Rod Marianne Arceo-Mendoza, MD; Pauline Camacho, MD

CME Released: 08/03/2015 ; Valid for credit through 08/03/2016

Abstract and Introduction

Abstract

Osteoporosis, a well-defined and growing public health problem, is a disease characterized by increased bone turnover and decreased bone mass with associated skeletal fragility, resulting in an increased risk of fracture. It is often unrecognized until the late stages when fragility fractures have occurred. In adults, early recognition of the disease prior to the occurrence of fractures followed by timely and efficient initiation of appropriate treatment can reduce fracture risk. In this article, we review clinical modalities available to effectively predict fracture risk in patients with osteoporosis. Bone mineral density and presence of clinical risk factors may be combined to provide a more comprehensive osteoporotic fracture risk assessment. Use of FRAX may serve as a general guideline for clinical management and deciding a threshold for cost-effective pharmacological intervention. Elevated bone turnover markers are predictive of high fracture risk and can provide additional clinical information as well.

Introduction

Osteoporosis is a disease characterized by increased bone turnover and decreased bone mass with associated skeletal fragility, resulting in an increased risk of fracture. It is a well-defined and growing public health problem. Prevalence of osteoporosis in the USA is anticipated to rise from 10 million to more than 14 million by the year 2020. By 2025, the burden in the country is projected to increase by almost 50% to more than 3 million fractures and US$25.3 billion per year.[1,2]

Osteoporosis, being a silent disease, is often unrecognized until the late stages when fragility fractures have occurred. Success in osteoporosis therapy should include preventive measures. Measures for osteoporosis prevention should begin in childhood and include physical activity, balanced nutrition and avoidance of risk factors such as smoking and alcohol use. Prospective clinical trials, however, are required to confirm efficacy of these preventive measures. In adulthood, early recognition of the disease prior to the occurrence of fractures followed by timely and effective initiation of appropriate treatment can reduce fracture risk.

Definition

In 1994, a Working Group of the WHO established an operational definition of osteoporosis based on bone mineral density (BMD). Osteoporosis is defined as a BMD 2.5 SD or more below the average value for premenopausal women.[3] Normal BMD is defined as T score of -1.0 or higher and a T score between -1.0 and -2.5 is defined as osteopenia or low bone mass. A history of fragility fractures in the absence of other metabolic bone disorders also defines osteoporosis.

There have been few studies of the relationship between BMD and fracture risk in men. Controversy exists whether the associations between BMD and risk of fracture are the same in men and women. In a prospective study of 5384 men,[4] hip BMD is found to be strongly associated with risk of hip fracture and may be useful in predicting fracture risk in men. Lumbar spine BMD in men has been shown to only be weakly related to hip fracture risk, same as in women. This study[4] demonstrated that regardless of whether female reference or sex-specific values were used, T scores correlated with different fracture risk in men than in women. There is a higher risk of nonvertebral fracture in women for all T scores of hip BMD, as compared with men. Furthermore, the study also demonstrated that for every standard deviation reduction in BMD, men have a relative risk of fracture at least as equal, or even greater than, the relative risk in women. In contrast, however, men have a lower age-specific prevalence and absolute risk for fracture and osteoporosis compared with women, at any T score.

The WHO recommends using the same BMD classification to define osteoporosis in men, age 50 years and above as in women, using a standardized reference database when calculating T score. The recommended reference range is the National Health and Nutrition Examination Survey (NHANES) III reference database for femoral neck measurements in women 20–29 years of age. In 2013, the International Society for Clinical Densitometry (ISCD) official position on this matter was in agreement with the WHO, recommending utilization of a uniform Caucasian (nonrace adjusted) female normative database for women and men of all ethnic group, with a caveat that application of the ISCD recommendation may vary according to local requirements, since most dual-energy x-ray absorptiometry (DXA) systems currently in use continue to report T scores in males using a male reference database and may choose to continue to report in this manner despite the current recommendation. Furthermore, ISCD recommends that BMD measurements alone should not be used to define osteoporosis in men younger than 50 years. In men with low BMD (Z-score ≤-2.0) below age 50 years, the diagnosis is made in the presence of clinical manifestations of osteoporosis such as presence of low trauma or fragility fracture and, possibly, if underlying secondary causes or risk factors for osteoporosis (such as hyperparathyroidism, glucocorticoid therapy, renal or liver disease, malabsorption, idiopathic hypercalciuria or hypogonadism) are present.

