Is There a Place for Bone Turnover Markers in the Assessment of Osteoporosis and its Treatment?

As populations age, the number of osteoporotic fractures will increase. Bone mineral density (BMD) measurement remains the major way to diagnose osteoporosis and to indicate therapy. The FRAX tool, based on clinical risk factors, estimates the 10-year risk of hip and major osteoporotic fractures. The association of BMD and FRAX measurements has improved the identification of patients who are most at risk. However, some patients can still be overlooked and denied therapy. It is sound that adding the measure of bone turnover markers to the former risk factors and their follow-up during therapy could best address the efficacy of treatment of osteoporosis. Whether this behavior is cost-effective remains to be settled.

Bone tissue is constantly remodeling in the adult skeleton. Bones must resist continuous different mechanical strains in daily life. The skeleton is influenced by various systemic hormonal stimuli. Moreover, local cytokines have a large role in bone turnover. It is generally considered that the skeleton is completely renewed every 10 years.

In normal circumstances in healthy adults, bone remodeling maintains bone mass as well as structural integrity and function. Moreover, it eventually adapts the skeleton to repetitive strains and injuries. This mechanism results from the action of specialized cells: bone resorption by osteoclasts whose role consists of eliminating old bone that has become unfit for its mechanical and/or metabolic functions, and bone formation by osteoblasts to rebuild new bone. Buried cells (osteocytes) control the mechanostat, responding to skeletal strain by secreting sclerostin, which circulates through interconnected canaliculi and communicate with the bone surface. This process stimulates the remodeling cells mainly through the action of the RANKL-RANK-OPG cytokine system in the basic multicellular units (BMUs). The normal rate of bone remodeling is still a matter of debate. It is difficult to establish reference values that are validated worldwide for healthy premenopausal women. For example, serum carboxy-terminal crosslinking telopeptide of type I collagen (sCTX) was found to be significantly higher in France, relative to the United Kingdom, and procollagen type I N-terminal propeptide (PINP) was higher in France and Belgium compared with the United Kingdom and United States. This could be still different in other countries. About 2.5% of young, healthy, premenopausal women have levels of bone turnover markers (BTMs) less than the lower limit of any reference interval. An International Osteoporosis Foundation (IOF) working group recently called for reference standards.

In normal postmenopausal women, the median remodeling period lasts about 8.2 months (range 3.4–54.0 months). Both cellular actions are coupled in BMUs, which are 20 times more numerous in trabecular bone than in cortical bone (which represents 80% of the skeleton mass). These characteristics explain the more rapid changes in bone metabolism observed in trabecular bone than in cortical bone in circumstances with enhanced bone remodeling (eg, after menopause). Bone loss associated with postmenopause, aging, or pathologic conditions is caused by a negative balance between osteoblastic and osteoclastic activities, which can be amplified by the activation frequency of the remodeling units. Nowadays, the global level of bone remodeling can be estimated by several biologic BTMs. However, it is not possible to discriminate trabecular from cortical bone remodeling. In growing children, bone is modeling to adapt the shape of bones to their lengthening, and is also remodeling (as for adults). It is also not possible to discriminate between modeling and remodeling with BTMs in children.

It has recently been suggested that bone fragility can at least partly be assessable independently of bone mineral density (BMD) by measuring bone remodeling activity with some BTMs.

Osteoporosis (OP) is a systemic skeletal condition characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. It is nowadays easy to measure BMD, and this led a World Health Organization (WHO) study group to define intervention definitions for OP based on the BMD assessment by dual-energy X ray absorptiometry (DXA). Contrary to BMD measurement, the microarchitecture assessment until recently exclusively needed the analysis of transilial bone biopsies by histomorphometry. Microcomputed tomography (μCT) and high-resolution magnetic resonance imaging (hrMRI), able to assess microarchitecture in vivo and atraumatically, are in development. They are not yet used clinically on a large scale.

FRAX is a new tool adopted by WHO and based on simple clinical risk factors such as age, weight, height, body mass index (BMI), personal or parental fracture history, secondary causes of OP, glucocorticoid (GC) use, smoking habits, and alcohol (ab)use. FRAX provides an estimation of the 10-year probability percentage of OP fractures (hip and major OP fractures). With the use of FRAX, either alone or in conjunction with DXA measurements, the indication for OP therapy should be refined.

BMD is an excellent predictor of the fracture risk based on large prospective studies. BMD measurements necessitate at least 1 to 2 years for quantifiable changes caused by therapeutic agents. However, it is not available everywhere. FRAX has the advantages of being clinically easily assessable and being adaptable to country-specific fracture risks. It can also be upgraded. FRAX is not modified by any therapy, however. Falls, particularly those that threaten to fracture if they are frequent, are not included in the FRAX tool assessment and need a personalized clinical judgment. Furthermore, a large study on risedronate (RIS) treatment did not show reduction of the risk of hip fracture in elderly women whose selection had only been based on nonskeletal (clinical) risk factors. The decrease in fracture risk was exclusively observed in patients with low BMD in this study. In the Nordic Research on Ageing (NORA) study, 82% of postmenopausal women with fractures had T-scores higher than − 2.5, but this was only based on appendicular bone densitometry. Thus, even if a therapeutic indication is based on FRAX and BMD measurements, several patients at risk may still not be considered for therapy.

Biochemical indices of bone remodeling provide dynamic information about bone status, regarding the bone turnover rate. They are central to the mechanisms involved both directly and indirectly in the mechanical resistance of the skeleton ( Fig. 1 ). Furthermore, they can change rapidly, in a few days to weeks following the action of potent antiosteoporotic therapies. They have been of utmost value in the development of new therapies for OP and have been largely used in trials involving thousands of patients, which have rendered them more familiar to the clinicians. However, the extrapolation of the trial data to the management of an individual patient is still questionable. Taking everything into account, the main questions are whether there is a place for BTMs in OP assessment, and whether BTMs are a further means to identify patients at risk of fracture.