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Biochemical markers of bone metabolism as they relate to osteoporosis.

Osteoporosis is a major health problem that is becoming increasingly important in our aging society. Noninvasive techniques for monitoring bone resorption have been the object of a great deal of research in recent years, driven partly by the increasing incidence of osteoporotic bone fractures with their attendant social and economic costs. Suitable means of measuring bone resorption rates are therefore important not only as an aid to detecting those at risk but also for effective monitoring of therapy. The development of new markers for bone resorption has been an area of intense research interest during the past few years, and them have been recent developments in techniques for bone markers.(1)

What is osteoporosis?

Bone tissue is undergoing renewal constantly in a process called remodeling. Bone is resorbed (degraded) by osteoclasts, and osteoblasts refill the resulting cavity with bone matrix (osteoid), which is subsequently mineralized. When less bone is formed than resorbed, bone loss results, and ultimately osteoporosis can develop over time.

Although all bones are affected, osteoporosis is most commonly accompanied by fractures of the spine, wrist, and hip. Osteoporosis is a disease of the bones characterized by a decrease in bone mass and density. Bone loss, or osteopenia, is an asymptomatic process unless fracture occurs.(2) Osteoporosis is bone loss that leads to fracture after only minimal trauma. It is a silent disease that progresses without any outward sign, sometimes for decades, until a fracture results. People may often lose height due to collapsed vertebrae without realizing they have osteoporosis.(3)

How common is osteoporosis?

The majority of bone mass is built up during childhood and reaches maximum levels between 25-35 years of age. After the age of 35, bones naturally begin to lose some of the calcium that gives them their density and strength.

In Europe, Japan, and the United States, an estimated 75 million people suffer from osteoporosis and as many as 200 million worldwide. If present trends continue, the prevalence of osteoporosis is expected to double by the year 2020. More than 1.6 million hip fractures occur worldwide annually that are attributed to osteoporosis.(3)

Each year about 1.3 million fractures are attributable to osteoporosis in people age 45 and older. Osteoporosis is a common condition affecting as many as 25 million individuals in the U.S. Among those who live to be age 90, 32% of women and 17% of men will suffer a hip fracture, mostly due to osteoporosis. The cost of osteoporosis in the U.S. has been estimated at $3.8 billion annually.(4)

Who is at risk?

The likelihood of developing osteoporosis increases with age, is higher in women than in men, and higher in Caucasians and Asians than in African-Americans. Osteoporosis is a major underlying cause of bone fractures in postmenopausal women and older persons in general.(4) After age 65, one in two women and one in five men will develop osteoporosis-related fractures. A hip fracture increases by 5%-20% the likelihood that an older person will die within one year.(5) Among survivors of hip fractures, 15%-25% of those who had lived independently will reside in a long-term care facility one year after hip fracture.(5)

The cause of osteoporosis is still not known. However, many factors are known to contribute to the development of this condition (see Table 1). Just because one has several risk factors for osteoporosis does not mean one will definitely develop the disease or get a fracture - only that one's chances of this happening are increased.

Sex. Women are approximately four times more likely to develop osteoporosis than men, because women generally have thinner, lighter bones and because rapid bone loss occurs at menopause.(3)

Race. Caucasian and Asian women are more likely to develop osteoporosis; however African American and Hispanic women are also at risk for developing this disease.

Family history. Susceptibility to fracture may be, in part, hereditary. Young women whose mothers have histories of vertebral fractures also seem to have reduced bone mass.(3)

Age. Risk is greatly increased over the age of 70. Roughly estimated, women lose about 10% of bone mass per decade of life after the age of 30.(3)

Menopause/menstrual history. Normal or early menopause (before age 45), brought about naturally or because of surgery, increases the risk of developing osteoporosis. In addition, women who stop menstruating prematurely because of conditions such as anorexia or bulimia, or excessive physical exercise, may also lose bone tissue and develop osteoporosis.

Lifestyle. Smoking, drinking too much alcohol or caffeine, consuming an inadequate amount of calcium, or getting little or no weight-bearing exercise increase your chances of developing osteoporosis.

Medications and disease. Osteoporosis is associated with the use of certain cortisone-like drugs and is recognized as a complication of a number of medical conditions that include endocrine disorders and rheumatoid arthritis.

How is osteoporosis diagnosed?

