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Should Bone Turnover Markers Be Used Routinely to Monitor Oral Bisphosphonate Osteoporosis Therapy? Yes: Measuring Adherence and Effectiveness of Therapy Benefits Patients
Nov 2023
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Editorials: Controversies in Family Medicine

Should Bone Turnover Markers Be Used Routinely to Monitor Oral Bisphosphonate Osteoporosis Therapy? No: Measurement Is Unnecessary and a Poor Use of Medical Resources

Herbert L. Muncie Jr. Muncie Jr., MD,
David J. Mohr, MD,
Madeleine L. Maras, MD,
Louisiana State University School of Medicine, New Orleans, Louisiana

American Family Physician. 2023;108(5):444-446.

No: Measurement Is Unnecessary and a Poor Use of Medical Resources

The International Osteoporosis Foundation, the Endocrine Society, and the consensus statement for the Asia-Pacific Region recommend measuring bone turnover markers to assess effectiveness of and adherence to osteoporosis therapy.1–3 The recommended bone turnover markers are procollagen I N-terminal propeptide and C-terminal telopeptide of type I collagen.4 The organizations recommend measuring these markers at baseline, three to six months after starting oral antiresorptive therapy, and, if levels are reduced by a certain amount, annually thereafter (Table 1).1–3,5–8 If bone turnover markers do not change, then physicians should suspect nonadherence to bisphosphonate therapy.

TABLE 1. Current Recommendations for Monitoring Bone Turnover Markers in Osteoporosis Treatment With Oral Bisphosphonates

OrganizationWhen to test bone turnover markersTarget goal
American Association of Clinical Endocrinology5 Consider using bone turnover markers initially and to monitor treatmentAt or below the median value for premenopausal women
Consensus statement for the Asia-Pacific region3 Baseline and three, six, and 12 months20% to 40% decrease in procollagen I N-terminal propeptide
30% to 60% decrease in C-terminal telopeptide of type I collagen
Endocrine Society 2 Alternative way of identifying poor response or nonadherence to therapy measured at three to six monthsNo specific target
International Osteoporosis Foundation and European Calcified Tissue Society1 Baseline and three, six, and 12 months after starting treatment> 38% decrease in procollagen I N-terminal propeptide
> 56% decrease in C-terminal telopeptide of type I collagen
If no baseline level available:
 Procollagen I N-terminal propeptide < 28 mcg per L
 C-terminal telopeptide of type I collagen < 32 ng per L
International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis6 More research using standardized analytes is required before robust evidence-based recommendations can be givenNot applicable
North American Menopause Society 7 Routine use is not recommendedNot applicable
UK National Osteoporosis Guideline Group8 Not evaluatedNot applicable

Information from references 1–3 and 5–8.

Bone Turnover Markers Are Unlikely to Uncover Treatment Ineffectiveness

It is uncommon for patients who regularly take an oral bisphosphonate to not respond to treatment. Fewer than 10% of patients taking bisphosphonates have no significant improvement in bone density based on repeat dual energy x-ray absorptiometry testing.9 More than 70% of patients respond to oral bisphosphonates, as shown by significant decreases in markers.10 In the TRIO study, the response rate at three months was high for the three oral bisphosphonates, alendronate, ibandronate, and risedronate; by 12 weeks, 70% to 90% of patients responded.10

Another argument for routinely measuring bone turnover markers is that it is better to have some data from the markers than none at all.4 Studies have yet to find improved patient outcomes with their use; therefore, the assessment of bone turnover markers should currently be limited to specific populations (e.g., patients at very high fracture risk) and research studies evaluating their effect.

Can the Lack of Response Help Identify Patients With a Secondary Cause of Osteoporosis?

