Post-traumatic osteoarthritis: A review of pathogenic mechanisms and novel targets for mitigation.

Post-traumatic osteoarthritis (PTOA) develops secondary to a joint injury and accounts for 12 % of all osteoarthritis. These injuries, often of the lower extremity joints, occur due to trauma or accidents related to athletic or military activities. They primarily affect younger individuals although PTOA can occur across the spectrum of age. Pain and functional disability caused by PTOA confer a heavy economic toll on patients, in addition to detrimentally affecting their quality of life. Both high energy injuries that cause articular surface fracture with or without subchondral bone disruption and low-energy injuries involving joint dislocations or ligamentous injury cause PTOA, albeit through different mechanisms. Regardless, chondrocyte death, mitochondrial dysfunction, reactive oxygen species production, subchondral bone remodeling, inflammation and cytokine release in the cartilage and synovium play integral roles in the pathogenesis of PTOA. Evolving surgical methods are focused on stabilizing articular surface and joint structure congruity. However, to date there are no disease modifying medical therapies against PTOA. Increased recent understanding of the pathogenesis of the subchondral bone and synovial inflammation as well as that of chondrocyte mitochondrial dysfunction and apoptosis have led to the investigation of new therapeutics targeting these mechanisms to prevent or delay PTOA. This review discusses new advances in our understanding of cellular mechanisms underlying PTOA, and therapeutic approaches that are potentially effective in reducing the self-propagating cycle of subchondral bone alterations, inflammation, and cartilage degradation. Within this context, we focus therapeutic options involving anti-inflammatory and anti-apoptotic candidates that could prevent PTOA.

Effect of Tobacco Use on Radiolucent Lines in Modern Cementless Total Knee Arthroplasty Tibial Components.

Background: The link between tobacco consumption and wound complications following total knee arthroplasty (TKA) is well established. However, the effect of tobacco use on biologic fixation in cementless TKA remains unknown. This study evaluated the influence of tobacco use on the presence of radiolucent lines of tibial components in cementless TKA. Methods: A total of 293 consecutive cementless TKAs of 2 contemporary designs were retrospectively reviewed. Tibial radiolucent lines and component alignment were measured using an established measurement protocol. Patients with any history of tobacco use or active tobacco use (tobacco users) were compared to those with no history of tobacco use (tobacco nonusers). No significant differences which influenced outcomes were detected between the tobacco user and tobacco nonuser groups (P ≥ .071). Results: Radiolucent lines decreased from 1-month to latest follow-up (mean 2.5 years) in all 10 radiographic zones regardless of tobacco use (P ≤ .084). However, evaluating intrapatient change in radiolucent line width, the tobacco nonuser group had more radiolucent lines resolve by the latest follow-up in nearly all radiographic zones, although most differences did not reach statistical significance, except for anteroposterior zone 1 (-31% vs -19%, P = .022). No tibial components were revised for aseptic loosening. Conclusions: Results from this study suggest that any tobacco use prior to cementless TKA has the potential to hinder biologic fixation of tibial components. While no tibial components were revised for aseptic loosening, follow-up was relatively short at 2.5 years and therefore warrants further study to discern the effect of persistent radiolucent lines on long-term fixation.

Diagnostic Utility and Thresholds for Commonly Obtained Serum and Synovial Markers Prior to Reimplantation in Periprosthetic Joint Infection.

BACKGROUND: Accurate diagnosis of persistent periprosthetic joint infection (PJI) during 2-stage exchange remains a challenge. This study evaluated the diagnostic performance and thresholds of several commonly obtained serum and synovial markers to better guide reimplantation timing. METHODS: This was a retrospective review of 249 patients who underwent 2-stage exchange with antibiotic spacers for PJI. Serum and synovial markers analyzed included white blood cell (WBC) count, polymorphonuclear percentage (PMN%), neutrophil-to-lymphocyte ratio (NLR), and absolute neutrophil count (ANC). Serum markers analyzed were erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), as well as percentage change in ESR and CRP from initial diagnosis to reimplantation. Area under the curve (AUC) analyses were performed to determine diagnostic accuracy of detecting PJI. RESULTS: In TKAs, synovial ANC and WBC had the highest AUCs (0.76), with thresholds of 2,952 and 3,800 cells/µL, respectively. The next best marker was serum CRP (0.73) with a threshold of 5.2 mg/dL. In THAs, serum CRP had the highest AUC (0.84) with a threshold of 4.3 mg/dL, followed by synovial PMN% (0.80) with a threshold of 77%. Percentage change in serum ESR or CRP provided low diagnostic value overall. CONCLUSION: Regarding serum markers, CRP consistently performed well in detecting persistent PJI in patients with antibiotic spacers. Absolute values of serum CRP and ESR had better diagnostic value than trends for guiding reimplantation timing. Diagnostic performance differed with joint type; however, synovial markers outperformed serum counterparts. No marker alone can be utilized to diagnose residual PJI in these patients, and further work is needed in this domain.

