Carboxyterminal propeptide of type I collagen (P1CP) and cross-linked carboxyterminal telopeptide of type I collagen (1CTP) are known as parameters of bone metastasis in patients with prostate cancer (PCa). We measured the serum P1CP and 1CTP levels in 52 PCa patients and evaluated the clinical usefulness of these serum markers. Both serum levels of P1CP and 1CTP were significantly higher in patients with extent of disease (EOD) grade 2 or 3 bone metastases than in patients without bone metastasis. Thus, P1CP and 1CTP are not as useful at first detection of bone metastases as bone scintigram. On the other hand, in the patients who indicated high serum levels of P1CP or 1CTP before initial treatment, the changes in the concentrations of these markers may be helpful in evaluating the response to treatment or the progression of disease. Our results suggest that P1CP and 1CTP are useful markers for monitoring the metastatic burden in the bone of PCa patients, but the efficacy is limited in high EOD grade cases.

The anxiety regarding no-bleed regimens is that breakthrough bleeding and endometrial hyperplasia may occur. We aimed to demonstrate that 25 mg oestradiol implants can be adequately opposed by a low dose of progestogen protecting against osteoporosis. Twenty-two patients were recruited to the study. The mean age was 62 years and body mass index of 26.5. Median oestradiol rose from 77 pmol/L at baseline to 275 pmol/L at one year. Median endometrial thickness remained unchanged at 4 mm and only two women withdrew with bleeding problems. There was one case of proliferative endometrium at one year--all others samples were either atrophic or secretory. Lumbar bone density (L2-L4) rose significantly from 0.939 to 0.992 g/cm2 (6%, P = 0.005) and the total femoral density rose from 0.872 to 0.890 g/cm2 (+2.1%). Bone formation markers increased significantly (serum type 1 procollagen C terminal peptide, P1CP = 112-114, P = 0.0376) and bone resorption fell (serum type 1 collagen C terminal telopeptide, 1CTP = 3.0-2.9, P = 0.2863). E25 implants and low dose progestogen appear to avoid endometrial hyperplasia and bleeding problems while increasing bone density.

Breast cancer (BC) is the most frequent malignancy and the first cause of cancer-related death in women. The majority of patients with advanced BC develop skeletal metastases which may ultimately lead to serious complications, termed skeletal-related events, that often dramatically impact on quality of life and survival. Therefore, the identification of biomarkers able to stratify BC patient risk to develop bone metastases (BM) is fundamental to define personalized diagnostic and therapeutic strategies, possibly at the earliest stages of the disease. In this regard, the advent of "omics" sciences boosted the investigation of several putative biomarkers of BC osteotropism, including deregulated genes, proteins and microRNAs. The present review revisits the current knowledge on BM development in BC and the most recent studies exploring potential BM-predicting biomarkers, based on the application of omics sciences to the study of primary breast malignancies.

