Return to sport following low-risk and high-risk bone stress injuries: a systematic review and meta-analysis.

OBJECTIVE: Bone stress injuries (BSIs) are classified in clinical practice as being at low- or high-risk for complication based on the injury location. However, this dichotomous approach has not been sufficiently validated. The purpose of this systematic review was to examine the prognostic role of injury location on return-to-sport (RTS) and treatment complications after BSI of the lower extremity and pelvis. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Web of Science, Cochrane CENTRAL and Google Scholar databases were searched from database inception to December 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Peer-reviewed studies that reported site-specific RTS of BSIs in athletes. RESULTS: Seventy-six studies reporting on 2974 BSIs were included. Sixteen studies compared multiple injury sites, and most of these studies (n=11) described the anatomical site of injury as being prognostic for RTS or the rate of treatment complication. Pooled data revealed the longest time to RTS for BSIs of the tarsal navicular (127 days; 95% CI 102 to 151 days) and femoral neck (107 days; 95% CI 79 to 135 days) and shortest duration of time for BSIs of the posteromedial tibial shaft (44 days, 95% CI 27 to 61 days) and fibula (56 days; 95% CI 13 to 100 days). Overall, more than 90% of athletes successfully returned to sport. Treatment complication rate was highest in BSIs of the femoral neck, tarsal navicular, anterior tibial shaft and fifth metatarsal; and lowest in the fibula, pubic bone and posteromedial tibial shaft. CONCLUSION: This systematic review supports that the anatomical site of BSIs influences RTS timelines and the risk of complication. BSIs of the femoral neck, anterior tibial shaft and tarsal navicular are associated with increased rates of complications and more challenging RTS. PROSPERO REGISTRATION NUMBER: CRD42021232351.

Radiolucent zones of biodegradable magnesium-based screws in children and adolescents-a radiographic analysis.

INTRODUCTION: Albeit the implantation of magnesium-based biodegradable implants can avoid a second surgery for implant removal, the postoperative occurrence of radiolucent zones around these implants based on corrosion processes has not been previously investigated in children and adolescents. We sought to characterize the distinct temporal and spatial dynamics for magnesium-based implants based on standard clinical routine radiographs. MATERIALS AND METHODS: We retrospectively analyzed 29 patients, treated with magnesium-based compression screws (MAGNEZIX® CS 2.7 mm, CS 3.2 mm, CSC 4.8 mm; Syntellix AG) for fracture fixation, osteotomy, or osteochondral refixation. During a follow-up examination, the clinical and functional status was evaluated. Based on digital radiographs, the ratio of the area of the radiolucent zone and that of the screw was evaluated to assess implant degradation at two follow-up visits (i.e., after 6-8 weeks and 12-24 weeks). RESULTS: In 29 patients (16/29 females, 14.03 ± 2.13 years), a total of 57 implants were evaluated that were used for osteotomy (n = 13, screws n = 26), fracture fixation (n = 9, screws n = 18), or osteochondral refixation (n = 7, screws n = 13). All patients healed without complications and regained full function. Radiolucent zones were observed in 27/29 patients at the first follow-up, with significantly decreased ratios at the second follow-up (2.10 ± 0.55 vs 1.64 ± 0.60, p = 0.0006). Regression analyses were performed to assess the temporal dynamics of radiolucent zones and revealed significant logarithmic developments for the 2.7 mm and 3.2 mm screws, marked by a strong ratio decrease during the first weeks and an almost complete disappearance after approximately 100 days and 200 days, respectively. In contrast, the ceramic-coated 4.8 mm screws presented a significant linear and slower decrease of radiolucent zones. CONCLUSION: Radiolucent zones are a common phenomenon in the course of implant degradation. However, they represent a self-limiting phenomenon. Remarkably, neither implant failure nor affected implant function is noted in this context. Yet, the microstructural changes accompanying the presence of radiolucent zones remain to be analyzed by three-dimensional high-resolution imaging.

Surgical outcome of avulsion fractures of the distal fibula: a systematic literature review.

