Osteoporosis

Dx
Screen
Monitor
Background
Lab Tests

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
  - If hypercalcemia present – rule out hyperparathyroidism, multiple myeloma, cancer
  - Hypophosphatemia – suggests osteomalacia
- 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 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 2009, ISCD 2007)
  - Estrogen-deficient female
  - All females ≥65 years old
  - Vertebral abnormalities suggestive of osteoporosis
  - Chronic glucocorticoid therapy
  - Primary hyperparathyroidism or other diseases with known risk for development of osteoporosis
  - Prior history of fragility fracture
- ACP 2008 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

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

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 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 correct WHO FRAX^® 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 (clinical or morphometric) DXA hip (femoral neck or total site) or spine T score ≤-2.5 Low bone mass (T score between -1 and -2.5 based on FRAX) and 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

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
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 correct WHO FRAX^® 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 (clinical or morphometric)
- DXA hip (femoral neck or total site) or spine T score ≤-2.5
- Low bone mass (T score between -1 and -2.5 based on FRAX) and 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 osteoporosis screening

Organization	Women ≥65 years	Women <65 years	Others
U.S. Preventive Services Task Force (2011)*	Yes	Any female with 10-year probability of fracture ≥9.3%
American Association of Clinical Endocrinologists (2003)	Yes	<65 years who have 1 or more risk factors History of fracture not caused by severe trauma
American College of Obstetricians and Gynecologists (2004)	Yes	<65 years who have 1 or more risk factors Postmenopausal with history of fracture Do not screen more than every 2 years
National Osteoporosis Foundation (2008)	Yes	50-70 years who have 1 or more risk factors	Men ≥70 years All adults >50 years with family history All adults considered for osteoporosis therapy Monitor anyone on therapy
American College of Physicians (2008)	No recommendation		Assess for risk in older men If male at risk for osteoporosis, obtain DXA
International Society for Clinical Densitometry (2008)	Yes	Fragility fracture	Men ≥70 years Men 50-69 years with risk factors All individuals with risk-factor history All adults considered for osteoporosis therapy Monitor anyone on therapy
*No trials available to document benefits of screening

QFracture™ scoring calculator – newest non-validated scoring system

Monitoring

Monitor patients receiving treatment
- Laboratory testing – useful for monitoring therapy; order 3-6 months after initiating antiresorptive therapy
  - Bone markers
    - Cannot be used to make decisions regarding treatment initiation
    - Need initial testing prior to therapy initiation and repeat testing 4-6 months later
  - Recommendations for markers (no markers proven to be better than others [Simon, 2007])
    - Bone formation synthesis markers – serum propeptide of type I procollagen (PINP)
      - Serum PINP – by-product of collagen synthesis
        Best monitoring marker for patients on parathyroid hormone (PTH) therapy
      - Increase from baseline level indicates therapeutic response
    - Bone resorptive markers – urinary C and T pyridinium and N- or C-telopeptides crosslinks (NTx or CTx)
      - Collagen breakdown products
      - ≥30% decrease in urinary NTx or serum CTx indicates therapeutic response
  - Creatinine clearance (annually)
    - If <35 mL/min/1.73m², biphosphate use not recommended
- Imaging studies
  - DXA (1–2 years after starting therapy)
    - Monitor while taking an FDA-approved drug
    - DXA measurements at 23-month intervals are 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)
- Medications – glucocorticoids, immunosuppressive therapy, thyroxine, aromatase inhibitors, thiazolidine, anticonvulsant therapy (eg, phenytoin)
- Cushing syndrome
- Chronic renal disease
- Hyperthyroidism
- Vitamin D deficiency
- Cancer therapy
- Malabsorptive disorders (eg, Crohn disease, celiac disease)
- Hypogonadism
- Amenorrhea

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
CBC with Platelet Count and Automated Differential 0040003 Method: Automated Cell Count/Differential	Results showing anemia are suggestive of multiple myeloma, cancer or malabsorption
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108 Method: Quantitative Electrochemiluminescent Immunoassay	Rule out hyperthyroidism change to evaluate for thyroid disease
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, Serum 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
C-Telopeptide, Beta-Cross-Linked, Serum 0070416 Method: Quantitative Electrochemiluminescent Immunoassay	Aid in monitoring antiresorptive therapies (eg, bisphosphonates and hormone replacement 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
N-Telopeptide, Cross-Linked, Urine 0070062 Method: Quantitative Chemiluminescent Immunoassay	Measure bone resorption and monitor bone formation 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 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
Procollagen Type I Intact N-Terminal Propeptide 0070236 Method: Quantitative Radioimmunoassay	Most effective marker of bone formation and is particularly useful for monitoring bone formation therapies and 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
Bone Specific Alkaline Phosphatase 0070053 Method: Quantitative Chemiluminescent Immunoassay	Measure percent of alkaline phosphatase that is related only to the bone	Liver alkaline phosphatase can affect the measurement of bone-specific alkaline phosphatase in this assay
Osteocalcin by Electrochemiluminescent Immunoassay 0020728 Method: Quantitative Electrochemiluminescent Immunoassay	Reflect and predict the rate of bone loss in postmenopausal women; measures bone formation May assist in choosing most effective treatment for osteoporosis When using test to monitor osteoporosis therapy, recommend initial testing prior to beginning therapy and reevaluate 3-6 months after starting therapy

Additional Tests Available

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Thyroid Stimulating Hormone 0070145 Method: Quantitative Electrochemiluminescent Immunoassay
Pyridinium Crosslinks (Total) 0070213 Method: Quantitative Enzyme Immunoassay	Monitor therapeutic response, especially in a short amount of time (2-3 months)
Deoxypyridinoline Crosslinks 0070212 Method: Quantitative Enzyme Immunoassay
Hydroxyproline, Total Urine 0080328 Method: Ion Exchange Chromatography
Pyridinoline & 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