The Effect of C2 Muscular Exposure Technique on Radiographic and Clinical Outcomes After C2-T2 Posterior Cervical Fusion.

STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: To determine whether the C2 exposure technique was a predictor of change in cervical alignment and patient-reported outcomes measures (PROMs) after posterior cervical decompression and fusion (PCDF) for degenerative indications. BACKGROUND: In PCDF handling of the C2 posterior paraspinal musculature during the operative approach varies by surgeon technique. To date, no studies have investigated whether maintenance of the upper cervical semispinalis cervicis attachments as compared with complete reflection of upper cervical paraspinal musculature from the posterior bony elements is associated with superior radiographic and clinical outcomes after PCDF. PATIENTS AND METHODS: All adult patients who underwent C2-T2 PCDF for myelopathy or myeloradiculopathy at multi-institutional academic centers between 2013 and 2020 were retrospectively identified. Patients were dichotomized by the C2 exposure technique into semispinalis preservation or midline muscular reflection groups. Preoperative and short and long-term postoperative radiographic outcomes (upper cervical alignment, global alignment, and fusion status) and PROMs (Visual Analog Scale-Neck, Neck Disability Index, and Short Form-12) were collected. Univariate analysis compared patient factors, radiographic measures, and PROMs across C2 exposure groups. RESULTS: A total of 129 patients met the inclusion/exclusion criteria (73 muscle preservation and 56 muscle reflection). Patients in the muscular preservation group were on average younger (P= 0.005) and more likely to have bone morphogenic protein (P< 0.001) and C2 pars screws (P= 0.006) used during surgery. Preoperative to postoperative changes in C2 slope, C2 tilt, C2-C3 segmental lordosis, C2-C3 listhesis, C0-C2 Cobb angle, proximal junctional kyphosis, ADI, C1 lamina-occiput distance, C2 sagittal vertical axis, C2-C7 lordosis, and PROMs at all follow-up intervals did not vary significantly by C2 exposure technique. Likewise, there were no significant differences in fusion status, C2-C3 pseudoarthrosis, C2 screw loosening, and complication and revision rates between C2 exposure groups. CONCLUSIONS: Preservation of C2 semispinalis attachments versus muscular reflection did not significantly impact cervical alignment, clinical outcomes, or proximal junction complications in long-segment PCDF. LEVEL OF EVIDENCE: Level III.

The effect of C2 screw type on perioperative outcomes and long-term stability after C2-T2 posterior cervical decompression and fusion.

PURPOSE: To determine if C2 pedicle versus pars screw type predicts change in fusion status, C2 screw loosening, cervical alignment, and patient-reported outcomes measures (PROMs) after C2-T2 posterior cervical decompression and fusion (PDCF). METHODS: All adult patients who underwent C2-T2 PCDF for myelopathy or myeloradiculopathy between 2013-2020 were retrospectively identified. Patients were dichotomized by C2 screw type into bilateral C2 pedicle and bilateral C2 pars screw groups. Preoperative and short- and long-term postoperative radiographic outcomes and PROMs were collected. Univariate and multivariate analysis compared patient factors, fusion status, radiographic measures, and PROMs across groups. RESULTS: A total of 159 patients met the inclusion/exclusion criteria (76 bilateral pedicle screws, 83 bilateral pars screws). Patients in the C2 pars relative to C2 pedicle screw group were on average more likely to have bone morphogenic protein (p = 0.001) and four-millimeter diameter rods utilized intraoperatively (p = 0.033). There were no significant differences in total construct and C2-3 fusion rate, C2 screw loosening, or complication and revision rates between C2 screw groups in univariate and regression analysis. Changes in C2 tilt, C2-3 segmental lordosis, C0-2 Cobb angle, proximal junctional kyphosis, atlanto-dens interval, C1 lamina-occiput distance, C2 sagittal vertical axis, C2-7 lordosis, and PROMs at all follow-up intervals did not vary significantly by C2 screw type. CONCLUSION: There were no significant differences in fusion status, hardware complications, and radiographic and clinical outcomes based on C2 screw type following C2-T2 PCDF. Accordingly, intraoperative usage criteria can be flexible based on patient vertebral artery positioning and surgeon comfort level.