PURPOSE: To provide a systematic overview of clinical and radiographic outcomes in patients who underwent surgical treatment of a painful avulsion fragment of the distal fibula also known as posttraumatic os subfibulare. METHODS: A systematic literature search across two major sources (PubMed and Scopus) was performed. Twenty-seven studies were included and analyzed using the modified Coleman score to assess the methodologic quality. RESULTS: The surgical treatment of symptomatic os subfibulare, with or without concomitant ankle instability, generally results in substantial improvement in clinical and radiographic outcomes with relative low complication rates. Clinical outcome measures may not be affected by the presence of ankle instability or by the fragment size. The methodological quality of analyzed studies was satisfactory. CONCLUSION: Posttraumatic os subfibulare may result in chronic pain and ankle instability. If surgery is indicated, ankle instability should be concomitantly addressed when present. Based on available literature, satisfactory postoperative outcomes can be reliably expected following surgical treatment. LEVEL OF EVIDENCE: Systematic Review of Level III and Level IV Studies, Level IV.

[Tumor localization and treatment of tumor-induced osteomalacia]. / Tumorlokalisation und Therapie der onkogenen Osteomalazie.

Tumor-induced osteomalacia (TIO) or oncogenic osteomalacia (OOM) is a rare paraneoplastic renal phosphate wasting syndrome. The disease is mostly triggered by small, benign mesenchymal tumors that express somatostatin receptors (SSTR) and produce excessive levels of fibroblast growth factor 23 (FGF 23) or other phosphatonins. These reduce the phosphate back resorption in the proximal tubules of the kidneys, thereby causing hypophosphatemia and lead to an absolute or relatively low calcitriol serum concentration. The main symptoms include muscle weakness, bone pain and recurrent insufficiency fractures secondary to sometimes pronounced osteomalacia. The suspected diagnosis can only be confirmed by determination of the phosphate level. It can often take years before the tumor is successfully localized. The necessary tumor localization is often the most difficult step in the treatment before the OOM can be curatively treated by open surgical resection of the tumor. In recent years new approaches for faster tumor localization and treatment of the tumor have been developed. Positron emission tomography (PET) in co-registration with computed tomography (68Ga-DOTA-TATE PET/CT) is currently the most sensitive imaging methodology for tumor detection. The application of the monoclonal FGF 23 antibody burosumab represents a promising new option in the treatment of inoperable adult OOM.

Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III.

PURPOSE: Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. METHODS: We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. RESULTS: The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. CONCLUSION: The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

Clinical and Radiological Characterization of Patients with Immobilizing and Progressive Stress Fractures in Methotrexate Osteopathy.

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

Genotype-Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia.

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.

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.

[Musculoskeletal laboratory diagnostics in competitive sport]. / Muskuloskelettale Labordiagnostik im Leistungssport.

BACKGROUND: Laboratory diagnostics represent a valuable tool for the optimization and assessment of the performance and regeneration ability in professional athletes. Blood parameters play an important role in the prevention, diagnosis and rehabilitation of injuries and physical overload. OBJECTIVES: The aim of this article is to present an overview of musculoskeletal laboratory parameters and to provide relevant information for the medical care of competitive athletes. METHODS: Literature search and narrative review. RESULTS: The laboratory assessment of bone metabolism includes vitamin D, calcium and bone turnover and aims to provide a preventive benefit with respect to skeletal complications (e.g., to minimize the risk of bone stress injuries). In addition, muscular serum markers, such as lactate dehydrogenase (LDH), creatine kinase (CK), myoglobin and aspartate aminotransferase (AST) can be used to monitor metabolic adaptation to physical exercise and to obtain information about the muscular workload and potential damage. The energy availability can be estimated and optimized by appropriate balancing and laboratory determination of macro- and micronutrients. CONCLUSIONS: Laboratory diagnostics have a clinical relevance across different sport disciplines. They are intended to support athletes and medical staff on their way to the highest possible performance and help to ensure the optimal prevention of bone and muscle injuries. Parameters with deficiency results (e.g., vitamin D) should be adequately compensated. A periodization of the laboratory tests, with at least two tests per year, and the establishment of individual variability and reference ranges can improve the assessment.

