Age-related osteoporosis and fragility fractures Robert J. Pignolo, M.D., Ph.D. Assistant Professor...

$: Age-related osteoporosis and fragility fractures Robert J. Pignolo, M.D., Ph.D. Assistant Professor University of Pennsylvania School of Medicine Department.$
Age-related osteoporosis and fragility fractures

Robert J. Pignolo, M.D., Ph.D.Assistant ProfessorUniversity of Pennsylvania School of MedicineDepartment of Medicine, Division of Geriatric MedicineFellow, Institute on Aging


Impact Mechanisms of Bone Loss Diagnosis Current Treatment


ImpactImpact Mechanisms of Bone Loss Diagnosis Current Treatment

Occurrence of Low Bone Mass and Osteoporosis

Currently estimated to affect 44 million U.S. women and men aged 50 and older.

By 2010, it is estimated that this number will exceed 52 million and by 2020, over 61 million.

In 2002, it was estimated that over 10 million people had osteoporosis, women accounting for about 80% of cases.

One in two women and one in four men over age 50 will have an osteoporosis-related fracture in their lifetime.

National Osteoporosis Foundation, February 2002

Functional Impact of Osteoporosis Pain, dependence, and depression.

Skeletal deformities, vertebral fractures > hip fractures. Women with a history of vertebral or hip fractures have

more difficulty with bending, lifting, reaching, walking, and ascending and descending stairs and experience impairment in dressing, cooking, shopping, and housework.

~40% of hip fracture survivors are able to return to their prior level of ADLs, whereas only 25% return to their prefracture level for IADLs.

~15-25% of patients with hip fractures requires institutionalization.

National Osteoporosis Foundation, February 2002

Osteoporosis and Fragility Fractures Up to 95% of fractures in patients > 75 years old

and 80-90% of those 60-74 who are hospitalized for a fracture can be attributed to osteoporosis.

Less than 15% of those with recent fragility fractures are evaluated and treated for osteoporosis.

Risk of future fracture increases 1.5-9.5-fold following a fragility fracture.

Bouxsein ML et al. JAAOS 12: 385-395 (2004)


Impact Mechanisms of Bone LossMechanisms of Bone Loss Diagnosis Current Treatment

Mechanisms of Osteoporosis

AGINGEastell, R, in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ch 50, 2003

Inadequate accumulationof bone in young life

Low peak bone mass

Excessive rates of bone loss Osteoporosis

Deterioration in bone microarchitecture

Decreased BMD

Determinants of Peak Bone Mass Genetic Factors

50-85% of bone mass variance

Polymorphisms or mutations in BMP2 COL1A1 Vitamin D receptor LRP5

Non-Genetic Factors diet/calcium intake low body weight at

maturity & at 1 year sedentary lifestyle delayed puberty

Eastell, R, in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ch 50, 2003

A.

B.

C.

Bone remodeling

Liver

Osteoblast

Osteoblast

Monocyte/Macrophage

CFU-F Osteoclast

M-CSF

M-CSF

M-CSF

Bone

BMPs, TGFβs, IGFs, FGFs

OPG

RANKL

RANKL

RANK

From Pignolo, RJ & Kaplan, FS, Bone Biology in Interventional Spine (2007)

Coupling of bone formation to resorption

Mechanisms of bone Loss: Uncoupling

Low-turnoverbone loss

High-turnoverbone loss

Normal BoneTurnover(Skeletal

Homeostatis)

High bone massPhenotype

Osteopetrosis

Bone Resorption

Bone formation

HypogonadismThyrotoxicosis

HyperparathyroidismCytokine Excess

AgingDisuse

SteroidsCalcineurin inhibitors

Skeletal metastasesPaget’s disease

Rheumatoid arthritisPeriodonitis

Based on Zaidi, M Nat. Med. 13: 791-801 (2007)

Mechanisms of Age-Related Bone Loss

Bone Loss

Remodeling Imbalance

Uncoupling of BoneFormation & Resorption

Random Remodeling Errors

↑PTH

↓ IntestinalCa resorption

↓ Vitamin D

↓ Renal Ca Resorption

↓ Estrogen

↑↓Local GFs & cytokines

ImpairedOsteoblast Function

OsteoblastSenescence

↓ GH

↓ Physical Activity

↑Relative Osteoclast Activity

↑Activation Frequency

Eastell, R, in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ch 50, 2003

High Vulnerability

Low Vulnerability

Predisposing Factors¹

Higher Intensity Trauma

Lower Intensity Trauma

Precipitating Factors²

Disuse Osteoporosis[Bed rest/bed-bound Status > 6 months]

History of Prior Fracture

Improper TransferTechniques

Poor Nutritional Status[Albumin < 3.0]

BMI < 20

Transfers

Positional Adjustment

Spontaneous

Predisposing and Precipitating Factors in Minimal Trauma Fractures

Advanced Age

¹ Based on representative cases, cases reviewed, and literature review .

