Bone Quality as Important as T Score

By Laura Brasseur

Clifford J.
Rosen, MD

SAN DIEGO—Instead of focusing only on bone quantity, usually referred to as bone mineral density (BMD) and measured by T score, Clifford J. Rosen, MD, director, Maine Center for Osteoporosis Research and Education, St. Joseph Hospital in Bangor, tells physicians to shift their attention to bone quality—the characteristics that influence resistance to fracture. Dr Rosen presented this new approach to the assessment of osteoporotic fracture risk at the recent American College of Physicians (ACP) annual meeting and discussed the latest information on drug therapy for osteoporosis.

"We're so trained to think about numbers, and less trained to think about imaging, or what the bone is really all about," says Dr Rosen, who is also professor of nutrition, University of Maine in Orono. He encourages physicians to move away from using T scores alone when assessing the risk for osteoporotic fracture and to start thinking more about the patient's bone quality.

Why Is Bone Quality So Important?

BMD is a good surrogate measure of bone capacity. The lower the bone density, the less load is needed to cause a fracture. Studies of thousands of women older than 65 years demonstrate that, compared with women in the highest BMD quartile, the absolute hip fracture risk increases by 10-fold in those in the lowest BMD quartile. "Very few clinical tests are as reliable for predicting fractures, especially in the elderly," Dr Rosen says.

But although BMD is a good reflection of bone strength, it is not sufficient to assess fracture risk. Some people with a T score of -3.5 will never have a fracture, and others will fracture at a T score of -1.0. This is where bone quality—the structure and geometry of the skeleton, as well as the rapidity of bone turnover—comes in.

"The physician's goal is to identify high-risk individuals, and this cannot be done with T scores alone," Dr Rosen insists.

He announced at the ACP meeting that the investigators who came up with the T-score measure will soon be introducing a new tool for assessing the 10year fracture risk, based not just on BMD but also on indicators of bone quality, such as:

• Age >65 years
• Low body weight
• Family history of fracture (particularly hip fracture in mothers of women aged 65-75 years)
• History of postmenopausal fracture
• Genetics.

Previous fracture is one of the strongest indicators of bone quality, as well as the biggest and most underestimated risk factor for future fracture. "Any postmenopausal fracture is an osteoporotic fracture and increases risk for future fracture," says Dr Rosen. "If a postmenopausal woman walks into your office, and she's had a fracture anywhere except the nose, she's at higher risk for future fracture."

He notes that "once a postmenopausal woman has a fracture, she has osteoporosis." There is no need to measure her BMD. "The T score may reinforce, or in some cases may confuse, the diagnosis, but she has osteoporosis. And her risk of future fracture is increased by 8- to 10-fold."

Age is another strong indicator of bone quality. Fracture risk increases nearly 10-fold between the ages of 45 and 80. Dr Rosen implores physicians not to assess fracture risk "solely on the basis of T score." The absolute risk for fracture within the next 10 years in a 45-year-old woman with a T score of -2.5 is negligible. The same cannot be said for an 80-year-old woman.

Antiresorptive Therapy

How long should your patient take antiresorptive therapy? Although antiresorptive therapy is known to increase BMD, no strong correlation has been found between increased BMD level and reduction of fracture risk.

Among the antiresorptive agents, raloxifene (Evista) increases BMD by 2% after 3 years of treatment, but it reduces the risk for spine fractures by 50%. Alendronate sodium (Fosamax) increases BMD by 6% but also reduces the risk for spine fractures by 50%. The 10% increase in BMD with parathyroid hormone (PTH; teriparatide [Forteo]) also results in 50% risk reduction for spine fractures.

This clearly demonstrates that the change in BMD is not reflecting the change in bone quality. More proof for this comes from the antifracture protection afforded by bisphosphonates as early as 6 months after starting therapy, long before any significant changes occur in BMD. Thus, Dr Rosen said, "A lot of changes that occur with antiresorptive therapy are protective changes occurring independent of BMD."

