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Clinical Evaluation, Management of Osteoporosis
By Ruthe Ann Falk, RT(R), MS, RD, and Sharon M. Miller, PhC, CLS(NCA), MT(ASCP)
Technological advances are making early detection of low bone mass possible and more affordable, and several treatment options for the prevention and management of osteoporosis are now available. The laboratorian's role is expanding; the use of biochemical markers continues to evolve as a cost-effective means of predicting fracture risk in older adults and in monitoring response to therapy. Along with this attention, the popular notion that osteoporosis is just a disease of older women is slowly being dispelled.
Osteoporosis is a major public health issue. Postmenopausal women are not the only group at risk. Children and young adults who receive insufficient amounts of calcium and vitamin D will fail to build adequate bone mass before the normal onset of bone loss begins in the third or fourth decade of life. Young females with eating disorders or who are amenorrheic from intensive exercise, persons with a long history of corticosteroid use (a common treatment for asthma and rheumatoid arthritis) and males who have undergone treatment for prostate cancer are only a few of the groups at risk for osteoporosis. To prevent an epidemic, it's crucial that individuals of all ages are proactive. Did you know that:
* 28 million Americans are affected (approximately 10 million with osteoporosis and 18 million with low bone mass).1
* A tremendous economic burden is associated with this disease—$14 billion in 1997 for the cost of osteoporosis-related fractures alone.2
* Bone is a living tissue with the process of bone remodeling, including linked formation and resorption, occurring throughout life.3
* Peak bone mass and bone mineral density (BMD) are typically attained at a young age (late 20s to early 30s), after which bone remodeling continues—but you begin to lose ground.
* An imbalance in bone remodeling occurs whenever bone formation lags behind resorption.
What's New?
Osteoporosis is now defined by the World Health Organization (WHO) as a disease of fracture risk, as determined by comparison of BMD measurements to a healthy, young reference group.4 According to the WHO definitions,1 a person with "normal" bone mass would have a BMD within one standard deviation (SD) of the mean for the reference group. Low bone mass, or osteopenia, is defined as a BMD between 1.0 and 2.5 SD below the mean, and osteoporosis is defined as a BMD that is greater than 2.5 SD below the mean (Figure). These cutoff points are subject to some discretion but are required for diagnostic purposes, much like the cutoff points for hypertension and hypercholesterolemia serve to guide the physician in the evaluation and treatment of patients.
The National Osteoporosis Foundation has issued the Physician's Guide to Prevention and Treatment of Osteoporosis.1 This booklet puts into the hands of the family practitioner a concise reference of the current knowledge about risk assessment, diagnosis and treatment of osteoporosis. The medical community now recognizes that osteoporosis is both preventable and treatable, and this guide should reinforce the expectation that the physician is needed to convey this knowledge to his or her patients.
Tools of Clinical Assessment
In addition to the latest definitions and physicians' guidelines, new techniques are being developed for baseline assessments and beyond—from aiding in treatment decisions to monitoring and documenting the response to therapy.
Changes in both bone quality and quantity increase the risk of fracture in patients with osteoporosis.5 While there is no available method for measuring changes in bone quality, the quantity of bone or bone mineral density can be measured by several available techniques. Assessments of BMD are conducted at sites rich in trabecular bone, such as the spine, hip, heel and wrist, where bone remodeling is abundant.
Dual-energy x-ray absorptiometry (DEXA) is a bone densitometry technique that's well-known for its high degree of accuracy in predicting future fracture risk. This technique imparts a minimal dose of radiation to the patient but can be used to measure BMD at the spine and hip, as well as at peripheral sites such as the wrist. DEXA scanning is expensive compared to other techniques. This is partially due to the need for a specially designed room to house the equipment and licensed technologists to operate the machines.
Ultrasound densitometry, a fairly recent development, measures bone density using high-frequency sound waves at peripheral sites, such as the heel.6 It offers several advantages over DEXA scanning, including portability, low cost and a radiation-free evaluation for the patient. DEXA measurements, however, reflect the BMD measurements of the central skeleton, which is more predictive of hip and spine fracture. Ultrasound may ultimately prove to be most valuable in the primary care setting and for large-scale screenings. Because it can be performed in the office, the physician is provided with immediate results for use in patient counseling.
While DEXA and ultrasound densitometry are extremely valuable in measuring baseline bone mineral density, it may take as long as one to two years before either bone gain or loss is great enough to be detected using these techniques. This limits the utility of these procedures in terms of monitoring a patient's response to therapy. Biochemical markers can provide information about significant changes in bone within three to six months following initiation of treatment.
Measurement of biochemical markers in the urine and serum provide information on the extent of bone remodeling. In a remodeling cycle, bone formation is coupled to bone resorption. Typically, the formation phase of a cycle lasts substantially longer than the resorption phase.
Two categories of bone markers have been identified: those that reflect bone formation and those indicating bone resorption (Table). During bone formation, which includes synthesis of the organic matrix of bone as well as its mineralization, activated osteoblasts release several proteins, including osteocalcin, bone-specific alkaline phosphatase and procollagen-I extension peptide. A number of agents activate osteoblasts, including the hormones estrogen and parathyrin. Assessment of the peptides in the serum, generally by radioimmunoassay (RIA) or enzyme-linked 
immunosorbent assays (ELISA), permits indirect measurement of bone formation. Serum markers of bone formation show little diurnal variation.