Comparison of Bone Microarchitecture Between Adult Osteogenesis Imperfecta and Early-Onset Osteoporosis.

Diagnosis and management of adult individuals with low bone mass and increased bone fragility before the age of 50 can be challenging. A number of these patients are diagnosed with mild osteogenesis imperfecta (OI) through detection of COL1A1 or COL1A2 mutations; however, a clinical differentiation from early-onset osteoporosis (EOOP) may be difficult. The purpose of this study was to determine the bone microstructural differences between mild OI and EOOP patients. 29 patients showed mutations in COL1A1 or COL1A2 and were classified as OI. Skeletal assessment included dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone turnover serum analyses. Bone microstructure of 21/29 OI patients was assessed and compared to 23 age- and sex-matched patients clinically classified EOOP but without mutations in the known disease genes as well as to 20 healthy controls. In the OI patients, we did not observe an age-dependent decrease in DXA Z-scores. HR-pQCT revealed a significant reduction in volumetric BMD and microstructural parameters in the distal radius and tibia in both the OI and EOOP cohorts compared to the healthy controls. When comparing the bone microstructure of OI patients with the EOOP cohort, significant differences were found in terms of bone geometry in the radius, while no significant changes were detected in all other HR-pQCT parameters at the radius and tibia. Taken together, adult mild OI patients demonstrate a predominantly high bone turnover trabecular bone loss syndrome that shows minor microstructural differences compared to EOOP without mutation detection.

Influence of variable hinge positioning on coronal and sagittal alignment in uniplanar medial open-wedge high tibial osteotomy.

Purpose: There is a high risk of increasing the posterior tibial slope (PTS) during medially opening-wedge high tibial osteotomy (mowHTO). Most recently, the idea of intentional simultaneous coronal and sagittal correction, using uniplanar cutting techniques has emerged. This study aims to examine the influences of variable hinge positioning and osteotomy gap height on the sagittal and coronal plane. Methods: Twenty uniplanar mowHTOs were performed in standardised (left) solid-foam proximal tibia models. In the different models, hinge position was rotated stepwise by 10°, between 90° (cutting straight medial to lateral) and 0° (cutting straight anterior to posterior) (n = 10). Additionally, gap heights of 5 and 10 mm were produced and analysed. Logistic regression analysis was performed to calculate a predictive regression formula for the relation between gap height, hinge rotation and the changes of medial proximal tibia angle (MPTA), medial and lateral PTS. Results: Between cutting angles of 90 and 20°, the MPTA was mainly influenced by the gap height (0.95° MPTA per 1 mm gap height), but not by the cutting angle. Between 20 and 0°, the MPTA was decreased by 3.6° per 10° of rotation, but not by the gap height. Between cutting angles of 90 and 10°, the PTS was increased linearly by 0.97° per 10° of rotation and by 0.61° per 1 mm gap height. Conclusion: In mowHTO with lateral hinge positions, the MPTA is mainly influenced by gap height. Changes of PTS can be avoided by a straight lateral hinge position. In posterior hinge locations (0-20°), changes of MPTA are mainly caused by hinge rotation, but not by gap height. Level of Evidence: Level III, Case-control study.

