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, bone marrow density (BMD) is recommended 12 to 24 months post therapy initiation (NOF, 2010; Endocrine Society, 2012; International Society for Clinical Densitometry, 2008).  However, with the addition of bone turnover markers (BTMs), treatment efficacy and patient compliance can be determined 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 Test

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

Bone Resorption Markers

ARUP Test

  • Serum collagen type I cross-linked telopeptide (s-CTX)
  • C-Telopeptide, Beta-Cross-Linked, Serum 0070416
  • Urine or serum N-telopeptide (u-NTX, S-NTX)
  • N-Telopeptide, Cross-Linked, Urine 0070062
  • N-Telopeptide, Cross-Linked, Serum 0070500
  • Urine pyridinoline (PYD)
  • Pyridinium Crosslinks (Total), Urine 0070213
  • Pyridinoline and Deoxypyridinoline by HPLC 0080342
  • Urine deoxypyridinoline (DPD)
  • Deoxypyridinoline Crosslinks, Urine 0070212
  • Pyridinoline and Deoxypyridinoline by HPLC 0080342  
  • Urine hydroxyproline
  • Older, nonspecific marker for bone resorption
  • Recommend
    • 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 3-6 months followup
    • Bone resorption markers – after 3 months
    • Bone formation markers – after 6 months
  • Sample collection
    • Suggest morning collection from fasting patients due to diurnal variation of markers and effect from foods  (Endocrine Society Clinical Practice Guideline, 2012)
    • If not possible, collect samples under the same circumstances (eg, same time)
  • Interpretation
    • Most societies consider ≥30% change from baseline as a true change

Which Tests to Use for Monitoring

  • No marker proven better than others (Lee, 2012)
  • IOF-IFCC (2011) goal is to standardize markers used in monitoring in an effort to allow for collaborative data collection
  • Bone formation markers
    • Recommended marker – PINP (IOF-IFCC, 2011)
      • ARUP test – Procollagen Type I Intact N-Terminal Propeptide 0070236
    • Best test for patients on PTH therapy or anabolic therapy
    • Interpretation
      • Increase from baseline levels indicates therapeutic response
  • Bone resorption markers
    • Recommended marker – s-CTX (IOF-IFCC, 2011)
      • ARUP test – C-Telopeptide, Beta-Cross-Linked, Serum 0070416
    • Best test for patients on antiresorptive therapy
    • Interpretation
      • Decrease from baseline levels indicates therapeutic response
      • Increased levels 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 
    • Serum calcium/phosphorus
    • CBC – if anemia present, rule out underlying conditions such as multiple myeloma, cancer, malabsorption
    • Alkaline phosphatase – rule out Paget disease
    • 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

Imaging Studies

  • Dual-energy x-ray absorptiometry (DXA)
    • Gold standard for diagnosis
    • Measures bone marrow density (BMD) of lumbar spine, total hip or femoral neck
      • Compares BMD to normal populations to generate T scores
      • T score ≤-2.5 confirms osteoporosis (WHO definition)
      • T score between -1.0 and -2.4 confirms osteopenia
    • Indications for measuring BMD by DXA (NOF 2010, ISCD 2007)
      • Women age 65 and older and men age 70 and older, regardless of clinical risk factors
      • Younger postmenopausal women and men age 50 to 69 for whom clinical risk factor profile indicates concern
      • Women in the menopausal transition with a specific clinical risk factor associated with increased fracture risk
      • Adults with fracture after 50
      • Adults with a condition associated with low bone mass or bone loss
      • Anyone considered for pharmacologic therapy for osteoporosis
      • Anyone on therapy for osteoporosis for monitoring
      • Anyone not receiving therapy in whom evidence of bone loss would lead to treatment
      • Postmenopausal women discontinuing estrogen
    • Endocrine Society 2012 recommends testing in "older men" and men who are "at risk"
  • Peripheral densitometry (portable machines for mass screening of populations)
    • Measures BMD of hand, heel, or radius
    • If abnormal, need confirmatory DXA
  • Vertebral fracture analysis (VFA)
    • Component of DXA
    • Assists in identifying possible vertebral fractures
    • Confirm fracture with x-ray
    • Indications
      • Documented height loss >2 cm
      • Fracture in person >50 years
      • Long-term glucocorticoid treatment
      • Other findings suggestive of fracture

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 men, women, or children outside the age range
        • Calculations available for 4 ethnic groups only (Caucasian, African American, Hispanic, Asian)
        • Other important risk factors not included (eg, falls, high-bone tumor, 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 fracture
        • Perform physical exam 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 this 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 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 >2 years or when medically appropriate
    • Guidelines for bone density screening

      Indications for Bone Density Screening – Summary of Society Recommendations

       

      ISCD 2010

      ACP 2011

      NOF 2010

      AACE 2010,2012

      USPSTF 2011

      ACOG 2012

      Women

      ≥65  

      Recommended regardless of clinical risk factors

      YES

      YES

      YES

      YES

      YES

      YES

      <65 

      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 

      Recommended regardless of clinical risk factors

      YES

      YES

      YES

      YES

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

      NA

      <70

      If clinical risk profile* indicates risk for fracture

      YES

      YES

      YES (ages 50-69)

      YES (ages 50-69)

      NA

      *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 OP
      • 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 College of Obstetrics and Gynecology
    • QFracture™ scoring calculator – newest non-validated scoring system

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 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 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 hormone

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

  • Indications for treatment (National Osteoporosis Foundation)
    • BMD T scores <-2.0 by hip/spine dual-energy x-ray absorptiometry (DXA) with no risk factors
    • BMD T scores <-1.5 by hip/spine DXA with 1 or more risk factors
    • Prior vertebral or hip fracture
  • Once treatment is initiated, recommend DXA 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

Prevention

  • Discontinue tobacco use
  • Avoid excess alcohol intake
  • Engage in weight-bearing activities (lifelong)
  • Adequate calcium and vitamin D intake in childhood and adolescence
  • Continued adequate intake of calcium and vitamin D as an adult
  • Preventative measures taken for the elderly to reduce falls

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

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

Test cannot replace bone mineral density to diagnose osteoporosis

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

  
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 CTx

  
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
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
Testosterone, Adult Male 0070130
Method: Quantitative Electrochemiluminescent Immunoassay

Rule out hypogonadism
Bone Specific Alkaline Phosphatase 0070053
Method: Quantitative Chemiluminescent Immunoassay

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