Keywords: ADAMTS1, a disintegrin-like and metalloproteinase with thrombospondin type 1; ALP, alkaline phosphatase; BALP (BSAP), bone-specific alkaline phosphatase; BC, breast cancer; BM, bone metastases; BOLCs, breast osteoblast-like cells; BTM, bone turnover markers; Biomarkers; Bone metastases; Breast cancer; CAPG, capping-protein; CCN3, cellular communication network factor 3; CDH11, cadherin-11; CNV, copy number variation; CTGF, connective tissue-derived growth factor; CTSK, cathepsin K; CTX, C-telopeptide; CXCL, C-X-C-ligand; CXCR, C–X–C motif chemokine receptor; DEGs, differentially expressed genes; DOCK4, dedicator of cytokinesis protein 4; DPD, deoxypyridoline; DTC, disseminated tumour cells; EMT, epithelial-to-mesenchymal transition; ER, estrogen receptor; ERRα, estrogen-related receptor alpha; FAK, focal adhesion kinase; FGF, fibroblast growth factor; FST, follistatin; GIPC1, PDZ domain-containing protein member 1; HR, hazard ratio; Her, human epidermal growth factor; ICAM-1, intercellular adhesion molecule 1; IGF, insulin-like growth factor; IHC, immunohistochemistry; IL, interleukin; LC/MS/MS, liquid chromatography/mass spectrometry/mass spectrometry; MAF, v-maf avian muscolo aponeurotic fibro-sarcoma oncogene homolog; MDA-MB, MD Anderson metastatic BC; MMP1, matrix metalloproteinase-1; NTX, N-telopeptide; OPG, osteoprotegerin; Omics sciences; Osteotropism; P1CP, pro-collagen type I C-terminal; P1NP, pro-collagen type I N-terminal; PDGF, platelet-derived growth factor; PRG1, proteoglycan-1; PTH-rP, parathyroid hormone-related protein; PYD, pyridoline; PgR, progesterone receptor; PlGF, placental growth factor; RANK, receptor activator of nuclear factor к-B; RT-PCR, real time-PCR; SILAC-MS, stable isotope labelling by amino acids in cell culture-mass spectrometry; SNPs, single nucleotide polymorphisms; SPP1, osteopontin; SREs, skeletal-related events; TCGA, the cancer genome atlas; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor-α; TRACP-5b, tartrate resistant acid phosphatase-5b; VEGF, vascular endothelial growth factor; ZNF217, zinc-finger protein 217; miRNAs, microRNAs; ncRNAs, noncoding RNA.

As the most common metabolic bone disease worldwide, osteoporosis and its associated morbidities have garnered significant attention as a public health concern and economic burden. The condition is characterized by progressive loss of bone mass and destruction of bone microarchitecture, both of which are independent risk factors for skeletal fragility and fracture. The primary goal of managing osteoporosis is the prevention of these fractures, termed fragility or low-trauma fractures, as they are the disease’s main source of morbidity and mortality. Consequently, the primary goal of osteoporosis management is fracture prevention, with early diagnosis being crucial. Unfortunately, osteoporosis is commonly indetectable clinically before a fracture event, and early indicators of disease are difficult to assess radiographically. This highlights the need for methods that allow early detection of loss of bone integrity to mitigate further disease progress and subsequent fracture. The pathogenesis of osteoporosis stems from detrimental alterations in the homeostasis of bone turnover, leading to decreased bone strength by loss of mass and quality. There are multiple known mechanisms capable of causing such derangement of the balance between bone breakdown and formation and are dependent on the individual risk factors of each patient, such as low estrogen state, advanced age, long term corticosteroid use or other disease states such as systemic inflammation, thyroid, and parathyroid disease. The most commonly utilized method for identifying osteoporosis is through T-score determination, a quantified measure of bone marrow density (BMD) using dual-energy x-ray absorptiometry (DXA). A BMD, represented by T-score, of the spine or hip greater than or equal to 2.5 standard deviations below the average for that of healthy young women is considered diagnostic. BMD values are also used to determine and monitor management, in addition to establishing fracture risk, despite profuse data showing that the majority of patients experiencing fragility fractures do not have a T-score indicating osteoporotic bone density. As a result, it is recognized that BMD is insufficient as a sole means for comprehensively evaluating bone strength. Moreover, BMD is not particularly useful as a singular surveillance tool of treatment response, as changes in density may be slow or minimal. This is particularly apparent within the first year of treatment, where serial DEXA scans are ineffective at detecting BMD change. Due to the limitations of BMD, researchers have explored other possible tools to support osteoporosis management, with bone turnover markers being a topic of particular interest. Bone turnover biomarkers (BTMs) are byproducts produced from the bone remodeling process that can be measured in urine or serum and are indicative of the rate of bone turnover. BTMs are classified as either markers of bone formation such as total alkaline phosphatase (total ALP, bone-specific alkaline phosphatase (B-ALP), procollagen type 1 N-terminal propeptide (P1NP), osteocalcin (O), and procollagen type 1 C-terminal propeptide (P1CP), or as markers of bone resorption such as hydroxyproline (HYP), pyridinoline, tartrate-resistant acid phosphatase 5b (TRAP 5b), deoxypyridinoline (DPD), carboxy-terminal cross-linked telopeptide of type 1 collagen (CTX-1), and amino-terminal cross-linked telopeptide of type 1 collagen (NTX-1). There is limited specificity with these markers, as BTMs are reflective of the rate of bone turnover in general. However, unlike DXA measurements, BTM levels show appreciable, rapid response to changes in turnover rate, making them of great use clinically for monitoring treatment response and adherence in osteoporotic patients from the onset of treatment initiation. Although all BTMs can shift in response to osteoporotic disease processes, the International Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry (IFCC) have recommended serum P1NP and CTX-1 as bone formation and resorption reference markers, respectively, for use in fracture risk prediction and monitoring of osteoporosis treatment. Studies looking at BTMs in various cohorts have shown that elevated markers are associated with increased bone turnover, which increases the deterioration of bone quality and, thus, the risk of fragility fracture. This correlation shows promise in osteoporosis management, where bone turnover biomarkers (BTMs) have already proved to be of clinical use as adjuvant tools for fragility fracture risk stratification and treatment response, as well as adherence monitoring. However, there is currently insufficient evidence to establish their ability to fulfill these roles without the concomitant assessment of BMD with DXA, nor their use as an independent diagnostic tool. As such, more research is needed to establish their utility, as well as how to adjust for the multiple physiological and pathological factors that can influence levels.

