Cost-effectiveness of implant movement analysis in aseptic loosening after hip replacement: a health-economic model.

OBJECTIVE: To investigate the cost-effectiveness of using Implant Movement Analysis (IMA) to follow up suspected aseptic loosening when the diagnosis after an initial X-ray is not conclusive, compared with a diagnostic pathway with X-ray follow-up. METHODS: A health-economic model in the form of a decision tree was developed using quality-adjusted life years (QALY) from the literature, cost-per-patient data from a university hospital and the probabilities of different events from expert physicians' opinions. The base case incremental cost-effectiveness ratio (ICER) was compared with established willingness-to-pay thresholds and sensitivity analyses were performed to account for assumptions and uncertainty. RESULTS: The base case ICER indicated that the IMA pathway was cost effective (SEK 99,681, compared with the SEK 500,000 threshold). In the sensitivity analysis, the IMA pathway remained cost effective during most changes in parameters. ICERs above the threshold value occurred in cases where a larger or smaller proportion of people receive immediate surgery. CONCLUSION: A diagnostic pathway using IMA after an inconclusive X-ray for suspected aseptic loosening was cost effective compared with a pathway with X-ray follow-up.

Computed tomography-based radiostereometric analysis in orthopedic research: practical guidelines.

Early implant migration is an indicator of the long-term survival/failure of implants. CT-based radio-stereometric analysis (CT-RSA) is a precise method for measuring and visualizing implant migration in vivo using image processing of CT scans. This makes the method widely applicable to orthopedic researcher. Since its development in the early 2000s, CT-RSA has benefited from breakthroughs in CT and computing technology. These advancements have allowed for the acquisition of images with higher resolution at a much lower radiation dose. As a result, the measurement precision of CT-RSA is now comparable to that of the current gold standard technology while still compatible with most ethical considerations regarding radiation exposure. In this review we present bests practices for the successful execution of CT-RSA research projects. These practices are based on experience from projects on the hip, knee, shoulder, lower back, cervical spine, foot, pelvis, and wrist.

Inducible displacement CT increases the diagnostic accuracy of aseptic loosening in primary total hip arthroplasty.

BACKGROUND AND PURPOSE: Inducible displacement CT compares 2 CTs acquired in series but with alternated rotation of the femur. This provides visual and quantitative clues as to the mechanical situation, i.e., loosening, of a total hip arthroplasty. We report the accuracy of this method as well as the experience of integrating it into a clinical workflow. PATIENTS AND METHODS: This was a retrospective single centre study of 72 cases of suspected aseptic loosening were the surgeon after reviewing a standard plain radiograph saw a need for more information. The displacement CT and plain radiograph were compared either to intraoperative findings or a 1-3 year follow up questionnaire for patients that did not have revision surgery. Patients reporting degradation in status since the time of the displacement CT were called for a follow up plain radiograph. Sensitivity and specificity were assessed, and user experience gathered. RESULTS: Of 72 enrolled patients 15 were lost to follow up. Of the remaining 57, 17 were judged by in-traoperative findings or follow-up to have had loose implants. For plain radiography the sensitivity and specificity were 59% (95% CI 35-82) and 85% (74-96). For displacement CT the corresponding values were 77% (56-97), and 100% (100-100) respectively. The tool was adaptable to clinical routine. CONCLUSION: Displacement CT with alternated rotations of the femur is a viable option to improve the diagnostic process for identifying aseptic loosening in a total hip arthroplasty.

Adverse Events due to Lack of Precision in Total Hip Arthroplasty: The Potential of Provocation-Based CT for Diagnosis of Implant Loosening.

Adverse events in total hip replacement (THR) may have several origins, one being lack of precision in diagnosis and/or during surgery. This study describes the pattern and frequency of avoidable injuries in THR and the potential value of a new tool for early diagnosis of implant loosening. This retrospective study was based on all (n = 1 456) settled claims regarding THR in the Swedish National Patient Insurance database from 2010 to 2017. The claims and medical records were analyzed for root causes, with special focus on adverse events where lack of precision could be the cause. In a second stage, we assessed in 10 patients (20 implants) the diagnostic precision of a new software tool based on provocation-CT. These were all patients where the implant loosening diagnosis was deemed as inconclusive after a first plain X-ray. The findings from the provocation-CT and plain X-ray were compared to the surgical findings at revision. While 3 of 20 implants were correctly diagnosed with plain X-ray, for dynamic CT, this number was 14 of 20 implants. The retrospective study showed that the most common types of injuries were infections (34%), nerve injury (29%), mechanical problems (14.5%), dislocation (6%), and miscellaneous complications (16.5%). Of the patients with mechanical complications, one-third had aseptic implant loosening. Statement of clinical significance: we estimated that almost 200 patients in our registry study had mechanical complications after THR, mainly implant loosening. A third of these could potentially have been diagnosed and treated if CT examination with a dedicated image analysis tool to assess implant loosening after THR had been available.

