Search tips
Search criteria 


Logo of clinbiorevLink to Publisher's site
Clin Biochem Rev. 2006 August; 27(3): 123–138.
PMCID: PMC1579289

Biochemical Markers of Bone Turnover Part II: Clinical Applications in the Management of Osteoporosis


With the ageing population in most countries, disorders of bone and mineral metabolism are becoming increasingly relevant to every day clinical practice. Consequently, the interest in, and the need for effective measures to be used in the screening, diagnosis and follow-up of such pathologies have markedly grown. Together with clinical and imaging techniques, biochemical tests play an important role in the assessment and differential diagnosis of metabolic bone disease. These biochemical indices are non-invasive, comparatively inexpensive and, when applied and interpreted correctly, helpful tools in the diagnostic and therapeutic assessment of metabolic bone disease.

This second part of the two part series reviews the current evidence regarding the clinical use of biochemical markers of bone remodelling in the management of osteoporosis.


Part I of this review, published late last year, provided an overview of the basic biochemistry of bone markers, and sources of non-specific variability.1 This second part of the series will review the current evidence regarding the clinical use of biochemical markers of bone remodelling in bone disease. Most of this article will deal with the use of bone markers in osteoporosis, as this is the major clinical application at the time of writing. Other conditions such as Paget’s or metastatic bone disease, in which bone markers may be used clinically, are only briefly mentioned towards the end of this review; these topics have been reviewed recently by Rodman and Windle2 and by Seibel.3

Menopause and Ageing

Once somatic growth subsides, the serum and urinary concentrations of most bone markers return to a level much below those seen during normal puberty and growth. This stabilisation usually occurs during the 3rd decade and in healthy men, levels of practically all markers remain more or less unchanged until 70 years of age. After that, a slight increase is usually seen in both formation and resorption markers.47 In contrast, menopause is associated with a substantial acceleration in bone turn over, mirrored by a 50–100% increase in both markers of bone formation and resorption.4,5,814 In early postmenopausal women, this increase in bone turnover can be attenuated by oral calcium supplementation.1519 Long-term treatment of women with oestrogen was shown to reduce resorption markers such as deoxypyridinoline (DPD) and N-telopeptide (NTX) to premenopausal levels.9,12,14,16,2024 A prospective study covering the perimenopausal transition in healthy women suggests that changes in bone turnover occur during the late premenopause with a decrease in bone formation, which only later is followed by a rise in bone resorption.25 It is now widely accepted that the accelerated rate of bone loss seen after the menopause is mainly due to an imbalance in bone turnover and an increase in bone resorption.26,27 Studies employing specific bone markers indicate that bone turnover continues to be increased (and to be associated with bone loss) during late menopause.2833 In some postmenopausal women,34 but particularly in the very elderly,3537 this increase in bone turnover is often, but not always found to due to vitamin D and/ or calcium deficiency and secondary hyperparathyroidism.


Bone Turnover in Osteoporosis

Osteoporosis is a heterogeneous disease. It is therefore not surprising that in untreated patients with this disorder, rates of bone turnover tend to vary over a wide range. Although most cross-sectional studies show accelerated bone turnover in a certain proportion of postmenopausal osteoporotic women, there is usually broad overlap between diseased and healthy populations.1113,3841 In this context, it is important to bear in mind that research studies usually include highly selective patient populations, which may not always represent the population seen in the typical clinical setting. Using a population-based data set, and there fore avoiding this selection bias, we have previously shown that none of the major biochemical markers of bone turnover provide sufficient diagnostic information to be useful in the screening for vertebral osteopenia or osteoporosis.13 However, another population-based study showed that urinary levels of NTX could discriminate between older individuals with normal hip bone density, osteopenia and osteoporosis.42 Again, this association did not hold true for men at the level of the spine.

In retrospective population-based studies, Akesson and co-workers have demonstrated that previous fractures were associated with abnormal bone turnover.28,29,43,44 After adjustment for age and bone mineral density (BMD), women with fractures occurring within six years prior to the study were characterised by lower serum levels of osteocalcin and carboxyterminal procollagen type I propeptide (PICP), but normal rates of bone resorption. In another investigation, the same authors found decreased serum levels of osteocalcin, and elevated urinary concentrations of collagen crosslinks in elderly women at the time of admission for a newly sustained hip fracture.2

Taken together, these data suggest that a long-term imbalance of bone metabolism may lead to increased fragility. Together with the fact that high bone turnover may be sustained for long periods and bone loss may increase with age,44 these findings may provide a rationale for designing more effective intervention strategies. However, other factors such as age (see above), medication,6,18,4651 immobilisation,32,35 thyroid function,52 co-morbidity35 and the fracture itself40,53,54 itself do influence bone metabolism and therefore need to be considered in the inter pretation of biochemical data and their use in individual patients. Clearly, none of the biochemical markers of bone turnover has proven useful as a single diagnostic index of osteoporosis.

Bone Turnover and Bone Loss

Bone mass, rates of bone loss, and the risk of osteoporotic fractures are interrelated, and both low bone mass and rapid bone loss have been shown to be in de pendent predictors of future fracture risk.5 The rate of bone loss is determined by a number of factors, one of which appears to be the rate of bone remodelling. Earlier observations demonstrated that bone formation and bone resorption increase shortly after natural menopause, a phase that in most women is also associated with significantly accelerated bone loss.4,5,814 Similar observations have been made in ovariectomised, pre menopausal women and in castrated men,56,57 indicating that the withdrawal of endogenous sex steroid induces both high bone turnover and rapid bone loss. Conversely, markers of bone metabolism return to premenopausal levels during hormone replacement therapy (HRT).9,12,13,16,2024 Other biochemical studies suggest that high rates of bone turnover may be sustained well into advanced ages.10,13,31,58,59 However, it is unclear whether this applies to all women.

Most longitudinal studies support the notion that individuals with high rates of bone turnover lose bone at a faster rate than subjects with normal or low bone turnover.16,20,30,6065 Following a small group of early postmenopausal women, Christiansen and colleagues demonstrated that the combined measurement of serum total alkaline phosphatase, osteocalcin, fasting urinary calcium, hydroxyproline or DPD can predict 60–70% of the variability in bone loss.60,61 These studies also showed that the correlation between baseline markers of bone turnover and the subsequent rate of postmenopausal bone loss is possibly consistent over a period of at least twelve years.55,61 Less optimistic estimates were reported by other groups using different combinations of markers.30,62 For example, a study in elderly women demonstrated that urinary NTX, serum osteocalcin and serum parathyroid hormone together explained only 43% of the variability of bone loss at the hip.30 Markers of bone resorption seemed to be stronger predictors of future bone loss than markers of bone formation, and correlations were stronger in elderly than in younger women.6265 In a retrospective study of 354 women (mean observation period: 13 years), Ross and Knowlton showed a continuous relationship between the measured levels of various bone turnover markers and the risk of rapid bone loss at the calcaneus: the odds of rapid bone loss (>2.2%/year) doubled for each standard deviation (SD) increase in serum bone specific alkaline phosphatase (BSAP), serum osteocalcin, urinary free pyridinoline (PYD) or DPD.65 In a study of 227 early postmenopausal women treated with calcium alone or HRT plus calcium, Chesnut et al. and Rosen et al. reported that women with high baseline rates of bone resorption were at higher risk of losing bone than women with normal turnover rates.16,20 (Figure 1). Different results were reported by Keen et al., who in a four-year prospective study were unable to detect any correlation between rates of bone turn over and changes in lumbar or hip BMD.66 Other groups argue that due to the high degree of variability in urinary markers of bone turnover, predicting either bone density or changes therein for an individual patient from a single marker measurement may not be possible.62,67 Vestergaard and colleagues showed that serum osteocalcin, BSAP and hydroxyproline are poor predictors of lumbar and hip bone loss in individual perimenopausal women.68

Figure 1
Association between rates of bone resorption and bone loss in untreated early postmenopausal women. High baseline rates of bone resorption (urinary NTX stratified by quartiles, x-axis) are associated with a higher risk of bone loss (% change in lumbar ...

