Long-term use of inhaled glucocorticoids in patients with stable chronic obstructive pulmonary disease and risk of bone fractures: a narrative review of the literature

Figures & data

Table 1 Characteristics of RCTs

Reference	Number of pts, length of ICS therapy (months), previous use of OCS and/or ICS	Mean age	Gender (%)	M/F ratio	% current and ex-smokers	Definition of former smokers	Ethnicity	Geographic area	Mean FEV1 (pre-post bd) absolute value in liters (% predicted)	ICS and dosage	Baseline bone mass density	Vit D before	Vit D during	Bone fractures
Renkema et al, Chest 1996^Citation22	58 24 No	Bud 56 Bud+Pred 58 pla 54	m (100%)	0	cs Bud 43 Bud+Pred 47 pla 44	Stopped smoking at least 1 year before	nr	Netherlands	Pre bd Bud 2.16 L (67%) Bud+Pred 1.86 L (61) pla 1.90 L (60)	Bud 1,600 μg/d Bud+Pred 1,600 μg/d +5 μg/d	nr	nr	nr	nr
Vestbo et al, Lancet 1999^Citation25	290 36 No in previous 6 months	Bud 59 pla 59.1	Bud m 58.6 pla m 62.1	1.52	cs Bud 75.9 pla 77.2	nr	nr	Denmark	Post bd Bud 2.36 L (86.2) pla 2.39 L (86.9)	Bud 1,200 μg/d (6 months), then Bud 800 μg/d (30 months)	nr	nr	nr	nr
Weir et al, Clin Exp Allergy 1999^Citation33	98 24 No	BdP 65.5 pla 67.6	BdP m 65.3 pla m 83.6	2.92	cs BdP 34.7 pla 42.8 es BdP 63.2 pla 57.1	nr	nr	UK	BdP pre bd 1.07 L (39.7) Post bd1.19 L pla Pre bd 1.13 L (41.4) Post bd 1.26 L	BdP 750 μg bid <50 kg 1,000 μg bid >50 kg	nr	nr	nr	nr
Pauwels et al, N Engl J Med 1999^Citation21	1,277 36 No in previous 6 months	Bud 52.5±7.5 pla 52.4±7.7	Bud m 73.5 pla m 72.2	2.60	100	nr	nr	Belgium, Denmark, Finland, Italy, Netherlands, Norway, Spain, Sweden, UK	Pre bd Bud 2.53±0.64 L (76.8) pla 2.54±0.64 L (76.9)	Bud 400 μg bid	Measured on 194 subjects. No change over time and no effect of treatment on bone density, except for a small, significant difference at the femoral trochanter in favor of budesonide	nr	nr	Baseline Vertebral Bud 13.4%; pla 11.5% End study Bud +8; pla +3 (P=0.50)
Lung Health Study Research Group, N Engl J Med 2000^Citation34	1,116 40 (mean) No in previous year	TA 56.2±6.8 pla 56.4±6.8	TA f 36% pla f 37.9%	1.70	cs TA 90.5 pla 89.8	Smoking cessation for over 2 years	Non-white TA 6.3% pla 4.1%	USA	TA pre bd 2.16 L (65) Post bd 2.28 L (68.5) pla pre bd 2.10 L (63.4) Post bd 2.22 L (67.2)	TA 600 μg bid	Measured at lumbar spine on 328 subjects, and at femoral neck on 359 subjects. After 3 years higher percentage decrease of bone density in those taking TA	nr	nr	nr
Burge et al, BMJ 2000^Citation26	751 36 FP 51% pla 57%	FP 63.7 pla 63.8	FP m 75 pla m 74	2.93	cs FP 36.4 pla 39.2 es FP 46.8 pla 45.8	nr	nr	UK	Post bd FP 1.42 L (0.47) pla 1.40 L (0.49)	FP 500 μg bid	nr	nr	nr	FP 9 pla 17 2% both groups
Calverley et al, Lancet 2003^Citation27	1,465 12 nr No in 4 weeks prior to study	FP 63.5 pla 63.4	FP m 70 pla m 75	2.61	cs FP 47 pla 53	nr	nr	UK	FP pre bd 1.26 L (45.0) Post bd 2.36 L pla 1.27 L (44.2) pla post bd 1.38 L	FP 500 μg bid	nr	nr	nr	nr
Calverley et al, Eur Respir J 2003^Citation20	1,022 12 nr	Bud 64 pla 65	Bud m 74 pla m 75	3.07	cs Bud 39 pla 30	nr	nr	Africa, Asia, Europe	Bud 1±0.32 L (36) pla 0.98±0.33 L (36)	Bud 400 μg/d	nr	nr	nr	nr
van Grunsven et al, Respir Med 2003^Citation29	48 24 nr	FP 46 pla 47	FP m 50% pla m 54%	1.08	cs FP 50 pla 50	nr	nr	Netherlands	FP pre bd 3.05 L (95) Post bd 3.16 L (98) pla pre bd 3.17 L (98) Post bd 3.19 L (99)	FP 250 μg bid	nr	nr	nr	nr
Szafranski et al, Eur Respir J 2003^Citation24	812 12 Bud 24% pla 26%	Bud 64 pla 65	Bud m 64% pla m 65%	1.27	cs Bud 36 pla 34	nr	nr	Argentina, Brazil, Denmark, Finland, Italy, Mexico, Poland, Portugal, South Africa, Spain, UK	Bud 1.01 L (37) pla 0.98 L (36)	Bud 200 μg bid	nr	nr	nr	nr
Calverley et al, N Engl J Med 2007^Citation9	6,112 36 FP 20% pla 22%	FP 65 pla 65	FP m 75 pla m 76	3.12	cs FP 43 pla 43	nr	mixed	Europe, Asia-Pacific, USA	FP pre bd 1.12±0.39 L (44.1) Post bd 1.22±0.41 L pla pre bd 1.12±0.40 L (44.1) Post bd 1.22±0.42 L	FP 500 μg bid	nr	nr	nr	Total, whole duration of the study FP 5.4% pla 5.1%
Calverley et al, Respir Res 2008^Citation30	911 12 No in 6 weeks prior to study	MF-DPI 800 μg 65.3 MF-DPI 400 μg 65 pla 65	MF-DPI 800 μg m 69% MF-DPI 400 μg m 67% pla m 69%	2.15	cs 28.3	Quitting smoking ≥12 months before the study	MF-DPI 800 μg white 88% MF-DPI 400 μg white 86% pla white 85%	UK	MF 800 μg qd pm pre bd 1.32 L (43) Post bd 1.45 L (47) MF 400 μg bid pre bd 1.25 L (42) Post bd 1.38 L (469) pla pre bd 1.26 L (42.1) Post bd 1.41 L (47)	MF 800 μg qd pm 400 μg bid	nr	nr	nr	≤1% in groups
Shaker et al, COPD 2009^Citation23	254 24–48 No in 6 months prior to study	Bud 63.6 pla 63.6	Bud m 62 pla m 54	1,39	cs 100	nr	Ca	Denmark, Netherlands	Post bd Bud 1.53 L (51) pla 1.53 L (53)	Bud 400 μg bid	nr	nr	nr	nr
Lapperre et al, Ann Intern Med 2009^Citation28	114 30 No in 6 months prior to study	FP 6m 64 FP 30m 62 pla 59	FP 6m m 84.6 FP 30m m 88.4 pla 83.3	6.21	cs FP 30 months 61.5 FP 6 months 53.8 pla 70.8	nr	Nr	Netherlands	FP 30 months pre bd (57); post bd (64) FP 6 months pre bd (59); post bd (65) pla pre bd (54); post bd (61)	FP 500 μg bid for 30 months FP 500 μg bid for 6 months	nr	nr	nr	nr
Tashkin et al, Int J Chron Obstruct Pulmon Dis 2012^Citation31	1,055 12 nr	MF400 60.2 pla 58.8	MF400 m 78% pla m 78%	3.22	cs MF 44; pla 46 es MF 56; pla 54	nr	ca: 71.9% as: 16.9% mr: 9.4%	Africa, Asia, Europe, North, Central, South America	MF 1.255 L pla 1.227 L	MF 400 μg bid	nr	nr	nr	MF 3 (radio, facial bone, rib) pla 1 (foot)
Doherty et al, Int J Chron Obstruct Pulmon Dis 2012^Citation32	1,196 12 No in previous 4 weeks	MF 60.5 pla 58.8	MF m 78 pla m 75	3.04	cs MF 53; pla 51 es MF 47; pla 49	≥10 pack/year history	MF white 70% pla white 66%	USA	MF post bd 40.2±11.7 pla post bd 38.5±11.5	MF 400 μg bid	nr	nr	nr	nr
Vestbo et al, Lancet 2016^Citation35	16,485 20 FF 33% pla 33%	FF 65 pla 65	FF m 74 pla m 75	3.92	cs FF 47 pla 47	nr	ca: 81% as: 17%	Africa, Asia, Australia, Europe, North, Central, South America	post bd FF 1.70 (59.6) pla 1.70 (59.7)	FF 92 μg qd	nr	nr	nr	FF 79 (2%) pla 78 (2%)