² Based on most common mechanisms.


Impact Mechanisms of Bone Loss DiagnosisDiagnosis Current Treatment

Definition

Systemic disease Low bone mass Microarchitectural

deterioration of bone tissue

Increase in bone fragility

Increase in susceptibility to fracture

Diagnosis of exclusion

Risk Factors Associated with Osteoporosis

Family history of osteoporosis or fracture

Lifelong low calorie intake

Personal history of fracture as an adult

Poor health/frailty Increasing age Immobilization Early menopause (< 45

years old) Sedentary lifestyle

Late menarche (>16 years old)

Thin body frame or low body weight

Amenorrhea or irregular menstrual periods Calcium/vitamin D-deficient diet

Female sex Heavy alcohol use White or Asian ancestry Cigarette smoking

NIH Consensus Development Panel: Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785-95, 2001

Medical Causes of Secondary Osteoporosis

_____________________________________________________________________

Secondary Causes of Low Bone Density _____________________________________________________________________

Endocrine Hyperthyroidism, hyperparathyroidism, Cushing'ssyndrome, diabetes mellitus, prolactinoma, estrogendeficiency, hypogonadism (men)

Rheumatologic Rheumatoid arthritis, ankylosing spondylitis, idiopathicscoliosis, sarcoidosis

Gastrointestinal/ Malabsorption, hepatobiliary dysfunction, vitamin DNutritional deficiency, parenteral nutrition

Hematological/ Mastocytosis, hemolytic anemia, malignacy (general),Oncological multiple myeloma, hemophilia, thalassemia

Renal Idiopathic hypercalciuria (on low calcium diet), renalosteodystrophy

Psychiatric Eating disorders (anorexia, bulimia), depression

Genetic Congenital porphyria, osteogenesis imperfecta, osteoporosis-pseudoglioma

Other Paget's disease, amyloidosis, epidermolysis bullosa,hemochromotosis, hypophosphatasia, multiple sclerosis

_____________________________________________________________________

Fitzpatrick LA, Mayo Clinic Proceedings 77:453-68 (2002)

Pharmacologic Causes of Secondary Osteoporosis

• Glucocorticoids • Anticonvulsants• Lithium • Tamoxifen (premenopausal)• Antacids (chronic use) • Vitamin A• Heparin • Methotrexate• Gonadotropin-releasing hormone • Warfarin agonist or antagonist • Excessive thyroid supplementation• Phenothiazines • Aluminum-containing medications• Cytotoxic drugs • Organ transplant therapy

Dawson-Hughes, B, NEJM 345:989- 91 (2001)

Diagnosis of Osteoporosis

Skeletal History and Risk Factor Assessment

Screening Laboratory Tests

Physical Examination

Bone Mineral Density (BMD) Testing

Skeletal History and Risk Factor Assessment Risk Factors for

Osteoporosis and Fractures

Known Secondary Causes of Low Bone Mass/Fractures

Independent Risk Factors for Fractures Impaired neuromuscular

function Decreased visual acuity Sedative/hypnotic drug

use Frequent falls

Kleerekoper M, Evaluation of the patient with osteoporosis or at risk for osteoporosis. In Osteoporosis, 2nd ed., 2001

Interaction between BMD and risk factors for the prediction of hip fracture

Risk factors: age > 80; maternal history of hip fracture; any fracture (except hip fracture) since the age of 50; fair, poor, or very poor health; previous hyperthyroidism; anticonvulsant therapy; current long-acting benzodiazepine therapy; current weight less than at the age of 25; height at the age of 25 < 168 cm; caffeine intake more than the equivalent of two cups of coffee per day; on feet 4 hours a day; no walking for exercise; inability to rise from chair without using arms; lowest quartile of depth perception; lowest quartile of contrast sensitivity; and pulse rate>80 per minute.