Three diagnostic procedures are available for evaluating metabolic bone diseases: bone density measurements, bone biopsies, and biochemical markers of bone turnover. Determination of bone density is essential for diagnosing osteoporosis, but it does not provide information on the dynamics of bone formation and bone resorption. Bone biopsies and biochemical markers provide this information. Bone biopsies are invasive procedures and cannot be routinely included in the management of patients with osteoporosis. Accordingly, there has been a great effort in recent years to develop biochemical markers of bone turnover.(6)

Bone mineral density measurements

Fracture risk in patients with osteoporosis can be predicted reliably from bone density measurements.(5) The four most widely used methods to measure bone mass are single-photon absorptiometry (SPA), dual-photon absorptiometry (DPA), quantitative computed tomography (QCT), and dual X-ray absorptiometry (DXA). These technologies estimate bone mass on the basis of tissue absorption of photons derived from a radionuclide source or an X-ray tube.

Site-specific measurements of bone mineral density (BMD) are recommended - femoral neck BMD, for example, is a better predictor of hip fracture than determination of the spinal BMD.(5) The choice of a test is based first on availability in your area. If available, DXA clearly is the method of choice because DXA is the most precise of the four most widely used technologies for measuring bone density.

In some studies, precision for whole body measures of BMD approaches a coefficient variation of 0.4% or (SD / mean) x 100.(5) This level of precision is clinically important because it allows the use of serial BMD measurements to follow the course of bone loss and measure response to treatment of osteoporosis. DXA also offers the advantage of the shortest scan times and lowest radiation exposure of the four techniques.(5) Bone densitometry is well accepted, is reimbursed by insurance carriers, and is the diagnostic test for osteoporosis endorsed by the National Osteoporosis Foundation and the World Health Organization.(6)

Biochemical markers

There are also biochemical markers of bone resorption. These are substances in the urine and blood. The quantity of these markers found in blood or urine indicate the rate at which bone is being broken down and can be used to assess the impact of treatment.

In contrast to DXA, the biochemical markers allow a more frequent determination and are not as invasive as histomorphometric methods. If markers of bone turnover are to attain practical use to monitor hormone replacement therapy, they should be able to detect differences in response between individuals. This is likely to depend on the magnitude and time course of the response, the heterogeneity of response between individuals, and the reproducibility of the marker measurements within each individual.(7)

The rate of formation or degradation of the bone matrix can be assessed either by measuring a prominent enzymatic activity of bone-forming or -resorbing cells, such as alkaline phosphatase activity, or by measuring bone matrix components released into the circulation during formation or resorption. These markers are of unequal specificity and sensitivity, and some of them have not been fully investigated. None of these markers are disease specific, but a given marker may be more sensitive to assess bone turnover in one metabolic bone disease than in another.(8)

Formation Markers

Alkaline phosphatase. Serum total alkaline phosphatase activity has been one of the most commonly used markers of bone formation and reflects osteoblastic activity. Unfortunately, total alkaline phosphatase lacks sensitivity and specificity. Several studies have shown that its total activity increases with aging in adults, especially in women after menopause.(9)

Several techniques that have been developed to differentiate the bone and liver isoenzymes have improved the specificity and sensitivity of alkaline phosphatase tests. Specific techniques to measure bone alkaline phosphatase (BAP) include heat inactivation, wheat-germ lectin precipitation, and immune electrophoresis. None of these methods, however, seem to provide the sensitivity, specificity, cost-effectiveness, and reliability required for routine clinical applications.

Most recently, research on new immunoassays using specific antibodies against human BAP tests, points toward an improved diagnostic accuracy with regard to bone disease and therapeutic drug monitoring.[10] Quantitative measurement of BAP activity in serum can provide an index for the rate of bone formation. Furthermore, increased BAP activity in serum is indicative of bone disorders.[11] Total and bone-specific alkaline phosphatase activities in serum appear to be affected by seasonal variation because values are higher in autumn than in spring.[12]

Osteocalcin. Osteocalcin, also called bone gamma-carboxyglutamate (Gla) protein, is a small, noncollagenous protein that is specific for bone tissue and dentin, but its precise function remains unknown.[8] Osteocalcin is synthesized predominantly by the osteoblast and is mostly incorporated into the extracellular matrix of the bone.

A fraction of newly synthesized osteocalcin is returned to the circulation, where it can be measured by radioimmunoassay or enzyme immunoassay. Serum osteocalcin correlates with skeletal growth at the time of puberty, and is increased in a variety of conditions characterized by increased bone turnover, such as primary and secondary hyperparathyroidism, hyperthyroidism, Paget's disease, and acromegaly.[13]

Osteocalcin is a truly bone-specific protein that may account for up to 3% of total bone protein. It is believed to play a role in the control of mineralization.[13] Estimations of the concentration of circulating osteocalcin can vary widely among the methods and laboratories. This variability may be a consequence of differences in antisera specificity and sensitivity; the purity, potency, and immunore-activity of osteocalcin calibrators; and various other analytical factors.[14] Osteocalcin levels are influenced by age, sex, and circadian rhythm. Serum osteocalcin concentrations apparently have seasonal variation with lower values in autumn than in spring.[12]

