Pharmacokinetics of inhaled glucocorticosteroids

Pharmacokinetics of inhaled glucocorticosteroids

Inhaled glucocorticosteroids (ICS) are first-line drugs that are used for long-term treatment of patients with bronchial asthma (BA) [2, 10]. They effectively block the inflammatory process in the respiratory tract, and the clinical manifestation of the positive effect of ICS is considered to be a decrease in the severity of symptoms of the disease and, accordingly, a decrease in the need for oral glucocorticosteroids (GCS), short-acting β2-agonists, a decrease in the level of inflammatory mediators in the bronchoalveolar lavage fluid, improvement indicators of pulmonary function, reducing variability in their fluctuations [10]. Unlike systemic corticosteroids, inhaled corticosteroids have high selectivity, pronounced anti-inflammatory and minimal mineralocorticoid activity. When drugs are administered via inhalation, approximately 10–30% of the nominal dose is deposited in the lungs [8]. The percentage of deposition depends on the ICS molecule, as well as on the drug delivery system into the respiratory tract (metered aerosols or dry powder), and when using dry powder, the proportion of pulmonary deposition doubles compared to the use of metered aerosols, including the use of spacers [4, 16]. Most of the ICS dose is swallowed, absorbed from the gastrointestinal tract and quickly metabolized in the liver, which provides a high therapeutic index of ICS compared to systemic GCS [3]

Drugs for local inhalation use include flunisolide (Ingacort), triamcinolone acetonide (TAA) (Azmacort), beclomethasone dipropionate (BDP) (Becotide, Beclomet) and modern generation drugs: budesonide (Pulmicort, Benacort), fluticasone propionate (FP) (Flixotide ), mometasone furoate (MF) and ciclesonide. For inhalation use, drugs are produced in the form of aerosols, dry powder with appropriate devices for their use, as well as solutions or suspensions for use with nebulizers

Due to the fact that there are many devices for inhalation of ICS, and also due to the insufficient ability of patients to use inhalers, it is necessary to take into account that the amount of ICS delivered to the respiratory tract in the form of aerosols or dry powder is determined not only by the nominal dose of the GCS, but also by the characteristics devices for drug delivery - the type of inhaler, as well as the patient’s inhalation technique [20].

Despite the fact that ICS has a local effect on the respiratory tract, there is conflicting information about the manifestation of adverse systemic effects (AE) of ICS, from their absence to pronounced manifestations that pose a risk to patients, especially children [23]. These NEs include suppression of the function of the adrenal cortex, effects on bone metabolism, bruising and thinning of the skin, and the formation of cataracts [3].

The manifestations of systemic effects are predominantly determined by the pharmacokinetics of the drug and depend on the total amount of GCS entering the systemic circulation (systemic bioavailability, F) and the clearance of GCS. Based on this, it can be assumed that the severity of the manifestations of certain NEs depends not only on the dosage, but also, to a greater extent, on the pharmacokinetic properties of the drugs.

Therefore, the main factor determining the effectiveness and safety of ICS is the selectivity of the drug in relation to the respiratory tract - the presence of high local anti-inflammatory activity and low systemic activity (Table 1).

In clinical practice, ICS differ in the value of the therapeutic index, which is the ratio between the severity of clinical (desirable) effects and systemic (undesirable) effects [3], therefore, with a high therapeutic index, there is a better effect/risk ratio.

Bioavailability

ICS are rapidly absorbed from the gastrointestinal tract and respiratory tract. The absorption of corticosteroids from the lungs may be influenced by the size of the inhaled particles, since particles smaller than 0.3 mm are deposited in the alveoli and absorbed into the pulmonary bloodstream [14].

When inhaling aerosols from metered dose inhalers through a large-volume spacer (0.75 l - 0.8 l), the percentage of drug delivery to the peripheral respiratory tract increases (5.2%). When using metered dose inhalers with aerosols or dry powder GCS through a dischaler, turbuhaler and other devices, only 10-20% of the inhaled dose is deposited in the respiratory tract, while up to 90% of the dose is deposited in the oropharyngeal region and is swallowed [8]. Next, this part of the ICS, absorbed from the gastrointestinal tract, enters the hepatic bloodstream, where most of the drug (up to 80% or more) is inactivated [19]. IGS enter the systemic circulation predominantly in the form of inactive metabolites, with the exception of the active metabolite of BDP - beclomethasone 17-monopropionate (17-BMP) (approximately 26%), and only a small part (from 23% TAA to less than 1% FP) - in the form unchanged drug. Therefore, the systemic oral bioavailability (Fora1) of ICS is very low, it is almost zero.

