The study confirmed that serum bone turnover markers including P1NP and β-CTX levels were in high value of normal range with the average of 48.69± 20.72 ng/ml and 0.522±0.282 ng/ml. respectively. P1NP and /or β-CTX were higher than upper normal range in 47.83% of the patients. The high bone turnover rate was significantly higher in the patients with fracture history than patients without fracture history. No impact of age and 25OHD level on the P1NP or β-CTX was confirmed in our series.
Effect of age and 25OHD on BTMs
Bone remodeling consists of resorption and formation throughout life. Bone turnover markers are some metabolites generated in the process of bone remodeling. P1NP and CTX were recommended as the preferred markers of bone formation and resorption, which reflect the activity of osteoblast and osteoclast. In Chinese Bone Turnover Marker Study, the levels of P1NP and β-CTX were peak in men aged 15-19 yrs. Thereafter, both markers gradually declined with age, remained at low levels between 40 and 69 years of age and declined further after age 70[8]. Fatayerji D and Eastell R[9] reported that BTMs were highest in the third decade and lowest in the fifth and sixth decade in the study of age-related changes in men. The epidemiological investigation of general population showed that P1NP and β-CTX levels were inversely associated with age in men between 20 and 60 years of age [2,8,9]. But the impact of age on BTMs in men aged >60 yrs is still controversial. Wishart JM et al [10]reported that all the markers of bone turnover fell with age. Fatayerji D and Eastell R [9]reported no change in osteocalcin or P1NP with aging, but a small increase in bALP in the eighth decade. Khosla S et al[11] reported that urinary NTX (N-telopeptide of type I collagen) increased 77% and 80% between age 50-85 yrs in the men and women, respectively. Szulc P and Delmas PD[12] suggested that imbalance between increased bone resorption and stable bone formation may be responsible for increasing bone loss in men after the age of 60. The data on the effect of 25OHD on BTMs is discordant. P1NP was negatively correlated and β-CTX was positively correlated with serum 25OHD level in Chinese Bone Turnover Marker Study[8]. No association of serum bone turnover markers with 25OHD was found in SIBLOS study [2]. We did not observe the impact of age and 25OHD level on the P1NP or β-CTX in 230 male patients aged ≥50 years with osteoporosis in our series.
Status of BTMs in male osteoporosis
Normal reference range of BTMs is important for us to judge the status of bone turnover and to evaluate drug efficacy in clinical practice. Normal reference range of BTMs comes from healthy pre-menopausal women because the BTMs levels are stable and the proposed goal of anti-resorptive therapy is to reduce BTMs to the lower half of the reference range for pre-menopausal women. In Chinese Bone Turnover Marker Study , median P1NP and β-CTX levels were 40.42 ng/mL and 0.26 ng/mL respectively in pre-menopausal Chinese women aged≥ 30 yrs and were recommended as normal reference range[8],which were similar to reference ranges reported in premenopausal European women[13,14]. At present, normal reference range of premenopausal women was generally referred to the male because of no normal reference range in men. The normal ranges of P1NP and β-CTX used in our study were recommended by ROCHE. In postmenopausal osteoporosis, BTMs including resorption and formation types are more increased in early postmenopausal period due to rapid reduction of estrogen [15,16]. Bone turnover often is high in early postmenopausal women. In male osteoporosis, men do not have the equivalent of menopause and do not experience accelerated bone loss ,because serum total testosterone level declines only marginally with age. It is worth for us to pay attention to what the change of BTMs in the male patients with osteoporosis happens. People habitually think that the levels of BTMs in male osteoporosis are similar to the epidemiological results of the general population, which suggest low bone turnover in men aged >50 yrs. But in the MrOS Study of men ≥65 yr of age, mean values of 39.0 ± 24.9 ng/ml for P1NP and 0.41 ± 0.21 ng/ml for β-CTX were slightly lower than values in the older postmenopausal women in the United States[17]. A study confirmed that the deoxypyridinoline levels were above the normal range for premenopausal women in 23% of the men aged > 75yrs, and N-telopeptide and C-telopeptide remained in the normal range[18]. Yuan Y et al[19] reported that the mean values of P1NP and β-CTX were 39.23±20.82 ng/mL and 0.38±0.21 ng/mL respectively in 357 male patients aged ≥50 years which were basically in the normal ranges, but the patients with osteoporosis diagnosed by DXA total hip T score had significantly higher levels of P1NP and β-CTX than those of patients with normal bone mass and osteopenia. The results of our study suggested high bone turnover in the male patients with osteoporosis, because the mean values of P1NP (48.69±20.72 ng/ml) and β-CTX (0.522±0.282 ng/ml) were higher than median P1NP and β-CTX levels recommended as normal range in Chinese Bone Turnover Marker Study[8], and P1NP and /or β-CTX were higher tnan upper normal range in 47.83% of the patients in our series. The proportion of P1NP and /or β-CTX above the upper normal range in our study was higher than the proportion of postmenopausal women with osteoporosis, because serum P1NP and CTX above the upper limit of reference interval from 87 premenopausal women were only 33% and 24% respectively in the postmenopausal women with osteoporosis defined by DXA BMD at the lumbar spine or proximal femur of (i) T-score≤−2.5 or (ii) T-score≤−1.0 plus a prevalent fragility fracture in the TRIO study[20]. The possible reasons for high bone turnover in the male patients with osteoporosis in our study are as follows. First, the higher bone turnover, the more bone loss. A cross-sectional and longitudinal study from 417 healthy men aged 25 to 45 years showed that higher baseline levels of P1NP、β-CTX and OC were associated with greater decreases in BMD at several skeletal sites over a 12-year follow-up period [2]. A study of 514 European men aged 40–79 yrs at baseline and a median follow-up of 4.3 years showed that age-related changes of BMD and bone geometry were greater in men with higher levels of BTMs including bone resorption markers (ICTP and β-CTX) and bone formation markers (P1NP and osteocalcin) at baseline[21]. Therefore, we have reasons to speculate that high bone turnover is common in the male osteoporosis. Second, the patients with high bone turnover have high fracture risk. P1NP and β-CTX levels were higher in the patients with hip fracture than the patients without hip fracture and higher in the patients with nonspine fracture than the patients without nonspine fracture in the MrOS Study [17]. In our study, the high bone turnover rate was significantly higher in the patients with fracture history than patients without fracture history. Third, Orthopedic is the main department for managing the patients with osteoporosis in our hospital. There were some patients with fresh fractures in our series. The bone turnover speeds up during the period of fracture healing, which shows up as increased levels of P1NP and β-CTX[22].Forth, the non-fracture patients in our series came to hospital for treating severe pain and had significant pain relief after use of bisphosphonates. High osteoclastic activity play a role in the mechanisms of musculoskeletal pain in osteoporosis. Bisphosphonates improved pain and quality of life by their anti-osteoclastic activity[23]. Kamimura M et al[24] found that serum BAP and the urinary NTX increased with aging , and that the increase in both markers was closely related to back pain. Takahara K et al reported that insufficiency fracture was present in the patients with osteoporosis who had severe low back pain or buttock pain without any prior history of major trauma and revealed that serum BAP and urine NTX were significantly increased in patients with insufficiency fracture[24].
Limitations
This study has some limitations. First , this study was retrospective and unrandomized. Second, we did not measure serum androgen levels and did not observe the effect of androgen on BTMs. Third, there was a relatively small sample and only inclusion of the patients treated with bisphosphonates in our series. However, this is a significant result of baseline level of P1NP and β-CTX in male osteoporosis from clinical practice.