Precision of CT-based micromotion analysis is comparable to radiostereometry for early migration measurements in cemented acetabular cups.

Background and purpose - CT (computed tomography) based methods have lately been considered an alternative to radiostereometry (RSA) for assessing early implant migration. However, no study has directly compared the 2 methods in a clinical setting. We estimated the precision and effective radiation dose of a CT-based method and compared it with marker-based RSA in 10 patients with hip arthroplasty.Patients and methods - We included 10 patients who underwent total hip replacement with a cemented cup. CT and RSA double examinations were performed postoperatively, and precision and effective dose data were compared. The CT data was analyzed with CT micromotion analysis (CTMA) software both with and without the use of bone markers. The RSA images were analyzed with RSA software with the use of bone markers.Results - The precision of CTMA with bone markers was 0.10-0.16 mm in translation and 0.31°-0.37° in rotation. Without bone markers, the precision of CTMA was 0.10-0.16 mm in translation and 0.21°-0.31° in rotation. In comparison, the precision of RSA was 0.09-0.26 mm and 0.43°-1.69°. The mean CTMA and RSA effective dose was estimated at 0.2 mSv and 0.04 mSv, respectively.Interpretation - CTMA, with and without the use of bone markers, had a comparable precision to RSA. CT radiation doses were slightly higher than RSA doses but still at a considerably low effective dose.

The anatomical SP-CL stem demonstrates a non-progressing migration pattern in the first year: a low dose CT-based migration study in 20 patients.

Background and purpose - RSA is the gold standard for evaluation of early implant migration. We report the results of a new CT-based method Sectra CT micromotion analysis (CTMA) applied to assess the migration pattern in 20 patients in the 1st year after surgery, both with and without the use of tantalum beads in the bone. The patients had an SP-CL anatomical stem that uses an S-shape, designed to better fit the curvature of the femur. Patients and methods - 20 THA patients (mean age 61 years, 10 female) received SP-CL stems, tantalum markers in the femur, and low-dose CT scans at 1 day, 3 months and 12 months postoperatively. In addition, precision as well as inter- and intra-observer variability of the 12-month migration was measured. Results - The 3-month subsidence was median 0.5 mm (95% CI 0.3-1.0) and the internal rotation 1.8° (CI 0.9-2.6). At 12 months the corresponding values were 0.6 (CI 0.3-1.6) mm and 1.9° (CI 0.8-2.4). Precision was 0.1 to 0.3 mm and 0.1° to 0.4° at 3 and 12 months. Intra- and inter- observer variability yielded R-values averaging 0.96 and 0.98. Interpretation - The migration mainly took place during the 1st 3 months, in line with other uncemented stems. The number of patients with subsidence over 2 mm in the first year (5) might be due to the design of the prosthesis with an anatomical shape. Alternatively, our results might indicate a challenge when choosing the correct size for these new anatomical stems. CTMA provided precise and highly repeatable measurements of migration without the need for tantalum markers.

Low-dose CT-based implant motion analysis is a precise tool for early migration measurements of hip cups: a clinical study of 24 patients.