A secondary cause of osteoporosis is rarely found. Because there is no significant correlation between elevated bone turnover markers and endocrine diseases, the markers are not recommended to help physicians identify endocrine diseases in patients diagnosed with osteoporosis or osteopenia.11

Bone Turnover Markers Do Not Independently Improve Adherence

Measuring bone turnover markers continues to be touted as a way to improve adherence to treatment.4,12,13 Although nonadherence has plausibly been associated with fractures, one of the few studies that assessed the relationship did not find correlation between adherence and fracture outcomes at 52 weeks.14

Only three studies have looked at the effect of measuring bone turnover markers on adherence. In a small study that measured urine bone turnover markers in patients with osteopenia who were treated with a selective estrogen receptor modulator, nurse monitoring improved adherence, but measuring urine bone turnover markers did not result in further improvement.15 The largest study (more than 2,000 patients), which evaluated daily oral bisphosphonate and urine bone turnover markers, found a statistically significant difference in adherence, but this difference was marginal.16 The final study found that providing urine bone turnover marker results did not improve adherence.17 The latest systematic review regarding ways to improve adherence did not mention routine measurement of bone turnover markers; the review found that multicomponent interventions based on patient education and counseling were the most effective interventions to increase adherence to osteoporosis medications.18

Problems With the Measurement of Bone Turnover Markers

The process of bone turnover marker measurement is problematic.19 First, unless a baseline measurement is obtained, measuring bone turnover markers after the onset of oral bisphosphonate therapy is almost useless; second, individual and diurnal variations in levels can occur. Because bone turnover markers are affected by food, patients must be fasting for the test.20 Multivitamins or supplements containing biotin should be stopped 24 hours before measuring the markers.13 Additionally, patients who are obese have lower bone turnover markers at baseline.21

A decision analysis indicated that monitoring at three months after starting antiresorptive osteoporosis treatment could slightly increase the expected benefit of treatment.22 However, the cost to monitor all patients would be significant because commercial laboratories currently charge $75 to $250 per assay.23 Testing 100% of patients to find the 10% who do not respond or are nonadherent is unwise and expensive. Taking an interval history, performing a physical examination, and noting medication refill data could identify nonadherence.

Although our recommendation differs from some expert guidelines, it is consistent with many published opinions.7,23–25 Bone turnover markers are not needed to assess bisphosphonate effectiveness, and they do not have a direct impact on adherence.1 Family physicians can manage osteoporosis and monitor its treatment by talking to their patients and noting refill data. Routine measurement of bone turnover markers in patients treated with an oral bisphosphonate does not benefit patients and is a poor use of medical resources.

Address correspondence to Herbert L. Muncie Jr., MD, at hmunci@lsuhsc.edu. Reprints are not available from the authors.

Author disclosure: No relevant financial relationships.

This is one in a series of pro/con editorials discussing controversial issues in family medicine.

A collection of Editorials: Controversies in Family Medicine published in AFP is available at https://www.aafp.org/afp/pro-con.