Complications of operatively treated distal radial fractures.

Distal radial fractures represent the most common fractures of the upper extremity. Operative treatment is performed for approximately one-third of distal radial fractures in the adult population. Complications following operative treatment of distal radial fractures vary depending on the treatment modality and can be stratified into preoperative and postoperative complications. Complications can occur in the near, intermediate and long term. The most common complications seen are tendon irritation and rupture, chronic regional pain syndrome (CRPS), carpal tunnel syndrome, ulnar or radial neuropathy, compartment syndrome, malunion, inadequate fixation or loss of fixation, symptomatic hardware, post-traumatic arthritis, stiffness and infection. Careful planning, treatment and patient selection can help to mitigate these complications.Level of evidence: V.

Management of giant cell tumors of the distal radius.

Background: The distal radius is the most common location for giant cell tumors (GCT) in the upper extremity. Treatment should balance the goals of maximizing function and minimizing recurrence and other complications. Given the complexity in surgical treatment, various techniques have been described without clear standards of treatment. Objectives: The purpose of this review is to provide an overview of evaluation of patients presenting with GCT of the distal radius, discuss management, and provide an updated summary on outcomes of treatment options. Conclusion: Surgical treatment should consider tumor Grade, involvement of the articular surface, and patient-specific factors. Options include intralesional curettage and en bloc resection with reconstruction. Within reconstruction techniques, radiocarpal joint preserving and sparing procedures can be considered. Campanacci Grade 1 tumors can be successfully treated with joint preserving procedures, whereas for Campanacci Grade 3 tumors consideration should be given to joint resection to prevent recurrence. Treatment of Campanacci Grade 2 tumors is debated in the literature. Intralesional curettage and adjuvants can successfully treat cases where the articular surface can be preserved, while en-bloc resection should be used in cases where the articular surface cannot undergo aggressive curettage. A variety of reconstructive techniques are used for cases needing resection, with no clear gold standard. Joint sparing procedures preserve motion at the wrist joint, whereas joint sacrificing procedures preserve grip strength. Choice of reconstructive procedure should be made based on patient-specific factors, considering relative functional outcomes, complications, and recurrence rates.

Flexor Pollicis Tendon Reconstruction With Allograft Tendon After Rupture: Technique and Case Series.

Division or rupture of the flexor pollicis longus (FPL) tendon can occur secondary to direct injury, laceration, or attritional rupture. Attritional rupture is particularly common in the setting volar plate fixation of a distal radius fracture. FPL tendon discontinuity can be restored through either primary repair or reconstruction. Primary repair can be challenging if not done within the first few days after injury secondary to contraction of the FPL muscle with retraction of the proximal tendon. Repair in this environment can lead to tension across the repair site as well as necessary flexion of the interphalangeal joint to accommodate primary repair. In the setting of attritional rupture, the proximal and distal ends are typically not viable for direct repair. We present our preferred technique for restoration of the FPL tendon, which is reconstruction with an allograft tendon.

