Prediction model to predict type 1 retinopathy of prematurity using gestational age and birth weight (PW-ROP).

PURPOSE: To develop a prediction model for type 1 retinopathy of prematurity (ROP) from an Asian population. METHODS: This retrospective cohort study included 1043 premature infants who had ROP screening in a tertiary hospital in Hong Kong from year 2006 to 2018. The ROP prediction model was developed by multivariate logistic regression analyses on type 1 ROP. The cut-off value and the corresponding sensitivity and specificity were determined by receiver operating characteristic curve analysis. A validation group of 353 infants collected from another tertiary hospital in another region of Hong Kong from year 2014 to 2017 was used for external validation. RESULTS: There were 1043 infants in the study group. The median gestational age (GA) was 30 weeks and 1 day and median birth weight (BW) was 1286 g. The prediction model required only GA and BW as parameters (prematurity-birth weight ROP (PW-ROP)). The area under curve value was 0.902. The sensitivity and specificity were 87.4% and 79.3%, respectively. Type 1 ROP developed in 0.9%, 17.4% and 50% of infants with PW-ROP scores<0, between 0 and <300, and ≥300 respectively (p<0.001). On external validation, our prediction model correctly predicted 95.8% of type 1 ROP (sensitivity=95.8%, specificity=74.8%) in the validation group. CONCLUSION: The PW-ROP model is a simple model which could predict type 1 ROP with high sensitivity and specificity. Incorporating this model to ROP examination would help identify infants at risk for ROP treatment.

Association between functional status and ocular surface disease among local elderly population in Hong Kong.

Purpose: To evaluate the correlation between ocular surface disease (OSD) and functional status among elderly population over 60 years old in Hong Kong.Methods: Chinese subjects above 60 years old were recruited from the Ophthalmology clinic in Hong Kong West Cluster. Subjects demographic and questionnaires to evaluate the functional status were used to correlate with OSD objectively with clinical examination to assess the meibomian gland dysfunction (MGD), corneal staining, Schirmer's test and tear break-up time (TBUT); and subjectively with ocular surface disease index (OSDI).Results: Twenty-eight patients were recruited, with a mean age of 71.5 ± 6.8 years. There was good correlation between the findings of the two eyes for bilateral measurements. Corneal staining was present in 75% of the subjects, while 92.9% of them had positive MGD grading. TBUT was reduced in 85.7% of the subjects. There is a negative association between MGD grading and Barthel index (r = -0.55, p< .01), indicating worse activities of daily living is related to worse MGD. OSDI is negatively associated with Schirmer's test (r = -0.49, p< .01). A negative correlation is also found between TBUT value and corneal staining (r = -0.58, p< .01).Conclusions: There is a high prevalence of OSD among our subjects. Lower Barthel index (indicating worse Lawton's instrumental activities of daily living) is associated with worse MGD grading. In elderly with poor functional status, care should be taken to manage their OSD.

The role of hepatic cytochrome P450s in the cytotoxicity of sertraline.

Sertraline, an antidepressant, is commonly used to manage mental health symptoms related to depression, anxiety disorders, and obsessive-compulsive disorder. The use of sertraline has been associated with rare but severe hepatotoxicity. Previous research demonstrated that mitochondrial dysfunction, apoptosis, and endoplasmic reticulum stress were involved in sertraline-associated cytotoxicity. In this study, we reported that after a 24-h treatment in HepG2 cells, sertraline caused cytotoxicity, suppressed topoisomerase I and IIα, and damaged DNA in a concentration-dependent manner. We also investigated the role of cytochrome P450 (CYP)-mediated metabolism in sertraline-induced toxicity using our previously established HepG2 cell lines individually expressing 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrated that CYP2D6, 2C19, 2B6, and 2C9 metabolize sertraline, and sertraline-induced cytotoxicity was significantly decreased in the cells expressing these CYPs. Western blot analysis demonstrated that the induction of É£H2A.X (a hallmark of DNA damage) and topoisomerase inhibition were partially reversed in CYP2D6-, 2C19-, 2B6-, and 2C9-overexpressing HepG2 cells. These data indicate that DNA damage and topoisomerase inhibition are involved in sertraline-induced cytotoxicity and that CYPs-mediated metabolism plays a role in decreasing the toxicity of sertraline.

