Clinical studies have confirmed that above normal levels of C-reactive protein, a well-known predictor of risk for heart attack and stroke, also strongly indicate increased risk for fracture.

C-reactive protein (CRP) is produced by the liver and sent into the bloodstream. It is one of a group of proteins, called acute phase reactants, that respond to inflammation.

The level of CRP in your blood rises when there is inflammation throughout the body.

Specifically, CRP levels go up when the immune and fat cells produce pro-inflammatory cytokines (like the interleukins IL-1, IL-6 and IL-8, and TNF-α).

In this article, we’ll look at the best way to assess CRP levels, the link between hsCRP and fracture, and tools you can use to help your patients improve their bone density.

Two lab tests are run to evaluate CRP. The test for plain “CRP” reports a much wider, higher range of CRP levels than hs-CRP.

CRP is the test that should be run in individuals suffering from inflammatory conditions, like rheumatoid arthritis or periodontal disease, because in highly inflammatory conditions like these, CRP levels will be far higher than the range detected by the test for hsCRP.

The test for CRP, however, doesn’t do a good job of capturing the lower ranges, which are what you need to check to see if the low-level, chronic inflammation that increases fracture risk is present.

For that, you need the CRP blood test that can give you information on your patients’ risk for fracture. That test is called “high sensitivity-CRP,” (hsCRP).

hsCRP is also used as a marker of heart attack risk in “healthy” people. Those whose hsCRP results are in the high end of the normal range (above 3.0 mg/L) have 1.5 to 4 times the risk of having a heart attack compared to those whose hsCRP values are at the low end of the normal range (1.0 mg/L or less).

A number of recently published papers have dismissed the importance of hsCRP in relation to bone health because hsCRP levels have not consistently been found to correlate with bone mineral density (BMD) in women.

What the research we’re talking about today adds to the discussion is that hsCRP levels strongly correlate with risk for fracture in women and men — and even more so in men.

For instance, recent studies have reported that both compressive and bending strength at the femoral neck are inversely related to CRP (higher CRP = less ability to compress and bend without breaking), and that individuals with higher hsCRP levels are at increased risk of fracture.

Additionally, at least seven previous studies have reported that increased CRP levels increase risk of fragility (non-traumatic) fractures (both vertebral and non-vertebral), after adjustment for BMD, comorbidity (presence of other diseases, e.g., cardiovascular disease) and lifestyle factors.

To further shine light on this issue, today we’re going to discuss a study that confirms that hsCRP levels strongly correlate with risk for fracture in women and men. This fact underscores that BMD alone is not a sufficient indicator of bones’ true health and ability to resist fracture.

In the study we’re discussing today, hsCRP levels and BMD at the total hip and femoral neck were measured in 1,902 women and 1,648 men ranging in age from 55 to 74 years when the study began.1

Study participants were followed for an average of 7.2 years, and the incidence of non-vertebral fractures was reported. (Non-vertebral fractures include fractures of the hip, femur, arm, wrist, ribs and legs. Vertebral fractures are those that occur in the vertebrae in the spine.)

CRP was not associated with BMD in women, but higher CRP was associated with lower BMD in men, in both the total hip and femoral neck.

However, CRP was associated, in both sexes, with risk for non-vertebral fracture. Each standard increase in CRP was associated with an increased risk for non-vertebral fracture of 13% in women and 22% in men.

Study participants were divided into 3 groups or “tertiles.” After adjustments were made for BMD and many other potential risk factors, women whose CRP was in the upper tertile had a 39% higher risk for fracture than those in the lowest tertile.

Men in the upper tertile had an 80% higher risk of fracture!

Men with higher CRP levels were slightly older, had higher BMI (i.e., were more likely to be overweight), were more likely to have cardiovascular disease and lower levels of physical activity, plus more were current smokers.

However, the increased risk of fractures remained after accounting for all these factors. Furthermore, hip fracture, the most serious type of fracture, constituted a larger proportion of all fractures in men (31%) than in women (13%).

What does this study tell us?

Your patients’ level of chronic low-grade inflammation, which can be assessed by running hsCRP, affects their risk for fracture just as much — and possibly more — than BMD.

An elevated hsCRP shows that the body is chronically producing proinflammatory messenger molecules (i.e., the cytokines mentioned above: IL-1, IL-6 and IL-8, and TNF-α).

These cytokines activate the cellular pathways in the bones that stimulate osteoclast production and bone resorption, plus they downregulate the production and activity of osteoblasts, the cells that build new bone.

So, not surprisingly, other studies have reported that higher CRP is associated with increased levels of bone turnover markers, like CTx and NTx.

Increased bone turnover most rapidly causes poor trabecular (but not cortical) microarchitecture. Why is trabecular bone affected more quickly? Because it is the interior, spongy, far more metabolically active portion of bones.