Assessment of Fracture Risk

DXA is the most widely used method for measuring BMD. Radiation exposure to the patient is small, and no shielding of the technologist is necessary. It entails shorter scan times and is widely available. Several studies demonstrated a relationship between fracture risk and BMD measured by DXA. Fracture risk increases with decreasing BMD.[2,5–7] In a large cohort of 9704 nonblack USA women aged 65 and older followed for more than 8 years, almost all types of fractures have an increased incidence in women with low BMD.[7] In a meta-analysis of data from 12 cohort studies (Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, EVOS/EPOS, EPIDOS, OFELY, CaMos, Rochester and two groups from Gothenburg) with 29,082 women and 9891 men followed for up to 16.3 years, hip fracture risk ratio increased by 2.94 in men and 2.88 in women for each SD decrease in femoral neck BMD.[5]

Individuals with T scores of less than -2.5 have the highest risk of fracture. However, because there are more individuals with osteopenia than osteoporosis, there are a greater number of fractures in subjects with T scores in the osteopenia range than in those in the osteoporosis range. A cohort study of 16,505 women 50 years of age or older with a mean observation of 3.2 years demonstrated that although fracture rates were significant among women with osteoporosis, most fractures occurred in women with nonosteoporotic value.[8] In prospective, population-based Rotterdam cohort study, 7806 men and women aged 55 years and older were followed for 6.8 years and only 44% of all nonvertebral fractures occurred in women with a T score below -2.5; with an even lower percentage in men (21%).[9]

These findings highlight the importance of considering fundamental clinical risk factors that operate independent of BMD when assessing fracture risk.

The Fracture Risk Assessment Tool & Clinical Risk Factor Assessment

The Fracture Risk Assessment Tool (FRAX) was developed in 2008.[10,11] The algorithm is based on a series of meta-analyses[12–16] using information derived from population-based cohorts from around the world, including centers from North America, Asia, Europe and Australia. FRAX has been validated in 11 independent cohorts, mainly comprised of women.[17] The statistical power of this vast dataset allows estimation of fracture probability from an individual's set of risk factors. This also permits determination of the predictive importance in a multivariable context of each of the risk factors, as well as interaction between risk factors, hence optimizing the accuracy whereby fracture probability can be computed. FRAX estimates the 10-year likelihood of hip and major osteoporotic fractures (hip, clinical spine, proximal humerus or forearm) for untreated patients between ages 40 and 90 years using femoral neck BMD and clinical risk factors for fracture, when available.

Since most fractures occur in patients with T scores better than -2.5, therapeutic strategies relying solely on BMD testing may likely miss several patients at risk for fracture who might benefit from interventions for fracture risk reduction. Assessment of clinical risk factors that are independent of BMD is as necessary for fracture prediction.

Combining clinical risk factors and BMD provide higher specificity and sensitivity than either alone. In nine population-based studies, BMD and clinical risk factors (CRFs) were documented at baseline and demonstrated that CRFs alone predicted hip fracture with a gradient of risk (GR; risk ratio/SD change in risk score) of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR, with a 3.7 increase in risk ratio for each SD decrease in femoral neck T score (3.7/SD). This was improved further with the combined use of CRFs and BMD (4.2/SD).[17]

Clinical risk factors used in FRAX include body mass index, a prior history of fracture, use of oral glucocorticoids, current smoking, alcohol intake three or more units daily, rheumatoid arthritis, a parental history of hip fracture and other secondary causes of osteoporosis.[3,12,18] Fracture risk can be calculated even without BMD data. Age is an important risk factor in the formula, and to illustrate, hip fracture probability in a woman can range from 0.2% for a 50 year old to as high as 22% in an 80 year old ( with a parental history of hip fracture). In a man, this would range from 0.1 to 11%. For a major osteoporotic fracture, the probability ranged from 3 to 15% in men and about 4–31% in women. This probability increases in an incremental manner with the presence of one or more clinical risk factors.[11] Use of systemic steroids confers the highest risk ratio for hip fracture when adjusted for age, with and without adjustment for BMD, with RR of 2.31 and 2.25, respectively.[12]

A study on a large prospective cohort of 35,764 women above age 50 years demonstrated that the FRAX tool can be used to predict fracture probability in women currently or previously treated for osteoporosis.[19] Baseline BMD testing from 1996 to 2007 had FRAX probabilities retrospectively calculated and women were categorized based on osteoporosis medication use as untreated, high adherence users with a medication possession ratio (MPR) ≥0.80 in the year after BMD testing and current low adherence users (MPR <0.80), and past users. In this analysis, the FRAX predicted risk and observed 10-year fracture incidence of major osteoporotic fracture in both untreated and each treated subgroup were concordant. Only in the subset of women who were at highest risk for fracture and who were highly adherent to at least 5 years of bisphosphonate use, was the observed hip fracture risk significantly less than predicted. The study demonstrated that although FRAX is not designed to assess fracture risk reduction in individuals on treatment, it may still have value for guiding the need for continued therapeutic intervention or treatment withdrawal.