Dynamics of Skeletal Status under Optimized Management during Subsequent Pregnancy in Three Women with a History of Pregnancy- and Lactation-Associated Osteoporosis Carrying pathogenic Variants in WNT1 and LRP5.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare but clinically highly relevant condition, characterized by reduced bone mineral density (BMD) and acute onset of severe pain due to symptomatic bone marrow edema of the hip or vertebral and/or insufficiency fractures, among others. Previous reports showed a high frequency of hereditary bone disorders unmasked by PLO, predisposing for more severe forms. To date, no data on the risk for additional fractures during subsequent pregnancy in women with PLO and genetic bone disorder have been available. To address this question, we retrospectively analyzed the clinical, biochemical, and densitometric course of three women with a history of PLO and detected variants in WNT1 or LRP5 and subsequent pregnancies. Calcium homeostasis and bone turnover were optimized by basic treatment, and timely initiation of weaning was recommended. Teriparatide treatment for 12 months under strict contraception was initiated in one woman after the diagnosis of PLO. In none of the women did additional fractures or symptomatic bone marrow edemas occur, and BMD by dual-energy X-ray absorptiometry as bone microarchitecture by high-resolution peripheral quantitative computed tomography remained stable. In conclusion, this report expands the understanding of this rare but severe condition and helps to improve clinical counseling and management. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Age-, sex-, and subregion-specific properties of distal fibular microarchitecture and strength: An ex vivo HR-pQCT study.

Despite its clinical relevance in the context of ankle fractures, little is known about the bone microarchitecture and strength of the distal fibula, especially regarding age-, sex-, and subregion-specific effects. To address this gap of knowledge, we obtained fibulae from 30 skeletally intact donors at autopsy (each 15 male and female), which were analyzed by high-resolution peripheral quantitative computed tomography including micro-finite element analysis. Scans were performed in a 7-cm volume of interest and evaluated in three subregions according to the Danis-Weber fracture classification. Group comparisons and linear regression analyses were applied to evaluate the effects of age, sex, and subregion. From distal to proximal, we observed an increase of cortical parameters and a decrease of trabecular parameters. Age was primarily associated with a cortical decrease in all subregions (Danis-Weber type A, B, and C) in women. While women showed a greater magnitude of decline, men also exhibited an age-associated decrease for some parameters, including cortical area and cortical thickness in the type C subregion. Stiffness and failure load were highest in the type C subregion in both women and men. A critical age-related decline in bone strength parameters in the type B subregion was observed in women, providing an explanation for the increased incidence of low-traumatic type B fractures in the elderly. Together, these findings extend the current understanding of distal fibular microarchitecture, likely explaining the epidemiologic features of distal fibula fractures and emphasizing the need for age-adapted treatment algorithms.

Impaired Bone Microarchitecture at Distal Radial and Tibial Reference Locations Is Not Related to Injury Site in Athletes With Bone Stress Injury.

BACKGROUND: Bone stress injuries (BSIs) are common sports injuries that occur because of an imbalance between microdamage accumulation and removal through bone remodeling. The underlying bone phenotype has been assumed to be a contributing factor. However, the bone microarchitecture of athletes with BSI is not well characterized, and no study has investigated whether impaired bone microarchitecture is associated with bone composition or anatomic site of injury. PURPOSE/HYPOTHESIS: This cross-sectional study characterizes the bone microarchitecture at distal radial and tibial reference locations in athletes with BSI. Based on previous dual-energy X-ray absorptiometry (DXA) findings, the aim was to compare anatomic injury sites, hypothesizing that athletes with BSIs in bones with greater trabecular composition show impaired bone microarchitecture parameters compared with those with BSIs in bones with greater cortical composition. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Athletes who had presented to our outpatient clinic because of a high-grade BSI (ie, stress fracture) were retrospectively included. Blood and urine samples were collected. Areal bone mineral density (aBMD) was assessed by DXA at the lumbar spine and both hips. Bone microarchitecture was analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and tibia. HR-pQCT parameters were expressed in relation to available sex-, age-, and device-adjusted reference values and compared with a cohort of 53 age- and sex-matched controls. RESULTS: In total, 53 athletes had a BSI of the foot (n = 20), tibia/fibula (n = 18), pelvis (n = 9), femur (n = 5), or sternum (n = 1). Based on DXA measurements, a Z-score of -1.0 or lower was found in 32 of 53 (60.4%) of the athletes, of whom 16 of 53 (30.2%) had a Z score -2.0 or lower. While an impairment of cortical area (P = .034 and P = .001) and thickness (P = .029 and P < .001) was detected at the distal radius and tibia in the BSI cohort compared with controls, no differences in BMD or bone microarchitecture were observed between anatomic injury sites. Furthermore, no difference was revealed when BSIs were grouped into cortical- and trabecular-rich sites. CONCLUSION: Reduced aBMD and impaired cortical bone microarchitecture were present in a considerable number of athletes with BSI. Neither aBMD nor bone microarchitecture was related to the injury site, highlighting the multifactorial etiology of BSI.

