the effects of ovarian hormone replacement therapy (HRT) on bone mineral density and disease activity in postmenopausal women
with rheumatoid arthritis (RA). METHOD--A placebo controlled double-blind study was carried out on 62 patients with RA, 22
on placebo and 40 on HRT (transdermal oestradiol patches twice weekly for 48 weeks plus norithisterone tablets when clinically
indicated). Bone mineral density of spine, hip and wrist was measured at 0 and 48 weeks and clinical and laboratory measures
of general well-being and disease activity at 0, 12, 24 and 48 weeks. RESULTS--Thirteen of 22 (59%) of placebo and 31 of 40
(78%) of the HRT group completed 48 weeks in the study. At entry, bone mineral density (BMD) values in the lumbar spine and
femoral neck were similar to those in age and sex matched controls in both treatment groups, whereas at the distal radius,
BMD was significantly reduced to approximately 50% of control values (both p < 0.001 from controls). In the HRT group, spine BMD increased significantly by a median of +0.94% at 48 weeks (p = 0.024), but did not
change significantly in the placebo group. BMD at the femoral neck and distal radius did not change in either group. In the HRT group, there was significant improvement in well being as assessed by the Nottingham Health
Care Profile (p < 0.01) and in the articular index (p < 0.05). There were no significant changes in ESR or CRP
in either group. CONCLUSION--Transdermal HRT was well tolerated, increased well being, reduced articular index and increased
lumbar spine bone density over a one year period in postmenopausal women with RA. Although no laboratory
evidence was found of a disease modifying effect, the symptomatic benefits and improvements in bone density indicate that
HRT may be a valuable adjunct to conventional antirheumatic therapy in RA.
Interaction with Estrogen Receptors as Treatment of Arthritis and Osteoporosis
in Experimental Medicine and Biology,
2007, Volume 602, 83-92, DOI: 10.1007/978-0-387-72009-8_11 http://www.springerlink.com/content/lg506007252607g0/
Estrogen is a steroid hormone having, in addition to
its effects on sexual differentiation and reproduction, important impact on the immune system and on bone. Estrogen exerts
its effects via activation of its two receptors ERα and ERβ. Our knowledge of how estrogen manages to mediate its
various properties in different organs has increased tremendously by studies of ER targeted mice (Matthews and Gustafsson
2003; Hewitt, Harrell and Korach 2005). It has been evident that the effects of estrogen on bone to a large extent are mediated
via its action on immune cells. Estrogen has a dichotomous impact on the immune system by down regulation of inflammatory
immune responses but simultaneous upregulation of immunoglobulin production. Consequently, immune mediated diseases in humans
and in animal models are modulated by estrogen. Estrogen deficiency after ovarectomy in mice and menopause in women are associated
with significant bone loss. In rheumatic diseases such as rheumatoid arthritis (RA) osteoporosis is frequent and in postmenopausal
RA the degree of bone loss is dramatically increased. Hormone replacement therapy (HRT) in murine and human arthritis has,
as expected beneficial effects on bone loss but
it also ameliorates inflammation and inflammation triggered joint destruction (Holmdahl, Jansson, and
Andersson 1986; Forsblad d’Elia, Larsen, Mattsson, et al. 2003b). RA is a chronic autoimmune disease with complex pathogenesis
(Holmdahl, Bockermann, Backlund, et al. 2002) displaying a variety of inflammatory mechanisms resulting in joint destruction
(Gravallese 2002) and generalized osteoporosis (Haugeberg, Orstavik and Kvien 2003). Hence, in order to understand the mechanisms
for estrogen mediated effects on bone loss in inflammatory diseases it is necessary to dissect the different stages at which
the estrogen has potential modulating properties. Long-term use of HRT has been associated with increased risk of breast cancer,
thrombosis and possibly also stroke (Prelevic, Kocjan, and Markou 2005). Accordingly, there is great need for new activators
of estrogen receptors (ERs) selectively reproducing only the beneficial effects of estrogen.
HRT reduces pain 21.7% and morning stiffness 25.2%, and improved articulation among those
who were good compliers (50 mg transdermal estradiol)
Rheum Dis. 1994 Feb;53(2):112-6.
A randomised controlled trial of the effect of hormone replacement therapy on
disease activity in postmenopausal rheumatoid arthritis.
Rheumatology, St Bartholomew's Hospital, London, UK.
OBJECTIVE: To assess the effects of hormone
replacement therapy (HRT) on disease activity in postmenopausal rheumatoid arthritis (RA).
METHODS: Two hundred postmenopausal outpatients
(aged 45-65 years) were admitted into a single blind randomised placebo controlled trial of transdermal oestradiol (50 micrograms
daily) over six months. Patients continued with routine antirheumatic medications. Compliance with HRT was monitored using
serum oestradiol (E2) levels. Disease activity was monitored at entry, three and six months using erythrocyte sedimentation
rate (ESR), articular index (AI), visual analogue pain scale (VPS) and early morning stiffness (EMS).
RESULTS: Ninety one and 77 patients completed
six months treatment with placebo and HRT respectively. There were no significant differences in baseline characteristics
between the groups and no overall effects of treatment. However, 35 patients (41.6%), who completed HRT, failed to achieve
serum E2 levels > 100 pmol/l at either three or six months and were considered 'poor-compliers'. In the remaining HRT 'compliers'
(58.4%) there were significant improvements after six months in articular index (28.9%; p < 0.01) and pain score (21.7%;
p < 0.05) compared with placebo, as well as reductions in ESR (8.9%; NS) and morning stiffness (25.2%; NS). Comparisons
between HRT 'compliers' and 'poor-compliers' confirmed significant improvements in articular index (p < 0.001), pain score
(p < 0.05) and morning stiffness (p < 0.001) in the 'compliers'.
CONCLUSIONS: This study did not show an overall
effect of HRT on disease activity when used as an adjunct therapy in postmenopausal patients. A subgroup of patients, who
had greater increments in serum E2 whilst taking HRT, demonstrated improvements in some parameters of disease activity, suggesting
a potential beneficial effect with good compliance and higher dose HRT. Most importantly, in the treatment of RA associated
bone loss, HRT can be prescribed without fear of a disease flare up.