Chemotherapeutic metabolism presenting as a recalcitrant case of hand-foot syndrome and mucositis.

INTRODUCTION: Mercaptopurine (6MP) and methotrexate (MTX) are commonly used for maintenance chemotherapy for acute lymphoblastic leukemia (ALL). These medications have been associated with various side effects such as myelosuppression, colitis, and thyroiditis in addition to numerous cutaneous adverse events. Cutaneous side-effects most reported include mucositis, alopecia, xerosis, and pruritus. We report an interesting case of hand-foot syndrome to 6MP in a child on maintenance therapy for B-cell ALL from an alteration in medication metabolism. CASE: We report a 10-year-old male on maintenance chemotherapy for pre-Bcell ALL who presented to the hospital with worsening oral lesions and erythematous, fissured plaques on the palms and soles. Maintenance therapy consisted of IV vincristine and 5-day pulse of steroids every 12 weeks, daily 6MP, and weekly MTX, which were increased to ≥ 150% of standard dosing due to persistent absolute neutrophil counts > 1500. Metabolites obtained on admission demonstrated elevated 6MMP metabolites at 35,761 (normal < 5700). TPMT and NUDT15 enzyme activity were normal and no alterations in genotyping were discovered. OUTCOME: Patient's oral chemotherapy, including both 6MP and MTX, were stopped and allopurinol 100 mg daily was initiated, which lead to overall improvement. DISCUSSION: Clinical findings of acute mucositis and worsening of hand-foot syndrome, in the setting of inadequate myelosuppression in a child on maintenance therapy for ALL should raise concerns to consider altered metabolism pathway leading to toxic metabolite buildup. Allopurinol can play in improving cutaneous manifestation and chemotherapeutic dosing in patients with altered metabolism.

Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism.

Mutations in many synaptic genes are associated with autism spectrum disorders (ASD), suggesting that synaptic dysfunction is a key driver of ASD pathogenesis. Among these mutations, the R451C substitution in the NLGN3 gene that encodes the postsynaptic adhesion molecule Neuroligin-3 is noteworthy because it was the first specific mutation linked to ASDs. In mice, the corresponding Nlgn3 R451C-knockin mutation recapitulates social interaction deficits of ASD patients and produces synaptic abnormalities, but the impact of the NLGN3 R451C mutation on human neurons has not been investigated. Here, we generated human knockin neurons with the NLGN3 R451C and NLGN3 null mutations. Strikingly, analyses of NLGN3 R451C-mutant neurons revealed that the R451C mutation decreased NLGN3 protein levels but enhanced the strength of excitatory synapses without affecting inhibitory synapses; meanwhile NLGN3 knockout neurons showed reduction in excitatory synaptic strengths. Moreover, overexpression of NLGN3 R451C recapitulated the synaptic enhancement in human neurons. Notably, the augmentation of excitatory transmission was confirmed in vivo with human neurons transplanted into mouse forebrain. Using single-cell RNA-seq experiments with co-cultured excitatory and inhibitory NLGN3 R451C-mutant neurons, we identified differentially expressed genes in relatively mature human neurons corresponding to synaptic gene expression networks. Moreover, gene ontology and enrichment analyses revealed convergent gene networks associated with ASDs and other mental disorders. Our findings suggest that the NLGN3 R451C mutation induces a gain-of-function enhancement in excitatory synaptic transmission that may contribute to the pathophysiology of ASD.

Interdisciplinary treatment of posterior fossa dural arteriovenous fistulas.

