Osteoporosis

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 (DEXA) with no risk factors
- BMD T scores < -1.5 by hip/spine DEXA with 1 or more risk factors
- Prior vertebral or hip fracture
Once treatment is initiated, recommend DEXA 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 known 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 for falls

Indications for Testing

Initiated through population screening or when patient presents with suspicious fracture

Laboratory Testing

May be useful to rule out secondary causes of osteoporosis
Serum calcium
- Hypercalcemia – rule out hyperparathyroidism, multiple myeloma, cancer
CBC demonstrating anemia – rule out underlying conditions such as multiple myeloma, cancer
Alkaline phosphatase – rule out Paget disease
Serum albumin – rule out malnutrition
Vitamin D 25(OH)D – measure for vitamin D deficiency; rule out malabsorption and celiac disease in patients >50 years
Thyroid stimulating hormone (TSH) – rule out hyperthyroidism

Imaging Studies

DEXA
- 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 DEXA
  - 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
Peripheral densitometry (portable machines for mass screening of populations)
- Measures BMD of hand, heel or radius
- If abnormal, need confirmatory DEXA
VFA (vertebral fracture analysis)
- Component of DEXA
- 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

Assessments, recommendations and scoring criteria

WHO FRAX® (Fracture Risk Assessment) tool – provides 10-year 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) DEXA 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)
- DEXA 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 (2009)*	Yes	≥60 years who are at increased risk
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 DEXA
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

Monitor patients receiving treatment
- Laboratory testing – useful for monitoring therapy; order 3-6 months after initiating antiresorptive therapy
  - Recommendations for markers (no markers proven to be better than others [Simon, 2007])
    - Synthesis markers – serum propeptide of type I procollagen (PINP)
      - Increase from baseline level indicates therapeutic response
    - Resorptive markers – urinary C and T pyridinium and N- or C-telopeptides crosslinks (NTx or CTx)
      - Urine and serum cross-linked N-telopeptides (NTx) – collagen breakdown products
        ≥30% decrease in urinary NTx indicates therapeutic response
      - Serum cross-linked C-telopeptides (CTx) – collagen breakdown products
        ≥30% decrease in serum CTx indicates therapeutic response
    - 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
    - Bone formation markers
    - Serum PINP – by-product of collagen synthesis
      - Best monitoring marker for patients on parathyroid hormone (PTH) therapy
    - Bone resorption markers
  - Creatinine clearance (annually)
    - If <35 mL/min/1.73m², biphosphate use not recommended
- Imaging studies
  - DEXA (1–2 years after starting therapy)
    - Monitor while taking an FDA-approved drug
    - DEXA 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

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Results showing anemia are suggestive of multiple myeloma, cancer or malabsorption

Test name: Thyroid Stimulating Hormone

ARUP #: 0070145

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use:

Rule out hyperthyroidism

Test name: Vitamin D, 25-Hydroxy

ARUP #: 0080379

Methodology: Quanititative Chemiluminescent Immunoassay

Use:

Assess for Vitamin D deficiency

Test name: Calcium, Serum or Plasma

ARUP #: 0020027

Methodology: Quantitative Spectrophotometry

Use:

Detect hypercalcemia

Test name: Alkaline Phosphatase, Serum or Plasma

ARUP #: 0020005

Methodology: Quantitative Enzymatic

Use:

Rule out Paget disease

Test name: Albumin, Serum by Nephelometry

ARUP #: 0050671

Methodology: Quantitative Nephelometry

Use:

Rule out malnutrition

Test name: C-Telopeptide, Beta-Cross-Linked, Serum

ARUP #: 0070416

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use:

Aids in monitoring antiresorptive therapies (eg, bisphosphonates and hormone replacement therapy) in postmenopausal women

Limitations:

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

Test name: Procollagen Type I Intact N-Terminal Propeptide

ARUP #: 0070236

Methodology: Quantitative Radioimmunoassay

Use:

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

Limitations:

Less biological variation

Test name: N-Telopeptide, Cross-Linked, Urine

ARUP #: 0070062

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

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

Test name: N-Telopeptide, Cross-Linked, Serum

ARUP #: 0070500

Methodology: Quantitative Enzyme-Linked Immunosorbent Assay

Use:

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

Limitations:

Urine test preferred over serum

Test name: Bone Specific Alkaline Phosphatase

ARUP #: 0070053

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Measures percent of alkaline phosphatase that is related only to the bone

Limitations: Liver alkaline phosphatase can affect the measurement of bone-specific alkaline phosphatase in this assay

Test name: Osteocalcin by Electrochemiluminescent Immunoassay

ARUP #: 0020728

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use:

Reflects and predicts 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

Test name: Pyridinium Crosslinks (Total)

ARUP #: 0070213

Methodology: Quantitative Enzyme Immunoassay

Comments:

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

Test name: Deoxypyridinoline Crosslinks

ARUP #: 0070212

Methodology: Quantitative Enzyme Immunoassay

Comments:

Test name: Hydroxyproline, Total Urine

ARUP #: 0080328