OsteoporosisDiagnosis and Therapy

Veronica Piziak MD, PhDScott & White

Professor of Endocrinology Texas A&M HSC

Objectives

Discuss: Diagnosis of osteoporosis Dosages of calcium and vitamin D and their role in

bone disease Risks and benefits of bisphosphonates Role of Denosumab

Disclosures: Warner Chilcott- speaker Novartis, P+G research support

Bone loss accelerates with menopause (~1%-2% per year)

Age-related bone loss (~0.5%-1.0% per year)

6 50 100

AGE in YEARS

HIGHER PEAK BONE MASS

MANOPAUSE

How much calcium?What kind?

Patients with renal insufficiency may not be able to clear usual doses of calcium and coronary artery calcification may progress

Russo D, Miranda I, Ruocco C, Battaglia Y, Buonanno E, Manzi S,et al. The progression of coronary artery calcification in predialysis patients on

calcium carbonate. Kidney Int 2007;72:1255-61.

700 mg

1200 mg

1000 mg 1300 mg

X

Institute of Medicine 2010

Calcium: How much and what kind? Do calcium supplements increase the

risk of heart attack? Meta analysis:Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010),

1-2 gms calcium no D in supplements Hazard ratio 1.31 p 0.0305 Dietary calcium no increased risk MI Boland et al BMJ 2010; 341:c3691

Calcium intake and vascular calcification

No correlation of coronary artery calcification or abdominal aortic calculations with dietary calcium or calcium intake in healthy men and women.

Wang TK et al JBMR Jul 2010 Calcium supplementation and the risks of

atherosclerotic vascular disease in older women: results of a 5‐year RCT and a 4.5‐year follow‐up

No increased incidence of CV disease -1200 mg/day

Joshua R Lewis JBMR on line 2010 Look at the ASBMR website

DIETARY CALCIUM 1200 mg very possible Remember fortified foods Total, OJ, pasta, granola bars, yogurt Bread, raisins Cheese 300 mg/ slice (Borden)

Vitamin D MetabolismVitamin D

Dehydrocholecalciferol (diet, skin)

25-hydroxylase

1a-hydroxylase

25-hydroxyvitamin D 1,25-dihydroxyvitamin D

increased GIcalcium absorption

increasedavailablecalcium

INCREASES PHOSPHORUS ABSORPTION

DECREASES PTH SYNTHESIS

CA x P

How much Vitamin D?

600 IU /day everyone thru age 70 800 IU for people > age 70 More then 4000 IU / day is not

recommended

THE 25(OH)D CONTINUUM

(ng/mL)

(nmol/L)

“deficiency”

“insufficiency”“normal”

(ng/ml)

modified after Heaney

0 10 20 30 40 50 60

0 25 50 75 100 125 150

PTH is elevated

CALCIUM ABSORPTION INCREASES

?

Who to Screen for Deficiency Patients who do not increase BMD on

bisphosphonates Patients with hip fracture, nonunion

fractures Young patients with fracture at any site Patients with hyperparathyroidism

Who to Screen for Deficiency

Breast fed infants not given vitamin D supplementation

Institutionalized elderly- decreased sunshine exposure

Obese individuals – decreased production Fibromyalgia patients ? Paget’s disease – Rapid bone turnover Medications that interfere with vitamin D

absorption or metabolism.

Who to Screen for Deficiency Malabsorption Pancreatic insufficiency Inflammatory bowel disease Gastric bypass Severe Liver dysfunction -

decreased 25 hydroxylation

Replacing Vitamin D

1000 IU daily from the 25-30 range Raises the level to about 40 ng/ml For significant deficiency 50,000 IU (D2) may give once a week for 8

weeks check 25OH D Holick et al 1998 lancet 351:805

May give 50,000 IU once a month safely for 5 years

Definition of Osteoporosis A skeletal disorder characterized by… Excessive osteoclast-mediated bone resorption Compromised bone strength Increased risk of fracture at all skeletal sites

Boyle WJ, et al. Nature. 2003;423:337-342.NIH Consensus Development Panel. JAMA. 2001;285:785-795.Images are of a paired iliac crest biopsy and courtesy of Yebin Jiang MD, PhD. Osteoporosis & Arthritis Lab, University of Michigan.

Normal

“Osteoporosis has financial, physical, and psychosocial consequences, all of which significantly affect the individual, the family,

and the community.” –NIH Consensus Statement

Osteoporosis

WHO. Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis; 1998.

T-Score

OsteopeniaOsteoporosis

Normal

–2.5 –2 –1 0

WHO = World Health Organization.