Synovial Fluid Absolute Neutrophil Count and Neutrophil-To-Lymphocyte Ratio are not Superior to Polymorphonuclear Percentage in Detecting Periprosthetic Joint Infection.

BACKGROUND: Serum and synovial biomarkers are currently used to diagnose periprosthetic joint infection (PJI). Serum neutrophil-to-lymphocyte ratio (NLR) has shown promise as an inexpensive test in diagnosing infection, but there are no reports of synovial NLR or absolute neutrophil count (ANC) for diagnosing chronic PJI. The purpose of this study was to investigate the diagnostic potential of both markers. METHODS: A retrospective review of 730 patients who underwent total joint arthroplasty and subsequent aspiration was conducted. Synovial white blood cell (WBC) count, synovial polymorphonuclear percentage (PMN%), synovial NLR, synovial ANC, serum erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), serum WBC, serum PMN%, serum NLR, and serum ANC had their utility in diagnosing PJI examined by area-under-the-curve analyses (AUC). Pairwise comparisons of AUCs were performed. RESULTS: The AUCs for synovial WBC, PMN%, NLR, and ANC were 0.84, 0.84, 0.83, and 0.85, respectively. Synovial fluid ANC was a superior marker to synovial NLR (P = .027) and synovial WBC (P = .003) but not PMN% (P = .365). Synovial NLR was inferior to PMN% (P = .006) but not different from synovial WBC (P > .05). The AUCs for serum ESR, CRP, WBC, PMN%, NLR, and ANC were 0.70, 0.79, 0.63, 0.72, 0.74, and 0.67, respectively. Serum CRP outperformed all other serum markers (P < .05) except for PMN% and NLR (P > .05). Serum PMN% and NLR were similar to serum ESR (P > .05). CONCLUSION: Synovial ANC had similar performance to PMN% in diagnosing chronic PJI, whereas synovial NLR was a worse diagnostic marker. The lack of superiority to synovial PMN% limits the utility of these tests compared to established criteria.

The Influence of Dorr Type and Femoral Fixation on Outcomes Following Total Hip Arthroplasty for Acute Femoral Neck Fractures: A Multicenter Study.

BACKGROUND: The American Academy of Orthopaedic Surgeons guidelines report moderate evidence for cementing femoral stems for hip fractures, mainly derived from hemiarthroplasty literature. This is the first large, nonregistry study examining the influence of femoral fixation, implant type, patient characteristics, and radiographic factors on outcomes after total hip arthroplasty (THA) for acute femoral neck fractures. METHODS: A multicenter retrospective study was performed of 709 THA cases (199 cemented, 510 cementless) for femoral neck fractures from 2006 to 2020 at three large academic institutions. Demographics, perioperative characteristics, and radiographs were reviewed. Kaplan-Meier survivorship curves were generated for multiple outcomes. Univariate and multivariate analyses were performed with P ≤ .05 denoting significance. RESULTS: Cementless stems had a higher all-cause aseptic femoral revision rate (5.1 versus 0.5%, P = .002) and periprosthetic femoral fracture rate (4.3 versus 0%, P = .001). Each successive Dorr type had a higher fracture rate with cementless implants: 2.3%, 3.7%, and 15.9% in Dorr A, B, and C, respectively (P < .001). Logistic regression analyses confirmed that cementless stems (P = .02) and Dorr C bone (P = .001) are associated with periprosthetic fractures; collared implants and prophylactic cables did not protect against fractures. There was no difference in rates of dislocation, septic revision, or mortality between groups. CONCLUSION: Cementless stems during THA for femoral neck fractures have a higher aseptic femoral revision rate, specifically for periprosthetic fractures. Dorr C bone was particularly prone with an alarmingly high fracture rate. All fractures occurred in cementless cases, suggesting that cemented stems may minimize this complication. LEVEL OF EVIDENCE: III.

Procedure Duration, Time Under Anesthesia, and Readmissions in Direct Anterior and Posterior Approach Total Hip Arthroplasty.