BACKGROUND

Candidate markers of prostatic metastases to bone, urinary deoxypyridinoline, serum carboxy-terminal propeptide of type 1 procollagen (P1CP), and pyridinoline cross-linked carboxy-terminal telopeptide of type 1 collagen (1CTP), were measured to evaluate their prognostic efficacy.

METHODS

Urinary levels (mean +/- SD) of deoxypyridinoline were measured by a competitive immunoassay, and serum levels of P1CP and 1CTP were measured by radioimmunoassay in 30 patients with benign prostatic hyperplasia, 18 patients with prostatic carcinoma without bone metastases, and 27 patients with prostatic carcinoma and bone metastases.

RESULTS

Urinary concentrations of deoxypyridinoline (pmol/micromol creatinine) in patients with prostatic carcinoma and bone metastases (10.4 +/- 7.7) were significantly higher than those in similar patients without bone metastases (4.3 +/- 1.3) and those in patients with benign prostatic hyperplasia (3.8 +/- 1.2). Serum levels of P1CP and 1CTP (ng/mL) in patients with prostatic carcinoma and bone metastases (262.6 +/- 188.7 and 10.3 +/- 9.5, respectively) were significantly higher than those in similar patients without bone metastases (118.1 +/- 30.2 and 4.3 +/- 1.4, respectively) and those in patients with benign prostatic hyperplasia (93.9 +/- 25.1 and 3.3 +/- 1.1, respectively). Serial measurements of urinary deoxypyridinoline and serum P1CP and 1CTP were correlated with a positive response to treatment (reduced measurements) and with the clinical progression of disease (increased measurements) before detection of new bone lesions by bone scintigram.

CONCLUSIONS

Urinary deoxypyridinoline, serum P1CP, and serum 1CTP should be useful markers in confirming and monitoring prostatic carcinoma metastases to bone.

Procollagen 1 carboxyterminal peptide (P1CP) is thought to be an indicator of new bone formation. The present report demonstrates that effective endocrine therapy induced an initial increase followed by a delayed decrease in serum levels of P1CP and alkaline phosphatase in spite of an immediate decrease in serum PSA and PAP and improvement of clinical symptoms in prostate cancer patients with bone metastases. The transient increase in P1CP and alkaline phosphatase is a healing reaction and is followed by apparent improvement. Short-term effects of endocrine therapy on prostate cancer patients with bone metastases should be comprehensively evaluated based upon the entire spectrum of clinical and laboratory findings including serial changes of serum prostate markers and bone markers as well.

