OREF grant recipient examines the impact of vitamin D

Wrist fractures may be a sentinel event," stated Tamara D. Rozental, MD, an orthopaedic surgeon at the Beth Israel Deaconess Medical Center and associate professor of medicine at Harvard Medical School. "Fractures of the distal radius are usually the first fragility fracture, so they give us, as orthopaedic surgeons, a unique opportunity to intervene, which might make a difference in preventing future injuries."

Fragility fractures—which result from a fall from a standing height or less rather than high-energy trauma—usually signify poor bone heath. The incidence of such injuries increases significantly with age. Fragility fractures of the distal radius generally occur at an earlier age than fractures of the hip and spine.

A clearer picture of modifiable risk factors may facilitate interventions even before the fracture occurs. To that end, Dr. Rozental investigated serum levels of vitamin D and bone turnover markers in postmenopausal women with distal radius fractures.

Dr. Rozental's work was underwritten in part by a 2012 Ruth Jackson Orthopaedic Society (RJOS)/Orthopaedic Research and Education Foundation (OREF)/DePuy Career Development Grant in Women's Musculoskeletal Health. This program supports female orthopaedic surgeons who are working to improve knowledge of women's musculoskeletal health and enhance the understanding of gender and ethnic differences in orthopaedic treatment outcomes.

A better understanding of risk
Decreased bone mineral density (BMD) is a well-documented risk factor for distal radius fracture, but low BMD is only part of the story. Because fragility wrist fractures also occur in people with normal BMD, other contributing factors are likely.

Similarly, vitamin D deficiency is strongly associated with hip fractures, and a small body of recent studies suggests that it may be associated with wrist fractures as well. Increased bone turnover is also associated with an increased risk of fragility fractures, independent of BMD, but no standardized clinical assessment measures of bone turnover risk factors exist.

The OREF-funded investigation involved 255 women aged 50 or older, 105 of them with fragility wrist fractures and an aged-matched control group of 150 women with no history of fractures before age 50. At the 3-month follow-up appointment, each fracture patient had a fasting blood draw to assess serum levels of 25-hydroxy vitamin D, three protein markers of bone formation, and one protein marker of bone resorption. The 3-month delay in testing was intended to minimize the effect that the fracture itself may have on bone metabolism.

Secondary outcome measures included BMD and fracture severity using standard measures. By comparing data between the two cohorts, Dr. Rozental and her colleagues at the University of Connecticut Health Center hoped to investigate the following hypotheses:

• Vitamin D is a risk factor for distal radius fracture.
• Bone turnover markers are predictive of fracture risk.
• Levels of vitamin D are predictive of fracture severity.
• Differences in vitamin D levels between fracture cases and controls are independent of possible differences in BMD.

The researchers also measured serum parathyroid hormone (PTH), which plays a role in calcium regulation. Because vitamin D increases calcium absorption in the intestines, a vitamin D deficiency may result in low serum calcium. Low calcium levels, in turn, trigger an increase in PTH, which pulls calcium from bone. The study, therefore, also enabled the investigators to examine the relationships among fractures, vitamin D levels, bone turnover markers, and PTH.

Fracture prevention opportunities
The ultimate goal of understanding risk factors is the prevention of fragility fractures—identifying those people at risk, monitoring risk and, when possible, lowering the risk. Dr. Rozental stated, "If vitamin D deficiency ends up being identified as a risk factor, then I think orthopaedic surgeons need to be more aggressive about monitoring that and encouraging people to take supplements."

A better characterization of bone turnover markers may lead to the regular use of these measures in clinical practice. "If we can determine a person's risk for fragility fractures because he or she has too much resorption or too little bone formation, perhaps we can better tailor medications," explained Dr. Rozental.

Dr. Rozental's study confirmed that a history of fracture and low BMD are strongly associated with distal radius fractures, but they are not the only factors that put patients at risk. Because vitamin D levels were similar in postmenopausal women with and without distal radius fractures, monitoring vitamin D levels may not be as useful as previously thought in determining fragility fracture risk.

However, the study also found that postmenopausal women with distal radius fractures have higher levels of bone formation markers than women without fractures. Based on these results, a bone formation marker, Serum type 1 procollagen (P1NP), may be a good indicator of bone fragility. These findings were published in the October 2015 issue of The Journal of Bone and Joint Surgery.

Funding research projects
The RJOS/OREF/DePuy grant was, according to Dr. Rozental, instrumental in getting this project off the ground.

"OREF's reputation is one of its greatest strengths. Other than the National Institutes of Health, every orthopaedic surgeon feels like OREF is the most prestigious orthopaedic research organization and foundation. When you think about getting research funding, an award from OREF is always highly regarded," she said.

Dr. Rozental noted that preliminary funding, such as that from OREF, is necessary before embarking on further investigations. Such studies could focus on identifying other risk factors for fragility fractures, determining whether younger patients with fractures also have vitamin D deficiencies, and better characterizing the etiology of age-related bone alteration.

"One of the reasons I like clinical medicine is that I'm making a difference one person at a time, and it's a very tangible thing," she said. "This research enables me to look at the big picture. Osteoporosis is a public health problem that affects millions of people every year. We hope the research makes a difference on a much larger scale."

Jay D. Lenn is a contributing writer for OREF. He can be reached at communications@oref.org

References:

1. Baron JA, Karagas M, BarrettJ, Kniffin W, Malenka D, Mayor M, Keller RB: Basic epidemiology of fractures of the upper and lower limb among Americans over 65 years of age. Epidemiology 1996;7(6):612-618. Available at http://www.ncbi.nlm.nih.gov/pubmed/8899387. Accessed on December 8, 2015.
2. Oyen J, Gjesdal CG, Brudvik C, et al: Low-energy distal radius fractures in middle-aged and elderly men and women—the burden of osteoporosis and fracture risk: A study of 1794 consecutive patients. Osteoporos Int Jul;21(7):1257-1267. Available at http://www.ncbi.nlm.nih.gov/pubmed/19813045. Accessed on December 8, 2015.
3. Oyen J, Apalset EM, Gjesdal CG, Brudvik C, Lie SA, Hove LM: Vitamin D inadequacy is associated with low-energy distal radius fractures: A case-control study. Bone 2011 May 1;48(5):1140-1145. Available at http://www.ncbi.nlm.nih.gov/pubmed/21295169. Accessed on December 8, 2015.
4. Sornay-Rendu E, Munoz F, Garnero P, Duboeuf F, Delmas PD: Identification of osteopenic women at high risk of fracture: The OFELY study. J Bone Miner Res Oct 2005;20(10):1813-1819. http://www.ncbi.nlm.nih.gov/pubmed/16160738. Accessed on December 8, 2015.
5. Rozental TD, Herder LM, Walley KC, Zurakowski D, Coyle K, Bouxsein ML, Wolf JM: 25-Hydroxyvitamin-D and bone turnover marker levels in patients with distal radial fracture. J Bone Joint Surg Am 2015 Oct 21; 97(20):1685 -1693. Available at http://dx.doi.org/10.2106/JBJS.O.00313. Accessed on December 8, 2015.