Effect of Disease-Modifying Anti-Rheumatic Drugs on Bone Structure and Strength in Psoriatic Arthritis Patients

David Simon; Arnd Kleyer; Sara Bayat; Koray Tascilar; Eleni Kampylafka; Timo Meinderink; Louis Schuster; Ramona Petrov; Anna-Maria Liphardt; Juergen Rech; Georg Schett; Axel J. Hueber

Disclosures

Arthritis Res Ther. 2019;21(162)

Abstract and Introduction

Abstract

Objectives: To address whether the use of methotrexate (MTX) and biological disease-modifying anti-rheumatic drugs (bDMARDs) impacts bone structure and biomechanical properties in patients with psoriatic arthritis (PsA).

Methods: This is a cross-sectional study in PsA patients receiving no DMARDs, MTX, or bDMARDs. Volumetric bone mineral densities (vBMDs), microstructural parameters, and biomechanical properties (stiffness/failure load) were determined by high-resolution peripheral quantitative CT and micro-finite element analysis in the respective groups. Bone parameters were compared between PsA patients with no DMARDs and those receiving any DMARDs, MTX, or bDMARDs, respectively.

Results: One hundred sixty-five PsA patients were analyzed, 79 received no DMARDs, 86 received DMARDs, of them 52 bDMARDs (TNF, IL-17- or IL-12/23 inhibitors) and 34 MTX. Groups were balanced for age, sex, comorbidities, functional index, and bone-active therapy, while disease duration was longest in the bDMARD group (7.8 ± 7.4 years), followed by the MTX group (4.6 ± 7.4) and the no-DMARD group (2.9 ± 5.2). No difference in bone parameters was found between the no-DMARD group and the MTX group. In contrast, the bDMARD group revealed significantly higher total (p = 0.001) and trabecular vBMD (p = 0.005) as well as failure load (p = 0.012) and stiffness (p = 0.012). In regression models, age and bDMARDs influenced total vBMD, while age, sex, and bDMARDs influenced failure load and stiffness.

Conclusion: Despite longer disease duration, bDMARD-treated PsA patients benefit from higher bone mass and better bone strength than PsA patients receiving MTX or no DMARDs. These data support the concept of better control of PsA-related bone disease by bDMARDs.

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease associated with psoriasis characterized by peripheral arthritis and enthesitis leading to structural damage.^[1–3] Bone erosions and enthesiophytes are hallmarks of local structural damage in PsA. More recently, the impact of PsA on systemic bone is increasingly appreciated. Hence, systemic bone loss has been documented to occur in PsA^[4,5] and increased prevalence of fractures in PsA patients is reported.^[6]

In contrast to RA, little is known about the effect of disease-modifying anti-rheumatic drugs (DMARDs) on bone structure in PsA. In rheumatoid arthritis (RA), biological DMARDs (bDMARDs) have shown to inhibit bone loss and thus may prevent pathological fractures.^[7–9] To date, no such studies have been done in PsA; however, it can be assumed that effective control of inflammation may also impact secondary bone loss and bone biomechanics in PsA patients. In support of this notion, bDMARD treatment in PsA patients retards the progression of periarticular bone erosions^[10–12] and periarticular bone loss.^[13–15] Whether systemic bone mass and bone biomechanical properties are influenced by DMARD treatment is unclear to date. Furthermore, methotrexate treatment may not necessarily share potential beneficial effects of bDMARDs on bone in PsA patients.

While dual-energy X-ray absorptiometry (DXA) or digital X-ray radiogrammetry (DXR) can quantify bone loss, they do not allow separate assessment of changes in the cortical and trabecular bone compartment or the biomechanical properties of bone. High-resolution peripheral quantitative CT (HR-pQCT) enables the analysis of bone mass and microstructure and via integration of micro-finite element analysis (μFEA) the assessment of bone strength.^[16] An HR-pQCT study in RA patients has already shown that the biomechanical properties of the bone are reduced in RA patients.^[17]

To investigate whether DMARD treatment influences systemic bone structure and function in PsA patients, we investigated bone density, bone microstructure, and biomechanical properties in patients receiving either no DMARDs, methotrexate (MTX) treatment, or biologic DMARDs (bDMARDs) by HR-pQCT. In this cross-sectional study, we were specifically interested, whether PsA patients treated with either MTX or bDMARDs show a better bone structure and function than PsA patients receiving no DMARDs.