BACKGROUND: Operative time is related to complications in primary total hip arthroplasty (THA). This study compared operative time in direct anterior (DA) and posterior approach THA and whether differences were related to increased hospital readmissions within 90 days of discharge. METHODS: Prospectively documented data on 3,152 consecutively performed THAs by 16 surgeons at a large Midwestern United States academic healthcare system were retrospectively reviewed. All surgeons were beyond their learning curve. Cases characterized by factors extending operative time were excluded. A total of 1,235 analysis cases were performed with the DA approach and 1,608 with the posterior approach. DA patients had lower mean body mass index (P < .001), were more likely to be classified as American Society of Anesthesiologists Physical Status 1 or 2 (P < .001), and more likely to have surgery in an ambulatory setting (P < .001). RESULTS: Time under anesthesia was significantly longer for DA procedures by 19 to 27 minutes in hospital and ambulatory settings, respectively (P < .001). Increasing body mass index had a greater impact on anesthesia time for DA patients (P = .020). There were no differences in nontraumatic readmissions within 90 days of surgery based on surgical approach (P ≥ .480); however, significantly more DA patients classified as ASA-PS 3 or 4 were readmitted compared to those classified as ASA-PS 1 or 2 (P < .001), a difference not observed for posterior approach patients. CONCLUSION: Anesthesia time is a modifiable risk factor for patient safety and an important factor in healthcare resource utilization. Consideration of ways to reduce DA operative times is encouraged.

Synovial Fluid and Serum Neutrophil-to-Lymphocyte Ratio: Novel Biomarkers for the Diagnosis and Prognosis of Native Septic Arthritis in Adults.

BACKGROUND: Septic arthritis (SA) is a musculoskeletal emergency for which prompt diagnosis and treatment are critical. However, traditional diagnostic criteria of a synovial fluid (SF) white blood-cell count (WBC) of >50,000 cells/mm 3 or >90% polymorphonuclear leukocytes (%PMN) are not particularly sensitive or specific for the diagnosis of SA. Furthermore, prognostic markers are lacking. The purposes of this study were to assess the discriminative ability of the SF neutrophil-to-lymphocyte ratio (NLR) in the diagnosis of SA and of the serum NLR in the prognosis of SA. METHODS: A multi-institution, retrospective study of 598 patients with native shoulder, hip, or knee SA in 2000 to 2018 was conducted. SF-NLR was calculated from the arthrocentesis cell count with differential. Receiver operating characteristic curves were analyzed, and the optimal threshold of SF-NLR for SA diagnosis was determined using the Youden index. Results were compared with traditional SF diagnostic criteria. Similar analyses assessed the association of serum NLR with 90-day treatment failure and mortality for the subset of patients with confirmed hip or knee SA and with serum complete blood-cell counts with differentials (n = 235). Results were compared with traditional serum prognostic markers (WBC, C-reactive protein [CRP], and erythrocyte sedimentation rate [ESR]). RESULTS: The SF-NLR (area under the receiver operating characteristic curve [AUC], 0.85 [95% confidence interval (CI), 0.82 to 0.88]) was significantly more accurate for an SA diagnosis than SF-WBC (AUC, 0.80 [95% CI, 0.76 to 0.83]; p = 0.002) and SF-%PMN (AUC, 0.81 [95% CI, 0.77 to 0.84]; p = 0.01). The optimal threshold of SF-NLR was 25 (78% sensitivity and 81% specificity), compared with >50,000 cells/mm 3 for SF-WBC (56% sensitivity and 80% specificity) and >90% for SF-%PMN (65% sensitivity and 78% specificity). Elevated serum NLR was independently associated with 90-day treatment failure (odds ratio [OR], 7.04 [95% CI, 3.78 to 13.14]; p < 0.001) and mortality (OR, 7.33 [95% CI, 2.00 to 26.92]; p = 0.003); elevated serum WBC and CRP were also associated with treatment failure, and WBC, CRP, and ESR were not associated with mortality. CONCLUSIONS: This study provides compelling data on the superior diagnostic and prognostic ability of serum NLR and SF-NLR for SA compared with current clinical standards. Given that this biomarker requires no additional cost or time to return than current laboratory tests already being performed, pending validation, it can readily be used to aid clinicians in the diagnosis and prognostication of SA. LEVEL OF EVIDENCE: Diagnostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Hyaluronic acid as an adjunct to microfracture in the treatment of osteochondral lesions of the talus: a systematic review of randomized controlled trials.