Paraspinal Sarcopenia is Associated With Worse Patient-Reported Outcomes Following Laminoplasty for Degenerative Cervical Myelopathy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The present study is the first to assess the impact of paraspinal sarcopenia on patient-reported outcome measures (PROMs) following cervical laminoplasty. BACKGROUND: While the impact of sarcopenia on PROMs following lumbar spine surgery is well-established, the impact of sarcopenia on PROMs following laminoplasty has not been investigated. METHODS: We performed a retrospective review of patients undergoing laminoplasty from C4-6 at a single institution between 2010 and 2021. Two independent reviewers utilized axial cuts of T2-weighted magnetic resonance imaging sequences to assess fatty infiltration of the bilateral transversospinales muscle group at the C5-6 level and classify patients according to the Fuchs Modification of the Goutalier grading system. PROMs were then compared between subgroups. RESULTS: We identified 114 patients for inclusion in this study, including 35 patients with mild sarcopenia, 49 patients with moderate sarcopenia, and 30 patients with severe sarcopenia. There were no differences in preoperative PROMs between subgroups. Mean postoperative neck disability index scores were lower in the mild and moderate sarcopenia subgroups (6.2 and 9.1, respectively) than in the severe sarcopenia subgroup (12.9, P =0.01). Patients with mild sarcopenia were nearly twice as likely to achieve minimal clinically important difference (88.6 vs. 53.5%; P <0.001) and six times as likely to achieve SCB (82.9 vs. 13.3%; P =0.006) compared with patients with severe sarcopenia. A higher percentage of patients with severe sarcopenia reported postoperative worsening of their neck disability index (13 patients, 43.3%; P =0.002) and Visual Analog Scale Arm scores (10 patients, 33.3%; P =0.03). CONCLUSION: Patients with severe paraspinal sarcopenia demonstrate less improvement in neck disability and pain postoperatively and are more likely to report worsening PROMs following laminoplasty. LEVEL OF EVIDENCE: 3.

Is Severe Neck Pain a Contraindication to Performing Laminoplasty in Patients With Cervical Spondylotic Myelopathy?

STUDY DESIGN: Retrospective review. OBJECTIVE: The purpose of this study was to investigate the surgical outcomes in a cohort of patients with severe preoperative axial neck pain undergoing laminoplasty for cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: No study has investigated whether patients with severe axial symptoms may achieve satisfactory neck pain and disability outcomes after laminoplasty. METHODS: We performed a retrospective review of 91 patients undergoing C4-6 laminoplasty for CSM at a single academic institution between 2010 and 2021. Patient-reported outcome measures (PROMs), including Neck Disability Index (NDI), visual analog scale (VAS) Neck, and VAS Arm, were recorded preoperatively and at 6 months and 1 year postoperatively. Patients were stratified as having mild pain if VAS neck was 0-3, moderate pain if 4-6, and severe pain if 7-10. PROMs were then compared between subgroups at all the perioperative time points. RESULTS: Both the moderate and severe neck pain subgroups demonstrated a substantial improvement in VAS neck from preoperative to 6 months postoperatively (-3.1±2.2 vs. -5.6±2.8, respectively; P <0.001), and these improvements were maintained at 1 year postoperatively. There was no difference in VAS neck between subgroups at either the 6-month or 1-year postoperative time points. Despite the substantially higher mean NDI in the moderate and severe neck pain subgroups preoperatively, there was no difference in NDI at 6 months or 1 year postoperatively ( P =0.99). There were no differences between subgroups in the degree of cord compression, severity of multifidus sarcopenia, sagittal alignment, or complications. CONCLUSIONS: Patients with moderate and severe preoperative neck pain undergoing laminoplasty achieved equivalent PROMs at 6 months and 1 year as patients with mild preoperative neck pain. The results of this study highlight the multifactorial nature of neck pain in these patients and indicate that severe axial symptoms are not an absolute contraindication to performing laminoplasty in well-aligned patients with CSM.