Cummings, SR et al., NEJM 332: 767-73 (1995)

Physical Examination

Detection of vertebral fracturesa. Height lossb. Upright posture becomes impossible (Dowager’s hump)c. Pulmonary volume loss due to anterior wedging of spined. 12th rib rests on iliac creste. Narrowed gap between ribs and iliumf. Protruding abdomeng. Distension, constipation, early satiety, eructationOther:

Paravertebral muscle spasmVertebral tenderness

Kleerekoper M, Evaluation of the patient with osteoporosis or at risk for osteoporosis. in Osteoporosis, 2nd ed., 2001

Physical Examination (cont.)

Assessment of Fall/Fracture Risk Ability to rise from chair

w/o using arms Resting pulse >80 Poor visual acuity Gait dysfunction,

including balance Longer hip-axis length

R/O Secondary Causes Bony deformities of RA Stigmata of chronic

alcoholism & liver disease

Scars suggesting thyroid/ parathyroid surgery

Skin changes consistent with endocrinopathies


Screening Laboratory Tests

Screening laboratory studies, incl. CBC, chem7, Ca, Mg, P, alb, LFTs, GGT, TSH, serum testosterone/LH, 25-OH vitamin D

renal osteodystrophy (↓Cr, ↓Ca, ↑P)1o hyperparathyroidism (↑Ca); check PTH, vit. D metabolitespossible malnutrition (↓Ca, ↓P, ↓alb, ↓Hgb w/ ↓↑MCV)BM malignancy/infiltration (↓Hgb, ↓WBC, ↓PLT)osteomalacia (↓P, ↓/low nL Ca, ↑alkP)hypogonadism (↓T, ↑LH, ↑FSH) vitamin D insufficiency (early sl. ↓P, ↑alkP)


Screening Laboratory Tests (cont.)


Screening laboratory studies, incl.CBC, chemistries, Ca, Mg, P, alb, LFTs,GGT, TSH, total T/LH, iPTH, 25(OH)vitamin D

24h urine on adequate Ca

intake, if nL screening

low urine Ca (< 50mg): vit. D deficiency osteomalacia malabsorption (e.g., celiac sprue)

include Cr, and Na 25-OH vit. D level,

ferritin, carotene, anti-gliadin or anti- endomyseal Abs

high urine Ca (>300mg): renal tubular Ca leak [> 4mg/kg] absorptive hypercalciuria

excessive bone resorption(malignancy, hyperparathyroid,hyperthyroid, Paget's disease)high sodium diet

Yield of lab testing to identify secondary causes of bone loss in otherwise healthy postmenopausal women

In women without a history of diseases or medications known to adversely affect bone, 32% had disorders of calcium metabolism (hypercalciuria, malabsorption, hyperparathyroidism, vitamin D deficiency)

Measurement of 24h urine calcium, serum calcium, PTH, and TSH (in those on thyroid replacement) would have been sufficient to diagnose 85% of underlying causes

Tannenbaum, C et al J. Clin Endo. Metabol. 87: 4431-4437 (2002)

Special Laboratory TestsBMD Testing,T-score < -2.5

Screening Lab Studies

Z-score < -2.0 orNo major risk factors SPEP/UPEP, 24h urine for free cortisol or overnight

DEX supression test, t/c bone alkP or acidP, osteocalcin or pyridinoline crosslinks of type 1 collagen, BM biopsy, urine histamine


_______________________________________________________________________

Technique Common Sites Time for Radiation Prediction of Evaluated Procedure Exposure Fracture Risk

(minutes) (relative units)_______________________________________________________________________DXA1 Spine, hip, 5-10 1-5 Strong, when done

whole body at site of interest

Peripheral Radius, 5-15 1 Less predictive thanDXA, SXA2 calcaneus DXA at hip or spine

for corresponding fractures

QCT3 Spine 10-30 50 Alternative to DXA at spine, but not well studied

Radiographic Hands 5-10 5 Similar to peripheralabsorptiometry4 DXA, SXA

Ultrasound Calcaneus, 5-10 0 Predicts hip and tibia nonvertebral fractures

almost as well as DXA at hip

_______________________________________________________________________1Dual-energy x-ray absorptiometry, 2Single-energy x-ray absorptiometry, 3Quantitativecomputed tomography; 4Compares the density of proximal phalanges to that of a wedge ofaluminum (with known densities) placed alongside the hand.

