Musculoskeletal/Rheumatology

A randomized, double-blind, placebo-controlled trial published in the Journal of the American Medical Association (JAMA) found that women who discontinued alendronate after 5 years demonstrated a moderate decline in bone mineral density (BMD) and a gradual increase in serum markers of bone turnover compared with women who continued taking alendronate for an additional 5 years, but mean levels among patients who discontinued therapy remained at or above baseline levels measured 10 years earlier. In addition, no greater fracture risk other than for clinically detected vertebral fractures was seen in the discontinuation group compared with patients who continued alendronate for 10 years.

Review of agents in late-stage development for the treatment of ankylosing spondylitis, osteoarthritis, and related pain (December 2006).

Review of agents in late-stage development for the treatment of juvenile idiopathic, psoriatic, and rheumatoid arthritis (November 2006).

TNF inhibitor approved for inhibiting joint damage, improving physical function in psoriatic arthritis

Disease-modifying antirheumatic drugs (DMARDs) reduce the risk of acute myocardial infarction (MI) in patients with rheumatoid arthritis (RA), according to results of an observational study published in the journal Arthritis & Rheumatism.

The selective estrogen-receptor modulator (SERM) raloxifene reduces the risks of invasive breast cancer and vertebral fracture in postmenopausal women but also increases the risks of venous thromboembolism and fatal stroke, a study in the New England Journal of Medicine (NEJM) concluded.

Abatacept (Orencia, Bristol-Myers Squibb) is the first T-lymphocyte co-stimulation modulator to be approved by FDA. The agent is indicated for use in patients with moderate-to-severe, active rheumatoid arthritis who have not had an adequate response to methotrexate, tumor necrosis factor (TNF) inhibitors, or other disease-modifying anti-rheumatic drugs (DMARDs).

A meta-analysis of 9 randomized, placebo-controlled studies of rheumatoid arthritis (RA) patients treated with the anti-tumor necrosis factor (anti-TNF) agents infliximab and adalimumab suggests an increased risk of malignancies dependent on dose and an increased risk of serious infections.

A matched-case control study comparing 378 Swedish patients with rheumatoid arthritis (RA) in whom malignant lymphoma developed with a control group of 378 RA patients who did not develop lymphoma found no observed association between lymphoma risk and various methods of RA treatment, according to an article in the journal Arthritis & Rheumatism.

Rheumatoid arthritis patients, hindered by an inadequate response to tumor necrosis factor-alpha (TNF-alpha) inhibitors, may find some relief in the form of a drug that belongs to a new class of selective costimulation modulators.

A pivotal phase 3 trial of a fully human monoclonal antibody, denosumab, that prevents bone destruction is under way and includes 7,800 postmenopausal, osteoporotic women aged 60 to 90 years. The primary endpoint is new vertebral fractures versus placebo and secondary end points are safety and tolerability of the new agent. Phase 2 clinical trials have demonstrated that denosumab is superior to aldendronate in preserving bone mineral density (BMD), reported researchers during the American College of Rheumatology Annual Scientific Meeting in San Diego, Calif.

This recombinant IgG1 monoclonal antibody exerts its therapeutic effect through inhibition of human tumor necrosis factor (TNF).

One year of bisphosphonate therapy maintains the gains in bone mineral density (BMD) experienced after 1 year of full-length parathyroid hormone (1–84) in postmenopausal women at risk of osteoporotic fracture. The findings were published in the New England Journal of Medicine (2005;353:555–565).

First once-monthly therapy approved for treatment and prevention of osteoporosis

A review of agents in late-stage development for the treatment of osteoporosis (March 2005)

A study conducted by researchers at the University of Wisconsin, Stanford University, and several rheumatology clinics across the United States found that rheumatoid arthritis (RA) patients who do not receive sufficient benefit with etanercept may experience improved disease control by switching to infliximab.

Etanercept/anakinra combination therapy for the treatment of rheumatoid arthritis (RA) provides no added benefit and has an increased risk compared to etanercept alone, according to a study published in Arthritis & Rheumatism, the journal of the American College of Rheumatology (ACR).

The opioid oxymorphone (Numorphan, Endo) delivered in a new extended-release (ER) formulation significantly improves standard measures of pain and physical function in osteoarthritis (OA) patients, researchers reported at the American College of Rheumatology 67th Annual Scientific Meeting.

