A One Year Case Control Study in Rheumatoid Arthritis Patients Indicates a Prevention of Bone Mineral Density Loss in Both Responders and Non Responders to Infliximab

Hubert Marotte; Beatrice Pallot-Prades; Laurent Grange; Philippe Gaudin; Christian Alexandre; Pierre Miossec

Arthritis Res Ther. 2007;9(3)

Abstract and Introduction

The goal of the present study was to record changes in bone mineral density (BMD) and markers of bone turnover in patients with rheumatoid arthritis (RA) who were treated with methotrexate combined (or not combined) with infliximab. Included were 90 patients with RA who required anti-TNF-α therapy with infliximab because of persistent active disease despite treatment with methotrexate. The historical control group included 99 patients with RA who were treated with methotrexate at a time when anti-TNF-α treatment was not yet available. Lumbar and femoral neck BMD was measured using dual energy X-ray absorptiometry at baseline and 1 year later. Osteocalcin, C-terminal cross-linked telopeptide of type I collagen, parathyroid hormone and 25-hydroxycholecalciferol were measured in plasma at baseline and 1 year later. At 1 year BMD had decreased in the control group at spine (P < 0.01) and femoral neck (P < 0.001). In contrast, BMD at spine and femoral neck did not change after 1 year of infliximab treatment. At the same time point, no change in bone remodelling markers was observed. No association was observed between clinical response and changes in BMD, indicating that even those who did not respond clinically did not lose bone over a 1-year period. These data confirm the BMD decrease observed in RA patients treated with methotrexate alone. This bone loss was prevented by infliximab therapy. Importantly, this beneficial effect was also observed in apparent nonresponders.

Rheumatoid arthritis (RA) is a chronic disease that is characterized by joint inflammation and local bone erosion. In addition, generalized bone loss has been demonstrated in RA patients.^[1,2] This could be due to the disease itself, to reduced exercise activity, or to treatment with steroids,^[3] but it could also result from common postmenopausal osteoporosis.

Among the factors that can influence bone resorption and osteoclast activity, tumour necrosis factor (TNF)-α plays a central role in the destructive process of RA and has been shown to increase bone resorption in systemic osteoporosis related to oestrogen deficiency^[4]. In transgenic mice expressing soluble TNF receptor to neutralize TNF-α, animals were protected from oestrogen deficiency-related bone loss.^[5] TNF-α is also a powerful inhibitor of bone formation.^[6]

Infliximab is a neutralizing chimeric monoclonal anti-TNF-α antibody that has been successfully used in RA treatment,^[7] and has an effect on joint destruction.^[8] However, its systemic effect on bone remains to be elucidated. In this study, we compared bone mineral density (BMD) values between RA patients treated with infliximab and those not receiving infliximab. Previous open studies have demonstrated either an increase in BMD or no change. A major limitation of these studies is that they did not include a control group.^[9,10] The optimal design for this type of study would be a double-blind randomized comparison with placebo. However, because TNF-α blockers are now on the market, ethical issues would prevent such a randomized, placebo-controlled trial. Another option is to perform a historical control study, with controls being active RA patients followed before the advent of TNF-α blocker therapy and who were treated with methotrexate alone. Such a historical control group is of great interest because it is not influenced by use of TNF inhibitors in patients with the most active disease.

This case-control study was conducted to compare changes in BMD between RA patients treated with infliximab and those not receiving this agent over 1 year. Moreover, we investigated bone turnover using biochemical markers of bone formation and resorption, and we studied the relationship between changes in BMD and clinical response to therapy.

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Arthritis Res Ther. 2007;9(3) © 2007 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.

Cite this: A One Year Case Control Study in Rheumatoid Arthritis Patients Indicates a Prevention of Bone Mineral Density Loss in Both Responders and Non Responders to Infliximab - Medscape - Jun 27, 2007.