However, it should be taken into account that part of the dose of ICS [approximately 20% of the nominally taken dose, and in the case of BDP (17-BMP) - up to 36%], entering the respiratory tract and being quickly absorbed, enters the systemic circulation. Moreover, this part of the dose can cause extrapulmonary systemic NE, especially when high doses of ICS are prescribed, and here the type of ICS inhaler used is of no small importance, since when dry budesonide powder is inhaled through a turbuhaler, the pulmonary deposition of the drug increases by 2 times or more compared with inhalation from metered aerosols [21].

Thus, a high percentage of drug deposition in the intrapulmonary respiratory tract normally provides a better therapeutic index for those ICS that have low systemic bioavailability when administered orally. This applies, for example, to BDP, which has systemic bioavailability due to intestinal absorption, in contrast to budesonide, which has systemic bioavailability mainly due to pulmonary absorption [24].

For ICS with zero bioavailability after an oral dose (fluticasone), the nature of the device and inhalation technique determine only the effectiveness of treatment, but do not affect the therapeutic index [5].

Therefore, when assessing systemic bioavailability, it is necessary to take into account the overall bioavailability, that is, not only the low oral bioavailability (almost zero for fluticasone and 6-13% for budesonide), but also inhalation bioavailability, the average values ​​of which range from 20 (FP) to 39% ( flunisolide) (Table 2) [8].

For ICS with a high fraction of inhaled bioavailability (budesonide, FP, BDP), systemic bioavailability may increase in the presence of inflammatory processes in the mucous membrane of the bronchial tree. This was established in a comparative study of systemic effects in terms of the level of reduction in plasma cortisol after a single administration of budesonide and BDP at a dose of 2 mg at 22 hours to healthy smokers and non-smokers [24]. It should be noted that after inhalation of budesonide, cortisol levels in smokers were 28% lower than in non-smokers.

This led to the conclusion that in the presence of inflammatory processes in the mucous membrane of the respiratory tract in asthma and chronic obstructive bronchitis, the systemic bioavailability of those ICS that have pulmonary absorption (in this study, budesonide, but not BDP, which has intestinal absorption) may change.

Of great interest is mometasone furoate (MF), a new ICS with very high anti-inflammatory activity, which lacks bioavailability. There are several versions explaining this phenomenon. According to the first of them, 1 MF from the lungs does not immediately enter the systemic circulation, like budesonide, which lingers in the respiratory tract for a long time due to the formation of lipophilic conjugates with fatty acids. This is explained by the fact that MF has a highly lipophilic furoate group at the C17 position of the drug molecule, and therefore it enters the systemic circulation slowly and in quantities insufficient for detection. According to the second version, MF is rapidly metabolized in the liver. The third version says: lactose-MF agglomerates cause low bioavailability due to a decrease in the degree of solubility. According to the fourth version, MF is quickly metabolized in the lungs and therefore does not reach the systemic circulation during inhalation. Finally, the assumption that MF does not enter the lungs is not confirmed, since there is evidence of the high effectiveness of MF at a dose of 400 mcg in patients with asthma. Therefore, the first three versions may, to some extent, explain the lack of bioavailability of MF, but this issue requires further study [1].

Thus, the systemic bioavailability of ICS is the sum of inhalation and oral bioavailability. Flunisolide and beclomethasone dipropionate have systemic bioavailability of approximately 60 and 62%, respectively, which is slightly higher than the sum of the oral and inhaled bioavailability of other ICS.

Recently, a new ICS drug, ciclesonide, has been proposed, the oral bioavailability of which is practically zero [23]. This is explained by the fact that ciclesonide is a prodrug; its affinity for GCS receptors is almost 8.5 times lower than that of dexamethasone. However, upon entering the lungs, the drug molecule is exposed to enzymes (esterases) and transforms into its active form (the affinity of the active form of the drug is 12 times higher than that of dexamethasone). In this regard, ciclesonide is devoid of a number of undesirable side reactions associated with the entry of ICS into the systemic circulation.