Background and purpose - Early implant migration is known to be a predictive factor of clinical loosening in total hip arthroplasty (THA). Radiostereometric analysis (RSA) is the gold standard used to measure early migration in patients. However, RSA requires costly, specialized imaging equipment and the image process is complex. We determined the precision of an alternative, commercially available, CT method in 3 ongoing clinical THA studies, comprising 3 different cups.Materials and methods - 24 CT double examinations of 24 hip cups were selected consecutively from 3 ongoing prospective studies: 2 primary THA (1 cemented and 1 uncemented) and 1 THA (cemented) revision study. Precision of the CT-based implant motion analysis (CTMA) system was calculated separately for each study, using both the surface anatomy of the pelvis and metal beads placed in the pelvis.Results - For the CTMA analysis using the surface anatomy of the pelvis, the precision ranged between 0.07 and 0.31 mm in translation and 0.20° and 0.39° for rotation, respectively. For the CTMA analysis using beads the precision ranged between 0.08 and 0.20 mm in translation and between 0.20° and 0.43° for rotations. The radiation dose ranged between 0.2 and 2.3 mSv.Interpretation - CTMA achieved a clinically relevant and consistent precision between the 3 different hip cups studied. The use of different hip cup types, different CT scanners, or registration method (beads or surface anatomy) had no discernible effect on precision. Therefore, CTMA without the use of bone markers could potentially be an alternative to RSA to measure early migration.

Accuracy and precision of a CT method for assessing migration in shoulder arthroplasty: an experimental study.

BACKGROUND: Radiostereometric analysis (RSA) is the gold standard to measure early implant migration which is a predictive factor for implant survival. PURPOSE: To validate an alternative computed tomography (CT) technique to measure implant migration in shoulder arthroplasty. MATERIAL AND METHODS: A cadaver proximal humerus and a scapula, which had tantalum beads incorporated within them, were prepared to accept a short-stemmed humeral component and a two-pegged glenoid component of a commercial total shoulder arthroplasty (TSA) system. A five degree of freedom micrometer and goniometer equipped rig was used to translate and rotate the implant components relative to the respective bone to predetermined positions. Double CT examinations were performed for each position and CT motion analysis software (CTMA) was used to assess these movements. The accuracy and precision of the software was estimated using the rig's micrometers and goniometers as the gold standard. The technique's effective dose was also assessed. RESULTS: The accuracy was in the range of 0.07-0.23 mm in translation and 0.22-0.71° in rotation. The precision was in the range of 0.08-0.15 mm in translation and 0.23-0.54° in rotation. The mean effective dose for the CT scans was calculated to be 0.27 mSv. CONCLUSION: In this experimental setting, accuracy, precision, and effective dose of the CTMA technique were found to be comparable to that of RSA. Therefore, we believe clinical studies are warranted to determine if CTMA is a suitable alternative to traditional RSA for migration measurements in TSA.

Volume fusion of CT images to measure femoral symmetricity.

PURPOSE: Pre-operative planning is widely used in orthopaedic surgery. In case of trauma with fracture or previous injury with malunion, the contralateral extremity is used as a surrogate for planning with an assumption of symmetry between sides. The aim of this study was to investigate femoral symmetricity in human adults. METHODS: Ten randomly selected lower extremity computerized tomography (CT) images were analyzed for femur symmetry using 3D Trauma and CT motion analysis (CTMA). Mirrored images of the left femur were created using the right as a template. The 3D images from each side were merged, and translational and rotational differences reported. RESULTS: There were no statistically significant differences between mirrored images of the left and right femurs. Differences in rotation and translation of bony segmentation showed a greater variation in internal and external rotation of the distal femur (CI - 0.7° to 4.9°) compared to varus/valgus (CI - 1.3° to 0.8°) or flexion/extension (CI - 0.5° to 0.6°), though none of these differences were significant. CONCLUSION: The left and right femurs of healthy adults are symmetrical. Pre-operative templating relying on the contralateral healthy femur is encouraged.

Shining dead bone-cause for cautious interpretation of [18F]NaF PET scans.

Background and purpose - [18F]Fluoride ([18F]NaF) PET scan is frequently used for estimation of bone healing rate and extent in cases of bone allografting and fracture healing. Some authors claim that [18F]NaF uptake is a measure of osteoblastic activity, calcium metabolism, or bone turnover. Based on the known affinity of fluoride to hydroxyapatite, we challenged this view. Methods - 10 male rats received crushed, frozen allogeneic cortical bone fragments in a pouch in the abdominal wall on the right side, and hydroxyapatite granules on left side. [18F]NaF was injected intravenously after 7 days. 60 minutes later, the rats were killed and [18F]NaF uptake was visualized in a PET/CT scanner. Specimens were retrieved for micro CT and histology. Results - MicroCT and histology showed no signs of new bone at the implant sites. Still, the implants showed a very high [18F]NaF uptake, on a par with the most actively growing and remodeling sites around the knee joint. Interpretation - [18F]NaF binds with high affinity to dead bone and calcium phosphate materials. Hence, an [18F]NaF PET/CT scan does not allow for sound conclusions about new bone ingrowth into bone allograft, healing activity in long bone shaft fractures with necrotic fragments, or remodeling around calcium phosphate coated prostheses.

