History of etidronate.

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.

Oral Dextromethorphan for the Treatment of Diabetic Macular Edema: Results From a Phase I/II Clinical Study.

PURPOSE: The activation of microglia, the primary innate immune cell resident in the retina, produces inflammatory mediators, which underlie changes in diabetic retinopathy including increased vascular permeability. This study evaluates the safety and efficacy of dextromethorphan, a drug capable of inhibiting microglial activation, in the treatment of diabetic macular edema (DME). METHODS: A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with macular involving DME who received oral dextromethorphan 60 mg twice daily for 6 months as monotherapy. Main outcome variables included central retinal subfield thickness (CST), best-corrected visual acuity (BCVA), macula sensitivity, and late leakage on fluorescein angiogram (FA). RESULTS: The study drug was well tolerated. At the primary end point of 6 months, mean CST decreased by -6.3% ± 6.8% and BCVA increased by +0.6 ± 5.11 (mean ± SEM) letters. Late leakage on FA was scored as improved in four of five study eyes. These findings were not correlated with changes in hemoglobin A1c (HbA1c), creatinine, or blood pressure. CONCLUSIONS: In this proof-of-concept study, dextromethorphan administration as the primary treatment for DME was associated with decreased vascular leakage, suggesting possible therapeutic effects. Additional studies investigating the modulation of microglial activation is warranted. TRANSLATIONAL RELEVANCE: These findings highlight microglial modulation as a potentially useful therapeutic strategy in the treatment of diabetic macular edema.

Evolution of Geographic Atrophy in Participants Treated with Ranibizumab for Neovascular Age-related Macular Degeneration.

PURPOSE: To evaluate the risk factors, incidence, and rate of progression of geographic atrophy (GA) in eyes with neovascular age-related macular degeneration (nAMD) treated with ranibizumab. DESIGN: Post-hoc analysis of a prospective clinical study. PARTICIPANTS: 69 participants with nAMD in at least one eye. METHODS: Participants were prospectively treated in the study eye with 0.5 mg intravitreal ranibizumab. Study eyes received 4 monthly injections followed by pro re nata injections until a fluid-free macula was achieved on optical coherence tomography. Risk factors assessed included baseline demographics, treatment, and ocular characteristics on imaging. Eyes were evaluated on fundus autofluorescence (FAF) for GA. The rate of GA area growth in study and fellow eyes was analyzed by linear regression of square-root transformed areas. MAIN OUTCOME MEASURES: Development of new-onset GA and rate of GA area growth measured on ocular imaging, including FAF images of the study eyes. RESULTS: Sixty-nine participants (mean age 78.8±7.8 years) with an average of 40.0±13.6 months of follow-up were analyzed. Twenty-two of 69 study eyes (32%) were treatment naïve. During their first year of the study, participants received an average of 9.2±3.3 injections in the study eye. Of 63 study eyes with quality baseline images, 22 (35%) had pre-existing GA. Of the remaining 41 eyes, 7 (17%) developed new-onset GA during study follow-up. Those who developed new GA were older (all ≥79 years old) and had received fewer study injections on average (6.9 vs. 10.4 injections at 1 year) compared to those who did not develop new GA. Of the 12 treatment naïve study eyes without GA at baseline, 1 (8.3%) developed new GA during the study. In 21 study eyes with quantifiable GA area, eyes with GA present at baseline (16/21) enlarged by 0.34±0.26 mm/year, compared to 0.19±0.12 mm/year in eyes developing new-onset GA (5/21). CONCLUSIONS: While 17% of study eyes without GA present at baseline receiving ranibizumab developed new GA, the role of ranibizumab in the development of GA is unclear. Further prospective longitudinal studies are required to determine the eyes most at risk of developing GA in the setting of anti-VEGF treatment.

Gevokizumab in the Treatment of Autoimmune Non-necrotizing Anterior Scleritis: Results of a Phase I/II Clinical Trial.