Abbreviations: as, Asian; bd, bronchodilator; BdP, beclomethasone dipropionate; bid, twice a day; Bud, budesonide; ca, Caucasian; cs, current smokers; DPI, dry powder inhaler; es, ex-smokers; f, females; FEV₁, forced expiratory volume in 1 s; FF, fluticasone furoate; FP, fluticasone propionate; ICS, inhaled corticosteroid; m, males; MF, mometasone furoate; mr, multiracial; nr, not reported; OCS, oral corticosteroid; pla, placebo; Pred, prednisolone; pm, evening; pt, patient; qd, once a day; RCT, randomized controlled trial; TA, triamcinolone acetonide; Vit, vitamin.

Figure 1 Flow chart of study selection.

Table 2 Main risk factors that may affect bone mineral density and/or the risk of bone fractures

Established:

Age

Gender

Ethnicity

Family history

Genes

Smoking

Vitamin D serum levels

Body composition

Physical activity

Menopause and hypogonadism

Comorbidities (diabetes mellitus)

Drugs (glucocorticoids, thiazide diuretics, statins, sex steroids, antidiabetic agents, acid-reducing drugs, selective serotonin reuptake inhibitors, heparin, beta 2 adrenergic

Systemic inflammation

Controversial:

Alcohol use

Tea use

Note: Data from references.^{8,13–19,37,39–41,48–50,52–54,56–60}

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