Marrow compartment contribution to cortical defect healing.

Background and purpose - Healing of shaft fractures is commonly described as regards external callus. We wanted to clarify the role of the bone marrow compartment in the healing of stable shaft fractures. Patients and methods - A longitudinal furrow was milled along the longitudinal axis of the femoral shaft in mice. The exposed bone marrow under the furrow was scooped out. The mice were then randomized to no further treatment, or to receiving 2 silicone plugs in the medullary canal distal and proximal to the defect. The plugs isolated the remaining marrow from contact with the defect. Results were studied with histology and flow cytometry. Results - Without silicone plugs, the marrow defect was filled with new bone marrow-like tissue by day 5, and new bone was seen already on day 10. The new bone was seen only at the level of the cortical injury, where it seemed to form simultaneously in the entire region of the removed cortex. The new bone seemed not to invade the marrow compartment, and there was a sharp edge between new bone and marrow. The regenerated marrow was similar to uninjured marrow, but contained considerably more cells. In the specimens with plugs, the marrow compartment was either filled with loose scar tissue, or empty, and there was only minimal bone formation, mainly located around the edges of the cortical injury. Interpretation - Marrow regeneration in the defect seemed to be a prerequisite for normal cortical healing. Shaft fracture treatment should perhaps pay more attention to the local bone marrow.

Temporal role of macrophages in cancellous bone healing.

Macrophages are important phagocytosing and cytokine producing cells with effects on fracture healing. We used clodronate-containing liposomes to reduce the number of macrophages, in order to study their role in the early phases of cancellous bone healing. Holes were drilled bilaterally into the cancellous bone of the proximal metaphysis of the tibia of 60 mice. A screw was inserted in the hole in the right tibia. The day of surgery was day 0. Clodronate-containing liposomes were injected intraperitoneally as a single injection either day -4 or -1 (before surgery) or day 1 or 3 (after surgery). A control group underwent surgery as above, but received no clodronate. The mice were killed day 7. The mechanical quality of the new formed cancellous bone holding the screw was evaluated by a pull-out test. The contents of the drill hole in the left tibia was analyzed by microCT. Another set of 20 mice received a drill hole in the metaphysis of the right tibia, and were given either clodronate or saline injections days -3 and -2. The animals were killed day 1 and 3. Flow cytometry was used to analyze the composition of macrophage subpopulations in the regenerating tissue. Flow cytometry showed that clodronate injections day -3 and -2 led to a decrease in mature monocytes day 1 together with an increase in immature monocytes. On day 3 this effect had mostly disappeared, suggesting that the effect of the injections lasted 3 to 5days. Mechanical testing revealed that the injections prior to surgery decreased the strength of the new formed bone, holding the screw, by about half. Bone density in the drill hole was similarly reduced. In contrast, the injections given day 1 and 3 had smaller and statistically insignificant effects. Since their depletion at later time points failed to produce a significant effect, it seems that the role of macrophages in cancellous bone is most crucial during the first two days after trauma.

Isolated metaphyseal injury influences unrelated bones.

Background and purpose - Fracture healing involves different inflammatory cells, some of which are not part of the traditional bone field, such as B-cells and cytotoxic T-cells. We wanted to characterize bone healing by flow cytometry using 15 different inflammatory cell markers in a mouse model of metaphyseal injury, and incidentally discovered a previously unknown general skeletal reaction to trauma. Material and methods - A bent needle was inserted and twisted to traumatize the cancellous bone in the proximal tibia of C57/Bl6 female mice. This is known to induce vivid bone formation locally in the marrow compartment. Cells were harvested from the injured region, the uninjured contralateral tibia, and the humerus. The compositions of the immune cell populations were compared to those in untraumatized control animals. Results - Tibial metaphyseal injury led to substantial changes in the cell populations over time. Unexpectedly, similar changes were also seen in the contralateral tibia and in the humerus, despite the lack of local trauma. Most leukocyte subsets were affected by this generalized reaction. Interpretation - A relatively small degree of injury to the proximal tibia led to systemic changes in the immune cell populations in the marrow of unrelated bones, and probably in the entire skeleton. The few changes that were specific for the injury site appeared to relate to modulatory functions.