Communication with blood plasma proteins

ICS have a fairly high association with blood plasma proteins (Table 2); for budesonide and fluticasone this relationship is slightly higher (88 and 90%) compared to flunisolide and triamcinolone - 80 and 71%, respectively. Usually, for the manifestation of the pharmacological activity of drugs, the level of the free fraction of the drug in the blood plasma is of great importance. For modern, more active ICS - budesonide and FP, it is 12 and 10%, respectively, which is slightly lower than for flunisolide and TAA - 20 and 29%. These data may indicate that in the manifestation of the activity of budesonide and AF, in addition to the level of the free fraction of drugs, other pharmacokinetic properties of drugs also play an important role [13].

Volume of distribution

The volume of distribution (Vd) of ICS indicates the extent of extrapulmonary tissue distribution of the drug. A large Vd indicates that a larger portion of the drug is distributed in peripheral tissues. However, a large Vd cannot serve as an indicator of high systemic pharmacological activity of ICS, since the latter depends on the amount of the free fraction of the drug that can interact with GCR. At the level of equilibrium concentration, the highest Vd, many times higher than this indicator for other ICS, was detected in AF (12.1 l/kg) (Table 2); in this case, this may indicate the high lipophilicity of the EP.

Lipophilicity

The pharmacokinetic properties of ICS at the tissue level are predominantly determined by their lipophilicity, which is a key component for the manifestation of selectivity and retention time of the drug in tissues. Lipophilicity increases the concentration of ICS in the respiratory tract, slows down their release from tissues, increases affinity and prolongs the connection with GCR, although the optimal lipophilicity of ICS has not yet been determined [6].

Lipophilicity is most pronounced in FP, followed by BDP, budesonide, and TAA and flunisolide are water-soluble drugs [11]. Highly lipophilic drugs - FP, budesonide and BDP - are absorbed more quickly from the respiratory tract and remain longer in the tissues of the respiratory tract compared to non-inhaled corticosteroids - hydrocortisone and dexamethasone, prescribed by inhalation. This fact may explain the relatively unsatisfactory antiasthmatic activity and selectivity of the latter [7, 18]. The high selectivity of budesonide is evidenced by the fact that its concentration in the respiratory tract 1.5 hours after inhalation of 1.6 mg of the drug is 8 times higher than in the blood plasma, and this ratio persists for 1.5-4 hours after inhalation [26]. Another study [13] revealed a large distribution of FP in the lungs, since 6.5 hours after administration of 1 mg of the drug, a high concentration of FP was found in lung tissue and low in plasma, in a ratio of 70:1 to 165:1.

Therefore, it is logical to assume that more lipophilic ICS can be deposited on the mucous membrane of the respiratory tract in the form of a “microdepot” of drugs, which allows them to prolong their local anti-inflammatory effect, since it takes more than 5-8 hours to dissolve BDP and FP crystals in the bronchial mucus, whereas for budesonide and flunisolide, which have rapid solubility, this indicator is 6 minutes and less than 2 minutes, respectively [11]. It has been shown that the water solubility of the crystals, which ensures the solubility of GCS in bronchial mucus, is an important property in the manifestation of the local activity of ICS [11].

Another key component for the manifestation of the anti-inflammatory activity of ICS is the ability of the drugs to remain in the tissues of the respiratory tract. In vitro studies conducted on lung tissue preparations showed that the ability of ICS to remain in tissues correlates quite closely with lipophilicity. For FP and beclomethasone it is higher than for budesonide, flunisolide and hydrocortisone [11]. At the same time, in vivo studies showed that budesonide and FP were retained longer on the tracheal mucosa of rats compared to BDP [9, 17], and budesonide was retained longer than FP [17]. In the first 2 hours after intubation with budesonide, FP, BDP and hydrocortisone, the release of radioactive label (Ra-label) from the trachea for budesonide was slow and amounted to 40% versus 80% for FP and BDP and 100% for hydrocortisone. In the next 6 hours, a further increase in the release of budesonide by 25% and BDP by 15% was observed, while in AF there was no further increase in the release of the Ra tag [18]