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Arthritis Res Ther. 2019;21(162) © 2019 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Demographic and disease-specific characteristics in the three treatment subgroups
	No DMARDs, N = 79	bDMARD, N = 52	Methotrexate, N = 34	p value a/b/c
Demographic characteristics
Sex (M/F)	31/48	29/23	17/17	−/−/−
Age, (mean ± SD)	49.3 ± 12.0	48.0 ± 11.7	50.9 ± 11.3	−/−/−
Body mass index, (mean ± SD)	28.6 ± 6.2	29.0 ± 6.0	28.8 ± 6.4	−/−/−
Smokers, N (%)	24 (30)	12 (23)	7 (21)	−/−/−
Menopause, N (%)	21 (27)	12 (23)	7 (21)	−/−/−
Previous fracture, N (%)^‡	4 (5)	2 (4)	2 (6)	−/−/−
Disease-specific characteristics
Duration of PSO (years), (mean ± SD)	18.1 ± 16.1	20.2 ± 11.1	20.3 ± 16.4	−/−/−
Duration of PsA (years), (mean ± SD)	2.9 ± 5.2	7.8 ± 7.4	4.6 ± 7.4	< 0.001/0.011/0.018
MDA, N (%)	28 (35)	25 (48)	22 (65)	−/0.004/−
DAPSA
DAPSA score, (mean ± SD)	17.0 ± 11.4	12.3 ± 9.6	15.8 ± 17.8	0.009/−/−
Remission, N (%)	7 (9)	10 (19)	6 (18)	−/−/−
Low activity, N (%)	29 (37)	25 (48)	13 (38)	−/−/−
Moderate activity, N (%)	24 (30)	12 (23)	9 (27)	−/−/−
High activity, N (%)	12 (15)	2 (4)	4 (12)	0.040/−/−
Nail involvement, N (%)	20 (25)	7 (14)	8 (24)	−/−/−
Scalp involvement, N (%)	35 (44)	8 (15)	8 (24)	0.002/−/−
PASI (units), (mean ± SD)	4.0 ± 4.7	1.2 ± 2.7	2.1 ± 7.9	< 0.001/0.001/−
DLQI (units), (mean ± SD)	7.5 ± 6.5	3.2 ± 5.3	6.0 ± 5.3	0.043/−/−
HAQ (units), (mean ± SD)	0.6 ± 0.5	0.5 ± 0.5	0.7 ± 0.8	−/−/−
Diabetes mellitus, N (%)	2 (3)	3 (6)	2 (6)	−/−/−
Hypertension, N (%)	19 (24)	14 (27)	5 (15)	−/−/−
Autoantibody status
Positive low-titer ACPA, N (%)*	1 (1)	0	1 (3)	−/−/−
Positive low-titer RF, N (%)**	3 (4)	0	1 (3)	−/−/−
Anti-rheumatic and bone treatments
Vitamin D supplementation, N (%)	10 (13)	11 (21)	9 (27)	−/−/−
Bisphosphonates, N (%)	0	1 (2)	0	−/−/−
Current glucocorticoids, N (%)	0	6 (12)	5 (15)	0.002/0.001/−
Former glucocorticoids intake, N (%)	4 (5)	13 (25)	5 (15)	0.001/−/−
Duration of glucocorticoids intake (years), (mean ± SD)	1.1 ± 1.0	2.8 ± 2.2	0.4 ± 0.2	−/−/0.034

Bonferroni-Holm adjustment: critical p values indicating significant results (italicize p values) for all investigated parameters were as follows: p ₁ = 0.0167, p ₂ = 0.025, p ₃ = 0.05
ACPA anti-citrullinated protein antibody, bDMARDs biologic disease-modifying anti-rheumatic drugs, N number, PASI Psoriasis Area and Severity Index, PsA psoriatic arthritis, PSO psoriasis, MDA minimal disease activity, DAPSA Disease Activity Index for Psoriatic Arthritis, DLQI Dermatology Life Quality Index, HAQ health assessment questionnaire, RF rheumatoid factor, a no therapy vs. bDMARD, b no therapy vs. methotrexate, c bDMARD vs. methotrexate
*< 20 U/mL; **> 50 IE/mL
^‡Fracture in adult life that occured spontaneously, or fractures caused by trauma that would not have led to a fracture in a healthy person
a no therapy vs. bDMARD
b no therapy vs. Methotrexate
c bDMARD vs. methotrexate