Lower Hounsfield Units and Severe Multifidus Sarcopenia Are Independent Predictors of Increased Risk for Proximal Junctional Kyphosis and Failure Following Thoracolumbar Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The purpose of the present study was to assess the impact of sarcopenia on the development of proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) following thoracolumbar spine fusion surgery using opportunistic evaluation of paraspinal fatty degeneration on preoperative magnetic resonance imaging. SUMMARY OF BACKGROUND DATA: While paraspinal sarcopenia has been shown to have detrimental consequences following posterior cervicothoracic fusions, the impact of paraspinal sarcopenia on PJK and PJF following thoracolumbar spine fusion surgery remains unknown. MATERIALS AND METHODS: We performed a retrospective review of patients who underwent posterior spine fusion surgery that extended caudally to the pelvis and terminated cranially between T10 and L2 between 2010 and 2017. The cohort was divided into three groups: (1) patients without PJK or PJF, (2) patients with PJK but no PJF, and (3) patients with PJF. Univariate and multivariate analyses were performed to determine risk factors for the development of proximal junctional complications. RESULTS: We identified 150 patients for inclusion in this study. Mean Hounsfield Units at the upper instrumented vertebra (UIV) was 148.3±34.5 in the cohort of patients without PJK or PJF, which was substantially higher than values recorded in the PJK (117.8±41.9) and PJF (118.8±41.8) subgroups (P<0.001). Severe multifidus sarcopenia was identified at a much higher rate in the subgroups of patients who developed PJK (76.0%) and PJF (78.9%) than in the subgroup of patients who developed neither PJK nor PJF (34.0%; P<0.001). Multivariate analysis demonstrated both low HU at the UIV and moderate-severe multifidus sarcopenia to be risk factors for the development of PJK and PJF. CONCLUSION: The results of this study suggest severe paraspinal sarcopenia and diminished bone density at the UIV impart an increased risk of developing PJK and PJF, while markers of systemic frailty such as modified Frailty Index and Charlson Comorbidity Index are not associated with an increased risk of these complications. LEVEL OF EVIDENCE: III.

Titanium Cervical Cage Subsidence: Postoperative Computed Tomography Analysis Defining Incidence and Associated Risk Factors.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Substantial variability in both the measurement and classification of subsidence limits the strength of conclusions that can be drawn from previous studies. The purpose of this study was to precisely characterize patterns of cervical cage subsidence utilizing computed tomography (CT) scans, determine risk factors for cervical cage subsidence, and investigate the impact of subsidence on pseudarthrosis rates. METHODS: We performed a retrospective review of patients who underwent one- to three-levels of anterior cervical discectomy and fusion (ACDF) utilizing titanium interbodies with anterior plating between the years 2018 and 2020. Subsidence measurements were performed by two independent reviewers on CT scans obtained 6 months postoperatively. Subsidence was then classified as mild if subsidence into the inferior and superior endplate were both ≤2 mm, moderate if the worst subsidence into the inferior or superior endplate was between 2 to 4 mm, or severe if the worst subsidence into the inferior or superior endplate was ≥4 mm. RESULTS: A total of 51 patients (100 levels) were included in this study. A total of 48 levels demonstrated mild subsidence (≤2 mm), 38 demonstrated moderate subsidence (2-4 mm), and 14 demonstrated severe subsidence (≥4 mm). Risk factors for severe subsidence included male gender, multilevel constructs, greater mean vertebral height loss, increased cage height, lower Taillard index, and lower screw tip to vertebral body height ratio. Severe subsidence was not associated with an increased rate of pseudarthrosis. CONCLUSION: Following ACDF with titanium cervical cages, subsidence is an anticipated postoperative occurrence and is not associated with an increased risk of pseudarthrosis.

Semispinalis Cervicis Sarcopenia is Associated With Worsening Cervical Sagittal Balance and Junctional Alignment Following Posterior Cervical Fusion for Myelopathy.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: The present study is the first to investigate whether cervical paraspinal sarcopenia is associated with cervicothoracic sagittal alignment parameters after posterior cervical fusion (PCF). SUMMARY OF BACKGROUND DATA: Few studies have investigated the association between sarcopenia and postoperative outcomes after cervical spine surgery. METHODS: We retrospectively reviewed patients undergoing PCF from C2-T2 at a single institution between the years 2017-2020. Two independent reviewers utilized axial cuts of T2-weighted magnetic resonance imaging sequences to perform Goutallier classification of the bilateral semispinalis cervicis (SSC) muscles. Cervical sagittal alignment parameters were compared between subgroups based upon severity of SSC sarcopenia. RESULTS: We identified 61 patients for inclusion in this study, including 19 patients with mild SSC sarcopenia and 42 patients with moderate or severe SSC sarcopenia. The moderate-severe sarcopenia subgroup demonstrated a significantly larger change in C2-C7 sagittal vertical axis (+6.8 mm) from the 3-month to 1-year postoperative follow-up in comparison to the mild sarcopenia subgroup (-2.0 mm; P =0.02). The subgroup of patients with moderate-severe sarcopenia also demonstrated an increase in T1-T4 kyphosis (10.9-14.2, P =0.007), T1 slope (28.2-32.4, P =0.003), and C2 slope (24.1-27.3, P =0.05) from 3-month to 1-year postoperatively and a significant decrease in C1-occiput distance (6.3-4.1, P =0.002) during this same interval. CONCLUSIONS: In a uniform cohort of patients undergoing PCF from C2-T2, SSC sarcopenia was associated with worsening cervicothoracic alignment from 3-month to 1-year postoperatively.