Factors Associated with Poor Eye Drop Administration Technique and the Role of Patient Education among Hong Kong Elderly Population.

OBJECTIVES: To identify the risk factors for poor eye drop application technique in treatment-naïve subjects and to assess if patient education can benefit these subjects. METHODS: Chinese subjects above 60 years were recruited. Questionnaires, including Barthel index; Lawton's instrumental activities of daily living (ADL); Fatigue, Resistance, Ambulation, Illnesses, and Loss of Weight (FRAIL) scale; and Montreal Cognitive Assessment (MoCA), were used to correlate with eye drop application technique (before and after patient education) using Spearman correlation analysis. A multiple linear regression was conducted to determine the predictors of successful administration technique and the improvement of technique after education. RESULTS: The data from 26 subjects (mean age 72) were analyzed. Eye drop instillation technique score improved from 5.42 at baseline to 7.33 after clear instructions. FRAIL score was an independent predictor of baseline score (p=0.003), as well as the improvement after patient education (p=0.012). Age, sex, education level, visual acuity, Barthel index, MoCA, and ADL score were not correlated with eye drop instillation technique, before nor after patient education. DISCUSSION: In patients with poor functional status as reflected by FRAIL score, eye drop application is prone to be ineffective. Education with step-by-step instructions could effectively improve the success of eye drop application.

Repeated intraocular crystallization of ganciclovir in one eye after bilateral intravitreal injections: a case report.

BACKGROUND: Cytomegalovirus (CMV) retinitis is an opportunistic infection that primarily affects immunocompromised individuals. Intravitreal ganciclovir injection monotherapy or in combination with systemic anti-CMV therapy are effective treatments for CMV retinitis. Crystallization of ganciclovir after intravitreal injection is extremely rare. Only two cases had been reported in literature. Crystallization in only one eye after bilateral injections had not been reported before. We hereby report a case of intraocular ganciclovir crystallization in one eye after bilateral intravitreal injections, and repeated crystallization in the same eye after repeated injections. CASE PRESENTATION: A 79-year-old patient had bilateral cytomegalovirus retinitis and received bilateral intravitreal ganciclovir injections of 2.5 mg in 0.05 ml sterile water. Fundus examination after injection showed formation of needle-shaped, golden-yellow crystals in the vitreous of right eye but not in left eye. The crystals dissolved spontaneously. Repeated bilateral intravitreal ganciclovir injections 4 days later resulted in repeated crystallization of ganciclovir in right eye but not in left eye. The crystals dissolved spontaneously and completely after 5 minutes. Visual acuity remained unchanged and intraocular pressure was normal. CONCLUSIONS: Intraocular ganciclovir crystallization could occur after intravitreal injections. It is important to perform fundus examination after injection. The crystals may dissolve rapidly and vitrectomy may not be necessary. Our case suggested intraocular ganciclovir crystallization is an idiosyncratic phenomenon, subjects to distinctive intraocular environment which could be different between two eyes of the same patient. The susceptible intraocular environment could be persistent leading to repeated crystallization.

Early epithelial complications of accelerated trans-epithelial corneal crosslinking in treatment of keratoconus: a case series.

BACKGROUND: To report a case series of early postoperative complications following combined accelerated corneal crosslinking (CXL) and trans-epithelial technique in keratoconus. CASE PRESENTATIONS: Eleven eyes underwent accelerated trans-epithelial CXL (18 mW/cm2 for 5 min). Seven eyes (64%) developed complications in the first week postoperatively. Five eyes had large epithelial defects, and two eyes were complicated with diffuse punctate epithelial erosions. Early transient stromal haze was seen in eyes with epithelial complications. Anterior segment optical coherence tomography showed a faint demarcation line in six eyes (55%) with epithelial complications. CONCLUSION: A significant number of eyes developed epithelial complications shortly after combined accelerated trans-epithelial CXL, which defeated the benefits of leaving the epithelium intact.

Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis.

BACKGROUND: Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. METHODS: We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated. RESULTS: Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed. CONCLUSIONS: In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214 .).

Romosozumab increases bone mineral density in postmenopausal Japanese women with osteoporosis: A phase 2 study.

