Are bone turnover markers useful in osteoporosis management?

This post is part of a series on bone markers standardization from the Committee on Bone Metabolism of the International Federation of Clinical Chemistry.

How is osteoporosis diagnosed?

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk. The diagnosis of osteoporosis is made based on a bone density (BMD) T score of -2.5 or lower, or the presence of a minimal-trauma fracture. Blood tests, including bone turnover marker (BTM) measurements, are not required for, nor contribute to, the diagnosis although investigations for secondary causes may include performance of laboratory tests. The decision to institute treatment is aided by absolute fracture risk calculation using algorithms such as FRAX which take into account a number of risk factors including, BMD, age, family history and co-existing diseases. Whilst increased BTM concentrations are associated with a higher fracture risk, they are not included in fracture risk calculations as there is inadequate information on their contribution to risk calculation in addition to those factors already included.

How is osteoporosis treatment monitored?

The aim of osteoporosis treatment is to prevent or reduce the risk of fractures. Treatment efficacy is confirmed by monitoring a surrogate marker such as BMD or BTM. The change in BTM predicts fracture risk independently of and better than change in BMD. BTM show rapid responses to treatment with changes becoming significant within days of initiating parenteral treatment and within weeks to months of starting oral medications.

What BTM are used for monitoring osteoporosis treatment?

The National Bone Health Alliance (NBHA) in the US has endorsed procollagen type I N propeptide (s-PINP), and cross-linked β-isomerized type I collagen C-telopeptide (s-βCTX), in blood as reference standard BTM, in agreement with the International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). PINP is a marker of bone formation and βCTX is a marker of bone resorption. These are measured by immunoassay either on an automated platform or by manual assay. One marker would be adequate for monitoring therapy. Optimum preanalytic practice would help minimize variability.

What treatment targets are recommended?

When monitoring anti-resorptive therapy (bisphosphonates, denosumab) for osteoporosis, a decrease from baseline greater than the reference change value, >20% for PINP ( >10ug/L) or 30% for CTX (>100ng/L) confirms response to therapy. In addition, an absolute value lower than the premenopausal median for the marker (35ug/L for PINP) and <280ng/L for CTX (the latter varies somewhat depending on the CTX assay) is considered the target for treatment. BTM may also be used during a drug holiday period, to help guide reinitiate therapy when BTM increase after cessation of antiresorptive therapy. With anabolic therapy such as teriparatide, the formation marker PINP is used, with an increase >10ug/L considered to indicate response although in most cases PINP increases by > 100%.

How about BTM use in other metabolic bone diseases?

Bone specific alkaline phosphatase (BALP) is the recommended BTM for monitoring metabolic bone disease of chronic kidney disease (CKD-MBD) in addition to parathyroid hormone (PTH). For the diagnosis and monitoring of Paget’s disease of bone, total alkaline phosphatase (ALP) is adequate in most cases. For localized (monostotic disease) where total ALP is not sensitive enough, BALP or PINP may be used.

REFERENCES

1. Bauer D, et al. National Bone Health Alliance Bone Turnover Marker Project: current practices and the need for US harmonization, standardization, and common reference ranges. Osteoporos Int 2012;23:2425–33.
2. Szulc P, et al; National Bone Health Alliance Bone Turnover Marker Project. Use of CTX-I and PINP as bone turnover markers: National Bone Health Alliance recommendations to standardize sample handling and patient preparation to reduce pre-analytical variability. Osteoporos Int 2017;28:2541–56.
3. Watts NB, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 2010;16(suppl 3):1–37.
4. Cavalier E, et al. European Biological Variation Study (EuBIVAS): within- and between-subject biological variation estimates of β-isomerized C-terminal telopeptide of type I collagen (β-CTX), N-terminal propeptide of type I collagen (PINP), osteocalcin, intact fibroblast growth factor 23 and uncarboxylated-unphosphorylated matrix-Gla protein-a cooperation between the EFLM Working Group on Biological Variation and the International Osteoporosis Foundation-International Federation of Clinical Chemistry Committee on Bone Metabolism. Osteoporos Int. 2020;31(8):1461-70.