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A. Introduction navigator

  1. Definitions [3]
    1. Functionally, osteoporosis is low bone mass and consequent increased fracture risk
    2. Osteoporosis is now defined using quantitative bone mineral density (BMD)
    3. Osteoporosis is symptomatic osteopenia (fractures) or BMD >2.5SD below mean
    4. Osteopenia means "thin bone", with BMD 1-2.5 standard deviations (SD) below mean
    5. Normal values for BMD are based on nomograms including age and sex corrections
  2. Fractures are the major morbidity due to osteoporosis
    1. >50% of women will develop osteoporotic fractures over lifetime
    2. ~30% of men will develop osteoporotic fractures
    3. Fractures, usually in elderly, forces bedrest, lung atelectasis, pneumonia
    4. Vertebral fractures lead to back pain, lost work, possible bed restriction
  3. Epidemiology [4]
    1. Screening by BMD in post-menopausal women age >49 years
    2. Osteopenia prevalence is ~40%
    3. Osteoporosis prevalence is 7.2%
    4. Fracture Rate is ~6 per 1000 women-years for white women >65 years old
    5. Fracture risk is 4X for osteoporosis and 1.8X for osteopenia compared with normal BMD
  4. Overview of Etiology
    1. Osteoporosis is due to progressive loss of bone mass in both both sexes
    2. Both sexes have "slow" phases of bone loss with aging
    3. Some women have "fast" phase, usually in the perimenopausal period
    4. Some post-menopausal women have a very rapid phase of bone loss
    5. Ca2+ absorption is also decreased with increased compensatory osteoblast activity
  5. Osteoporosis During Lactation
    1. Bone density decreases ~5% in women who lactate for 6 months
    2. Increases (unknown if back to baseline) after weaning
    3. May be related to calcium loss through breast milk
    4. However, calcium supplementation alone does not prevent bone loss during lactation

B. Mechanisms [6,10,15] navigator

  1. Normal bone turnover is a lifelong continuous process
  2. One cycle of normal bone turnover takes about 8 months
  3. Bone turnover involves breakdown by osteoclasts and resynthesis by osteoblasts
    1. Osteoclasts are derived from granulocyte-macrophage precursors (hematopoietic cells)
    2. Osteoblasts are derived from nonhematopoietic cells (mesenchymal)
    3. Turnover is a coupled process: osteoblasts and osteoclasts interact
    4. Normal osteoblast-clast interactions lead to appropriate bone formation, degradation
  4. Osteoclast Activity [15]
    1. Increased, unbalanced osteoclast activity is major contributor to bone loss in peri-menopausal women
    2. This is a rapid process just after menopause begins and continues for up to 3 years
    3. Osteoblast activity also increases due to coupling, but is not sufficient for balance
    4. Estrogen (and androgens) both inhibit interleukin 6 (IL-6) production
    5. Interleukin (IL-) 6, IL-11, RANKL and chronic PTH all stimulate osteoclasts
    6. RANKL (receptor activator of nuclear kappa B ligand) on osteoblastic stromal cells binds to RANK on osteoclasts and induces differentiation [12]
    7. Blockade of RANKL with a monoclonal antibody improves bone density in humans [13]
    8. Pulsatile (normal) PTH primarily stimulates osteoblasts
    9. Chronic constant PTH stimulates osteoclasts
    10. Osteoclasts bind to bone via integrin alpha V beta 3 (aVß3)
  5. Osteoblast activity decreases in both sexes with age
    1. Mainly due to decreases osteoblast cell numbers
    2. Reduction in osteoblast activity is chronic and occurs in both sexes with aging
    3. Leptin also negatively impacts BMD, probably through inhibiting osteogenesis [7]
    4. Thus, obesity (with leptin resistance) is associated with increased bone mass
  6. Perimenopausal Bone Mineral Density (BMD) [8]
    1. BMD decreases ~2% per year without therapy
    2. At the distal radius, medullary bone diameter increases ~1.1% per year after menopause
    3. However, periosteal bone diameter increases ~0.7% per year after menopause
    4. Overall, bone strength index decreases ~0.7% per year after menopause
  7. Factors Affecting Perimenopausal BMD
    1. Overall reduction in bone strength after menopause has many factors
    2. May be related to reduced calcium absorption and increased renal loss with age
    3. Absorption (and renal loss) defect may be related to abnormal vitamin D action
    4. Relative hypocalcemia may lead to low grade hyperparathyroidism leading to bone loss
    5. Oral calcium therapy (with vitamin D) may suppress PTH secretion, protect bones
  8. Effects of Glucocorticoids on Bone Metabolism
    1. Decreases in gastrointestinal calcium absorption
    2. Increase urinary excretion of calcium
    3. These effects lead to secondary hyperparathyoidism
    4. Glucocorticoids also directly potentiate the effects of PTH
    5. Inhibit new bone formation: block osteoblast protein synthesis (collagen, osteocalcin)
    6. Reduce testosterone and other androgen levels
  9. LDL-Receptor-Related Protein 5 (LRP5) [9]
    1. Modulator of osteobast function and therfore bone formation
    2. Acts as a core receptor for Wnt (a signalling pathway) with Frizzled and Kremen proteins
    3. Target for inhibitory effects of Dickkopf (Dkk) on Wnt
    4. LRP5 mutations cause osteoporosis-pseudoglioma syndrome (autosomal recessive)
    5. LRP5 V171 mutation causes high BMD
    6. Other LRP5 mutations associated with osteoporosis and fractures [33]
  10. Other Genetic Associations [32,33,34]
    1. Genomewide DNA sequence variations evalatuated for osteporosis and fracture risk
    2. Five genomic regions associated with BMD in 5861 Icelanders; confirmed in over 6500 subjects
    3. RANKL idenitifed on chromosome 13q14
    4. Osteoprotegerin (OPG on chrom 8q24), which interacts with RANKL and RANK
    5. Estrogen receptor 1 gene (ESR1) on chrom 6q25
    6. Two additional loci idetified including zinc finger protein ZBTB40 on chrom 1p36
    7. OPG and LRP5 associated with osteoporosis and fractures in a seperate genomewide study [33]
  11. Sclerostin (product of SOST gene) also inhibits Wnt signalling, affects BMD

C. Risks and Protective Factorsnavigator

  1. Risk for Osteoporosis [5]
    1. Increasing age
    2. History of spinal or other fracture
    3. Reduced BMD - particularly in white (less so in black) women [18]
    4. Family history of osteoporosis
    5. Weight <51kg
    6. Tooth count <20
    7. Rib-pelvis distance <2 finger breadths
    8. Self-reported humped back
    9. Subclinical hypercortisolism may be a cause of "idiopathic" osteoporosis [14]
    10. Rheumatoid Arthritis is not associated with abnormalities in overall bone mass
  2. Risk Factors for hip fracture in White Women >65 years old
    1. Major morbidity associated with osteoporosis is hip fracture
    2. Previous fractures of any type after age 50 are a risk
    3. Hyperthyroidism - subclinical, active or previously - 1.8X risk [11]
    4. History of Maternal Hip Fractures - 2.0X risks
    5. Currentf anti-convulsants - 2.8X risk
    6. Inability to rise from a chair - 2.1X risk
    7. Calcaneal BMD - 1.6X increased risk per each Standard Deviation below mean
    8. Current use of benzodiazepines - 1.6X risk
    9. Smoking may adversely affect bone mass and reduce effects of hormones on bone
    10. Solid organ transplantation
    11. Undetectable serum estrogen levels
    12. Elevated serum concentrations of sex hormone binding globulin
  3. Factors which Increase Bone Mass in Women
    1. Estrogen Use
    2. Type II Diabetes Mellitus
    3. Thiazide Diuretic Use (particularly hydrochlorothiazide) [16]
    4. Increased Weight and Body Size (probably through leptin) [7,17]
    5. Muscle Strength
    6. Later age at menopause
    7. Greater Height
    8. Raloxifene, a mixed estrogen agonist-antagonist, clearly increases bone mass [1]
    9. Tamoxifen increases bone mass slightly
    10. Calcium intake (with vitamin D) is usually associated with increased bone mass
  4. Medications which Reduce Bone Mass [1]
    1. Aluminum containing compounds - antacids, anti-diarrheals, sucralfate
    2. Anticonvulsants
    3. Glucocorticoids - systemic > inhaled [20]
    4. Nonthiazide Diuretics
    5. Excess Thyroxine Replacement - with TSH levels below normal [11]
    6. Heparin (long term)
    7. Warfarin
    8. Cisplatinum
    9. Radiation Therapy
    10. Gonadotropin Releasing Hormone Blockade: pharmacologic menopause or castration
    11. Androgen or estrogen blockers - hormonal ablation therapy for malignancies [62]
    12. Vitamin D intoxication
    13. Vitamin A - excessive intake [22] and serum levels [59]
    14. Plicamycin
    15. Cyclosporin A
  5. Amenorrhea
    1. In absence of physical exercise is also a risk factor for osteoporosis
    2. Likely related to estrogen deficiency
    3. Particularly prevalent in women with anorexia nervosa [23]
  6. Endocrine and Metabolic Disorders leading to Osteopenia
    1. Diabetes mellitus
    2. Hyperparathyroidism
    3. Hyperthyroidism - clinical or subclinical [11]
    4. Glucocorticoid Excess (Cushing's Syndrome) including subclinical disease [14]
    5. Hypogonadism (pituitary or end organ)
    6. Renal Osteodystrophy
    7. Marked weight loss
    8. Anorexia nervosa - related to weight loss and estrogen deficiency [23]
    9. Inflammatory Bowel Disease - osteopenia associated fracture risk increased 40% [24]
  7. Hereditary Disorders with Osteopenia
    1. Homocysinuria
    2. Osteogenesis imperfecta
    3. Rickets / Osteomalacia
    4. Turner's and Klinefelter's Syndromes - gonadal failure
    5. Family history of osteoporosis is associated with reduced bone mass
  8. Genetic Predisposition to Osteoporosis
    1. Vitamin D receptor polymorphisms - data are unclear
    2. Estrogen Receptors
    3. Collagen I-alpha1
    4. Apolipoprotein E
    5. Transforming growth factor ß1 (TGF-ß1) gene polymphorphisms correlate with bone density and vertebral fractures [26]
  9. Risk factors for Osteoporosis in Men [21,25,31]
    1. Majority of cases of osteoporosis in men are secondary (should prompt BMD measure):
    2. Age >70 years
    3. Any fracture after minor trauma or possible vertebral fracture
    4. Physical inactivity
    5. Body-mass index <20 and significant weight loss
    6. Glucocorticoid Treatment: >5mg/day for >3 months
    7. Hypogonadism - surgically or medically induced [28,62], or disease-related
    8. Smoking
    9. Cushing's Syndrome
    10. Excessive alcohol consumption
    11. Anticonvulsants - phenytoin, carbamazepine, valproate (unclear for newer agents)
    12. Hyperthyroidism (severe) or excessive thyroid hormone replacement
    13. Hypercalciuria or reduced calcium index
    14. Inflammtory arthritis: rheumatoid arthritis, ankylosing spondylitis
    15. Malabsorption: including celiac disease
    16. Chronic kidney or liver disease
    17. Bone marrow neoplasia, particularly multiple myeloma
  10. Bone Loss in Liver Transplantation []
    1. Osteoporotic fractures are a frequent complication
    2. Lack of vitamin D from the liver is a major contributing factor
    3. Glucocorticoids, cyclosporine and bed rest also contribute
    4. The vitamin D receptor has a common polymorphism which may play a role
    5. Commonly, BB, Bb, and bb genotypes are found
    6. Patients with genotypes Bb and BB had a substantially higher bone loss within 3 months of transplantation
    7. From 3-24 months after transplant, all groups gained equal bone mass
    8. In non-transplanted persons, unclear if vitamin D receptor genotype plays a role
  11. Fracture Reduction
    1. Use of ß-adrenergic blockers associated with ~20% reduced risk for fractures [61]
    2. ESR1 (estrogen receptor alpha) polymorphisms associated with fracture, not BMD [19]
    3. In another study, estrogen receptor 1 gene polymorphisms were associated with BMD [32]
  12. Risk factor analyses are not sufficiently predictive to determine which patients should undergo BMD determination [2]

D. Symptoms and Evaluation [3] navigator

  1. Fractures are Main Symptom
    1. Approximately 1.5 million fractures annually
    2. Vertebral (compression) fractures are most common (usually low back pain)
    3. Hip fractures suggest that bone loss has progressed considerably
    4. Risk of fractures in Blacks and Hispanics is ~30% that of Whites and Orientals
    5. One vertebral fracture increases risk of a new vertebral fracture within 1 year by 5X [29]
  2. Indications for Bone Densitometry [30,45,56,57]
    1. Postmenopausal women >65 years old
    2. Postmenopausal women <65 years old with additional risk factors
    3. Premenopausal women or men with fragility fracture or secondary causes
    4. Consider BMD measure in men >60-65 years old with any risk factors (see above) [31]
    5. Finding low BMD may help persuade patients who are resistant to therapy
    6. Finding low BMD may also help determine level of therapeutic aggressiveness
  3. Bone Density Tests [45,54,55]
    1. Dual Energy, X-Ray Absortiometry (DEXA) Scan is most reliable screening test
    2. This screening uses two photon beams aimed at bone targetted for measurement
    3. Differential absorption of beams allows excellent estimate of BMD
    4. DEXA should be performed on both vetebrae and femoral neck areas (most useful)
    5. BMD at femoral neck is best predictor for hip fracture risk
    6. In older persons, osteoarthritis may interfere with accurate vertebral measurements
    7. Persons with BMD >2.5 SD below mean have very high risk of osteoporotic fractures
    8. BMD screening for women with increased osteoporosis risk is recommended [54,55]
    9. General screening in postmenopausal women >60 years is not clearly beneficial [55]
    10. Screening for osteoporosis associated with 35% reduction in fractures [37]
    11. BMD correlates better with nonspinal fractures in white compared with black women [18]
    12. Quantitative ultrasound is not sufficiently accurate for detection of osteoporosis [70]
  4. Biochemical Markers of Bone Formation
    1. Osteocalcin
    2. Serum Alkaline phosphatase - bone derived is sometimes elevated (not very sensitive)
    3. Procollagen extension peptides
  5. Biochemical Markers of Bone Resorption
    1. Acid Phosphatase, tartrate resistant
    2. Urine Calcium
    3. Urine Hydroxyproline
    4. Urine Pyridinoline (Deoxypyridinoline)
    5. N-telopeptide (urinary NTx) - type I collagen degradation; 30% changes are significant
  6. Search for underling causes as described above for high turnover osteoporosis

E. Overview of Treatments navigator

  1. Calcium + Vitamin D [35]
    1. Essentially all persons at risk for osteoporosis should be taking calcium + vitamin D
    2. Many elderly persons are deficient in vitamin D, particularly in nursing homes
    3. Calcium citrate is acceptable in most persons with history of renal stones [35]
    4. Calcium + Vitamin D did not reduce fractures in elderly with previous low-trauma fractures [63]
    5. Men with osteoporosis are treated in a fashion similar to women [21]
  2. Bisphosphonate Therapy
    1. Usually reserved for patients with demonstrated osteoporosis (by BMD or similar test)
    2. These agents are extremely potent and generally well tolerated (over 3-5 years)
    3. Discontinuation of alendronate associated with stable BMD (compared with ERT) [64]
    4. Most patients do not derive benefit after 5 years of bisphosphonate (alendronate)
  3. Selective Estrogen Receptor Modifiers (SERMs) [65,66]
    1. SERMs recomended over any hormone replacement therapy (HRT or ERT)
    2. Raloxifene is very effective and is currently only approved SERM
    3. ERT/HRT not routinely recommended in menopausal women due to overall side effects
  4. PTH
    1. Most potent of all agents
    2. Only approved agent that directly stimulates osteoblasts
    3. Only available as subcutaneous (sc) injection at this time
  5. Oral strontium ranelate 2gm daily stimulates bone formation and reduce fractures [67]
  6. Calcitonin is now considered third line; use for patients intolerant of other agents
  7. Inhibition of RANKL [12,13]
    1. Denosumab, humanized monoclonal, blocks RANKL action
    2. Denosumab sc treatment every 3-6 months for 1 year increased lumbar spine BMD similar to alendronate, and reduced serum C-telopeptide and other markers of bone turnover
  8. Combination Therapies
    1. Bisphosphonates may be added safely to calcium and vitamin D
    2. PTH and bisphosphonates should not be combined
  9. Monitoring Therapy [68]
    1. BMD often used to follow drug efficacy, though correlation with fracture risk is inexact
    2. Markers of bone turnover (such as Urinary N-Tx) can be used to assess acute effects
    3. BMD is useful for longer term effects on bone density [45]
    4. In patients whose BMD decreases at year 1 on active therapy, recommend continuing treatment for additional year since >80% will have increases on BMD in year 2 [69]
    5. Current monitoring markers are poor for predicting fracture risk in individual patients

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