The correlation between serum total alkaline phosphatase and bone mineral density in young adults

Osteoporosis is a progressive bone disease characterized by decreased bone mineral density and mass caused by a plethora of factors. It can gradually lead to increased bone fragility, and thus, the bone becomes more susceptible to fracture and systemic bone diseases [1]. It is a debilitating disease that affects approximately 200 million people worldwide and demands immediate attention [2]. Due to osteoporosis, there is an imbalance in the trabecular microstructure and the bone remodelling rate, leading to reduced bone strength and a series of clinical symptoms such as discomfort, fracture, and deformity [3]. Thus, early detection and diagnosis of osteoporosis are essential for its effective treatment.

Bone mineral density (BMD) is an fundamental predictor of fracture risk, bone strength, and overall bone condition [4]. Quantifying BMD enables the timely characterization and assessment of osteoporosis and the risk of bone fractures, respectively. However, BMD cannot be used as a solitary measure of a comprehensive evaluation of bone strength [5]. Additionally, it is not particularly valuable as a single monitoring tool for initiating therapy response, as changes in the bone density might be moderate or minor. This is especially notable in the first year of interventional therapy, as DEXA scans cannot adequately detect minor BMD changes [5]. Due to these limitations, more tools, such as biomarkers, need to be explored to support the timely management of osteoporosis [6].

Alkaline phosphatase (ALP) is a homodimer protein with phosphorylation properties and exists as many isozymes [7]. ALP changes can be estimated in a variety of diseases, such as liver disease, cholestatic jaundice, arteriosclerosis, cognitive disorders, and even cerebrovascular diseases [8‐12]. Total alkaline phosphatase (T-ALP) and bone-specific alkaline phosphatase (B-ALP) are byproducts produced during bone remodelling. They can be measured in urine or serum and can indicate the bone turnover rate [5]. As serum T-ALP levels have been considered a potential biomarker of bone formation and are widely used in routine screening tests [13], several studies have demonstrated that serum T-ALP is a useful indicator for assessing and tracking the presence or absence of osteoporosis [14]. However, there is no consistent conclusion about the association between serum T-ALP and BDM. Therefore, the present cross-sectional study aimed to determine the association of serum T-ALP with lumbar BMD among young adults included in the National Health and Nutrition Examination Survey (NHANES). All our methods are in accordance with the relevant guidelines and regulations [15‐17].

All 6,331 enrolled participants aged 20–40 years were categorized based on serum T-ALP quartiles (Q1:7–50 IU/L; Q2:51–60 IU/L; Q3:61–74 IU/L; and Q4:75–326 IU/L, Table 1). The basic features were significantly different among diverse serum T-ALP quartiles, except for alcohol consumption and calcium supplementation levels. Relative to other subjects, young adults having the highest serum T-ALP quartile were more likely to be male (61.26%); while the participants with the highest serum T-ALP quartile had a greater waist circumference, total protein, total cholesterol, and serum uric acid levels along with considerably decreased lumbar BMD and income poverty ratio.

Table 2 displays a set of multiple regression results. Serum T-ALP showed a negative association with lumbar BMD in the unadjusted model (β = -0.0010, 95% CI: –0.0012– –0.0008, P < 0.000001). After adjusting for confounders, this negative association was still present in model 2 (β = -0.0008, 95% CI: –0.0010– –0.0007, P < 0.000001) and model 3 (β = -0.0007, 95% CI: –0.0009– –0.0005, P < 0.000001). As the serum T-ALP quartile levels were depicted as a categorical variable, the lumbar BMD score gradually decreased with increasing serum T-ALP quartiles which were statistically significant (P < 0.001). The BMD of the subjects who were within the greatest quartile decreased by 0.0459 g/cm² as compared to the subjects present within the smallest quartile. Additionally, smooth curve fitting and weighted generalized additive models were applied to assess their association and the conclusions were consistent (Fig. 1).

