Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial.

UNLABELLED: In a phase 2 study, continued denosumab treatment for up to 8 years was associated with continued gains in bone mineral density and persistent reductions in bone turnover markers. Denosumab treatment was well tolerated throughout the 8-year study. INTRODUCTION: The purpose of this study is to present the effects of 8 years of continued denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTM) from a phase 2 study. METHODS: In the 4-year parent study, postmenopausal women with low BMD were randomized to receive placebo, alendronate, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo for two more years. The parent study was then extended for 4 years where all subjects received denosumab. RESULTS: Of the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab treatment, BMD at the lumbar spine (N = 88) and total hip (N = 87) increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in BTM were sustained over the course of continued denosumab treatment. Reductions also were observed when the placebo group transitioned to denosumab. Adverse event profile was consistent with previous reports and an aging cohort. CONCLUSION: Continued denosumab treatment for 8 years was associated with progressive gains in BMD, persistent reductions in BTM, and was well tolerated.

Human adipose-derived stem cells as future tools in tissue regeneration: osteogenic differentiation and cell-scaffold interaction.

Tissue engineering is now contributing to new developments in several clinical fields, and mesenchymal stem cells derived from adipose tissue (hASCs) may provide a novel opportunity to replace, repair and promote the regeneration of diseased or damaged musculoskeletal tissue. Our interest was to characterize and differentiate hASCs isolated from twenty-three donors. Proliferation, CFU-F, cytofluorimetric and histochemistry analyses were performed. HASCs differentiate into osteogenic, chondrogenic, and adipogenic lineages, as assessed by tissue-specific markers such as alkaline phosphatase, osteopontin expression and deposition of calcium matrix, lipid-vacuoles formation and Glycosaminoglycans production. We also compared osteo-differentiated hASCs cultured on monolayer and loaded on biomaterials routinely used in the clinic, such as hydroxyapatite, cancellous human bone fragments, deproteinized bovine bone granules, and titanium. Scaffolds loaded with pre-differentiated hASCs do not affect cell proliferation and no cellular toxicity was observed. HASCs tightly adhere to scaffolds and differentiated-hASCs on human bone fragments and bovine bone granules produced, respectively, 3.4- and 2.1-fold more calcified matrix than osteo-differentiated hASCs on monolayer. Moreover, both human and deproteinized bovine bone is able to induce osteogenic differentiation of CTRL-hASCs. Although our in vitro results need to be confirmed in in vivo bone regeneration models, our data suggest that hASCs may be considered suitable biological tools for the screening of innovative scaffolds that would be useful in tissue engineering.

Surgical versus non-surgical endodontic re-treatment for periradicular lesions.

BACKGROUND: Though success rates of endodontic initial treatment have been improving over the years, persistence of periapical disease is far from being a rare condition. The most common therapeutical options for the re-treatment of teeth with periapical pathosis are non-surgical orthograde treatment and surgical treatment. Selection between alternative treatments should be based on assessment of respective benefits (mainly healing) and risks from studies consistent with a high level of evidence. OBJECTIVES: To test the null hypothesis of no difference in outcome between surgical and non-surgical therapy for endodontic re-treatment of periradicular lesions. SEARCH STRATEGY: The Cochrane Oral Health Group Trials Register, CENTRAL, MEDLINE and EMBASE were searched with appropriate search strategies. Handsearching included eight dental journals. The bibliographies of relevant clinical trials and relevant articles were checked for identifying studies outside the handsearched journals. Seven manufacturers of instruments in the field of endodontics or endodontic surgery or both, as well as the authors of the identified randomised controlled trials (RCTs) were contacted in order to identify unpublished or ongoing RCTs. No language restriction was placed. The last electronic search was conducted on 3rd April 2007. SELECTION CRITERIA: All RCTs about re-treatment of teeth with periapical pathosis in which both surgical and non-surgical approaches were used and having a follow up of at least 1 year were considered for the analysis. DATA COLLECTION AND ANALYSIS: A quality assessment of the included RCTs was carried out and the authors were contacted for missing information. We independently extracted the data in duplicate. We followed the Cochrane Oral Health Group's statistical guidelines. MAIN RESULTS: Three RCTs were identified, two of them reporting different data from the same clinical study. The risk of bias was judged as moderate for one study and high for the other one. 126 cases were followed up for at least 1 year, and 82 had a follow up of 4 years. At the 1-year follow up the success rate for surgical treatment was slightly better than non-surgical (risk ratio (RR) 1.13; 95% confidence interval (CI) 0.98 to 1.30). When the follow up was extended to 4 years (only one RCT made it) the outcome for the two procedures became similar. AUTHORS' CONCLUSIONS: The finding that healing rates can be higher for cases treated surgically as compared to those treated non-surgically, at least in the short term, is based on two RCTs only. A single RCT reported that in the medium to long term healing rates for the two procedures are very similar. There is currently scarce evidence for a sound decision making process among alternative treatments for the re-treatment of a periradicular pathosis. More well-designed RCTs should be performed with follow up of at least 4 years, and with a consistent sample size, to detect a true difference in the long term between the outcomes of the two alternative treatments, if any exist.