PURPOSE: To evaluate the safety and potential efficacy of gevokizumab, an anti-interleukin 1ß (IL-1ß) monoclonal antibody, in the treatment of active, noninfectious, non-necrotizing anterior scleritis. DESIGN: Phase 1/2, open label, nonrandomized, prospective, single-arm pilot trial. METHODS: Eight patients with active, noninfectious, non-necrotizing anterior scleritis with a scleral inflammatory grade of +1 to +3 in at least 1 eye were enrolled. In 1 patient both eyes were enrolled, for a total of 9 eyes (4 eyes with +1, 1 eye with +2, and 4 eyes with +3). Patients received 1 subcutaneous injection of 60 mg gevokizumab at baseline and then every 4 weeks for 12 weeks. Complete physical and ocular examinations were performed at each visit. The primary outcome was at least a 2-step reduction or reduction to grade 0 in scleral inflammation on a 0 to +4 scale according to a standardized photographic scleritis grading system by 16 weeks in the study eye compared to baseline. Secondary outcomes included changes in visual acuity, intraocular pressure, and trends in scleral grading. Participants who met the primary outcome were eligible to continue in the study for up to 52 weeks and received additional gevokizumab injections every 4 weeks until week 36, followed by 2 safety visits at weeks 40 and 52. RESULTS: Seven eyes from 7 patients met the primary outcome within a median time of 2 weeks following the first gevokizumab injection. No definitive changes in visual acuity or intraocular pressure were identified. There were no serious adverse events related to the study drug. A total of 43 adverse effects were reported, with 93% described as mild, 95% as nonocular, and only 14% deemed possibly caused by the investigational treatment. CONCLUSIONS: The results of this small study suggest that blockage of IL-1ß using gevokizumab may be beneficial in treating active, noninfectious anterior scleritis and that gevokizumab is well tolerated. Larger randomized trials are warranted to assess the true efficacy of gevokizumab in the treatment of non-necrotizing anterior scleritis.

Embyronal carcinoma of testis metastatic to ciliary body presenting as spontaneous hyphema and painful secondary glaucoma.

PURPOSE: To report a rare presentation of metastatic testicular cancer to the uvea. METHODS: Observational case report. RESULTS: A 24-year-old man without known systemic illness presented with acute total loss of vision and severe pain in his left eye and associated nausea, anorexia, and dehydration. He was found to have a total hyphema, high intraocular pressure, and a ciliary body mass (by computed tomography scan and ultrasound biomicroscopy). The affected eye was enucleated, and pathologic study showed a hemorrhagic poorly differentiated neoplasm of the ciliary body. Subsequent patient evaluation revealed a primary testicular embryonal carcinoma with widespread metastasis. CONCLUSION: This case represents the first report of a metastasis from a testicular carcinoma to the ciliary body and the first tumor of this type to be associated with spontaneous hyphema.

Type 2 diabetes in the pediatric population: Are we meeting ADA clinical guidelines in Ohio?

Several studies have demonstrated the importance of achieving the American Diabetes Association (ADA) clinical guidelines in adults. However, research is limited on adherence to these guidelines in the pediatric population. This retrospective chart review examined 56 charts from 6 physician offices and 1 multispecialty health care system in Ohio. Variables of interest included recommendations from the 2007 ADA Standards of Medical Care in Diabetes. HgA1c was measured every 3 months in 44.6% of patients, while 55% achieved A1c goal. Blood pressure was monitored in all patients, with 57% meeting goal. Lipids and urine microalbumin were tested annually in 51.7% and 26.7% of patients, respectively. Dilated eye and foot exams were performed on 53.5% and 37.5% of patients, respectively. Adherence to ADA clinical guidelines for pediatric patients with type 2 diabetes is suboptimal. The authors recommend that specific evidence-based guidelines be evaluated for children with type 2 diabetes.

Hospitalization-related bone loss and the protective effect of risedronate.

