Osteoporosis: Pathophysiology and ManagementDr. Frank Waldron-Lynch M.D Ph D MRCPI MRCP(UK),

Section of Endocrinology, Yale University School of Medicine.

Outline

• Definition of osteoporosis• Pathogenesis• Diagnosis• Therapy• Future development

http://www.med.yale.edu/intmed/endocrin/patient/bonecenter.html

Classic presentation

Definition

• Clinical– Loss of bone mass sufficient to significantly

increase the risk of fracture

• Diagnostic– T score – number of standard deviations above or

below the mean for a similar healthy 30 year old• Normal BMD = T: 0 to -1• Osteopenia BMD = T: -1 to -2.5• Osteoporosis BMD = T: less than -2.5

– Z score – number of standard deviations above or below the mean for the patients age, sex and ethnicity

Epidemiology

• United States– 10 million individuals with osteoporosis– 34 million individuals with osteopenia

• Fracture Risks over age 50– 50% of women will have an osteoporosis related

fracture– 25 % of men will have an osteoporosis related

fracture

• Estimated costs– Direct health care $14 billion each year

http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/default.asp

Pathogenesis

• Peak bone mass

• Etiology Bone loss

• Age

• Secondary causes

Peak Bone Mass

• Genetically determined– 70-75%– Driven by sex hormones during puberty– Depends on site measured – spine, femur, radius

• Ethnicity– Chinese American later than Caucasians

• Women– Peak accrual ages 11-15– 95 per cent achieved by late teens

• Men– Peak accrual later teens– Maximum spine age 20– Radius and femur by mid twenties

Factors Affecting Peak Bone Mass

• Delay or Failure of puberty– Primary Hypogonadism

• Turners syndrome• Klinefelter syndrome• Absent cervix, uterus, cervix and/or vagina • Cryptorchidism • Chemotherapy, Radiotherapy• Chronic systemic diseases

– Secondary Hypogonadism• Kallmann syndrome• CNS tumors, infiltrative disorders• Malnutrition • Chronic systemic illness

Etiology of Bone loss in Osteoporosis

OSTEOCLAST - RESORPTIONOSTEOBLAST - FORMATION

Primary cause is estrogen deficiency+

Estrogen Deficiency

• Women – Occurs earlier– At menopause bone loss rates to increase by 2

to 6 fold– For subsequent 6-8 years– Impairs calcium absorption from gut

• Men– Testosterone declines age– Estrogen declines age– Both androgens and estrogen contribute

Riggs B. N Engl J Med 1986;314:1676 Age (years)

Ann

ual F

ract

ure

Inci

denc

e,

per 1

00,0

00

0

1000

2000

3000

4000

35 45 55 65 75 85+

Vertebrae

Hip

Colles'

Fracture Risk with Aging

Caucasian women

Hip Fracture Risk for a Given T-score Depends on Age

10 year risk of fracture in Swedish women

Secondary causes of accelerated bone loss• Inherited disorders

– Osteogenesis imperfecta tarda– Thallasemia

• Amenorrhea – Eating disorders– Low weight– Excess Exercise– Female athlete triad

• Energy deficiency• Low bone mineral density• Amenorrhea

– Premature ovarian failure

Secondary causes of accelerated bone loss• Respiratory

– Cystic fibrosis• Gastrointestinal

– Celiac sprue– Post Gastric by pass– Inflammatory bowel disease

• Renal– Idiopathic hypercalciuria– Chronic renal failure

• Post organ transplant– Immunosuppressive therapy

Secondary causes of accelerated bone loss• Endocrine

– Hyperthyroidism– Hyperparathyroidism– Cushing’s syndrome– Hypogonadism– Vitamin D deficiency

• Rheumatology– Rheumatoid arthritis– Seronegative athropathies

• Lifestyle– Smoking– Alcohol

Secondary causes of accelerated bone loss• Drugs

– Glucocorticoids– Cyclosporine– Anti seizure medications

• Phenobarbital• Phenytoin

– Heparin– Chemotherapy

• Aromatase inhibitors

– Thyroxine• Over replacement

Diagnosis

• Approach to patient

• Investigations– Bloods– Urine– Imaging

• FRAX use

• Calcium and Vitamin D

Approach to patient with suspected osteoporosis – guide investigations• Focused history

– Fracture history– Loss of height– Exercise– Menstrual history– Hypogonadism men– Diet– Smoking– Alcohol

