Bone turnover markers: Emerging tool in the management of osteoporosis

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Abstract

Bone is a dynamic tissue which undergoes constant remodeling throughout the life span. Bone turnover is balanced with coupling of bone formation and resorption at various rates leading to continuous remodeling of bone. A study of bone turnover markers (BTMs) provides an insight of the dynamics of bone turnover in many metabolic bone disorders. An increase in bone turnover seen with aging and pathological states such as osteoporosis leads to deterioration of bone microarchitecture and thus contributes to an increase in the risk of fracture independent of low bone mineral density (BMD). These microarchitectural alterations affecting the bone quality can be assessed by BTMs and thus may serve as a complementary tool to BMD in the assessment of fracture risk. A systematic search of literature regarding BTMs was carried out using the PubMed database for the purpose of this review. Various reliable, rapid, and cost-effective automated assays of BTMs with good sensitivity are available for the management of osteoporosis. However, BTMs are subjected to various preanalytical and analytical variations necessitating strict sample collection and assays methods along with utilizing ethnicity-based reference standards for different populations. Estimation of fracture risk and monitoring the adherence and response to therapy, which is a challenge in a chronic, asymptomatic disease such as osteoporosis, are the most important applications of measuring BTMs. This review describes the physiology of bone remodeling, various conventional and novel BTMs, and BTM assays and their role in the assessment of fracture risk and monitoring response to treatment with antiresorptive or anabolic agents.

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Most cited references 38

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The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis.

Pierre Meunier, Christian Roux, Ego Seeman … (2004)

Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events. Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures. Copyright 2004 Massachusetts Medical Society

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Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.

P. Delmas, P Garnero, B Claustrat … (2000)

The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex-hormone-binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50-89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow-up. Women with levels in the highest quartile of four bone resorption markers including urinary-free deoxypyridinoline (D-Pyr), urinary type I collagen N-telopeptides (NTX), and urinary and serum type I collagen C-telopeptides (CTX) had about a 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0-3.4) for free D-Pyr, 1.7 (0.9-3.2) for urinary NTX, 2.3 (1.3-4.1) for urinary CTX, and 2.1 (1.2-3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3-4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2-4.0) and 2.1 (1.2-3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0-3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.

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The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation.

José Ferreras-Amez, Morten A. Karsdal, Niels T. Foged … (2003)

Bone resorption may generate collagen fragments such as ICTP and CTX, which can be quantified in serum and/or urine by using specific immunoassays, and which are used as clinical markers. However, the relative abundance of ICTP and CTX varies according to the type of bone pathology, suggesting that these two fragments are generated through distinct collagenolytic pathways. In this study, we analyzed the release of ICTP and CTX from bone collagen by the proteinases reported to play a role in the solubilization of bone matrix. Cathepsin K released large amounts of CTX, but did not allow a detectable release of ICTP. Conversely, the matrix metalloproteinases (MMPs) MMP-2, -9, -13, or -14 released ICTP, but did not allow a detectable release of CTX. Next we analyzed the release of ICTP and CTX from bone explants cultured in the presence of well-established inhibitors of these proteinases and of matrix solubilization. An inhibitor of cysteine proteinases including cathepsin K, inhibited the release of CTX, but not the release of ICTP. MMP inhibitors inhibited the release of ICTP, but also that of CTX, in agreement with the putative role of MMPs in the initiation of bone resorption in addition to matrix solubilization. Similarly the treatment of mice bearing bone metastasis with an MMP inhibitor led to a significant reduction of serum ICTP and CTX, and osteolytic lesions. We conclude that the generation of ICTP and CTX depends on different collagenolytic pathways. This finding may explain why these two markers may discriminate between different bone pathologies.

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Journal

Journal ID (nlm-ta): Indian J Endocrinol Metab

Journal ID (iso-abbrev): Indian J Endocrinol Metab

Journal ID (publisher-id): IJEM

Title: Indian Journal of Endocrinology and Metabolism

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 2230-8210

ISSN (Electronic): 2230-9500

Publication date (Print): Nov-Dec 2016

Volume: 20

Issue: 6

Pages: 846-852

Affiliations

[1] Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India

[1 ] Department of Clinical Biochemistry, Christian Medical College, Vellore, Tamil Nadu, India

Author notes

Corresponding Author: Dr. Thomas Vizhalil Paul, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore - 632 004, Tamil Nadu, India. E-mail: thomasvpaul@ 123456yahoo.com

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Publisher ID: IJEM-20-846

DOI: 10.4103/2230-8210.192914

PMC ID: 5105571

PubMed ID: 27867890

SO-VID: b60229bb-c4ba-4e74-abc3-7f5e1a1b0b67

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Bone turnover markers: Emerging tool in the management of osteoporosis

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 38

The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis.

Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.

The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation.

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