BACKGROUND: Osteochondral lesions of the talus (OLT) are common after ankle trauma. Studies have shown that bioactive substances, such as hyaluronic acid (HA), alone, or in combination, with surgical treatment could improve cartilage regeneration and repair, but the effect of HA on patient reported outcomes is unclear. METHODS: Literature searches were performed across four databases (PubMed, SPORTDiscus, Scopus, and The Cochrane Library) for randomized controlled trials in which at least one treatment arm involved use of HA as an adjunct to microfracture to treat patients with OLT. Primary outcomes included the American Orthopaedic Foot and Ankle Society scores (AOFAS), and the Visual Analog Scale (VAS) for pain. The level of evidence and methodological quality were evaluated using the Modified Coleman Methodology Score (MCMS). RESULTS: Three randomized studies were eligible for review with a total of 132 patients (35, 40, 57 patients, respectively) and follow-up ranged from 10.5 to 25 months. Utilization of HA at the time of microfracture resulted in greater improvement in AOFAS scores compared to microfracture alone. The pooled effect size was moderate (Standardized Mean Difference [SMD] 0.45, 95% Confidence Interval [CI] 0.06, 0.84; P = .02) and between-study heterogeneity was low (I-squared = 0%). Utilization of HA during microfracture also led to greater improvement in VAS-pain scores compared to microfracture alone. The pooled effect size was very large (SMD -3.86, 95% CI -4.75, - 2.97; P < .001) and heterogeneity was moderate (I-squared = 69%). CONCLUSION: Hyaluronic acid injection as an adjunct to arthroscopic MF in OLT provides clinically important improvements in function and pain at short-term follow-up compared to MF alone. Future longer-term follow-up studies are warranted to investigate the durability of MF with HA for treatment of OLT.

The AAHKS Clinical Research Award: Extended Oral Antibiotics Prevent Periprosthetic Joint Infection in High-Risk Cases: 3855 Patients With 1-Year Follow-Up.

BACKGROUND: Surgical and host factors predispose patients to periprosthetic joint infection (PJI) after primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). While surgical factors are modifiable, host factors can be challenging, and there are limited data demonstrating that preoperative patient optimization decreases risk of PJI. The goal of this study was to evaluate whether extended oral antibiotic prophylaxis reduces the one-year infection rate in high-risk patients. METHODS: A total of 3855 consecutive primary THAs and TKAs performed between 2011 and 2019 at a suburban academic hospital with modern perioperative and infection-prevention protocols were retrospectively reviewed. Beginning in January 2015, a 7-day oral antibiotic prophylaxis protocol was implemented after discharge for patients at high risk for PJI. The percentage of high-risk patients diagnosed with PJI within 1 year was compared between groups that did and did not receive extended antibiotic prophylaxis. Univariate and logistic regression analyses were performed, with P ≤ .05 denoting statistical significance. RESULTS: Overall 1-year infection rates were 2.26% and 0.85% after THA and TKA, respectively. High-risk patients with extended antibiotic prophylaxis had a significantly lower rate of PJI than high-risk patients without extended antibiotic prophylaxis (0.89% vs 2.64%, respectively; P < .001). There was no difference in the infection rate between high-risk patients who received antibiotics and low-risk patients (0.89% vs 1.29%, respectively; P = .348) with numbers available. CONCLUSION: Extended postoperative oral antibiotic prophylaxis for 7 days led to a statistically significant and clinically meaningful reduction in 1-year infection rates of patients at high risk for infection. In fact, the PJI rate in high-risk patients who received antibiotics was less than the rate seen in low-risk patients. Thus, extended oral antibiotic prophylaxis may be a simple measure to effectively counteract poor host factors. Moreover, the findings of this study may mitigate the incentive to select healthier patients in outcome-based reimbursement models. Further study with a multicenter randomized control trial is needed to further validate this protocol. LEVEL OF EVIDENCE: Therapeutic level III.

Greater Blood Loss in Contemporary Cementless Total Knee Arthroplasty than Cemented Total Knee Arthroplasty despite Tranexamic Acid Use: A Match-Controlled Retrospective Study.