Taken together, there is evidence that rates of bone remodelling are associated with bone loss. However, the strength of this association seems to depend on a number of factors, such as menopausal age, skeletal site and gender. Bone remodelling markers are no substitute for individual bone mass measurements, or for a careful assessment of the patient’s personal and family history.

Bone Turnover and Fracture Risk

Bone turnover is an independent predictor of fracture risk. Earlier post-hoc analysis of data from clinical trials suggested that in untreated osteoporotic women, vertebral fracture rates increase as a direct function of either increased bone turn over or of decreased vertebral BMD.69 Thus, at a given level of vertebral BMD, the rate of vertebral fractures increases with the rate of bone turnover. When bone turnover is normal, however, the main determinant of vertebral fractures is vertebral BMD.69

Using the large population-based sample of the Rotterdam study (7983 individuals, 60% women aged 55 years and over), van Daele et al. showed that women with increased urinary DPD levels had an increased risk of hip fracture.70 The relative risk per SD increase in urinary DPD was 3.0 (95% confidence interval (CI) 1.3–8.6). Interestingly, part of this association appeared to be related to disability at baseline. However, when the data were corrected for disability, a relative risk of 1.9 (95% CI 0.6–5.6) remained. This number is very similar to the increase in fracture risk calculated for 1 SD decrease in BMD at the lumbar spine. Later analyses of the same study revealed that low serum osteocalcin concentrations were also associated with an increased risk of hip fracture (odds ratio (OR) : 3.1; 95% CI 1.0–9.2).

In a five-year follow-up of the same population, Weel et al. later showed that an increase in baseline urinary DPD above the premenopausal mean value was associated with an increased future risk of osteoporotic fractures.71 All types of non-vertebral fractures, but especially fractures of the hip (OR 5–6) and the upper humerus (OR 3–5) were associated with urinary levels of DPD above the premenopausal mean, independent of bone mineral density and disability. Fracture risk increased dramatically when elevated rates of bone resorption were combined with low BMD.

Similar results have been published for the French EPIDOS study.72 The relative fracture risks as defined by either BMD or marker measurements were similar (RR ~2) to those reported earlier by van Daele. Again, combined measurements of hip bone density and of bone resorption markers increased the predictive power for hip fractures (RR 5–6). Thus, in elderly women, the relative risk of hip fracture seems to be highest in individuals with both low hip BMD and high rates of bone resorption.

A nested case control study from the same group later suggested that levels of serum under-carboxylated osteocalcin (ucOC), but not of total osteocalcin, were predictive of future hip fractures (OR 2.0; 95% CI: 1.2–3.2).73 These data confirm and extend previous reports, which suggest that increased serum levels of ucOC are predictive of hip fractures in elderly, institutionalised women.7476 These earlier results, however, may merely indicate an association between poor nutritional status and hip fracture risk among institutionalised subjects, and not a general bio logical mechanism possibly relevant to a more representative sampling of the population. The significance of vitamin K deficiency to the under-carboxylation of osteocalcin had been demonstrated earlier by Price et al.,77 and subsequent clinical studies showed that overt vitamin K deficiency may lead to a disproportionate increase in ucOC in the circulation.78,79 In addition, vitamin K2 levels have been shown to be lower in women with osteoporotic fractures than in healthy individuals.78 Although measurement of ucOC may be useful in providing an integrated assessment of the factors that are responsible for the gamma-carboxylation of osteocalcin, such as vitamins K and D, the underlying biochemical mechanisms by which ucOC could be associated with impaired bone metabolism are, as yet, unknown.

In another prospective study from Sweden, low serum levels of both the carboxy terminal propeptide and telopeptide of type I collagen were associated with an increased risk of hip fracture, independent of age and BMD.43 Thus, increased rates of bone resorption or decreased rates of bone formation seem to be associated with future osteoporotic fractures.

Recently, Meier and colleagues demonstrated in a case-cohort control study of 151 elderly men followed prospectively over 6.3 years that accelerated bone resorption was associated with increased risk of osteoporotic fracture, independent of BMD. Combining measurements of BMD and bone turnover improved fracture prediction in elderly men.80 (Figure 2).

Figure 2
Fracture risk and bone turnover in men. Incidence of any osteoporotic fracture according to serum carboxyterminal crosslinked telopeptide of type I collagen (S-ICTP) levels and femoral neck BMD. Case-cohort control study of 151 older men from the Dubbo ...

Prospective data from the Australian FREE study of 1112 frail elderly men and women indicate that high bone turnover is also an independent predictor of all cause mortality. This association appeared to be mainly manifested in deaths from cardiovascular causes.33 (Figure 3).

Figure 3
High bone turnover is associated with all cause mortality in the frail elderly. In a prospective analysis of 1112 frail persons (79% female, mean age 86 years) recruited into the Australian FREE Study, high bone turnover was an independent predictor of ...

In summary, data from several independent and large prospective studies indicate that in both postmenopausal women and healthy men, increased rates of bone resorption are associated with an increased risk of vertebral and non-vertebral fractures, independent of BMD, age and disability. In the future, markers of bone turnover, in combination with other risk factors for osteoporotic fracture, may be used to define fracture risk and intervention thresholds.

Pretreatment Bone Turnover and Therapeutic Effect

From both a theoretical and clinical point of view, it is conceivable that intervention strategies may differ between patients with accelerated, normal or even abnormally low bone turnover at the time of diagnosis; hence, a patient presenting with high rates of bone resorption may benefit from antiresorptive therapy, whereas in an individual with low bone turnover, a stimulator of bone formation may yield better long-term results. So, are pretreatment bone marker measurements helpful in guiding the selection of therapy for individual patients? Some studies have shown that in osteoporotic patients treated with sub cutaneous calcitonin, increases in lumbar (but not necessarily in hip) BMD were significantly greater in individuals with high than with normal or low base line rates of bone turnover.8183 Similar results were later reported for short term Alendronate treatment,84 although one report (with an equally small number of subjects) suggests that changes in BMD during treatment with Alendronate are independent of pre-therapeutic bone turnover rates.31