BACKGROUND: Romosozumab is a monoclonal antibody that inhibits sclerostin and rapidly increases bone mineral density (BMD) through a dual effect on bone by increasing bone formation and decreasing bone resorption, as shown in a global phase 2 study in postmenopausal women with low bone mass. Here, we report the key results of a phase 2, double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of romosozumab in postmenopausal Japanese women with osteoporosis. METHODS: Participants were postmenopausal Japanese women with osteoporosis aged 55-85years with a lumbar spine, total hip, or femoral neck dual-energy X-ray absorptiometry T-score≤-2.5. Women were randomized to receive placebo or romosozumab (70, 140, or 210mg) subcutaneously once monthly (QM) for 12months. The primary efficacy endpoint was the percentage change from baseline in lumbar spine BMD at month 12. Secondary efficacy endpoints included the percentage change from baseline in lumbar spine BMD at month 6, total hip and femoral neck BMD at months 6 and 12, and serum bone turnover markers procollagen type 1N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at multiple visits. RESULTS: This study enrolled 252 women who had a mean age of 67.7years and mean T-scores of -2.7, -1.9, and -2.3 at the lumbar spine, total hip, and femoral neck, respectively. All romosozumab doses significantly increased BMD at month 12 compared with placebo (p<0.01), with the largest mean gains from baseline observed with romosozumab 210mg QM (lumbar spine=16.9%, total hip=4.7%, and femoral neck=3.8%). All doses of romosozumab significantly increased the levels of bone-formation marker P1NP and reduced the levels of bone-resorption marker CTX by week 1 (p<0.001 vs placebo). In the 210mg QM group, P1NP levels peaked at month 1 and fell below placebo levels by month 12; CTX levels were lowest at week 1 and remained below placebo through month 12. The patient incidences of adverse events and serious adverse events were generally comparable between treatment groups. CONCLUSIONS: In postmenopausal Japanese women with osteoporosis, romosozumab treatment resulted in large and significant gains in BMD from baseline and compared with placebo. Romosozumab 210mg QM showed the largest gains in BMD and was generally well tolerated. The efficacy and safety of romosozumab 210mg QM in this phase 2 study of postmenopausal women with osteoporosis were similar to those in an international phase 2 study.

Predictability and stability of laser-assisted subepithelial keratectomy with mitomycin C for the correction of high myopia.

The purpose of this study was to evaluate the predictability and stability of laser-assisted subepithelial keratectomy (LASEK) with mitomycin C (MMC) in correction of high myopia (≤-6.0 diopters [D]) as compared to low-to-moderate myopia (>-6.0 D).This is a retrospective, comparative, cohort study which included 43 eyes of 43 consecutive patients who underwent LASEK with MMC in a private hospital in Hong Kong by a single surgeon. Twenty-five eyes had high myopia (mean spherical equivalent [SE] = -8.53 ±â€Š1.82 D) and 18 eyes had low-to-moderate myopia (mean SE = -3.99 ±â€Š1.37 D) before surgery.In terms of refractive predictability, mean SE was significantly better in eyes with preoperative low-to-moderate myopia than high myopia at 6 months (0.04 ±â€Š0.23 vs 0.31 ±â€Š0.52 D, P = .035). In terms of refractive stability, between 1 and 3 months, both groups had mean absolute change of SE of around 0.25 D. Between 3 and 6 months, preoperative low-to-moderate myopia group had significantly less absolute change of SE compared to high myopia group (0.07 vs 0.23 D, P = .003). More eyes with preoperative high myopia changed SE by more than 0.25 D than those with low-to-moderate myopia between 3 and 6 months (32.0% vs 5.6%, P = .057).In conclusion, LASEK with MMC is more unpredictable and unstable in correction of high myopia than low-to-moderate myopia. The refractive outcome of most low-to-moderate myopia correction stabilizes at 3 months. Stability is not achieved until after 6 months in high myopia correction.

Serial Spectral-Domain Optical Coherence Tomography Findings in Acute Retinal Pigment Epitheliitis and the Correlation to Visual Acuity.