The purpose of this retrospective study was to assess whether tranexamic acid (TXA) reduces blood loss in cementless total knee arthroplasty (TKA) comparable to levels observed with cemented fixation. After exclusions from 109 consecutive TKAs, 76 cementless knees were matched to 78 cemented knees of identical implant and surgeon. Blood loss with and without TXA was compared. There was no difference between cohorts in sex, age, body mass index, American Society of Anesthesiologists Physical Status classification, or preoperative hemoglobin (p ≥ 0.119). Use of TXA reduced median drain output by only 205 mL in cementless knees compared to 470 mL in cemented knees (p < 0.001). Median drain output per hour was highest in cementless knees without TXA (39.5 mL) followed by cemented knees without TXA (38.2 mL), cementless knees with TXA (28.5 mL), and cemented knees with TXA (12.7 mL; p < 0.001). Hemoglobin drop and total blood loss did not differ between cohorts regardless of TXA use. Cementless fixation in TKA resulted in greater intra-articular blood loss as measured by drain output, despite the use of TXA. Further research is warranted to examine whether a higher TXA dose, TXA delivery method, or the application of bone wax sealant would mitigate blood loss in cementless TKA, and subsequently whether intra-articular blood accumulation resulting in postoperative hemarthrosis affects recovery, function, and clinical outcomes.

Osteocytic miR21 deficiency improves bone strength independent of sex despite having sex divergent effects on osteocyte viability and bone turnover.

Osteocytes play a critical role in mediating cell-cell communication and regulating bone homeostasis, and osteocyte apoptosis is associated with increased bone resorption. miR21, an oncogenic microRNA, regulates bone metabolism by acting directly on osteoblasts and osteoclasts, but its role in osteocytes is not clear. Here, we show that osteocytic miR21 deletion has sex-divergent effects in bone. In females, miR21 deletion reduces osteocyte viability, but suppresses bone turnover. Conversely, in males, miR21 deletion increases osteocyte viability, but stimulates bone turnover and enhances bone structure. Further, miR21 deletion differentially alters osteocyte cytokine production in the two sexes. Interestingly, despite these changes, miR21 deletion increases bone mechanical properties in both sexes, albeit to a greater extent in males. Collectively, our findings suggest that miR21 exerts both sex-divergent and sex-equivalent roles in osteocytes, regulating osteocyte viability and altering bone metabolism through paracrine actions on osteoblasts and osteoclasts differentially in males vs females, whereas, influencing bone mechanical properties independent of sex.

Age- and sex-dependent role of osteocytic pannexin1 on bone and muscle mass and strength.

Pannexins (Panxs), glycoproteins that oligomerize to form hemichannels on the cell membrane, are topologically similar to connexins, but do not form cell-to-cell gap junction channels. There are 3 members of the family, 1-3, with Panx1 being the most abundant. All Panxs are expressed in bone, but their role in bone cell biology is not completely understood. We now report that osteocytic Panx1 deletion (Panx1Δot) alters bone mass and strength in female mice. Bone mineral density after reaching skeletal maturity is higher in female Panx1Δot mice than in control Panx1fl/fl mice. Further, osteocytic Panx1 deletion partially prevented aging effects on cortical bone structure and mechanical properties. Young 4-month-old female Panx1Δot mice exhibited increased lean body mass, even though pannexin levels in skeletal muscle were not affected; whereas no difference in lean body mass was detected in male mice. Furthermore, female Panx1-deficient mice exhibited increased muscle mass without changes in strength, whereas Panx1Δot males showed unchanged muscle mass and decreased in vivo maximum plantarflexion torque, indicating reduced muscle strength. Our results suggest that osteocytic Panx1 deletion increases bone mass in young and old female mice and muscle mass in young female mice, but has deleterious effects on muscle strength only in males.

Extended Oral Antibiotic Prophylaxis in High-Risk Patients Substantially Reduces Primary Total Hip and Knee Arthroplasty 90-Day Infection Rate.

BACKGROUND: Total joint arthroplasty (TJA) episodic payment models shift risk and cost of periprosthetic joint infection (PJI) to surgeons and hospitals, causing some to avoid treating high-risk patients. Furthermore, there are little data to support optimization of host factors preoperatively to decrease PJI, and recent literature supports using extended antibiotic prophylaxis following reimplantation TJA. The purpose of this study was to evaluate whether extended oral antibiotic prophylaxis minimized PJI after primary TJA in high-risk patients. METHODS: A retrospective cohort study was performed of 2,181 primary total knee arthroplasties (TKAs) and primary total hip arthroplasties (THAs) carried out from 2011 through 2016 at a suburban academic hospital with modern perioperative and infection-prevention protocols. Beginning in January 2015, extended oral antibiotic prophylaxis for 7 days after discharge was implemented for patients at high risk for PJI. The percentages of patients diagnosed with PJI within 90 days were identified and compared between groups that did and did not receive extended oral antibiotic prophylaxis, with p ≤ 0.05 indicating significance. RESULTS: The 90-day infection rates were 1.0% and 2.2% after the TKAs and THAs, respectively. High-risk patients without extended antibiotic prophylaxis were 4.9 (p = 0.009) and 4.0 (p = 0.037) times more likely to develop PJI after TKA and THA, respectively, than high-risk patients with extended antibiotic prophylaxis. CONCLUSIONS: Extended postoperative antibiotic prophylaxis led to a statistically significant and clinically meaningful reduction in the 90-day infection rate of selected patients at high risk for infection. We encourage further study and deliberation prior to adoption of a protocol involving extended oral antibiotic prophylaxis after high-risk TJA, with the benefits weighed appropriately against potential adverse consequences such as increasing the development of antimicrobial resistance. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Tourniquetless Total Knee Arthroplasty With Modern Perioperative Protocols Decreases Pain and Opioid Consumption in Women.