BACKGROUND: Posterior fossa dural arteriovenous fistulas (dAVFs) are rare vascular lesions with variable risk of hemorrhage, mostly depending on the pattern of the venous drainage. While endovascular embolization is the mainstay treatment for most dAVFs, some posterior fossa lesions require a multidisciplinary approach including surgery. The goal of our study was to examine the outcome of an interdisciplinary treatment for posterior fossa dAVFs. METHODS: A retrospective review of patients treated for posterior fossa dAVFs was conducted. RESULTS: A total of 28 patients with a mean age of 57.8 years were included. Patients presented with a Cognard grade I in 2 (7%), II a in 5 (18 %), II b in 7 (25%), II a + b in 5 (18%), III in 3 (11%), and IV in 6 (21%) cases. Hemorrhage was the initial presentation in 2 (22%) patients with Cognard grade IV, in 3 with Cognard grade III (33%), in 1 (11%) with Cognard II a + b, and 3 (33%) with Cognard II b. A complete angiographic cure was achieved in 24 (86%) patients-after a single-session embolization in 16 (57%) patients, multiple embolization sessions in 2 (7%), a multimodal treatment with embolization and surgical disconnection in 3 (11%), and with an upfront surgery in 3 (11%). Complete long-term obliteration was demonstrated in 18/22 (82%) at the mean follow-up of 17 months. Fistulas were converted into asymptomatic Cognard I lesion in 4 (14%) patients. CONCLUSION: Posterior fossa dAVFs represent a challenging vascular pathology; however, despite their complexity, an interdisciplinary treatment can achieve high rates of angiographic and symptomatic cure with low morbidity and mortality rates. Long-term surveillance is warranted as late recurrences may occur.

Sources of residuals after endoscopic transsphenoidal surgery for large and giant pituitary adenomas.

BACKGROUND: Giant and large pituitary adenomas (PA) constitute a specific subset of PAs, with gross total resection (GTR) rates frequently not exceeding 50%. Both an anatomical inaccessibility and an inadequate tumor visualization are thought to play a role. This study analyzes risk factors for postoperative residuals after endoscopic transsphenoidal pituitary surgery for large and giant pituitary adenomas. METHODS: A retrospective analysis of patients with giant and large PA operated between 2015 and 2018 was performed. RESULTS: Forty patients (13 females, 27 males) were included in the analysis (30 large and 10 giant PAs). The mean MRI follow-up time was 5.9 ± 6.54 months. Overall, GTR was achieved in 29 patients (72.5%), subtotal resection in 9 (22.5%), and the inconclusive result was in 2 (5%). Unexpected residuals represented 7 (77.7%) of all 9 residual tumors. The most frequent intraoperative factor associated with unexpected residual tumors was improper identification of residual tumor due to obstruction of view in 2 (28.5%) cases and inability to distinguish normal tissue from tumor in the other two (28.5%). Sub-analysis based on tumor size revealed that with large PAs, GTR was achieved in 25 (83.3%), STR in 4 (13.3%), and inconclusive in 1 (3.3%) patient. In patients with giant PAs, GTR was achieved in 4 (40%), STR in 5 (50%), and inconclusive in 1 (10%). Analysis of preoperative factors showed a significant association of residual tumors with larger suprasellar AP distance (p = 0.041), retrosellar extension (p = 0.007), and higher Zurich Score (p = 0.029). CONCLUSION: Large and giant PAs are challenging lesions with high subtotal resection rates. Suprasellar AP distance, retrosellar extension, and higher Zurich Score seem to be significant predictors of degree of resection in these tumors. Improving the intraoperative ability to distinguish tumor from a normal tissue might further decrease the number of unexpected residuals.

Repeat Assault Injury Among Adolescents Utilizing Emergency Care: A Statewide Longitudinal Study.

BACKGROUND: Violent injuries are a leading cause of morbidity and mortality among youths. Little is known about adolescents' patterns of and risk factors for repeat assault injuries, yet understanding who is at risk for repeated assaults is important for intervention and prevention efforts. Investigating these questions in population-based adolescent samples is particularly critical. OBJECTIVE: Our aim was to estimate the 5-year cumulative incidence of and risk factors for repeat emergency department (ED) visits for assault injury among adolescents experiencing an index assault visit, and compare the method of injury for adolescents' first and second visits. METHODS: Statewide, longitudinal data from California were used to follow 17,845 adolescents who reported to an ED with assault-related injuries in 2010. Incidence rate ratios were estimated to examine risk factors for repeat assault injury within 1 year and 5 years following the index visit. RESULTS: A total of 3273 (18.3%) assaulted adolescents experienced one or more additional assault injury ED visits during the full follow-up period. Only 37.3% of these repeat assaults occurred within the first year following the index assault. Of adolescents with a repeat assault injury, the method of injury often changed and followed no clear pattern. Sociodemographic characteristics (e.g., older age, black race) and history of prior ED visits for assault and mental health problems predicted increased risk of repeat assault. CONCLUSIONS: Previous work may underestimate the rate of repeated assault among adolescents. Adolescents with a history of violence involvement and mental health problems are at elevated risk for repeated assault, and should be targeted for intervention.

