Differences of bone alkaline phosphatase isoforms in metastatic bone disease and discrepant effects of clodronate on different skeletal sites indicated by the location of pain

Abstract

We compared clodronate with placebo administration in 42 primarily or secondarily hormone-refractory prostate cancer patients with skeletal metastases and persisting pain. Serum total alkaline phosphatase (ALP), bone ALP isoforms, osteocalcin, cross-linked carboxy-terminal telopeptide of type I collagen, and prostate-specific antigen were analyzed before and after 1 month of treatment. Six ALP isoforms were quantified by HPLC: one bone/intestinal, two bone (B1, B2), and three liver ALP isoforms. The most apparent difference compared with healthy males was observed for the bone ALP isoform B2. Patients and healthy males had a B2 activity corresponding to 75% and 35% of the total ALP activity, respectively (P <0.0001). We propose that the different bone ALP isoforms reflect different stages of osteoblast differentiation during the extracellular matrix maturation phase of osteogenesis. All bone markers except osteocalcin increased after 1 month of clodronate administration. These increases were associated with pain only in the upper part of the body. We suggest that the uptake of clodronate by the skeleton was not uniform during our treatment period.

Isoforms of Bone Alkaline Phosphatase: Characterization and Origin in Human Trabecular and Cortical Bone

“…As presented, we found significant differences between B1 and B2; however, neither of these isoforms were totally specific for cortical or trabecular bone. Therefore, taken together with previously reported clinical data, we propose that B1 and B2 may reflect different stages in osteoblast differentiation during osteogenesis, where one isoform is presented before and the other during the extracellular matrix maturation phase (2,13,44) . The BALP isoforms may indicate further osteoblast differentiation, for example when osteoblasts are entrapped in bone matrix becoming osteocytes, or remain on the surface as bone lining cells, or undergo apoptosis (45) …”

“…Furthermore, patients with prostate cancer and skeletal metastases have B2 activities which correspond to 75% of the total ALP activity, significantly higher than the value of 35% found in healthy men (13) . These increased B2 levels could be explained by the fact that secondary bone tumors often develop in vertebral bones (43) .…”

“…In addition, we also present data on the osteocalcin content of the various bone fractions, and of BALP isoforms in patients with severe renal insufficiency undergoing dialysis therapy. The results are evaluated and discussed in relation to recent findings of selective differences between the BALP isoforms in other disorders of bone and mineral metabolism (2,9,12–13,21) …”

“…In this study, we have used a previously described weak anion‐exchange high‐performance liquid chromatography (HPLC) method which can resolve six different ALP isoforms in serum from healthy adults: three BALP (B/I, B1, and B2), and three LALP (L1, L2, and L3) isoforms (9,10) . Selective differences between these BALP isoforms have previously been described during the pubertal growth spurt, (11) and in disease states such as growth hormone deficiency, (2) hypophosphatasia, hypophosphatemic vitamin D–resistant rickets, Paget's disease, stress fractures, (9,12) and metastatic bone disease (13) …”

The transformation in biomarker detection and management of drug‐induced liver injury

“…Additionally, release of cellular injury biomarkers such as ALT and AST into the circulation takes place when hepatocyte injury has already occurred and therefore these biomarkers cannot be utilized to identify a potential for DILI prior to the appearance of overt liver injury. 7,8 Moreover, elevations in serum ALT/AST can occur during treatment with drugs that do not pose much or any risk of progressive liver injury (eg statins, tacrine, heparins and cholestyramine). [9][10][11] Even when drugs are capable of causing progressive and clinically important liver injury, most drug-induced elevations in serum ALT and AST resolve despite continued treatment with the offending drug-a process termed "adaptation."…”