[Double blind placebo-controlled study on efficacy, acceptability and safety of mouthwash diclofenac in oral or periodontal postoperative period]. / Studio controllato a doppia cecità verso placebo su efficacia, accettabilità e tollerabilità di diclofenac collutorio nel posoperatorio orale o parodontale.

BACKGROUND: In a double blind clinical study the efficacy, acceptability and safety of a mouthwash containing diclofenac 0.074% DI-CO in patients undergone to oral or periodontal surgery was evaluated compared to placebo. METHODS: The design was a randomised double blind controlled clinical study. The patients rinsed for 1 min twice a day with diclofenac mouthwash or placebo (15 mL) at least after 1 hour since the chlorhexidine rinse for 7 days. Indistinguishable bottles and same appearance of the formulations guaranteed the reliability of the blindness. Pain at 8.00 pm the day of surgery and at 8.00 am the following day, inflammatory condition 24 hours after intervention, acceptability and safety were the parameters evaluated. Fifty (30 M, 20 F), mean aged 31.7 years, with pain score at the end of anaesthesia effect equivalent to 3.25 (semi-quantitative scale) were treated. At baseline the vital characteristics and the severity of the clinical condition were homogeneous in the two groups. RESULTS: The mean severity score was significantly lower on DI-CO than the one showed on placebo both at 8.00 pm the day of surgery (p=0.003) and at 8.00 am the following day (p= 0.001). The gingival inflammatory condition were significantly improved by DI-CO versus placebo (p<0.001). The good safety and pleasant palatability were similar for both treatments. CONCLUSIONS: Diclofenac mouthwash presented very good efficacy and safety in the treatment of oral cavity phlogosis due to oral or periodontal surgery.

Immediate loading of Osseotite implants: a case report and histologic analysis after 4 months of occlusal loading.

A growing number of clinical reports show that early and immediate loading of endosseous implants may lead to predictable osseointegration; however, these studies provide mostly short- to mid-term results based only on clinical mobility and radiographic observation. Other methods are needed to detect the possible presence of a thin fibrous interposition of tissue that could increase in the course of time and lead to clinical mobility A histologic evaluation was performed on two immediately loaded Osseotite implants retrieved after 4 months of function from one patient. He had received a total of 12 implants in the mandible, of which six were immediately loaded and six were left to heal in a submerged way Clinical and histologic osseointegration was consistently achieved for both of the retrieved immediately loaded implants. Osteogenesis and bone remodeling on the Osseotite surface were not impeded by immediate loading as shown by histomorphometric evaluation, which revealed high levels of bone-to-implant contact ranging from 78% to 85%. This immediate loading protocol involving bilateral splinting of six Osseotite implants in the mandible proved to be successful after 4 months of loading. Further long-term clinical and histologic studies are needed before introducing this immediate loading protocol as a routine procedure in implant therapy.

Fluid dynamics of gingival tissues in transition from physiological condition to inflammation.