Chesnut et al. and Rosen et al. demonstrated in 227 women treated with either calcium alone or a combination of HRT plus calcium, that individuals within the highest quartile for baseline measures of bone turnover also experienced the greatest gain in BMD after six and twelve months of treatment with HRT and calcium.16,20 In this study, baseline urinary NTX and serum osteocalcin showed the highest predictive values for a change in spinal BMD after one year of either HRT or calcium. In reverse, those women showing a gain in BMD after one year of HRT had significantly higher base line rates of bone resorption (as determined by urinary NTX) than non-responders or subjects losing bone during HRT16 (Figure 1). This observation is in agreement with the hypothesis that changes in bone turnover affects the risk of vertebral fractures only if bone turnover is significantly accelerated, while more subtle changes appear to be without major effect.69 In contrast, Stevenson et al. in a three-year prospective study on the effect of HRT on spine and hip BMD were unable to distinguish between responders and non-responders by means of either base line or follow-up measures of bone turnover.85 Both groups showed the same pretreatment values of bone formation and resorption, and the change in bone markers in response to HRT was identical in the affected and unaffected groups.85

Post-hoc analyses of the Risedronate clinical phase III programs show that the reduction in fracture risk during one and three years of Risedronate treatment is similar in patients with baseline urinary DPD below or above the premenopausal median (ie with normal or accelerated bone resorption).86 (Figure 4). However, the number of patients needing treatment to avoid one fracture during one and three years of treatment with Risedronate is significantly lower in patients with elevated baseline bone turnover as compared to patients with low baseline bone turnover. Thus, although the reduction in overall fracture risk seems to occur independent of baseline bone turnover, patient stratification by pretreatment bone resorption rates seems to make some sense from a pharmacoeconomic point of view.86

Figure 4
Pretreatment bone turnover and change of nonvertebral fracture risk in response to risedronate treatment. Post-hoc analysis of a subset of the risedronate phase III clinical programs using urinary DPD as an index of pretreatment bone resorption (PBR). ...

A similar post-hoc analysis of the Fracture Intervention Trial (FIT), examining the influence of pretreatment bone turnover on the anti-fracture efficacy of daily alendronate in postmenopausal women found that the non-spine fracture efficacy of alendronate was significantly greater among both osteoporotic and non-osteoporotic women with higher baseline levels of the bone formation marker aminoterminal propeptide of type I collagen (PINP). However, no such association was observed for vertebral fractures, and changes in both BSAP and the carboxyterminal crosslinked teleopeptide (CTX-I) were not associated with fracture outcomes at any site.87 (Figure 5).

Figure 5
Pretreatment bone turnover and reduction in nonvertebral fracture risk in response to alendronate treatment (Fracture Inter vention Trial). Osteoporotic women treated with alendronate are represented by dotted lines and the placebo group by solid lines. ...

Taken together, it remains unclear whether there is a clinically relevant relationship between bone turnover at baseline and the response to antiresorptive treatment. Drugs even of the same class may differ in this respect.

Bone Turnover Markers and Therapeutic Monitoring

Bisphosphonates, raloxifene, denosumab, strontium ranelate, oestrogens, calcium, calcitonin and teriparatide all improve BMD to varying degrees. In contrast, the effects of these anti-osteoporotic drugs on bone turnover differ greatly: bisphosphonates (Figure 6), oestrogens, denosumab (Figure 7), calcitonin and raloxifene tend to reduce bone resorption and bone formation in a dose dependent manner.8896 Strontium ranelate, in contrast, has only subtle effects on bone turnover, showing a slight reduction in bone resorption markers and a mild increase in bone formation markers.97 (Figure 8). Finally, teriparatide strongly increases both bone formation and, after a certain gap period, bone resorption markers.98102 (Figure 9).

Figure 6
Change in markers of bone turnover following treatment with intravenous zoledronate. Patients were injected with varying doses of zoledronate as shown in the legend. Of note, a single dose of 4 mg zoledronate resulted in a suppression of bone turnover ...
Figure 7a
Change in markers of bone turnover following a 3-monthly dosing of sc. Denosumab. Patients received 3- monthly sc. injection of varying doses of denosumab (AMG 162), as shown in the legend. Percentage change from baseline in serum levels of CTX-I (upper ...
Figure 8
Change in markers of bone turnover during treatment with oral strontium ranelate. The graph shows the differences in biochemical markers between the strontium treated and placebo groups over time. For each marker (upper panel: BSAP; lower panel: CTX-I), ...
Figure 9
Change in markers of bone turnover during therapy with daily s.c. teriparatide and/ or alendronate. Patients received teriparatide, alendronate or a combination of both agents. Teriparatide results in an increase of both bone formation and resorption ...

Most bisphosphonates, raloxifene, strontium ranelate, oestrogens and teriparatide have also been shown to reduce the risk of osteoporotic fractures. However, the observed reduction in fracture risk is only partly explained by the documented changes in BMD, with the reduction in fracture risk being much greater than predicted from improvements in BMD only.103106 Hence, it has been estimated that changes in BMD explain only 4% to 28% of the reduction in vertebral fracture risk attributed to antiresorptive treatments.107109 It is therefore likely that changes in other determinants of bone strength, including the rate of bone turnover and its changes during antiresorptive therapy, may be better predictors of anti-fracture efficacy. In fact, several studies confirmed that short-term reductions in bone turnover were associated with a reduction in vertebral and/or non-vertebral fracture risk in women treated with HRT,69 raloxifene 94,95,111 risedronate,112 alendronate92 and ibandronate.110

The relationship between six and 12 months changes in bone turnover markers and vertebral fracture risk after three years of raloxifene treatment in postmenopausal women clearly favours bone turnover markers as the better predictor of outcome.111 A decrease of 9.3 pg/mL in serum osteocalcin after one year of raloxifene treatment was associated with an OR for new vertebral fractures after 3 years of 0.69 (CI 0.54–0.88, p=0.003). Similarly, for a decrease of 5.91 μg/L in BSAP the OR was 0.75 (CI 0.62–0.92, p=0.005). Importantly, these relationships remained after adjustment for baseline vertebral fracture status and BMD. Two subsequent analyses including postmenopausal women with osteoporosis from

the same cohort (MORE trial) extended and confirmed these results showing that both, one year percentage changes in serum PINP and osteocalcin are able to predict the reduction in vertebral fracture risk after three years of treatment.94,95

Two studies have investigated the change in bone turnover markers and fracture risk in bisphosphonate treated postmenopausal women.92,112 Post-hoc analyses of data from the VERT studies including postmenopausal women with at least one vertebral fracture demonstrated that reductions in urinary CTX-I (by 60%) and NTX-I (by 51%) at three to six months of risedronate treatment were significantly associated with the reduction in vertebral and non-vertebral fracture risk after three years.112 The change in bone resorption markers explained 50–60% of the risedronate-related fracture risk reduction for both vertebral and non-vertebral fractures. Bauer et al. reported that in alendronate-treated women, greater reductions in bone turnover were associated with fewer osteoporotic fractures.92 In their study, each SD reduction in the change in BSAP at one year was associated with fewer spine (OR 0.74; CI: 0.63, 0.87), non-spine (relative hazard (RH) 0.89; CI: 0.78, 1.00) and hip fractures (RH 0.61; CI: 0.46, 0.78). Furthermore, alendronate-treated women with at least a 30% reduction in BSAP had a lower risk of non-spine (RH 0.72; CI: 0.55, 0.92) and hip fractures (RH 0.26; CI: 0.08, 0.83) relative to those with reductions <30%. Again, this effect was at least as strong as the anti-fracture effect observed with one year change in BMD.2

In summary, changes in bone turnover during raloxifene and bisphosphonate therapy seem to be related to subsequent fracture risk with a far greater effect on fracture reduction than has been attributed to treatment-induced changes in BMD. These data suggest that biochemical markers of bone turnover are useful tools to evaluate therapeutic effects after a relatively short period of time, and that serial measurements of bone markers may help to decide whether or not a patient responds to a specific antiresorptive treatment. Whether changes in bone turnover during treatment with agents such as strontium ranelate, denosumab or teriparatide predict fracture outcomes is presently not clear.