These data contradict the generally accepted view that there is a correlation between the lipophilicity of ICS and their ability to bind to tissues, since the less lipophilic budesonide is retained longer than FP and BDP. This fact should be explained by the fact that under the action of acetyl-coenzyme A and adenosine triphosphate, the hydroxyl group of budesonide at the carbon atom in position 21 (C-21) is replaced by a fatty acid ester, that is, esterification of budesonide occurs with the formation of budesonide conjugates with fatty acids. This process occurs intracellularly in the tissues of the lungs and respiratory tract and in liver microsomes, where fatty acid esters (oleates, palmitates, etc.) are identified [25]. Conjugation of budesonide in the respiratory tract and lungs occurs quickly, since already 20 minutes after administration of the drug, 70-80% of the Ra-label was determined in the form of conjugates and 20-30% in the form of intact budesonide, while after 24 hours only 3. 2% of conjugates of the initial level of conjugation, and in the same proportion they were detected in the trachea and lungs, indicating the absence of unidentified metabolites [18]. Budesonide conjugates have very low affinity for GCR and therefore do not have pharmacological activity [28].

Intracellular conjugation of budesonide with fatty acids can occur in many cell types, and budesonide can accumulate in an inactive but reversible form. Lipophilic conjugates of budesonide are formed in the lungs in the same proportions as in the trachea, indicating the absence of unidentified metabolites [27]. Budesonide conjugates are not detected in plasma or peripheral tissues.

Conjugated budesonide is hydrolyzed by intracellular lipases, gradually releasing pharmacologically active budesonide, which can prolong receptor saturation and prolong the glucocorticoid activity of the drug.

If budesonide is approximately 6-8 times less lipophilic than FP, and, accordingly, 40 times less lipophilic compared to BDP, then the lipophilicity of budesonide conjugates with fatty acids is tens of times higher than the lipophilicity of intact budesonide (Table 3), than explains the duration of its stay in the tissues of the respiratory tract [18].

Studies have shown that esterification of budesonide with the fatty acid leads to prolongation of its anti-inflammatory activity. With pulsating administration of budesonide, a prolongation of the GCS effect was noted, in contrast to AF. At the same time, in an in vitro study in the constant presence of FP, it was 6 times more effective than budesonide [27]. This may be explained by the fact that FP is more easily and quickly removed from cells than the more conjugated budesonide, resulting in an approximately 50-fold decrease in the concentration of FP and, accordingly, its activity [27]).

Thus, after inhalation of budesonide, a “depot” of the inactive drug is formed in the respiratory tract and lungs in the form of reversible conjugates with fatty acids, which can prolong its anti-inflammatory activity. This is undoubtedly of great importance for the treatment of patients with asthma. As for BDP, which is more lipophilic than FP (Table 4), its retention time in the respiratory tract tissues is shorter than that of FP and coincides with this indicator for dexamethasone, which is apparently the result of hydrolysis of BDP to 17- BMP and beclomethasone, the lipophilicity of the latter and dexamethasone are the same [18]. Moreover, in an in vitro study [18], the duration of Ra-label residence in the trachea after inhalation of BDP was longer than after its perfusion, which is associated with the very slow dissolution of BDP crystals deposited in the respiratory lumens during inhalation [11].

The long-term pharmacological and therapeutic effect of ICS is explained by the connection of the GCS with the receptor and the formation of the GCS+GCR complex. Initially, budesonide binds to GCR more slowly than AF, but faster than dexamethasone, but after 4 hours there was no difference in the total amount of binding to GCR between budesonide and AF, while for dexamethasone it was only 1/3 of the bound fraction of AF and budesonide.

Dissociation of the receptor from the GCS+GCR complex differed between budesonide and FP; compared to FP, budesonide dissociates faster from the complex. The duration of the budesonide + receptor complex in vitro is 5-6 hours, this figure is lower compared to FP (10 hours) and 17-BMP (8 hours) [12], but higher than dexamethasone [18]. It follows from this that differences in the local tissue connection of budesonide, FP, BDP are not determined at the receptor level, and differences in the degree of nonspecific connection of GCS with cellular and subcellular membranes have a predominant influence on the difference in indicators.