Rapid growth of the elderly USA population will result in an increased prevalence of osteoporosis. Economically efficient approaches to osteoporosis care, hence warrant consideration.[15] Treatment guidelines based upon FRAX allow clinicians to identify patients likely to benefit from therapy better. A USA-specific cost–effectiveness analysis suggests that the 10-year hip fracture probability at which treatment becomes cost-effective ranges from 2.5 to 4.7% for women and from 2.4 to 4.9% in men, depending upon age and using an annual treatment cost of US$600 until a cost of US$60,000 per quality-adjusted life-year gained. The absolute 10-year hip fracture probability at which intervention became cost effective tend to be higher for men compared with women, but is similar across ethnicity groups.[20]

FRAX is a very helpful tool in determining who needs to be treated and is an excellent objective tool when T scores are not available. In situations when DXA scans reveal significant artifacts (such as when patients have degenerative changes in the spine and hip replacement) or perhaps are not available, having the fracture risk calculations using FRAX is very helpful.

In addition, increasing patient concern about long-term side effects of osteoporosis agents has made it difficult to convince patients to accept treatment for osteoporosis. Having a realistic estimate of fracture risk is helpful in illustrating the gravity or severity of the disease to patients.

It should be emphasized that a fracture risk calculator such as FRAX is likely to be most useful in evaluating patients with BMD T scores in the osteopenia range, who may benefit from interventions for fracture risk reduction. The need for therapeutic intervention in higher-risk patients, such as individuals with T scores of less than -2.5 or those with a history of fragility fractures, can be readily identified on clinical grounds.

As with all clinical tools, FRAX has its limitations. These include lack of extensive validation in treated patients[19] and limitation to only four ethnicities (Caucasian, black, Hispanic, Asian) in the USA.

Other limitations that may result in over or underestimation of fracture risk include lack of consideration of other risk factors (i.e., falls, multiple fractures, bone turnover markers) and dichotomous (yes or no) input for clinical risk factors that are associated with variable risk depending on dose and duration of exposure (i.e., systemic steroids). Furthermore, FRAX may underestimate fracture probability in individuals with history of low lumbar spine but normal femoral BMD, multiple fractures, high-dose glucocorticoid exposure (prednisone dose >7.5 mg/day),[21] prevalent severe vertebral fractures and a parental history of nonhip fragility fractures.[22] It must be emphasized that the use of FRAX or any other various fracture risk assessment models (QFractureScores and Garvan fracture risk calculator) should only serve as a general guideline for clinical decisions. Ultimately, osteoporosis treatment should remain individualized through shared decision-making between clinician and patients.

Bone Turnover Markers in Fracture Prediction

Bone turnover is the principal factor that controls both the quality and the quantity of bone in the adult skeleton. An imbalance between bone resorption and bone formation ultimately results in a net loss or gain of the bone tissue. High bone turnover, characterized by increased activity of osteoclasts, leads to bone loss, abnormal bone microarchitecture and potential deterioration in bone quality. Low bone turnover, characterized by a reduction of both bone formative and bone resorptive activities may result in increased bone mass, accumulation of micro-damage and bone fragility. Changes in bone turnover markers (BTM), which include bone resorption and bone formation markers, account for a significant portion of fracture risk reduction from osteoporosis agents. Changes in BTMs are more dynamic and become evident within months of therapy. BTMs may have a useful role in predicting patients who will lose bone at a faster rate, which agents are ideal for that individual, and assessment of compliance and response to therapy.[23]

The OFELY study[24] which included 435 postmenopausal women ages 50–89 years (mean of 64 years) found that those with the highest levels of bone resorption urinary-free deoxypyridinoline (D-Pyr), urinary type 1 collagen N-telopeptide (NTX) and urinary and serum type 1 collagen C-telopeptide (CTX) had a twofold increase in fracture risk compared with women in the three lowest quartiles. Adjustment for hormone levels did not alter the results. The study concludes that high levels of biochemical markers of bone turnover are concomitant with increased risk of osteoporotic fracture in postmenopausal women, independent of each other and of BMD. This may suggest that BMD combined with BTM may improve fracture prediction. The mechanism by which elderly women have elevated bone turnover rate leading to an increased fracture risk, remains to be elucidated. Although elevated BTMs have been shown to be associated with increased likelihood of fracture in postmenopausal women, their utility in predicting fracture is yet to be established.[23]

