osteoporosis for the generalist daniel g. malone md associate professor of medicine, rheumatology,...

OSTEOPOROSIS FOR THE GENERALIST

DANIEL G. MALONE MD

ASSOCIATE PROFESSOR OF MEDICINE,

RHEUMATOLOGY,

UNIVERSITY OF WISCONSIN, MADISON

[email protected]

LEARNING OBJECTIVES

•RECOGNIZE RISK FACTORS FOR OP AND FOR FRACTURE

•UNDERSTAND LIMITATIONS OF DEXA SCANNING

•KNOW DIFFERENCES IN MECHANISMS OF ACTION OF THE ANTI-OP AGENTS

•KNOW WHEN, AND FOR HOW LONG TO TREAT, AND WHICH DRUGS TO USE

•CHOOSE THE RIGHT DRUG FOR EACH INDIVIDUAL PATIENT

BALANCE IS HEALTH, IMBALANCE IS ILLNESS

RESORPTION-OSTEOCLASTS

BUILDING-OSTEOBLASTS

BONE TURNOVER/BONE REMODELING

+-

RESORPTION BUILDING

BUILDING=RESPORPTION, SO BONE MASS AND STRENGTH ARE MAINTAINED

0 0

YOUNGADULT

NORMAL BALANCE IN YOUNG ADULT

YOUNGADULT

RESORPTION HAS INCREASED AND BUILDING HAS DECREASED, SO BONE

MASS AND STRENGTH DECREASE

0 0

RESORPTION

BUILDING

YOUNG ADULT

OSTEOPOROSIS OF AGING/MENOPAUSE

YOUNG ADULT

CASE QE53 YEAR OLD CAUCASIAN WOMAN, IN FOR ROUTINE YEARLY CHECKUP, NO COMPLAINTS EXCEPT ONSET OF MENOPAUSAL SYMPTOMS.

NO OTHER MAJOR MEDICAL PROBLEMS, NO OP RISK FACTORS AND NO HISTORY OF FX. EXAM NORMAL. SLENDER BODY HABITUS. ALL LABS FINE…LH AND FSH ELEVATED AT POST-MENOPAUSAL LEVELS, ESTRADIOL 10.

WE DO NOT KNOW EXTENT OF HER RISK FACTORS EXCEPT SHE IS POST MENOPAUSAL, CAUCASIAN AND SLENDER. WE DO NOT KNOW HER GENETICS, OR WHERE ON THE PROVERBIAL BELL-SHAPED CURVE SHE IS WITH REGARD TO BONE MASS.

THEREFORE, WE HAVE INSUFFICIENT INFORMATION ON WHICH TO BASE A THERAPY DECISION.

MY PRACTICE IS TO GET A FEW BASELINE LABS AND A BASELINE DEXA.

CASE QE

CASE QE1. ADVISE INTAKE OF CALCIUM 1500 mg/d,

AND VITAMIN D, DOSE DEPENDENT ON OUTCOME OF #3.

2. ADVISE EXERCISE OF HER CHOOSING.

3. ORDER DEXA.

4. ORDER 25-OH VITAMIN D LEVEL, CBC, VITAMIN B12.

5. RE-DO DEXA IN 2-3 YEARS TO ESTABLISH RATE OF BONE MASS LOSS.

CASE QETOTAL 25-OH VITAMIN D <15 ng/ml: CHECK

intact PTH, VITAMIN D3 10,000 IU* PO/day FOR 3 WEEKS, THEN 4000 IU/day FOR 3 WEEKS THEN RE-CHECK VIT D LEVEL.

TOTAL 25-OH VITAMIN D 16-22 ng/ml: VITAMIN D3 10,000 IU PO/d FOR TWO WEEKS THEN 4000 IU/d FOR 1 MONTH, THEN RE-CHECK VIT D LEVEL.

TOTAL 25-OH VITAMIN D 22-29 ng/ml: VITAMIN D3 2000 UI/d FOR 6 WEEKS, RE-CHECK VIT D.

CASE QE

TARGET FOR TOTAL 25-OH VITAMIN D:

30-60 ng/ml

REMINDER

25-OH VITAMIN D2+ 25-OH VITAMIN D3

TOTAL 25-OH VITAMIN D

CASE QE TEACHING POINT 1

YOUR MOM WAS RIGHT:

PREVENTION=16 (CURE)

LOSS OF BONE MASS OCCURS RAPIDLY IN THE FIRST 5-7 YEARS AFTER MENOPAUSE. THEREFORE, GET DEXA NOW AND IN 2 YEARS. BONE MASS HAS MANY CONTRIBUTING FACTORS e.g. AGE, GENDER, HABITUS, LIFESTYLE, GENETICS. RATHER THAN GUESS AT WHAT HER BONE MASS WILL DO OVER THE YEARS AFTER MENOPAUSE, MEASURE IT! FINDING AND CORRECTING BONE MASS LOSS NOW PREVENTS PROBLEMS IN 20 YEARS!


