Osteoporosis treatments, such as bisphosphonate (BP), denosumab, and anabolic therapies, can be monitored by observing the fracture results and surrogate markers, including bone mineral density (BMD) and bone turnover markers (BTMs).¹ In the 24^th Asia-Pacific League of Associations for Rheumatology (APLAR) Congress, Dr. Sumapa Chaiamnuay from Phramongkutklao Hospital, Thailand, shared an overview of osteoporosis treatment monitoring, along with an understanding of the clinical application and interpretation of BTMs.

The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) released an algorithm for using BTMs in monitoring osteoporosis and the preferred markers, including N-terminal propeptide of type I collagen (PINP), for bone formation and C-terminal telopeptide of type I collagen (CTX) for bone resorption.¹ CTX measures bone resorption activity but may be falsely high in patients with severe renal impairment.¹ It is also affected by diurnal variations, whereby it is the highest in the morning (8-10am), making it the best period to draw CTX.¹ Patient should fast for at least 10-12 hours beforehand as food will suppress the bone resorption marker (BRM) by 20%-40% and the bone formation marker (BFM) by <10%, and they should also cease exercise at least 24 hours as it will increase BFMs and decrease BRMs.¹ When compared with CTX, PINP measures bone formation activity and is less affected by food and time.¹ Moreover, PINP is a trimer subsequently converted to a monomer, which is hepatically cleared and may be elevated in chronic kidney disease and fibrosis patients.¹

The TRIO study, an open-label randomized controlled trial (RCT) following the BTMs and BMDs of post-menopausal women receiving oral BPs for 2 years, observed that >70% of patients had suppressed BTMs, and responders acquired more BMDs at the lumbar spine (LS).¹ Another antiresorptive trial showed that a reduction in BTMs, in particular bone alkaline phosphatase (ALP) and PINP, at 6 months was associated with a 3-year reduction of vertebral fracture risk.¹ This reduction in BTM at 6 months led to 80%-100% of reduction in vertebral fracture, but not hip or non-vertebral fractures.¹ Therefore, the International Osteoporosis Foundation (IOF) proposed that BTM to be measured at baseline and 3 months post-treatment, and if not suppressed less than the least significant change (LSC), reassessment for compliance, inappropriate administration, secondary causes, and occult fractures should be undertaken.¹

The FLEX study found that BTMs increased with discontinuation of alendronate and returned to baseline within 3-5 years.¹ The PROSA study on post-menopausal women and men found that with alendronate discontinuation, hip BMD and LS trabecular bone scores were significantly reduced.¹ BTMs started rising significantly after 3 months of alendronate discontinuation, and a 30% rise in CTX at 3 months post-discontinuation predicted BMD reduction at 1 year post-discontinuation.¹ It was thus suggested that BTMs to be monitored at baseline before BPs drug holiday after 3 and 6 months, reinitiating treatment is needed if BTMs are increased above LSC and/or the premenopausal or young men median level.¹ With a propensity match control, BTM-tested patients were found to be associated with lower odds of fracture than untested patients (OR=0.87; 95% CI: 0.85-0.88).¹

Denosumab rapidly suppresses BTMs, while discontinuation of denosumab rapidly increases BTMs and decreases BMD, hence leading to an increased risk of vertebral fracture and multiple vertebral fractures.¹ A Japanese study on 53 patients receiving denosumab, switching to raloxifene, oral BP, or zoledronic acid found that patients on raloxifene had the highest BTMs, the most significant BMD loss, and the highest fracture frequency, followed by oral BPs and zoledronic acid.¹ The European Calcified Tissue Society (ECTS) thus recommends that oral anti-resorptive therapy or intravenous BPs, such as zoledronic acid, should be used after denosumab discontinuation.¹

Teriparatide increases the PINP levels rapidly, significantly after 1 month, with a subsequent increase in CTX, thus creating an anabolic window in which patients may have more bone formation than resorption.¹ The PFT trial showed that PINP was best for monitoring teriparatide response, in terms of signal-to-noise ratio.¹ Moreover, a BMD responder of 94% was identified in patients with a PINP increase of >10mcg/L, further highlighting their correlation.¹ Besides, the GIO trial found that a PINP increase of >10mcg/L was associated with less vertebral fracture.¹ However, the post-hoc analysis of the STRUCTURE trial showed that PINP was less predictive for LS BMD gain and not predictive for hip BMD gain with teriparatide treatment in patients who had previously received BPs.¹

In summary, the testing of preferred BTMs, CTX and PINP has become popular as it helps fill the clinical gaps in osteoporosis management, and that BTM testing is associated with a lower risk of fracture.¹ BTM levels can be monitored more accurately by controlling variables, such as diurnal variations of food and alcohol intake, and exercise.¹ The clinical application of BTM should also include monitoring BP, denosumab, and anabolic therapies.¹