Multifidus Sarcopenia Is Associated With Worse Patient-reported Outcomes Following Posterior Cervical Decompression and Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The present study is the first to assess the impact of paraspinal sarcopenia on patient-reported outcome measures (PROMs) following posterior cervical decompression and fusion (PCDF). SUMMARY OF BACKGROUND DATA: While the impact of sarcopenia on PROMs following lumbar spine surgery is well-established, the impact of sarcopenia on PROMs following PCDF has not been investigated. MATERIALS AND METHODS: We performed a retrospective review of patients undergoing PCDF from C2 to T2 at a single institution between the years 2017 and 2020. Two independent reviewers who were blinded to the clinical outcome scores utilized axial cuts of T2-weighted magnetic resonance imaging sequences to assess fatty infiltration of the bilateral multifidus muscles at the C5-C6 level and classify patients according to the Fuchs Modification of the Goutalier grading system. PROMs were then compared between subgroups. RESULTS: We identified 99 patients for inclusion in this study, including 28 patients with mild sarcopenia, 45 patients with moderate sarcopenia, and 26 patients with severe sarcopenia. There was no difference in any preoperative PROM between the subgroups. Mean postoperative Neck Disability Index scores were lower in the mild and moderate sarcopenia subgroups (12.8 and 13.4, respectively) than in the severe sarcopenia subgroup (21.0, P <0.001). A higher percentage of patients with severe multifidus sarcopenia reported postoperative worsening of their Neck Disability Index (10 patients, 38.5%; P =0.003), Visual Analog Scale Neck scores (7 patients, 26.9%; P =0.02), Patient-Reported Outcome Measurement Information System Physical Component Scores (10 patients, 38.5%; P =0.02), and Patient-Reported Outcome Measurement Information System Mental Component Scores (14 patients, 53.8%; P =0.02). CONCLUSION: Patients with more severe paraspinal sarcopenia demonstrate less improvement in neck disability and physical function postoperatively and are substantially more likely to report worsening PROMs postoperatively. LEVEL OF EVIDENCE: 3.

Shoulder Periprosthetic Joint Infection and All-Cause Mortality: A Worrisome Association.

BACKGROUND: Periprosthetic joint infection (PJI) can be a devastating complication following shoulder arthroplasty. PJI following hip and knee arthroplasties has been found to increase mortality. However, anatomical and bacteriologic differences could potentially result in a different trend after shoulder arthroplasties. Thus, the purpose of the present study was to determine whether there is an association between shoulder PJI and all-cause mortality. METHODS: Our institutional Total Joint Registry Database was queried to identify patients who underwent revision shoulder arthroplasty procedures between 2000 and 2018. A total of 1,160 procedures were then classified as either septic (21.8%) or aseptic (78.2%). Septic revisions were further subdivided into (1) debridement, antibiotics, irrigation, and implant retention (9.1%); (2) 2-stage reimplantation for deep infection (61.3%); (3) implant resection without reimplantation (3.6%); and (4) unexpected positive cultures at revision surgery (26.1%). The most common bacterium isolated was Cutibacterium acnes (64.4%). All-cause patient mortality was determined with use of our registry and confirmed with use of a nationwide mortality database. All-cause crude and adjusted mortality rates were then compared between groups. RESULTS: The 1-year crude mortality rate was 1.8% (95% confidence interval [CI], 0.9% to 2.6%) for the aseptic group and 2.8% (95% CI, 0.7% to 4.8%) for the septic group (p = 0.31). Multivariate Cox regression analysis demonstrated an elevated but statistically similar adjusted hazard ratio for 1-year all-cause mortality of 1.9 (95% CI, 0.8 to 4.6) when comparing the septic to the aseptic group (p = 0.17). The risk of 2-year all-cause mortality was significantly higher in the septic group, with a hazard ratio of 2.2 (95% CI, 1.1 to 4.5; p = 0.029). In univariate analyses, increased 5-year mortality in the septic revision group was associated with age, Charlson Comorbidity Index, and methicillin-resistant Staphylococcus aureus infection, whereas C. acnes infection was associated with lower mortality. CONCLUSIONS: Shoulder PJI is associated with an adjusted 2-year all-cause mortality rate that is double that of aseptic patients. The results of the present study should be utilized to appropriately counsel patients who are considered to be at risk for infection following shoulder arthroplasty. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Improved Sagittal Alignment Is Associated with Early Postoperative Neck Disability and Pain-Related Patient-Reported Outcomes Following Posterior Cervical Decompression and Fusion for Myelopathy.

