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From: The Rheumatologist, February 2010

What’s in the Pipeline for Osteoporosis?

Updated guidelines, online assessment tool, and new therapies coming this year

by Kathy Holliman, MEd

PHILADELPHIA—Updated recommendations for treatment of glucocorticoid-induced osteoporosis are expected to be released in 2010. In a presentation about the updated guidelines at the ACR Annual Scientific Meeting in October 2009, Jennifer M. Grossman, MD, principal investigator on the guideline development project, said that many patients on long-term glucocorticoid therapy do not get the interventions they need, despite the availability of therapies that would reduce their fracture risk.

The guidelines, updated from the 2001 recommendations, were submitted to the ACR in December, with the board of directors expected to review them this month. Pending peer review and acceptance, the final guidelines will be published in Arthritis Care & Research.

In addition to an overview of the preliminary recommendations, speakers at the session on osteoporosis care presented information about the online fracture risk assessment tool, known as FRAX, and provided an update on treatment options, including those in the pipeline.

Decreased Bone Mass

Dr. Grossman, associate clinical professor of medicine in the department of rheumatology at the David Geffen School of Medicine at the University of California, Los Angeles, said there “may be no safe dose” of daily steroids, a class of medications that is “not without complications.”

The effects of glucocorticoids on osteocytes, osteoclasts, the neuroendocrine system, and calcium metabolism lead to decreased bone mass; their effect on muscle heightens the risk of falls and subsequent fractures, she said. Risk of nonvertebral fracture increases with daily doses as low as 2.5 mg to 5 mg.

Even though these risks are known, only about 50% of women and 20% of men on glucocorticoids are given bone density studies; 10% to 50% of women and 10% to 20% of men receive prescription therapy for prevention or treatment of glucocorticoid-induced osteoporosis, Dr. Grossman said.

In her overview of the preliminary guidelines, Dr. Grossman said that any patient expected to use a glucocorticoid for three months or longer should be counseled about the need for adequate calcium and vitamin D intake and should be asked about any history of minimal trauma fractures. Physicians should observe their patient’s gait, take an annual height measurement, encourage smoking cessation, and urge limitation of alcohol intake to no more than two drinks daily. A bone density scan should be ordered if the patient has an established history of glucocorticoid use.

Recommendations for therapy in the updated guidelines will be based on an individual patient’s 10-year fracture risk as determined by FRAX. However, according to Dr. Grossman, the guidelines panel concluded that data are limited to guide treatment decisions for premenopausal women and men younger than 50 years.

Using FRAX

Michael McClung, MD, founding director of the Oregon Osteoporosis Center in Portland and an advisor to the World Health Organization’s fracture risk task force, said that the strength of FRAX is that the “interrelationships among the independent fracture risks are incorporated into the computer model,” rather than simply basing fracture risk on bone mineral density (BMD).

These risk factors include prior fracture, current age, body mass index (without BMD), femoral neck BMD, parent’s history of hip fracture, use of corticosteroids, consumption of more than two alcoholic drinks per day, smoking status, presence of rheumatoid arthritis, and secondary osteoporosis (without BMD).

Easy to use and accessible online at www.shef.ac.uk/FRAX, the program is based on data from 12 large observational cohorts in Europe, North America, Australia, and Asia that included over 60,000 cases and 250,000 patient-years of observation; 26% were men. The online algorithm computes a patient’s 10-year risk of hip and major osteoporotic (clinical vertebral, forearm, hip, and shoulder) fractures.

According to the National Osteoporosis Foundation’s (NOF) 2008 Guidelines, therapy should be initiated in postmenopausal women and men over age 50 years considering the following criteria:

  • If the patient has a hip or spine fracture;
  • If the BMD T-score in the spine or proximal femur is –2.5 or lower; or
  • If the BMD is between –1 and –2.5, and the patient has one of the following: 20% or higher 10-year risk of major fracture, or 3% or higher 10-year risk of hip fracture, as calculated by FRAX.

“The new [ACR] guidelines [will shift] the emphasis of treatment away from a large group of young, healthy, postmenopausal women with low BMD but no other risk factors toward treating an older population with non-BMD risk factors,” Dr. McClung said.

One related criticism of the NOF guidelines is that they do not incorporate the concept of drug treatment to prevent osteoporosis. “But the idea to prevent osteoporosis is a relic from previous times and is neither cost effective nor clinically effective,” Dr. McClung said.

Treatment for Osteoporosis

In an overview of the several pharmacologic strategies now available or in development for osteoporosis, John P. Bilezikian, MD, professor of medicine and pharmacology at the College of Physicians and Surgeons at Columbia University in New York, said that antiresorptive agents increase bone strength by reducing bone turnover. The antiresorptive bisphosphonates include alendronate, risedronate, zoledronate, and ibandronate. These drugs were originally given as daily medications, but less frequent dosing is as effective as daily doses, he said.

The advent of intravenous quarterly ibandronate and yearly zoledronic acid injections has improved compliance with therapy. The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial with 8,000 patients found that yearly 5-mg IV zoledronic acid reduced the incidence of vertebral and nonvertebral fractures, and the cumulative risk of hip fractures by 40%.1

Bisphosphonates have a rapid onset of action, a sustained effect, and the clinical practice experience with the agents now spans 14 years, he said. Problems with these agents include upper gastrointestinal intolerance with the oral medications; this is usually not a problem with IV administration. An acute phase reaction can occur with the IV formulations, but generally only at the initial stage.

Other side effects are rare, he said. Osteonecrosis of the jaw and subtrochanteric fractures are extremely rare, and reports of an association between bisphosphonate use and atrial fibrillation and esophageal cancer have not been supported by any data, Dr. Bilezikian said.

The search continues for alternate and “even better” osteoporosis drugs, he said, including newer antiresorptives, new formulations of anabolic therapy, and new approaches to combination therapy.

One promising new drug that has not yet won Food and Drug Administration approval is denosumab, a human immunoglobulin G antibody to RANKL, which controls osteoclast differentiation, activation, and survival. In the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every Six Months (FREEDOM) trial, denosumab was administered as a subcutaneous injection every six months. Dr. Bilezikian, a researcher on that trial, said the agent reduced new vertebral and nonvertebral fractures and the incidence of hip fractures.2

Other agents under investigation include odanacatib, a cathepsin K inhibitor; new potential indications for parathyroid hormone (such as glucocorticoid-induced osteoporosis and fracture healing); and combination therapies. Antisclerostin antibody therapy is being developed, after research revealed that sclerostin inhibits the Wnt signaling pathway, Dr. Bilezikian said.

Calling the future bright for new drug development, Dr. Bilezikian said several challenges remain. “We have to figure out how to prove efficacy and decide how to demonstrate that these drugs improve bone strength, improve bone quality, are safe, specific to bone, and affordable.”

Kathy Holliman is a medical journalist based in New Jersey.

References

  1. Black D, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. New Engl J Med. 2007;356:1809-1822
  2. Cummings SR, Martin JS, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. New Engl J Med. 2009;361:756-765.

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