  1. 1.Diez-Perez A, Naylor KE, Abrahamsen B, et al.; Adherence Working Group of the International Osteoporosis Foundation and the European Calcified Tissue Society. Recommendations for the screening of adherence to oral bisphosphonates. Osteoporos Int. 2017;28(3):767-774.
  2. 2.Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women. J Clin Endocrinol Metab. 2019;104(5):1595-1622.
  3. 3.Wu C-H, Chang Y-F, Chen C-H, et al. Consensus statement on the use of bone turnover markers for short-term monitoring of osteoporosis treatment in the Asia-Pacific region. J Clin Densitom. 2021;24(1):3-13.
  4. 4.Keller S. Making best use of bone turnover markers to monitor oral bisphosphonate therapy [editorial]. Cleve Clin J Med. 2023;90(1):32-34.
  5. 5.Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the diagnosis and treatment of postmenopausal osteoporosis—2020 update. Endocr Pract. 2020;26(suppl 1):1-46.
  6. 6.Kanis JA, Cooper C, Rizzoli R, et al.; Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women [published corrections appear in Osteoporos Int. 2020;31(1):209, and Osteoporos Int. 2020;31(4):801]. Osteoporos Int. 2019;30(1):3-44.
  7. 7.Management of osteoporosis in postmenopausal women. The 2021 position statement of the North American Menopause Society. Menopause. 2021;28(9):973-997.
  8. 8.Gregson CL, Armstrong DJ, Bowden J, et al. UK clinical guideline for the prevention and treatment of osteoporosis [published correction appears in Arch Osteoporos. 2022;17(1):80]. Arch Osteoporos. 2022;17(1):58.
  9. 9.Bonnick SL. Monitoring changes in bone density. Womens Health (Lond). 2008;4:89-97.
  10. 10.Naylor KE, Jacques RM, Paggiosi M, et al. Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study. Osteoporos Int. 2016;27(1):21-31.
  11. 11.Biver E, Chopin F, Coiffier G, et al. Bone turnover markers for osteoporotic status assessment? A systematic review of their diagnosis value at baseline in osteoporosis. Joint Bone Spine. 2012;79(1):20-25.
  12. 12.Hamdy RC. Bone turnover markers: a new year resolution?. J Clin Densitom. 2021;24(1):1-2.
  13. 13.Ashcherkin N, Patel AA, Algeciras-Schimnich A, et al. Bone turnover markers to monitor oral bisphosphonate therapy. Cleve Clin J Med. 2023;90(1):26-31.
  14. 14.Eastell R, Vrijens B, Cahall DL, et al. Bone turnover markers and bone mineral density response with risedronate therapy. J Bone Miner Res. 2011;26(7):1662-1669.
  15. 15.Clowes JA, Peel NFA, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis. J Clin Endocrinol Metab. 2004;89(3):1117-1123.
  16. 16.Delmas PD, Vrijens B, Eastell R, et al.; Improving Measurements of Persistence on Actonel Treatment (IMPACT) Investigators. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis [published correction appears in J Clin Endocrinol Metab. 2007;92(6):2285]. J Clin Endocrinol Metab. 2007;92(4):1296-1304.
  17. 17.Silverman SL, Nasser K, Nattrass S, et al. Impact of bone turnover markers and/or educational information on persistence to oral bisphosphonate therapy: a community setting-based trial. Osteoporos Int. 2012;23(3):1069-1074.
  18. 18.Cornelissen D, de Kunder S, Si L, et al.; European Society for Clinical and Economic Aspect of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Interventions to improve adherence to anti-osteoporosis medications: an updated systematic review. Osteoporos Int. 2020;31(9):1645-1669.
  19. 19.Vasikaran SD, Miura M, Pikner R, et al.; IOF-IFCC Joint Committee on Bone Metabolism (C-BM). Practical considerations for the clinical application of bone turnover markers in osteoporosis. Calcif Tissue Int. 2023;112(2):148-157.
  20. 20.Lorentzon M, Branco J, Brandi ML, et al. Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment and follow-up of treatment for osteoporosis. Adv Ther. 2019;36(10):2811-2824.
  21. 21.Eastell R, Szulc P. Use of bone turnover markers in post-menopausal osteoporosis. Lancet Diabetes Endocrinol. 2017;5(11):908-923.
  22. 22.Chapurlat RD, Cummings SR. Does follow-up of osteoporotic women treated with antiresorptive therapies improve effectiveness?. Osteoporos Int. 2002;13(9):738-744.
  23. 23.Bauer DC. Clinical use of bone turnover markers. JAMA. 2019;322(6):569-570.
  24. 24.Mauck KF, Clarke BL. Diagnosis, screening, prevention, and treatment of osteoporosis. Mayo Clin Proc. 2006;81(5):662-672.
  25. 25.Hiligsmann M, Cornelissen D, Vrijens B, et al. Determinants, consequences and potential solutions to poor adherence to anti-osteoporosis treatment: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Osteoporosis Foundation (IOF). Osteoporos Int. 2019;30(11):2155-2165.

This is one in a series of pro/con editorials discussing controversial issues in family medicine.

A collection of Editorials: Controversies in Family Medicine published in AFP is available at https://www.aafp.org/afp/pro-con.

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Should Bone Turnover Markers Be Used Routinely to Monitor Oral Bisphosphonate Osteoporosis Therapy? Yes: Measuring Adherence and Effectiveness of Therapy Benefits Patients
Nov 2023
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