Procollagen I extension peptides, During the extracellular processing of type I collagen, there is a cleavage of the amino terminal and carboxyterminal extension peptides before fibril formation. These peptides circulate in blood and might serve as a useful marker of bone formation because collagen is by far the most abundant organic component of bone matrix? Because these markers have not been investigated thoroughly, their clinical value has yet to be established.[14]

Resorption markers

Urinary calcium. The least expensive assay of bone resorption is a fasting urinary calcium test performed on a morning sample and corrected for creatinine excretion. Although useful for detecting a marked increase in bone resorption, urinary calcium tests lack sensitivity because the amount of calcium excreted in the urine reflects not only skeletal resorption, but also intestinal absorption as well as renal tubular filtration and reabsorption of calcium? Under fasting conditions, however, the intestinal and renal components are relatively fixed, and calcium excretion in the fasting state may be used to assess the skeletal component.

Hydroxyproline. Hydroxyproline is found mainly in collagen and represents about 13% of the amino acid content of the molecule. Hydroxyproline is derived from proline, and most of the endogenous hydroxyproline present in biological fluids is derived from the degradation of various forms of collagen.[9] Because half of human collagen resides in bone, where its turnover is probably faster than in soft tissues, hydroxyproline excretion in urine is regarded as a marker of bone resorption.

Urinary hydroxyproline, however, is not specific for bone function because it is influenced by various diseases and other factors including diet. The use of a spot second-voided urine specimen obtained after an overnight fast may avoid the influence of dietary hydroxyproline.[14] Methods for measuring hydroxyproline include photometry, fluorometry and high pressure liquid chromatography (HPLC).

Urinary hydroxylysine glycosides. Hydroxylysine is another amino acid unique to collagen and proteins containing collagen, but it is much less abundant than hydroxyproline. Urinary galactosyl hydroxylysine increases with aging and might be a useful marker in patients with osteoporosis. This marker deserves further evaluation in osteoporosis. Its usefulness at this time is limited by the current HPLC technique.[8]

Pyridinium cross-links. Pyridinoline (pyr) and deoxypyridinoline (dpyr) are the two nonreducible pyridinium cross-links present in the mature form of collagen. They can be found in connective tissue, articular cartilage, and in tendons and the aorta, but bone is by far the most abundant source.

Because the rate of bone turnover is markedly higher than in other tissues in which these analytes are found, their presence in biological fluids is likely to be derived predominantly from bone. The ratio of pyr to dpyr is close to three to one. These analytes are likely to be released from bone matrix during its degradation by osteoclasts. Urinary concentrations of pyr and dpyr are markedly higher in children than in adults, are increased by 50%-100% at the time of menopause, and go down to premenopausal levels with estrogen therapy.[9]

Methods have been developed using HPLC of hydrolyzed urine, and recently immunoassays have become available. These methods are limited by the lack of synthetic calibrators, controversy over molar fluorescence yield of pyridinolines, and the variability of acid hydrolysis. These factors have been suggested as contributors to the differences observed among laboratories.[14] Excretion of pyr and dpyr is affected by a circadian rhythm with a peak during the night and its lowest point during the afternoon.[9] These analytes also appear to vary with seasons. The concentrations of pyr were lower and dpyr higher in autumn compared to spring. The ratio of pyr to dpyr, therefore, varies depending upon the time of year.[12]

N-telopeptides. N-telopeptides, found at the end of collagen fibers, are released when osteoclasts break down bone. Measurement of the cross-linking, domain-containing fragments of type I collagen specific to bone (and which is released during resorption) is a measure of bone resorption. This assay can be used to identify osteoporotic patients who are losing bone rapidly and therefore are more likely to benefit from antiresorptive therapy.[5] Immunoassay methods have been developed.

Plasma tartrate-resistant acid phosphatase. Acid phosphatase is a lysosomal enzyme that is present primarily in bone, prostate, platelets, erythrocytes, and the spleen. Tartrate-resistant acid phosphatase (TRAP) is released into the blood. Plasma TRAP is increased in a variety of metabolic bone disorders characterized by increased bone turnover and is elevated after oophorectomy and in vertebral osteoporosis.[8] Its clinical utility in osteoporosis remains to be investigated. The lack of specificity of plasma TRAP activity for the osteoclast, its instability in frozen samples, and the presence of enzyme inhibitors in serum are potential drawbacks.

Summary

Osteoporosis and broken bones raise the frightening specter of immobility and loss of independence to millions of adults.[5] According to the American College of Obstetricians and Gynecologists, more than one-third of all women in the United States are over the age of 50, and another 20 million women of the baby boom generation will make the transition to menopause in the next decade.[15] These women are, or soon will be, at risk for osteoporosis.

