Osteoporosis

Primary Author Meikle, A. Wayne, MD.

Key Points

Monitoring Therapeutic Efficacy of Antiresorptive Drugs for Osteoporosis

Patients at high risk for fracture by bone mineral density testing (BMD) are usually placed on antiresorptive drug therapy in an effort to reduce their risk for fracture. To determine the efficacy of the treatment or confirm patient’s compliance with oral therapy, BMD is recommended 12 to 24 months post therapy initiation (National Osteoporosis Foundation [NOF], 2013; Endocrine Society, 2012; International Society for Clinical Densitometry [ISCD], 2008).  The addition of bone turnover markers (BTMs) allows treatment efficacy and patient compliance determinations within 3-6 months post therapy initiation (Lee, 2012).  BTMs should not be used to screen for osteoporosis (International Osteoporosis Foundation/International Federation of Clinical Chemistry and Lab Medicine [IOF-IFCC], 2011).

Commonly Used Bone Turnover Markers (BTMs)

Commonly Used Bone Turnover Markers (BTMs)

Bone Formation Markers

ARUP Tests

  • Serum procollagen type 1 N-terminal propeptide
  • Procollagen Type I Intact N-Terminal Propeptide 0070236
  • Serum osteocalcin
  • Osteocalcin by Electrochemiluminescent Immunoassay 0020728
  • Serum bone-specific alkaline phosphatase
  • Bone Specific Alkaline Phosphatase 0070053

Bone Resorption Markers

ARUP Tests

  • Serum collagen type I cross-linked telopeptide
  • C-Telopeptide, Beta-Cross-Linked, Serum 0070416
  • Urine or serum N-telopeptide
  • N-Telopeptide, Cross-Linked, Urine 0070062
  • N-Telopeptide, Cross-Linked, Serum 0070500
  • Urine pyridinoline
  • Pyridinium Crosslinks (Total), Urine 0070213
  • Pyridinoline and Deoxypyridinoline by HPLC 0080342
  • Urine deoxypyridinoline
  • Deoxypyridinoline Crosslinks, Urine 0070212
  • Pyridinoline and Deoxypyridinoline by HPLC 0080342  
  • Urine hydroxyproline
  • Nonspecific marker for bone resorption
    • Deoxypyridinoline Crosslinks 0070212
    • Pyridinoline and Deoxypyridinoline by HPLC 0080342
    • N-Telopeptide, Cross-Linked, Urine 0070062  

When to Monitor

  • For oral therapy monitoring – recommend baseline and follow-up testing at 3-6 months for both resorptive and formation markers (NOF, 2013)
  • Serum and urine specimen collection
    • Suggest morning collection from fasting patients due to diurnal variation of markers and effect from foods  (Endocrine Society Clinical Practice Guideline, 2012; NOF, 2013)
    • If not possible, collect specimens under the same circumstances (eg, at same time of day)
  • Interpretation
    • Most societies consider ≥30% change from baseline a true change

Which Tests to Use for Monitoring

  • No marker proven better than others (Lee, 2012)
  • IOF-IFCC (2011) goal – to standardize markers used in monitoring in an effort to allow for collaborative data collection

Recommended Markers (IOF-IFCC, 2011)

Recommended Marker

ARUP Tests

Interpretation

Bone Formation

Serum procollagen type 1 N-terminal propeptide

Procollagen Type I Intact N-Terminal Propeptide 0070236

Increase from baseline level indicates therapeutic response

Bone Resorption

Serum collagen type I cross-linked telopeptide (best test for patients on antiresorptive therapy)

C-Telopeptide, Beta-Cross-Linked, Serum 0070416

Decrease from baseline level indicates therapeutic response

Increased level in postmenopausal women associated with increased risk of hip and nonvertebral fracture

Diagnosis

Indications for Testing

  • Initiated through population screening or when patient presents with suspicious fracture

Laboratory Testing

  • Most useful tests to rule out secondary causes of osteoporosis (NOF, 2013)
    • Serum calcium, phosphorus, magnesium
    • CBC – if anemia present, rule out underlying conditions, such as multiple myeloma, cancer, malabsorption
    • Renal function testing – rule out renal disease
    • Alkaline phosphatase – rule out Paget disease
    • 24-hour urine calcium – detect hypercalcemia
    • Serum albumin – rule out malnutrition
    • Vitamin D 25(OH)D – rule out vitamin D deficiency; rule out malabsorption and celiac disease in patients >50 years
    • Thyroid stimulating hormone (TSH) – rule out hyperthyroidism
    • Liver function tests – rule out chronic liver disease
    • Testosterone (males) – rule out hypogonadism; use in younger men
    • Parathyroid hormone (PTH) – rule out hyperparathyroidism