As shown above (Table 2), FP has the greatest affinity for GCR (approximately 20 times higher than that of dexamethasone, 1.5 times higher than that of 17-BMP, and 2 times higher than that of budesonide) [8]. The affinity of ICS for the GCS receptor can also be influenced by the configuration of the GCS molecule. For example, in budesonide, its dextro- and levorotatory isomers (22R and 22S) have not only different affinities for GCR, but also different anti-inflammatory activity [8] (Table 4).

The affinity of 22R for GCR is more than 2 times greater than the affinity of 22S, and budesonide (22R22S) occupies an intermediate position in this gradation, its affinity for the receptor is 7.8, and the power of suppression of edema is 9.3 (the parameters of dexamethasone are taken as 1.0 ) (Table 4).

Metabolism

BDP is quickly, within 10 minutes, metabolized in the liver to form one active metabolite - 17-BMP and two inactive ones - beclomethasone 21-monopropionate (21-BMN) and beclomethasone [7].

In the lungs, due to the low solubility of BDP, which is a determining factor in the degree of formation of 17-BMP from BDP, the formation of the active metabolite may be delayed. The metabolism of 17-BMP in the liver occurs 2-3 times slower than, for example, the metabolism of budesonide, which may be a limiting factor in the transition of BMP to 17-BMP.

TAA is metabolized to form 3 inactive metabolites: 6β-trioxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6β-hydroxytriamcinolone acetonide.

Flunisolide forms the main metabolite - 6β-hydroxyflunisolide, the pharmacological activity of which is 3 times greater than the activity of hydrocortisone and has a half-life of 4 hours.

FP is quickly and completely inactivated in the liver with the formation of one partially active (1% of FP activity) metabolite - 17β-carboxylic acid.

Budesonide is rapidly and completely metabolized in the liver with the participation of cytochrome p450 3A (CYP3A) with the formation of 2 main metabolites: 6β-hydroxybudesonide (forms both isomers) and 16β-hydroxyprednisolone (forms only 22R). Both metabolites have weak pharmacological activity.

Mometasone furoate (pharmacokinetic parameters of the drug were studied in 6 volunteers after inhalation of 1000 mcg - 5 inhalations of dry powder with radiolabel): 11% of radiolabel in plasma was determined after 2.5 hours, this figure increased to 29% after 48 hours. Excretion of radiolabel with bile was 74% and in urine 8%, the total amount reached 88% after 168 hours [1].

Ketoconazole and cimetidine may increase plasma levels of budesonide following an orally administered dose as a result of CYP3A blockade.

Clearance and half-life

ICS have rapid clearance (CL), its value approximately coincides with the value of hepatic blood flow, and this is one of the reasons for minimal manifestations of systemic NE. On the other hand, rapid clearance provides ICS with a high therapeutic index. The clearance of ICS ranges from 0.7 l/min (TAA) to 0.9-1.4 l/min (FP and budesonide, in the latter case there is a dependence on the dose taken). System clearance for the 22R is 1.4 l/min and for the 22S 1.0 l/min. The fastest clearance, exceeding the rate of hepatic blood flow, was found in BDP (150 l/h, and according to other data - 3.8 l/min, or 230 l/h) (Table 2), which suggests the presence of extrahepatic metabolism of BDP , in this case in the lungs, leading to the formation of the active metabolite 17-BMP [15]. The clearance of the 17-BMP is 120 l/h.

The half-life (T1/2) from blood plasma depends on the volume of distribution and the magnitude of systemic clearance and indicates changes in drug concentration over time. For ICS, T1/2 from blood plasma varies widely - from 10 minutes (BDP) to 8-14 hours (AF) (Table 2). T1/2 of other ICS is quite short - from 1.5 to 2.8 hours (TAA, flunisolide and budesonide) and 2.7 hours for 17-BMP [8]. For fluticasone, T1/2 after intravenous administration is 7-8 hours, while after inhalation from the peripheral chamber this figure is 10 hours [8]. There are other data, for example, if T1/2 from blood plasma after intravenous administration was equal to 2.7 (1.4-5.4) hours, then T1/2 from the peripheral chamber, calculated according to the three-phase model, averaged 14 .4 hours (12.5-16.7 hours), which is associated with relatively rapid absorption of the drug from the lungs - T1/2 2 (1.6-2.5) hours compared to its slow systemic elimination [15]. The latter can lead to the accumulation of the drug with long-term use, which was shown after a seven-day administration of FP through a discahaler at a dose of 1000 mcg 2 times a day to 12 healthy volunteers, in whom the concentration of FP in the blood plasma increased by 1.7 times compared with the concentration after single dose 1000 mcg. Accumulation was accompanied by an increase in suppression of plasma cortisol levels (95% versus 47%) [22].