Monitoring Patient Compliance Using Bone Markers

Long-term compliance with treatment for osteoporosis is usually poor.113 Several studies reported that up to 50% of postmenopausal women were not adherent to their treatment after one to five years of HRT.114118 A major cause of non-compliance were unwanted side-effects or fear of side-effects, inconvenience caused by medication, and high drug costs.119.120 Hence, monitoring patients on antiresorptive medication is an eminent part of patient management in order to improve adherence and persistence to therapy, and ultimately treatment effectiveness.

Biochemical markers of bone turnover have been advocated to facilitate follow-up of patients receiving antiresorptive treatments for osteoporosis. As bone turnover markers, in particular indices of bone resorption, decrease rapidly after initiation of treatment within three to six months, they might represent useful surrogate markers for monitoring patient compliance. Only few data, however, are available to support this theoretical approach. Using a decision analysis model, Chapurlat et al.121 compared two strategies of follow-up: a) treatment of a woman without specific monitoring, and b) treatment of this woman with measurement of a serum marker of bone resorption after three months of treatment, with change of treatment if response to treatment as assessed by this marker was not satisfactory. This study suggests that monitoring osteoporotic women with measurements of bone markers early during the treatment course may increase effectiveness of treatment with greater quality adjusted life years than no follow-up. In another study of 75 postmenopausal women treated with raloxifene, Clowes et al. examined whether monitoring (nurse-monitoring or marker-monitoring) enhances adherence and persistence with antiresorptive therapy, and whether presenting information on the biochemical response to therapy provided additional benefit.122 Survival analyses showed that in the group being monitored, cumulative adherence to therapy increased by 57% compared with no monitoring; also, there was a trend for the monitored group to persist with therapy for longer periods of time. However, presentation of results of effects on NTX-I levels did not improve compliance to therapy compared with nurse-monitoring alone. Nevertheless, results from the IMPACT study in postmenopausal women on risedronate have shown that a reinforcement message based on bone marker response influences persistence with long-term treatment.123 In patients in whom a verbal feedback on the change of urinary NTX-I was provided, one-year persistence was higher than in non-reinforced subjects. Interestingly, the message given to patients with a bone turnover marker response considered “good” was associated with significant improvement in persistence, whereas the information given to those with a poor resorption marker response led to a lower persistence.123 Another large study investigating patient compliance using measurements of urinary CTX-I is under way and should give further evidence whether monitoring osteoporosis treatment using bone turnover markers should be encouraged in clinical practice.124

Other Conditions

An abundance of experimental and clinical studies have demonstrated that markers of bone formation and resorption are useful tools in the assessment of the skeletal response to a great variety of influences. For example, markers of bone turnover may reflect changes in bone metabolism induced by oophorectomy,57,125 hyperparathyroidism,126,127 Paget’s disease,128 physical exercise,129 immobilisation,32,130 alcoholism, 131 smoking,132 vitamin D deficiency, 33,35,37,133 chronic inflammatory bowel disease,134,135 chronic starvation,136 thyroid disorders,52,137 as well as the pharmacological effects of glucocorticosteroids,48,139,140 androgens,6,7,141 gonadotropin-releasing hormone agonists,142 warfarin,143 growth hormone or insulin-like growth factors.144 Bone turnover markers may in useful in the diagnosis and management of certain of the above conditions, but in most cases have not been rigorously examined.

The situation is somewhat different in cancer: as bone metastases profoundly perturb normal bone remodelling,145 biochemical markers of bone turnover have been shown to reflect these tumour-induced changes in bone remodelling and may therefore be useful in the diagnosis, follow-up and prognosis of patients with malignant (bone) disease.146,147 (Figure 10). Most markers of bone turn over, particularly those of bone resorption, are elevated in patients with established bone metastases (recently reviewed3). While this may indicate a role of bone markers as diagnostic tools in cancer patients, available evidence does not provide any final conclusions as to the accuracy and validity of the presently used markers in the early diagnosis of bone metastases.

Figure 10
Probability of survival according to serum Bone Sialoprotein (BSP) values in patients with multiple myeloma. Patients were stratified by serum BSP concentrations at baseline (solid line: serum BSP <21 ng/mL, dashed line: serum BSP >21 ...

Markers of bone resorption respond promptly and profoundly to bisphosphonate and anti-neoplastic therapy, and this response appears to be associated with a favourable clinical outcome in patients with bone metastases.148149 Recent evidence indicates that the aim of bisphosphonate therapy should be to normalise increased rates of bone remodelling.150,151 However, it remains unknown whether the use of bone markers in the routine clinical setting has any defined beneficial effects on overall outcome in cancer patients. In particular, no study has addressed the question whether patients with bone metastases should be treated according to their rate of bone turnover, and what the treatment goals are in this respect. While it is unlikely that bone turnover markers have sufficient diagnostic or prognostic value to be used in isolation, the combination of these markers with other diagnostic techniques may be the way forward to improve the clinical assessment of patients with bone seeking cancers.

Although the above mentioned studies represent only a small selection of the available literature, they all demonstrate that markers of bone turnover are extremely helpful tools in evaluating the physiology and pathophysiology of bone metabolism, and in elucidating the pathogenesis of bone disease.


Competing Interests: None declared.


1. Seibel MJ. Biochemical Markers of Bone Turnover. Part I: Biochemistry and Variability. Clin Biochem Rev. 2005;26:97–122. [PMC free article] [PubMed]
2. Roodman GD, Windle JJ. Paget disease of bone. J Clin Invest. 2005;115:200–8. [PMC free article] [PubMed]
3. Seibel MJ. Clinical use of markers of bone turnover in metastatic bone disease. Nat Clin Pract Oncol. 2005;2:504–17. [PubMed]
4. Beardsworth LJ, Eyre DR, Dickson IR. Changes with age in the urinary excretion of lysyl- and hydroxylysyl-pyridinoline, two new markers of bone collagen turnover. J Bone Miner Res. 1990;5:671–6. [PubMed]
5. Midtby M, Magnus J, Joakimsen R. The Tromso Study: a population-based study on the variation in bone formation markers with age, gender, anthropometry and season in both men and women. Osteoporos Int. 2001;12:835–43. [PubMed]
6. Meier C, Liu PY, Handelsman DJ, Seibel MJ. Endocrine regulation of bone turnover in men. Clin Endocrinol (Oxf) 2005;63:603–16. [PubMed]
7. Meier C, Liu PY, Seibel MJ, Handelsman DJ. Sex steroids and skeletal health in men. In Lane NE, Sambrook PN, Editors. Osteoporosis and Osteoporosis of Rheumatic Diseases. San Diego:Elsevier;2006
8. Epstein S, McClintock R, Bryce G, Poser J, Johnston C, Hui S. Differences in serum bone gla protein with age and sex. Lancet. 1984;11:307–10. [PubMed]
9. Hassager C, Risteli J, Risteli L, Christiansen C. Effect of the menopause and hormone replacement therapy on the carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen. Osteoporosis Int. 1994;4:349–52.
10. Khosla S, Atkinson E, Melton LJ, Riggs BL. Effects of age and estrogen status on serum parathyroid hormone levels and biochemical markers of bone turnover in women: a population based study. J Clin Endocrinol Metab. 1997;82:1522–7. [PubMed]
11. Kushida K, Takahashi M, Kawana K, Inoue T. Comparison of markers for bone formation and resorption in premenopausal and postmenopausal subjects, and osteoporosis patients. J Clin Endocrinol Metab. 1995;80:2447–50. [PubMed]
12. Seibel MJ, Cosman F, Shen V, et al. Urinary hydroxypyridinium crosslinks of collagen as markers of bone resorption and estrogen efficacy in postmenopausal osteoporosis. J Bone Miner Res. 1993;8:881–9. [PubMed]
13. Seibel M, Woitge H, Scheidt-Nave C, et al. Urinary hydroxypyridinium crosslinks of collagen in population-based screening for overt vertebral osteoporosis: results of a pilot study. J Bone Miner Res. 1994;9:1433–40. [PubMed]
14. Uebelhart D, Schlemmer A, Johansen JS, et al. Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium crosslinks. J Clin Endocrinol Metab. 1991;72:367–73. [PubMed]
15. Cleghorn DB, O’Loughlin PD, Schroeder BJ, Nordin BE. An open, crossover trial of calcium-fortified milk in prevention of early postmenopausal bone loss. Med J Aust. 2001;175:242–5. [PubMed]
16. Rosen C, Chesnut CH, 3rd, Mallinak NJ. 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;82:1904–10. [PubMed]
17. Rosen HN, Parker RA, Greenspan SL, et al. Evaluation of ability of biochemical markers of bone turnover to predict a response to increased doses of HRT. Calcif Tissue Int. 2004;74:415–23. [PubMed]
18. Meier C, Woitge HW, Witte K, Lemmer B, Seibel MJ. Supplementation with oral vitamin D3 and calcium during winter prevents seasonal bone loss: a randomized controlled open-label prospective trial. J Bone Miner Res. 2004;19:1221–30. [PubMed]
19. Meunier PJ, Jenvrin C, Munoz F, de la Gueronniere V, Garnero P, Menz M. Consumption of a high calcium mineral water lowers biochemical indices of bone remodeling in postmenopausal women with low calcium intake. Osteoporos Int. 2005;16:1203–9. [PubMed]
20. Chesnut CH, 3rd, Bell N, Clark G, et al. Hormone replacement therapy in post menopausal women: Urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. Am J Med. 1997;102:29–37. [PubMed]
21. Harris ST, Eriksen EF, Davidson M, et al. Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 2001;86:1890–7. [PubMed]
22. Heikkinen AM, Parviainen M, Niskanen L, et al. Biochemical bone markers and bone mineral density during postmenopausal hormone replacement therapy with and without vitamin D3: A prospective, controlled, randomized study. J Clin Endocrinol Metab. 1997;82:2476–82. [PubMed]
23. Prestwood KM, Pilbeam CC, Burleson JA, et al. The short-term effects of conjugated estrogen on bone turnover in older women. J Clin Endocrinol Metab. 1994;79:366–71. [PubMed]
24. Greenspan SL, Resnick NM, Parker RA. Early changes in biochemical markers of bone turnover are associated with long-term changes in bone mineral density in elderly women on alendronate, hormone replacement therapy, or combination therapy: a three-year, double-blind, placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab. 2005;90:2762–7. [PubMed]
25. Seifert-Klauss V, Mueller JE, Luppa P, et al. Bone metabolism during the perimenopausal transition: a prospective study. Maturitas. 2002;41:23–33. [PubMed]
26. McKane W, Khosla S, Risteli J, Robins S, Muhs J, Riggs B. Role of estrogen deficiency in pathogenesis of secondary hyperparathyroidism and increased bone resorption in elderly women. Proc Assoc Am Physicians. 1997;109:174–80. [PubMed]
27. Wasnich RD, Bagger Y, Hosking D, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11:622–30. [PubMed]
28. Akesson K, Ljunghall S, Gardsell P, Sernbo I, Obrant KJ. Serum osteocalcin and fracture susceptibility in elderly women. Calcif Tissue Int. 1993;53:86–90. [PubMed]
29. Akesson K, Vergnaud P, Gineyts E, Delmas PD, Obrant KJ. Impairment of bone turnover in elderly women with hip fracture. Calcif Tissue Int. 1993;53:162–9. [PubMed]
30. Dresner-Pollak R, Seibel MJ, Greenspan S, et al. Biochemical markers of bone turn over reflect femoral bone loss in elderly women. Calcif Tissue Int. 1993;59:328–33. [PubMed]
31. Garnero P, Sornay-Rendu E, Chapuy M-C, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Min Res. 1996;11:337–49.
32. Chen JS, Cameron ID, Cumming R, et al. Effect of age-related chronic immobility on markers of bone turnover. J Bone Miner Res. 2006;21:324–31. [PubMed]
33. Sambrook PN, Chen JS, March L, et al. High bone turnover is an independent predictor of mortality in the frail elderly. J Bone Miner Res. 2006;21:549–55. [PubMed]
34. Mezquita-Raya P, Munoz-Torres M, Luna JD, et al. Relation between vitamin D insufficiency, bone density, and bone metabolism in healthy postmenopausal women. J Bone Miner Res. 2001;16:1408–15. [PubMed]
35. Sambrook PN, Chen JS, March LM, et al. Serum parathyroid hormone predicts time to fall independent of vitamin D status in a frail elderly population. J Clin Endocrinol Metab. 2004;89:1572–6. [PubMed]
