Osteoporosis

Osteoporosis is a skeletal disorder characterized by decreased bone strength and density. Dual-energy x-ray absorptiometry (DXA) is the gold standard test for diagnosis. Laboratory testing is useful in ruling out secondary causes of osteoporosis. Bone turnover marker testing is available but is not the primary method for diagnosing or monitoring osteoporosis.

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

Bone mineral density (BMD) testing (DXA) is recommended for women ≥65 years, postmenopausal women with risk factors, and men ≥70 years or younger men with risk factors (see Screening for details).

Criteria for Diagnosis

Postmenopausal women (Camacho, American Association of Clinical Endocrinologists [AACE], 2016)
- T-score of -2.5 or less in lumbar spine, femoral neck, total hip, and/or one-third radius, even without marked fracture
  - T-score is defined as standard deviation of individual’s BMD from the mean value for healthy young Caucasian women
- Low-trauma fracture in spine or hip, irrespective of BMD
- Low bone mass or osteopenia (T-score from -1 to -2.5) with fragility fracture of the proximal humerus, pelvis, or distal forearm
- Low bone mass or osteopenia and high fracture probability based on fracture risk assessment tool (FRAX)
Other populations
- T-score of -2.5 or less at the femoral neck (WHO standard for osteoporosis diagnosis; International Society for Clinical Densitometry [ISCD], 2015)
- Z-scores for BMD, rather than T-scores, are preferred in premenopausal women/girls and in boys/men <50 years (ISCD, 2015)

Laboratory Testing

Testing for causes of secondary osteoporosis should be considered
- Serum calcium, phosphorus, magnesium
  - If hypercalcemia present – evaluate for hyperparathyroidism, multiple myeloma, cancer
  - Hypophosphatemia – suggests osteomalacia
- CBC – if anemia present, evaluate for underlying conditions, such as multiple myeloma, cancer, malabsorption
- Renal function testing – for renal disease assessment
- Alkaline phosphatase – evaluate for Paget disease
- 24-hour urine calcium – to detect hypercalciuria
- Serum albumin – malnutrition, malabsorption assessment
- Vitamin D 25(OH)D – for vitamin D deficiency; evaluate patients >50 years for malnutrition, malabsorption, and celiac disease
- Thyroid stimulating hormone (TSH) – evaluate for hyperthyroidism
- Liver function tests – evaluate for chronic liver disease
- Testosterone (males) – evaluate younger men for hypogonadism
- Parathyroid hormone (PTH) (intact or PTH-related protein [PTHrP]) – evaluate for hyperparathyroidism
Testing for bone turnover
- Consider testing at initial diagnosis and at follow-up (Camacho, AACE, 2016; Cosman, National Osteoporosis Foundation [NOF], 2014)
- Higher rates of bone turnover are associated with higher fracture risk

Bone Turnover Markers
Bone Formation Markers	ARUP Tests	Comments
Serum procollagen type 1 N-terminal propeptide Serum procollagen type 1 C-terminal propeptide	Procollagen Type I Intact N-Terminal Propeptide 0070236	Most frequently used marker of bone formation Expect reduced levels when on antiresorptive therapy
Serum osteocalcin	Osteocalcin by Electrochemiluminescent Immunoassay 0020728	Limited use in clinical practice due to variability
Serum bone-specific alkaline phosphatase	Bone Specific Alkaline Phosphatase 0070053	Expect increased levels with antiresorptive therapies
Bone Resorption Markers
Serum collagen type I cross-linked telopeptide	C-Telopeptide, Beta-Cross-Linked, Serum 0070416	Most frequently used resorptive marker
Urine or serum N-telopeptide	N-Telopeptide, Cross-Linked, Urine 0070062 N-Telopeptide, Cross-Linked, Serum 0070500	Fasting AM urine spot is optimal
Urine pyridinoline	Pyridinium Crosslinks (Total), Urine 0070213 Pyridinoline and Deoxypyridinoline by HPLC 0080342	Expect reduced levels with antiresorptive therapies Early AM spot urine sample is preferred
Urine deoxypyridinoline	Deoxypyridinoline Crosslinks, Urine 0070212 Pyridinoline and Deoxypyridinoline by HPLC 0080342	Expect reduced levels with antiresorptive therapies Early AM spot urine sample is preferred
Urine hydroxyproline	n/a	Nonspecific marker; also reflects bone formation
HPLC, high-performance liquid chromatography