Compartment-specific effects of muscle strength on bone microarchitecture in women at high risk of osteoporosis.

BACKGROUND: It is well known that skeletal integrity is influenced by the musculature. Poor muscle strength (i.e. sarcopenia) is considered a major predictor of fragility fractures. While this observation appears particularly relevant for older women with increased risk of osteoporosis, there has been no comprehensive investigation to determine the influence of muscle performance on compartment-specific bone microarchitecture in multiple body regions. METHODS: We retrospectively analysed data from different muscle performance and bone microarchitecture assessments in 230 women (aged 21 to 87 years) at high risk of osteoporosis. Muscle performance tests included grip strength and chair rising test (CRT) combined with mechanography. Balance was determined by Romberg posturography. Areal bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine. Compartment-specific volumetric BMD, microarchitecture, and geometry were assessed by second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT) at multiple skeletal sites (distal radius, tibia, and fibula). Regression models were applied to test for interactions between muscle and bone parameters. Subgroups were defined to compare women with osteoporosis and osteosarcopenia regarding BMD and microarchitecture. RESULTS: While osteoporosis was diagnosed in 115/230 (50.0%) women, sarcopenia was detected in 38/230 (16.5%). Positive associations of both grip strength and CRT maximum force with cortical geometric and microarchitectural parameters were detected at all measured sites, with the strongest effect applying to CRT maximum force and tibial parameters (e.g. tibial cortical area R2  = 0.36, P < 0.0001, and tibial cortical thickness R2  = 0.26, P < 0.0001). Balance parameters showed much weaker or no associations with HR-pQCT parameters. Major associations between muscle strength and trabecular parameters could not be confirmed. Age and body mass index were confirmed as negative and positive predictors for several microarchitectural parameters, respectively. An independent predictive value of grip strength on radial, tibial, and fibular (all P < 0.01) cortical area and of CRT maximum relative force on cortical thickness (all P < 0.05) was revealed. Women with osteosarcopenia showed significantly reduced cortical HR-pQCT parameters but no differences in DXA values compared with women with osteoporosis but no sarcopenia. Stratification by fracture and treatment status revealed that vertebral fractures and denosumab treatment altered the muscle-bone interaction. CONCLUSIONS: A systemic interaction between muscle strength and bone microarchitecture was demonstrated, and this interaction appears to be primarily with the cortical bone compartment. The value of muscle assessments in fracture risk evaluation may be partly mediated by their effects on bone microarchitecture.

Superior Bone Microarchitecture in Anatomic Versus Nonanatomic Fibular Drill Tunnels for Reconstruction of the Posterolateral Corner of the Knee.

Background: Several fibula-based reconstruction techniques have been introduced to address ligamentous injuries of the posterolateral corner of the knee. These techniques involve a drill tunnel with auto- or allograft placement through the proximal fibula. Purpose: To determine the skeletal microarchitecture of the proximal fibula and its association with age and to compare the microarchitecture within the regions of different drill tunnel techniques for reconstruction of the posterolateral corner. Study Design: Descriptive laboratory study. Methods: A total of 30 human fibulae were analyzed in this cadaveric imaging study. High-resolution peripheral quantitative computed tomography measurements were performed in a 4.5 cm-long volume of interest at the proximal fibula. Three-dimensional microarchitectural data sets of cortical and trabecular compartments were evaluated using customized scripts. The quadrants representing the entry and exit drill tunnel positions corresponding to anatomic techniques (LaPrade/Arciero) and the Larson technique were analyzed. Linear regression models and group comparisons were applied. Results: Trabecular microarchitecture parameters declined significantly with age in women but not men. Analysis of subregions with respect to height revealed stable cortical and decreasing trabecular values from proximal to distal in both sexes. Along with a structural variability in axial slices, superior values were found for the densitometric and microarchitectural parameters corresponding to the fibular drill tunnels in the anatomic versus Larson technique (mean ± SD; bone volume to tissue volume at the entry position, 0.273 ± 0.079 vs 0.175 ± 0.063; P < .0001; cortical thickness at the entry position, 0.501 ± 0.138 vs 0.353 ± 0.081 mm; P < .0001). Conclusion: Age represented a relevant risk factor for impaired skeletal microarchitecture in the proximal fibula in women but not men. The region of drill tunnels according to anatomic techniques showed superior bone microarchitecture versus that according to the Larson technique.

