Current evidences continue to support the clinical application of bone turnover markers (BTMs) in the management of postmenopausal osteoporosis. The limitations of bone mineral density measured by dual energy X-ray absorptiomet especially emphasize the beneficial roles of BTMs, such as serum C-terminal telopeptide of type I collagen and serum procollagen type I N-propeptide, as monitoring tools to assess the responses to treatment. Therefore, the proper application and assessment of BTM in clinical practice is very important. However, their use in Korea is still insufficient. Therefore, the BTM committee has set up by the Korean Society for Bone and Mineral Research have been constituted and provided a position statement which will suggest on the clinical application of BTM for the management of postmenopausal osteoporosis in Korea.
Osteoporosis is a major health burden and its impact is expected to rise throughout the world. Osteoporosis is defined as a disease characterized by low bone mass and deteriorated bone quality, which leads to decreased bone strength and subsequent increase in the risk of fracture.[
Bone turnover, which is the process of removal of old bones by bone resorption and followed by replacement of new bones by bone formation, is continuously occurring.[
There is emerging evidence on clinical use of BTMs to predict bone loss and fracture risk and to monitor the response to osteoporosis treatment.[
Despite this current attention in the clinical implication of BTMs for the management of postmenopausal osteoporosis, the use of BTMs is still insufficient in Korea. Therefore, the Korean Society for Bone Mineral Research organized the BTM committee to provide recommendations on their use to clinicians in Korea.
BTMs are classified as either bone formation markers or bone resorption makers.
Bone formation markers include osteocalcin, bone specific alkaline phosphatase (BSALP), carboxyterminal propeptide of type I procollagen (PICP), and PINP. BSALP and osteocalcin are released by osteoblasts and play a major role in bone mineralization. PICP and PINP are cleaved from procollagen type I during collagen synthesis. In Korea, osteocalcin and BSALP are most commonly used bone formation markers.[
Bone resorption markers include CTX-I, N-terminal telopeptide of collagen type I (NTX-1), free and total pyridinoline (PYD), and free and total deoxyPYD.
In Korea, CTX-I is the most commonly used as a bone resorption marker and has been mainly measured by the ECLIA using β-CrossLaps kit (Roche Diagnostics).
The primary challenge to the adoption of many BTMs in routine practice has been the poor reproducibility within-subject and between-laboratory. For clinical utility of BTMs, the pre-analytical sources of variability, along with the underlying disease process, must be identified, minimized, and controlled through carefully standardized patient preparation and sample handling procedures.[
Because serum PINP and CTX-I have recently been recommended as a reference BTM,[
Although either serum or plasma sample may be used for the measurements of CTX-I and PINP, ethylenediaminetetraacetic acid plasma has the advantage over the serum as it has superior sample stability.[
The patient related factors can be divided into controllable and uncontrollable factors (
The reference intervals of BTMs are useful for interpreting the results in patients with osteoporosis. Several prospective studies have reported that the presence of increased BTMs have an additive effect on the increase risk of fracture in women.[
Several BTMs were introduced as having an additive effect on fracture risk in women with a low BMD.[
Nonetheless, uncertainties over their clinical use still remains, and the routine use of BTMs to assess the fracture risk is not recommended. Despite with the association between BTMs and the risk of fracture, the previous studies have shown inconsistent findings due to their large variability.[
Therefore, the measurement of absolute risks, such as 10-year probabilities, should be evaluated in a further study with large population. Another possible avenue remains the development of international reference standards and standardization of their measurement that may help minimize or eliminate old problems.[
Inhibition of bone resorption by anti-resorptive drugs results in a decrease in bone resorption markers followed by a plateau. Changes in BTMs during anti-resorptive therapy depend on the mechanism of action of the drug, degree of inhibition of bone resorption, and the route of administration. This inhibition of bone resorption secondarily causes a decrease in bone formation markers, due to physiologic mechanisms linking osteoclast and osteoblast activity.
