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BONE MARKERS
Getting to the Core of Skeletal Bone Disease
Biochemical bone markers may become the new "gold standard" for monitoring skeletal disease treatment and progression.
By Michelle L. Paquette
Milk does a body good" is more than a slogan from the dairy industry. In fact, calcium and vitamin D intake early on can supply your body with the right amount of bone mineral density for later in life.
Most people experience a net increase in bone mass until the third or fourth decade of life. This is then followed by a balanced period where total mass remains constant for a few years, becomes defective in the organization of bone formation or bone resorption and results in substantial changes in functional integrity. Although this build up usually occurs slowly over time, changes can occur rapidly when the rate of bone turnover increases.1
Bone Diseases
Every year, diseases of the bone such as osteoporosis affect approximately one-half of all women and one-fourth of all men in the 50+ age population.2
"Osteoporosis is the most prevalent of bone diseases," says Michael Kleerekoper, MD, professor of Medicine, Wayne State University, Detroit.
With approximately 1.5 million Americans suffering fractures related to osteoporosis, experts estimate that this disease cumulates costs of $10 billion each year. For 1998 alone, osteoporosis costs generated $14 billion. In fact, if nothing is done to ensure early detection of osteoporosis, costs could accrue to $250 billion by the year 2050.1
Women, particularly those who are athletic with a lean body mass and prone to abnormal menstrual cycles, often don't experience the correct skeletal framework. To assess the effects of this problem upon the female population, skeletal maturity of young girls progressing through puberty is part of a study run by Lawrence Demers, PhD, distinguished professor of Pathology and Medicine at Hershey (PA) Medical Center. Dr. Demers is studying girls between the ages of 10 and 20, which are key years of bone formation. At 20 years old, women already begin to lose more bone than what's being formed. By the time they reach menopause, therefore, women will have a reduced skeletal mass.
"One major driving force for improving skeletal remodeling is estrogen, which is the reason women entering menopause lose more bone than men," says Dr. Demers.
Besides osteoporosis, metabolic bone diseases like Paget's disease and hyperparathyroidism, as well as cancer of the bone, are also of concern.
Bone Screening
Considered the "gold standard" in screening bone loss, dual-energy X-ray absorptiometry (DEXA) provides an accuracy of >= 95 percent and a precision of ~1 percent for diagnosing bone mass decrement and predicting fractures. Using DEXA, however, is costly. This technology is limited because the efficacy can only be measured after two to three years of treatment.
Providing the timely assessment of bone resorption, formation and turnover, biochemical bone markers are anticipated to slowly replace DEXA. These markers can help with clinical therapeutic decisions as well as provide monitoring results within three months from treatment onset. The problem of moving from the research stages to the clinical applications is still in the works.1
"These markers aren't diagnostic substitutes for measuring bone density, but they can help the clinician monitor the effects of the drug," says Dr. Kleerekoper.
By quickly and effectively measuring byproducts of osteoclast and osteoblast activity, bone markers measure the bone collagen breakdown process and bone turnover rate. Based on bone cycle phases, biochemical markers are indicators of bone formation, bone resorption or bone turnover. Bone turnover can be determined by comparing marker concentrations released during resorption and formation.2
"Bone markers are finding their use for monitoring therapy and the progression of therapy," says Robert Christenson, PhD, professor of Pathology, director of Clinical Chemistry/Rapid Response Laboratories, director of Point of Care, University of Maryland School of Medicine, Baltimore. "Since you can't tell the quality of bone by just density, markers are needed to illustrate that the two are independent measurements."
Bone Formation Markers
Responsible for assessing osteoblastic synthetic activity or metabolism of procallogen, bone formation markers are a valid diagnostic tool and include:
* Alkaline phosphatase (ALP). Although the exact function of ALP is unknown, four ALP isoenzymes may be found in blood, each one relatively specific for respective liver, bone, placental and intestinal tissues with which it's associated. Due to the large molecular size of ALP, all assays are serum based.
* Bone alkaline phosphatase (B-ALP). Identified by researchers in buds, which are derived from the cell membrane, these deposits appear to play an important role in bone formation. Since B-ALP is produced in high amounts during the formation process, it's a good indicator of bone formation activity. B-ALP is also useful for therapeutic monitoring of patients. A rise in B-ALP, for instance, may indicate estrogen deficiency. B-ALP is measured by a variety of methods, including electrophoresis, wheat germ lecithin, precipitation, heat stability and immunoassay.
"Immunoassay is considered the method of choice by many labs because these assays have better analytical sensitivity and reported imprecision in the range of 5 percent to 8 percent," according to Dr. Christenson.