WHO Diagnostic Categoriesfor Osteopenia

REMEMBER BONE STRENGTH ,DISEASE STATE

BMD Testing

Recommended by the Surgeon General’s report in 2004: US Preventive health task force 3/2011

Postmenopausal women with FRAX score 9.3% risk osteoporotic fracture

Women>/=65 years of age with fractures - required by NCQA

Younger women with risk factors Men and Women with fragility fractures People on medications or with diseases

that can increase the risk of fractures

Who to treat?Goal - prevent fracturesPatients at significant risk

Fracture rate

60

50

40

30

20

10

0Fra

ctu

re p

er

100

0 P

ers

on

-Ye

ars

Adapted from Siris ES, et al. Arch Intern Med. 2004;164:1108-1112.

BMD distribution

BMD T-Scores (Peripheral)

>1.01.0 to 0.5

0.5 to 0.00.0 to –0.5

–0.5 to –1.0–1.0 to –1.5

–1.5 to –2.0–2.0 to –2.5

–2.5 to –3.0–3.0 to –3.5

< –3.5

No. of women with fractures

450

350

300

250

200

100

0

150

50

400

No

. of W

om

en

With

Fra

ctu

res

Population BMD Distribution, Fracture Rates, and Number of Women With Fractures

http://www.shef.ac.uk/FRAX/index.htm

http://www.shef.ac.uk/FRAX/index.htm

Updated NOF Clinician’s GuideIncorporation of WHO Algorithm New NOF Guide (2008)

Initiate Treatment in PM women and men age ≥50 with:•Hip or vertebral fracture•Other prior fracture and low bone mass (T-score -1.0 to -2.5)•T-score <-2.5 (2º causes excl.)•Low bone mass and 2º causes associated with high risk of fracture•Low bone mass AND 10-yr hip fracture probability ≥3% or 10-yr major OP-related fracture probability of ≥20%

PreviousNOF Guide (2003)

Initiate Treatment in those with :

•T-score <-2.0 & no risk factors

•T-score <-1.5 & ≥ risk factors

•Hip or Vertebral Fracture

OSTEOPOROSIS How to Treat? Approved medications Raloxifene Bisphosphonates PTH 1-34 Denosumab

ALENDRONATE

Approved for: Prevention and therapy Postmenopausal osteoporosis Steroid induced osteoporosis 70mg/week Generic available! Long life in bone, most commonly

associated with bone suppression

Risedronate and Ibandronate

Risedronate 150 mg Once a Month Minimum of 30-minute wait before eating Approved for prevention and therapy of Postmenopausal osteoporosis, male

osteoporosis, steroid induced osteoporosis Enteric coated form now availableIbandronate 150 mg Once a MonthMinimum of 60 minute wait before eating

Approved for prevention of vertebral fractures

IV Bisphosphonates: Considerations Potentially increased compliance Only eliminate GI adverse events Adverse events and considerations

Flu-like syndromes Injection-site reactions Renal toxicities (Check creatinine) Long-term use

Osteonecrosis of the jaw Electrolyte abnormalities (hypocalcemia)

Conte et al. Oncologist. 2004;9(suppl 4):28.

IV Ibandronate

15 second IV push Store at room temperature 3 mg/every three months Creatinine clearance at least 37 ml/min

Zoledronic acid/ Reclast

Approved as a once / year IV therapy for postmenopausal and male osteoporosis,

15 minute infusion 5 mg/100 ml Side effects – hypocalcemia, fever, muscle

pain, flu-like symptoms and headache Not for use in pregnancy or with creatinine

clearance < 35ml/min MAKE SURE PATIENTS TAKE CALCIUM! MAKE SURE THEY ARE WELL HYDRATED Consider obtaining 25 OH Vitamin D

Code properly

Billed under Medicare Part B Must have “senile/postmenopausal

osteoporosis 733.01 T- score -2.5 + 995.29 Unspecified adverse effect of other

drug V12.79 Personal Hx of digestive system

disease V49.84 bed confined status = payment

RISEDRONATE CONTROL

P < 0.01

VS CONTROL

Hip fracture reduction by 9 months

ALENDRONATE OVER 10 YEARS BONE AND LIBERMAN ET AL NEJM 2004;350:1189-1199

BUT does over suppression result in fractures?

In the past 4 years, reports have been published implying that long-term bisphosphonate therapy could be linked to atraumatic femoral diaphyseal fractures

Long-term alendronate therapy 8+ years ? Associated with unilateral low-energy subtrochanteric and diaphyseal femoral fractures in a small number of patients.

JBMR Publishes ASBMR Task Force Report on Atypical Femoral FracturesWho is at risk?