Identification of ethyl pyruvate as a NLRP3 inflammasome inhibitor that preserves mitochondrial integrity.

BACKGROUND: The NLRP3 inflammasome, a cytosolic complex that mediates the maturation of IL-1ß and IL-18 as well as the release of high mobility group box 1 (HMGB1), contributes to the lethality of endotoxic shock. Ethyl pyruvate (EP) was previously shown to inhibit HMGB1 release and promote survival during endotoxemia and experimental sepsis. However, the underlying protective mechanism remains elusive. RESULT: EP dose-dependently inhibited the ATP-, nigericin-, alum-, and silica-induced caspase-1 activation and HMGB1 release in mouse macrophages. EP failed to inhibit DNA transfection- or Salmonella Typhimurium-induced caspase-1 activation and HMGB1 release. Mechanistically, EP significantly attenuated mitochondrial damage and cytoplasmic translocation of mitochondrial DNA, a known NLRP3 ligand, without influencing the potassium efflux, the lysosomal rupture or the production of mitochondrial reactive oxygen species (mtROS). CONCLUSION: Ethyl pyruvate acts as a novel NLRP3 inflammasome inhibitor that preserves the integrity of mitochondria during inflammation.

JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation.

Extracellular high-mobility group box (HMGB)1 mediates inflammation during sterile and infectious injury and contributes importantly to disease pathogenesis. The first critical step in the release of HMGB1 from activated immune cells is mobilization from the nucleus to the cytoplasm, a process dependent upon hyperacetylation within two HMGB1 nuclear localization sequence (NLS) sites. The inflammasomes mediate the release of cytoplasmic HMGB1 in activated immune cells, but the mechanism of HMGB1 translocation from nucleus to cytoplasm was previously unknown. Here, we show that pharmacological inhibition of JAK/STAT1 inhibits LPS-induced HMGB1 nuclear translocation. Conversely, activation of JAK/STAT1 by type 1 interferon (IFN) stimulation induces HMGB1 translocation from nucleus to cytoplasm. Mass spectrometric analysis unequivocally revealed that pharmacological inhibition of the JAK/STAT1 pathway or genetic deletion of STAT1 abrogated LPS- or type 1 IFN-induced HMGB1 acetylation within the NLS sites. Together, these results identify a critical role of the JAK/STAT1 pathway in mediating HMGB1 cytoplasmic accumulation for subsequent release, suggesting that the JAK/STAT1 pathway is a potential drug target for inhibiting HMGB1 release.

Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Nonobese Diabetic Mice.

Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic ß-cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B-cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin (KLH) significantly suppressed splenocyte release of immunoglobulin G (IgG) and interleukin (IL)-4 and IL-6 during KLH challenge ex vivo. Administration of galantamine beginning at 1 month of age in nonobese diabetic (NOD) mice significantly delayed the onset of hyperglycemia, attenuated immune cell infiltration in pancreatic islets and decreased anti-insulin antibodies in serum. These observations indicate that galantamine attenuates experimental type 1 diabetes in mice and suggest that activation of the inflammatory reflex should be further studied as a potential therapeutic approach.

α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release.