BACKGROUND: An increase in gingival sulcular fluid filtration is a common clinical sign of early gingivitis. The aim of this study was to describe the fluid dynamics of the gingival interstitial tissues at the level of the sulcus in the transition towards inflammation. METHODS: In 13 anesthetized rabbits, a silk ligature was placed around incisors close to the gingival margin, in order to prevent mechanical cleaning of plaque deposition. After 2 to 7 days, animals were anesthetized and interstitial fluid pressure measured using glass micropipettes connected to a servonull pressure system at the level of the free and attached gingiva. RESULTS: Interstitial pressure was 3.8 +/- 2.9 cmH2O, significantly higher than the normal physiological value (about -1 cmH2O). Colloid osmotic pressure of interstitial fluid samples collected using the wick technique was measured using an osmometer whose membrane had a molecular cut-off of 30 kD and averaged 12.8 +/- 2.8 cmH2O (unchanged relative to control). Mean gingival sulcular fluid flow, measured by placing a PE tube (0.5 mm OD, 0.28 mm ID) in the sulcus, was 0.16 +/- 0.12 microl/h; the mean colloid osmotic pressure was 13.6 +/- 6.6 cmH2O, corresponding to a protein concentration of approximately 2.8 g/dl. Proteins of gingival fluid may leak from inflamed gingival interstitium or derive from bacteria of dental plaque. Histological analysis of gingival biopsies showed neutrophilic polymorphonuclear leukocyte infiltrates in both the dermis and epidermis layer. CONCLUSIONS: Based on hydraulic and colloid osmotic data, the Starling pressure gradient favored filtration from gingival interstitium to the sulcular space, a condition opposite to that observed in healthy gingiva where fluid filtration is absent.

[Neutrophil physiology: role and mechanism of action in the immune response at gingival level]. / Fisiologia dei neutrofili: ruolo e meccanismi di azione nella risposta immune a livello dei tessuti gengivali.

Polymorphonuclear neutrophil granulocytes (PMN) are considered the most important cells of the host immune response against bacterial challenge. The functional mechanism of PMN consists of different steps: tethering, rolling, primary adhesion to the vascular wall, firm adhesion to the activated endothelium in the inflamed region, trans-migration across endothelium, chemotaxis, contact with the bacterium and phagocytosis and, finally, killing of the micro-organism by releasing hydrolytic enzymes and/or by production of toxic substances such as free radicals. Each of these steps is controlled by interactions between cells and many components of the immune system or inflammatory mediators. These interactions generate specific signals, important for cell regulation. Recent technological advances in molecular biology and immunobiology allowed to disclose the precise role of various molecules involved in the immune response, that regulate PMN function; conversely, more factors have been identified, whose role is still unknown. In the process of adhesion, for example, many classes of molecules are involved (selectins, integrins, ICAMs). The interaction of these molecules (es.: selectin) with their ligands (non completely discovered) is characteristic of specific stages, but may also regulate the successive steps (integrin activation). In periodontal infections, PMNs of gingival tissue migrate towards bacteria of dental plaque along a chemotactic gradient of specific factors (ICAM-1, IL-8) produced by cells of the junctional epithelium. Such gradient is essential to drive PMNs through molecular traffic. Among the mechanisms used by PMNs to kill bacteria, the importance of nitric oxide (NO) production has been recently pointed out.

Chlorhexidine spray versus chlorhexidine mouthwash in the control of dental plaque after periodontal surgery.

BACKGROUND/AIMS: This clinical trial aimed at comparing 2 different means of delivering chlorhexidine digluconate (CHX) in the oral hygiene phase during the 2 weeks following periodontal surgery. METHOD: 40 patients were randomly divided into 2 groups: A (using CHX mouthwash) and B (using CHX spray). Professional oral hygiene was carried out immediately before surgical operation. For 7 days after surgery, group A used CHX mouthwash and group B CHX spray on the teeth involved in the surgical procedure, while mechanical oral hygiene was maintained only on the teeth not involved surgically. After suture removal, on the 7th day, patients were allowed to perform mechanical oral hygiene also on surgical sites. Plaque index (PI) and stain index (SI) were evaluated on the 7th and 14th days after the operation. RESULTS: In both groups, PI increased similarly with respect to the baseline in surgically involved teeth, being 0.25+/-0.41 (SD) and 0.15+/-0.26, respectively, in A and B, on day 7, and 0.14+/-0.23 (A) and 0.10+/-0.22 (B), on day 14. There was no significant difference between A and B on either day 7 or 14. On the contrary, SI increased significantly in respect to the baseline over the 14 days in group A at both involved and not involved sites, while it did not differ from the baseline in group B. CONCLUSIONS: The present results indicate that the efficacy of CHX spray in the post-surgical control of dental plaque is not different from that of CHX mouthwash. Tooth staining, on the contrary, was significantly lower in the group using CHX spray. The observed effects might be related to the way of delivering CHX and to the total dose administered, about 80% lower in group B in respect to A. Further studies are needed to validate the preliminary findings of the present study.