HYPOVITAMINOSIS D IS EPIDEMIC! YOU SHOULD ASSUME YOUR PATIENT’S TOTAL 25-OH VITAMIN D LEVEL IS LESS THAN DESIRABLE UNTIL PROVEN OTHERWISE.

TREAT TO MAINTAIN AT 30-60 ng/ml


IF QE IS A MALE, EVERYTHING THE SAME EXCEPT NO NEED TO ORDER DEXA UNLESS THERE IS A MAJOR RISK FACTOR (etoh, hypgonad, steroids, transplant, etc.)

CASE QETEACHING POINT SUMMARY

1. Ca++ 1500 mg/d, VITAMIN D >32ng/ml

2. GET BASELINE DEXA IN FEMALES AT MENOPAUSE

3. SCREEN MALES ONLY IF MAJOR RISK FACTOR PRESENT

CASE AF63 YEAR OLD WOMAN, NEVER HAD ANY EVALUATION OR RX FOR OSTEOPOROSIS.

16 YRS p MENOPAUSAL. TAKES CALCIUM 1500 mg/d AND VITAMIN D 1000 IU DAILY. NO OTHER MEDICAL PROBLEMS, NO OP RISK FACTORS AND NO HISTORY OF FX. IN FOR ROUTINE CHECKUP, NO COMPLAINTS. EXAM NORMAL. IDEAL BODY WEIGHT. ALL LABS FINE. TOTAL 25-OH VITAMIN D 36 ng/ml. DEXA SHOWS T SCORE –1.6 IN SPINE AND –1.4 IN HIPS.

RX?

BY STRICT CRITERIA, THIS LADY HAS OSTEOPENIA BY DEXA, BUT SHE HAS NO RISK FACTORS, NO FRACTURES, AND SHE TAKES ADEQUATE CALCIUM AND VITAMIN D. NO FURTHER TREATMENT IS NEEDED AT THIS TIME. REPEAT DEXA IN 2 OR 3 YEARS TO ESTABLISH TREND. IF AT THAT TIME SHE SHOWS FURTHER BMD LOSS, CONSIDER USE OF ANY OF THE ANTIRESORPTIVE THERAPIES.

CASE AF

CASE AF TEACHING POINT 1

ALL POSTMENOPAUSAL WOMEN SHOULD TAKE AT LEAST 1500 mg CALCIUM AND ENOUGH VITAMIN D TO KEEP TOTAL 25-OH VITAMIN D LEVEL >30 ng/ml.

REMINDER

25-OH VITAMIN D2+ 25-OH VITAMIN D3

TOTAL 25-OH VITAMIN D

NormalLow Bone Mass

(Osteopenia)

1. JAMA.2001;285:785-795.2. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003.

-4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 - 0.5 0 +0.5

Osteoporosis

OSTEOPOROSIS DEFINITIONS:

OSTEOPOROSIS IS A SKELETAL DISORDER CHARACTERIZED BY COMPROMISED BONE STRENGTH PREDISPOSING A PERSON TO AN INCREASED RISK OF FRACTURE. BONE STRENGTH PRIMARILY REFLECTS THE INTEGRATION OF BONE QUALITY AND BONE DENSITY.1

T-Score


BY DEXA2

GENERAL


RISK FACTORS FOR OSTEOPOROSIS

FEMALE

CAUCASION/ASIAN

POSTMENOPAUSAL

THIN BODY HABITUS

CIGARETTE SMOKING

EXCESSIVE ALCOHOL USE

FAMILY HISTORY OF OSTEOPOROSIS

SEDENTARY LIFESTYLE

WHEN TO INITIATE THERAPY

HIP T-SCORES < –2.0 NO OP RISK FACTORS

HIP T-SCORES < –1.5 AT LEAST ONE OP RISK FACTOR

PRIOR VERTEBRAL OR HIP FRACTURE

1. National Osteoporosis Foundation. Physician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003:22.

2. J Clin Densitometry. 2002;5:S29-S38.


NOTE: NOT ALL PATIENTS NEED DRUGS TO TREAT THEIR BONE MINERAL

ISSUES.

FDA-APPROVED DRUGS FOR OSTEOPOROSIS IN

POSTMENOPAUSAL WOMEN

• BISPHOSPHONATES – RISEDRONATE – ALENDRONATE

• ESTROGEN THERAPY• ESTROGEN+PROGESTI

N THERAPY • SELECT. ESTR. REC.

MOD. (SERM) –RALOXIFENE HCL

FOR PREVENTION: FOR TREATMENT:

• BISPHOSPHONATES

• TERIPARATIDE • CALCITONIN• SERM

THE MAIN OBJECTIVE OF SERIAL BMD MEASUREMENTS IS TO IDENTIFY PATIENTS WITH SIGNIFICANT LOSS IN BMD

IF THE BMD INCREASES OR STAYS THE SAME, NO CHANGE IN THERAPY IS INDICATED

IF BMD HAS SIGNIFICANTLY DECREASED:• NONCOMPLIANCE• ADD A NEW AGENT • CHANGE TO A DIFFERENT AGENT

International Society for Clinical Densitometry (ISCD) 2002 Position Statement

MONITORING THERAPY BY DEXACASE AF TEACHING POINT 5

CASE AFTEACHING POINT SUMMARY

1. Ca++ 1500 mg/d, VITAMIN D >32ng/ml

2. DEFINITIONS OF OSTEOPOROSIS AND OSTEOPENIA

3. RISK FACTORS FOR OP

4. WHEN TO TREAT

5. GOALS USING DEXA TO MONITOR

CASE VN

65 Y/O FEMALE SMOKER WHO COMES IN FOR OP ASSESSMENT BECAUSE HER SISTER TOLD HER TO. WANTS IBANDRONATE, “BECAUSE IT’S ON TV.” MOTHER HAD A DOWAGER HUMP, AND WAS “ALL BENT OVER.” HER SISTER HAD A URI LAST MONTH, COUGHED, AND FRACTURED 2 RIBS. SHE WAS DX’D WITH OP BY HER DOC. PATIENT REPORTS LOSS OF 2 INCHES OF HEIGHT SINCE HIGH SCHOOL. HAD BILAT THA FOR AVASCULAR NECROSIS/DJD. REPORTS BACK PAIN, BUT HAS BEEN TOLD IT IS DUE TO “BAD ARTHRITIS” AND “BAD DISKS.”

CASE VN

TREATS HER BACK PAIN WITH “A FEW” BRANDIES PER NIGHT. TAKES VITAMIN D 3000 IU PER DAY BECAUSE HER SISTER WAS GIVEN THAT DOSE, SO PT STARTED TOO.

EXAM: YOUR 1ST CRANIAL DETECTS ETOH. PT IS 64” TALL, WEIGHTS 105. HAS DUPUYTREN’S CONTRACTURES AND TOBACCO STAINS ON NAILS. TENDER OVER SEVERAL LUMBAR VERTEBRAE. OTHERWISE EXAM UNREMARKABLE. LABS OK EXCEPT ALT AND AST MILDLY ELEVATED.

X-RAYS SHOW SEVERE DDD AND DJD OF SPINE WITH COMPRESSION FX AT T11 AND L1. DEXA: TOO MUCH SPINE SCLEROSIS FOR INTERPRETATION.

W.H.O. ESTIMATE OF 10 YEAR FRACTURE RISK WILL INCLUDE SUCH FACTORS AS:

T-SCOREHX OF FRACTUREAGEFAMILY HXMEDICAL HX

MEDICATIONSLIFESTYLESMOKINGETOHGENDER

CASE VN TEACHING POINT 1DEXA IS NOT THE ONLY FACTOR! THERE’S MORE

TO THIS THAN T SCORES

CASE VN TEACHING POINT 2

THE BEST TREATMENT OPTION FOR HER DEPENDS ON HER FUTURE RISK FOR FRACTURE.

REGARDLESS, START VIT D, AND Ca++.

WE CANNOT ASSESS HER T SCORES, BUT, SHE HAS ALREADY FRACTURED AT LEAST TWICE, SO THE BMD READINGS ARE IRRELEVANT, AND SHE HAS SEVERE OSTEOPOROSIS BY DEFINITION.

SHE IS AT HUGE RISK FOR FUTURE FRACTURES. BESIDES, THE DJD LIKELY WOULD FALSELY ELEVATE THE BMD READING.


ASSOCIATION OF VERTEBRAL FRACTURES WITH SUBSEQUENT

FRACTURE RISK

# Vertebral Fracture(s) Fracture Risk

1 Vertebral: 5x increase1, 2

> 2 Vertebral: 12x increase1, 2

1 symptomatic Hip: 2x increase3

1Ross P.D. et al. Ann. Intern Med 1991;114:919-923 2Lindsay R. et al. JAMA 2001;285:320-3233Kanis K.A. Osteoporosis and its Consequences, Osteoporosis, Blackwell Science Ltd. p 8

REMINDER

HALF OF ALL LOW TRAUMA FRACTURES OCCUR IN WOMEN WHO DO NOT HAVE OSTEOPOROSIS BY DEXA CRITERIA.


DEXA MAY BE MISLEADING IN PATIENTS WITH HIGH FUTURE FRACTURE RISK, e.g. PATIENTS WHO HAVE ALREADY FRACTURED, AND/OR HAVE OTHER RISK FACTORS.


GIVEN THE WHOLE PICTURE, I WOULD CHOOSE AN ANABOLIC

AGENT BECAUSE FUTURE FRACTURE RISK IS SO HIGH.