The mammalian immune system and the nervous system coevolved under the influence of cellular and environmental stress. Cellular stress is associated with changes in immunity and activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, a key component of innate immunity. Here we show that α7 nicotinic acetylcholine receptor (α7 nAchR)-signaling inhibits inflammasome activation and prevents release of mitochondrial DNA, an NLRP3 ligand. Cholinergic receptor agonists or vagus nerve stimulation significantly inhibits inflammasome activation, whereas genetic deletion of α7 nAchR significantly enhances inflammasome activation. Acetylcholine accumulates in macrophage cytoplasm after adenosine triphosphate (ATP) stimulation in an α7 nAchR-independent manner. Acetylcholine significantly attenuated calcium or hydrogen oxide-induced mitochondrial damage and mitochondrial DNA release. Together, these findings reveal a novel neurotransmitter-mediated signaling pathway: acetylcholine translocates into the cytoplasm of immune cells during inflammation and inhibits NLRP3 inflammasome activation by preventing mitochondrial DNA release.

Medial Patellofemoral Ligament Augmentation Repair for Primary Patellar Dislocation With Concomitant Chondral or Osteochondral Injury in Children and Adolescents: Outcomes at Minimum 2-Year Follow-up.

Background: Treatment of primary patellar dislocation (PPD) with chondral or osteochondral injury without patellar stabilization in the adolescent population may lead to unsatisfactory outcomes. Surgical treatment, with or without traditional medial patellofemoral ligament (MPFL) reconstruction, is a topic of interest. Purpose: To compare postoperative outcomes and rates of patellar redislocation and return to the operating room (OR) in patients who sustained a PPD with chondral or osteochondral injury and were surgically treated with versus without suture tape augmentation repair of the MPFL. Study Design: Cohort study; Level of evidence, 3. Methods: Adolescents who sustained a PPD with chondral or osteochondral injury confirmed via magnetic resonance imaging (MRI) and who were treated by a single surgeon between January 2009 and November 2020 were retrospectively reviewed. Patients were grouped into those who underwent chondral or osteochondral treatment with suture tape augmentation repair of the MPFL (ST group; n = 20) and those who did not have suture tape augmentation or repair (no-ST group; n = 20; 11 patients within the no-ST group did undergo medial imbrication). Demographic characteristics, postoperative knee range of motion, pre- and postoperative radiographic measurements, and preoperative MRI parameters were recorded, and minimum 2-year patient-reported outcomes were collected. Data were compared between the ST and no-ST groups. Results: The mean patient age was 15.02 years (range, 12.64-17.61 years) in the ST group and 14.18 years (range, 10.56-16.38 years) in the no-ST group, with a mean follow-up of 3.63 years (range, 2.01-6.11 years) in the ST group and 4.98 years (range, 2.23-9.03 years) in the no-ST group. Significantly more patients returned to the OR in the no-ST group compared with the ST group (7 [35%] vs 0 [0%]; P = .008). Further patellar stabilization with an MPFL allograft (n = 5) and manipulation under anesthesia (n = 2) were reasons for returning to the OR. There were no redislocation events in the ST group. Conclusion: Treating PPDs with chondral or osteochondral injury using suture tape to augment and repair the MPFL has promising advantages over not repairing it-including lower rates of postoperative patellar instability and return to the OR.

Keloid treatments: an evidence-based systematic review of recent advances.

BACKGROUND: Keloids are pathologic scars that pose a significant functional and cosmetic burden. They are challenging to treat, despite the multitude of treatment modalities currently available. OBJECTIVE: The aim of this study was to conduct an evidence-based review of all prospective data regarding keloid treatments published between 2010 and 2020. METHODS: A systematic literature search of PubMed (National Library of Medicine), Embase (Elsevier), and Cochrane Library (Wiley) was performed in November of 2020. Search strategies with the keywords "keloid" and "treatment" were performed by a medical librarian. The search was limited to prospective studies that were peer-reviewed, reported on clinical outcomes of keloid therapies, and were published in the English language between January 1, 2010, and November 24, 2020. RESULTS: A total of 3462 unique citations were identified, of which 108 studies met inclusion criteria. Current literature supports silicone gel or sheeting with corticosteroid injections as first-line therapy for keloids. Adjuvant intralesional 5-fluorouracil (5-FU), bleomycin, or verapamil can be considered, although mixed results have been reported with each. Laser therapy can be used in combination with intralesional corticosteroids or topical steroids with occlusion to improve drug penetration. Excision of keloids with immediate post-excision radiation therapy is an effective option for recalcitrant lesions. Finally, silicone sheeting and pressure therapy have evidence for reducing keloid recurrence. CONCLUSIONS: This review was limited by heterogeneity of subject characteristics and study outcome measures, small sample sizes, and inconsistent study designs. Larger and more robust controlled studies are necessary to further understand the variety of existing and emerging keloid treatments, including corticosteroids, cryotherapy, intralesional injections, lasers, photodynamic therapy, excision and radiation, pressure dressings, and others.