Imaging Studies

  • Dual-energy x-ray absorptiometry (DXA)
    • Gold standard testing for diagnosis
    • Measures bone marrow density (BMD) of lumbar spine, total hip or femoral neck
      • Compares BMD to normal populations to generate T score
      • T score ≤-2.5 confirms osteoporosis (WHO definition)
      • T score between -1.0 and -2.5 confirms osteopenia
    • Indications for measuring BMD by DXA
      • NOF, 2013
        • Women ≥65 years and men ≥70 years, regardless of clinical risk factors
        • Postmenopausal women and men 50-69 years with clinical risk factors for facture  
      • Endocrine Society, 2012
        • Test "older men" and men who are "at risk"
  • Peripheral dual-energy x-ray absorptiometry (pDXA) – portable machines for mass screening of populations
    • Measures BMD of forearm, finger, or heel
    • If abnormal result, need confirmatory DXA
  • Vertebral fracture analysis (VFA)
    • Component of DXA
    • Assists in identifying possible vertebral fractures
    • Confirm fracture with x-ray
    • Indications for VFA
      • Women ≥70 years and men ≥80 years
      • Women 65-69 years and men 75-79 years if BMD T-score is ≤-1.5
      • Postmenopausal women 50-64 years and men 50-69 years with specific risk factors
        • Low-trauma fracture
        • Historical height loss of ≥1.5 inches (4 cm)
        • Prospective height loss of  ≥0.8 inches (2 cm)
        • Recent or ongoing glucocorticoid treatment

Other Testing

  • Calcaneal quantitative ultrasound – sensitivity (21-45%) and specificity (88-96%) too low to recommend use
  • Quantitative computed tomography – not enough research to recommend at this time

Differential Diagnosis

Screening

  • Assessments, recommendations and scoring criteria
    • WHO FRAX (Fracture Risk Assessment) tool – provides fracture probability based on patient’s risk (eg, clinical risk factors, BMI)
      • Benefits
        • Useful in estimating fracture risk over 10-year period
        • Country-specific
      • Limitations
        • Not validated in treated patients or in individuals outside the age range (≤40 years or ≥90 years)
        • Not validated for use of lumbar spine BMD
        • Calculations available for only four ethnic groups (Caucasian, African American, Hispanic, Asian)
        • Other important risk factors not included (eg, falls, high rate of bone loss)
    • National Osteoporosis Foundation (NOF) clinical assessment criteria
      NOF Clinical Assessment Criteria for Osteoporosis 
      in Postmenopausal Women and Men ≥50 Years
      • Obtain a detailed patient history pertaining to clinical risk factors for osteoporosis-related fractures and falls
      • Perform physical exam and diagnostic studies to evaluated the signs of osteoporosis and its secondary causes
      • Modify diet/supplements and other clinical risk factors for fracture
      • Estimate patient’s 10-year probability of hip and/or any major osteoporosis-related fracture using the U.S.-adapted WHO algorithm
      • Decisions on whom to treat and how to treat should be based on clinical judgment using the NOF guide and all available clinical information
      • Consider FDA-approved medical therapies based on the following
        • Vertebral or hip fracture
        • DXA hip (femoral neck or total site) or lumbar spine T score ≤-2.5
        • Low bone mass and a U.S.-adapted WHO 10-year probability of a hip fracture ≥3% or probability of any major osteoporosis-related fracture ≥20%
        • Patient preferences may indicate treatment for people with 10-year fracture probabilities below these levels
      • Consider non-medical therapeutic interventions
        • Modify risk factors related to falling
        • Consider physical and occupational therapy, including walking aids and hip-pad protectors
        • Perform weight-bearing activities daily
      • Patients not requiring medical therapies at time of initial evaluation should be clinically reevaluated when medically appropriate
      • Patients taking FDA-approved medications should have laboratory and bone density reevaluation after 2 years or when medically appropriate
      • Vertebral imaging should be repeated if there is documented height loss, new back pain, postural change or suspicious finding on chest x-ray, following the last (or first) vertebral imaging test
      • Regularly, and at least annually, assess compliance and persistence with the therapeutic regimen
    • Guidelines for bone density screening

      Indications for Bone Density Screening – Summary of Society Recommendations

       

      ISCD 2010

      ACP 2011

      NOF 2013

      AACE 2010,2012

      USPSTF 2011

      ACOG 2012

      Women

      ≥65 years

      Recommended regardless of clinical risk factors

      YES

      YES

      YES

      YES

      YES

      YES

      <65 years

      Postmenopausal

      • Meets clinical risk profile* for increased risk of fracture
      • Discontinuing estrogen therapy