36. Sambrook PN, Chen JS, March LM, et al. Serum parathyroid hormone is associated with increased mortality independent of 25-hydroxy vitamin D status, bone mass, and renal function in the frail and very old: a cohort study. J Clin Endocrinol Metab. 2004;89:5477–81. [PubMed]
37. Zochling J, Chen JS, Seibel M, et al. Calcium metabolism in the frail elderly. Clin Rheumatol. 2005;24:576–82. [PubMed]
38. Charles P, Hasling C, Risteli L, Risteli J, Mosekilde L, Eriksen E. Assessment of bone formation by biochemical markers in metabolic bone disease: separation between osteoblastic activity at the cell and tissue level. Calcif Tissue Int. 1992;51:406–11. [PubMed]
39. Garnero P, Shih WJ, Gineyts E, Karpf DB, Delmas PD. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab. 1994;79:1693–700. [PubMed]
40. McLaren AM, Hordon LD, Bird HA, Robins SP. Urinary excretion of pyridinium crosslinks of collagen in patients with osteoporosis and the effects of bone fracture. Ann Rheum Dis. 1992;51:648–51. [PMC free article] [PubMed]
41. Meier C, Meinhardt U, Greenfield JR, Nguyen TV, Dunstan CR, Seibel MJ. Serum Cathepsin K Levels Reflect Osteoclastic Activity in Women with Postmenopausal Osteoporosis and Patients with Paget’s Disease. Clin Lab. 2006;52:1–10. [PubMed]
42. Schneider DL, Barrett-Connor EL. Urinary N-telopeptide levels discriminate normal, osteopenic, and osteoporotic bone mineral density. Arch Intern Med. 1997;157:1241–5. [PubMed]
43. Akesson K, Ljunghall S, Jonsson B, et al. Assessment of biochemical markers of bone metabolism in relation to the occurrence of fracture: A retrospective and prospective population-based study in women. J Bone Miner Res. 1995;10:1823–9. [PubMed]
44. Akesson K, Vergnaud P, Delmas PD, Obrant KJ. Serum osteocalcin increases during fracture healing in elderly women with hip fracture. Bone. 1995;6:427–30. [PubMed]
45. Ensrud KE, Palermo L, Black DM, et al. Hip and calcaneal bone loss increase with advancing age: Longitudinal results from the study of osteoporotic fractures. J Bone Miner Res. 1995;10:1778–87. [PubMed]
46. Meier C, Liu PY, Ly LP, et al. Recombinant human chorionic gonadotropin, but not dihydrotestosterone alone stimulates osteoblastic collagen synthesis in older men with partial age related androgen deficiency. J Clin Endocrinol Metab. 2004;89:3033–41. [PubMed]
47. Reid IR, Lucas J, Wattie D, et al. Effects of a beta-blocker on bone turnover in normal postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab. 2005;90:5212–6. [PubMed]
48. Ton FN, Gunawardene SC, Lee H, Neer RM. Effects of low-dose prednisone on bone metabolism. J Bone Miner Res. 2005;20:464–70. [PubMed]
49. Jamal SA, Cummings SR, Hawker GA. Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial. J Bone Miner Res. 2004;19:1512–7. [PubMed]
50. Rejnmark L, Buus NH, Vestergaard P, et al. Effects of simvastatin on bone turnover and BMD: a 1-year randomized controlled trial in postmenopausal osteopenic women. J Bone Miner Res. 2004;19:737–44. [PubMed]
51. Parkinson C, Kassem M, Heickendorff L, Flyvbjerg A, Trainer PJ. Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal. J Clin Endocrinol Metab. 2003;88:5650–5. [PubMed]
52. Meier C, Beat M, Guglielmetti M, Christ-Crain M, Staub JJ, Kraenzlin M. Restoration of euthyroidism accelerates bone turnover in patients with subclinical hypo thyroidism: a randomized controlled trial. Osteoporos Int. 2004;15:209–16. [PubMed]
53. Mallmin H, Ljunghall S, Larsson K. Biochemical markers of bone metabolism in patients with fracture of the distal forearm. Clin Orthop Relat Res. 1993;295:259–63. [PubMed]
54. Obrant KJ, Merle B, Bejui J, Delmas PD. Serum bone-gla protein after fracture. Clin Orthop Relat Res. 1990;258:300–3. [PubMed]
55. Hansen M. Assessment of age and risk factors on bone density and bone turnover in healthy premenopausal women. Osteoporosis Int. 1994;4:123–8.
56. Stepan JJ, Pospichal J, Presl J, Pacovsky V. Bone loss and biochemical indices of bone remodeling in surgically induced postmenopausal women. Bone. 1987;8:279–84. [PubMed]
57. Stepan JJ, Presl J, Broulik P, Pacovsky V. Serum osteocalcin levels and bone alkaline phosphatase isoenzyme after oophorectomy and in primary hyperparathyroidism. J Clin Endocrinol Metab. 1987;64:1079–82. [PubMed]
58. Ledger GA, Burritt MF, Kao PC, O’Fallon WM, Riggs BL, Khosla S. Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption. J Clin Endocrinol Metab. 1995;80:3304–10. [PubMed]
59. Melton L, Khosla S, Atkinson EJ, O’Fallon WM, Riggs BL. Relationship of bone fractures to bone density and fractures. J Bone Miner Res. 1997;12:1083–91. [PubMed]
60. Christiansen C, Riis BJ, Rodbro P. Prediction of rapid bone loss in postmenopausal women. Lancet. 1987;1:1105–8. [PubMed]
61. Christiansen C, Riis BJ, Rodbro P. Screening procedure for women at risk of developing postmenopausal osteoporosis. Osteoporosis Int. 1990;1:35–40.
62. Cosman F, Nieves J, Wilkinson C, Schnering D, Shen V, Lindsay R. Bone density change and biochemical indices of skeletal turnover. Calcif Tissue Int. 1996;58:236–43. [PubMed]
63. Mole PA, Walkinshaw MH, Robins SP, Paterson CR. Can urinary pyridinium crosslinks and urinary oestrogens predict bone mass and rate of bone loss after the menopause? Eur J Clin Invest. 1992;22:767–71. [PubMed]
64. Reeve J, Pearson J, Mitchell A, et al. Evolution of spinal bone loss and biochemical markers of bone remodeling after menopause in normal women. Calcif Tissue Int. 1995;57:105–10. [PubMed]
65. Ross PD, Knowlton W. Rapid bone loss is associated with increased levels of biochemical markers. J Bone Miner Res. 1998;13:297–302. [PubMed]
66. Keen RW, Nguyen T, Sobnack R, Perry LA, Thompson PW, Spector TD. Can biochemical markers predict bone loss at the hip and spine?: a 4-year prospective study of 141 early post menopausal women. Osteoporos Int. 1996;6:399–406. [PubMed]
67. Blumsohn A, Eastell R. Prediction of bone loss in postmenopausal women. Eur J Clin Invest. 1992;22:764–6. [PubMed]
68. Vestergaard P, Hermann AP, Gram J, et al. Evaluation of methods for prediction of bone mineral density by clinical and biochemical variables in perimenopausal women. Maturitas. 2001;40:211–20. [PubMed]
69. Riggs BL, Melton LJ, III, O’Fallon WM. Drug therapy for vertebral fractures in osteoporosis: Evidence that decreases in bone turnover and increases in bone mass both determine antifracture efficacy. Bone. 1996;18:S197–S201.
70. Van Daele PL, Seibel MJ, Burger H, et al. Case control analysis of bone resorption markers, disability and hip fracture risk: the Rotterdam study. BMJ. 1996;312:482–3. [PMC free article] [PubMed]
71. Weel A, Seibel MJ, Pols HA, et al. Which fractures are associated with high bone resorption in elderly women: The Rotterdam study. J Bone Miner Res. 1999;14:S356.