Clinical, Biological and Densitometry Data at Baseline
Parameter	Whole population	Infliximab (n = 90)	No infliximab (n = 99)	P
Age	52.5 ± 14.2	50.9 ± 11.8	53.9 ± 15.9	NS
Women (n [%])	152 (80)	74 (82)	78 (79)	NS
Disease duration (years)	10.6 ± 9.0	10.2 ± 9.1	10.9 ± 8.9	NS
Patients on steroids (n [%])	118 (62)	56 (62)	62 (63)	NS
Mean dose steroids (mg/day)	5.30 ± 5.79	5.40 ± 5.75	5.26 ± 5.83	NS
DAS28 score	5.17 ± 1.07	5.37 ± 0.94	5.00 ± 1.15	NS
Patients on biphosphonates (n [%])	35 (19)	15 (17)	20 (20)	NS
Calcaemia (mmol/l)	2.28 ± 0.13	2.32 ± 0.12	2.24 ± 0.12	NS
Alkaline phosphatase (U/l)	74.6 ± 25.6	77.5 ± 29.5	72.0 ± 21.2	NS
Osteocalcin (ng/ml)	19.9 ± 11.8	18.4 ± 9.7	21.2 ± 13.4	NS
CTX-I (pg/ml)	446 ± 307	482 ± 386	418 ± 227	NS
Parathyroid hormone (pg/ml)	30.5 ± 17.6	28.7 ± 15.4	32.0 ± 19.1	NS
25-hydroxycholecalciferol (ng/ml)	19.7 ± 10.3	18.2 ± 10.1	21.2 ± 10.4	NS
Femoral neck BMD (g/cm²)	0.801 ± 0.159	0.807 ± 0.156	0.797 ± 0.162	NS
Lumbar BMD (g/cm²)	0.911 ± 0.143	0.930 ± 0.142	0.896 ± 0.142	NS
Patients with neck osteopenia (n [%])	96 (51)	47 (52)	49 (50)	NS
Patients with lumbar osteopenia (n [%])	93 (49)	40 (45)	53 (54)	NS
Patients with neck osteoporosis (n [%])	37 (20)	18 (20)	19 (19)	NS
Patients with lumbar osteoporosis (n [%])	37 (19)	15 (17)	23 (23)	NS

Values are shown for each parameter at baseline, expressed as mean ± standard deviation or n (%). Data for both groups (case and control) were compared using the unpaired Student's t-test for continuous variables and the χ² test for discrete variables. BMD = bone mineral density; CTX-I = C-terminal cross-linking telopeptide of type I collagen; DAS = Disease Activity Score; NS = not signficant.

Clinical, Biological and Densitometry Data at Baseline
Parameter	Whole population	Infliximab (n = 90)	No infliximab (n = 99)	P
Age	52.5 ± 14.2	50.9 ± 11.8	53.9 ± 15.9	NS
Women (n [%])	152 (80)	74 (82)	78 (79)	NS
Disease duration (years)	10.6 ± 9.0	10.2 ± 9.1	10.9 ± 8.9	NS
Patients on steroids (n [%])	118 (62)	56 (62)	62 (63)	NS
Mean dose steroids (mg/day)	5.30 ± 5.79	5.40 ± 5.75	5.26 ± 5.83	NS
DAS28 score	5.17 ± 1.07	5.37 ± 0.94	5.00 ± 1.15	NS
Patients on biphosphonates (n [%])	35 (19)	15 (17)	20 (20)	NS
Calcaemia (mmol/l)	2.28 ± 0.13	2.32 ± 0.12	2.24 ± 0.12	NS
Alkaline phosphatase (U/l)	74.6 ± 25.6	77.5 ± 29.5	72.0 ± 21.2	NS
Osteocalcin (ng/ml)	19.9 ± 11.8	18.4 ± 9.7	21.2 ± 13.4	NS
CTX-I (pg/ml)	446 ± 307	482 ± 386	418 ± 227	NS
Parathyroid hormone (pg/ml)	30.5 ± 17.6	28.7 ± 15.4	32.0 ± 19.1	NS
25-hydroxycholecalciferol (ng/ml)	19.7 ± 10.3	18.2 ± 10.1	21.2 ± 10.4	NS
Femoral neck BMD (g/cm²)	0.801 ± 0.159	0.807 ± 0.156	0.797 ± 0.162	NS
Lumbar BMD (g/cm²)	0.911 ± 0.143	0.930 ± 0.142	0.896 ± 0.142	NS
Patients with neck osteopenia (n [%])	96 (51)	47 (52)	49 (50)	NS
Patients with lumbar osteopenia (n [%])	93 (49)	40 (45)	53 (54)	NS
Patients with neck osteoporosis (n [%])	37 (20)	18 (20)	19 (19)	NS
Patients with lumbar osteoporosis (n [%])	37 (19)	15 (17)	23 (23)	NS

