Using biochemical markers of bone turnover in clinical practice
ABSTRACTBiochemical markers of bone turnover provide clinically useful evidence of the normal and pathologic processes that reflect bone cell activity in the skeleton. Understanding the behavior of markers of bone formation and bone resorption should aid in managing patients with a variety of skeletal disorders.
KEY POINTS
- Biomarkers of bone formation and resorption reflect the overall osteoblastic and osteoclastic activity in the skeleton and in some situations may serve as surrogates for histologic examination of bone.
- Biomarkers of bone turnover can be used to document the effects of therapeutic agents in some patients with osteoporosis and possibly reduce the need for frequent bone density testing.
- In cancer patients with bone metastases, biomarkers of bone resorption provide evidence of the efficacy of antiresorptive therapy. The baseline levels also have prognostic value: patients with the highest levels have the worst prognosis.
Collagen cross-links
Urinary pyridinoline and deoxypyridinoline are more specific markers of bone resorption.1
Pyridinolines are cross-linking amino acids that strengthen collagen fibrils in the extra-cellular matrix. They are found in the main fibril-forming collagens (types I, II, and III) of many tissues. Pyridinoline is the major chemical form, but deoxypyridinoline is also unusually abundant in bone collagen and hence is a relatively selective bone marker.
NTx. Since pyridinolines are not metabolized and are largely excreted as small peptides when produced by osteoclastic bone resorption, immunoassays have been developed that selectively measure cross-link-containing peptide fragments in urine and serum. The first was an assay that recognizes an N-telopeptide of collagen type I (NTx) in urine10 and serum.11 The recognized feature in this sequence is fully generated during the process of osteoclastic proteolysis and so requires no further metabolism by the liver or kidney for its production. Results from second-morning urine collections correlate well with those from 24-hour collections, which simplifies patient evaluation.
CTx. Several other assays target structural variants of a peptide sequence that originates from the carboxy-terminal cross-linking region of collagen type I (CTx).12,13
Other markers of bone resorption
Two enzymes found in osteoclasts have received attention as markers of osteoclast activity.
Serum tartrate-resistant acid phosphatase (TRAP) 5b has not been studied extensively in patients but appears to correlate with other markers of bone resorption.14
Serum cathepsin K is of interest because it is the primary proteolytic enzyme used by osteoclasts to degrade bone type I collagen during resorption. Several studies suggest it may be valuable as a marker of bone resorption,15 but more studies are required to evaluate its performance relative to established bone resorption markers.
Receptor activator of nuclear factor kappa (RANK), RANK ligand, and its decoy receptor osteoprotegerin are the pivotal regulators of osteoclast recruitment and activity.16 They may eventually be used as markers of bone metabolism, though the broad role of RANK ligand signaling in the immune system may limit its specificity.
FACTORS THAT INFLUENCE ASSAY RESULTS
To avoid being misled, clinicians who use biochemical markers of bone turnover should be familiar with factors that influence assay results.3
Diurnal and day-to-day variability
The most important biologic factors probably are diurnal and day-to-day variability in bone-forming and bone-resorbing activities. Levels of bone turnover markers are highest in the early morning and lowest in the afternoon and evening.
Levels of urinary markers can vary 20% to 30% from the highest to lowest value of the day. Serum markers change to a smaller degree except for serum CTx, which can vary by more than 60% during the day.17
In general, the day-to-day variability of urinary markers of bone resorption is similar in range to their diurnal variability. The serum markers of bone formation appear to vary less from day to day.
Eating, calcium intake
Blood for measurement of serum CTx should be taken in the morning after overnight fasting to avoid the large decrease that occurs after eating. An increase in calcium intake also can lower the levels of bone resorption markers, particularly in people whose calcium intake was previously low.18 Presumably, this effect is mediated by inhibition of parathyroid hormone secretion.
Sample handling
Improper collection and handling of specimens can seriously affect assay precision. The optimal time to collect samples is in the morning. Careful sample collection and storage are particularly important in measuring serum osteocalcin and TRAP. It is also important to use the same laboratory for serial measurements, since assay results can vary considerably among laboratories, even if they use identical methods.
BONE TURNOVER THROUGHOUT LIFE
In children, bone turnover can be more than 10 times greater than in adults because of three physiologic processes interacting in the skeleton: bone modeling, remodeling, and growth. Levels of bone formation and resorption markers therefore are much higher in children than in adults.19 Unfortunately, no studies have compared all the available markers in the same pediatric reference population.
In puberty, bone growth accelerates, with an increase in bone turnover markers that reflects the effect of hormones that induce the growth spurt.1
Postmenopausal women who do not use hormone replacement therapy have higher levels of bone resorption and formation markers than premenopausal women.20 Levels in postmenopausal women on hormone replacement are no different than in premenopausal women.20,21 In postmenopausal women not on estrogen, urinary levels of NTx have been reported to discriminate between normal bone mineral density (lowest NTx levels), osteopenia, and osteoporosis (highest levels).22 Normal levels of NTx are found in a small percentage of women. This may be explained by the variable levels of serum estradiol in post-menopausal women.23
Elderly men, in contrast, have variable findings.24–28 However, accelerated bone turnover has been noted in men with full-blown hypogonadism caused by androgen suppression therapy.29