BPs are the most commonly used drugs for treatment of osteoporosis. Bone resorption markers are maximally suppressed after 8 weeks of treatment and bone formation markers are maximally suppressed after 26 weeks of treatment. The oral BPs, such as alendronate, ibandronate, and risedronate, have been compared in the TRIO study [
Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-κB ligand, is administrated subcutaneously inhibited bone resorption 12 hr after administration.[
SERM such as raloxifene have a weaker effect on the change of bone turnover than BPs and denosumab. In 60% to 65% of women with osteopenia, a significant response could be demonstrated using the LSC approach with CTX-I or PINP.[
The linkage between osteoclasts and osteoblasts can also function in the opposite direction, with anabolic drugs compared to anti-resorptive drugs.
Teriparatide is typically characterized as an anabolic agent, but results in increases in both bone formation and resorption markers.[
For monitoring of early response to teriparatide therapy, PINP is measured prior to the initiation of teriparatide, and then after 1 to 3 months of therapy. Because patients who were pretreated with alendronate then switched to teriparatide showed PINP response rates of 79% at 1 month and 97% at 3 months, follow up assessment of PINP at 3 months may be more helpful than earlier assessments in this group of patients.[
The increase in serum PINP concentration by >10 pg/mL may be predictive of a greater increase in BMD.[
Abaloparatide, recombinant human PTH related peptide (1–34), is a newly licensed anabolic therapy for osteoporosis.[
Romosozumab, anti-sclerostin monoclonal antibody, also works in a dose-dependent manner and increases bone formation markers. But, unlike teriparatide, there is an early but transient increase in PINP level and a decrease in serum CTX-I.[
Monitoring of BTM at an individual level may improve the compliance of patients on anti-osteoporotic treatment.[
According to recently published Consensus Statement in Asia-Pacific region,[
However, further studies are necessary to define an adequate response through the change in BTM concentration that is associated with a greater reduction in fracture incidence. The reference range of BTMs concentration for the adequate response could be helpful when used as target for anti-osteoporotic treatment.
BPs are considered as a first-line treatment for osteoporosis. It is effective in reduction of fracture risk over 3 to 5 years of treatment. However, long-term use of BPs is associated with the rare but serious adverse effects such as osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF). Therefore, the concept of a ‘drug holiday’ from BPs has emerged as being potentially beneficial in avoiding these adverse effects. The effect of BP such as anti-resorption and fracture prevention persist for a long period after cessation of drugs because of long-term deposition of BPs in bones. However, despite BP has long skeletal retention time, fracture risk will increase after discontinuation of it. Therefore, continuous monitoring during drug holiday will be needed for the assessment of fracture risk and to restart treatment if needed. There are limited clinical practice guidelines on BTM monitoring during drug holiday. There are few studies about an assessment of fracture risk using BTMs during drug holiday. A recent retrospective study showed that those in newly developed fracture group during drug holiday was older and had lower BMD than non-fracture group. Other factors associated with fracture such as BTMs, vitamin D level, body mass index, and PTH were not significantly different between 2 groups.[
Prolonged BP therapy has been related with rare adverse events such as ONJ and AFF. ONJ is a rare oral disease in which the jaw bone's healing power is impaired because of use of BP or other antiresorptive agents. Patients may be considered to have ONJ if they had current or previous treatment with antiresorptive or antiangiogenic agents and as if there is exposed bone in the jaw that has persisted for more than 8 weeks but without history of radiation therapy or obvious metastatic disease.[
Because of urinary and some serum BTMs are excreted into urine by kidney, the serum level of those are affected by renal dysfunction. BSALP, intact PINP, and TRACP-5b are not affected by renal impairment.