PURPOSE: To evaluate the features of acute retinal pigment epitheliitis (ARPE) at onset and in the course of recovery by serial spectral-domain optical coherence tomography (SD OCT) and the correlation to visual acuity (VA). DESIGN: Retrospective cohort study. PARTICIPANTS: Consecutive patients with ARPE. METHODS: A review of medical records was performed. MAIN OUTCOME MEASURES: Integrity of SD OCT retinal bands at onset and in the course of disease, time required to achieve each retinal band restoration, corresponding VA change, and final VA. RESULTS: Four patients were included. Initial SD OCT showed a dome-shaped hyper-reflective lesion at the photoreceptor outer segment layer disrupting the ellipsoid zone (EZ) and interdigitation zone (IZ) (100%). In the early phase, there was also upward displacement of the external limiting membrane (ELM) and mild transient thickening of the retinal pigment epithelium (RPE)/Bruch's complex (Bc). Acute retinal pigment epitheliitis resolved in a sequence of (1) a decrease in height of SD OCT hyper-reflective lesion and the upwardly displaced ELM returning to its normal position with irregularity; (2) complete disappearance of the hyper-reflective lesion; (3) restoration of ELM; (4) restoration of EZ; and (5) restoration of IZ. The average time to restore ELM, EZ, and IZ was 4.3±5.2, 7.3±7.2, and 12.5±12.4 weeks, respectively, and the corresponding logarithm of the minimum angles of resolution (logMAR) VAs were 0.24±0.23, 0.09±0.07, and 0.05±0.06, respectively. Visual acuity improved when IZ was restored. CONCLUSIONS: Early SD OCT revealed an inflammatory lesion in the photoreceptor outer segment layer displacing ELM. The RPE was involved only mildly and transiently. Recovery occurred in a sequence of ELM, EZ, and IZ restoration, and VA improved when the IZ was restored. These features suggested that the IZ (i.e., the contact between photoreceptors and RPE) is the primary site of inflammation in ARPE.

Adiporedoxin suppresses endothelial activation via inhibiting MAPK and NF-κB signaling.

Adiporedoxin (Adrx) is a recently discovered redox regulatory protein that is preferentially expressed in adipose tissue and plays a critical role in the regulation of metabolism via its modulation of adipocyte protein secretion. We here report that Adrx suppresses endothelial cell activation via inhibiting MAPK and NF-kB signaling pathways. Adrx is constitutively expressed in human vascular endothelial cells, and significantly induced by a variety of stimuli such as TNFα, IL-1ß, H2O2 and OxLDL. Overexpression of Adrx significantly attenuated TNFα-induced expression of VCAM-1 and ICAM-1, and thus reduced monocyte adherence to human umbilical vein endothelial cells (HUVECs). Conversely, siRNA-mediated knockdown of Adrx increased TNFα-induced expression of adhesion molecules and monocyte adherence to HUVECs. Furthermore, forced expression of Adrx decreased TNFα-induced activation of ERK1/2, JNK, p38 and IKKs in HUVECs. Adrx mutant in the CXXC motif that lost its anti-redox activity is less efficient than the wild-type Adrx, suggesting that Adrx-mediated inhibition of endothelial activation is partially dependent on its antioxidant activity. Finally, Adrx expression was markedly increased in human atheroma compared with normal tissue from the same carotid arteries. These results suggest that Adrx is an endogenous inhibitor of endothelial activation, and might be a therapeutic target for vascular inflammatory diseases.

A Case Report: Anti-Psychotic Agents Related Ocular Toxicity.

Chlorpromazine is known to cause ocular pigmentary deposits. However, delayed presentation after cessation of chlorpromazine has not been reported. There are also no reports on whether newer generation of anti-psychotic agents contribute to ocular toxicity. We describe a case of ocular toxicity related to anti-psychotic agents. To the best of our knowledge, this is the first reported case of anterior segment pigmentary deposits associated with olanzapine use, 2 years after the cessation of chlorpromazine. We report a case of ocular toxicity in a patient with history of chlorpromazine usage of 100 mg per day for 13 years and subsequently switched to olanzapine 5 mg for 2 years. There were no signs of ocular toxicity while the patient was on chlorpromazine. However, when the patient switched to olanzapine, she developed the ocular side effect as described for chlorpromazine-induced ocular toxicity, with pigmentary depositions on both corneas and the anterior lens surface and decrease in vision. Olanzapine, a newer anti-psychotic agent, may play a role in the ocular pigmentary deposition, either directly causing pigmentary deposition itself or accentuating the effect of chlorpromazine as the 2 drugs act on the same receptors, although further studies are required to support this hypothesis. As patients with psychiatric conditions may not voluntarily complain of visual symptoms, ocular screening could be considered in these patients receiving chronic anti-psychotic treatment, so that any ocular toxicity could be diagnosed in a timely manner.