Intercurrent illness and episodes of hospitalization and surgery are common in an aging population, who, at the same time, are experiencing age-related bone loss. The objective was to test the hypotheses (1) that intercurrent illness severe enough to require hospitalization produces clinically important bone loss, and (2) that antiresorptive therapy will reduce that loss. The study was a retrospective analysis of bone mineral density (BMD) change at hip and spine in subjects of the risedronate postmenopausal osteoporosis phase III trials experiencing serious adverse events (SAEs). Subjects were 243 hospitalized for non-skin cancers, pneumonia, myocardial infarction, cerebrovascular accident, gallbladder disease, and pancreatitis, on whom BMD data were available both before and after the SAE; and 286 non-hospitalized control subjects matched to those with SAEs by age, height, weight, prevalent fracture, and visit interval. In hospitalized, placebo-treated participants, the annualized percent change in BMD (mean+/-SEM) across the period of hospitalization was -0.65+/-0.39 at lumbar spine, -1.13+/-0.55 at femoral neck, and -2.66+/-0.58 at femoral trochanter; the corresponding values for the non-hospitalized, placebo controls were +0.46+/-0.28, -0.77+/-0.34, and -0.67+/-0.34. These values were more negative at all three sites for the hospitalized subjects, and significantly so at lumbar spine and femoral trochanter (P=0.019 and 0.002, respectively). By contrast, in the risedronate-treated participants, all sites exhibited bone gain and there was no significant difference between hospitalized and non-hospitalized participants. Intercurrent illness resulting in hospitalization produced a rapid bone loss across the period of illness comparable in magnitude to documented age-related loss. Risedronate in a dose of 5 mg/day effectively abolished this loss.

Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173].

To determine the efficacy and safety of risedronate in patients with knee osteoarthritis (OA), the British study of risedronate in structure and symptoms of knee OA (BRISK), a 1-year prospective, double-blind, placebo-controlled study, enrolled patients (40-80 years of age) with mild to moderate OA of the medial compartment of the knee. The primary aims were to detect differences in symptoms and function. Patients were randomized to once-daily risedronate (5 mg or 15 mg) or placebo. Radiographs were taken at baseline and 1 year for assessment of joint-space width using a standardized radiographic method with fluoroscopic positioning of the joint. Pain, function, and stiffness were assessed using the Western Ontario and McMaster Universities (WOMAC) OA index. The patient global assessment and use of walking aids were measured and bone and cartilage markers were assessed. The intention-to-treat population consisted of 284 patients. Those receiving risedronate at 15 mg showed improvement of the WOMAC index, particularly of physical function, significant improvement of the patient global assessment (P < 0.001), and decreased use of walking aids relative to patients receiving the placebo (P = 0.009). A trend towards attenuation of joint-space narrowing was observed in the group receiving 15 mg risedronate. Eight percent (n = 7) of patients receiving placebo and 4% (n = 4) of patients receiving 5 mg risedronate exhibited detectable progression of disease (joint-space width >or= 25% or >or= 0.75 mm) versus 1% (n = 1) of patients receiving 15 mg risedronate (P = 0.067). Risedronate (15 mg) significantly reduced markers of cartilage degradation and bone resorption. Both doses of risedronate were well tolerated. In this study, clear trends towards improvement were observed in both joint structure and symptoms in patients with primary knee OA treated with risedronate.

Efficacy of risedronate on clinical vertebral fractures within six months.

OBJECTIVE: Postmenopausal osteoporotic women with pre-existing or new incident vertebral fractures are at high risk for future fracture, so prompt treatment is warranted. Risedronate has been shown to reduce the incidence of radiographically-defined vertebral fractures by approximately two-thirds within 1 year. RESEARCH DESIGN: This study examined the effects of risedronate treatment on the time course of the reduction in the risk of clinical vertebral fractures (i.e., symptomatic fractures), on the risk of moderate-to-severe radiographic vertebral fractures, and on height. RESULTS: In 2442 postmenopausal women with prevalent vertebral fractures from the Vertebral Efficacy with Risedronate Therapy (VERT) studies who received either risedronate 5 mg or placebo, daily risedronate reduced the risk of clinical vertebral fractures within 6 months (RR = 0.08, 95% CI 0.01-0.63), and by 69% at 1 year (RR = 0.31, 95% CI 0.12, 0.78). At 1 year, risedronate also reduced the risk of moderate-to-severe radiographically-defined vertebral fractures by 71% (RR = 0.29 95% CI 0.16, 0.54). Height loss was attenuated with treatment, most notably in patients who experienced new vertebral fractures, with a median difference of 0.73 cm compared with subjects receiving placebo (p = 0.005). CONCLUSION: Risedronate reduces the risk of clinical vertebral fractures in postmenopausal women with osteoporosis within 6 months of commencing treatment.