BACKGROUND: This study examined whether a modern total knee arthroplasty (TKA) protocol without a tourniquet results in less patient-reported pain and in-hospital opioid consumption compared to TKA with a tourniquet. METHODS: A retrospective study of 203 primary unilateral cemented TKAs consecutively performed with or without tourniquet was performed. Identical perioperative pain and blood loss protocols were used in all cases. In tourniquetless TKAs, the tourniquet was not inflated at any time, and sterile CO2 gas compression maximized cement interdigitation. RESULTS: After exclusions for scientific confounds, 184 TKAs (93 with tourniquet; 91 tourniquetless) were analyzed. Controlling for multiple covariates, females with a tourniquet reported significantly more pain (P = .002) and opioid consumption (P < .001) the first 24 hours after surgery compared to females without a tourniquet. There were no differences in pain (P = .192) or amount of opioids consumed (P = .203) among males with and without a tourniquet. Tourniquet use resulted in a significant reduction in blood loss for both females (P ≤ .040) and males (P ≤ .020), although the total blood savings of approximately 200 mL is of unknown clinical significance. CONCLUSION: Avoiding tourniquet use during TKA for females may be a relatively risk-free adjunct to minimize opioid consumption during hospitalization. Further study is warranted to elucidate the factors accounting for different outcomes in females and males.

Reversal of loss of bone mass in old mice treated with mefloquine.

Aging is accompanied by imbalanced bone remodeling, elevated osteocyte apoptosis, and decreased bone mass and mechanical properties; and improved pharmacologic approaches to counteract bone deterioration with aging are needed. We examined herein the effect of mefloquine, a drug used to treat malaria and systemic lupus erythematosus and shown to ameliorate bone loss in glucocorticoid-treated patients, on bone mass and mechanical properties in young and old mice. Young 3.5-month-old and old 21-month-old female C57BL/6 mice received daily injections of 5 mg/kg/day mefloquine for 14 days. Aging resulted in the expected changes in bone volume and mechanical properties. In old mice mefloquine administration reversed the lower vertebral cancellous bone volume and bone formation; and had modest effects on cortical bone volume, thickness, and moment of inertia. Mefloquine administration did not change the levels of the circulating bone formation markers P1NP or alkaline phosphatase, whereas levels of the resorption marker CTX showed trends towards increase with mefloquine treatment. In addition, and as expected, aging bones exhibited an accumulation of active caspase3-expressing osteocytes and higher expression of apoptosis-related genes compared to young mice, which were not altered by mefloquine administration at either age. In young animals, mefloquine induced higher periosteal bone formation, but lower endocortical bone formation. Further, osteoclast numbers were higher on the endocortical bone surface and circulating CTX levels were increased, in mefloquine- compared to vehicle-treated young mice. Consistent with this, addition of mefloquine to bone marrow cells isolated from young mice led to increased osteoclastic gene expression and a tendency towards increased osteoclast numbers in vitro. Taken together our findings identify the age and bone-site specific skeletal effects of mefloquine. Further, our results highlight a beneficial effect of mefloquine administration on vertebral cancellous bone mass in old animals, raising the possibility of using this pharmacologic inhibitor to preserve skeletal health with aging.

Alcohol Drinking and Blood Alcohol Concentration Revisited.