When bone is resorbed, the calcium-phosphate mineral phase is lost first, followed by attack of the osteoclastic acid hydrolases on the organic matrix. The highly stable configuration of collagen is achieved by the alignment and cross-linking of polypeptide chains. Type I collagen, which makes up about 95 percent of the organic material in the bone matrix, is stabilized by pyridinoline and deoxypyridinoline crosslinks and also contains characteristic N- and C-terminal peptide sequences. Increased urinary excretion of these fragments, as well as the increased loss of less bone-specific markers such as hydroxyproline, provides evidence of osteoclastic degradation of bone.
Clinical conditions in which biomarkers reflect predominating osteoclastic activity include estrogen deficiency, Paget's disease, hyperthyroidism, hyperparathyroidism, myeloma, recent fracture or immobilization. Assays available to evaluate bone matrix turnover include measurement of urinary N-telopeptide type I collagen (Osteomark-N-Tx) or free deoxypyridinoline (Pyrilinks-D). Because excretion of urinary markers shows diurnal variation, the first or second morning specimen should be collected for testing.7
Bone resorption is not constant and can occur at different rates. It's important for the physician to differentiate between slow losers or rapid losers for prevention and treatment purposes. Rapid bone loss (3 percent to 5 percent per year) would require more aggressive treatment strategies than would be needed for individuals with slower rates of bone loss.
Unfortunately, biochemical markers are not mentioned in the new physicians' guidelines, despite reports of their increased acceptance as a valid tool to monitor therapy.8 It is, therefore, essential that the laboratorian become familiar with these markers and their usefulness in order to educate staff and assist physicians when needed.
Prevention, Treatment
While several of the risk factors for osteoporosis are genetic (small, thin frame, Caucasian descent, family history), others are modifiable with appropriate lifestyle and dietary habits. Suggestions based on the National Osteoporosis Foundation's guidelines include:
* regular weight-bearing and weight-lifting exercises (at least three times per week) to increase bone density and improve muscle strength and balance, thus reducing the risk of falls and fractures;
 * adequate calcium and vitamin D intake—throughout one's lifetime (at least 1200 mg calcium and 400-800 IU vitamin D per day);
* limited alcohol intake;
* avoidance of tobacco smoking.
Prevention is a lifelong process that begins with the individual. However, various health professionals play important roles in promoting these recommendations, offering exercise and smoking cessation programs, and providing dietary analysis and advice.
Four therapeutic options are currently FDA-approved for the prevention and/or treatment of osteoporosis. Hormone replacement therapy (HRT) is well established as an effective, primary intervention for inhibiting early postmenopausal bone loss and reducing the incidence of fractures in women. Additional benefits of HRT include prevention of cardiovascular disease, a reduced risk of colon cancer, decreased menopausal symptoms and possibly a reduction in the incidence of dementia. Despite its beneficial effects, lifelong compliance with HRT is reported to be poor. Based on 1997 data, only one quarter of postmenopausal women had taken HRT for more than nine months.2 A possible explanation is that HRT is not without risks and side effects, including a possible increase in the risk of breast cancer, deep vein thrombosis and the resumption of vaginal bleeding.
Alendronate sodium (Fosamax) is a bisphosphonate drug that reduces bone resorption by inhibiting the action of osteoclasts. Alendronate is considered to be the most effective alternative to HRT. Possible side effects include upper gastrointestinal problems such as esophagitis.
Salmon calcitonin, a synthetic hormone administered as a nasal spray (Miacalcin), is approved for osteoporosis treatment but not for prevention. Calcitonin is considered by specialists to be a safe alternative to HRT or alendronate; however, calcitonin is less effective.
Raloxifene (Evista), a selective estrogen receptor modulator (SERM), is the most recently-approved pharmacologic agent for osteoporosis prevention. Like estrogen, raloxifene increases the risk of deep vein thrombosis and an increase in hot flashes is possible.
Looking to the Future
The annual costs associated with osteoporotic fractures have been projected to reach $50 billion by the year 2040—greater than most other age-related chronic diseases.2 With such a staggering forecast, it's not surprising that large-scale studies are under way
 to evaluate bone integrity and assess new methods of prevention and treatment. New pharmacologic options also are on the horizon, including agents that (like the current FDA-approved therapies) act by inhibiting bone resorption, as well as agents that act by stimulating bone formation. Advances in biochemical markers should enhance the convenience and cost-effectiveness of testing, particularly for individuals with geographic limitations or mobility restrictions. In the future, user-friendly, at-home monitoring of crosslink excretion could make evaluation of bone loss and response to therapy as routine as home pregnancy tests.
Ruthe Ann Falk, a radiologic technologist and registered dietitian, recently completed a Master of Science degree in Nutrition and Dietetics at Northern Illinois University, DeKalb. Sharon M. Miller is professor and Associate Dean, College of Health and Human Sciences, Northern Illinois University.
References
1. National Osteoporosis Foundation. The Physician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 1998.
2. Miller PD. Management of osteoporosis. Disease-a-Month. 1999;45(2):21-56.
3. Falk RA, Dagenais RJ. Osteoporosis: Can a future epidemic be prevented? ADVANCE for Administrators of the Laboratory. 1997;6(8):46-52.
4. Goddard D, Kleerekoper M. The epidemiology of osteoporosis. Postgrad Med. 1998;104(4):54-72.
5. Bracker MD, Watts NB. How to get the most out of bone densitometry. Postgrad Med. 1998;104(4):77-86.
6. Baker K. Detecting osteoporosis with sound. Machine Design. 1998;70(5):S84-S86.
7. Kleerekoper M. Evaluating and managing osteoporosis. The emerging role of biochemical bone markers. CLN. 1997;23(12):6-7.
8. Sainato D. Biochemical bone markers in osteoporosis. CLN 1999;25(3):1,6-7.
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