Bone Markers and Densitometry Data at Baseline and 1 Year Later
Group	Baseline	1 year	P
Control
Osteocalcin	21.2 ± 13.4	20.7 ± 11.5	NS
CTX-I	418 ± 227	391 ± 259	NS
Parathyroid hormone	32.0 ± 19.1	36.0 ± 19.7	NS
25-hydroxycholecalciferol	21.2 ± 10.4	22.8 ± 10.5	NS
Femoral neck BMD	0.797 ± 0.162	0.770 ± 0.162	<0.001
Lumbar BMD	0.896 ± 0.142	0.861 ± 0.142	<0.001
Infliximab
Osteocalcin	18.4 ± 9.7	15.7 ± 10.9	NS
CTX-I	482 ± 386	452 ± 271	NS
Parathyroid hormone	29.1 ± 15.4	32.6 ± 15.5	NS
25-hydroxycholecalciferol	17.9 ± 10.1	19.6 ± 9.2	NS
Femoral neck BMD	0.807 ± 0.156	0.809 ± 0.151	NS
Lumbar BMD	0.930 ± 0.142	0.928 ± 0.136	NS

Values are shown for each parameter at baseline and at 1 year, expressed as mean ± standard deviation. In each group, data were compared using the Student's paired t-test for continuous variables, between baseline and 1 year. BMD = bone mineral density; CTX-I = C-terminal cross-linking telopeptide of type I collagen.

Analysis of the Effect of Infliximab on BMD Using Different Linear Regression Models
Models	Cofactors	Femoral neck BMD		Lumbar BMD
Models	Cofactors	BMD variation	P	BMD variation	P
1	Infliximab	0.027	0.001	0.030	0.001
2	Infliximab	0.027	0.001	0.031	0.001
	Male sex	-0.009	0.40	0.008	0.47
	Age	0.002	0.56	0.005	0.09
3	Infliximab	0.020	0.03	0.033	0.001
	Male sex	-0.014	0.22	0.006	0.64
	Age	0.001	0.86	0.005	0.15
	Patients on steroids	-0.012	0.20	-0.001	0.92
4	Infliximab	0.023	0.01	0.034	0.001
	Male	-0.014	0.22	0.006	0.61
	Age	-0.001	0.90	-0.001	0.88
	Menopause	0.005	0.75	0.022	0.20
	Patients on steroids	-0.010	0.29	-0.002	0.87
	DAS28	-0.008	0.04	-0.006	0.17
5	Infliximab	0.023	0.02	0.035	0.001
	Male	-0.015	0.20	0.007	0.58
	Age	-0.001	0.85	0.000	0.95
	Menopause	0.006	0.70	0.020	0.25
	Patients on steroids	-0.009	0.37	-0.004	0.65
	DAS28	-0.008	0.05	-0.006	0.15
	Patients on biphosphonates	-0.012	0.29	0.022	0.07
6	Infliximab	0.028	0.002	0.041	0.001
	Male	-0.007	0.53	0.010	0.39
	Age	-0.002	0.61	0.002	0.63
	Patients on steroids	-0.008	0.35	-0.001	0.91
	DAS28	-0.007	0.06	-0.007	0.10
	Baseline BMD values	-0.042	0.16	-0.080	0.01

All 189 patients were included in several analysis of covariance models for bone mineral density (BMD) variations (final values minus initial values) to analyze the effect of cofactors (continuous variables and discrete variables) on that of infliximab. DAS = Disease Activity Score.

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