OBJECTIVE: To compare patient-reported outcomes measures (PROMs) following posterior cervical decompression and fusion (PCDF) based on changes in perioperative cervical sagittal alignment. METHODS: We reviewed patients who underwent PCDF from C2 to T2 between the years 2015 and 2020. C2 sagittal vertical axis (SVA) and C2-C7 lordosis were assessed preoperatively and 1-year postoperatively. Neck Disability Index (NDI) and visual analog scale (VAS) Neck scores were collected preoperatively, 3 months' postoperatively, and 1-year postoperatively. PROMs were compared based on perioperative radiographic parameters. RESULTS: Eighty-five patients were included in this study. Patients with preoperative C2 SVA <40 mm had a larger improvement in VAS Neck pain scores at 3 months' postoperatively (-4.9 vs. -3.0, P = 0.03) and a larger decrease in NDI scores at 1-year postoperatively (7.2 vs. 3.1, P = 0.04) than patients with C2 SVA ≥40 mm. Patients with postoperative C2 SVA <40 mm demonstrated lower VAS Neck pain scores at 3 months' postoperatively (2.0 vs. 3.4, P = 0.049). The cohort of patients with a decrease of C2 SVA by ≥5 mm demonstrated lower NDI at 3 months' postoperatively but not at 1-year postoperatively in comparison with patients whose C2 SVA increased or remained unchanged (11.7 vs. 23.8 vs. 18.2; P < 0.001). Patients in whom both C2 SVA and C2-C7 lordosis improved demonstrated superior NDI (P < 0.001) and VAS Neck (P = 0.007) at 3 months' but not at 1-year postoperatively. CONCLUSIONS: In a uniform cohort of patients undergoing PCDF from C2 to T2, improvements in C2 SVA and C2-C7 lordosis were associated with improved early postoperative PROMs.

Partially overlapping sensorimotor networks underlie speech praxis and verbal short-term memory: evidence from apraxia of speech following acute stroke.

We tested the hypothesis that motor planning and programming of speech articulation and verbal short-term memory (vSTM) depend on partially overlapping networks of neural regions. We evaluated this proposal by testing 76 individuals with acute ischemic stroke for impairment in motor planning of speech articulation (apraxia of speech, AOS) and vSTM in the first day of stroke, before the opportunity for recovery or reorganization of structure-function relationships. We also evaluated areas of both infarct and low blood flow that might have contributed to AOS or impaired vSTM in each person. We found that AOS was associated with tissue dysfunction in motor-related areas (posterior primary motor cortex, pars opercularis; premotor cortex, insula) and sensory-related areas (primary somatosensory cortex, secondary somatosensory cortex, parietal operculum/auditory cortex); while impaired vSTM was associated with primarily motor-related areas (pars opercularis and pars triangularis, premotor cortex, and primary motor cortex). These results are consistent with the hypothesis, also supported by functional imaging data, that both speech praxis and vSTM rely on partially overlapping networks of brain regions.

The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling.

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbß3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin ß3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.