RESORPTION HAS INCREASED AND BUILDING HAS DECREASED, SO BONE

MASS AND STRENGTH DECREASE

YOUNG ADULT

0 0

RESORPTION

BUILDING

YOUNG ADULT

OSTEOPOROSIS OF AGING/MENOPAUSE

BISPHOSPHONATESAND ALL OTHER ANTI-RESORPTIVES

0 0

BUILDING

RESORPTION

NO CHANGEDECREASE

YOUNG ADULT

YOUNG ADULT

INHIBIT RESORPTION, SO TIP THE BALANCE BACK IN FAVOR OF BUILDING, BUT DO NOT STIMULATE HIGHER LEVEL OF SYNTHESIS

STIMULATES BOTH BUILDING AND RESPORPTION, IN FAVOR OF BUILDING,

SO NET EFFECT IS THAT BONE MASS AND STRENGTH INCREASE

BUILDING INCREASES MORE THAN RESORPTION

RESORPTIONINCREASES

TERIPARATIDE-FORTEO

0 0

- 70

- 68

Months0 1 3 6 12

-100

-50

0

50

100

150

200

250

Months0 1 3 6 12

-100

-50

0

50

100

150

200

250

ANTI-RESORPTIVE AGENTS: ALENDRONATE

1. Arch Intern Med. 2005;165:1762-1768.

P1NP

NTx

Mea

n %

Ch

ang

e ±

SE

197

40

BIOCHEMICAL MARKERS OF BONE TURNOVER1

ANABOLIC AGENTS: TERIPARATIDE

BONE TURNOVER MARKERSBONE BUILDUP/OSTEOBLASTIC:BSAP (bone specific alk phosphatase)S-OC (serum osteocalcin)PYRIDINOLINE CROSS LINKSTYPE 1 COLLAGENCOLLAGENASE 3OSTEOPONTINBSP (bone sialoprotein)

BONE BREAKDOWN/OSTEOCLASTIC:P1NP (N-terminal propeptide)P1CP (C-terminal propeptide)NTx 1 (crosslinked N-telopeptide of type1 collagen)CTx 1 (crosslinked C-telopeptide of type1 collagen)TRAP (tartrate-resistant acid phos)U-OC (urine osteocalcin)CATHEPSIN K

CASE VNTEACHING POINT SUMMARY1. WHO 10 YEAR RISK FOR FRACTURE

2. CHOICE OF AGENT DEPENDS ON FRACTURE RISK.

3. DEXA AND T SCORES MAY BE IRRELEVANT OR MISLEADING IN HIGH RISK PATIENTS

4. ANTI-RESORPTIVE VS ANABOLIC

CASE AM

72 YO CAUCASIAN FEMALE WITH CHRONIC, UNCHANGED MILD LOW BACK PAIN, AND KNOWN SEVERE DDD AND DJD OF SPINE, SENT FOR OP EVALUATION. NO OTHER KNOWN OP RISK FACTORS, BASELINE LABS ALL NORMAL INCLUDING TOTAL 25-OH VITAMIN D. TAKES CALCIUM AND D AS SHE SHOULD. NO OTHER SIGNIFICANT HX.

DEXA SHOWS T SCORE IN L1-L4 OF -1.8. HIPS NOT ASSESSED DUE TO BILATERAL THA. L1 +1.9L2 -3.2L3 -3.8L4 +1.7

L1-L4 -1.8

WHAT SHOULD YOU DO?

CASE AM

CASE AM

HER T SCORES SUGGEST THAT HER RISK OF FRACTURE IS NEGLIGIBLE, SO NO TREATMENT IS NEEDED, AND I’M DONE, RIGHT?

WRONG. MAJOR DISCREPANCIES AMONGST THE VERTEBRAE SHOULD RAISE A RED FLAG. THE NEXT STEP IS TO HAVE A LOOK AT THE DEXA, OR SHOW IT TO SOMEONE WHO KNOWS HOW TO READ THEM PROPERLY. YOU DO THIS, AND THE DEXA IMAGES SHOW SEVERE DDD, DJD, AND A LOT OF BONY SCLEROSIS. YOU ORDER SPINE FILMS WHICH SHOW THE DDD AND DJD, BUT ALSO COMPRESSION FRACTURES AT T11, T12, L1 AND L4.

THE DEXA WAS INCORRECTLY INTERPRETED. SHE IS AT VERY HIGH RISK FOR ANOTHER FRACTURE AND NEEDS AGGRESSIVE TREATMENT.

CASE AM

CASE AM TEACHING POINT 1

DEXA IS A GOOD, BUT FAR FROM PERFECT, TOOL FOR ASSESSING FRACTURE RISK. ESTIMATED TO ACCOUNT FOR ONLY ABOUT 25% OF RISK. NONETHELESS, AT THIS TIME IT IS THE BEST WE HAVE, AND THERE IS CORRELATION BETWEEN DEXA READINGS AND FRACTURE RISK.

DEXA: RELATIONSHIP OF T-SCORE TO FRACTURE RISK

RATIO

FX RISK RATIO ≈ 2FOR T-SCORE<0

|T-SCORE|

e.g. IF T-SCORE IS –3, RISK RATIO

FOR FRACTURE IS 2 = 8-FOLD

ELEVATED ABOVE NORMAL

3

X-RAY BEAM DETECTOR

DEXA READING IS PROPORTIONAL TO THE AMOUNT OF X-RAY

ABSORBED BY BONE:

THEREFORE DEXA CAN ONLY TELL US HOW MUCH CALCIUM LIES

BETWEEN THE SOURCE AND THE DETECTOR—IT CANNOT TELL US

ANYTHING ABOUT HOW THAT MASS OF CALCIUM IS ARRANGED.

