparathyroidism and secondary hyperparathyroidism due to chronic kidney disease. However, it is very rare to encounter a brown tumor in the setting of nutritional vitamin D deficiency. We describe the case of a 16-year-old girl who presented with brown tumor-like lytic lesion of femur caused by severe longstanding vitamin D deficiency. Treatment with elemental calcium and cholecalciferol resulted in correction of hyperparathyroid state, with the resultant disappearance of the bony lesion and remarkable symptomatic improvement. Unnecessary orthopaedic intervention may be avoided using a high index of suspicion and performing targeted investigations in such cases.

Picking up the pieces: Utilizing the diagnostic potential of poorly preserved remains.

With pressures on time and resources available to those undertaking research in paleopathology, poorly preserved archaeological human remains can often receive limited attention or be completely excluded from the analysis of archaeological sites. Although incomplete skeletons often yield minimal demographic information and can complicate the diagnosis of some pathological conditions, this is not universal. Significant information can be obtained even in partial remains on metabolic bone diseases (where, by definition, the whole skeleton is involved), and for conditions such as osteoarthritis and fractures which can be diagnosed in isolation. We present an example of an incomplete skeleton that provided valuable new information on pathological changes associated with osteomalacia, a condition that has been little studied to date in paleopathology. This skeleton also contributes to our understanding of the factors surrounding the classification of fractures, and provides new insight into the full range of circumstances in which eburnation can develop. This example demonstrates the value of including partial and poorly preserved skeletons in paleopathological analysis and the extent of information that can be obtained.

False femoral neck fracture detected during shaft nailing: a Mach band effect.

Femoral neck fractures are associated with femoral shaft fractures in 1% to 9% of cases. Undisplaced neck fractures are susceptible to displacement during shaft nailing. We report the case of a 57-year-old male patient in whom we performed standard intramedullary nailing for a femoral shaft fracture. In doing so, we identified a vertical radiolucent line at the femoral neck, which was thought to be further displacement of a hidden silent fracture or an iatrogenic fracture that developed during nail insertion. Consequently, we decided to switch to reconstructive femoral nailing. Postoperative hip imaging failed to show the femoral neck fracture that we saw in the operating room. Here, we discuss the aforementioned case and review the literature concerning this artifact.