Latest Review Date: January 2024

Category: Laboratory/Medicine

POLICY:

Measurement of bone turnover markers is considered investigational in the diagnosis and management of osteoporosis.

Measurement of bone turnover markers is considered investigational to determine fracture risk in individuals with osteoporosis or with age-related risk factors for osteoporosis.

Measurement of bone turnover markers is considered investigational to determine response to therapy in individuals who are being treated for osteoporosis.

Measurement of bone turnover markers is considered investigational in the management of individuals with conditions associated with high rates of bone turnover, including but not limited to Paget disease, primary hyperparathyroidism and renal osteodystrophy.

DESCRIPTION OF PROCEDURE OR SERVICE:

Bone turnover markers are biochemical markers of either bone formation or bone resorption. Commercially available tests are available to assess some of these markers in urine and/or serum by high performance liquid chromatography or immunoassay. Assessment of bone turnover markers is proposed to supplement bone mineral density measurement in the diagnosis of osteoporosis and aid in treatment decisions. Bone turnover markers could also potentially be used to evaluate treatment effectiveness before changes in bone mineral density can be observed.

Bone Turnover

After cessation of growth, bone is in a constant state of remodeling (or turnover), with initial absorption of bone by osteoclasts followed by deposition of new bone matrix by osteoblasts. This constant bone turnover is critical to the overall health of the bone, by repairing microfractures and remodeling the bony architecture in response to stress. Normally, the action of osteoblasts and osteoclasts is balanced, but bone loss occurs if the two processes become uncoupled. Bone-turnover markers can be categorized as bone-formation markers or bone-resorption markers, and can be identified in serum and/or urine. There is interest in the use of bone turnover markers to evaluate age-related osteoporosis, a condition characterized by slow, prolonged bone loss, resulting in an increased risk of fractures at the hip, spine, or wrist. Measurement of bone turnover markers may aid in the diagnosis (by determining fracture risk) and therapeutic monitoring (by determining response to treatment) of osteoporosis. Bone turnover markers may also be used for the management of other diseases associated with high bone turnover (eg, primary hyperparathyroidism, Paget disease, renal osteodystrophy). The table below summarizes the various bone-turnover markers.

Bone Turnover Markers

KEY POINTS:

The most recent literature review was updated through November 10, 2023.

Summary of Evidence

For individuals with osteoporosis or risk factors for age-related osteoporosis who receive a measurement of bone turnover markers to determine fracture risk, the evidence includes observational studies on the association between markers and osteoporosis and fracture risk, and systematic reviews of those studies. Relevant outcomes are test validity and morbid events. Few studies have directly addressed whether any bone turnover markers beyond bone mineral density (BMD) measurements are independent predictors of fracture risk. One meta-analysis investigated the independent role of bone turnover markers in fracture risk prediction and found a statistically significant but modest association between bone turnover markers (specifically, PINP and CTX) and future fracture risk after adjusting for BMD and clinical risk factors. Other studies have suggested that bone turnover marker levels may be independently associated with osteoporosis and fracture risk in some groups, but there is insufficient evidence reporting on an association with any specific marker. Questions remain whether bone turnover markers are sufficiently sensitive to determine reliably individual treatment responses. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are being treated for osteoporosis who receive a measurement of bone turnover markers to determine response to therapy, the evidence includes an observational studies, randomized controlled trials (RCTs), and a systematic review of these RCTs. Relevant outcomes are test validity and morbid events. There is limited evidence on the impact of bone turnover markers on the management of osteoporosis. Individual RCTs and a systematic review of these RCTs have not found that feedback on bone turnover marker improves treatment adherence rates. No studies were identified that evaluated whether the use of bone turnover markers leads to management changes that are expected to improve outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with conditions associated with high rates of bone turnover other than age-related osteoporosis (eg, primary hyperparathyroidism, Paget disease, renal osteodystrophy) who receive a measurement of bone turnover markers, the evidence includes observational studies on the association between markers and disease activity and a systematic review of those studies. Relevant outcomes are test validity and morbid events. The largest amount of evidence has been published on Paget disease; a systematic review found correlations between several bone turnover markers and disease activity prior to and/or after bisphosphonate treatment. There is a lack of evidence on how the measurement of bone turnover markers can change patient management or improve health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