Lumiracoxib (Prexige, Novartis) appears to be the next COX-2 specific inhibitor that will be marketed in the United States. Currently, lumiracoxib is being studied for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. Lumiracoxib has been shown in vitro to be more selective for the COX-2 isoenzyme compared to rofecoxib and celecoxib, but clinical head-to-head studies between these agents are lacking. Small controlled trials, presented in abstract form, have shown lumiracoxib to have comparable efficacy to diclofenac and celecoxib in osteoarthritis. It has an adverse effect profile similar to other COX-2 inhibitors and superior to traditional NSAIDs concerning gastrointestinal safety, but cardiovascular and renal safety data are still not available. While existing clinical data on lumiracoxib are minimal and only published in abstract form, research is ongoing, including comparing lumiracoxib to ibuprofen and naproxen in the largest arthritis trial undertaken to date. When the results of this study are published, lumiracoxib?s efficacy and safety profile will be better understood. (Formulary 2003;38:528?536.)

Cyclooxygenase-2 selective inhibitiors, better known as coxibs, may not be cost-effective for treatment of chronic arthritis pain in patients at average risk for ulcer complications as compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), according to a study recently published in the Annals of Internal Medicine. Using a coxib versus a NSAID cost an incremental $275,809 per year to gain 1 additional quality-adjusted life-year (QALY). For patients with a history of bleeding ulcers, however, the incremental cost per QALY gained decreased to $55,803.

Treatment and prevention of osteoporosis

Adalimumab is the newest addition to a class of medications called tumor necrosis factor-alpha (TNF-a) inhibitors. Adalimumab (Humira, Abbott) is the first fully human monoclonal antibody approved to treat rheumatoid arthritis, distinguishing it from the other TNF inhibitors. FDA approval was received in December 2002, which was earlier than expected, based on clinical trial results that demonstrated a slowed progression of joint damage in addition to an improved quality of life in adalimumab-treated RA patients. Adalimumab has been found to be effective when used alone or in combination with methotrexate and/or other disease-modifying antirheumatic drugs. Existing TNF inhibitors for RA are associated with inconvenient or complicated dosing schedules. Adalimumab offers patients the convenience of an infrequent dosing schedule. In the absence of clinical trials directly comparing adalimumab with other biologic therapies, choice will largely depend on patient factors. Pricing information places adalimumab in line with its competitors.

Osteoporosis affects more than 10 million Americans and accounts for 1.5 million fractures annually. Several treatment options have been shown to prevent fractures and improve outcomes in patients with osteoporosis. Alendronate and risedronate clearly reduce fractures and are good initial choices in many patients. Raloxifene and calcitonin reduce the risk of vertebral fractures and may be appropriate in certain patients. Teriparatide was recently approved by FDA for the treatment of osteoporosis and may offer another treatment option. Combination therapy has been shown to increase bone mineral density; however, a reduction in the risk of fractures remains to be established. Zoledronic acid may offer an advantage of reduced frequency of administration.

NME: New treatment for rheumatoid arthritis

Although the commonly used HMG CoA reductase inhibitors (statins) are well tolerated and relatively safe, muscle toxicity and rhabdomyolysis can occur with administration and can be severe. This risk is higher with more bioavailable and lipophilic statins. This article summarizes what is known about the etiology of statin-associated muscle toxicity, the risks for each statin, and the current recommendations for monitoring and management.

In studies reported this month at the European League Against Rheumatism meeting in Stockholm, the anti-TNF antibody adalimumab (D2E7) for rheumatoid arthritis is showing good long-term results, even in patients for whom other disease modifying antirheumatic drugs (DMARDs) have failed.

Leflunomide, etanercept, infliximab, and anakinra represent the four latest additions to the therapeutic armamentarium for rheumatoid arthritis. All four of these DMARDs have demonstrated clinical and radiographic evidence of efficacy that is changing the therapeutic approach to treatment. The authors of this article summarize the pivotal clinical trial and efficacy data up through the perimarketing period, provide the latest efficacy and safety update on these agents, discuss the financial implications of their use, and offer insights into their place in therapy.

New indication: Biologic cleared for psoriatic arthritis

Prompted by the proliferation of new therapies in the field, the American College of Rheumatology has updated its guidelines for the management of rheumatoid arthritis.

Medications currently available to treat osteoporosis slow the rate of bone loss primarily by reducing bone resorption. The purported advantage of the anabolic agent teriparatide is that it actually promotes new bone growth. Clinical trials have shown the drug to be effective for vertebral fracture prevention in postmenopausal women at high risk. Additional evidence is accumulating to support teriparatide's use in other populations (including men) with osteoporosis. This injectable is likely to receive FDA approval in the second half of this year.