Int J Clin Pract. 2009 January; 63(1): 19–26.
Objectives:
To review the clinical value of bone turnover markers (BTM), to initiate and/or monitor anti-resorptive treatment for osteoporosis compared with bone mineral density (BMD) and to evaluate suitable BTM and changes in BTM levels for significance of treatment efficiency.Methodology:
Consensus meeting generating guidelines for clinical practice after review and discussion of the randomised controlled trials or meta-analyses on the management of osteoporosis in postmenopausal women.Results:
Although the correlation between BMD and BTM is statistically significant, BTM cannot be used as predictive markers of BMD in an individual patient. Both are independent predictors of fracture risk, but BTM can only be used as an additional risk factor in the decision to treat. Current data do not support the use of BTM to select the optimal treatment. However, they can be used to monitor treatment efficiency before BMD changes can be evaluated. Early changes in BTM can be used to measure the clinical efficacy of an anti-resorptive treatment and to reinforce patient compliance.Discussion:
Determining a threshold of BTM reflecting an optimal long-term effect is not obvious. The objective should be the return to the premenopausal range and/or a decrease at least equal to the least significant change (30%). Preanalytical and analytical variability of BTM is an important limitation to their use. Serum C-terminal cross-linked telopeptide of type I collagen (CTX), procollagen 1 N terminal extension peptide and bone specific alkaline phosphatase (BSALP) appear to be the most suitable.Conclusion:
Consensus regarding the use of BTM resulted in guidelines for clinical practice. BMD determines the indication to treat osteoporosis. BTM reflect treatment efficiency and can be used to motivate patients to persist with their medication.

Choice of markers
•Serum markers do not need correction for glomerular filtration rate; automated technology for measurement available for serum CTX and serum P1NP.
•Osteocalcin not optimal in routine clinical practice because of its fragility.
•Serum BSAP can be added in patients without liver problems (less sensitive to circadian rhythm).
•Measurements for one individual must be performed in the same lab using standard procedures; samples should be taken while fasting and always at the same time of day.
•There are no data to determine the optimal postintake period to take a blood sample for follow-up of the markers, but at least 7 days after the intake seems to have some support, understanding that it is always the same period in one individual patient.
Use of markers (pretreatment)
•Baseline BTM levels cannot be the base of anti-resorptive drug choice, nor do they predict treatment effect.
•Bone turnover markers are an independent risk factor of fracture.
Use of markers (follow-up)
•This use relies on the definition of LSC (around 30% for serum markers and 50–60% for urine markers).
•Only a decrease higher than the LSC can be interpreted as showing a biological effect.
•Early changes in BTM (baseline vs. posttreatment) show a biological effect of the medication, proving patient compliance and persistence.
•The early decrease in BTM level is probably predictive of bone gain and anti-fracture efficacy. However, it is not known to which level BTM should be decreased to optimise anti-fracture efficacy.
•As we cannot link BTM decrease to a threshold, using premenopausal range seems a rational objective to achieve.
1.The levels of osteoporotic patients whose BTM levels are still in premenopausal range must still decrease by 30%.
2.Premenopausal ranges have been well defined.
3.Analytical differences must be resolved by using the same lab for one individual patient.

Recent Progress in Hormone Research 57:385-409 (2002)

The adult skeleton is periodically remodeled by temporary anatomic structures that comprise juxtaposed osteoclast and osteoblast teams and replace old bone with new. Estrogens and androgens slow the rate of bone remodeling and protect against bone loss. Conversely, loss of estrogen leads to increased rate of remodeling and tilts the balance between bone resorption and formation in favor of the former. Studies from our group during the last 10 years have elucidated that estrogens and androgens decrease the number of remodeling cycles by attenuating the birth rate of osteoclasts and osteoblasts from their respective progenitors. These effects result, in part, from the transcriptional regulation of genes responsible for osteoclastogenesis and mesenchymal cell replication and/or differentiation and are exerted through interactions of the ligand-activated receptors with other transcription factors. However, increased remodeling alone cannot explain why loss of sex steroids tilts the balance of resorption and formation in favor of the former. Estrogens and androgens also exert effects on the lifespan of mature bone cells: pro-apoptotic effects on osteoclasts but anti-apoptotic effects on osteoblasts and osteocytes. These latter effects stem from a heretofore unexpected function of the classical “nuclear” sex steroid receptors outside the nucleus and result from activation of a Src/Shc/extracellular signal-regulated kinase signal transduction pathway probably within preassembled scaffolds called caveolae. Strikingly, estrogen receptor (ER) alpha or beta or the androgen receptor can transmit anti-apoptotic signals with similar efficiency, irrespective of whether the ligand is an estrogen or an androgen. More importantly, these nongenotropic, sex-nonspecific actions are mediated by the ligand-binding domain of the receptor and can be functionally dissociated from transcriptional activity with synthetic ligands. Taken together, these lines of evidence strongly suggest that, in sex steroid deficiency, loss of transcriptional effects may be responsible for the increased osteoclastogenesis and osteoblastogenesis and thereby the increased rate of bone remodeling. Loss of nongenotropic anti-apoptotic effects on mature osteoblasts and osteocytes, in combination with an opposite effect on the lifespan of mature osteoclasts, may be responsible for the imbalance between formation and resorption and the progressive loss of bone mass and strength. Elucidation of the dual function of sex steroid receptors has important pathophysiologic and pharmacologic implications. Specifically, synthetic ligands of the ER that can evoke the nongenotropic but not the genotropic signal may be bone anabolic agents, as opposed to natural estrogens or selective estrogen receptor modulators that are antiresorptive agents. The same ligands may also circumvent the side effects associated with conventional hormone replacement therapy.