A prospective study of 7598 healthy women more than 75 years of age,[25] demonstrated higher levels of urinary C-telopeptide and free deoxypyridinoline in patients with hip fracture than in age-matched controls. Women with both femoral BMD value of 2.5 SD or more below the mean for young adults and higher levels of these urinary markers of bone resorption were at greater risk of hip fracture, compared with those with only low BMD or high bone resorption. The study concluded that combining measurement of BMD and bone resorption further improves hip fracture risk assessment in elderly women.

While BTMs have been widely used clinical trials, their role in patient care remains not well established. Potential roles may include monitoring response to therapy and fracture risk prediction. Biologic and individual variability values have confounded the widespread use of bone turnover markers in clinical practice.

Conclusion

In summary, bone mineral density and presence of clinical risk factors may be combined to provide a more comprehensive osteoporotic fracture risk assessment than BMD or clinical risk factors alone. Use of FRAX may serve as a general guideline for clinical management and deciding the threshold for cost-effective pharmacological intervention. Bone turnover markers may also have a useful role in predicting patients who will lose bone at a faster rate, which agents are ideal for that individual, and assessment of compliance and response to therapy. Osteoporosis treatment, however, should still remain individualized through shared decision-making between clinician and patients

Future Perspective

Over the past decade, the use of BTMs to determine whether or when patients should discontinue bisphosphonates and whether or when they should resume therapy has been of significant interest in the management of osteoporosis. Some clinicians follow BTMs after discontinuing bisphosphonates and restart when the BTM is in the mid-range of young adults or more than 20% above the mean premenopausal level. There are still insufficient data, however, to support the use of bone turnover markers for this purpose. Biologic and individual variability values have confounded the widespread use of these markers in clinical practice. In 2012, in acknowledgment of the need to advance the field of bone turnover markers, The National Bone Health Alliance (NBHA), introduced a project[26] to standardize bone turnover marker assays and sample collection procedures in the USA and aims to establish a reference range for one bone formation (serum procollagen type I N propeptide [s-PINP]) and one bone resorption (serum C-terminal telopeptide of type I collagen [s-CTX]) markers. This project is ongoing and once completed, will help strengthen the use of bone turnover markers in osteoporosis management.

Several studies have been investigating the association of other clinical factors and fracture risks which are not included in the FRAX algorithm, independent of BMD and the other CRFs. From a speculative viewpoint, further trials aiming to assess whether adding other clinical risk factors to FRAX including those known to cause secondary osteoporosis, would improve the ability to identify young postmenopausal women at high likelihood of fracture, will continue to evolve and hopefully further strengthen fracture risk prediction in patients.

Executive Summary

•       Osteoporosis is defined as a bone mineral density (BMD) 2.5 SD or more below the average value for premenopausal women or the presence of fragility fractures that are not due to other metabolic bone disorders. Normal BMD is defined as T score of -1.0 or higher and a T score between -1.0 and -2.5 is defined as osteopenia or low bone mass.

•       Dual-energy x-ray absorptiometry is the most widely used method for measuring BMD.

•       In adulthood, early recognition of the disease prior to the occurrence of fractures followed by timely and effective initiation of appropriate treatment can reduce fracture risk.

•       The fracture risk assessment tool estimates the 10-year probability of hip fracture and major osteoporotic fracture for an untreated patient (40–90 years of age) using femoral neck BMD and clinical risk factors for fracture.

•       Clinical risk factors include body mass index, a prior history of fracture, a parental history of hip fracture, use of oral glucocorticoids, current smoking, alcohol intake three or more units daily, rheumatoid arthritis and other secondary causes of osteoporosis.

•       Bone turnover markers may also have a useful role in predicting patients who will lose bone at a faster rate, which agents are ideal for that individual and assessment of compliance and response to therapy.

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Reprint Address

Rod Marianne Arceo-Mendoza, MD, Department of Endocrinology, Osteoporosis & Metabolic Bone Disease Center, Loyola University Medical Center, 2160 South 1st Avenue, Maywood, IL 60153, USA. rmmendoza@lumc.edu

資料來源: Women's Health

http://www.futuremedicine.com/doi/pdfplus/10.2217/whe.15.14