Long-term Follow-up of Cytomegalovirus Retinitis in Non-HIV Immunocompromised Patients: Clinical Features and Visual Prognosis.

PURPOSE: To evaluate clinical features and long-term visual outcome of cytomegalovirus (CMV) retinitis in patients without human immunodeficiency virus (HIV) infection, and to determine factors that predict visual outcome. DESIGN: Retrospective cohort study. METHODS: Consecutive patients with CMV retinitis without HIV infection were reviewed. Main outcome measures included clinical features, proportion of eyes with 6-month and final visual acuity (VA) <20/70 and <20/400, and odds ratios of factors associated with poor visual outcome. RESULTS: A total of 20 eyes from 13 patients were included with a median follow-up time of 17 months. All had at least 6 months of follow-up except 1 patient who died from sepsis at 1 month. At presentation, 50% of eyes had VA <20/70 and 25% had VA <20/400. Zone 1 involvement occurred in 55% and vitreous haze ≥grade 2+ occurred in 25%. Recurrence occurred in 33.3% at a mean time of 6.4 ± 3.3 weeks after discontinuation of anti-CMV therapy. The retinal detachment rate was 21.7% per eye-year and mortality rate was 11.7% per person-year. At final visit, 60% had VA <20/70 and 35% had VA <20/400. Macular involvement was significantly associated with poor final VA <20/400 (odds ratio = 25.00, P = .016). CONCLUSIONS: CMV retinitis without HIV infection was often aggressive at presentation. Significant intraocular inflammation was not uncommon. The long-term visual outcome was poor, especially in those with macular involvement.

Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid.

PURPOSE: Denosumab was shown to be superior to zoledronic acid in preventing skeletal related events (SRE) in patients with breast cancer and bone metastases in a randomized, double-blind phase III study. We evaluated further results from this study related to skeletal complications and health-related quality of life (HRQoL). EXPERIMENTAL DESIGN: Patients were randomized 1:1 to receive subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. Analyses reported here include the proportion of patients with one or multiple on-study SREs, time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in HRQoL (functional assessment of cancer therapy-general). RESULTS: Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%, P = 0.006). The incidence of first radiation to bone was 12% (n = 123) with denosumab versus 16% (n = 162) with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid (HR, 0.74; 95% confidence interval [CI], 0.59-0.94, P = 0.012) and prolonged the time to first SRE or hypercalcemia of malignancy by 18% (HR, 0.82; 95% CI, 0.70-0.95; P = 0.007). Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels. CONCLUSIONS: Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained HRQoL, providing an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer.

Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.

PURPOSE: This randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases. PATIENTS AND METHODS: Patients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n = 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). RESULTS: Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P = .39). CONCLUSION: Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.

Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate.

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double-blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C-telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (-2.1% to -0.8%) at the distal radius after 12 months. Alendronate prevented the decline (-0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p < or = .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab.

Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study.

Denosumab increased lumbar spine bone mineral density (BMD) versus placebo in a 2-year, randomized, placebo-controlled, phase 3 study of patients with hormone-receptor-positive, non-metastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy. In subgroup analyses at 12 and 24 months, we evaluated factors (duration and type of aromatase inhibitor, tamoxifen use, age, time since menopause, body mass index, T-score) that might influence BMD at the lumbar spine, total hip, femoral neck, and 1/3 radius. Patients were randomized to receive placebo (n = 125) or 60 mg denosumab (n = 127) subcutaneously every 6 months. In all subgroups, 12 or 24 months' treatment with denosumab was associated with larger BMD gains than placebo across multiple skeletal sites. Most increases were statistically significant (P < 0.05). Twice-yearly administration of denosumab, regardless of patient subgroup or skeletal site, resulted in consistent increases in BMD versus placebo at 12 and 24 months.