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

[Guest guest]

I forgot my English-Doctorspeak dictionary at home today. I guess

I'll have to read this one later, when it's quiet, and I can really

really focus.

> 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