      Menopausal transition

      • Specific clinical risk factors for fracture (eg, prior low-trauma fracture, low body weight, medications associated with bone loss, medical condition associated with bone loss)

      YES

      YES

      YES

      YES

       

      YES

      10 year probability of major fracture ≥9.3%, which is equal to 10-year fracture risk in a 65-year-old white woman without additional risk factors

          

      YES

      YES

      Men 

      ≥70 years

      Recommended regardless of clinical risk factors

      YES

      YES

      YES

      YES

      No recommendation for men without previous known fractures of secondary causes of osteoporosis

      N/A

      <70 years

      If clinical risk profile* indicates risk for fracture

      YES

      YES

      YES (50-69 years)

      YES (50-69 years)

      No recommendation for men without previous known fractures of secondary causes of osteoporosis

      N/A

      *Clinical risk profile (one or more of the following)

      • Fragility fracture after 50
      • Medications associated with bone loss
      • Diseases or condition associated with bone loss (eg, rheumatoid arthritis, alcoholism)
      • May be considered for pharmacologic therapy for osteoporosis
      • Low body weight
      • Parental medical history of hip fracture

      Organizations

      • ISCD – The International Society for Clinical Densitometry
      • ACP – American College of Physicians
      • NOF – National Osteoporosis Foundation
      • AACE – American Association of Clinical Endocrinologists
      • USPSTF – U.S. Preventive Services Task Force
      • ACOG – American Congress of Obstetrics and Gynecology
    • QFracture scoring calculator – newest scoring system (non-validated)

Monitoring

  • Laboratory testing – useful for monitoring therapy; refer to Key Points section
  • Imaging studies
    • DXA – for monitoring while taking an FDA-approved drug
      • 1–2 years after initiation of therapy
      • Follow-up in 23-month intervals is sufficient for monitoring therapy response
    • Peripheral densitometry (portable machines for mass screening of general populations) cannot be used for monitoring therapy

Clinical Background

Osteoporosis is a skeletal disorder characterized by decreased bone strength and density.

Epidemiology

  • Prevalence – 74% of females >80 years have osteoporosis
  • Age – onset usually >50 years
  • Sex – M<F
  • Ethnicity – lower incidence in African Americans

Risk Factors

  • Relative risk factors for primary osteoporosis (bone loss as a result of normal aging)
    • Caucasian or Asian race – increases by 1.5-3.0 for each T score decrease of 1.0 on bone mineral density (BMD)
    • Female sex
    • Older age – increases by 2-3 each decade >50 years
    • Low body weight (<127 lbs. or BMI ≤21) – increases by 1.2-2.0
    • Family history of osteoporosis
    • Personal history of fracture – increases up to 8
    • Tobacco history – increases by 1.2-2.0
    • History of hip fracture in first-degree relative – increases by 1.2-2.0
  • Risk factors for secondary osteoporosis (bone loss as a result of disease or medication)

Pathophysiology

  • Usually a result of age-related bone loss due to abnormal bone remodeling
  • May occur because patient did not reach optimal bone mass as an adolescent
  • Bone metabolism regulated by vitamin D, calcium, estrogens, androgens, parathyroid hormones

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 with a traumatic event)
  • Most common presentation in symptomatic patients
    • Height loss
    • Kyphosis
    • Bone pain
    • History of previous fractures

Treatment

  • Treatment recommendations (NOF, 2013)
    • Initiate treatment in individuals with
      • Hip or vertebral fractures (clinical or asymptomatic)
      • T-scores ≤-2.5 at femoral neck, total hip, or lumbar spine by DXA
      • Postmenopausal women and men ≥50 years with low bone mass (T-score between -1.0 and -2.5) at femoral neck, total hip, or lumbar spine by DXA and 10-year hip fracture probability ≥3% or 10-year major osteoporosis-related facture probability ≥20% (based on FRAX)
    • Once treatment is initiated, recommend DXA testing every 2 years
  • Rare complication – jaw osteonecrosis due to osteoporosis therapy
    • Majority of patients are on high-dose IV therapy with nitrogen-containing drug (bisphosphonates)
    • Occurs almost exclusively in oncology patients with dental problems
    • No monitoring tests available to predict this complication

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
C-Telopeptide, Beta-Cross-Linked, Serum 0070416
Method: Quantitative Electrochemiluminescent Immunoassay

