Animal studies suggest combining bisphosphonates and anti-inflammatories may prevent bone loss in RA

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Animal studies suggest combining bisphosphonates and anti-inflammatories

may prevent bone loss in RA

Rheumawire

Aug 9, 2004

Janis

Rheumatoid arthritis (RA) joint damage has 2 major components:

inflammation and structural damage to the cartilage and bone.

Disease-modifying antirheumatic drugs (DMARDs) such as the TNF

inhibitors can cool inflammation, but that does not always translate

into preventing bone loss. The bisphosphonates are used to prevent bone

loss in other settings, and animal studies reported by 2 research groups

in the July 2004 issue of Arthritis & Rheumatism suggest that the

amino-bisphosphonate zoledronic acid (Zometa, Novartis) may be effective

for this purpose in RA, particularly if combined with TNF inhibition [1,

2].

Dr Evan Romas (University of Melbourne, Australia), senior author on 1

of the studies, tells rheumawire, " The efficacy of zoledronate should

embolden investigators to pursue low-dose steroid therapy in RA, which

is believed to prevent erosion but carries a risk of osteoporosis.

Bisphosphonates may blunt generalized bone loss while enhancing the

joint protection offered by steroid therapy. In fact, we believe that

aggressive conventional (nonbiologic) DMARD therapy, incorporating low

doses of glucocorticoids and a potent bisphosphonate (ie, zoledronic

acid), should be directly compared with anti-TNF strategies for clinical

efficacy, side effects, and cost in rheumatoid arthritis. "

Dr Petra Herrak (University of Vienna, Austria) et al tested zoledronic

acid in human-TNF-transgenic mice, which develop severe destructive

arthritis and osteoporosis. Mice were treated with phosphate-buffered

saline single or repeated doses of zoledronic acid, calcitonin, or

infliximab at the onset of arthritis.

Senior author Dr Georg Schett (University of Vienna) tells rheumawire

that his group's most important finding was that treatment did not

reduce synovial inflammation but did slow bone erosion and increase

systemic bone mass.

Zoledronic acid is known to be 1 of the most potent agents for blocking

osteoclast function. " This emphasizes the role of osteoclasts in joint

destruction and suggests that any effective blockade of osteoclasts as

here with zoledronic acid and as previously shown with osteoprotegerin

(OPG) is effective in reducing inflammatory bone damage, " Schett says

Schett says that the clinical implication is that if a therapeutic

regimen cannot completely suppress the inflammatory process in the

joint, addition of a drug that preserves the joint architecture might be

a reasonable approach.

" Joint inflammation and structural damage use different pathways.

Therefore, the best approaches to treat RA in an optimal way will need

to combine best anti-inflammatory and best antiresorptive effects, "

Schett says.

Dr A Sims (University of Melbourne) et al used zoledronic acid

to target osteoclasts in the collagen-induced arthritis (CIA) model of

RA. Rats with CIA were treated with phosphate buffered saline or with

single subcutaneous doses of zoledronic acid (1.0, 10, 50, or 100

µg/kg). They found that although zoledronic acid slightly exacerbated

synovitis, it significantly suppressed structural joint damage,

including radiographic bone erosions, Larsen scores, and juxta-articular

trabecular bone loss.

" Zoledronic acid prevented increased type I collagen (bone) breakdown in

CIA and diminished histologic scores of local bone erosion by up to

80%, " the researchers report.

Romas says that the increased synovitis was mild, transient, and

significant only for the very highest dose of zoledronate. " It most

likely reflects proinflammatory cytokine release, which is well

documented for the amino-bisphosphonates, " he tells rheumawire. " We

envisage that zoledronate will be used in conjunction with low-dose

steroids and aggressive DMARD therapy, so that the direct effects of

zoledronate on synovitis should not be limiting in clinical practice. "

Like Schett, Romas stresses the importance of the discovery that there

are different mechanisms of bone destruction and inflammation. " There

are 2 main reasons that conventional therapy cannot be relied on to

prevent structural joint damage and long-term disability in RA, " he

tells rheumawire. " First, the severity of synovitis is generally

underestimated by clinical methods (a limitation that was demonstrated

by techniques such as power Doppler ultrasound and MRI), often resulting

in undertreatment of synovitis. Second, traditional DMARDs do not

necessarily address osteoclastic bone erosion, even though they reduce

synovitis. In contrast, structural bone protection is consistently

achieved with agents such as TNF antagonists and (in preclinical

studies) osteoprotegerin and potent bisphosphonates because these

interventions either directly target the cytokines mainly responsible

for osteoclastogenesis (TNF-alpha and RANKL) or reduce the lifespan of

osteoclasts. We now have 'proof of concept' that bone destruction can be

effectively 'uncoupled' from inflammation, and we can use this insight

to generate novel strategies to prevent joint damage. "

In an accompanying editorial [3], Drs R Goldring and Ellen M

Gravallese (Harvard Medical School and New England Baptist Bone and

Joint Institute, Boston, MA) say, " Although the treatment regimens

differed, both studies demonstrated a reduction in the progression of

focal joint erosions as well as a decrease in systemic bone resorption

with [zoledronic acid] treatment. "

Sources

Sims NA, Green JR, Glatt M, et al. Targeting

osteoclasts with zoledronic acid prevents bone destruction in

collagen-induced arthritis. Arthritis Rheum 2004; 50:2338-2346.

Herrak P, Gortz B, Hayer S, et al. Zoledronic acid

protects against local and systemic bone loss in tumor necrosis

factor-mediated arthritis. Arthritis Rheum 2004; 50:2327-2337.

Goldring SR, Gravallese EM. Bisphosphonates:

Environmental protection for the joint? Arthritis Rheum 2004;

50:2044-2047.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org