Using biochemical bone markers in osteoporosis

By Ivy M. Alexander, MS, C-ANP

Adult Nurse Practitioner, Assistant Professor
Yale University School of Nursing
Adult and Family Nurse Practitioner Programs
New Haven, CT

Osteoporosis or osteopenia is a significant health problem, estimated to affect 23 million women in the United States. Each of these women is at risk for fracture and the potentially devastating associated consequences.1,2 Recently, several important advances in identifying, treating, and managing osteoporosis have occurred.

Osteopenia and osteoporosis can be identified readily using bone mineral densitometry (BMD) measurement. New pharmacologic treatments, such as alendronate (Fosamax, manufactured by Merck & Co. of Whitehouse Station, NJ) and raloxifene (Evista, manufactured by Eli Lilly and Co. of Indianapolis), have been approved for preventing and/or treating osteoporosis.1,3 In addition to those advances, serum and urinary bone markers have been found valuable in evaluating treatment efforts in women with osteoporosis and predicting bone loss among postmenopausal women.4-6

Managing osteoporosis requires a holistic approach, providng education about exercise and calcium intake, identifying those at risk, measuring bone density, prescribing appropriate pharmacologic agents, and evaluating treatment. This column will describe serum and urinary bone markers and their use for evaluating treatment and risk for bone loss. Biochemical mar kers of bone formation and resorption are produced during bone remodeling processes. Remod el ing begins with osteoclast digestion of the bone surface, which creates an erosion cavity. These cavities are filled by osteoblasts, which migrate to the surface of the bone, synthesize, and secrete bone matrix proteins, which consist mostly of type I collagen.

Next, a modified form of the lysine amino acid forms crosslinks between the newly formed collagen and previously existing mature collagen. These crosslinks enhance the mechanical strength of the new collagen surface. Noncollagen proteins, consisting mostly of osteocalcin, make up the rest of the protein matrix. After the protein matrix is formed, calcium salts mineralize the surface over a one- to two-week period.

Resorption and formation processes produce byproducts measurable in urine or ser um. Resorp tion occurs when osteoclasts digest bone collagen. This breakdown of the lysine crosslinks produces byproducts, which are released into the bloodstream and excreted directly through the urine.

The levels of these byproducts, including plasma tartrate-resistant acid phosphatase and urinary hydroxyproline, pyridinoline, deoxy pyrid inoline, and N-teleopeptide crosslinks, rise in relation to bone resorption activity.3-5 Likewise, by - products of bone formation increase as bone formation increases. Osteoblasts synthesize the new protein matrix and release osteocalcin, bone-specific alkaline phosphatase, and procollagen I extension peptides into the bloodstream.3-5

Urinary crosslinks are used most often to assess bone resorption. Several urinary crosslinks can be measured, including pyridinoline (found in type I and II collagen), deoxypyridoline (found only in type I collagen), and N-teleopeptide (highly specific to type I collagen). Of these, the crosslinked N-teleopeptides (NTx) are most commonly evaluated. NTx is measured by enzyme-linked immunoassay (ELISA) using the Osteomark assay. This assay requires a first- or second-morning void specimen (prior to 10 am) and preferably fasting. The cost of the Osteomark assay varies depending on the laboratory, but is generally about $50.4 Normal (premenopausal) NTx levels in women range from 5-65 nmol/L BCE/mol/L creatinine.6

In 1995, the Food and Drug Administration (FDA) approved urine immunoassays of bone markers for use in clinical practice for osteoporosis.4,7 A compact, portable dipstick machine, similar to home blood glucose monitoring devices, likely will be available in the near future for office measurement of urinary NTx levels.8

Osteocalcin is the biochemical marker most frequently used to evaluate bone formation. Levels are measured using serum radioimmunoassay; fasting morning specimens are generally preferred. Normal serum osteocalcin levels in postmeno pausal women range from 1.5-11.0 ng/ml.6 Osteo calcin levels often are used in research on osteoporosis, and FDA approval for use monitoring osteoporosis treatment is expected soon.4

Because bone markers give an indication of bone remodeling process rates but do not give specific data regarding actual bone mass,7 they are used with BMD measurement. Actual bone mass is determined using BMD, and baseline NTx is evaluated. Repeat NTx measurements are determined in three to six months with a decrease of 30% to 60% (indicating reduced resorption) indicating treatment effectiveness.4,6 Likewise, decreases in osteocalcin levels indicate slowing of bone formation, which signals a decrease in bone turnover and stabilizing of remodeling processes.

Bone markers were identified as valuable for predicting bone loss among postmenopausal women in a large multicenter trial. NTx levels below 38 predicted no bone loss in the next year, but, levels between 49 and 64 predicted losses of 1.5%, and levels over 64 predicted losses of 2.5% over the next year.6 When BMD is unavailable, due to rural location, or difficult to interpret, due to fracture or degenerative changes, NTx can aid in determining response to treatment and estimating rates of bone loss. These biochemical markers offer a cost-effective method of evaluating treatment without waiting to reassess BMD. Not all insurers cover bone marker measurements, so coverage consideration should be weighed before use.


1. Hodgson SF, Johnson CC. AACE clinical practice guidelines for the prevention and treatment of postmenopausal osteoporosis. American Association of Clinical Endocrinologists (on-line version, updated Aug. 27, 1998). [Editor’s note: Access the guidelines at http://www.aace com. Click on "Clinical Information," then "AACE Clinical Practice Guidelines," then "Osteoporosis Guidelines."]

2. National Osteoporosis Foundation. Osteoporosis Prevalence Figures: State-by-State Report. Washington, DC; 1997.

3. Eastell, R. Treatment of postmenopausal osteoporosis. NEJM 1998; 338:736-746.

4. Arnaud CD. Osteoporosis: Using bone markers’ for diagnosis and monitoring. Geriatrics 1996; 51:24-30.

5. Daly PA. Office management of osteoporosis: A guide for the primary care provider. Comprehensive Therapy 1995; 21:565-574.

6. Rosen CJ, Chestnut CH, Mallinak N. The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation. J Clin Endocrinol Metab 1997; 82:1,904-1,910.

7. Lindsay R, Marcus R, Recker R. Osteoporosis: what’s new in prevention and treatment. Patient Care 1996; Aug 15:24-53.

8. Daniel Baran, MD, Osteoporosis Clinic, University of Massachusetts Medical Center, Worcester MA. Personal communication. Oct. 7, 1998.