Earlier effect of alendronate in mouse metaphyseal versus diaphyseal bone healing.

Healing of injured cancellous bone is characterized by a transient stage of rapid bone formation throughout the traumatized bone volume, often followed by similarly rapid resorption. This is different from the slower diaphyseal healing via an external callus. We, therefore, hypothesized that antiresorptive treatment might have an earlier positive effect in cancellous bone healing than in diaphyseal fractures. One hundred and twenty-three male C57bl6 mice received either an internally stabilized diaphyseal osteotomy of the femur or a screw inserted into the tibial metaphysis. The mice were randomized to daily alendronate injections (200 µg/kg/day), or control injections, and killed for mechanical testing after 14, 21, or 28 days. The hypothesis was tested by a three-way Anova (time, site, and drug). The ultimate force was increased by bisphosphonate treatment in both models. There was a significant interaction between time, site, and drug (p < 0.001) so that the full positive effect of alendronate was evident in the metaphysis at 14 days, but first after 28 days in the diaphysis. While the early effect in the metaphysis might be translated into earlier healing, the late effect in the diaphysis was due to delayed remodeling of the callus, which might have less clinical importance. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:793-799, 2017.

Inter-trabecular bone formation: a specific mechanism for healing of cancellous bone.

Background and purpose - Studies of fracture healing have mainly dealt with shaft fractures, both experimentally and clinically. In contrast, most patients have metaphyseal fractures. There is an increasing awareness that metaphyseal fractures heal partly through mechanisms specific to cancellous bone. Several new models for the study of cancellous bone healing have recently been presented. This review summarizes our current knowledge of cancellous fracture healing. Methods - We performed a review of the literature after doing a systematic literature search. Results - Cancellous bone appears to heal mainly via direct, membranous bone formation that occurs freely in the marrow, probably mostly arising from local stem cells. This mechanism appears to be specific for cancellous bone, and could be named inter-trabecular bone formation. This kind of bone formation is spatially restricted and does not extend more than a few mm outside the injured region. Usually no cartilage is seen, although external callus and cartilage formation can be induced in meta-physeal fractures by mechanical instability. Inter-trabecular bone formation seems to be less sensitive to anti-inflammatory treatment than shaft fractures. Interpretation - The unique characteristics of inter-trabecular bone formation in metaphyseal fractures can lead to differences from shaft healing regarding the effects of age, loading, or drug treatment. This casts doubt on generalizations about fracture healing based solely on shaft fracture models.

Influence of a lower leg brace on traction force in healthy and ruptured Achilles tendons.

BACKGROUND: we investigated how ruptured Achilles tendons are loaded in a brace. There is an ongoing discussion whether patients should be recommended to bear weight on the injured limb. However, little is known about the effects of bracing on tensional loading of the healing Achilles tendon: it is uncertain if load-bearing actually stresses the Achilles tendon inside a brace. METHODS: we measured plantar flexion moment inside the brace, in order to estimate tensional loading of the tendon, by use of an insole with pressure transducers. RESULTS: after wearing the brace for 1 hour, young healthy individuals reduced their maximum flexion moment during gait by half. Patients with Achilles tendon rupture showed no measurable flexion moment during gait with the brace, 4 or 7 weeks after injury. Only when specifically instructed, they could produce a considerable plantar flexion moment. We noted that gait speed with the brace at 4 weeks correlated with a heel-raise functional test at 1 year: the higher the spontaneous gait speed, the less the functional difference between the injured and the uninjured leg (r(2)=0.68; p=0.002). CONCLUSION: the correlation with gait speed suggests that the patients' general physical aptness has an impact on the end result.

Experimental models for cancellous bone healing in the rat.