Conclusion

The bioavailability of inhaled corticosteroids depends on the molecule of the drug, on the drug delivery system to the respiratory tract, on the inhalation technique, etc. With local administration of inhaled corticosteroids, drugs are significantly better captured from the respiratory tract, they remain longer in the tissues of the respiratory tract, and high selectivity of drugs is ensured, especially fluticasone propionate and budesonide, a better effect/risk ratio and a high therapeutic index of drugs. Intracellular esterification of budesonide with fatty acids in the tissues of the respiratory tract leads to local retention and the formation of a “depot” of inactive but slowly regenerating free budesonide. Moreover, the large intracellular supply of conjugated budesonide and the gradual release of free budesonide from the conjugated form can prolong receptor saturation and anti-inflammatory activity of budesonide, despite its lower affinity for the GCS receptor compared to fluticasone propionate and beclomethasone monopropionate [22]. To date, there is limited information on pharmacokinetic studies of the very promising and highly effective drug mometasone furoate, which, in the absence of bioavailability during inhalation administration, exhibits high anti-inflammatory activity in patients with asthma.

Long-term exposure and delayed receptor saturation prolong the anti-inflammatory activity of budesonide and fluticasone in the respiratory tract, which may serve as a basis for a single dose of drugs.

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Methods

• The information search was carried out in two databases MEDLINE and EMBASE since July 2013. In December 2014, it was updated with the latest data from PubMed.
• The authors selected randomized clinical trials (RCTs) and controlled analytical studies that compared the effects of ICS (for at least 12 months) with the effects of other therapies in patients with asthma.
• A meta-analysis was conducted to determine odds ratios (ORs) for fractures and standard deviations of bone mineral density.
• Heterogeneity was assessed using I2.

Strengths and weaknesses of this study

1) Extensive search of two databases with random sample extraction

2) Inclusion of both analytical and RCTs conducted in children and adults with asthma

3) Heterogeneous nature of studies and outcome measures available for analysis

4) Failure to properly assess differences in effects when using different drugs, using different types of inhalers, and differences in reactions depending on the dose of the drug taken.

Introduction

Asthma is a chronic inflammatory disease that affects both children and adults. There is compelling evidence that ICS significantly reduces symptoms, improves pulmonary function, and relieves exacerbations. As a result, ICS are the gold standard drug of choice for preventive therapy and are widely recommended in national and international guidelines. However, their long-term use can contribute to the development of undesirable consequences such as cataracts, osteoporosis, fractures, and slow growth in children. Concerns about the development of these conditions may negatively impact patient adherence to ICS treatment and thus lead to poor asthma control and a high risk of requiring oral ICS during an acute attack. Certain age groups, namely women and children, may be particularly sensitive to side effects on bone metabolism and osteogenesis, and therefore the use of ICS in these patient groups remains unresolved.

Available meta-analyses that combine data on the effects of ICS and their side effects on bone tissue tend to include patients with chronic obstructive pulmonary disease (COPD) - and, to date, less emphasis has been placed on the effects of their use only in asthma. accent. Patients with asthma are less susceptible to developing osteoporosis compared to patients with COPD due to the absence of risk factors such as smoking, multipathology and trophic disorders, which are common among the latter. Therefore, it remains unclear whether patients with asthma have a greater or lesser risk of bone-related adverse events compared with patients with COPD; Further research is needed to clarify the risks of only the first category of patients.

For this reason, the authors of the article set out to analyze the effects of long-term (at least 12 months) ICS therapy in patients with asthma alone, with particular attention to the effect of these drugs on the risk of fractures and on bone mineral density.