Imaging Studies

DXA – gold standard for diagnosis

Differential Diagnosis

Fracture
- Metastatic cancer
- Primary cancer
- Paget disease
- Gaucher disease
- Osteomalacia
- Fibrous dysplasia
Decreased bone density
- Drugs
- Cushing syndrome
- Chronic renal disease
- Chronic liver disease
- Thyroid disease
- Vitamin D deficiency
- Cancer therapy
- Hypogonadism
- Amenorrhea
- Malabsorption
- Crohn disease
- Celiac disease
- Primary hyperparathyroidism
- Renal calcium leak

Screening

Recommended Populations to Screen for Osteoporosis
	Women	Women (postmenopausal)	Men
USPSTF, 2018	Women ≥65 years	Postmenopausal women <65 years considered at risk for osteoporosis based on formal risk assessment tool	Men – evidence is insufficient for a recommendation for or against screening in men
NOF, 2014	Women >65 years	Postmenopausal women >50 years with either risk factors or fracture (new or historical adult age fracture)	Men >70 years, or >50 years with risk factors or fracture (new or historical adult age fracture)
ACR, 2017	Women or men on glucocorticoids for 6 months, who are <40 years with risk factors or osteoporotic fracture, or ≥40 years
ACR, American College of Radiology; USPSTF, U.S. Preventive Services Task Force Sources: Cosman, NOF, 2014; Buckley, ACR, 2017; USPSTF, 2018

Monitoring

Laboratory testing
- Bone turnover markers may be useful for monitoring therapy response (Camacho, AACE, 2016; Cosman, NOF, 2014)
- Vitamin D 25(OH)D – consider reevaluating for adequate concentrations after supplementation
Imaging studies
- DXA – for monitoring during treatment
- Reevaluate at 1-2 years until stable, then repeat every 1-2 years, or less frequently if clinically indicated (Cosman, NOF, 2014)

Background

Epidemiology

Prevalence – ~10 million people in the U.S. have osteoporosis (NOF, 2014)
Age – onset usually >50 years
Sex – M<F
Ethnicity – lower incidence in African Americans

Risk Factors

Risk factors for primary osteoporosis (bone loss as a result of normal aging)
- Caucasian or Asian race
- Female sex
- Older age – up to 50% of women and 25% of men >50 years will have osteoporosis-related fracture (NOF, 2018)
- Low body weight (<127 lbs or body mass index [BMI] ≤21), weight loss, or malnutrition
- Family history of hip fracture
- Personal history of fracture
- Tobacco use or history of use
- History of alcohol intake >3 units daily
Risk factors for secondary osteoporosis (bone loss as a result of disease or medication)
- Medications – glucocorticoids, immunosuppressive therapy, thyroxine, aromatase inhibitors, thiazolidine, anticonvulsant therapy (eg, phenytoin)
- Cushing syndrome
- Secondary hyperparathyroidism
- Hyperthyroidism
- Vitamin D deficiency
- Cancer therapy
- Malabsorptive disorders (eg, Crohn disease, celiac disease)
- Hypogonadism
- Amenorrhea

Pathophysiology

Bone metabolism regulated by vitamin D, calcium, estrogens, androgens, PTH
Age-related bone loss due to abnormal bone remodeling results in decreasing bone density
Osteoporosis may be worse if optimal bone mass was not achieved

Clinical Presentation

Often asymptomatic, discovered during screening
Sentinel fractures
- Also called fragility fractures
- Often the first sign of osteoporosis in an asymptomatic patient
- Defined as wrist, hip, or vertebral fracture (even in the presence of trauma)
Most common presentation in symptomatic patients
- Height loss
- Kyphosis
- Bone pain
- History of previous fractures

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

C-Telopeptide, Beta-Cross-Linked, Serum 0070416
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

Preferred test to measure bone resorption and monitor response to antiresorptive therapy (eg, bisphosphonates, hormone replacement therapy) in postmenopausal women and individuals with osteoporosis