The diagnosis of primary osteoporosis is established by documentation of reduced bone density or mass in a patient with a typical fracture syndrome after exclusion of known causes of excessive bone loss. Prevention of fracture in susceptible patients is the primary goal of intervention. Preventive strategies include assuring estrogen replacement in postmenopausal women; adequate nutrition, including an elemental calcium intake of 1,000-1,500 mg/day; and a program of modest weight-bearing exercise.[4]

Biochemical markers hold great potential for the evaluation of treatment of osteoporosis. Many of the newer assays are still being evaluated clinically for specificity and sensitivity, but exciting strides have been made, not only for the diagnosis of osteoporosis, but also in the prevention of this disease. Today women in the United States can expect to live 30 years beyond the onset of menopause. They and their physicians will need information on bone health so that the best possible healthcare can be given to ensure optimum quality of life in the later years.

Table 1

Risk factors for osteoporosis

Female sex Caucasian or Asian race Positive family history Age Early menopause/menstrual history Diet low in calcium Smoking Excessive alcohol or caffeine intake Sedentary lifestyle Medications, disease

Table 2

Bone markers

Bone formation (osteoblast activity)

Alkaline phosphatase, bone-specific alkaline phosphatase Procollagen I extension peptides Osteocalcin

Bone resorption (osteoclast activity)

Urinary calcium Urinary hydroxyproline Urinary pyridinoline/deoxypyridinoline Teleopeptides Tartrate-resistant acid phosphatase Hydroxylysine glycosides

Table 3

Prevention of osteoporosis

* Increased weight-bearing exercise, such as walking or playing tennis

* Limiting alcohol consumption and cigarette use

* Adequate vitamin D and calcium intake

* For women at menopause, talking with their doctors about their level of risk and the subsequent possible need for testing and treatment

References

1. Robins SP. Collagen crosslinks in metabolic bone disease. Acta Orthop Scand. 1995;66(suppl 266):171-175.

2. Bouman AA, Scheffer PG, Ooms ME, Lips P, Netelenbos C. Two Bone alkaline phosphatase assays compared with osteocalcin as a marker of bone formation in healthy elderly women. Clin Chem. 1995;4(2): 196-199.

3. World Summit of Osteoporosis Societies. http://www.bogo.co.uk/blue/summit/backgrnd.htm, March 7, 1997.

4. Osteoporosis NIH Consens Dev Conf Consens Statement Online 1984, April 2-4; 5(3):1-6.

5. Gamble CL. Osteoporosis: Making the diagnosis in patients at risk for fracture. Geriatrics. 1995;50:7,24-33.

6. Bettica P, Moro L, Robins SP, et al. Bone resorption markers galactosyl hydroxylysine, pyridinium crosslinks, and hydroxyproline compared. Clin Chem. 1992;38(11): 2313-2318.

7. Hannon R, Blumsohn A, Al-Dehaimi AW, Eastell R. The use of biochemical markers of bone turnover to monitor the skeletal response to hormone replacement therapy. Bone. 1995;16(suppl 1);109S.

8. Delmas P. Biochemical markers of bone turnover. Journal of Bone and Mineral Research. 1993;8(suppl 2):S549-S555.

9. Delmas PD. Biochemical markers for the assessment of bone turnover. In: Riggs BL, Melton J, eds. Osteoporosis: Etiology, Diagnosis, and Management, 2nd ed. Philadelphia, Pa.: Lippincott-Raven; 1995.

10. Woitge HW, Siebel MJ, Ziegler R. Comparison of total and bone-specific alkaline phosphatase in patients with nonskeletal disorders or metabolic bone diseases. Clin Chem. 1996;42(11):1796-1804.

11. Gomez B, Ardakani S, Ju J, et al. Monoclonal antibody assay for measuring bone-specific alkaline phosphatase activity in serum. Clin Chem. 1995;41(11):1560-1566.

12. Douglas AS, Miller MD, Reid DM, et al. Seasonal differences in biochemical parameters of bone remodeling. J Clin Pathol. 1996;49:284-289.

13. Fraher L. Biochemical markers of bone turnover. Clin. Biochem. 1993;26: 431-432.

14. Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry, 2nd ed. Philadelphia Pa.: W.B. Saunders; 1994.

15. Cooper JR. Insights into menopause. The Medical Reporter. Denver, Colo.: Joel R Cooper Creative Services. http://www.coolware.com/health/joel/menopause.html.

Sandy K. Gallagher is supervisor of the analytical biochemistry department at the Human Nutrition Research Center (HNRC) in Grand Forks, N.D.
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Date:Aug 1, 1997
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