BACKGROUND: It is widely assumed that the amount of alcohol in the blood reflects the amount of alcohol consumed. However, several factors in addition to amount of alcohol consumed can influence blood alcohol concentration (BAC). This study examines the effect of alcohol dose, concentration, and volume on BAC in rats with a high-alcohol-drinking (HAD) phenotype. METHODS: Study 1 examined the relationship between the amount of alcohol consumed and BAC. Alcohol-naïve, male, HAD rats (N = 7) were given access to alcohol for 2 h/d for 9 consecutive days with food and water ad libitum. Alcohol intake and BAC were measured at 30, 60, and 90 minutes after onset of access. Study 2 examined the effects of altering alcohol dose, concentration, and volume on BAC (as measured by area under the curve). Alcohol-naïve, male, HAD rats (N = 39) were infused, via an intragastric cannulus, with 1.16, 2.44, or 3.38 g alcohol/kg body weight (BW), produced by varying alcohol volume while holding concentration constant or by holding volume constant while varying concentration. Other rats were infused with 10, 15, or 20% v/v alcohol solutions while holding dose constant. RESULTS: BAC was more strongly correlated with the ratio of alcohol intake (g/kg BW) to total fluid intake (mls) (R = 0.85 to 0.97, p < 0.05 to p < 0.001) than it was with the amount of alcohol consumed (g/kg BW) (R = 0.70 to 0.81, p < 0.05). No effect of alcohol dose was seen during the first hour following the onset of an alcohol infusion regardless of whether dose was achieved by altering alcohol volume or concentration. After 1 hour, higher alcohol doses were predictive of greater BACs. CONCLUSIONS: The fact that a 3-fold difference in alcohol dose did not result in significant differences in BACs during the first 30 minutes after ingestion of alcohol has potentially important implications for interpretation of studies that measure alcohol-sensitive end points during this time.

Co-Administration of Low-Dose Naltrexone and Bupropion Reduces Alcohol Drinking in Alcohol-Preferring (P) Rats.

BACKGROUND: This study examined whether combining naltrexone (NTX) with bupropion (BUP) is more effective in reducing alcohol drinking in alcohol-preferring (P) rats with a genetic predisposition toward high voluntary alcohol intake than either drug alone. METHODS: Alcohol-experienced, adult, male, P rats were fed NTX alone in a dose of 10.0 mg/kg BW, BUP alone in a dose of 10.0 mg/kg BW, BUP alone in a dose of 20.0 mg/kg BW, NTX (10.0 mg/kg BW) + BUP (10.0 mg/kg BW), or vehicle (VEH) at 1 hour prior to onset of a daily 2-hour alcohol access period for 5 consecutive days. RESULTS: When administered alone, neither NTX (10.0 mg/kg BW) nor BUP, in either of 2 doses (10.0 mg/kg BW or 20.0 mg/kg BW), reduced voluntary alcohol intake in P rats. However, NTX combined with BUP (10.0 mg/kg NTX + 10.0 mg/kg BUP) and given as a single medication significantly reduced alcohol consumption throughout prolonged treatment. CONCLUSIONS: Combining low doses of NTX and BUP, each of which is ineffective when given alone, increases the efficacy of the medication. Low drug doses circumvent the problem of negative side effects that can occur with higher doses of either drug. A reduction in side effects can facilitate patient compliance and improve clinical outcomes for alcoholics and heavy drinkers who want to reduce their alcohol intake. The results, together with those from our prior studies, demonstrate the strength of a combinatorial pharmacotherapeutic approach to the treatment of alcohol use disorder.

Varenicline Reduces Alcohol Intake During Repeated Cycles of Alcohol Reaccess Following Deprivation in Alcohol-Preferring (P) Rats.

BACKGROUND: Most alcoholics experience periods of voluntary alcohol abstinence or imposed alcohol deprivation followed by a return to alcohol drinking. This study examined whether varenicline (VAR) reduces alcohol intake during a return to drinking after periods of alcohol deprivation in rats selectively bred for high alcohol drinking (the alcohol preferring or "P" rats). METHODS: Alcohol-experienced P rats were given 24-hour access to food and water and scheduled access to alcohol (15% and 30% v/v) for 2 h/d. After 4 weeks, rats were deprived of alcohol for 2 weeks, followed by reaccess to alcohol for 2 weeks, and this pattern was repeated for a total of 3 cycles. Rats were fed either vehicle (VEH) or VAR, in doses of 0.5, 1.0, or 2.0 mg/kg BW, at 1 hour prior to onset of the daily alcohol reaccess period for the first 5 days of each of the 3 alcohol reaccess cycles. RESULTS: Low-dose VAR (0.5 mg/kg BW) reduced alcohol intake during the 5 days of drug treatment in alcohol reaccess cycles 1 and 2. Higher doses of VAR (1.0 mg/kg BW and 2.0 mg/kg BW) reduced alcohol intake during the 5 days of treatment in all 3 alcohol reaccess cycles. The decrease in alcohol intake disappeared with termination of VAR treatment in all alcohol reaccess cycles. CONCLUSIONS: The results demonstrate that VAR decreases alcohol intake during multiple cycles of alcohol reaccess following alcohol deprivation in rats and suggests that it may prevent a return to heavy alcohol drinking during a lapse from alcohol abstinence in humans with alcohol use disorder.