Bisphosphonate therapy may eventually be intermittent, Dr Rosen says. Research has shown continued suppression of bone resorption in patients who have stopped taking bisphosphonates for as long as 5 years. Thus, a patient who has been taking alendronate for 5 years and who does not have recurrent spine fractures "could probably stop therapy for 1 to 3 years, or even up to 5 years, if you monitor her BMD," he says. For the minority of patients who have clinical fractures while taking alendronate, continued therapy is probably advisable.

Combination Therapy, PTH

Is there any benefit to combining antiosteoporosis drugs? Should you combine bisphosphonates and anabolics? "We see this often in our referral practice," Dr Rosen says. Many patients take 3 to 5 antiosteoporosis medications. But "the effects are not additive." Using PTH with alendronate is probably not beneficial.

PTH is a very safe and effective treatment that improves bone quality as much as bone quantity. Both spine and nonspine fracture risk are reduced by 50%. Its greatest drawback is its cost—about $8200 annually, which few insurers cover. Perhaps the most distinctive advantage of PTH is its ability to decrease back pain, making it the ideal drug for patients with spine fractures and significant back pain.

However, if you prescribe PTH, "it is very important that you use it properly," Dr Rosen cautions. After the recommended treatment period of 18 to 20 months, patients must begin taking a bisphosphonate, or they could lose virtually all of the beneficial effects of PTH.

New Treatments

The agent that is probably closest to being approved for the treatment of osteoporosis is zoledronic acid (Zometa), which is currently indicated for the treatment of multiple myeloma. A new version of this drug has just been approved for the treatment of Paget's disease.

A recently published 3-year randomized controlled trial (N Engl J Med. 2007;356:1809-1822) demonstrated striking reductions in osteoporotic fracture risk with 2 once-yearly injections of zoledronic acid. The risk for hip fracture was reduced by 41%, for clinical vertebral fractures by 77%, for all clinical fractures by 33%, and for nonvertebral fractures by 25%. There was also a 70% reduction in morphometric vertebral fractures (ie, fractures that you see on x-ray rather than the clinical fractures that are heralded by patients' complaints of back pain).

"If you're going to use zoledronic acid off-label for the treatment of osteoporosis—which a lot of people do, since it's a single infusion—be sure to check vitamin D levels," Dr Rosen emphasizes. At least 50% of all patients seen in primary care are vitamin D deficient, and their risk of hypocalcemia would greatly increase if they were given zoledronic acid. "If your patient's 25-hydroxyvitamin D level is <20 ng/mL, be careful about using it [ie, zoledronic acid]."

A worrisome adverse effect that emerged from the zoledronic acid trial was an increased incidence of significant atrial fibrillation, a side effect that has also been reported with alendronate. The mechanism has not yet been identified, and no one knows if it is a class effect. Until this issue is resolved, Dr Rosen says, "I'm not treating anyone in my office with zoledronic acid yet."

Other Options on the Horizon

• AMG 162 (Amgen), an antibody to receptor activator of nuclear factor κB ligand (RANKL), administered as a twice-yearly subcutaneous injection, which Dr Rosen says has "huge potential"
• New anabolic agents, including PTH-related peptide, which is now in clinical trials
• A monoclonal antibody (Amgen), which has shown a 30% increase in BMD in monkeys after just 3 months of treatment
• A vibration platform (Dynamic Motion Therapy; Juvent), which delivers low-amplitude, high-frequency sound waves, and is being evaluated in 3 government-sponsored trials.

Drug Alert

Dr Rosen alerts physicians to emerging reports of an increased incidence of fractures among postmenopausal women taking the antidiabetes agents rosiglitazone maleate (Avandia) and pioglitazone (Actos). The FDA issued a warning that rosiglitazone may increase the risk of fracture of the extremities. As Dr Rosen says, "Stay tuned."