Clinical Spectrum of Hereditary Hypophosphatemic Rickets With Hypercalciuria (HHRH).

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) represents an FGF23-independent disease caused by biallelic variants in the solute carrier family 34-member 3 (SLC34A3) gene. HHRH is characterized by chronic hypophosphatemia and an increased risk for nephrocalcinosis and rickets/osteomalacia, muscular weakness, and secondary limb deformity. Biochemical changes, but no relevant skeletal changes, have been reported for heterozygous SLC34A3 carriers. Therefore, we assessed the characteristics of individuals with biallelic and monoallelic SLC34A3 variants. In 8 index patients and 5 family members, genetic analysis was performed using a custom gene panel. The skeletal assessment comprised biochemical parameters, areal bone mineral density (aBMD), and bone microarchitecture. Pathogenic SLC34A3 variants were revealed in 7 of 13 individuals (2 homozygous, 5 heterozygous), whereas 3 of 13 carried monoallelic variants of unknown significance. Whereas both homozygous individuals had nephrocalcinosis, only one displayed a skeletal phenotype consistent with HHRH. Reduced to low-normal phosphate levels, decreased tubular reabsorption of phosphate (TRP), and high-normal to elevated values of 1,25-OH2 -D3 accompanied by normal cFGF23 levels were revealed independently of mutational status. Interestingly, individuals with nephrocalcinosis showed significantly increased calcium excretion and 1,25-OH2 -D3 levels but normal phosphate reabsorption. Furthermore, aBMD Z-score <-2.0 was revealed in 4 of 8 heterozygous carriers, and HR-pQCT analysis showed a moderate decrease in structural parameters. Our findings highlight the clinical relevance also of monoallelic SLC34A3 variants, including their potential skeletal impairment. Calcium excretion and 1,25-OH2 -D3 levels, but not TRP, were associated with nephrocalcinosis. Future studies should investigate the effects of distinct SLC34A3 variants and optimize treatment and monitoring regimens to prevent nephrocalcinosis and skeletal deterioration. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Impaired bone quality in the superolateral femoral neck occurs independent of hip geometry and bone mineral density.

Skeletal adaptation is substantially influenced by mechanical loads. Osteocytes and their lacuno-canalicular network have been identified as a key player in load sensation and bone quality regulation. In the femoral neck, one of the most common fracture sites, a complex loading pattern with lower habitual loading in the superolateral neck and higher compressive stresses in the inferomedial neck is present. Variations in the femoral neck-shaft angle (NSA), i.e., coxa vara or coxa valga, provide the opportunity to examine the influence of loading patterns on bone quality. We obtained femoral neck specimens of 28 osteoarthritic human subjects with coxa vara, coxa norma and coxa valga during total hip arthroplasty. Bone mineral density (BMD) was assessed preoperatively by dual energy X-ray absorptiometry (DXA). Cortical and trabecular microstructure and three-dimensional osteocyte lacunar characteristics were assessed in the superolateral and inferomedial neck using ex vivo high resolution micro-computed tomography. Additionally, BMD distribution and osteocyte lacunar characteristics were analyzed by quantitative backscattered electron imaging (qBEI). All groups presented thicker inferomedial than superolateral cortices. Furthermore, the superolateral site exhibited a lower osteocyte lacunar density along with lower lacunar sphericity than the inferomedial site, independent of NSA. Importantly, BMD and corresponding T-scores correlated with microstructural parameters at the inferomedial but not superolateral neck. In conclusion, we provide micromorphological evidence for fracture vulnerability of the superolateral neck, which is independent of NSA and BMD. The presented bone qualitative data provide an explanation why DXA may be insufficient to predict a substantial proportion of femoral neck fractures. STATEMENT OF SIGNIFICANCE: The femoral neck, one of the most common fracture sites, is subject to a complex loading pattern. Site-specific differences (i.e., superolateral vs. inferomedial) in bone quality influence fracture risk, but it is unclear how this relates to hip geometry and bone mineral density (BMD) measurements in vivo. Here, we examine femoral neck specimens using a variety of high-resolution imaging techniques and demonstrate impaired bone quality in the superolateral compared to the inferomedial neck. Specifically, we found impaired cortical and trabecular microarchitecture, mineralization, and osteocyte properties, regardless of neck-shaft angle. Since BMD correlated with bone quality of the inferomedial but not the superolateral neck, our results illustrate why bone densitometry may not predict a substantial proportion of femoral neck fractures.