A Trabecular Bone Score (TBS) test can report the health of this portion of your patients’ bones. It uses the same x-rays as those taken for DEXA. And it evaluates your patients’ bones’ resistance to fracture.

It does this by analyzing the internal texture of the bones, their “micro architecture”. A higher TBS means the internal structure of the bones is stronger, while a lower score means it’s weaker.

So, the TBS tells you about the quality of your patients’ bones, and their BMD tells you about their density. And these are the two main factors that contribute to bone strength and reduce fracture risk.

Since the TBS is calculated using your patients’ DEXA results, it’s possible to run this test after your patient’s receive their DEXA scan.

Millions are screened for osteoporosis using a DEXA scan. So administering this test can provide an ideal opportunity to identify any potential associations between thinning bones and those most at risk of heart disease.⁶

According to the National Osteoporosis Foundation’s guidelines the following people should get a DEXA:

• women age 65 or older
• men age 70 or older
• anyone who has broken a bone after age 50
• women of menopausal age with risk factors
• postmenopausal women under age 65 with risk factors
• men age 50-69 with risk factors

There are numerous factors that can increase your patients’ risk of osteoporosis. Below are a few to watch out for. If your patients fall under two or more categories on this list, it may be a good idea to recommend a DEXA scan.

Gender: Women are at higher risk of developing osteoporosis. As you know, this is because estrogen decreases sharply during menopause which accelerates bone loss. In fact, in the five to seven years following menopause, a woman can lose up to 20% of her bone density.²

Age: Bone mass increases from childhood to about the mid-thirties — when bone mass peaks. Then, after age 40, people lose about 1% bone density every year.³

Lack of Exercise: Weight-bearing exercise is one of the best things your patients can do to strengthen their bones. This type of exercise places stress on their bones, which helps them become stronger. On the other hand, if your patients don’t exercise, their bones will become weaker over time.

Diet: A diet lacking in essential nutrients plays a major role in the development of osteoporosis. As you’re no doubt aware, calcium is crucial for healthy bones.

Family History: Having a family member with osteoporosis puts your patient at greater risk because osteoporosis has a strong genetic component.⁴

Body Size: Women and men who have small body frames tend to have a higher risk for osteoporosis.⁵

Although a number of recently published papers have dismissed the importance of hsCRP in relation to bone health, research has confirmed that above normal levels of hsCRP strongly indicate increased risk for fracture.

What is more, several studies have confirmed that women with osteopenia/osteoporosis are significantly more likely to have cardiovascular disease (which typically involves calcification of the blood vessels and/or heart, such as high blood pressure, atherosclerosis or coronary artery disease).

In fact, a review of 25 studies involving 10,299 patients found that risk for having atherosclerosis was more than doubled (2.23 or a 223% increase in risk) in postmenopausal women with low BMD.7

And while testing your patients’ BMD is important, remember that your patients’ level of chronic low-grade inflammation, which can be assessed by running hsCRP, affects their risk for fracture just as much — and possibly more — than BMD.

So it’s also important to test your patients’ hsCRP level.

If it is higher than 1 mg/L, help your patient pinpoint all the factors in their diet and lifestyle that could be promoting inflammation. Then introduce ways to minimize those factors. For instance, recommend that they consume omega-3s.

1. Dahl K, Ahmed LA, Joakimsen RM, et al. “High-sensitivity C-reactive protein is an independent risk factor for non-vertebral fractures in women and men: The Tromsø Study.” Bone. 2015 Mar;72:65-70. doi: 10.1016/j.bone.2014.11.012. Epub 2014 Nov 20. PMID: 25460573 https://www.ncbi.nlm.nih.gov/pubmed/25460573
2. https://www.bonehealthandosteoporosis.org/preventing-fractures/general-facts/what-women-need-to-know/#menopause
3. Oddom Demontiero, Christopher Vidal, and Gustavo Duque. "Aging and bone loss: new insights for the clinician." Ther Adv Musculoskelet Dis. 2012 Apr; 4(2): 61–76. doi: 10.1177/1759720X11430858
4. T L Stewart, S .H Ralston. "Role of genetic factors in the pathogenesis of osteoporosis." J Endocrinol. 2000 Aug;166(2):235-45. doi: 10.1677/joe.0.1660235.
5. https://www.nia.nih.gov/health/osteoporosis
6. https://www.news-medical.net/news/20210506/Thin-weakened-bones-associated-with-heightened-risk-of-heart-attack-or-stroke-in-women.aspx 
7. Chenyi Ye, Mingyuan Xu, Shengdong Wang, Shuai Jiang, Xi Chen, Xiaoyu Zhou, Rongxin He. "Decreased Bone Mineral Density Is an Independent Predictor for the Development of Atherosclerosis: A Systematic Review and Meta-Analysis." PLoS One. 2016 May 5;11(5):e0154740. doi: 10.1371/journal.pone.0154740.eCollection 2016.