Techniques Used to Measure Bone Density

Cummings SR, Bates D and Black DM, JAMA 288:1889 (2002)

Differences in T scores between different skeletal measurement technologies

Faulkner KG et al, J Clin Densit 2: 343-50 (1999).

Benito, M et al. JBMR 20: 1785-91 (2005)

The virtual bone biopsy: Micro MRI and the future of bone imaging

Cross-sectional area through tibia(circle = 6.85 mm diameter)

Same trabecular bone volume before (left) and after (right) treatment of a hypogonadal man with testosterone. Right panel shows a 33% increase in surface-to-curve ratio and 22% decrease in erosion index.

Indications for Bone Density Screening

Age > 65 years Patients with history of fractures Estrogen-deficient women Hypogonadal men Persons taking long-term corticosteriods Persons with endocrinopathy (hyperthyroidism, hyperparathyroidism, Cushing's

disease/syndrome) Patients with significant risk factors, regardless of age Assessment of treatment efficacy Postmenopausal women considering therapy for osteoporosis when BMD will facilitate

treatment decisions

Nelson HD, et al., Ann. Intern. Med. 137:529 ( 2002)

DXA Report

Value T- Score Z-Score > 1 to 0 Normal Normal -1 to -2.5 Osteopenia < -2.5 Osteoporosis

Low Peak Bone Mass and/or Secondary Osteoporosis

Intervention thresholds in postmenopausal women based on WHO criteria

Risk of Osteoporotic Fracture

Generally, a drop of 1 SD doubles the risk of fracture.

Cummings SR, Bates D, and Black DM, JAMA 288:1889 (2002)

Osteoporosis in Men

Less common in men larger skeletons bone loss starts later in life slower progression no rapid bone loss phase

Fewer fractures 1/5 to 1/3 of all hip fractures 1/2 as many symptomatic

vertebral fractures but, much higher mortality

rates and chronic disability after a hip fracture

More secondary causes declines in testosterone

levels or hypogonadism history of steroid therapy alcohol abuse significant smoking history hyperparathyoidism intestinal disorders malignancies immobilization

Pignolo, RJ et al., Osteoporosis in Geriatric Secrets, Ch. 44 (2004)


Impact Mechanisms of Bone Loss Diagnosis Current TreatmentCurrent Treatment

Current Therapies

Bone Loss

Remodeling Imbalance

Uncoupling of BoneFormation & Resorption

Random Remodeling Errors

↑PTH

↓ IntestinalCa resorption

↓ Vitamin D

↓ Renal Ca Resorption

↓ Estrogen

↑↓Local GFs & cytokines

ImpairedOsteoblast Function

OsteoblastSenescence

↓ GH

↓ Physical Activity

↑Relative Osteoclast Activity

↑Activation Frequency

EstrogenSERMs

Vit D

Ca

X

X

X

Bisphos-phonates

Rodan, GA and Martin, TJ, Science 289: 1508-1514 (2000)

*****************

*****************

*****

*****

*****

Teriparatide*****************

Antifracture efficacy of the most frequently used treatments of postmenopausal osteoporosis from randomized, placebo-controlled trials* ________________________________________________________________________ Drug Vertebral fractures Non-vertebral fractures Alendronate +++ ++ Calcitonin + 0 Etidronate + 0 HRT + 0 Parathyroid Hormone +++ ++ Raloxifene +++ 0 Risedronate +++ ++ Vitamin D Derivatives +/- 0 ________________________________________________________________________ *In addition to the effects of calcium, vitamin D, or both. +++, strong evidence; ++, good evidence; +, some evidence; +/-, equivocal evidence; -, negative effects

Delmas, PD, Lancet 359:2018-26 (2002)

Skeletal Health Maintenance Adequate nutrition and

body weight Balanced, adequate calorie

diet containing age-appropriate calcium and vitamin D

Avoid diet high in protein, caffeine, phosphorus, or sodium

Regular physical activity, especially resistance and high-impact exercise

Undisrupted sex hormones at puberty Evaluation of absent/

infrequent menstrual cycles in younger women, menopause, pathologically delayed puberty in young men, & male hypogonadism