IS CALCIUM ARRANGEMENT IMPORTANT?

1. J Bone Miner Res . 2003;18:1932-1941.

BONE QUALITY, WHICH IS CLOSELY RELATED TO BONE MICROARCHITECTURE, IS A CRUCIAL DETERMINANT OF FRACTURE RESISTANCE

BRIDGE #1

BMD READING = X

X

BLOCKS OF SCRAP IRON LEFT BY WORKERS

BRIDGE #2

BMD READING ALSO = X*

X

*WITHIN THE ERROR OF THE MACHINE

X

DEXA IS UNABLE TO DISTINGUISH BETWEEN THE 3 BRIDGES, YET BRIDGE #3 HAS FAR GREATER STRENGTH

BRIDGE #3

BMD READING ALSO = X

DEXA TELLS YOU NOTHING ABOUT BONE

MICROARCHITECTURE, AND THEREFORE ONLY A SMALL PART OF THE STORY WITH REGARD TO

STRENGTH AND FRACTURE RESISTANCE!!!


(REITERATED)

DEXA ARTIFACTS CAN BE MISLEADING:

DJD OF VERTERAE

VERTEBRAL FRACTURES

SCLEROSIS

CALCIFICATIONS OF AORTA

ROTATION OF PATIENT/SPINE

INCORRECT READING


CASE AM TEACHING POINT SUMMARY

1. DEXA IS AN IMPERFECT TOOL FOR FRACTURE RISK ASSESSMENT

2. COMMONLY MISINTERPRETED

3. SUBJECT TO ARTIFACTUAL ELEVATION OF READINGS-CAN BE “NORMAL” WHEN PATIENT ACTUALLY IS AT HIGH FRACTURE RISK

CASE ST

60 Y/O FEMALE WHO COMES IN BECAUSE HER CXR DONE FOR COUGH SHOWED “WASHED OUT BONES” IN THE THORACIC SPINE. C/O FATIGUE AND TINGLING OF FINGERS. H/O FMS W/ IBS.

MCV=103, HCT 30, VIT D 10, VIT B12 100, PTH 365 (VERY HIGH), ALK PHOS ELEVATED—BONE FRACTION

OTHER LABS OK.

BMD SHOWS T SCORES –4.0 IN BOTH.

LOW B12 AND VIT D LEVELS WITH MACROCYTIC ANEMIA STRONGLY SUGGEST MALABSORPTION. PTH IS HIGH DUE TO VERY LOW VITAMIN D. ELEVATED BONE ALK PHOS SUGGESTS OSTEOMALACIA, PROBABLY SECONDARY TO LOW VITAMIN D.

SUSPICION IS THAT THE ”IBS” COULD BE SOMETHING ELSE!

INITIATE GI WORKUP. LIKELY YOU WILL FIND SPRUE. TREAT SPRUE, GIVE HIGH DOSE VITAMIN D PO AND DOCUMENT THAT THE VITAMIN D STAYS AT 60 ng/ml FOR 6 MONTHS, THEN 32-60 THEREAFTER, AND THAT THE PTH NORMALIZES, INSURE ADEQUATE Ca++ INTAKE. REEVALUATE BMD IN 1 YEAR.

CASE ST

SOME CAUSES OF OSTEOPOROSIS

1. GENETIC PREDISPOSITION2. ORAL STEROIDS FOR LONGER THAN 3 MONTHS3. MALABSORPTION DISORDERS/POOR NUTRITION4. HYPERPARATHYROIDISM, 1º, 2º OR 3 º5. HYPERTHYROIDISM6. MENOPAUSE + FAILURE TO TREAT7. INFLAMMATORY ILLNESSES 8. TESTOSTERONE DEFICIENCY IN MALES, ? FEMALES8. ALCOHOL AND TOBACCO ABUSE9. INACTIVITY (BEDRIDDEN PATIENTS)10.DRUGS e.g. CYCLOSPORIN, HEPARIN, ANTI-

CONVULSANTS

CASE HL TEACHING POINT 1


25-OH VIT D--HYPOVITAMINOSIS D, MALABSORPTION

VIT B12--------MALABSORPTION CBC-------------MALABSORPTION

ESR-------------INFLAMMATORY ILLNESSES, MYELOMA

Ca++ ------------HYPERPARATHYROIDISM

PO4 -------------OSTEOMALACIA

CREATININE-2º/3º HYPERPARATHYROIDISM

ALK PHOS----OSTEOMALACIA, BASELINE

INTACT PTH--HYPERPARATHYROIDISM

8 AM TESTOSTERONE (MALES)- HYPOGONADISM

ALBUMIN------CALCIUM INTERPRETATION

URINE NTx----BASELINE FOR ANTI-RESORPTIVE

LABS TO BE ACQUIRED BEFORE Rx DECISION

CASE ST TEACHING POINT 1

1. OSTEOPOROSIS CAN HAVE ANY OF SEVERAL UNDERLYING CAUSES.

2. BEFORE DECIDING ON TREATMENT, IT IS NECESSARY TO DETERMINE IF THERE IS AN UNDERLYING CAUSE OF THE OSTEOPOROSIS, BECAUSE IF MISSED, THERAPY FOR OSTEOPOROSIS WILL PROBABLY FAIL.