72. Garnero P, Hausherr E, Chapuy MC, et al. Markers of bone resorption predict hip fractures in elderly women. The EPIDOS Prospective Study. J Bone Miner Res. 1996;11:1531–8. [PubMed]
73. Vergnaud P, Garnero P, Meunier P, Breart G, Kamihagi K, Delmas PD. Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women. The EPIDOS Study. J Clin Endocrinol Metab. 1997;82:719–24. [PubMed]
74. Szulc P, Arlot M, Chapuy MC, Dubouef F, Meunier P, Delmas PD. Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res. 1994;9:1591–5. [PubMed]
75. Szulc P, Chapuy MC, Meunier P, Delmas P. Serum under carboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest. 1993;91:1769–74. [PMC free article] [PubMed]
76. Szulc P, Chapuy MC, Meunier P, Delmas P. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: a three year follow-up study. Bone. 1996;18:487–8. [PubMed]
77. Price PA, Kaneda Y. Vitamin D counteracts the effect of warfarin in liver but not in bone. Thromb Res. 1987;46:121–31. [PubMed]
78. Hodges S, Pilkington M, Stamp T, et al. Depressed levels of circulating menaqui nones in patients with osteoporotic fractures of the spine and femoral neck. Bone. 1991;12:387–9. [PubMed]
79. Knapen MH, Hanulyak K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin and urinary calcium excretion. Ann Intern Med. 1989;111:1001–5. [PubMed]
80. Meier C, Nguyen TV, Center JR, Seibel MJ, Eisman JA. Bone resorption and osteoporotic fractures in elderly men: the Dubbo osteoporosis epidemiology study. J Bone Miner Res. 2005;20:579–87. [PubMed]
81. Civitelli R, Gonnelli S, Zacchei F, et al. Bone turnover in postmenopausal osteoporosis. Effect of calcitonin treatment. J Clin Invest. 1988;82:1268–74. [PMC free article] [PubMed]
82. Nielsen NM, von der Recke P, Hansen MA, Overgaard K, Christiansen C. Estimation of the effect of salmon calcitonin in established osteoporosis by biochemical bone markers. Calcif Tissue Int. 1994;55:8–11. [PubMed]
83. Overgaard K, Hansen MA, Nielsen VA, Riis BJ, Christiansen C. Discontinuous calcitonin treatment of established osteoporosis - effects of withdrawal of treatment. Am J Med. 1990;89:1–6. [PubMed]
84. Gonnelli S, Cepollaro C, Pondrelli C, et al. Bone turnover and the response to alendronate treatment in postmenopausal osteoporosis. Calcif Tissue Int. 1999;65:359–64. [PubMed]
85. Stevenson JC, Hillard TC, Lees B, Whitcroft SI, Ellerington MC, Whitehead MI. Post menopausal bone loss: does HRT always work? Int J Fertil Menopausal Stud 1993;38:S2:88–91.
86. Seibel MJ, Naganathan V, Barton I, Grauer A. Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic women treated with risedronate. J Bone Miner Res. 2004;19:323–9. [PubMed]
87. Bauer DC, Garnero P, Hochberg MC, et al. for the Fracture Intervention Research Group. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res. 2006;21:292–9. [PubMed]
88. McClung MR, Lewiecki EM, Cohen SB, et al. AMG 162 Bone Loss Study Group. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821–31. [PubMed]
89. Nenonen A, Cheng S, Ivaska KK, et al. Serum TRACP 5b is a useful marker for monitoring alendronate treatment: comparison with other markers of bone turnover. J Bone Miner Res. 2005;20:1804–12.
90. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002;346:653–61. [PubMed]
91. Tahtela R, Seppanen J, Laitinen K, Katajamaki A, Risteli J, Valimaki MJ. Serum tartrate-resistant acid phosphatase 5b in monitoring bisphosphonate treatment with clodronate: a comparison with urinary N-terminal telopeptide of type I collagen and serum type I procollagen amino-terminal propeptide. Osteoporos Int. 2005;16:1109–16. [PubMed]
92. Bauer DC, Black DM, Garnero P, et al. Fracture Intervention Trial Study Group. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res. 2004;19:1250–8. [PubMed]
93. Recker R, Stakkestad JA, Chesnut CH, 3rd, et al. Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone. 2004;34:890–9. [PubMed]
94. Sarkar S, Reginster JY, Crans GG, Diez-Perez A, Pinette KV, Delmas PD. Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res. 2004;19:394–401. [PubMed]
95. Reginster JY, Sarkar S, Zegels B, et al. Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk. Bone. 2004;34:344–51. [PubMed]
96. Tanko LB, Mouritzen U, Lehmann H, et al. Oral ibandronate: changes in markers of bone turnover during adequately dosed continuous and weekly therapy and during different suboptimally dosed treatment regimens. Bone. 2003;32:687–93. [PubMed]
97. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459–68. [PubMed]
98. Black DM, Greenspan SL, Ensrud KE, et al. PaTH Study Investigators. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:1207–15. [PubMed]
99. Cosman F, Nieves J, Zion M, Woelfert L, Luckey M, Lindsay R. Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med. 2005;353:566–75. [PubMed]
100. Black DM, Bilezikian JP, Ensrud KE, et al. PaTH Study Investigators. One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. N Engl J Med. 2005;353:555–65. [PubMed]
101. Arlot M, Meunier PJ, Boivin G, et al. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res. 2005;20:1244–53. [PubMed]
102. Chen P, Satterwhite JH, Licata AA, et al. Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res. 2005;20:962–70. [PubMed]
103. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3- year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637–45. [PubMed]
104. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999;282:1344–52. [PubMed]
105. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med. 1990;322:1265–71. [PubMed]
106. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077–82. [PubMed]
107. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med. 2002;112:281–9. [PubMed]
108. Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res. 2002;17:1–10. [PubMed]
109. Li Z, Meredith MP. Exploring the relationship between surrogates and clinical outcomes: analysis of individual patient data vs. meta-regression on group-level summary statistics. J Biopharm Stat. 2003;13:777–92. [PubMed]
110. Delmas PD, Recker RR, Chesnut CH, 3rd, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos Int. 2004;15:792–8. [PubMed]
111. Bjarnason NH, Sarkar S, Duong T, Mitlak B, Delmas P, Christiansen C. Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis. Osteoporos Int. 2001;12:922–30. [PubMed]
112. Eastell R, Barton I, Hannon RA, Chines A, Garnero P, Delmas P. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res. 2003;18:1051–6. [PubMed]
113. McCombs JS, Thiebaud P, McLaughlin-Miley C, Shi J. Compliance with drug thera pies for the treatment and prevention of osteoporosis. Maturitas. 2004;48:271–87. [PubMed]
114. Marwick C. Hormone combination treats women's bone loss. JAMA. 1994;272:1487. [PubMed]
