The Clinical Utility of Bone Resorption and Bone Formation Markers in Multiple Myeloma
Authors: Faraz Shahdabul , Pearse Roger N , Yadlapati Sujitha , Jayabalan David , Rossi Adriana C , Mark Tomer M , Niesvizky Ruben , Lane Joseph 
Published: October 2019

Abstract
Introduction: While bone resorption markers such as urinary N-terminal telopeptide (NTx) have long been used in research, serum C-terminal telopeptide (CTx) has become the preferred marker of bone status in multiple myeloma (MM). A full understanding of the clinical utility of CTx, as well as the bone formation markers osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), in MM is still lacking. In this study, we evaluated levels of CTx, OC, and BSAP in a cohort of MM patients to better understand their roles.
Methods: One set of CTx, OC, and BSAP data was obtained by random sampling in patients during a 60-day window at the Weill Cornell Medical College Myeloma Center. Bone marker changes were assessed with respect to type of myeloma therapy, response status, use of anti-resorptive therapy, and presence of osteolytic lesions or fractures. Additionally, we tested the ability of the bone markers to isolate a high fracture risk group, as defined by radiologic evidence of impending fracture. The Wilcoxon-Mann-Whitney test was used to assess clinical variables, and a 2-sided t value of less than 0.05 indicated statistical significance.
Results: 50 patients were identified with bone marker data, of which 47 had MM and 3 had MM precursor diseases. The mean age was 64 years, with 25 males and 25 females. All three markers CTx (p=0.001), OC (p=0.004), and BSAP (p<0.001) significantly decreased with myeloma therapy initiation. Only CTx, however, was significantly lower in patients who achieved a partial response or greater, compared to non-responders (p=0.010). Moreover, only CTx decreased significantly in patients using anti-resorptive therapy within one year of bone marker date (p=0.006). Both CTx (p=0.011) and BSAP (p=0.005) were significantly higher in patients with more than 5 osteolytic lesions compared to those without such lesions. Additionally, only CTx predicted which patients were at risk for impending fracture (p<0.001). Of 8 patients in this high-risk group for fractures, 2 developed new pathological fractures within 1 month of the CTx test. CTx values were significantly higher in patients who were taking both proteasome inhibitor (PI) and alkylating agents compared to those only taking PIs (p<0.001). Choice of PI also affected levels of bone markers, with patients receiving bortezomib having significantly higher levels of CTx (p=0.019) than those on carfilzomib. BSAP levels were similarly higher, with a trend toward significance (p=0.064).
Discussion: Of the evaluated bone markers, only CTx correlated with response to anti-MM therapy and risk of impending fracture. Additionally, CTx reflects the extent of bone disease. CTx levels decreased with use of anti-resorptive therapy within one year of bone marker date, but not with longer time points. This suggests the clinical benefit of at least annual dosing of anti-resorptive therapy and indicates the dynamic nature of this marker. The high CTx values in the PI plus alkylating group may also suggest that PI alone is more effective in addressing bone disease in such patients. Differences in CTx between individual proteasome inhibitors points to agent-specific effects of PI on bone remodeling, which warrant further investigation. The potential increase in BSAP with bortezomib versus carfilzomib treatment is consistent with recent findings, which show that bortezomib promotes osteoblastic differentiation and bone formation. As opposed to our CTx data, OC and BSAP did not prognosticate disease response or future fractures or correlate with use of anti-resorptive therapy, suggesting limited utility of these bone formation markers in MM.
Table 1. Bone Marker Category MM Therapy Initiation MM Therapy Responders ART Use Within 1 Year ART Use Before 1 Year Lytic Lesions Present 5+ lytic Lesions Present Risk of Future Fracture PI Plus Alkylator CTx Bone Resorption ↓↓ ↓ ↓↓ NS ↑ ↑↑ ↑↑ ↑↑↑ OC Bone Formation ↓↓ NS NS NS NS NS NS NS BSAP Bone Formation ↓↓ NS NS NS ↑ ↑↑ NS ↑ Abbreviations: CTx, C-terminal telopeptide; OC, osteocalcin; BSAP, bone-specific alkaline phosphatase; MM, multiple myeloma; ART, anti-resorptive therapy; NS, not significant; PI, proteasome inhibitor. Single arrow represents a change by a factor of less than 2. Double arrows represent a change by a factor of greater than 2. Triple arrows represent a change by a factor of greater than 3.

Disclosures
Pearse: Celegen: Consultancy. Rossi:Calgene: Speakers Bureau. Mark:Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Niesvizky:Celgene: Consultancy, Speakers Bureau. Lane:Agnovos Healthcare, LLC: Consultancy; Bone Therapeutics: Membership on an entity's Board of Directors or advisory committees; CollPlant Holdings, Ltd.: Consultancy; D'Fine, Inc.: Consultancy; Gradtys: Membership on an entity's Board of Directors or advisory committees; ISTO Technologies, Inc: Membership on an entity's Board of Directors or advisory committees; Kuros: Membership on an entity's Board of Directors or advisory committees; Royal Consulting & Marketing: Consultancy.