Incidence, mechanism, and protective strategies for 2-year pelvic fixation failure after adult spinal deformity surgery with a minimum six-level fusion.

OBJECTIVE: The purpose of this study was to determine the incidence, mechanism, and potential protective strategies for pelvic fixation failure (PFF) within 2 years after adult spinal deformity (ASD) surgery. METHODS: Data for ASD patients (age ≥ 18 years, minimum of six instrumented levels) with pelvic fixation (S2-alar-iliac [S2AI] and/or iliac screws) with a minimum 2-year follow-up were consecutively collected (2015-2019). Patients with prior pelvic fixation were excluded. PFF was defined as any revision to pelvic screws, which may include broken rods across the lumbosacral junction requiring revision to pelvic screws, pseudarthrosis across the lumbosacral junction requiring revision to pelvic screws, a broken or loose pelvic screw, or sacral/iliac fracture. Patient information including demographic data and health history (age, sex, BMI, smoking status, American Society of Anesthesiologists score, osteoporosis), operative (total instrumented levels [TIL], three-column osteotomy [3CO], interbody fusion), screw (iliac, S2AI, length, diameter), rod (diameter, kickstand), rod pattern (number crossing lumbopelvic junction, lowest instrumented vertebra [LIV] of accessory rod[s], lateral connectors, dual-headed screws), and pre- and postradiographic (lumbar lordosis, pelvic incidence, pelvic tilt, major Cobb angle, lumbosacral fractional curve, C7 coronal vertical axis [CVA], T1 pelvic angle, C7 sagittal vertical axis) parameters was collected. All rods across the lumbosacral junction were cobalt-chrome. All iliac and S2AI screws were closed-headed tulips. Both univariate and multivariate analyses were performed to determine risk factors for PFF. RESULTS: Of 253 patients (mean age 58.9 years, mean TIL 13.6, 3CO 15.8%, L5-S1 interbody 74.7%, mean pelvic screw diameter/length 8.6/87 mm), the 2-year failure rate was 4.3% (n = 11). The mechanisms of failure included broken rods across the lumbosacral junction (n = 4), pseudarthrosis across the lumbosacral junction requiring revision to pelvic screws (n = 3), broken pelvic screw (n = 1), loose pelvic screw (n = 1), sacral/iliac fracture (n = 1), and painful/prominent pelvic screw (n = 1). A higher number of rods crossing the lumbopelvic junction (mean 3.8 no failure vs 2.9 failure, p = 0.009) and accessory rod LIV to S2/ilium (no failure 54.2% vs failure 18.2%, p = 0.003) were protective for failure. Multivariate analysis demonstrated that accessory rod LIV to S2/ilium versus S1 (OR 0.2, p = 0.004) and number of rods crossing the lumbar to pelvis (OR 0.15, p = 0.002) were protective, while worse postoperative CVA (OR 1.5, p = 0.028) was an independent risk factor for failure. CONCLUSIONS: The 2-year PFF rate was low relative to what is reported in the literature, despite patients undergoing long fusion constructs for ASD. The number of rods crossing the lumbopelvic junction and accessory rod LIV to S2/ilium relative to S1 alone likely increase construct stiffness. Residual postoperative coronal malalignment should be avoided to reduce PFF.

How common is acute pelvic fixation failure after adult spine surgery? A single-center study of 358 patients.