115. Cano A. Compliance to hormone replacement therapy in menopausal women controlled in a third level academic centre. Maturitas. 1994;20:91–9. [PubMed]
116. Faulkner DL, Young C, Hutchins D, McCollam JS. Patient noncompliance with hormone replacement therapy: a nationwide estimate using a large prescription claims database. Menopause. 1998;5:226–9. [PubMed]
117. Kotzan JA, Martin BC, Wade WE. Persistence with estrogen therapy in a postmenopausal Medicaid population. Pharmacotherapy. 1999;19:363–9. [PubMed]
118. Kayser J, Ettinger B, Pressman A. Postmenopausal hormonal support: discontinuation of raloxifene versus estrogen. Menopause. 2001;8:328–32. [PubMed]
119. Bjorn I, Backsrom T. Drug related negative side-effects is a common reason for poor compliance in hormone replacement therapy. Maturitas. 1999;32:77–86. [PubMed]
120. Segal E, Tamir A, Ish-Shalom S. Compliance of osteoporotic patients with different treatment regimens. Isr Med Assoc J. 2003;5:859–62. [PubMed]
121. Chapurlat RD, Cummings SR. Does follow-up of osteoporotic women treated with antiresorptive therapies improve effectiveness? Osteoporos Int. 2002;13:738–44. [PubMed]
122. Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:1117–23. [PubMed]
123. Delmas PD, Vrijens B, Roux C, et al. A reinforcement message based on bone turnover marker response influences long-term persistence with risedronate in osteoporosis: The IMPACT Study. J Bone Miner Res. 2003;18:S374.
124. Di Munno O, Mazzantini M, Braga V, Adami S. The DOMINO Project: To improve the compliance of osteoporotic patients with periodic feedback of urinary CTX values. J Bone Miner Res. 2002;17:S374.
125. Hashimoto K, Nozaki M, Yokoyama M, Sano M, Nakano H. Urinary excretion of pyridinium crosslinks of collagen in oophorectomized women as markers for bone resorption. Maturitas. 1994;18:135–42. [PubMed]
126. Seibel MJ, Gartenberg F, Silverberg SJ, Ratcliffe A, Robins SP, Bilezikian JP. Urinary hydroxypyridinium cross-links of collagen in primary hyperparathyroidism. J Clin Endocrinol Metabol. 1992;74:481–6.
127. Seibel MJ. Bone Turnover in Primary Hyperparathyroidism. In: The Parathyroids, Bilezikian JP, Marcus R (eds), Academic Press, San Diego, 2001, pp 399–410.
128. Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N Engl J Med. 2005;353:898–908. [PubMed]
129. Woitge HW, Friedman B, Suttner S, et al. Changes in bone turnover induced by aerobic and anaerobic exercise in young males. J Bone Miner Res. 1998;13:1797–804. [PubMed]
130. Yamauchi M, Young DR, Chandler GS, Mechanic GL. Cross-linking and new bone collagen synthesis in immobilized and recovering primate osteoporosis. Bone. 1998;9:415–8. [PubMed]
131. Nyquist F, Ljunghall S, Berglund M, Obrant K. Biochemical markers of bone metabolism after short and long time ethanol withdrawal in alcoholics. Bone. 1996;19:51–4. [PubMed]
132. Szulc P, Garnero P, Claustrat B, Marchand F, Duboeuf F, Delmas PD. Increased bone resorption in moderate smokers with low body weight: the Minos study. J Clin Endocrinol Metab. 2002;87:666–74. [PubMed]
133. Meunier P. Prevention of hip fractures by correcting calcium and vitamin D insufficiencies in elderly people. Scand J Rheumatol Suppl. 1996;103:75–8. [PubMed]
134. Cortet B, Cortet C, Blanckaert F, et al. Quantitative ultrasound of bone and markers of bone turnover in Cushing's syndrome. Osteoporos Int. 2001;12:117–23. [PubMed]
135. Schoon E, Geerling B, Van Dooren I, et al. Abnormal bone turnover in long-standing Crohn's disease in remission. Aliment Pharmacol Ther. 2001;15:783–92. [PubMed]
136. Zipfel S, Seibel MJ, Löwe B, Beumont PJ, Kasperk C, Herzog C. Osteoporosis in eating disorders: a follow-up study of patients with anorexia and bulimia nervosa. J Clin Endocrinol Metab. 2001;86:5227–33. [PubMed]
137. Garnero P, Vassy V, Bertholin A, Riou JP, Delmas PD. Markers of bone turnover in hyperthyroidism and the effects of treatment. J Clin Endocrinol Metab. 1994;78:955–9. [PubMed]
138. Lems WF, Gerrits MI, Jacobs JW, van Vugt RM, van Rijn HJ, Bijlsma JW. Changes in (markers of) bone metabolism during high dose corticosteroid pulse treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 1996;55:288–93. [PMC free article] [PubMed]
139. King CS, Weir E, Gundberg C, Fox J, Insogna K. Effects of continuous gluco corticoid infusion on bone metabolism in the rat. Calcif Tissue Int. 1996;59:184– 91. [PubMed]
140. Meeran K, Hattersley A, Burrin J, Shiner R, Ibbertson K. Oral and inhaled corticosteroids reduce bone formation as shown by plasma osteocalcin levels. Am J Respir Crit Care Med. 1995;151:333–6. [PubMed]
141. Anderson FH, Francis RM, Peaston RT, Wastell HJ. Androgen supplementation in eugonadal men: effects of six months’ treatment on markers of bone formation and resorption. J Bone Miner Res. 1997;12:472–8. [PubMed]
142. Sillem M, Parviz M Woitge HW, et al. Addback medrogestone does not prevent bone loss in premenopausal women treated with goserelin. Exp Clin Endocrinol Diabetes 1999;107:379–85.
143. Philip WJ, Martin JC, Richardson JM, Reid DM, Webster J, Douglas AS. Decreased axial and peripheral bone density in patients taking long-term warfarin. QJM. 1995;88:635–40. [PubMed]
144. Valk NK, Erdtsieck RJ, Algra D, Lamberts SW, Pols HA. Combined treatment of growth hormone and the bisphosphonate pamidronate, versus treatment with GH alone, in GH-deficient adults: The effects on renal phosphate handling, bone turnover and bone mineral mass. Clin Endocrinol (Oxf) 1995;43:317–24. [PubMed]
145. Blair JM, Zhou H, Seibel MJ, Dunstan CR. Mechanisms of Disease: roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis. Nat Clin Pract Oncol. 2006;3:41–9. [PubMed]
146. Woitge H, Pecherstorfer M, Horn E, et al. Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma. Br J Cancer. 2001;84:344–51. [PMC free article] [PubMed]
147. Brown JE, Cook RJ, Major P, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 2005;97:59–69. [PubMed]
148. Lipton A, Demers L, Curley E, et al. Markers of bone resorption in patients treated with pamidronate. Eur J Cancer. 1998;34:2021–6. [PubMed]
149. Chen T, Berenson J, Vescio R, et al. Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol. 2002;42:1228–36. [PubMed]
150. Luftner D, Richter A, Geppert R, Wernecke KD, Possinger K. Normalisation of biochemical markers of bone formation correlates with clinical benefit from therapy in metastatic breast cancer. Anticancer Res. 2003;23:1017–26. [PubMed]
151. Vinholes JJ, Purohit OP, Abbey ME, Eastell R, Coleman RE. Relationships between biochemical and symptomatic response in a double-blind randomised trial of pamidronate for metastatic bone disease. Ann Oncol. 1997;8:1243–50. [PubMed]

Articles from The Clinical Biochemist Reviews are provided here courtesy of The Australian Association of Clinical Biochemists