A Combination of Naltrexone + Varenicline Retards the Expression of a Genetic Predisposition Toward High Alcohol Drinking.

BACKGROUND: This study examined whether naltrexone (NTX) or varenicline (VAR), alone or in combination, can retard the phenotypic expression of a genetic predisposition toward high alcohol drinking in rats selectively bred for high alcohol intake when drug treatment is initiated prior to, or concomitantly with, the onset of alcohol drinking. METHODS: Alcohol-naïve P rats were treated daily with NTX (15.0 mg/kg BW), VAR (1.0 mg/kg BW), a combination of NTX (15.0 mg/kg BW) + VAR (1.0 mg/kg BW), or vehicle (VEH) for 2 weeks prior to, or concomitantly with, their first opportunity to drink alcohol and throughout 21 days of daily 2-hour alcohol access. Drug treatment was then discontinued for 3 weeks followed by reinstatement of drug treatment for an additional 3 weeks. RESULTS: When P rats were pretreated with drug for 2 weeks prior to onset of alcohol access, only NTX + VAR in combination blocked the acquisition of alcohol drinking in alcohol-naïve P rats. When drug treatment was initiated concomitantly with the first opportunity to drink alcohol, NTX alone, VAR alone, and NTX + VAR blocked the acquisition of alcohol drinking. Following termination of drug treatment, NTX + VAR and VAR alone continued to reduce alcohol drinking but by the end of 3 weeks without drug treatment, alcohol intake in all groups was comparable to that seen in the vehicle-treated group as the expression of a genetic predisposition toward high alcohol drinking emerged in the drug-free P rats. After 3 weeks without drug treatment, reinstatement of NTX + VAR treatment again reduced alcohol intake. CONCLUSIONS: A combination of NTX + VAR, when administered prior to, or concomitantly with, the first opportunity to drink alcohol, blocks the acquisition of alcohol drinking during both initial access to alcohol and during a later period of alcohol access in P rats with a genetic predisposition toward high alcohol intake. The results suggest that NTX + VAR may be effective in curtailing alcohol drinking in individuals at high genetic risk of developing alcoholism.

Combining Varenicline (Chantix) with Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in a Rodent Model of Alcoholism.

BACKGROUND: This study examined whether varenicline (VAR), or naltrexone (NTX), alone or in combination, reduces alcohol drinking in alcohol-preferring (P) rats with a genetic predisposition toward high voluntary alcohol intake. METHODS: Alcohol-experienced P rats that had been drinking alcohol (15% v/v) for 2 h/d for 4 weeks were fed either vehicle (VEH), VAR alone (0.5, 1.0, or 2.0 mg/kg body weight [BW]), NTX alone (10.0, 15.0, or 20.0 mg/kg BW), or VAR + NTX in 1 of 4 dose combinations (0.5 VAR + 10.0 NTX, 0.5 VAR + 15.0 NTX, 1.0 VAR + 10.0 NTX, or 1.0 VAR + 15.0 NTX) at 1 hour prior to alcohol access for 10 consecutive days, and the effects on alcohol intake were assessed. RESULTS: When administered alone, VAR in doses of 0.5 or 1.0 mg/kg BW did not alter alcohol intake but a dose of 2.0 mg/kg BW decreased alcohol intake. This effect disappeared when drug treatment was terminated. NTX in doses of 10.0 and 15.0 mg/kg BW did not alter alcohol intake but a dose of 20.0 mg/kg BW decreased alcohol intake. Combining low doses of VAR and NTX into a single medication reduced alcohol intake as well as did high doses of each drug alone. Reduced alcohol intake occurred immediately after onset of treatment with the combined medication and continued throughout prolonged treatment. CONCLUSIONS: Low doses of VAR and NTX, when combined in a single medication, reduce alcohol intake in a rodent model of alcoholism. This approach has the advantage of reducing potential side effects associated with each drug. Lowering the dose of NTX and VAR in a combined treatment approach that maintains efficacy while reducing the incidence of negative side effects may increase patient compliance and improve clinical outcomes for alcoholics and heavy drinkers who want to reduce their alcohol intake.