American Association of Clinical Endocrinologists and the American College of Endocrinology

The 2020 guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE) gave a Grade B recommendation to consider using bone turnover markers for assessing patient compliance and therapy efficacy. AACE/ACE reviewed evidence that markers respond quickly to therapeutic intervention, and changes in markers have been associated with bone response to therapy and fracture risk reduction.

Bone Health and Osteoporosis Foundation

In 2022, the Bone Health and Osteoporosis Foundation (formerly the National Osteoporosis Foundation) published updated guidelines on the prevention and treatment of osteoporosis to prevent fractures. Regarding biochemical markers of bone turnover, the guidelines stated: "Biochemical bone turnover markers can play a role in assessing fracture risk in appropriate individuals."

Furthermore, biochemical markers of bone turnover may:

• Predict rapidity of bone loss in untreated postmenoupausal women
• Predict extent of fracture risk reduction when repeated after 3-6 months of treatment with FDA [Food and Drug Administration]-approved therapies
• Predict magnitude of BMD [bone mineral density] increases with FDA-approved therapies
• Help determine adequacy of patient compliance and persistence with osteoporosis therapy using a serum CTX for an antiresorptive medication and P1NP for an anabolic therapy (least significant change [LSC] is approximately a 40% reduction in CTX)
• Help determine duration of ‘drug holiday’ and when and if medication should be restarted (Data are quite limited to support this use, but studies are underway.)

Endocrine Society

In 2019, guidelines from the Endocrine Society recommended that in postmenopausal women with a low BMD and at high-risk of fractures who are being treated for osteoporosis, monitoring should be conducted by dual-energy X-ray absorptiometry (DXA) at the spine and hip every 1 to 3 years. The Society considers measuring bone turnover markers (serum C-telopeptide [CTX] for antiresorptive therapy or procollagen type 1 N-terminal propeptide [PINP] for bone anabolic therapy) as an alternative way of monitoring for poor response or nonadherence to therapy. The Society notes that there is uncertainty over what constitutes an optimal response to treatment, but some experts suggest that a meaningful change is approximately 40% when compared from before to 3 to 6 months after starting treatment. A guideline update was published in 2020, in which the statements concerning measurement of bone turnover markers remained unchanged.

The Endocrine Society also published guidelines regarding the management of Paget disease in 2014. The guideline states:

• “We recommend measurement of serum total alkaline phosphatase or, when warranted, a more specific marker of bone formation or bone resorption to assess the response to treatment or evolution of the disease in untreated patients.”
• “In patients with monostotic disease who have a normal serum total alkaline phosphatase, we suggest that a specific marker of bone formation and bone resorption be measured, although these may still be normal. Serial radionuclide bone scans may determine the response to treatment if the markers are normal.”
• "In assessing the response to treatment: “For most patients, measurement of total ALP [alkaline phosphatase] or other baseline disease activity markers at 6 to 12 weeks, when bone turnover will have shown a substantial decline, is an acceptable and cost-effective option.”

North American Menopause Society

In 2021, the North American Menopause Society (NAMS) issued a position statement on the management of osteoporosis in postmenopausal women. Per the NAMS:

• “Bone turnover markers cannot diagnose osteoporosis and have varying ability to predict fracture risk in clinical trials. Bone turnover markers have been used primarily in clinical trials to demonstrate group responses to treatment. Although used by some osteoporosis specialists, the routine use of bone turnover markers in the evaluation of patients with osteoporosis is not recommended.”
• “Although changes in bone turnover markers are used by some specialists to assess adherence and effectiveness of therapy, routine use of bone markers is not recommended.”