LOW VITAMIN D RESULTS IN ELEVATION OF PTH, AND IF SUFFICIENTLY SEVERE AND PROLONGED, IN ELEVATION OF ALKALINE PHOSPHATASE, INDICATING OSTEOMALACIA.


CORRECTION OF HYPOVITAMINOSIS D SHOULD BE DONE IMMEDIATELY, BUT RETURN OF PTH AND ALK PHOS TO NORMAL MAY TAKE MONTHS.


IN CASES OF SEVERE HYPO-VITAMINOSIS D AND OSTEOMALACIA, IT IS ESSENTIAL TO INSURE ADEQUATE CALCIUM INTAKE DURING TREATMENT!---YOU NEED BRICKS TO BUILD HE WALL.

1. ID UNDERLYING CAUSES OF OP

2. EFFECTS OF HYPOVITAMINOSIS D

3. PTH AND ALK PHOS NORMALI-ZATION MAY TAKE MONTHS

4. INSURE ADEQUATE CALCIUM INTAKE

CASE STTEACHING POINT SUMMARY

CASE ML55 YO FEMALE 6 YEARS POST MENOPAUSAL HAS BEEN STABLE ON IV BISPHOSPHONATE FOR 3 YEARS. COMES IN HORRIFIED, AND WANTS TO STOP ALL OSTEOPOROSIS TREATMENT, BECAUSE “I HAVE A TOOTH THAT NEEDS TO BE REPAIRED, AND WHEN HE DOES IT, ALL MY TEETH ARE GOING TO FALL OUT AND I WILL BE IN HORRIBLE PAIN.”

SHE READ IN COSMOPOLITAN THAT THERE IS A TERRIBLE DENTAL PROBLEM WITH OP DRUGS, AND THAT ALL WOMEN SHOULD IMMEDIATELY SEE THEIR DOCTORS ABOUT IT BEFORE THEIR HEADS FALL OFF.

CASE ML

REASSURE HER THAT THIS IS LARGELY MEDIA HYSTERIA. “ONJ” OF THE JAW IS QUITE RARE, IS NOT ACTUALLY “AVASCULAR NECROSIS” OR EVEN “NECROSIS” FOR THAT MATTER.

CASE ML TEACHING POINT 1

SO-CALLED “OSTEONECROSIS OF THE JAW” IS DEFINED IN THE DENTAL LITERATURE AS AN EXPOSED AREA OF BONE IN THE MOUTH THAT DOES NOT HEAL AFTER 8 WEEKS.

DESCRIBED IN PATIENTS WITH HYPERCALCEMIA OF MALIGNANCY WHO WERE RECEIVING FREQUENT TREATMENT WITH IV BISPHOSPHONATES TO LOWER SERUM CALCIUM. DOSES ROUGHLY TENFOLD ABOVE USUAL OP DOSES.

THE HISTOLOGY IS COMPLETELY DIFFERENT THAN THAT OF AVASCULAR NECROSIS.

THE MYTHOLOGY AND HYSTERIA OF ONJ:


•IN FACT, THE HISTOLOGY OF THE ONJ LESION BEARS NO RESEMBLANCE TO AVASCULAR NECROSIS, RATHER, IT IS INDISTINGUISHABLE FROM OSTEOMYELITIS, BUT THERE IS NO EVIDENCE OF INFECTION.

•MOST PATIENTS HAVE LITTLE OR NO PAIN.

•THERE IS ABSOLUTELY NO RELIABLE EVIDENCE THAT CESSATION OF BISPHOSPHONATES PRIOR TO DENTAL PROCEDURES IS IN ANY WAY PREVENTATIVE OR BENEFICIAL. NONETHELESS, TO KEEP THE LAWYERS AT BAY, THE ADA HAS RECOMMENDED POSTPONEMENT OF PROCEDURES UNTIL PATIENTS ARE OFF DRUG FOR SEVERAL WEEKS.



•MOST OF THE CONCERN ABOUT THIS IS UNFOUNDED, SINCE THE LESION IS EXTREMELY RARE.

•WELL OVER 90% OF CASES HAVE BEEN DESCRIBED IN CANCER PATIENTS ON CHEMOTHERAPY.

•NO PREDISPOSING FACTOR HAS BEEN IDENTIFIED, EXCEPT THAT IN SOME CASES LESIONS OCCUR AT SITES OF RECENT DENTAL PROCEDURES.


www.ncs.org/lrs/statinfo/odds.htm

20

15

10

5

0MVA Murder Drowning Fire ONJ

1216

THE RISK OF DEATH FROM MANY THINGS IS MUCH HIGHER THAN THE RISK OF ONJ !

Penicillin

Neugut, et. al., Arch Int Med, 2001 15-21

CASE QW

62 Y/O FEMALE W/O COMPLAINT. SENT FOR EVAL OF OP THERAPY. MENOPAUSE AGE 53, PUT ON HRT THEN, AND TOOK IT UNTIL 1 YR AGO. QUIT BECAUSE OF ADVERSE PUBLICITY.