BACKGROUND AND PURPOSE: Cancellous bone appears to heal by mechanisms different from shaft fracture healing. There is a paucity of animal models for fractures in cancellous bone, especially with mechanical evaluation. One proposed model consists of a screw in the proximal tibia of rodents, evaluated by pull-out testing. We evaluated this model in rats by comparing it to the healing of empty drill holes, in order to explain its relevance for fracture healing in cancellous bone. To determine the sensitivity to external influences, we also compared the response to drugs that influence bone healing. METHODS: Mechanical fixation of the screws was measured by pull-out test and related to the density of the new bone formed around similar, but radiolucent, PMMA screws. The pull-out force was also related to the bone density in drill holes at various time points, as measured by microCT. RESULTS: The initial bone formation was similar in drill holes and around the screw, and appeared to be reflected by the pull-out force. Both models responded similarly to alendronate or teriparatide (PTH). Later, the models became different as the bone that initially filled the drill hole was resorbed to restore the bone marrow cavity, whereas on the implant surface a thin layer of bone remained, making it change gradually from a trauma-related model to an implant fixation model. INTERPRETATION: The similar initial bone formation in the different models suggests that pull-out testing in the screw model is relevant for assessment of metaphyseal bone healing. The subsequent remodeling would not be of clinical relevance in either model.

Anti-RANKL treatment improves screw fixation in cancellous bone in rats.

Bisphosphonates improve implant fixation in randomised clinical trials of knee prostheses, hip prostheses and dental implants. However, a limited amount of bone resorption is required for bisphosphonates to exert an effect. Anti-RANKL treatment does not have this limitation, and we therefore tested whether if they might be more effective for improvement of implant fixation. This is of interest, as anti-RANKL treatment with denosumab is now in common clinical use. Male SD rats received a stain-less steel screw in the right proximal tibia and a drill hole in the left (n = 42). They were randomised to subcutaneous injections of either alendronate (20 µg/kg/day), alendronate (200 µg/kg/day), osteoprotegerin with an Fc tag (OPG-Fc; 8 mg/kg, twice weekly), or saline control. After 4 weeks, the fixation of the steel screw was measured by pull-out test. The tibia with the drill hole was evaluated with µCT. OPG-Fc increased the pull-out force compared to saline controls by 153% (p < 0.001). There was no significant difference between OPG-Fc and the alendronate groups. OPG-Fc increased the bone density (BV/TV) in the previous drill hole compared to controls 7-fold (p < 0.001). This increase was higher than with any alendronate dose (p < 0.001). OPG-Fc increased the bone density of the L5 vertebral body, but there was no significant difference between OPG-Fc and alendronate. Our results suggest that screw fixation in cancellous bone can be dramatically improved by an anti-RANKL agent. The effect was comparable to very high bisphosphonate doses. Screw insertion in cancellous bone elicits a metaphyseal fracture healing response, and our findings might be relevant not only for implant fixation, but also for fracture healing in cancellous bone.

Different effects of indomethacin on healing of shaft and metaphyseal fractures.

BACKGROUND AND PURPOSE: NSAIDs are commonly used in the clinic, and there is a general perception that this does not influence healing in common types of human fractures. Still, NSAIDs impair fracture healing dramatically in animal models. These models mainly pertain to fractures of cortical bone in shafts, whereas patients more often have corticocancellous fractures in metaphyses. We therefore tested the hypothesis that the effect of an NSAID is different in shaft healing and metaphyseal healing. METHODS: 26 mice were given an osteotomy of their left femur with an intramedullary nail. 13 received injections of indomethacin, 1 mg/kg twice daily. After 17 days of healing, the femurs were analyzed with 3-point bending and microCT. 24 other mice had holes drilled in both proximal tibias, to mimic a stable metaphyseal injury. A screw was inserted in the right tibial hole only. After 7 days of indomethacin injections or control injections, screw fixation was measured with mechanical pull-out testing and the side without a screw was analyzed with microCT. RESULTS: In the shaft model, indomethacin led to a 35% decrease in force at failure (95% CI: 14-54). Callus size was reduced to a similar degree, as seen by microCT. Metaphyseal healing was less affected by indomethacin, as no effect on pull-out force could be seen (95% CI: -27 to 17) and there was only a small drop in new bone volume inside the drill hole. The difference in the relative effect of indomethacin between the 2 models was statistically significant (p = 0.006). INTERPRETATION: Indomethacin had a minimal effect on stable metaphyseal fractures, but greatly impaired healing of unstable shaft fractures. This could explain some of the differences found between animal models and clinical experience.

Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.

The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.