1. DEFINITIONS

   Osteoporosis is a disease characterized by decreased bone mass, increased bone fragility, and a higher incidence of fractures. Primary osteoporosis accounts for 80% of the disease. Secondary osteoporosis refers to bone loss due to an identifiable cause such as disease, drugs, or immobility.

2. DIAGNOSIS

   The diagnosis is made by evaluating the patient's history, conducting a physical exam, and measuring bone density. The practical dividing line between normal bone density and osteoporosis is a bone mineral density greater than 2.5 SD below the mean. By definition a BMD 1.0 SD below the mean is called osteopenia.

3. INCIDENCE

   Osteoporosis is a considerable public health problem in the United States. It affects 25 million Americans and is the underlying cause of 1.5 million fractures annually. Osteoporosis related fractures will occur in 50% of women older than 65 years. Within one year of a fracture, 8% will die and 25% will be confined to long-term care facilities. At age 80, 20% of hip fractures will lead to death.

4. BONE METABOLISM AND REMODELING

   The human skeleton is made of 25% trabecular bone and 75% cortical bone. Cortical (compact) bone forms the outer shell of all bones. Cortical bone has a slower turnover rate and is metabolically less active than trabecular bone. Trabecular or cancellous bone is a spongy network that forms the internal support within the cortical bone shell. It is concentrated in the vertebral bodies, pelvis, and ends of the long bones. Trabecular bone is metabolically very active and has a high turnover rate.

   Bone resorption is carried out by the osteoclasts, and osteoblasts are the bone forming cells. Osteoblasts synthesize and release most of the protein constituent of the bone's matrix including Type I collagen and noncollagenous proteins. These cells are rich in alkaline phosphatase. 10-30% of the adult skeleton is remodeled each year.

5. PRACTICAL ASPECTS OF BONE MINERAL MEASUREMENT
   1. General Information

      Over the past 15 years there has been a rapid evolution of noninvasive techniques to quantitate bone mineral density (BMD). There are five basic techniques currently used for noninvasive assessment of the skeleton:

      1. Photo densitometry
      2. Single photon absorptiometry (SPA)
      3. Dual photon absorptiometry (DPA)
      4. Dual energy x-ray absorptiometry (DEXA or DXA) = Dual energy radiography (DER) = Digital radiographic absorptiometry (DRA) = Quantitative radiography (QRA)
      5. Quantitative computer tomography (QCT),

      and three experimental techniques:

      1. Quantitative ultrasound, Ultrasound transmission velocity (UTV)
      2. Triple photon absorptiometry
      3. Neutron activation analysis

      Amount of trabecular vs. cortical bone at different sites:

      1. Distal radius 2. Ultradistal radius 3. Calcaneus 4. Vertebral body (lumbar)

      Cortical (%) 96 40 5 40

      Trabecular (%) 4 60 95 60

      The National Osteoporosis Foundation has identified the following as indications for BMD measurement.

      1. In estrogen deficient women to diagnose osteoporosis for making decisions about HRT.
      2. In patients with vertebrae abnormalities
      3. In patients on long-term glucocorticoid therapy
      4. In asymptomatic hyperparathyroidism

   2. Techniques
      1. Conventional X-ray Studies (Photo Densitometry): One of the first quantitative techniques developed. Standardized radiographs of various bones together with an aluminum wedge are obtained. Density of the bone is compared to the defined density of the wedge by using an optical densitometer. Not very sensitive.
      2. SPA: Used since the 1960's, SPA uses a photon beam from a radionucleotide source, iodine 125, and a scintillation detector to assess bone mass in the peripheral skeleton at sites of principally cortical bone, such as the distal third of the radius. To keep the absorption through the soft tissue constant, the extremity is placed in water. Not possible to measure thick body sites. Accuracy of 6%; Precision 1-3%. The major problem is the great change in density over a small area. Because of the complex nature of the radius, positioning errors can be made. Low radiation dose.
      3. DPA and DXA: DPA is an evolutionary product of SPA incorporating a multi-energy source gadolinium 153, which permits the scanning of thicker body parts. Traditionally, spine and hip measurements are used. In the past 5 years this modality has been replaced by DXA. The DXA is based on the same principle as DPA except DXA utilizes an x-ray tube instead of a radionucleotide source. DXA is the most precise of the commonly available scanning techniques. The use of the x-ray source results in a shorter scan time (2 minutes vs. 40 minutes), greater accuracy and precision, higher resolution, and lack of radionucleotide decay. There is a strong correlation between DXA and DPA (r=0.98), therefore, normative data generated by DPA can be extrapolated to DXA. The usual locations for DXA measurements are the lumbar spine, proximal femur, and whole body. Hip measurement usually taken at Ward's triangle which consists mostly of trabecular bone. Ward's triangle is on the proximal femur in the intertrochanteric region. Best brands of DXA machines are Halogic or Lunar. A total body scan takes less than 5 minutes. Radiation dose is low.