• Past medical history– Secondary causes

Focused history

• Medications– Any drugs effect BMD– Any drug affect calcium absorption

• Family history– History osteoporosis

• Systems review– Gastrointestinal system

• GERD• Esophageal stricture• Malabsorption

Examination – Key points

• Weight– Calculate body mass index

• Height– Measure and follow– Loss greater than 1 inch may indicate spinal

fracture• Muscular skeletal

– Spine• Deformity• Tenderness• Mobility

– Muscle strength• Proximal muscle weakness

Investigations

• Bloods -Basic– CBC– Electrolytes and eGFR– Serum calcium and phosphate– TSH– Testosterone (Men)– Serum protein electrophoresis – Bone markers (consider)

• Urine– 24 hour urine– Volume– Creatinine and calcium

OSTEOCLAST - RESORPTIONOSTEOBLAST - FORMATION

Intact Osteocalcin (OCI) Mineralization

Bone Alkaline phosphatase (Bone AP) MaturationDeoxypyridinoline (fDPD/Cr)

N-Terminal cross-linking telopeptide

(NTx/Cr)

Procollagen Type 1N Propeptide (PINP) Synthesis

Bone re modelling – Bone markers

Bone markers - Use

• Diagnosis– Identification high bone turnover states– Not as well validated as DXA

• Monitor therapy– Commencing– During treatment– Urinary Ntx

• Should decrease on bisphosphates

Direct measurement of BMD by DXA and as well as CT allows us to diagnose osteopenia

• Bone mineral density testing – Important means of assessing fracture risk– Not stand alone test

• Other risk factors have impact on fracture risk – occasionally more significant impact than bone

density results alone– Glucorticoids

• All known risk factors should be considered when deciding to treat patients– Mostly treating patients based on risk– No overt disease

• We need better tools for assessing fracture risk

Bone mineral density testing

FRAX - Fracture Risk Assessment Tool

WHO has recently released FRAX, the WHO Fracture Risk Assessment Tool. Patients and clinicians can access this tool at:

http://www.shef.ac.uk/FRAXhttp://www.shef.ac.uk/FRAX

– Data from 9 cohorts around the world– Validated in 11 independent cohorts with similar

geographic distribution

FRAX - Use

FRAX variables

Treatment recommended

• Consider FDA-approved medical therapies in postmenopausal women and men aged 50 years and older, based on the following:– A hip or vertebral fracture – T-score ≤ -2.5 at the femoral neck or spine after

appropriate evaluation to exclude secondary causes

– Low bone mass (T-score between -1.0 and -2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture ≥ 3% or a 10-year probability of a major osteoporosis-related fracture ≥ 20%

– Clinicians judgment and/or patient preferences may indicate treatment for people with 10-year fracture probabilities above or below these levels

Caveats regarding FRAX

• Prospective data on the efficacy of FRAX in making pharmacologic treatment decisions are lacking

– Can osteoporosis medication help equally well with all risk factors? (likely not!)

– That is, not everyone with a high FRAX should be treated with a medication

– We need intervention trials with FRAX as an outcome

• It does not capture spinal osteoporosis

Non Pharmacologic Treatment

• Essential – Are as important as any medication

• Nutritional– Calcium– Vitamin D– Vitamin A

• Lifestyle– Smoking– Exercise

• Falls risk reduction

Calcium and Vitamin D

• Calcium– Total sufficient to prevent calcium

malabsorption and secondary hyperprathyroidism

– Test adequate by 24 hour urine if eGFR > 60cc/min

– Total daily intake 1500 mg/day

• Vitamin D– Aim serum 25(OH) vitamin D > 25 ng/dl (ideally

25-35)– Total daily intake 800 IU– Higher if malabsorption

Effects of Vitamin D supplementation

• Double-blind community-based RCT in the UK

• 2686 individuals (2037 men; 649 women)– Over age 65

• 100,000 U of vitamin D3 orally every 4 months for 5 years

• mailed to the study subjects so compliance not confirmed

Trivedi et al. BMJ;326:469

Drug Therapy for Low Bone Mass

Prior to drug therapy treat any secondary causes

Drug Therapy for Low Bone Drug Therapy for Low Bone MassMass

• Bisphosphates

• Parathyroid hormone

• Selective Estrogen Receptor Modulators

• Denosumab

Targeting the bone resorption side of thebone remodeling cycle

ETIDRONATEETIDRONATE

PAMIDRONATE

ALENDRONATE

IBANDRONATE

RISEDRONATE

TILUDRONATE

CLODRONATECLODRONATE

ZOLEDRONATE

Bisphosphonates

Bisphosphonates are the most effective antiresorptive agents available for the

prevention and treatment of bone loss.