Table 2. Comparison of bone structure and biomechanical properties in no-DMARD-, methotrexate-, and bDMARD-treated PsA patients
	No DMARDs (N = 79)	Methotrexate (N = 34)	bDMARDs (N = 52)	p value a/b
Finite element analysis
Stiffness (kN/mm), (mean ± SD)	45.2 ± 13.7	46.7 ± 14.2	52.1 ± 15.0 ^b	−/0.012
Failure load (N), (mean ± SD)	2154 ± 621	2242 ± 645	2473 ± 704 ^b	−/0.012
Bone parameters
Volumetric bone mineral density
Dtotal mg HA/cm ³, (mean ± SD)	290 ± 54	299 ± 63	320 ± 44 ^b	−/0.001
Dtrab, mg HA/cm ³, (mean ± SD)	156 ± 39	166 ± 40	174 ± 36 ^b	−/0.005
Dmeta, mg HA/cm ³, (mean ± SD)	214 ± 38	222 ± 39	236 ± 35 ^b	−/0.001
Dinn, mg HA/cm ³, (mean ± SD)	116 ± 41	127 ± 43	132 ± 40 ^b	−/0.026
Dcomp, mg HA/cm ³, (mean ± SD)	817 ± 57	817 ± 72	831 ± 43	−/−
Meta/Inn, %, (mean ± SD)	1.9 ± 0.5	1.9 ± 0.8	2.0 ± 0.8	−/−
Bone microstructure
BV/TV, %, (mean ± SD)	0.13 ± 0.03	0.14 ± 0.03	0.15 ± 0.03 ^b	−/0.005
Tb.N, 1/mm, (mean ± SD)	1.99 ± 0.35	2.05 ± 0.36	2.12 ± 0.32 ^b	−/0.022
TbTh, mm, (mean ± SD)	0.065 ± 0.010	0.067 ± 0.011	0.069 ± 0.010 ^b	−/0.030
Tb.Sp, mm, (mean ± SD)	0.47 ± 0.18	0.44 ± 0.10	0.42 ± 0.11 ^b	−/0.010
Tb.1/N.SD, mm, (mean ± SD)	0.21 ± 0.16	0.19 ± 0.08	0.19 ± 0.13 ^b	−/0.017
Ct.Th, mm, (mean ± SD)	0.71 ± 0.16	0.73 ± 0.18	0.80 ± 0.15 ^b	−/0.001
Bone area
Cross-sectional area (mean ± SD)	321 ± 76	335 ± 88	325 ± 80	−/−

Bonferroni-Holm adjustment: critical p values indicating significant results (bold p values) for all investigated parameters were as follows: p ₁ = 0.0167, p ₂ = 0.025, p ₃ = 0.05
bDMARDs biologic disease-modifying anti-rheumatic drugs, Dtotal total vBMD, Dtrab trabecular vBMD, Dcomp compact vBMD, Dmeta meta trabecular vBMD, Dinn inner trabecular vBMD, meta/inn ratio of meta-to-inner density, BV/TV trabecular bone volume fraction, Tb.N number of trabeculae, Tb.Th trabecular thickness, Tb.Sp trabecular separation, Tb.1/N.SD inhomogeneity of network, Ct.Th cortical thickness, a/b: a no DMARDs vs. methotrexate, b no DMARDs vs. bDMARD

Table 3. Regression models
	Estimates	CI	p value
Total vBMD
Intercept	362.37	325.84–398.90	< 0.001
Age	− 1.57	− 2.23 to − 0.91	< 0.001
Female	9.09	− 13.47–31.65	0.427
bDMARDs	43.52	18.18–68.86	0.001
Methotrexate	12.12	− 17.47–41.71	0.420
Stiffness
Intercept	68.65	60.90–76.40	< 0.001
Age	− 0.28	− 0.42 to − 0.14	< 0.001
Female	− 15.66	− 20.51 to − 10.82	< 0.001
bDMARDs	6.81	1.43–12.18	0.013
Methotrexate	− 0.67	− 7.06–5.72	0.835
Failure load
Intercept	3227.06	2879.26–3574.86	< 0.001
Age	− 12.77	− 19.06 to − 6.49	< 0.001
Female	− 732.60	− 949.97 to − 515.22	< 0.001
bDMARDs	322.23	80.84–563.63	0.009
Methotrexate	− 4.88	− 291.73–281.97	0.973

Reference for the change is the no treatment group. Models are adjusted for age, gender, and treatment-gender interaction
vBMD volumetric bone mineral density, bDMARDs biologic disease-modifying anti-rheumatic drugs, CI confidence interval

Table S1. Regression models
Total vBMD
	Estimates	CI	p-Value
Intercept	363.03	326.19–399.88	<0.001
Age	-1.56	-2.22 – -0.89	<0.001
Female	9.65	-13.22 – 32.52	0.406
bDMARDs	43.75	18.30 – 69.20	0.001
Methotrexate	11.47	-18.46 – 41.39	0.450
MDA	-2.74	-18.90 – 13.43	0.739
Stiffness
	Estimates	CI		p-Value
Intercept	68.21	60.41 – 76.02		<0.001
Age	-0.29	-0.43 – -0.15		<0.001
Female	-15.95	-20.83 – -11.07		<0.001
bDMARDs	6.70	1.31 – 12.08		0.015
Methotrexate	-0.19	-6.66 – 6.29		0.954
MDA	1.64	-1.82 – 5.10		0.352
Failure Load
	Estimates	CI		p-Value
Intercept	3203.37	2853.47 – 3553.26		<0.001
Age	-13.27	-19.61 – -6.93		<0.001
Female	-748.30	-967.17 – -529.43		<0.001
bDMARDs	316.38	74.99 – 557.76		0.011
Methotrexate	-21.66	-268.59 – 311.91		0.883
MDA	89.48	-65.57 – 244.53		0.256

vBMD, volumetric bone mineral density; bDMARDs, biologic disease modifying anti-rheumatic drugs; CI, confidence interval; MDA, minimal disease activity. Reference for the change is the no treatment group. Models are adjusted for age, gender and treatment gender interaction.