OBJECTIVE: There is a paucity of literature on pelvic fixation failure after adult spine surgery in the early postoperative period. The purpose of this study was to determine the incidence of acute pelvic fixation failure in a large single-center study and to describe the lessons learned. METHODS: The authors performed a retrospective review of adult (≥ 18 years old) patients who underwent spinal fusion with pelvic fixation (iliac, S2-alar-iliac [S2AI] screws) at a single academic medical center between 2015 and 2020. All patients had a minimum of 3 instrumented levels. The minimum follow-up was 6 months after the index spine surgery. Patients with prior pelvic fixation were excluded. Acute pelvic fixation failure was defined as revision of the pelvic screws within 6 months of the primary surgery. Patient demographics and operative, radiographic, and rod/screw parameters were collected. All rods were cobalt-chrome. All iliac and S2AI screws were closed-headed screws. RESULTS: In 358 patients, the mean age was 59.5 ± 13.6 years, and 64.0% (n = 229) were female. The mean number of instrumented levels was 11.5 ± 5.5, and 79.1% (n = 283) had ≥ 6 levels fused. Three-column osteotomies were performed in 14.2% (n = 51) of patients, and 74.6% (n = 267) had an L5-S1 interbody fusion. The mean diameter/length of pelvic screws was 8.5/86.6 mm. The mean number of pelvic screws was 2.2 ± 0.5, the mean rod diameter was 6.0 ± 0 mm, and 78.5% (n = 281) had > 2 rods crossing the lumbopelvic junction. Accessory rods extended to S1 (32.7%, n = 117) or S2/ilium (45.8%, n = 164). Acute pelvic fixation failure occurred in 1 patient (0.3%); this individual had a broken S2AI screw near the head-neck junction. This 76-year-old woman with degenerative lumbar scoliosis and chronic lumbosacral zone 1 fracture nonunion had undergone posterior instrumented fusion from T10 to pelvis with bilateral S2AI screws (8.5 × 90 mm); i.e., transforaminal lumbar interbody fusion L4-S1. The patient had persistent left buttock pain postoperatively, with radiographically confirmed breakage of the left S2AI screw 68 days after surgery. Revision included instrumentation removal at L2-pelvis and a total of 4 pelvic screws. CONCLUSIONS: The acute pelvic fixation failure rate was exceedingly low in adult spine surgery. This rate may be the result of multiple factors including the preference for multirod (> 2), closed-headed pelvic screw constructs in which large-diameter long screws are used. Increasing the number of rods and screws at the lumbopelvic junction may be important factors to consider, especially for patients with high risk for nonunion.

Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials.

Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30-40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood-brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.

Time to onset of efficacy in fracture reduction with current anti-osteoporosis treatments.

Early prevention of future fracture is an important goal in those at risk. A similar 3-year fracture efficacy is reported for most osteoporosis agents. Onset of fracture efficacy may be useful to help tailor treatment based on risk. We reviewed the peer-reviewed literature for onset of fracture efficacy data on the commonly prescribed osteoporosis treatments. All papers were reviewed independently by at least two reviewers for onset of efficacy for morphometric vertebral fracture (MVF), clinical vertebral fracture (CVF), nonvertebral fracture (NVF), hip fracture, and any clinical fracture (ACF). Alendronate is reported to reduce multiple CVF by 6 months; all CVF, NVF, and multiple ACF by 12 months; and all ACF and hip fracture by 18 months. Ibandronate is reported to reduce MVF by 12 months and NVF by 36 months. Raloxifene is reported to reduce CVF by 3-6 months and NVF by 36 months. Risedronate is reported to reduce CVF and NVF by 6 months, and hip fracture by 12 months. Strontium ranelate is reported to reduce MVF, CVF, NVF, and ACF by 12 months, and hip fracture by 36 months. Zoledronic acid is reported to reduce MVF, CVF, and ACF by 12 months, NVF by 24 months, and hip fracture by 36 months. Although direct comparisons are limited, based on the available literature, risedronate, followed by alendronate, have the earliest onset of benefit across the range of fracture types. Onset of efficacy may be an important consideration in the selection of treatment for some patients.