First Report®

American Society for Bone and Mineral Research (ASBMR) 2011 Annual Meeting

September 16-20, 2011; San Diego, CA

Experts Debate Appropriate Target Levels of Serum Vitamin D for Preventing Fracture

A 60-minute presentation at the recent ASBMR meeting discussed the 2010 Institute of Medicine (IOM) report revising daily recommended allowances for vitamin D. Cliff Rosen, MD, IOM Committee Member and Senior Scientist, Maine Medical Center Research Institute, Scarborough, spoke in support of the IOM position that 20 ng/mL serum levels of 25-hydroxy vitamin [25(OH)D] are sufficient for the general population. Bess Dawson-Hughes, MD, Professor of Medicine, Tufts University, Boston, MA, spoke after Rosen and argued that target levels of 25(OH)D should be increased to 30 ng/mL to prevent fractures, especially in older adults and high-risk individuals.

Rosen began by acknowledging the controversy the IOM report has generated. He said everyone recognizes vitamin D is essential for optimal skeletal health, but the committee’s evidence-based analysis shows more is not necessarily better. “In general, for a healthy population, we recommended intakes of 600 to 800 IU per day as protective for skeletal health,” he said.

In establishing 20 ng/mL as a sufficient 25(OH)D level, the IOM scrutinized commonly held beliefs about levels below 30 ng/mL. Data did not support a relationship between 25(OH)D and parathyroid hormone levels or calcium absorption. Although levels below 20 ng/mL correlated with a higher risk of fracture and falls, Rosen said randomized, controlled trials provide “very strong evidence” that administering vitamin D supplements to older women with a 25(OH)D level at 25 ng/mL does not improve fracture risk. While levels below 20 ng/mL contribute to frailty, he said a somewhat controversial study involving 6307 women (mean age, 69 years) also observed greater frailty among those with 25(OH)D levels exceeding 30 ng/mL.

“I don’t want you to leave saying I don’t believe that vitamin D is important, and I think the IOM recognized it was important,” said Rosen. “But the real question is, is it necessary to get to 30 ng/mL?”

Although the IOM answered that question in the negative, Dawson-Hughes disagrees, at least when it comes to older adults. Her argument is based primarily on studies linking higher 25(OH)D levels to lower fracture risk. Although evidence also suggests 25(OH)D levels above 26 ng/mL reduce fall risk, she said too few studies had examined the incidence in elderly patients with levels between 20 and 26 ng/mL to make a comparison.

Studies investigating fractures in community-dwelling and institutionalized older adults, however, have consistently found administering vitamin D supplements to achieve target 25(OH)D levels between 20 and 26 ng/mL does not prevent nonvertebral or hip fractures. “The lowest level of 25(OH)D associated with any movement downward in risk reduction for hip fractures is at 30 ng/mL. In nonvertebral fractures, you start to see movement downward at around 26 ng/mL,” Dawson-Hughes explained. She said the IOM review identified no safety concerns with 25(OH)D levels up to 50 ng/mL, and she was therefore comfortable setting a target level of 30 ng/mL, based on the “current best evidence.” She recommended targets be reviewed regularly, to ensure evidence-based practices are maintained.

Although the speakers disagreed over appropriate 25(OH)D target levels, they concurred that more randomized, controlled trials are needed to investigate vitamin D supplementation and 25(OH)D levels in different patient populations. Together, they are planning a randomized, controlled trial to study the relationship between vitamin D supplementation and various health concerns.—Christin Melton

Studies Indicate Long-Term Effectiveness of Denosumab in Postmenopausal Women With Osteoporosis

Denosumab is the first in a new class of agents called RANK ligand inhibitors approved by the US Food and Drug Administration to treat women with osteoporosis. Multiple abstracts at the ASBMR meeting presented data on the long-term safety and effectiveness of this relatively new drug in postmenopausal patients.

McClung and associates reported that postmenopausal women given 60 mg of denosumab every 6 months for 8 years (n=80) experienced a 16.8% increase in lumbar spine bone mineral density (BMD) and a 6.9% increase in total hip BMD compared with baseline levels. Compared with BMD gains for women who took placebo for 4 years followed by denosumab for 4 years (n=11), those women receiving 8 years of denosumab therapy realized an average gain in lumbar spine DMB that was 5.8% greater and in total hip BMD that was 2.0% greater. Patients who crossed over to denosumab after placebo had BMD gains described as “comparable with those observed during the first 4 years” in women randomized to denosumab. Women in the crossover and continuous groups had decreases in carboxyterminal cross-linking telopeptide of bone collagen and bone-specific alkaline phosphatase, both markers of bone turnover, at 8 years.