[Congenital neutrophil defects and periodontal diseases]. / Difetti congeniti dei neutrofili e malattia parodontale.

An alteration of the immune system function is one of the main factors involved in the development of periodontal disease. Polymorpho-nuclear neutrophil leukocytes (PMN) play a crucial role in the cell-mediated immune response against bacterial challenge. The mechanism of neutralization of pathogen microorganisms by PMNs involves many different steps: adhesion to capillary endothelium in the inflamed region, trans-endothelial migration, chemotaxis, phagocytosis and, ultimately, bacterial killing by oxidative and non-oxidative mechanisms. A defect in one of these steps leads to altered neutrophil function and, consequently, to a higher host susceptibility to periodontal tissue infection. The main intrinsic neutrophil diseases such as neutropenia, leukocyte adhesion deficiency (LAD-1), Chediak-Higashi syndrome, Papillon-Lefèvre syndrome, chronic granulomatous disease (CGD), are often related to severe and early-onset forms of periodontitis, as described by many evidences in the literature. Therefore PMN dysfunctions, both intrinsic and extrinsic, represent an important risk factor for periodontal disease. Studies on the basic molecular mechanisms of such dysfunctions, also in terms of genetic polymorphisms, recently allowed to identify some specific markers related to a higher susceptibility to the development of disease. Many researches have yet to be performed aiming to gain insight on the dynamics of PMN activation and interaction with other cells, in order to improve and modulate neutrophil function and to develop specific approaches for care and prevention of periodontal diseases.

Success and failure in periradicular surgery: a longitudinal retrospective analysis.

The objective of the present study was to compare the success rates of 2 different periapical surgical techniques, the traditional technique with rotary instruments and the ultrasonic technique, which uses ultrasonic retrotips. A longitudinal retrospective study was carried out on 302 apices (181 teeth) that had undergone periapical surgery. Surgical outcome was evaluated by 2 independent operators using standardized periapical radiographs. Each radiographic finding was classified into 1 of 4 groups: complete healing, incomplete healing, uncertain healing, and unsatisfactory outcome (failure). An SAS statistical analysis system was used for data management and analysis. Prognostic factors were determined by means of the Fisher exact test. Complete healing after 4.6 years (the average follow-up period) was observed in 68% of the teeth treated through the use of the standard technique and 85% of those treated through the use of the ultrasonic technique. The success rate increased as the follow-up period lengthened (68.4% at 2 years vs 80% at 6 years). The success rate was higher in maxillary (77.9%) than in mandibular (66.1%) teeth. A comparison between the retrofilling materials was not feasible because all teeth in the standard technique group were retrofilled with amalgam and all teeth in the ultrasonic group were retrofilled with Super-EBA.

A human histologic analysis of osseotite and machined surfaces using implants with 2 opposing surfaces.

A human histologic study was conducted to compare the percentage of bone-to-implant contact (BIC) at 6 months for Osseotite and machined, commercially pure titanium implant surfaces. To eliminate potential influences caused by differences in bone density at different intraoral locations, 2 mm x 5 mm, threaded, 2-surfaced titanium implants were manufactured; 1 side received the Osseotite surface modification and the opposite side maintained a machined surface. In each of 11 patients, 1 test implant was placed in the posterior maxilla (Types III and IV bone) during conventional dental implant surgery. Following 6 months of unloaded healing, the conventional implants were uncovered, and the test implants and surrounding hard tissue were removed. Histologic analysis indicated that at 6 months of unloaded healing, the mean BIC value for the Osseotite surfaces (72.96% +/- 25.13%) was statistically significantly higher (P < 0.05) than the mean BIC value for the machined surfaces (33.98% +/- 31.04%). When the BIC values for the machined and Osseotite surface pairs were ranked from high to low based on the machined BIC value range of 93% to 0%, the upper 50th percentile (20 surface pairs) mean BIC value was 86.1% +/- 16.7% for the Osseotite surfaces and 60.1% +/- 18.3% for the machined surfaces. The lower 50th percentile (19 surface pairs) mean BIC value was 59.1% +/- 25.3% for the Osseotite surfaces and 6.5% +/- 10.8% for the machined surfaces. Differences between mean BIC values for the 2 surfaces in both the upper and lower 50th percentiles were statistically significant (P < 0.05). The results of this study indicate that in the poorer quality bone typically found in the posterior maxilla, a statistically significantly higher percentage of bone contacts Osseotite surfaces when compared to opposing machined surfaces on the same implant.

