We have studied the association between nine bone turnover markers, representing different aspects of bone turnover, and total skeletal metabolism, as assessed by scintigraphic measurement of total skeletal uptake of 99mTc-MDP. All bone turnover markers were highly correlated to bone metabolism assessed by total skeletal uptake of 99mTc-MDP.
S-TRACP5b and S-CTX-I, the markers of bone resorption, were found to be numerically best correlated with TSU of 99m
Tc-MDP. The correlations for bone formation markers were, however, also highly significant and it was not evident which of the bone turnover markers were associated to total skeletal metabolism the most. Studies with 99m
Tc-MDP suggest that MDP uptake reflects a combination of skeletal blood flow and osteoblastic activity [22
]. However, markers of bone formation not seemed to be more correlated with such uptake than markers of bone resorption. The lack of difference between formation and resorption markers could be due to the coupling of these two processes. Moreover, studies with radio-labelled bisphosphonates have shown that bisphosphonates localize to regions where new bone is being deposited and newly formed crystals provide a surface area of exposed mineral available to adsorb bisphosphonates, but are also incorporated where osteoclasts are resorbing bone [24
In addition, the precision and accuracy of the assays for bone turnover markers differ. These differences in assay performance may have influenced the correlations between bone markers and TSU of 99mTc-MDP, making the comparison of markers more difficult.
The highest r-value (0.90) was observed for S-TRACP5b. TRACP5b is an enzyme produced by bone-resorbing osteoclasts and the activity of TRACP5b in serum reflects the number of active osteoclasts [25
]. The r-value for S-CTX-I was almost as high (0.80) as for S-TRACP5b. CTX-I results from cathepsin K-mediated degradation of type I collagen by osteoclasts [27
]. The number of bone-resorbing osteoclasts (TRACP5b), as well as the amount of degraded type I collagen (CTX-I) should be tightly correlated to the rate of skeletal metabolism. The collection of samples at non-fasting status may, however, have interfered with the correlation for CTX-I, as it's levels are known to be influenced by food intake [8
The r-values for formation markers S-OC and S-bone ALP were slightly lower (0.65 – 0.72). S-OC has a short half-life in circulation [28
] and it may be more susceptible to preanalytical variability, such as in vitro
]. Moreover, circulating OC may contain molecules derived from both formation and resorption processes [30
]. Bone-specific alkaline phosphatase is an enzyme originating from osteoblasts and needed in osteoid formation and mineralization. Although the methods currently available detect preferentially the bone-specific isoform of the enzyme, they still show a certain degree of cross-reactivity between bone and liver isoforms [31
]. The r-values for two of the three urinary OC assays were of similar magnitude (0.72 and 0.76) than for serum OC (0.65, 0.67 and 0.72).
Previous studies on healthy individuals, individuals with endocrine disorders (such as Cushing's syndrome, thyrotoxicosis and primary hyperparathyroidism) or other skeletal diseases (such as heterotrophic pulmonary ostoarthropathy) have shown TSU of 99m
Tc-MDP to be correlated to conventional bone turnover markers such as osteocalcin, urinary deoxypyridinoline [18
], total alkaline phosphatase, and urinary hydroxyproline [13
] but data on many currently available, more specific and sensitive bone turnover markers has been lacking.
We did not detect correlation for TSU and age or for TSU and BMD. Previous studies on healthy women, have shown that the TSU of 99m
Tc-MDP is positively correlated with age (n = 40, 84) [16
] and negatively correlated with BMD (n = 86) [33
]. The absence of such correlation in our study may be due to limited sample size.
When the women who had sustained fractures within two years prior to the study were compared to the others, women with recent fracture had higher level of bone formation markers and higher level of TSU of 99m
Tc-MDP. This is in line with our previous findings that bone formation markers remains elevated up to 1–2 years after fracture [34
]. Only one out of eight women had visible focal uptake on the scintigram, on the site of prior fracture. Most probably the increase of bone turnover in the fractured individuals is due to the generalized post traumatic skeletal process taking place after fracture [36
] as well local increase at the fracture site.
A main strength of this study is that we analyzed several BTMs reflecting different aspects of bone metabolism. In particular, the novel bone turnover markers such as S-TRACP5b and urinary osteocalcins have not been evaluated by using TSU of 99m
Tc-MDP in any of the earlier studies. There are also limitations. Small sample size hindered us to compare which of the BTMs that correlated most with TSU of 99m
Tc-MDP. This should be possible with larger sample sizes, including also samples for relatively high and low levels of formation and resorption, such as children, and patients on anabolic treatments (high bone formation rate), patients with osteolytic bone metastases (high bone resorption rate) or patients on anti-resorptive therapy (low bone formation and resorption rate). Another limitation was with the scanning of scintigraphic procedure used. When we take the whole body image at 3 min, with the speed of 40 cm/min, it took about 3 minutes for the camera to reach the thighs where soft tissue uptake was calculated. It was assumed that 100% of radioisotope is in soft tissue at this early image, but by this time (approximately 6 minutes) some of radioisotope could have already entered the skeleton or filtered by the kidneys. When the study was initiated, information on the effect of feeding on BTMs was not available. Samples were collected without fasting and the non-fasting status may have had minor influence on the results of a few markers, in particular S-CTX-I [8