Bone Turnover Markers
The adult skeleton is continuously undergoing remodeling. Existing bone is resorbed by osteoclasts and replaced with new bone produced by osteoblasts. During skeletal growth, rates of formation exceed resorption resulting in net gain of bone. Later in life, resorption exceeds formation, particularly among estrogen-deficient postmenopausal women and all older individuals. Prolonged bone loss leads to low bone mineral density and eventually osteoporosis.
Biochemical or cellular products produced during either bone resorption or bone formation are called bone turnover markers (BTM). Resorption-specific BTM are breakdown products of type 1 collagen such as N-telopeptide [NTX] and C-telopeptide of type 1 collagen [CTX]). Bone formation-specific markers include those involved in type 1 collagen synthesis (N-terminal propeptide type I procollagen [PINP]), osteoblast enzymes (bone-specific alkaline phosphatase [BAP]), and bone matrix proteins (osteocalcin).
Several BTM assays are commercially available. A working group convened by the International Osteoporosis Foundation and International Foundation for Clinical Chemistry has recommended preferential use of 2 BTM measured in blood: CTX for resorption and PINP for formation.In the United States, only the CTX automated assay has been approved by the Food and Drug Administration.
Several prospective studies have demonstrated a weak association between elevated bone turnover and accelerated bone loss. Among older men and women, elevated resorption and formation markers are associated with a modestly increased risk of several types of fracture, including hip and nonspine fracture,but these relationships are much weaker than those observed with low bone mineral density. It remains unclear if BTM measurements will further improve fracture risk prediction beyond clinical risk factors and bone mineral density.
Most antiresorptive and anabolic treatment trials have reported that higher baseline bone turnover is associated with greater increases in bone mineral density after treatment. Some specialists have advocated serial BTM measurements to promote treatment adherence and to identify oral medication nonadherence. However, several randomized trials have shown that serial measurements of BTM have no overall effect on osteoporosis medication adherence or persistence.
After 3 to 5 years of bisphosphonate therapy, temporary or permanent discontinuation is now commonly recommended. Some providers have advocated BTM monitoring after discontinuation to detect rising levels. However, BTM levels at the time of discontinuation have not been associated with subsequent fracture risk.
In summary, BTM have proven to be important tools for drug development and clinical research studies but have proven less useful in clinical practice. Of the many potential clinical uses, serial monitoring to detect a suboptimal therapeutic response is the most promising, but evidence is currently insufficient to establish a preferred assay or the optimal threshold indicating an adequate response to therapy. There is also inadequate evidence to support the clinical use of BTMs to select specific treatments or to predict fracture risk during bisphosphonate drug holidays. BTM measurements are not useful in clinical practice to predict bone loss or fracture risk among untreated individuals or to increase adherence among those who are receiving treatment. Thus, most BTM measurements are not recommended for use in clinical practice.
Reference
Bauer DC. Clinical Use of Bone Turnover Markers, JAMA Published Online: July 11, 2019. doi:10.1001/jama.2019.9372
