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ABSTRACT Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue‐nonspecific alkaline phosphatase. Adult‐onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first‐line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64‐year‐old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6‐minute walk test (525 to 606 m). The EQ‐5D‐5L index was also improved (0.757 to 0.895). Within a follow‐up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

ABSTRACT Nearly half of adult fracture patients are vitamin D deficient (serum 25‐hydroxyvitamin D [25(OH)D] levels

ABSTRACT Macrophages are important for repair of injured tissues, but their role in healing after surgical repair of musculoskeletal tissues is not well understood. We used single‐cell RNA sequencing (RNA‐seq), flow cytometry, and transcriptomics to characterize functional phenotypes of macrophages in a mouse anterior cruciate ligament reconstruction (ACLR) model that involves bone injury followed by a healing phase of bone and fibrovascular interface tissue formation that results in bone‐to‐tendon attachment. We identified a novel “surgery‐induced” highly inflammatory CD9+ IL1+ macrophage population that expresses neutrophil‐related genes, peaks 1 day after surgery, and slowly resolves while transitioning to a more homeostatic phenotype. In contrast, CX3CR1+ CCR2+ macrophages accumulated more slowly and unexpectedly expressed an interferon signature, which can suppress bone formation. Deletion of Ccr2 resulted in an increased amount of bone in the surgical bone tunnel at the tendon interface, suggestive of improved healing. The “surgery‐induced macrophages” identify a new cell type in the early phase of inflammation related to bone injury, which in other tissues is dominated by blood‐derived neutrophils. The complex patterns of macrophage and inflammatory pathway activation after ACLR set the stage for developing therapeutic strategies to target specific cell populations and inflammatory pathways to improve surgical outcomes. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Bisphosphonates have been found to be effective in preventing fragility fractures. However, their comparative effectiveness in populations at risk has yet to be defined. In light of recent clinical trials, we aimed to compare four bisphosphonates (alendronate, ibandronate, risedronate, and zoledronate) and to identify which are the most effective for the prevention of fragility fractures. This is an update of a systematic review previously published as part of a NICE HTA report. We conducted a systematic review and network meta‐analysis, updating the estimates regarding the comparative effectiveness of the aforementioned bisphosphonates. Studies identified from published and unpublished sources between 2014 and 2021 were added to the studies identified in the previous review. Screening, data extraction and risk of bias assessment were independently undertaken by two reviewers. Outcomes were fractures, femoral neck bone mineral density (BMD), mortality, and adverse events. We identified 25 additional trials, resulting in a total population of 47,007 participants. All treatments had beneficial effects on fractures versus placebo with zoledronate being the most effective treatment in preventing vertebral fractures (hazard ratio [HR] 0.38; 95% credibility interval [CrI], 0.28–0.49). Zoledronate (HR 0.71; 95% CrI, 0.61–0.81) and risedronate (HR 0.70; 95% CrI, 0.53–0.84) were found to be the most effective treatments in preventing nonvertebral fractures. All treatments were associated with increases in femoral neck BMD versus placebo with zoledronate being the most effective treatment mean difference (MD 4.02; 95% CrI, 3.2–4.84). There was a paucity of data regarding hip and wrist fractures. Depending on its cost‐effectiveness, zoledronate could be considered a first‐line option for people at increased risk of fragility fractures. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Hypophosphatasia (HPP) is caused by loss‐of‐function mutations in ALPL resulting in decreased alkaline phosphatase (ALP) activity. Metatarsal stress fracture (MSF) is a common clinical feature of hypophosphatasia in adults. In this study, the primary objectives were to determine whether new cases of ALPL variants could be identified in patients with MSF and who also had serum ALP concentration below the reference range and to phenotype their clinical course. Electronic health records were queried for adult patients with MSF using International Classification of Disease codes (ICD‐9, ICD‐10CM) and ALP measurements. Patients with ALP levels below the normal limit were invited to receive mutational analysis of ALPL and to complete the following surveys: the Short Form 36 version 2 (SF36v2), the Brief Pain Inventory‐Short Form (BPI), and the Health Assessment Questionnaire Disability Index (HAQ‐DI). Cases with and controls without ALPL pathogenic variants were compared by survey scores and clinical variables relevant to fracture. In 1611 patients with MSF presenting to a podiatry clinic (10/1/2011–10/1/2017), 937 had ALP measurement, of whom 13 (1.4%) had ALP levels below the lower normal limit. In eight patients consenting to participate, two had heterozygous pathogenic ALPL variants. ALPL variants were found in 2 of 1611 patients (0.12%) with MSF, 2 patients of 937 (0.21%) in those with MSF and any ALP measurement, and 2 of 13 patients (15%) in MSF and decreased ALP level. Cases versus controls rated lower scores on eight of eight SF36v2 scales (range, 0–100); higher scores for worst pain (8.0 vs. 0.8) and average pain (6.0 vs. 0.7) on the BPI (range, 0–10); and higher standard disability score (1.4 vs. 0) on the HAQ‐DI (range, 0–3). These data provide proof‐of‐concept for HPP case identification in patients presenting to a podiatry clinic with MSF, suggesting a search for historically low ALP levels may be a useful step for consideration of HPP diagnosis, and supports a prospective study to determine an optimal case‐finding strategy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Clinical evaluation of fracture healing is often limited to an assessment of fracture bridging from radiographic images, without consideration for other aspects of bone quality. However, recent advances in HRpQCT offer methods to accurately monitor microstructural bone remodeling throughout the healing process. In this study, local bone formation and resorption were investigated during the first year post fracture in both the fractured (n = 22) and contralateral (n = 19) radii of 34 conservatively treated patients (24 female, 10 male) who presented with a unilateral radius fracture at the Innsbruck University Hospital, Austria. HRpQCT images and clinical metrics were acquired at six time points for each patient. The standard HRpQCT image acquisition was captured for all radii, with additional distal and proximal image acquisitions for the fractured radii. Measured radial bone densities were isolated with a voxel‐based mask and images were rigidly registered to images from the previous imaging session using a pyramid‐based approach. From the registered images, bone formation and resorption volume fractions were quantified for multiple density‐based thresholds and compared between the fractured and contralateral radius and relative to demographics, bone morphometrics, and fracture metrics using regression. Compared with the contralateral radius, both bone formation and resorption were significantly increased in the fractured radius throughout the study for nearly all evaluated thresholds. Higher density cortical bone formation continually increased throughout the duration of the study and was significantly greater than resorption during late‐stage healing in both the fractured and intact regions of the radius. With the small and diverse study population, only weak relationships between fracture remodeling and patient‐specific parameters were unveiled. However this study provides methods for the analysis of local bone remodeling during fracture healing and highlights relevant considerations for future studies, specifically that remodeling postfracture is likely to continue beyond 12‐months postfracture. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background: Mesenchymal stem/stromal cells (MSC) have been employed successfully in immunotherapy and regenerative medicine, but their therapeutic potential is reduced considerably by the ischemic environment that exists after transplantation. The assumption that preconditioning MSC to promote quiescence may result in increased survival and regenerative potential upon transplantation is gaining popularity. Methods: The purpose of this work was to evaluate the anti-inflammatory and regenerative effects of human bone marrow MSC (hBM-MSC) and their extracellular vesicles (EVs) grown and isolated in a serum-free medium, as compared to starved hBM-MSC (preconditioned) in streptozotocin-induced diabetic fractured male C57BL/6J mice. Results: Blood samples taken four hours and five days after injection revealed that cells, whether starved or not, generated similar plasma levels of inflammatory-related cytokines but lower levels than animals treated with EVs. Nonetheless, starved cells prompted the highest production of IL-17, IL-6, IL-13, eotaxin and keratinocyte-derived chemokines and induced an earlier soft callus formation and mineralization of the fracture site compared to EVs and regularly fed cells five days after administration. Conclusions: Preconditioning may be crucial for refining and defining new criteria for future MSC therapies. Additionally, the elucidation of mechanisms underpinning an MSC’s survival/adaptive processes may result in increased cell survival and enhanced therapeutic efficacy following transplantation.