Methods

Study selection criteria:

• The goal is to study important but infrequent bone side effects.
• At least 20 patients taking one of the types of ICS
• Duration - at least 12 months

Inclusion criteria for RCTs:

• RCT in parallel groups
• Participants included patients with asthma of varying degrees of severity
• In the main group, ICS was used as therapy, in the control group - other drugs recommended for asthma, or a combination of ICS with long-acting β-agonists, or only the latter.
• The aim was to assess the risk of fractures or changes in bone mineral density

Inclusion criteria for analytical studies:

• case-control
• prospective
• retrospective cohort

informative from the point of view of assessing the risk of fractures or changes in bone mineral density in patients taking ICS (main group) and taking alternative drugs (control group).

Exclusion criteria:

• Studies that included mixed groups of patients (asthma/COPD), the results of which were not reported separately for each disease
• Cross-sectional studies
• Studies that took into account only the effect of oral glucocorticosteroids without taking into account the effect of inhaled ones

Search strategy:

• The authors of the article searched MEDLINE and EMBASE in June 2013, using the general strategy of searching for various side effects associated with ICS use.
• In December 2014, the data was updated through a more targeted search on PubMed
• The reference lists of included studies were carefully manually reviewed to identify any other articles that might be useful.

Selection strategy:

• Two reviewers (Menaka Thavarajah and Patricia Blanco) independently double-checked all titles and abstracts of articles and excluded all that were not RK or analytical studies of the effects of ICS in patients with asthma.
• The full texts of potentially relevant articles were further reviewed and the selection criteria were tightened. Only articles related to bone side effects were selected
• A third reviewer (Yoon K Loke or Andrew M Wilson) made the final decision on inclusion or exclusion of the article from the review.

Study characteristics and data extraction

• Two reviewers (Menaka Thavarajah and Patricia Blanco) independently selected results that had a primary focus on fracture risk and a second and final reviewer that focused on changes in lumbar spine bone mineral density or femoral bone mineral density.
• A third reviewer (Yoon K Loke or Andrew M Wilson or Daniel Gilbert) corrected any discrepancies after cross-checking the source of the article.

Risk of estimation bias

• Two reviewers independently assessed reports of blinding of patients and staff, generation of random sequences, concealment of patient allocation order, withdrawal from study participation, or discontinuation of follow-up.
• To assess the validity of the relationship between the development of adverse effects and the use of ICS, information was extracted on the sample of participants, duration of use of these drugs and results, as well as methods for accounting for systematic errors in analytical studies.
• Funnel plots and skewed distributions were used to assess bias, provided that the meta-analysis included data from more than 10 studies, and to assess the absence of heterogeneity.

Statistical analysis

• Study data were pooled using Review Manager (RevMan) V.5.3.2 (Nordic Cochrane Centre, Copenhagen, Denmark)
• The inverse variance method was used to combine data regarding absolute fracture risks and standard deviation in bone mineral density (g/cm2)
• In accordance with the recommendations of the Cochrane guidelines, data with a confidence level of less than 95% were excluded.
• Statistical heterogeneity was assessed using I2, with I2 > 50% indicating a significant level of heterogeneity
• If a study included more than one control group (consisting of patients not taking ICS), when possible, preference was given to comparing ICS with placebo rather than comparing ICS with active drugs such as nedocromil, montelukast and sodium cromoglycate
• When studying combined dosage forms, a separate comparative analysis was carried out of the combination of ICS with another drug and this drug alone
• If the study included several types of ICS in different dosages, they were combined by the authors of the meta-analysis, as recommended by the Cochrane guidelines
• No preliminary protocol was kept.

results

• The systematic review included 18 studies (7 RCTs and 11 analytical studies).
• A meta-analysis of analytical studies did not reveal any significant correlation between the use of ICS and the incidence of fractures in children (OR 1.02, 95%, CI 0.94-1.10, in 2 studies) and adults (OR 1.09, 95%, CI 0.45-2.62, in 4 studies).
• Based on the results of 3 RCTs and 4 analytical clinical trials, bone mineral density in the lumbar spine was determined in children, and according to the results of the meta-analysis conducted by the authors, there was no significant decrease in indicators with the use of ICS.
• Three RCTs and four analytical studies measured lumbar spine bone mineral density and femoral bone mineral density in adults taking ICS, and the meta-analysis found no significant reductions compared with controls.