         		Accuracy	Precision
         DPA
         	lumbar	5-10%	2-4%
         	femur	5-10%	3-5%
         DXA
         	lumbar	4-8%	1%
         	femur	4-8%	2%

         Vertebral osteophytes, aortic calcification, and fractures can alter the reliability of a DPA or DXA scan.

      4. QCT: Uses commercially available CT scanners operating in a quantitative mode instead of an imaging mode. This technique allows the direct measurement of trabecular bone found principally in the spine. This method allows for three dimensional true density measurements. Bone measurements of trabecular and cortical bone can be figured separately in the same bone. Phantoms are used for calibration. When measuring vertebral density, a phantom is placed under the patient's back and scanned simultaneously. QCT are unaffected by vertebral osteophytes and aortic calcification. Single energy 5-15% 4% Dual energy 3-10% 6% (more radiation than single)
      5. Ultrasound: Measures distal phalanges of the second or third finger or the heel. Main advantages are the complete absence of radiation and the low cost of the equipment. Many questions need to be answered about this modality before its widespread use, but it shows great promise for screening programs.
      6. Triple photon absorptiometry: In dual photon, errors occur because of the false assumption that there is a homogenous deposition of fat throughout the torso. To overcome this problem, the use of three gamma ray energies separate bone from soft tissue from fat. Only measures cortical bone.
      7. Neutron activation analysis: A method of gamma ray neutron activation analysis for the absolute measurement of total body calcium (TBC) utilizing total body chloride measurements.

   3. Interpretation of Results of BMD Studies

      Bone density measurements should be compared with age-matched, sex-matched, and race-matched controls. A normatative database is mandatory for the interpretation of BMD. Usually, BMD is given a Z-score or a T-score. The Z-score shows the results as the difference from the mean of age-matched controls divided by the standard deviation. Z-scores indicate biologic variability. The T-score refers to the peak bone mass of young normal adults and is calculated the same as a Z-score.

   4. Biochemical Tests

      Bone mass measurements are relatively static indicators of bone health and do not reflect the activity of the bone remodeling cycle.

      1. Fasting urinary calcium corrected by creatinine excretion is used commonly but lacks sensitivity.
      2. Alkaline phosphatase - an enzyme localized in the membranes of osteoblasts and released into the circulation. Serum total alkaline phosphates activity is frequently used as a marker of bone formation despite its low sensitivity and specificity.
      3. Osteocalcin - also called bone Gla protein. Is released into the circulation during bone formation. Serum levels of osteocalcin correlate with the spontaneous rate of bone loss assessed by serial bone mineral measurements of the radius and lumbar spine. Noncarboxylated osteocalcin is the first biochemical marker of bone fragility.
      4. Pryridinoline and deoxpyridinoline - present in mature Type I collagen are released from the bone matrix during degradation by osteoclasts and levels can be detected in the urine. Assays are not clinically available, however.
      5. C-terminal telopeptide - commercially available urinary ELISA assays quantify crosslinked N terminal telopeptide and is a specific and sensitive indicator of Type I collagen resorption from bone. These assays can help identify accelerated bone loss as well as monitor effects of therapy.

6. TREATMENT OPTIONS FOR OSTEOPOROSIS
   1. Estrogen (ERT)
      1. Loss of sex steroids is the primary pathogenic factor for bone loss.
      2. Retards bone loss regardless of age. Best benefits seen in first 10 years after menopause which is the time of highest bone loss.
      3. When ERT is stopped, bone loss resumes and is not at an accelerated rate. Therefore, even short treatment periods with ERT will decrease incidence of fractures later in life.

   2. Calcium

      Peak bone mass at age 18-22. Therefore Ca++ important in adolescence. Calcium absorption from the intestine declines with age. By age 65, most women absorb less than 50% of their dietary calcium.

      1. Daily requirements
         1. 1000 mg for adult women in reproductive years
         2. 1500 mg for adult postmenopausal women not on ERT
         3. 1200 mg for adolescents
         4. Ca++ plays an important role but need ERT to be really effective
      2. Calcium forms - only elemental calcium can be absorbed
         1. Calcium carbonate - 40% elemental calcium
         2. Calcium citrate - 24% elemental calcium (more bioavailable)
         3. Calcium lactate - 13% elemental calcium

   3. Calcitonin
      1. Cannot be administered orally. There are subcutaneous and nasal spray forms. Salmon calcitonin is more potent than human calcitonin.
      2. Inhibits bone resorption. Is useful in osteoporosis with high bone turnover.
      3. Exhibits a significant analgesic effect in 50% of patients (have relief of osteoporotic and fracture pain within 2 weeks).