Investigation of distal femur microarchitecture and factors influencing its deterioration: An ex vivo high-resolution peripheral quantitative computed tomography study.

While fractures of the distal femur are often considered as fragility fractures, detailed knowledge of the bone microarchitecture at this skeletal site is largely unavailable. Initial evaluation of a patient cohort with distal femur fractures showed a markedly increased occurrence in elderly women. The purpose of this study was to determine the extent to which demographic characteristics of distal femur fractures are reflected by general age- and sex-specific variations in local microarchitectural parameters. Fifty cadaveric femora were collected from 25 subjects (12 females, 13 males, age 25-97 years). A volume of interest within 3 cm proximal to the condyles was analyzed using high-resolution peripheral quantitative computed tomography (HR-pQCT), which revealed impaired trabecular and cortical bone microarchitecture in women compared to men as well as in osteoporotic compared to normal or osteopenic subjects, as classified by dual-energy X-ray absorptiometry (DXA) T-score. Linear regression analyzes showed negative associations between age and HR-pQCT parameters in women (e.g., cortical thickness -14 µm/year, 95% CI: -21 to -7 µm/year), but not in men (e.g., cortical thickness 1 µm/year, 95% CI: -12 to 14 µm/year). HR-pQCT parameters showed strong positive associations with areal bone mineral density (aBMD) determined by DXA at the hip in both sexes. Taken together, our findings suggest that female sex, advanced age, and low aBMD represent major risk factors for impaired microarchitecture at the distal femur. Both the diagnostic value of DXA for predicting distal femur fractures and the efficacy of bone-specific agents on fracture risk reduction should be investigated in the future.

Increased concentrations of conjugated bile acids are associated with osteoporosis in PSC patients.

Primary sclerosing cholangitis (PSC) is an idiopathic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of intra- and extrahepatic bile ducts. Osteoporosis is a frequent comorbidity in PSC, and we could previously demonstrate that IL17-dependent activation of bone resorption is the predominant driver of bone loss in PSC. Since we additionally observed an unexpected heterogeneity of bone mineral density in our cohort of 238 PSC patients, the present study focused on a comparative analysis of affected individuals with diagnosed osteoporosis (PSCOPO, n = 10) or high bone mass (PSCHBM, n = 7). The two groups were not distinguishable by various baseline characteristics, including liver fibrosis or serum parameters for hepatic function. In contrast, quantification of serum bile acid concentrations identified significant increases in the PSCOPO group, including glycoursodeoxycholic acid (GUDCA), an exogenous bile acid administered to both patient groups. Although cell culture experiments did not support the hypothesis that an increase in circulating bile levels is a primary cause of PSC-associated osteoporosis, the remarkable differences of endogenous bile acids and GUDCA in the serum of PSCOPO patients strongly suggest a yet unknown impairment of biliary metabolism and/or hepatic bile acid clearance in this patient subgroup, which is independent of liver fibrosis.