Its serum concentration seems to be independent of glomerular filtration rate. Combination of a low PTH (<150 pg/mL) and a low BSALP (<27 IU/L) improved the specificity of diagnosing adynamic bone disease in 103 dialysis patients with bone biopsy. In the newer automated Ostase BSALP assay, the cut-off <20 IU/L is used.[
Since osteocalcin is cleared by kidney, its use in CKD patients is limited. The combination of osteocalcin (<41 ng/L) and BSALP (<23 U/L) improved the positive predictive value for diagnosing adynamic bone disease to 77% in a CKD-5 cohort.[
PINP is present in 2 major forms, an intact trimeric form and a monomeric one. Some assays recognize both forms (‘Total PINP’; Roche Elecsys, Mannheim, Germany) while other assays recognize the trimeric form only (‘Intact PINP’, Orion Diagnostica and IDS iSYS). The proportion of the monomeric form is elevated in patients with CKD, whereas the apparent concentration of intact PINP is unaffected by glomerular filtration rate in kidney disease patients.[
CTX-I is renally excreted and accumulates in CKD patients. CTX-I is cleared by dialysis and therefore pre-dialysis sampling is required for longitudinal monitoring.[
TRACP-5b is an enzyme released by osteoclasts to breakdown bone matrix. High serum levels of TRACP-5b therefore reflect increased osteoclastic activity and resorption. Levels of TRACP-5b correlate with PTH and ALP and are unaffected by renal function. However, its use is limited by availability of automated assays.[
The KDIGO guidelines recommended that the bone derived markers of collagen synthesis and breakdown, including CTX-I, should not be routinely measured in patients with CKD stages 3 to 5D.[
The appropriate use of BTMs in treatment of osteoporosis could be helpful to predict fracture risk and monitor treatment response and patient compliance. But, BTMs have not been used widely in clinical practice due to their poor within-subject and between-lab reproducibility. Researchers are constantly trying to automate and standardize the measurement of bone markers to minimize variability of BTMs. In addition, insurance coverage for BTMs have recently been possible in Korea. Thus, BTMs could be used easily as a dynamic index reflecting bone quality, complementary to BMD. More studies about the efficacy of BTMs are needed in the future.
- Consider using BTMs in the initial evaluation and follow-up of patients with osteoporosis. - Elevated levels of BTMs can predict more rapid rates of bone loss and higher fracture risk. - BTMs can reflect the therapeutic responses to anti-osteoporosis therapies earlier than BMD and help in selecting osteoporosis treatment and in assessing response to therapies. - CTX-I and/or PINP can be used to evaluate patient adherence and response to anti-resorptive drugs with measurement at baseline, 3 to 6 months after starting treatment. - PINP can be used to evaluate patient adherence and responses to anabolic agents with measurement at baseline, 1 to 3 months after starting treatment. - For patients taking anti-resorptive agents, target range for successful treatment is to have levels of BTMs in the reference range for premenopausal women. Also, relative change of BTMs from baselines above LSC can be also used. - Monitoring BTMs during drug holiday can be helpful to decide to resume treatment, but the evidence was insufficient yet. - Although there is still controversy, BTMs can be used carefully as a predictor of long-term side effects of BPs such as ONJ and AFF. - The various serum and urine BTMs are affected by renal dysfunction. The measurement of BASLP and PTH is recommended as a BTM in patients with CKD.
GnRH, gonadotropin-releasing hormone.
a)Described in kit manufacturer's package insert or manufacturer's in-house data.
BSALP, bone specific alkaline phosphatase; PINP, propeptide of type I collagen; CTX-I, C-terminal telopeptide of type I collagen; NTX-I, N-terminal telopeptide of collagen type I; DPD, deoxypyridinoline; CLIA, chemiluminescence assay; EIA, enzyme immunoassay; RIA, radioimmunoassay; IRMA, immunoradiometric assay; ECLIA, electrochemiluminescence assay; ELISA, enzyme-linked immunosorbent assay; CLEIA, chemiluminescence enzyme immunoassay.
CKD, chronic kidney disease; PTH, parathyroid hormone; CKD G5D, chronic kidney disease stage 5 receiving dialysis.