HAD BMD STUDY AGE 56 THAT WAS NML. REPEAT STUDY AGE 61 ALSO OK. BMD DONE THIS MONTH SHOWS LOSS OF BONE DENSITY IN VERTEBRAL AND FEMORAL HEAD. T SCORES –1.9.

ALL LABS NORMAL. NO UNDERLYING CAUSE FOR OSTEOPOROSIS.

?THERAPY?

BECAUSE HRT MAINTAINED HER BMD QUITE NICELY FOR 8 YEARS, A S.E.R.M. (e.g. RALOXIFENE) IS PROBABLY ADEQUATE, ALONG WITH Ca++ AND VIT D.

TREAT FOR 2 YEARS AND REPEAT BMD.

CASE QW

CASE QW TEACHING POINT 1

NOT EVERY PATIENT NEEDS BISPHOSPHONATES, FOR MANY PATIENTS THE SERMS WORK FINE.

DO NOT USE IN PATIENTS WITH HX OF CLOTS.

CASE QW TEACHING POINT 2

DEXA SHOULD BE DONE EVERY TWO OR THREE YEARS WHEN MONITORING A NEW THERAPY. LEAST SIGNIFICANT CHANGE IN DEXA CANNOT OCCUR FASTER THAN THAT USING ANTI-RESORPTIVE DRUGS.

1. THERE AE ALTERNATIVES TO BISPHOSPHONATES.

2. DO DEXA SCANS q 2-3 YEARS TO MONITOR RX WITH ANTI-RESORPTIVES.

CASE QWTEACHING POINT SUMMARY

CASE JG

70 Y/O CAUCASIAN WOMAN NEVER HAD A BMD OR ANY SORT OF OP THERAPY. +FAMILY HX OF OP. NO FRACTURE HX. MENOPAUSE AGE 49.

ALL LABS NORMAL, EXCEPT TOTAL 25-OH VITAMIN D 20 ng/ml. BMD SHOWS T SCORES OF –2.5 IN VERTEBRAE AND FEMUR.

?THERAPY?

CASE JG

SHE HAS OSTEOPOROSIS, ALSO HAS A RISK FACTOR OR TWO, SO NEEDS TREATMENT. START VIT D3 2000 IU/d AND Ca++ 1500 mg/d, AND BISPHOSPHONATE OR SERM. YOU CHOOSE A BISPHOSPHONATE.

RE-MEASURE TOTAL 25-OH VIT D IN 3 MONTHS, AND BMD IN 2 YEARS

CASE JG TEACHING POINT 1

RISK FACTORS FOR OSTEOPOROSIS

FEMALE

CAUCASIAN/ASIAN

POSTMENOPAUSAL

THIN BODY HABITUS

CIGARETTE SMOKING


FAMILY HISTORY OF OSTEOPOROSIS

SEDENTARY LIFESTYLE

CASE JG

3 MONTHS LATER, TOTAL 25-OH VITAMIN D IS 24 ng/ml. SHE IS RELIABLE AND YOU BELIEVE HER THAT SHE TAKES THE VITAMIN D, 2000 IU/d, AS PRESCRIBED.

CASE JG

INCREASE VITAMIN D3 DOSE TO 3000 IU/d AND CHECK IT AGAIN IN 2 MONTHS. ADJUST DOSE TO MAINTAIN TOTAL 25-OH VITAMIN D LEVEL AT 32-50 ng/ml.


THE CORRECT DOSE OF VITAMIN D IS THAT DOSE THAT MAINTAINS THE TOTAL 25-OH VITAMIN D LEVEL IN THE RANGE 32-55 ng/ml.

CASE JG

SHE RETURNS 2 YEARS LATER, AND REPEAT DEXA SHOWS SOME IMPROVEMENT. SHE CAN NO LONGER TOLERATE ANY OF THE ORAL BISPHOSPHONATES DUE TO GERD. SAYS SHE FORGETS TO TAKE MED SOME WEEKS.

NOW WHAT?

CASE JG

BISPHOSPHONATES HAVE WORKED FOR HER, THUS YOU WANT TO CONTINUE HER ON THAT CLASS OF DRUG.

SWITCH TO AN IV BISPHOSPHONATE.


•IBANDRONATE (BONIVA) q 3 MO.

•PAMIDRONATE (AREDIA) q 3 MO.

•ZOLEDRONATE (RECLAST) 1/yr

IV BISPHOSPHONATES:

CASE JGTEACHING POINT SUMMARY

1. USE IV BISPHOSPHONATES IN PATIENTS INTOLERANT TO ORALS.

2. KEEP TOTAL 25-OH VITAMIN D 32-60 ng/ml

3. DIFFERENT SCHEDULES FOR IV BISPHOSPHONATES

CASE CP

77 YEAR OLD ASYMPTOMATIC ACTIVE FEMALE WITH OSTEOPOROSIS. ON ORAL BISPHOSPHONATE FOR 8 YEARS. BMD READINGS STABLE AT -2.6 IN HIPS AND SPINE. LABS ALL OK. THIS YEAR’S DEXA UNCHANGED. NO HX FRACTURE. TOTAL 25-OH VITAMIN D LEVEL 44 ng/ml.