Does not replace BMD screening to diagnose osteoporosis

Procollagen Type I Intact N-Terminal Propeptide 0070236
Method: Quantitative Radioimmunoassay

Recommended Use

Measure bone formation and monitor antiresorptive therapies

When using test to monitor osteoporosis therapy, recommend initial testing should occur prior to beginning therapy; evaluate response 3-6 months after starting therapy

Medical Experts

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology and Automated Core Laboratory at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

International Society for Clinical Densitometry. ISCD. Middletown, CT [Accessed: May 2018]
Practice Bulletin 129: Osteoporosis (September 2012, Reaffirmed 2016) (Replaces Practice Bulletin Number 50, January 2004). American College of Obstetricians and Gynecologists (ACOG). Washington, DC [Reaffirmed: 2016; Accessed: Jan 2018]
McCloskey E, Johansson H, Oden A, Kanis JA. Fracture risk assessment. Clin Biochem. 2012; 45(12): 887-93. PubMed
Hans DB, Kanis JA, Baim S, Bilezikian JP, Binkley N, Cauley JA, Compston JE, Cooper C, Dawson-Hughes B, Fuleihan GE, Leslie WD, Lewiecki M, Luckey MM, McCloskey EV, Papapoulos SE, Poiana C, Rizzoli R, FRAX(®) Position Development Conference Members. Joint Official Positions of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX(®). Executive Summary of the 2010 Position Development Conference on Interpretation and use of FRAX® in clinical practice. J Clin Densitom. 2011; 14(3): 171-80. PubMed
Camacho PM, Petak SM, Binkley N, Clarke BL, Harris ST, Hurley DL, Kleerekoper M, Lewiecki M, Miller PD, Narula HS, Pessah-Pollack R, Tangpricha V, Wimalawansa SJ, Watts NB. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016. Endocr Pract. 2016; 22(Suppl 4): 1-42. PubMed
Buckley L, Guyatt G, Fink HA, Cannon M, Grossman J, Hansen KE, Humphrey MB, Lane NE, Magrey M, Miller M, Morrison L, Rao M, Robinson AB, Saha S, Wolver S, Bannuru RR, Vaysbrot E, Osani M, Turgunbaev M, Miller AS, McAlindon T. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Care Res (Hoboken). 2017; 69(8): 1095-1110. PubMed
Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R, National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014; 25(10): 2359-81. PubMed
U.S. Preventive Services Task Force. Final Recommendation Statement: Osteoporosis to Prevent Fractures: Screening. Rockville, MD [Current as of: Jun 2018; Accessed: Aug 2018]

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Meier C, Nguyen TV, Handelsman DJ, Schindler C, Kushnir MM, Rockwood AL, Meikle W, Center JR, Eisman JA, Seibel MJ. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch Intern Med. 2008; 168(1): 47-54. PubMed

Stevenson DA, Schwarz EL, Viskochil DH, Moyer-Mileur LJ, Murray M, Firth SD, D'Astous JL, Carey JC, Pasquali M. Evidence of increased bone resorption in neurofibromatosis type 1 using urinary pyridinium crosslink analysis. Pediatr Res. 2008; 63(6): 697-701. PubMed

Terry AH, Sandrock T, Meikle W. Measurement of 25-hydroxyvitamin D by the Nichols ADVANTAGE, DiaSorin LIAISON, DiaSorin RIA, and liquid chromatography-tandem mass spectrometry. Clin Chem. 2005; 51(8): 1565-6. PubMed

Tran TS, Center JR, Seibel MJ, Eisman JA, Kushnir MM, Rockwood AL, Nguyen TV. Relationship between Serum Testosterone and Fracture Risk in Men: A Comparison of RIA and LC-MS/MS. Clin Chem. 2015; 61(9): 1182-90. PubMed

Wyness SP, Straseski JA. Performance characteristics of six automated 25-hydroxyvitamin D assays: Mind your 3s and 2s. Clin Biochem. 2015; 48(16-17): 1089-96. PubMed

Educational Videos

Content Review:

May 2018

Last Update: December 2018

Osteoporosis

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Imaging Studies

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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Osteoporosis

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Imaging Studies

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult