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Osteoporosis. Tracie Wilcox MD Assistant Professor of Medicine University of Chicago PGY 2 Lecture Series. Learning Objectives. Know when to screen for osteoporosis Know how to interpret bone mineral density tests Become familiar with the Frax Bone Treatment Algorithm

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osteoporosis

Osteoporosis

Tracie Wilcox MD

Assistant Professor of Medicine

University of Chicago

PGY 2 Lecture Series

learning objectives
Learning Objectives
  • Know when to screen for osteoporosis
  • Know how to interpret bone mineral density tests
  • Become familiar with the Frax Bone Treatment Algorithm
  • Become familiar with the different medications available to treat osteopenia & osteoporosis
  • Know when and how to screen for secondary causes of osteoporosis
case 1
Case 1:
  • CD is a 60 y.o. WF who presents to her PCP for her annual physical. She has no medical problems, takes no prescription medicines but does take OTC multivitamin and calcium supplements.
  • Medical History:
    • postmenopausal since age 55
    • HRT from age 55 until 59
case 1 cont
Case 1 cont:
  • Social History:
    • Rare alcohol
    • Denies smoking
    • Walks about 30 minutes 3x per week
    • Consumes 2 servings of dairy/day + 1000mg Calcium Carbonate
  • FHX:
    • Mother suffered hip fracture at age 75
case 1 cont5
Case 1 cont:
  • Physical Exam
    • Ht: 61.5in wt: 152 lbs
    • Rest of her examination was within normal limits
case 1 continued
Case 1 continued
  • Would you screen her for osteoporosis?
  • If so, how would you screen?
background
Background
  • Approximately 1.5 million fractures annually in US due to osteoporosis
    • 700,000 vertebral fractures

= most common clinical presentation of osteoporosis

    • 300,000 hip
    • Increasing risk with age regardless of sex due to combination of decreased bone density and increased risk of falls
costs
Costs
  • Hip fractures carry 10-20% mortality rate in first year after fracture
  • Vertebral fractures silent in 2/3 of cases
  • Estimates of annual costs of osteoporotic fractures $20 billion in US
risk factors
Risk Factors

Major Risk Factors

  • Previous Fragility fracture
  • Fragility fracture in first degree relative
  • Low body weight < 127 lbs (BMI <= 20)
  • Current smoker (>1PPD)
  • Postmenopausal status
  • Age

Additional Risk Factors:

  • >2 drinks/day alcohol
  • Asian / Caucasian race
  • Certain medication use and certain clinical conditions – see later
screening guidelines
Screening guidelines
  • USPSTF, NOF, AFP, ISCD all recommend:
    • Routine screening for women >/= 65 y.o.
    • For above average risk women (i.e. risk factors other than menopause) begin screening < age 65
      • USPTF and AFP recommend starting at age 60 in higher risk women
      • NOF does not give age for earlier screening
diagnosis of osteoporosis
Diagnosis of Osteoporosis
  • DXA: dual x-ray absorptiometry
    • Measures bone density at hip and central spine
    • Can be used to diagnosis osteopenia and osteoporosis
    • Calculates T and Z scores based upon BMD
t and z scores
T and Z scores
  • T score: the discrepancy between an individuals BMD and mean peak BMD in a healthy reference population
  • Z score: the discrepancy between an individuals BMD and an age matched BMD
    • Can define the relative risk of fracture for age
    • Score of -2 SD is considered below expected range for age
other screening modalities
Other Screening Modalities
  • Ultrasonography
    • Indirect assay of bone density
      • Measures speed or attenuation of ultrasound waves through bone
    • Can not be used to make diagnosis of osteoporosis as does not measure bone density or bone mineral content directly
    • Can not be used for monitoring therapy
    • Benefits: portable and cheap and low levels can predict future fracture risk
screening continued
Screening Continued
  • Markers of bone turnover
    • High values can predict rates of future bone loss
    • Not used for diagnosis
    • Used primarily to monitor compliance and efficacy of therapy in patients with continued bone density loss
      • Check at baseline and then in 6 months after starting therapy
      • Most commonly check cross-linked N-telopeptide (NTX) and serum carboxy-terminal collagen crosslinks (CTX)
who definitions
WHO Definitions
  • Osteoporosis: T-score < -2.5 at lumbar spine, total hip, or femoral neck on bone mineral density scan
    • Hx of fragility fracture
  • Osteopenia: -1.0 < T-score <-2.5
classification
Classification
  • Primary Osteoporosis: describes conditions in which low bone mass is attributed to menopause or aging
  • Secondary Osteoporosis: describes conditions in which low bone mass is attributed to identifiable factors other than aging and menopause
secondary osteoporosis
Secondary Osteoporosis
  • 20% -30%women thought to have postmenopausal osteoporosis have a secondary cause (1,2)
  • 2002 Study of 667 postmenopausal women with osteoporosis and low Z scores found 32% had an unrecognized disorder of bone and mineral metabolism(3)

1Harper KD, Weber TJ. Secondary Osteoporosis Diagnostic Considerations. Endocrinology and Metabolism Clinics 1998;27:326-348

2 Lorraine Fitzpatrick. Secondary causes of osteoporosis. Mayo Clinical Proceedings. 2002. 453-468.

3Tannenbaum C, Clark J, Schwartzman K et. Al. Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J Clin Endocrinol Metab 87:4431-4437;2002

secondary osteoporosis22
Secondary Osteoporosis
  • No clear consensus guidelines on when to workup for secondary causes
  • Consider checking in:
    • All premenopausal women with osteoporosis
    • Men
    • Postmenopausal women with low Z scores (-2.0 or more)
    • Women who do not respond adequately to initial therapy
secondary causes of osteoporosis
Secondary causes of osteoporosis

I) Medications:

  • Glucocorticoids
  • Aromatase Inhibitors
  • Depo-medroxyprogesterone acetate
  • Unfractionated heparin
  • GnRH agonist
  • Anticonvulsants: Phenobarbital, Phenytoin, Carbamezapine
    • via accelerating vitamin D metabolism
  • Phenothiazine
  • Methotrexate
  • Excess vitamin A intake
  • Cyclosporine-causes severe trabecular bone loss
  • Tacrolimus-in animal models has demonstrated bone loss
secondary causes of osteoporosis cont
Secondary causes of osteoporosis cont:
  • 2) Malnutrition/Malabsorption
    • Celiac Disease
    • IBD – vitamin D2,D3 largely absorbed in jejunum
    • Gastric and bowel resection-calcium absorbed in duodenum
    • Alcohol- inhibits osteoblasts
    • Vitamin D deficiency/insufficiency
vitamin d deficiency
Vitamin D Deficiency
  • Role of vitamin D:
    • Increases calcium absorption in the gut
    • Suppresses PTH release
    • Decreases renal calcium and phosp excretion
  • Generation of bioactive vitamin D
    • During exposure to UV light cholecalciferol ( vit D3) is produced in the skin
    • Cholecalciferol and ergocalciferol (vitamin D2) also obtained from diet
    • Vitamin D2 and D3 converted in liver to 25-OH vitamin D (calcidiol)
    • 1,25-OHD (calcitrol) formed in kidneys through renal conversion
vitamin d deficiency26
Vitamin D Deficiency
  • Inadequate levels result in secondary hyperparathyroidism with resultant increase in bone turnover
  • 25-OH vitamin D levels are regarded as more reliable measure of vitamin D stores
  • levels >= 30 ng/ml necessary to maximize intestinal calcium absorption and minimize changes in PTH
vitamin d deficiency27
Vitamin D Deficiency
  • Prevalence depends on definition
    • Deficiency: 25-OHD levels < 20 ng/ml
    • Insufficiency: 25-OHD levels 20 – 30 ng/ml
  • High prevalence especially in elderly, northern latitudes, pregnancy, IBD, celiac disease
increased risk in elderly
Increased Risk in Elderly
  • Average person needs 3000-5000 IU of cholecalciferol (D3) per day
  • Low levels associated with:
    • Reduced sunlight exposure
    • Age related decline in 7-dehydrocholesterol in skin
      • 70 y.o. person has about 25% the level of young adult
    • Low dietary intake
      • Oily fish: salmon, mackerel, sardines (400 IU/3.5 oz)
      • Egg yolks (20 IU)
      • Fortified foods (milk 100 IU per 8 oz)
treatment
Treatment
  • Vitamin D preparations
    • Choleocalciferol ( vitamin D3)
      • Preferred therapy for supplementation as increases 25-OD levels more efficiently than other preparations
      • give 50,000 IU Q week for 8 weeks then 800 – 1000 IU if deficient
      • 800-1000 IU per day for insufficiency
    • Ergocalciferol ( vitamin D2)
    • Vitamin D metabolites – ex: calcitrol ( 1-25 OHD)
  • Monitor 25-OHD level 3 months after starting therapy
secondary causes of osteoporosis cont30
Secondary causes of osteoporosis cont:
  • 3) Endocrine:
    • Hyperthyroidism
    • Hyperparathyroidism
      • Cortical bone loss > trabecular
      • Forearm fracture rates increase
      • Surgical resection improves BMD
    • Cushings
    • Hyperprolactinemia
secondary causes of osteoporosis cont31
Secondary causes of osteoporosis cont:
  • 4) Genetic:
    • Glycogen storage
    • Marfans
    • Ehlers-Danlos Syndrome
    • Turners
    • Hemochromatosis-via pituitary involvement
secondary causes of osteoporosis cont32
Secondary causes of osteoporosis cont:
  • 5) Chronic Disease
    • Multiple Myeloma
      • uncoupling of bone resorption
      • stimulation of osteoclast activity (via IL-1, IL6, TNF)
    • RA
    • Chronic Renal Disease
    • Chronic Liver Disease
    • Systemic Mastocytosis
secondary causes of osteoporosis cont33
Secondary causes of osteoporosis cont:
  • 6) Other
    • Immbolization-
      • Study of health volunteers undergoing 12 weeks of bed rest BMD declined 2.9% in spine and 3.8% in hip (1)
    • Smoker
    • Post organ transplant- especially first 3-6 months post transplant.
      • 18-50% prevalence of vertebral fractures postcardiac transplant

(1) Zerwekh JE, Ruml LA, Gottschalk F, Pak CY. The effects of twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis iin eleven normal subjects. J Bone Miner Res. 1998;13:1594-1601.

work up of secondary causes
Work Up of Secondary Causes
  • Influenced by history and physical exam
  • If no obvious cause consider the following for initial work up
    • CBC, CMP, 25-OH vitamin D level and calcium excretion
  • More extensive testing includes urine cortisol, SPEP, UPEP, screening for celiac disease, TSH, PTH, serum or urine markers of bone turnover
prevention treatment of osteoporosis37
Prevention/Treatment of Osteoporosis
  • Calcium and Vitamin D
  • Weight bearing exercise
  • Medications:
    • Bisphosphonates
    • SERM
    • PTH analogue
    • Calcitonin
calcium intake
Calcium Intake
  • 1000-1200mg QD for pre-menopausal and postmenopausal on anti-resorptive therapy
  • 1500 mg QD for postmenopausal women not on anti-resorptive therapy
vitamin d intake
Vitamin D Intake
  • Multiple metanalyses of studies evaluating the effectiveness of vitamin D supplementation on fracture risk
    • Most evidence shows benefit of supplementation in addition to calcium
    • Doses need to be 800IU or more / day to decrease fracture risk
      • Doses of 400 IU/day has not been shown to be effective
  • Goal of 800 IU / day for prevention to keep 25-OHD levels > 30 ng/ml
exercise
Exercise
  • 30 min three times per week
  • Small Improvement of BMD
    • 1 year study of 40 women between ages 50-70 undergoing high intensity (running) exercise showed increase in femoral neck by 0.9% and hip by 1%
  • In older women has been shown to decrease risk of hip fracture
    • likely due to increase in muscle strength
when to start medication nof recommendations
When To Start Medication – NOF recommendations
  • Begin medication in patients with BMD T scores </- 2.5 at femoral neck, total hip, or spine by DXA
  • Initiate therapy in patients with hip or vertebral fractures
previous guidelines
Previous Guidelines

National Osteoporosis Foundation (NOF)

  • T score < -2.0 without risk factors
  • T score <-1.5 with risk factors
  • T score based on hip DXA results

American Academy of Clinical Endocrinology (AACE)

  • T score <-2.5 without risk factors
  • T score < -1.5 with risk factors
who fracture risk assessment tool frax
WHO Fracture Risk Assessment Tool - FRAX
  • Released in 2/08
  • Algorithm for assessing the 10 year probability of hip fracture and 10 year probability of major osteoporosis-related fracture
  • Clinical risk factors in the algorithm validated in 60,000 men and women from 12 prospective, population-based cohorts and confirmed in f/u studies
frax calculation tool
Frax Calculation Tool
  • Available at http://www.shef.ac.uk/frax
  • Clinical risk factors:
    • Age
    • Sex
    • Weight / ht
    • Previous frx
    • Parent fractured hip
    • Current smoker
    • Current steroid use or previous prednisone 5 mg qd/3 mths
    • RA
    • Secondary osteoporosis
    • Alcohol 3 or more units per day
    • Femoral neck BMD
frax calculation tool46
Frax Calculation Tool
  • NOF committee collaborated with WHO to perform a cost-effectiveness analysis to estimate the levels of fracture risk above which it is reasonable to consider treatment
new nof recommendations
New NOF recommendations
  • Initiate pharmacotherapy in patients with osteopenia and 10 yr hip fracture probability of 3% or 10 year major osteoporosis related fracture probability of 20% based upon the FRAX model
treatment options
Treatment options
  • Antiresorptive agents:
    • Bisphosphonates – first line therapy
    • SERM
    • Calcitonin
    • Estrogen
  • Anabolic agents:
    • PTH analogue
bisphosphonates
Bisphosphonates
  • Analogues of naturally occurring pyrophosphate
  • Bind to hydroxyapatite crystals and accelerate osteoclast turnover
  • Increases BMD and reduces vertebral and nonvertebral fracture rates
bisphosphonates50
Bisphosphonates

Alendronate (fosamax)

  • 10 mg po Q day, 70 mg po Q week
  • 44% decrease in new vertebral fracture
  • 56% decrease in hip fracture over average of 4 years

Risedronate (Actonel)

5 mg po q day

    • 41% decrease in new vertebral fracture over 3 years
    • 39% decrease in nonvertebral fracture
  • 35 mg po q week, 75 mg po 2x/month
    • As effective as daily medication and well tolerated
  • Lancet 1996;348:1535-41.
  • JAMA 1998;280:2077-82
  • JAMA 1999;282:1344-52
bisphosphonates51
Bisphosphonates
  • Ibandronate (Boniva)
    • Oral 2.5 mg/day or 20mg QOD
      • 50% decrease in vertebral fracture
      • No decrease in nonvertebral fracture
    • 150 mg po once monthly
      • Increased lumbar and hip bone density as compared to daily therapy
      • Fracture data not reported
    • IV 3 mg q 3 months
  • J Bone Miner Res 2004;19:1241-9
  • Ann Rheum Dis.2006 May;65(5):654-61.
iv bisphosphonates
IV Bisphosphonates

Zoledronic acid 5 mg IV once yearly (15 minute infusion)

  • HORIZON trial
    • 7765 postmenopausal women with osteoporosis
    • ZA group - 77% decrease in clinical vertebral fracture over 3 years, 41% decrease in hip fracture
  • HORIZON recurrent fracture trial
    • 2127 men and women with hip fracture
    • Median follow up of 1.9 years
    • Less recurrent fractures occurred in ZA group (8.6% vs 13.9%)
  • N Engl J Med 2007;356:1809-1822
  • N Engl J Med 2007;357:1799-1809
iv bisphosphonate se
IV Bisphosphonate - SE
  • Flu like syndrome after infusion
  • Hypocalcemia after infusion
  • Increased risk of Afib in HORIZON trial
  • No increased risk of jaw osteonecrosis
  • Safety over 3 years not established
gi side effects of oral bisphoshonates
GI Side Effects of Oral Bisphoshonates
  • Poorly absorbed
    • must be taken on an empty stomach at least 30 minutes before eating (60 min for ibandronate)
  • Esophagitis
      • Must remain upright for one hour after ingestion
      • Contraindicated in those with achalasia and esophageal stricture
      • GERD is a relative contraindication
duration of treatment
Duration of Treatment
  • No consensus
  • Fracture Intervention Trial Long Term- Extension
    • Placebo group – stop after 5 years
      • Gradual decline in BMD
      • Gradual rise in biochemical markers of bone turnover
      • No difference in nonvertebral or morphometric vertebral fractures
      • Slightly higher risk of clinically detected vertebral fractures
      • No difference in adverse events
  • Consider trial of stopping medication after 5 years unless patients very high risk

JAMA.2006;296:2927-2938

osteonecrosis of the jaw
Osteonecrosis of the jaw
  • 2006 - 368 reported cases in the literature
  • 94% occurred in patients receiving IV bisphosphonates and most had malignancy
  • Of the few cases involving oral bisphosphonates, most of the cases occurred in the setting of a dental procedure
  • Ann Int Med.2996 May16;144(10):753-61
  • J Bone Miner Res.2007 Oct;22(10):1479-91
osteonecrosis of jaw
Osteonecrosis of Jaw
  • Recommendations
    • Dental exam prior to starting IV therapy
    • No dental procedures while on IV therapy
    • ? Need to stop oral bisphosphonate therapy for invasive dental procedure
      • American Association of Oral and Maxillofacial Surgeons suggests holding for 3 months prior to procedure in patients on oral therapy > 3 yrs and then restarting after healing complete
atrial fibrillation
Atrial Fibrillation

HORIZON trial:

  • Higher rate of AF in patients receiving zoledronic acid than in placebo ( 50 vs 20 p<0.001)

Use of Alendronate and Risk of Incident Atrial Fibrillation in Women:

  • Population based case control study of 719 women w/ afib b/w 2001-2004 and 966 female patients w/o
  • More AF patients than controls had ever used alendronate (6.5% vs 4.1%)
  • N Engl J Med 2007;356:1809-1822
  • Archives Int Med 2008;168(8):826-831.
bisphosphonates in renal disease
Bisphosphonates in Renal Disease
  • Not recommended in patients with creatinine clearance < 35 ml/min
    • Little data about efficacy or long term effects in these patients
slide60
SERM
  • Raloxifene: FDA approved for prevention and treatment of osteoporosis
  • Binds estrogen receptors - acts as an agonist in some sites, antagonist at other
  • Increase in BMD of lumbar spine by 2.4%, hip by 2.4% within 3 years
  • 30-50% reduction in vertebral fractures
  • No reduction in non-vertebral fractures
slide61
SERM
  • SE: Increased thrombosis risk, vasomotor symptoms
  • Decreases risk of invasive breast cancer
  • Second line agent behind bisphosphonates as is less potent anti-resptive agent and data against hip fracture prevention missing
calcitonin
Calcitonin
  • Potent Antiresorptive agent
  • Approved for osteoporosis treatment in postmenopausal women
  • Rapid action on osteoclast (inhibits function)
  • Intranasal Dose of 200 IU decreases vertebral fracture risk by 33%
  • Not as effective as bisphosphonates or PTH
calcitonin cont
Calcitonin cont:
  • Unclear long-term efficacy
  • Has analgesic effect thus useful for patients with acute or chronic pain from fracture
parathyroid hormone teriparatide
Parathyroid Hormone (Teriparatide)
  • recombinant PTH
  • Intermittent dosing stimulates osteoblast function, increases GI calcium absorption, and increases renal tubular reabsorption of calcium leading to bone formation
  • Dose: 20 mcg/day SQ
parathyroid hormone teriparatide65
Parathyroid Hormone (Teriparatide)
  • Increases BMD in spine and hip
  • Decreases vertebral fractures and non-vertebral fractures
  • No more than 1-2 year treatment
    • Osteosarcoma in rats
  • Decreased fracture risk continues even after treatment has been discontinued
  • Neer R, Arnaud C, Zanchetta J, et al.. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med.2001;344:1434-1441.
pth cont
PTH cont:
  • Side effects: N/V, dizziness, hypercalcemia, leg cramps
  • Monitoring:
    • BMD one year after starting
    • Calcium levels 1, 6, and 12 months
    • Renal function
    • Uric acid
pth continued
PTH continued
  • Use of Bisphosphonates with PTH analogue together not recommended
    • Coexistent therapy blunts the response of PTH
      • Start PTH after 3 month washout period
    • Sequential therapy with PTH followed by bisphosphonate can be beneficial in further increasing BMD
  • The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. AUBlack DM; Greenspan SL; Ensrud KE; Palermo L; McGowan JA; Lang TF; Garnero P; Bouxsein ML; Bilezikian JP; Rosen CJ SON Engl J Med 2003 Sep 25;349(13):1207-15. Epub 2003 Sep 20.
candidates for pth therapy
Candidates for PTH therapy
  • T score < -3.5 without fracture
  • T score < -2.5 with fragility fracture
  • Patients who fail other treatment options or are not able to tolerate other treatment modalities
monitoring response
Monitoring Response
  • Recommended to repeat BMD in one year after trx started and then every two years once stabilized
  • Also can check levels of bone turnover after 6 months of treatment
      • Urinary NTX excretion – decreases > 50%
      • Serum carboxy-terminal collagen crosslinks – decreases > 30%
      • = sign of compliance and efficacy of medication
monitoring therapy con t
Monitoring Therapy Con’t
  • Patients on systemic corticosteroids
    • Baseline BMD measurement when initiating long-term (> 3 months) GC therapy
    • Monitor at 6 months and then every 6-12 months if not on therapy
    • annual follow-up measurements once on therapy
monitoring response continued
Monitoring Response Continued
  • BMD that is stable or improving is sign of response to treatment
  • If BMD continues to decrease then look further for underlying causes and confirm patient compliance
    • If w/u negative and patient compliant either recheck in one year to confirm continued loss or change therapy
osteoporosis in men
Osteoporosis in Men
  • Epidemiology
    • Incidence of fracture increases with age though usually starts ten years later than women
      • 60 yr old male has 25% chance of having osteoporotic fracture in lifetime
    • Mortality from hip and vertebral fractures higher in men
    • Secondary causes identified in 40-60% of men with osteoporotic fractures
osteoporosis in men73
Osteoporosis in Men
  • Screening
    • Men age >70
    • Radiographic osteopenia, loss of height, fragility fracture, long term steroids, intestinal disorders
  • Diagnosis
    • WHO diagnosis for osteoporosis in women
    • Evaluate for secondary causes
  • Approved therapies
    • Bisphosphonates – alendronate and risedronate
    • PTH analogue
case presentation
Case Presentation
  • BC is an 87 y.o AAF with HTN and osteoarthritis. She has been postmenopausal since age 50 and has never had a bone mineral density test
  • She denies ever smoking
  • Due to her lactose intolerance she consumes almost no dairy but does take a senior MVI every day
  • You order a DXA which reveals the following:
work up and trx
Work – up and Trx
  • What is the diagnosis?
  • Would you look for secondary causes in this patient?
  • If so, what labs would you send?
case continued
Case Continued
  • Dx: osteoporosis
  • Yes: look for secondary causes due to severely decreased Z scores
  • Check CBC, CMP, serum 25 vitamin D level, calcium
follow up
Follow Up
  • 25 OH vitamin D: 6ng/ml
  • TSH 1.9 mcU/mL
  • Calcium 10.0 mg/dl
  • 24 hour urine calcium: 40mg/24 hour
diagnosis
Diagnosis
  • What is the diagnosis?
  • How would you treat her?
diagnosis treatment
Diagnosis & Treatment
  • Vitamin D deficiency
  • Treat with Choleocalciferol ( vitamin D3) 50,000 IU Q week for 8 weeks then 800 – 1000 IU
references
References

1Harper KD, Weber TJ. Secondary Osteoporosis Diagnostic Considerations. Endocrinology and Metabolism Clinics 1998;27:326-348

2 Lorraine Fitzpatrick. Secondary causes of osteoporosis. Mayo Clinical Proceedings. 2002. 453-468.

3Tannenbaum C, Clark J, Schwartzman K et. Al. Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J Clin Endocrinol Metab 87:4431-4437;2002

4. Zerwekh JE, Ruml LA, Gottschalk F, Pak CY. The effects of twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis iin eleven normal subjects. J Bone Miner Res. 1998;13:1594-1601

5. J Bone Miner Res 2004;19:1241-9

6. Ann Rheum Dis.2006 May;65(5):654-61

7. N Engl J Med 2007;356:1809-1822

8. N Engl J Med 2007;357:1799-1809

9. Neer R, Arnaud C, Zanchetta J, et al.. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med.2001;344:1434-1441.

10. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. AUBlack DM; Greenspan SL; Ensrud KE; Palermo L; McGowan JA; Lang TF; Garnero P; Bouxsein ML; Bilezikian JP; Rosen CJ SON Engl J Med 2003 Sep 25;349(13):1207-15. Epub 2003 Sep 20.