[Alcohol and smoking. The risk factors for the oral cavity]. / Alcol e fumo. Fattori di rischio per il cavo orale.

A higher risk for the development of oral cancer was associated with heavy smoking and heavy drinking, but alcohol drinking and tobacco smoking are also correlated with other oral cavity disease. Tobacco is the most important factor of leukoplakia, but other diseases like ANUG, periodontitis, median rhomboid glossitis, chronic hyperplastic candidiasis and others are also correlated to cigarette smoking. It was observed that smokers have more plaque than non-smokers, even if no difference in the bacteria composition was found between smokers and non-smokers samples, and the vascular reaction associated with plaque induced gingivitis is suppressed in smokers. Periodontitis are generally considered to be a consequence of an unfavourable host-parasite interaction, but personal factors that diminish the efficiency of the host defence, like tobacco smoking and alcohol drinking, can play an important role in the development of periodontal diseases. Cigarette smoking may be considered a major risk factor for periodontitis and it can also increase its severity; therefore, alveolar bone loss increases with tobacco smoking. Recent investigations show that smokers respond less favourably than no smokers to the different modalities of periodontal therapy, as surgical and non surgical, or guided tissue regeneration. Moving from these observations the authors critically analyze the literature concerning these important risk factors which appear to be strongly correlated with periodontal diseases.

[An analysis of the diagnostic criteria in assessing peri-implant tissues. A critical analysis of the literature]. / Analisi dei criteri diagnostici nella valutazione dei tessuti perimplantari. Analisi critica della letteratura.

The long-term success rate of dental implants has been considerably increased by the osseointegration concept and in the last decades, a lot of different implant systems have been developed to replace missing natural teeth. The predictable long-term success of osseointegrated dental implants seems to result from the determination of specific problems correlated with the system itself and the identification of factors which can affect the success of therapy: these considerations lead to the conclusion that monitoring each patient is absolutely necessary. In the paper presented, the various clinical parameters habitually used in the evaluation of dental implants during the maintenance phase of therapy are reviewed. The parameters which are discussed include probing and attachment level measurement, the evaluation of inflammation indexes, mobility, suppuration, tissue temperature, radiology and microbial monitoring. Unfortunately, many clinical signs of failure appear only when an irreversible stage has been reached: for example, when mobility is detected, we know that osseointegration, defined as "a direct structural and functional connection between ordered, living bone and the surface of a load-carrying implant" by Albrektsson and Brånemark has been lost. According to the fact that little evidence of the etiological and pathogenetic mechanisms implant failure exists, great attention should be given to the establishment of a comprehensive preventive, diagnostic and therapeutic approach to the problem.

[The role of antibiotics in periodontology. A review of the literature]. / Il ruolo degli antibiotici in parodontologia. Revisione della letteratura.

This review deals with antibiotic treatment of periodontitis. Antibiotic therapy aims at eradicating or controlling specific pathogens in patients with recently diagnosed active periodontitis or a history of recurrent disease, who fail to stabilize after mechanical/surgical therapy. A variety of microbes may cause periodontitis, and the choice of the antibiotic should be guided by accurate microbiological and sensitivity testings. Review of recent literature shows that appropriate systemic antibiotic therapy may increase the chance of healing in patients with recent or high risk of periodontal breakdown. Topical administration of antibiotic should be reserved to selected cases, such as Actinobacillus actinomycetemcomitans infections, in whom it is to be used in conjunction with mechanical treatment.