* Osteocalcin (Ocn). As a relatively small protein, Ocn is produced by osteoblasts during the matrix mineralization phase, released into blood and incorporated into bone matrix where it's the most abundant non-collagenous protein. The body degrades Ocn during bone resorption with up to 70 percent entering the circulatory system.
Since circulating Ocn may be either newly synthesized during bone formation or released during bone resorption, there is some question as to whether Ocn should be considered a marker of osteoblast activity or an indicator of bone matrix metabolism and turnover. If considered a marker of bone turnover, Ocn may hold substantial clinical utility for monitoring coupled formation/resorption process. When formation and resorption are uncoupled, Ocn is considered a marker of osteoblast activity.2
"Bringing these markers inhouse will allow the clinical lab to become more competitive with the reference lab," says Dr. Demers.
Bone Resorption Markers
These markers are necessary for reflecting osteoclast activity or collagen degradation and include:
* Acid Phosphatase. Due to its large molecular size, assays for acid phosphatase are serum or plasma based. Data for the use of acid phosphatase as a marker of bone metabolism is incomplete, which may be the result of analytical problems and/or the enzyme was released into the sealed osteoclast microenvironment rather than directly into the blood stream.
* N-telopeptide. Since the majority of fragments from the N-terminus (which are released into circulation as a result of osteoclast degradation of type I collagen during the resorption process) are small they pass through the glomerulus into urine. A urine assay for N-telopeptides that monitors bone resorption is commercially available and is based on a monoclonal antibody that specifically recognizes the c-2 chain N-telopeptide fragment containing pyridinium crosslinks.
* C-telopeptide. Fragments from the C-terminus are released into circulation as a result of the osteoclast-mediated degradation of type I collagen during the bone resorption process. Companies offer both serum and urine assays for these peptides.
* Pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) crosslinks. Essential for stabilizing the mature forms of collagen fibers and elastin, Pyr and D-Pyr crosslinks result from post-transnational processing of lysine and hydroxylsine residues. D-pyr is more bone specific, but both are found in the bone. Detection of Pyr and D-pyr include high performance liquid chromatography, which provides a specific marker for bone resorption but isn't routinely offered in clinical laboratories and immunoassays for free Pyr and free D-pyr. These assays provide a quantitative measure of free crosslinks that reflect bone resorption and have been evaluated in menopause and hormone replacement therapies as well as for osteoporosis, hyperthyroidism, hyperparathyroidism and Paget's disease.2
"Blood and urine tests are available to measure bone resorption," says Dr. Kleerekoper. "If a drug is working, for instance, the level of blood or urine levels should fall to illustrate it."
"You can provide positive reinforcement to patients by showing them the therapeutic results," says Dr Christenson.
Concerns
Although the average cost of a bone marker is $60, which is a more cost-effective approach for identifying and managing skeletal diseases, some concerns still need to be addressed with these devices.
"Before determining the clinical value of these markers, some fundamental issues must be hammered out, such as assay standardization, minimizing result variability, uniform results reporting and control of preanalytical variables," says Dr. Christenson. "The role of bone markers in the monitoring of bone diseases hasn't been widely accepted due to the lack of studies, which makes their role unclear."
Reimbursement is another debate, although a provision of the Balanced Budget Act of 1997 requires Medicare to begin reimbursing health care providers for FDA-approved procedures for measuring bone mass.
"The timeframe to receive reimbursement for these bone markers isn't very responsive," comments Dr. Christenson. "But, there's great evidence of clinical benefit."
With 43 states currently approved for reimbursement of these markers, there is hope. However, for states like New York, Florida and Pennsylvania, which include the highest Medicare population, approval hasn't yet occurred.
Bone Disease in the Future
Refinements are being made to existing tests, from point-of-care devices to fingersticks. As assays become more sensitive, markers are being developed with individual variability. Improvements to serum markers are being made so that more information can be accessed. In addition, the areas of automation are anticipated to become more prevalent.
"Improvements have already been made in the delivery of drugs," says Dr. Christenson. "Calcitonin, for example, can be used in a nasal spray."
There's also hope for bone disease screening. Vitamin D screening, for instance, could isolate high-risk populations for women in their 20s and 30s.
"It would be great to find a marker for screening and identifying those people at high risk of skeletal disease today," says Dr. Christenson.
Michelle L. Paquette is an assistant editor.
References
1. Auxter S. Biochemical bone markers making inroads. Clinical Laboratory News. 24(5):12-13.
2. Christenson RH. The basics of bone markers. Clinical Laboratory News. 24(5):8-12.
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