Anti-fracture efficacy of bisphosphonates in osteoporotic women

Vertebralfracture

Hip fracture

Non-vertebral fracture

Alendronate (Fosamax®)

√√ √√ √√

Risedronate (Actonel®)

√√ √√ √√

Zolendronate (Reclast®)

√√ √√ √√

Ibandronate(Boniva®

√√ ?? √√

When can the patient have a drug holidayfrom bisphosphonates?

The Flex Trial

1. Time to non vertebral fracture2. Time to vertebral fracture after 5 years

JAMA 296:2927

Management of patients taking bisphosphates

• Dental examination prior to treatment• Repeat BMD 1-2 years of treatment

– Demonstrate efficacy• Check BMD 1-2 years later

– Improve patient compliance• 5 years

– Stop drug individuals with a good response– No longer osteoporotic

• 10 years– Stable BMD– No recent fractures

Raloxifene

• Selective Estrogen Receptor Modulators (SERMs)

• Raloxifene– Reduces vertebral fracture– No reduction in hip fracture

• Reserve use with women without hip involvement

• Other beneficial actions– Reduces risk invasive breast cancer– No increase on cardiovascular motality of

mobidity

Denosumab: therapy targeted atthe RANKL/OPG system

Not approved by FDA yet

Osteoclast precursorRANKRANK

OPGOPG

RANKRANK -Ligand-Ligand

Osteoblast

DenosumabDenosumab

Humanized anti-RANK-Ligand

Mechanism of action Denosumab

Denosumab: The FREEDOM trial

• 7,868 women ages 60 to 90• Mean L-spine T-score -2.8• 23% of had prevalent vertebral fractures at

baseline• 60 mg of denosumab subQ every six months or

placebo for 3 years• 68% reduction in vertebral fractures p<0.0001.• 20% reduction in non-vertebral fractures p=0.011.• 40% reduction in hip fracture at p=0.036.• No increased incidence of malignancy • Some increase in erysipelas

Targeting the bone formation side of thebone remodeling cycle

Parathyroid Hormone

PTH - Mechanism of Action

PTH binds to cell surface

G protein-coupled receptor

Decreased apoptosis andstimulation of osteoblasts

Stimulation of differentiationof proosteoblasts to osteoblasts

Net increase in number andaction of bone forming

osteoblasts

Effect of rhPTH(1-34) on the Risk of New Effect of rhPTH(1-34) on the Risk of New Vertebral FracturesVertebral Fractures

*p <0.001 vs. Placebo

Ris

k R

edu

ctio

n (

RR

)

Placebo(n=448)

rhPTH 20(n=444)

rhPTH 40(n=434)

64 22 19100%

75%

50%

0%

25%

% o

f Wo

men

8

0

246

101214

RR 0.31 (95% CI, 0.19 to 0.50)*

RR 0.35 (95% CI, 0.22 to 0.55)*

65% 69%

No. of women who had > 1 fracture

PTH plus ALENDRONTE may not be better than PTH alone

PTH

• Advantages– First anabolic therapy– Good efficacy data

• Use first prior to bisphosphate• 18 months – 2 years treatment

PTH

• Disadvantages– Must be given by subcutaneous injection– Risk Osteosacroma– Cost

• Monitoring– Hypercalcemia and hypercalciuria– Check one week and then six months after

initiation treatment

• Not use in patients with calcium oxalate renal stone disease

Summary

• Osteoporosis is an important public health problem

• Accurate diagnosis and treatment requires the use of bone densitometry.

• Radiologists play a central role in the diagnosis and management– of this disease:– measuring bone density– diagnosing fractures– pointing out secondary causes of bone loss

• There needs to be greater attention paid to fall risk-reduction and other modifiable environmental factors.

Summary

• A variety or antiresorptive agents are available for the prevention and treatment of osteoporosis of which the bisphosphonates are the most efficacious.

• Parathyroid hormone is the 1st truly anabolic therapy for the treatment of osteoporosis and is an important addition to our therapeutic regimen.

• Additional anabolic therapies are on the horizon

Thank you for your attention