A radioimmunoassay kit for measurement of carboxyterminal propeptide of type 1 procollagen (P1CP) was developed and can be purchased commercially for clinical use. Using the kit, we measured serum concentration in healthy controls and in patients with bone metastasis and other various skeletal disorders. In healthy controls, serum concentration of P1CP ranged within 37-177 ng/ml under age 50, while in serum concentration of women over 50, it elevated upto 350 ng/ml. In patients with skeletal metastasis, in most of patients, it stayed within a normal range, whereas in patients with bone metastasis from prostatic cancer, it raised significantly. In some of patients with primary hyperparathyroidism or hyperthyroidism, serum concentration for P1CP was also elevated. In comparison with other serum bone metabolic markers such as osteocalcin or alkaline phosphatase, P1CP showed less occurrence of an elevation in patients with non-skeletal disease. Serum concentration of P1CP was not affected by renal function, while mild elevation was observed in patients with severely damaged liver diseases. In conclusion, the newly developed radioimmunoassay for P1CP was an excellent assay system and would provide us easily evaluation of type 1 collagen formation.

In 27 patients on periodic haemodialysis, serum levels of alkaline phosphatase (ALP), osteocalcin (BGP), intact parathyroid hormone (PTHi) and its two fragments, terminal COOH (PTH-Cter) and middle molecule (PTH-MM), and procollagen type 1 carboxy-terminal extension peptide (P1CP) were measured. The same patients underwent radiography of the skull and of the hands, ultrasonography of the parathyroids and scintigraphy of the skeleton with 99mTc-MDP. The study was completed by the measurement of aluminium (Al) in the blood and the deferoxamine test (DFO). Two groups of patients emerged, one (group A, n = 14) with PTHi greatly increased (201.07 +/- 109.72 pg/mL) and the other (group B, n = 13) with values within the normal range (32.69 +/- 17.06 pg/mL) (p < 0.001). In group A, ALP, BGP and particularly P1CP were increased with a statistically significant difference compared to group B. Specific radiographic alterations were found in 12 patients of group A; 7 patients also had hypertrophy of the parathyroids. There was no difference in the scintigraphic alterations of the skeleton between the two groups. The authors conclude that it is the association of the high values of PTHi with those of the markers of bone metabolism, the normal level of Al, the negativity of the DFO test and the radiological alterations which together allow the diagnosis of renal osteodystrophy with hyperparathyroidism.

Background: Myocardial histology from autopsies of young adults with giant coronary artery aneurysms following Kawasaki disease (KD) shows bridging fibrosis beyond the territories supplied by the aneurysmal arteries. The etiology of this fibrosis is unknown, but persistent, low-level myocardial inflammation and microcirculatory ischemia are both possible contributing factors. To investigate the possibility of subclinical myocardial inflammation or fibrosis, we measured validated biomarkers in young adults with a remote history of KD.

Methods: We measured plasma calprotectin, galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and serum procollagen type 1C-terminal propeptide (P1CP) in 91 otherwise healthy young adults with a remote history of KD and in 88 age-similar, healthy controls. KD subjects were stratified by coronary artery aneurysm (CAA) status and history of remote myocardial infarction (MI).

Results: After correction for multiple testing, calprotectin, Gal-3, and GDF-15 levels were significantly higher in subjects with persistent CAA (n = 26) compared with KD subjects with remodeled CAA (n = 20, p = 0.005, 0.001, 0.0036, respectively). In a multivariable regression model with CA status as the main predictor and adjusting for sex, MI history, and interval from KD onset, CA status was a significant predictor (Persistent CAA vs KD Normal CA) of calprotectin, Gal-3, GDF-15 and sST2 levels (p = 0.004, <0.001, 0.007, and 0.049, respectively).

Conclusions: These results suggest that ongoing inflammation and fibrosis may be occurring in individuals with persistent CAA. Longitudinal follow-up is needed to clarify the clinical significance of these elevated biomarker levels in this patient population that requires life-long monitoring.

Keywords: Calprotectin; Coronary artery aneurysms; Galectin-3; Growth differentiation factor-15; Procollagen type I C-terminal propeptide.