Preferred test to measure bone resorption and monitor response to antiresorptive therapy (bisphosphonates, hormone replacement therapy)

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

Baseline concentration of CTX must be established before treatment begins

Intraindividual variability of CTX must be considered when interpreting test results (eg, diet, exercise, time of day)

May be significant overlap in CTX between individuals with and without osteoporosis

Test result cannot be used to predict fractures

CTX concentration may be higher than expected in individuals with reduced kidney function (reduced excretion of CTX)

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

Measure bone formation and monitor antiresorptive therapies

When using test to monitor osteoporosis therapy, recommend initial testing prior to beginning therapy and reevaluate 3-6 months after starting therapy

Less biological variation than s-CTX

Test cannot replace BMD screening to diagnose osteoporosis

Intraindividual variability of test due to diet, exercise, time of day, etc., must be taken into account when interpreting test results

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Screening test for osteoporosis

Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Rule out thyroid disease as etiology of osteoporosis

Vitamin D, 25-Hydroxy 0080379
Method: Quantitative Chemiluminescent Immunoassay

Assess for Vitamin D deficiency; rule out malabsorption and celiac disease in patients >50 years

Calcium, Serum or Plasma 0020027
Method: Quantitative Spectrophotometry

Detect hypercalcemia

Calcium, Urine 0020472
Method: Quantitative Spectrophotometry

Detect hypercalcemia

Phosphorus, Inorganic, Plasma or Serum 0020028
Method: Quantitative Spectrophotometry

Detect hypophosphatemia

Alkaline Phosphatase, Serum or Plasma 0020005
Method: Quantitative Enzymatic

Rule out Paget disease

Albumin by Nephelometry 0050671
Method: Quantitative Nephelometry

Rule out malnutrition

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Rule out chronic liver disease

Panel includes albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin, and protein

Renal Function Panel 0020144
Method: Quantitative Chemiluminescent Immunoassay/Quantitative Enzyme-Linked Immunosorbent Assay

Rule out renal disease

Panel includes albumin, calcium, carbon dioxide, creatinine, chloride, glucose, phosphorous, potassium, sodium, and BUN

Testosterone, Adult Male 0070130
Method: Quantitative Electrochemiluminescent Immunoassay

Rule out hypogonadism

Bone Specific Alkaline Phosphatase 0070053
Method: Quantitative Chemiluminescent Immunoassay

Measure bone formation and monitor antiresorptive therapies

When using test to monitor osteoporosis therapy, recommend initial testing prior to beginning therapy and reevaluate 3-6 months after starting therapy

N-Telopeptide, Cross-Linked, Urine 0070062
Method: Quantitative Chemiluminescent Immunoassay

Measure bone resorption and monitor antiresorptive therapy (eg, bisphosphonates and hormone replacement therapy)

When using test to monitor osteoporosis therapy, recommend initial testing prior to beginning therapy and reevaluate 3-6 months after starting therapy

N-Telopeptide, Cross-Linked, Serum 0070500
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Measure bone resorption and monitor antiresorptive therapy (eg, bisphosphonates and hormone replacement therapy)

When using test to monitor osteoporosis therapy, recommend initial testing prior to beginning therapy and reevaluate 3-6 months after starting therapy

Urine test preferred over serum

Osteocalcin by Electrochemiluminescent Immunoassay 0020728
Method: Quantitative Electrochemiluminescent Immunoassay

Measure bone formation and  monitor antiresorptive therapies

When using test to monitor osteoporosis therapy, recommend initial testing prior to beginning therapy and reevaluate 3-6 months after starting therapy

Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay

Rule out thyroid disease

Pyridinium Crosslinks (Total), Urine 0070213
Method: Quantitative Enzyme Immunoassay

Monitor therapeutic response, especially in a short amount of time (2-3 months)

Deoxypyridinoline Crosslinks, Urine 0070212
Method: Quantitative Enzyme Immunoassay

Alternate test for monitoring osteoporosis therapy

Pyridinoline and Deoxypyridinoline by HPLC 0080342
Method: High Performance Liquid Chromatography

Alternate test for monitoring osteoporosis therapy

Vitamin D, 1, 25-Dihydroxy 0080385
Method: Quantitative Radioimmunoassay

Primarily indicated during patient evaluations for hypercalcemia and renal failure

Should not be used to diagnose vitamin D deficiency; however, normal result does not rule out vitamin D deficiency

Recommended test for diagnosing vitamin D deficiency is Vitamin D 25-hydroxy

Parathyroid Hormone, Intact 0070346
Method: Quantitative Electrochemiluminescent Immunoassay

Rule out hyperparathyroidism