International Society for Clinical Densitometry

In 2011, a joint statement by the International Society for Clinical Densitometry (ISCD) and the International Osteoporosis Foundation on the Fracture Risk Assessment Model (FRAX) fracture risk prediction algorithms indicated that the “Evidence that bone turnover markers predict fracture risk independent of BMD is inconclusive. Therefore, bone turnover markers are not included as risk factors in FRAX.”

In the 2019, ISCD position statement on repeating measurement of BMD when monitoring with DXA, there is a comment on bone turnover markers: “Serial BMD testing in combination with clinical assessment of fracture risk, bone turnover markers, and other factors…can be used to determine whether treatment should be initiated in untreated patients, according to locally applicable guidelines.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force (2018) recommended screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. The Task Force recommended screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years who are at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. The recommendations on osteoporosis screening addressed DXA testing but did not mention bone turnover markers.

KEY WORDS:

Bone Turnover Markers, Collagen Cross links, Osteoporosis

APPROVED BY GOVERNING BODIES:

Several tests for bone turnover markers have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. Examples are listed in the table below.

 FDA-Cleared Tests for Bone Turnover Markers

ELISA: enzyme-linked immunosorbent assay; FDA: Food and Drug Administration.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP:  Special benefit consideration may apply. Refer to member’s benefit plan. 

CURRENT CODING:

CPT Codes:

REFERENCES:

1. Abe Y, Ishikawa H, Fukao A. Higher efficacy of urinary bone resorption marker measurements in assessing response to treatment for osteoporosis in postmenopausal women. Tohoku J Exp Med 2008; 214(1):51-9.
2. Al Nofal AA, Altayar O, BenKhadra K, et al. Bone turnover markers in Paget's disease of the bone: A Systematic review and meta-analysis. Osteoporos Int. Jul 2015; 26(7):1875-1891.
3. Bauer DC, Garnero P, Harrison SL et al. Biochemical markers of bone turnover, hip bone loss and fracture in older men: the MrOS Study. J Bone Mineral Res 2009; 24(12):2032-8.
4. Bauer DC, Garnero P, Hochberg MC et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res 2006; 21(2):292-9.
5. Baxter I, Rogers A, Eastell R et al. Evaluation of urinary N-telopeptide of type I collagen measurements in the management of osteoporosis in clinical practice. Osteoporos Int 2013; 24(3):941-7.
6. Bergmann P, Body JJ, Boonen S et al. Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club. Int J Clin Pract 2008; 63(1):19-26.
7. 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):20-5.
8. Blumsohn A, Eastell R. The performance and utility of biochemical markers of bone turnover: do we know enough to use them in clinical practice? Ann Clin Biochem 1997; 34(pt 5):449-59.
9. Burch J, Rice S, Yang H, et al. Systematic review of the use of bone turnover markers for monitoring the response to osteoporosis treatment: the secondary prevention of fractures, and primary prevention of fractures in high-risk groups. Health Technol Assess. Feb 2014; 18(11):1-180.
10. 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. May 2020; 26(Suppl 1): 1-46.
11. Chopin F, Biver E, Funch-Brentato T et al.  Prognostic interest of bone turnover markers in the management of postmenopausal osteoporosis.  Joint Bone Spine 2012; 79(1):26-31.
12. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. Oct 2014; 25(10):2359-2381.
13. Eastell R, Rosen CJ, Black DM, et al. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society* Clinical Practice Guideline. J Clin Endocrinol Metab. May 01 2019; 104(5): 1595-1622.
14. Federal Register, November 23, 2001. Vol. 66, No. 226. Rules and Regulations.
15. Funck-Brentano T, Biver E, Chopin F et al. Clinical utility of serum bone turnover markers in postmenopausal osteoporosis therapy monitoring: a systematic review. Semin Arthritis Rheum 2011; 41(2):157-69.
16. Garnero P, Hausherr E, Chapuy MC et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J Bone Miner Res 1996; 11(10):1531-8.
17. Greenblatt MB, Tsai JN, Wein MN. Bone Turnover Markers in the Diagnosis and Monitoring of Metabolic Bone Disease. Clin Chem. Feb 2017; 63(2): 464-474.
18. Gutierrez-Buey G, Restituto P, Botella S, et al. Trabecular bone score and bone remodelling markers identify perimenopausal women at high risk of bone loss. Clin Endocrinol (Oxf). Sep 2019; 91(3): 391-399.
19. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
20. Johansson H, Oden A, Kanis JA, et al. A meta-analysis of reference markers of bone turnover for prediction of fracture. Calcif Tissue Int. May 2014; 94(5):560-567.
21. Kashii M, Kamatani T, Nagayama Y, et al. Baseline serum PINP level is associated with the increase in hip bone mineral density seen with Romosozumab treatment in previously untreated women with osteoporosis. Osteoporos Int. Mar 2023; 34(3): 563-572.
22. Kendler DL, Compston J, Carey JJ, et al. Repeating Measurement of Bone Mineral Density when Monitoring with Dual-energy X-ray Absorptiometry: 2019 ISCD Official Position. J Clin Densitom. 2019; 22(4): 489-500.
23. Kim JM, Lin C, Stavre Z, et al. Osteoblast-Osteoclast Communication and Bone Homeostasis. Cells. Sep 10 2020; 9(9).
24. Looker AC, Bauer DC, Chestnut CH et al. Clinical use of biochemical markers of bone remodeling: current status and future directions. Osteoporosis Int 2000; 11(6):467-80.
25. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Available online at: www.guideline.gov.
26. Marcus R, Holloway L, Wells B. Turnover markers only weakly predict bone response to estrogen: the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI). J Bone Miner Res 1997; 12(suppl 1):S103.
27. Martlı HF, Saylam B, Er S, et al. Evaluation of preoperative procollagen type 1 N-terminal peptide and collagen type 1 C-telopeptide levels in the prediction of postoperative hypocalcemia in patients undergoing parathyroidectomy due to primary hyperparathyroidism. Langenbecks Arch Surg. Jan 31 2023; 408(1): 71.
28. McCloskey EV, Vasikaran S, Cooper C. Official Positions for FRAX(R) clinical regarding biochemical markers from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX(R). J Clin Densitom 2011; 14(3):220-2.
29. McClung MR, Pinkerton JV, Blake J, et al. Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. Menopause. Sep 01 2021; 28(9): 973-997
30. National Osteoporosis Foundation. 2013 Clinician's guide to prevention and treatment of osteoporosis. Available online at: www.nof.org/professionals/clinical-guidelines.
31. National Osteoporosis Foundation. 2014 Clinician's guide to prevention and treatment of osteoporosis. nof.org/files/nof/public/content/file/2610/upload/895.pdf.
32. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 2010; 17(1):25-54; quiz 55-6.
33. Reid IR, Davidson JS, Wattie D et al. Comparative responses of bone turnover markers to bisphosphonate therapy in Paget's disease of bone. Bone 2004; 35(1):224-30.
34. Rianon N, Alex G, Callender G et al. Preoperative serum osteocalcin may predict postoperative elevated parathyroid hormone in patients with primary hyperparathyroidism. World J Surg 2012; 36(6):1320-6.
35. Roux C, Giradeau B, Rouanet S et al.  Monitoring of bone turnover markers does not improve persistence with ibandronate treatment.  Joint Bone Spine 2012; 79(4):389-92.
36. Shetty S, Kapoor N, Bondu JD, et al. Bone turnover markers: Emerging tool in the management of osteoporosis. Indian J Endocrinol Metab. 2016; 20(6): 846-852
37. Shieh A, Greendale GA, Cauley JA, et al. Urinary N-Telopeptide as Predictor of Onset of Menopause-Related Bone Loss in Pre- and Perimenopausal Women. JBMR Plus. Apr 2019; 3(4): e10116.
38. Shiraki M, Itabashi A. Short-term menatetrenone therapy increases gamma-carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis: a randomized prospective study. J Bone Miner Metab 2009; 27(3):333-40.
39. Shiraki M, Kuroda T, Tanaka S et al. Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner Metab 2008; 26(1):93-100.
40. Shoback D, Rosen CJ, Black DM, et al. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Guideline Update. J Clin Endocrinol Metab. Mar 01 2020; 105(3).
41. 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):1069-74.
42. Singer FR, Bone HG, Hosking DJ, et al. Paget's disease of bone: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. Dec 2014; 99(12): 4408-22
43. Szulc P, Naylor K, Hoyle NR, et al. 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. Jun 19 2017.
44. Tamaki J, Iki M, Kadowaki E et al. Biochemical markers for bone turnover predict risk of vertebral fractures in postmenopausal women over 10 years: the Japanese Population-based Osteoporosis (JPOS) Cohort Study. Osteoporos Int 2013; 24(3):887-97.
45. Tian A, Ma J, Feng K, et al. Reference markers of bone turnover for prediction of fracture: a meta-analysis. J Orthop Surg Res. Feb 28 2019; 14(1): 68.
46. U.S. Preventive Services Task Force (USPSTF). Osteoporosis to Prevent Fractures: Screening. June 2018 www.uspreventiveservicestaskforce.org/uspstf/recommendation/osteoporosis-screening#fullrecommendationstart.
47. Vasikaran S, Cooper C, Eastell R et al.  International Osteoporosis Foundation and Internationals Federation of Clinical Chemistry and Laboratory Medicine Position on bone marker standards in osteoporosis.  Clin Chem L Med 2011; 49(8):1271-4.
48. Woitge HW, Oberwittler H, Heichel S et al. Short- and long-term effects of ibandronate treatment on bone turnover in Paget disease of bone. Clin Chem 2000; 46(5):684-90.
49. Zhang T, Liu P, Zhang Y, et al. Combining information from multiple bone turnover markers as diagnostic indices for osteoporosis using support vector machines. Biomarkers. Mar 2019; 24(2): 120-126.