The negative association between serum T-ALP and lumbar BMD remained significant in age, sex, and race-stratified subgroup analyses (Table 3). Furthermore, a smooth curve fitting was executed to assess their nonlinear relationship with each other; thus, leading to consistent results. (Figs. 2, 3, and 4).

One of the study findings suggested that participants in the highest serum T-ALP quartile had increased waist circumference, total protein, total cholesterol, and serum uric acid levels as well as lower lumbar BMD and a lower income poverty ratio which was consistent with previously published studies. A retrospective study conducted at King Fahd Hospital, Khobar University, suggested that serum T-ALP levels can be used as a predictor of osteoporosis in combination with BMD in evaluating osteoporosis, while controlling dyslipidaemia levels might improve overall bone health [20]. As another study reported that increased blood uric acid levels played a significant role in osteoporosis [21], these variables were adjusted accordingly in our study.

The relationship of serum T-ALP with BMD score has rarely been investigated before, which was attempted in our study. Based on our multiple regression analysis, serum T-ALP showed a negative association with lumbar BMD score. The depiction of the serum T-ALP quartile levels as categorical variables led to a decrease in the BMD of subjects within the greatest quartile by 0.0459 g/cm² when compared with the subjects within the smallest quartile. Statistical negative significance was observed when the association of serum T-ALP level with lumbar BMD was examined in all sex-, age-, and race-stratified subgroup analyses, while the conclusions from smooth curve fittings were consistent. Elevated serum T-ALP levels are usually indicative of bone formation activity [20]. In our study, the negative correlation between serum T-ALP and lumbar BDM may be explained by the following factors. First, osteoporosis leads to a decline in bone strength, which is determined by bone mass and bone quality [22]. Bone mass is mainly expressed by BMD, while bone quality is determined by microstructure, bone turnover, mineralization and microdamage accumulation [23]. Serum T-ALP is one of the markers reflecting osteogenic activity in bone turnover [5], and it is synthesized during bone matrix maturation and is closely related to bone matrix mineralization [24]. When BMD is low, static osteoblasts are stimulated to become active osteoblasts. This results in bone-like tissue that cannot be mineralized and osteoblasts cannot be transformed into osteocytes. Osteoblasts proliferate in feedback, synthesize large amounts of B-ALP, the serum T-ALP increases significantly. Second, osteogenic activities, including serum T-ALP, are not absolutely independent of osteoclastic activities in the process of bone turnover [25]. In other words, there is some interaction between the two processes, and elevated serum T-ALP may indicate accelerated bone turnover. the negative correlation between bone turnover markers and BMD is more pronounced in the elderly population, suggesting that accelerated bone turnover underlies age-related bone loss [26]. These are possible reasons for the negative correlation between the two. Of course, the underlying mechanism needs to be further examined by in future studies.

A retrospective study of 3242 adults in southern Taiwan showed that serum T-ALP levels were inversely associated with BMD and T-score [27]. It was evident that postmenopausal women demonstrated a more obvious negative correlation between serum T-ALP and osteoporosis [28, 29]. However, our study found that male subjects occupied a large proportion within the greatest serum T-ALP quartile due to age and ethnic differences in the survey population. Our study concluded that higher serum T-ALP levels are associated with decreased lumbar BMD, which is consistent with other reported studies [30‐32]. However, an in vitro study used Alizarin Red S staining and serum T-ALP measurements in cultured bone marrow mesenchymal stem cells to evaluate osteogenesis and suggested that increased BMD and T-ALP activity can prevent OVX-induced osteoporosis in rats [33]. Furthermore, a cross-sectional Pakistani study showed no correlation between BMD and serum T-ALP levels by linear regression analysis (p = 0.869) [13]. Thus, further studies based on larger statistical samples are required to substantiate the significance of the serum T-ALP and BMD correlations.

To conclude, our research indicates a negative association between serum T-ALP levels and lumbar BMD scores in young adults. This relationship remained significant after conducting the subgroup and smooth curve fitting analyses. Subsequently, it is also suggested that serum T-ALP measurement might become an effective biomarker for diagnosing and treating osteoporosis in future cases.