   4. Biphosphonates [Didronel (Etidronate), Fosamax (Alendronate), Aredia (Pamidronate)]
      1. The biphosphonates are analogues of inorganic pyrophosphate. Biphosphonates bind tightly to the bones hydroxyapatite crystal matrix. Hydroxyapatite is the calcium phosphate mineral present in bone. Biologically, biphosphonates reduce bone resorption by inhibiting osteoclasts function. Bone surfaces coated with biphosphonates are less likely to attract, bind, and activate osteoclasts.
      2. Biphosphonates have a strong long-term inhibitory effect on bone resorption.
      3. Biphosphonates can inhibit the growth and dissolution of hydroxyapatite crystals and their amphorous precursors.
      4. Biphosphonates bind to calcium phosphate (hydroxyapatite) surfaces.
      5. Only 3% of Didronel (Etidronate disodium) is absorbed after an oral dose. Bone clearance takes 165 days to years. Fosamax (Alendronate) has a half-life of 10 years in bone.
      6. Therapy should be withheld from patients with colitis as it causes significant diarrhea in these patients. Intestinal absorption is very poor and diminished in the presence of food, especially calcium and iron.
      7. Etidronate also inhibits the mineralization of newly synthesized bone limiting its use. However, alendronate inhibits bone resorption at a 1000-fold lower dose and does not inhibit mineralization. Furthermore, bone formed during alendronate treatment is biochemically and histologically normal.
      8. Dosage: Biphosphonates are given in a single oral dose and patients should avoid eating food high in calcium, milk, milk products, vitamins, mineral supplements, antacids, and foods high in "metals" such as calcium.
         Etidronate:
         5-10 mg/kg/day not to exceed 6 months of use, or
         11-20 mg/kg/day not to exceed 3 months of use
         Alendronate:
         10 mg daily
         
         Patients must be out of bed for the day, take the medication with a full 8 ounces of water, and must not lie down for 30 minutes or eat for 1 hour.
         Must not be taken at bedtime.
         In two identical double blind placebo controlled trials, 994 women aged 44-84 years with osteoporosis were treated with alendronate. Studies revealed 7-10% increase in BMD of the lumbar spine, 5-6% of the femoral neck, and 7-8% at the hip compared to placebo. These increases were associated with a reduction in vertebral fracture.

   5. Fluoride
      1. Increases bone formation in the trabecular part of bone, especially the spine. Stimulates osteoblast mediated new bone growth.
      2. Adverse GI effects in 50% of patients, limiting its use. May form abnormal bone and lead to increased bone fragility.
      3. Adverse lower extremity pain in 50-60% of patients.
      4. Adverse GI effects overcome by giving calcium carbonate with fluoride. Lower extremity pain resolved when discontinuing therapy (within 6 weeks) and rarely recurs when therapy reinstituted at a lower dose. Narrow margin of safety between safe and toxic doses.

   6. Vitamin D
      1. 400-500 IU vitamin D daily for older homebound adults.
      2. Limited data suggest reduction in fracture frequency.
      3. Enhances intestinal calcium absorption.

   7. PTH
      1. Low-dose injections stimulate bone formation, high doses lead to increases in bone resorption.
      2. Still very investigational, not approved for use.

   8. Selective Estrogen Receptor Modulators (SERM's)

      Raloxifene is a nonsteroidal benzothiophene in the class of selective estrogen receptor modulators (SERM's). Daily therapy increases BMD compared to controls (2% hip, 2.5% spine). However, when compared to estrogen, estrogen improves BMD better than raloxifene (dose 30-150 mg daily).

   9. Progestins

      When administered alone in high doses, progestins have been shown to preserve bone density and decrease the levels of biochemical markers of bone remodeling through an antiresorptive process in some trials. However, these data are controversial as one trial using Provera 20 mg daily for 2 years showed no benefit with progestins (Gallagher 1991).

   10. Tibolone

       Tibolone is a synthetic steroid that has estrogenic, progestational and androgenic effects. It has been shown to increase BMD in the spine and forearm in prospective trials. Side effects include vaginal bleeding (15%) and breast tenderness (18%). There is also an associated decrease in HDL. Tibolone is not available in the United States.

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