POLICY HISTORY:

Medical Policy Group, February 2011, (2)

Medical Policy Administration Committee, February 2011

Available for comment February 24 through April 11, 2011

Medical Policy Panel, September 2011

Medical Policy Group, September 2011 (2): Key points, References updated

Medical Policy Panel, October 2012

Medical Policy Group, January 2013 (2): 2012 Update to policy statement – added investigational in the management of patients with conditions associated with high rates of bone turnover, including but not limited to Paget’s disease, primary hyperparathyroidism and renal osteodystrophy; Key Points and References also updated.

Medical Policy Administration Committee, February 2013

Available for comment February 21 through April 7, 2013

Medical Policy Panel, October 2013

Medical Policy Group, October 2013 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, September 2014

Medical Policy Group, September 2014 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, December 2016

Medical Policy Group, December 2016 (3): 2016 Updates to Title & Key Points; no new References to add; no change to policy statement

Medical Policy Panel, December 2017

Medical Policy Group, January 2018 (3): 2018 Updates to Description, Key Points & References; no change in policy statement.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): 2019 Updates to Description, Key Points & References. No change to policy statement.

Medical Policy Panel, January 2020

Medical Policy Group, January 2020 (9): 2020 Updates to Description, Key Points, References. Investigational statements added to policy section related to determining fracture risk in osteoporosis/age related risk factors for osteoporosis and response to therapy in patients with osteoporosis. No change to policy statement intent.

Medical Policy Administration Committee, February 2020.

Medical Policy Panel, January 2021

Medical Policy Group, January 2021 (9): 2021 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Group, February 2021 (9): Policy statement updated to remove “not medically necessary,” no change to policy intent.

Medical Policy Panel, January 2022

Medical Policy Group, January 2022 (9): 2022 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, January 2023

Medical Policy Group, January 2023 (9): 2022 Updates to Key Points, References. No change to policy statement.

Medical Policy Panel, January 2024

Medical Policy Group, January 2024 (5): Updates to Description, Key Points; Practice Guidelines and Position Statements, Benefit Application, and References. No change to Policy Statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider; and
4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.