Simon and colleagues reported data from the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial, which randomized women to placebo (n=3906) or a 60-mg dose of denosumab (n=3902) every 6 months for 3 years. They assessed the drug’s effects on cortical and trabecular bone at the radius and the incidence of wrist fracture. In a subgroup of patients who underwent dual energy X-ray absorptiometry scanning at 12, 24, and 36 months, denosumab was found to have significantly increased radial BMD compared with placebo (P<.05). Similar improvement in radial BMD was also observed for a subgroup of patients scanned with quantitative computed tomography (P<.05).

The overall incidence of wrist fractures was 2.9% in the denosumab group versus 2.5% for the placebo arm. A subgroup analysis of patients with a baseline femoral neck BMD T-score ≤-2.5, and thus at higher risk of nonvertebral fracture, correlated denosumab with a 40% reduction in the relative risk of wrist fracture (absolute risk reduction, 1.6%; P=.03) compared with placebo. The authors described the incidence of wrist fracture among high-risk patients treated with denosumab as comparable to that for lower risk patients taking placebo. Denosumab was also associated with significant gains in strength along the radius.

Chapurlat and colleagues analyzed the safety of long-term denosumab use in a 2-year extension study following the FREEDOM trial. All women enrolled in the extension phase received 2 years of denosumab regardless of whether they took denosumab or placebo in the trial’s main phase. Year-to-year rates of serious adverse events (SAEs) of infection and adverse events of malignancies were assessed for all 5 years of participation. Yearly rates of SAEs of infection were low in both arms (<2% in any given year), with pneumonia consistently the most common. The 12-month rate of SAEs of infection varied more among crossover patients than among those given denosumab from the study’s outset. In year 3 of the FREEDOM study, the adverse event malignancy rate was 1.5% in the crossover group versus 2.2% in the continuous denosumab arm. In year 2 of the extension study, the rate was 1.4% for crossover patients compared with 2.2% for continuous denosumab users. The women in the extension study will be followed for up to 5 more years.—Christin Melton

All abstracts discussed in this report received funding from Amgen, Inc.

Study Shows Elevated Cytokine Levels May Contribute to Spine and Hip Fracture Risk in Older Men

Cytokines, a category of signaling molecules that are used in cellular communication, are thought to play significant roles in regulating bone remodeling in the bone microenvironment, but the relationship between cytokines and incident fractures in older men is undefined. Using data from MrOs (Osteoporotic Fracture in Men Study), a team of researchers from the University of Pittsburgh and Minneapolis VA Medical Center tested the hypothesis that men with higher levels of circulating cytokines at baseline will have a higher risk of fracture. The team, led by Jane A. Cauley, DrPH, University of Pittsburgh Graduate School of Public Health, shared the findings of their study at the recent ASBMR meeting. 

In a case-cohort study, cytokines were measured in a random sample of 980 men (average age, 73.8 years) and in 538 men (average age, 75.3 years) with incident fractures, including 98 clinical spine fractures and 97 hip fractures. The average follow-up period was 6.96 years. The study also measured levels of proinflammatory cytokines, including interleukin (IL)-6, high-sensitivity C-reactive protein (CRP), tumor necrosis factor (TNF-a), soluble receptors (SRs) of IL-6 and TNF (TNF-SR1, TNF-SR2), and IL-10, an inflammatory cytokine. Cytokines and SRs were measured in fasting frozen serum using enzyme-linked immunosorbent assay. The average inter-assay coefficients of variations ranged from 1.5% to 10.7%. Total hip bone mineral density was measured by dual energy X-ray absorptiometry scanning.

The risk of nonspine, hip, and clinical spine fracture was compared across quartiles of cytokines (quartile 1=referent) using Cox proportional hazard models. Quartile cutoffs were determined based on the distributions in the random cohort. The team performed tests for linear trend. In multivariable adjusted models, the team observed that risk of hip and clinical spine fracture increased with increasing TNF-a, TNF-SR1, TNF-SR2, and IL-6. Men with the highest cytokines levels (Q4) had a 1.9-4.35–fold higher risk of hip and clinical spine fracture than men with the lowest cytokine levels (Q1). Similar results were observed for all nonspine fractures, but the magnitude of the association was lower (data not shown). There was no association between CRP and IL-6SR. Men with the highest IL-10 (Q4) had a 41% lower risk of hip fracture and a 64% lower risk of spine fracture compared to men with the lowest IL-10.

In an interview with Clinical Geriatrics, Cauley explained that the implications that inflammation contributes to fracture apply to both men and women. The next step of research is to examine spine fractures, the most common osteoporotic fracture. “The most important finding of the study is the suggestion that inflammation may be one of many contributing factors in osteoporotic fractures in older men,” she said. “This raises the possibility that efforts to decrease inflammation may decrease risk.”—Allison Musante