ABSTRACT Delayed union or nonunion are relatively rare complications after fracture surgery, but when they do occur, they can result in substantial morbidity for the patient. In many cases, the etiology of impaired fracture healing is uncertain and attempts to determine the molecular basis for delayed union and nonunion formation have been limited. Prospectively isolating skeletal stem cells (SSCs) from fracture tissue samples at the time of surgical intervention represent a feasible methodology to determine a patient's biologic risk for compromised fracture healing. This report details a case in which functional in vitro readouts of SSCs derived from human fracture tissue at time of injury predicted a poor fracture healing outcome. This case suggests that it may be feasible to stratify a patient's fracture healing capacity and predict compromised fracture healing by prospectively isolating and analyzing SSCs during the index fracture surgery. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Leucine‐rich repeat‐containing G protein‐coupled receptors (LGRs) are adult stem cell markers that have been described across various stem cell niches, and expression of LGRs and their corresponding ligands (R‐spondins) has now been reported in multiple bone‐specific cell types. The skeleton harbors elusive somatic stem cell populations that are exceedingly compartment‐specific and under tight regulation from various signaling pathways. Skeletal progenitors give rise to multiple tissues during development and during regenerative processes of bone, requiring postnatal endochondral and intramembranous ossification. The relevance of LGRs and the LGR/R‐spondin ligand interaction in bone and tooth biology is becoming increasingly appreciated. LGRs may define specific stem cell and progenitor populations and their behavior during both development and regeneration, and their role as Wnt‐associated receptors with specific ligands poses these proteins as unique therapeutic targets via potential R‐spondin agonism. This review seeks to outline the current literature on LGRs in the context of bone and its associated tissues, and points to key future directions for studying the functional role of LGRs and ligands in skeletal biology. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Abstract Weight‐bearing physical activity may decrease or prevent bone deterioration after hip fracture. This study investigated the effects of a home‐based physical rehabilitation program on tibial bone traits in older hip fracture patients. A population‐based clinical sample of men and women operated for hip fracture (mean age 80 years, 78% women) was randomly assigned into an intervention (n = 40) and a standard care control group (n = 41) on average 10 weeks postfracture. The intervention group participated in a 12‐month home‐based rehabilitation intervention, including evaluation and modification of environmental hazards, guidance for safe walking, nonpharmacological pain management, motivational physical activity counseling, and a progressive, weight‐bearing home exercise program comprising strengthening exercises for the lower legs, balance training, functional exercises, and stretching. All participants received standard care. Distal tibia (5% proximal to the distal end plate) compressive bone strength index (BSI; g2/cm4), total volumetric BMD (vBMDTOT; mg/cm3), and total area (CSATOT; mm2), as well as midtibia (55%) strength–strain index (SSI; mm3), cortical vBMD (vBMDCO; mg/cm3), and ratio of cortical to total area (CSACO/CSATOT) were assessed in both legs by pQCT at baseline and at 3, 6, and 12 months. The intervention had no effect (group × time) on either the distal or midtibial bone traits. At the distal site, BSI of both legs, vBMDTOT of the fractured side, and CSATOT of the nonfractured side decreased significantly over time in both groups 0.7% to 3.1% (12 months, p