Cholelithiasis in patients treated with a very-low-calorie diet.

One hundred seventy-nine obese patients (mean body mass index = 36.3) were retrospectively evaluated for the development of cholelithiasis associated with the use of a 2530-kJ/d (605-kcal) very-low-calorie diet (VLCD). Nine percent of patients had preexisting gallstones and 11% of patients developed gallstones either during or within 6 mo of completing the diet. Six percent had subsequent cholecystectomy. Ursodeoxycholic acid administered to one patient resulted in spontaneous stone dissolution whereas spontaneous dissolution occurred in three patients. Surveys of patients at three other programs using the same diet yielded similar incidence of gallstones. We conclude that rapid weight loss associated with the use of VLCD is associated with a significant incidence of gallstone formation. VLCD should be physician supervised because resolution of cholelithiasis spontaneously, with stone passage, or dissolution with ursodeoxycholic acid therapy may reduce the need for cholecystectomy.

Body composition and weight maintenance with a very-low-calorie diet for the treatment of moderate obesity.

We report body composition in 11 moderately obese patients (mean BMI less than 30) treated for 8 wk with a 2530-kJ/d (605-Kcal) diet. Mean weight loss was 9.4 kg. Fat-free mass (FFM) loss of 2.3 kg was 23% of total weight loss and essentially equal to loss of total body water (2.5 L). Body composition was measured by the Futrex-5000 near-infrared technique. We conclude there is no excess loss of FFM in moderately obese patients treated with MNP 70/70, a 70-g protein, 70-g carbohydrate dietary supplement for 8 wk.

Repeated use of the very-low-calorie diet in a structured multidisciplinary weight-management program.

Forty-eight obese patients (mean body mass index = 36.4) were retreated with a very-low-calorie diet (VLCD) at a mean of 104-wk after first VLCD. Mean weight regain was 23 kg or 86% regain of initial loss. Retreatment with VLCD required weekly physician monitoring and indepth psychotherapy group attendance. Five patients (10%) lost an average of 4.55 kg and withdrew within the first 4 wk (group AO. Thirteen patients (27%) lost 13.8 kg over 11.5 wk, an average weight loss of 1.2 kg/wk and enrolled in maintenance (group B). Thirty patients (63%) lost 10.2 kg over 20 wk, an average weight loss of 0.5 kg/wk and did not enroll in the maintenance program (group C). Although weight loss occurs in patients retreated with the VLCD, adherence to the VLCD and commitment to the maintenance program are not optimal.

Calcium, magnesium, phosphorus, and parathyroid hormone interrelationships in pregnancy and newborn infants.

The ability to measure directly human parathyroid hormone (hPTH) and ionized calcium (Ca++) is of fundamental importance in understanding their interrelation in pregnancy and the newborn. hPTH and Ca++ progressively increase throughout pregnancy. Since Ca++ is the direct determinant of hPTH levels, a different "set point" appears to be operative throughout pregnancy. The newborn infant, on the other hand, has higher serum Ca++ levels than its mother, and the infant's plasma hPTH is suppressed to undetectable or low levels. Ca++, total serum Ca, magnesium, and phosphorus are all significantly elevated in the serum of the mother at delivery. An active transport mechanism of all these minerals appears to be operative and lowers the maternal serum levels at the termination of labor in relation to serum levels in the third trimester of pregnancy.

Long-term intramuscular administration of triamcinolone acetonide. Effect on the hypothalamic-pituitary-adrenal axis.

Five patients received intramuscular injections of triamcinolone acetonide for periods ranging from five months to three years. Metyrapone tartrate testing was used to assess the function of the hypothalamic-pituitary-adrenal (HPA) axis during, after, and, in one case, before the drug therapy. The HPA axis function was found to be suppressed during the period of treatment and up to ten months after cessation of therapy. Lens opacities appeared in two of the five patients while they were receiving triamcinolone acetonide. Results of this study indicate that patients to whom triamcinolone acetonide has been administered should be given supportive doses of corticosteroids during stressful situations (eg, major surgery). They should also receive ophthalmologic examinations every three to six months while they are receiving the medication.