Date: September 14, 2010

In the most comprehensive scientific report to date on the topic, the task force reviewed 310 cases of "atypical femur fractures," and found that 94 percent (291) of patients had taken the drugs, most for more than five years.   The task force members emphasized that atypical femur fractures represent less than one percent of hip and thigh fractures overall and therefore are very uncommon. They MAY be related to long term use.

More than half of patients with atypical femur fractures reported groin or thigh pain for a period of weeks or months before fractures occurred, according to the report.  More than a quarter of patients who experienced atypical femur fractures in one leg experienced a fracture in the other leg as well

Warnings PI: Thigh or groin pain look for fracture – Plan film of the area may show sclerosis.

FLEX – FIT EXTENSION

WHO SHOULD NOT STOP?

PREVIOUS VERTEBRAL OR NONVETEBRAL FRACTURE

VERY LOW BMD <- 2.5 BLACK ET AL JAMA 2006;296:2927-38 EDITORIAL JAMA 2006;296:2968-2969

FDA agrees 2010

Reanalysis of FLEX/FITwho could stop?

In previous studies, ALN efficacy for NVF prevention in women without prevalent vertebral fracture was limited to those with femoral neck (FN) T-score </= -2.5.

Continuing alendronate for 10 years instead of stopping after 5 years reduces non-vertebral fracture risk in women without prevalent vertebral fracture whose FN T-score, achieved after 5 years of ALN, is </= -2.5, but does not reduce risk of NVF in women whose

T-score is > -2 after 5 years could stop

Long Term Use– a Plan

Drug holiday after 5-10 years Duration of the treatment and holiday depend

on fracture risk. Continue for 10 years if osteoporosis or if

holiday use another agent (? PTH 1-34) Low fracture risk then stop at 5 years and

monitor the DXA stay off if stable and no fractures.

Watts et al JCE&M 95: 1555-1565 2010

Human Parathyroid Hormone 1-34 and 1-84

1 10

20

30

Ser Val Ser Glu Ile Gln Leu Met His AsnLeu

GlyLysHisLeuAsnSerMetGluArgValGlu

Trp

LeuArg Lys Lys Leu Gln Asp Val His Asn Phe

50

40

6070

80

-COOH

H2N-

When to use

Severe osteoporosis T score – 3, previous fractures Fractures on bisphosphonate Unresponsive to bisphosphonates Few side effects Very expensive

Role of RANK Ligand in Bone Resorption

HormonesGrowth factorsCytokines

RANKL

RANK

OPG

Bone Formation

Adapted from Boyle WJ, et al. Nature. 2003;423:337-342. Bone Resorption

Activated Osteoclast

CFU-M Pre-FusionOsteoclast

MultinucleatedOsteoclast

In the presence of M-CSF

CFU-M=colony forming unit macrophageM-CSF=macrophage colony stimulating factor

Provided as an educational resource. Do not copy or distribute.© 2007 Amgen. All rights reserved.

Osteoblasts

Cytokines Growth factors

HormonesPrefusion osteoclast

RANKL-Inhibitors: Mechanism of Action

Adapted from Boyle et al. Nature. 2003;423:337.

CFU-M

Multinucleatedosteoclast

RANKL

OPG

BONE

OPG RANKL

Stromal

cells

InhibitorsRANK

Active OsteoclastOsteoblast

Denosumab SC q6mo: Effect on Lumbar Spine BMD

Placebo (n=46)

Denosumab 60 mg (n=46)Denosumab 100 mg (n=41)

Alendronate 70 mg/wk (n=46)

Denosumab 14 mg (n=53)

Denosumab 210 mg (n=46)

Months

Me

an

ch

an

ge

fro

m b

as

elin

e (

%)

-2

-1

0

1

2

3

4

5

6

0 2 4 6 8 10 12

Adapted from McClung et al. N Engl J Med. 2006;354:821.

60 mg dose sub q every 6 months

Spine 6.5% 2 years, Hip 3.4%, Radius 1.4% (cortical bone)

96% responder rate 4/1/08 Endo Soc

Steven R. Cummings, M.D., Javier San Martin, M.D., Michael R. McClung, M.D., NEJM 2009;361 Aug 19th

Approved by the FDA!

Denosumab (Prolia) Indication: postmenopausal osteoporosis With a high risk of fracture Sub q every 6 months (prefilled syringe) Contraindicated in hypocalcemia May use in renal insufficiency ( monitor

calcium, phosphorus, magnesium)

Side Effects

Side effects: dermatitis, significant infections, pancreatitis

ONJ has been reported Examine the mouth If patient has an infection they need to

call

TREAT OSTEOPOROSIS

10 million Americans with osteoporosis and it is treatable

Yet Calcium intake is low in the US

After hip fracture <25% given calcium and vitamin d <10% treated with bone active agents

50% no longer take medications at 1 year

Keep trying