Avoidance of cigarette smoking

Pignolo, RJ et al., Osteoporosis in Geriatric Secrets, Ch. 44 (2004)

AAOS Recommendations on Enhancing the Care of Patients with Fragility Fractures

Consider osteoporosis as a predisposing factor Advise patients that evaluation and treatment of

osteoporosis can reduce the risk of future fractures Initiate an investigation of osteoporosis Establish partnerships within the medical community to

facilitate evaluation and treatment Establish clinical pathways that ensure optimal care

FRAGILITY FRACTURE PATHWAYALL PATIENTSObtain the following tests: □ 25(OH) Vitamin D level□ Total or ionized calcium□ PhosphateOUTPATIENT□ Rx for calcium 1,200 mg daily□ Rx for Vitamin D 800 IU daily□ Rx for PT fall prevention□ Referral to Robert Pignolo, MD, PhDOsteoporosis Clinic (215) 662-2746INPATIENT□ Consult Geriatrics (Presby) or Endocrine (HUP)□ Administer OsCal 1 tab PO BID (Ca 500mg + Vit D 200 IU)Please do not write Rx or give meds if labs have not been drawn

A clinical pathway for the optimal care of the fragility fracture patient: Our first attempt

Barriers to initiating treatment of patients who have or are at risk for osteoporosis Lack of patient and primary physician knowledge Lack of awareness and use of current osteoporosis guidelines Perception by orthopaedic surgeons that evaluation and

treatment of osteoporosis is not their responsibility Cost of therapy Time and cost of diagnosing osteoporosis Side effects of medications Confusion about medications or their effectiveness Complex medical conditions in elderly patients Reluctance of elderly patients to add more medications Lack of access to BMD testing Lack of time to address secondary prevention

Bogoch, ER et al JBJS 88:25-34 (2006)

In-hospital medical management of the fragility fracture patient Pre-operative evaluation and timing of surgical

intervention Antibiotic prophylaxis Thromboembolic prophylaxis Prevention of delirium Evaluation and treatment of osteoporosis Pain control- No NSAIDS Nutritional evaluation Prevention of pressure ulcers Physical rehabilitation Assessment of fall risk

Summary

>80% of fractures in older patients are due to osteoporosis.

Mechanisms of bone loss are multifactorial and on the cellular and molecular levels always involve an uncoupling of bone formation to resorption.

Radiological evaluation of bone loss is not optimal.

Treatment should be multi-pronged and individualized.

New mechanistic-based therapies are on the horizon.

Fracture should not be the sentinel event that triggers evaluation and treatment of osteoporosis, but if it is, the opportunity should not be missed.

Clinical pathways to ensure optimal care of patients with fragility fractures should be initiated.

Acknowledgements

Research support Richard Lackman Lou Soslowsky Fred Kaplan Eileen Shore

FOP/POH Fred Kaplan Eileen Shore David Glaser

NHHO Mary Ann Keenan Nader Hebela

Osteoblast differentiation & aging Craig Israelite

“Fractures in the Elderly” Mary Ann Keenan Orthopaedic Surgery faculty &

residents Fragility fracture clinical

pathway Nader Hebela Mary Ann Keenan

John Esterhai Ernest Gentchos David Glaser Fred Kaplan

Thank you.

New Generation SERMs


Bisphosphonates in Clinical Use and Development

O=P C P=O

O (CH2)3O

NH2

O OH O


Bisphosphonates, the Mevalonate Pathway, and Other Mechanisms of Action

Cummings, SR and Bauer, JAMA 283: 3255-57 (2000)Zaidi, M et al., J. Bone Min. Res. 18: 599-609 (2003)

Apoptosis

Nitrogen-Containing Bisphosphonates

Osteoclast Osteoblast

Cytoskeletal OrganizationVesicle TransportMembrane RufflingCell Survival

Mobilization ofmineral phase

MMPs, Secreted acidphosphatase, ?Other proteases

Inhibition of apoptosis

Release of osteoclast inhibitory factory ?

Bisphosphonates in Clinical Use and Development

O=P C P=O

O O

O O

R1

R2

Modification Examples R1 R2 Relative

Potency

1st Gen Etidronate OH CH3 1

Clodronate Cl Cl 10

2nd Gen Tiludronate H SC6H3Cl 10

Pamidronate OH (CH2)2NH2 102

Alendronate OH (CH2)3NH2 102-103

3rd Gen Risedronate OH CH2-3-pyridinyl

103-104

Ibandronate OH (CH2)2N

(CH3)2

103-104

Zolendronate OH CH2C3N2H3 104+

Watts, NB, in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ch 55, 2003

Potential complications of bisphosphonate use Short-term

GI intolerance (heartburn, esophageal irritation, esophagitis, abdominal pain, diarrhea)

Severe bone, joint, and/or muscle pain

Ocular inflammation (abnormal or blurred vision, ocular pain, conjunctivitis, uveitis, scleritis)

Acute-phase reaction (fever, myalgias, flu-like syndrome)

Long-term Osteonecrosis of the jaw Suppression of bone formation

Wysowski, DK & Chang, JT Arch Intern Med 165:346 (2005); Fraunfelder, FW & Fraunfelder, FT NEJM 348: 1187 (2003);Odivina, CV et al. J Clin Ednocrinol Metab 90: 1294 (2005).

Osteonecrosis of the jaw

Mechanism is probably sever suppression of bone turnover 94% are treated with zoledronic acid or pamidrate, or both 85% have multiple myeloma or metastatic breast cancer 4% have osteoporosis Prevalence in patients with cancer is 6-10% Estimated incidence in patients taking oral bisphosphonate is

1 in 100,000 patient years 60% occur after dentoalveolar surgery (e.g., tooth extraction)

to treat infections; 40% related to infection, denture trauma, or other physical trauma

Bilezikian, JP, NEJM 355:2278-81 (2006); Treister, N, & Woo, S-B, NEJM 355: 2348 (2006); Woo, S-B et al. Ann Int Med 144: 753-61 (2006)

Osteoclastogenesis

Teitelbaum, SL, Science 289: 1504-1508 (2000)

Osteoclastogenesis and Bone Resorption

Teitelbaum, SL, Science 289: 1504-1508 (2000)

Potential Therapeutic Osteoclast Targets

10 Inhibition of MMP-9

9 Inhibition of p60c-SRC

kinase

1-4 Blocking signaling of OPG/RANKL/RANK

5 Blocking ligands of αvβ3 integrin6 Inhibition of cathepsin K protease

7 Inhibition of vacuolar H+ -ATPase8 Inhibition of p38 kinase

11 Better calcitonin receptor ligands 12 Inhibition of CA2


Denosumab functions like Osteoprotegerin (OPG)

Denosumab Increases BMD in the Spine and Hip

Biological Basis of PTH Action

GsGDP

AGONIST

GTP Gs

ATP

cAMP

PKA(active)

AdenylyCyclase

PTH PTH

PTH1 Receptor

Other signaling:PKC pathways

Anabolic Effects of hPTH(1-34) on Bone

hPTH (1-34)

Continuous... Discontinuous…

Hyperparathyroid-like State

Increased Bone Resorption

Recruitment of quiescentbone lining cells

Prevention of apoptosis

New bone formation

Reeve, J, in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ch 57, 2003

Other Anabolic Bone Therapies

rhPTH(1-84), rhPTH(1-36) Statins Fluoride Bone growth factors: IGF-I,

TGF-β, FGFs, BMPs


Telomerase expression and Osteogenic Potential

Shi, S et al., Nature Biotech. 20: 587-91 (2002)Simonsen, JL et al., Nature Biotech. 20: 592-96 (2002)

In vivo Bone Formation by hMSC-TERTs

Simonsen, JL et al., Nature Biotech. 20: 592-96 (2002)

BMD Scores in a Family with High Bone Mass

Little, RD et al., Am. J. Hum. Genet. 70: 11-19 (2002)

High Bone Density Due to a Mutation in LDL-Receptor-Related Protein 5

Boyden, LM et al., NEJM 346: 1513-21 (2002)

HBM mutation and domain structure of the LRP5 protein

Little, RD et al., Am. J. Hum. Genet. 70: 11-19 (2002)

Mutations in LRP5 Cause New Bone Formation

Patel, MS and Karsenty, G, NEJM 346:1572-73 (2002)

Wild-type LRP5

New Bone Formation No New Bone Formation

Mutant LRP5

New Bone Formation

Age-related osteoporosis and fragility fractures Robert J. Pignolo, M.D., Ph.D. Assistant Professor...

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