WHILE DATA ON THIS ISSUE ARE NOT ABUNDANT, RECENT STUDIES SUGGEST THAT A “DRUG HOLIDAY” IS IN ORDER. THIS MEANS STOPPING THE BISPHOSPHONATE FOR TWO YEARS. CONTINUE CALCIUM AND VITAMIN D AS BEFORE.

CASE CP

CASE MA

77 YEAR OLD ASYMPTOMATIC ACTIVE FEMALE WITH OSTEOPOROSIS. ON ORAL BISPHOSPHONATE FOR 6 YEARS. BMD READINGS STABLE AT -3.0 IN HIPS AND SPINE. LABS ALL OK. TRIPPED ON RUG IN HOME AND FELL AGAINST A WALL, USING HER WRIST TO CUSHION THE IMPACT. SUSTAINS FX OF WRIST. CXR SHOWS COMPRESSION FX OF T12. THIS FX WAS NOT THERE ON CXR 4 YEARS AGO.

SHE HAS 2 LOW TRAUMA FRACTURES WHILE TAKING A BISPHOSPHONATE FOR 6 YEARS. SHE HAS NO SECONDARY CAUSE FOR OP, AND HER FUTURE FX RISK IS VERY HIGH. STOP BISPHOSPHONATE, START TERIPARATIDE, CONTINUE VITAMIN D AND CALCIUM AS BEFORE.

CASE MA

PATIENT WHINES ABOUT GIVING HERSELF SHOTS, WORRIED THAT IT WILL HURT AND THAT SHE CANNOT DO IT. AFRAID HER INSURANCE COMPANY WILL NOT PAY FOR IT, EVEN THOUGH SHE HAS GOOD DRUG COVERAGE.

CASE MA

EXPLAIN THAT THE SHOTS ARE REALLY EASY TO DO, THE NEEDLE STAYS QUITE SUPERFICIAL, AND DOES NOT GO INTO MUSCLE OR VEINS, BECAUSE THE NEEDLE IS VERY SHORT AND VERY FINE (31 G)

AND CAN BARELY BE FELT.

FURTHERMORE, MILLIONS OF DIABETICS OF ALL AGES, ALL OVER THE WORLD, GIVE THEMSELVES IDENTICAL SUB Q. SHOTS WITH THE IDENTICAL EQUIPMENT, SEVERAL TIMES A DAY.

CASE MA

CASE MA TEACHING POINT 1

PATIENTS WHO FRACTURE, OR WHO CONTINUE TO LOSE BONE MINERAL BY DEXA WHILE ON A BISPHOSPHONATE OR SERM, ARE CANDIDATES FOR AN ANABOLIC AGENT. TERIPARATIDE IS THE ONLY ONE AVAILABLE IN THE USA AT PRESENT. FOR THESE HIGH RISK PATIENTS, DO NOT BE AFRAID TO PRESCRIBE IT, OR TO REFER TO OP CLINIC. LAB MONITORING IS NOT NECESSARY AND SIDE EFFECTS ARE MINIMAL/ABSENT.

ANOTHER ANABOLIC AGENT, ORAL STRONTIUM RANELATE, IS USED IN EUROPE AND ASIA, AND SOMEDAY MAY COME TO A PHARMACY NEAR YOU.

CASE MA TEACHING POINT 2PATIENTS’ PERCEPTION OF THE DOWNSIDE OF TERIPARATIDE USUALLY IS FAR WORSE THAN REALITY:

SUB CUT INJECTIONS-THE PRE-LOADED SYRINGE IS EASY TO USE, AND ALMOST ALL PATIENTS LEARN THE TECHNIQUE QUICKLY AND HAVE NO PROBLEM GIVING THEMSELVES THE MEDICATION. FREE TRAINING SESSIONS ARE AVAILABLE FROM MANUFACTURER, IN THE PATIENT’S HOME IF NECESSARY. 30 GAUGE NEEDLES ARE NEARLY PAINLESS.

COST-BENEFITS OUTWEIGH THE HIGH COST BECAUSE TERIPARATIDE CANDIDATES HAVE THE HIGHEST RISK FOR FUTURE FX. CO-PAY AND FINANCIAL ASSISTANCE ARE AVAILABLE FROM THE MANUFACTURER FOR PATIENTS WHO QUALIFY. INSURANCE COMPANIES NO LONGER GIVE DOCTORS PROBLEMS WITH APPROVAL EXCEPT WHEN THE PATIENT APPEARS NOT TO BE A CANDIDATE FOR TERIPARATIDE.

CASE MA TEACHING POINT SUMMARY

1. TERIPARATIDE IS A USEFUL AND EFFECTIVE AGENT, AND SHOULD BE PRESCRIBED FOR THE HIGHEST RISK PATIENTS, OR THOSE WHO FAIL, OR WHO CANNOT TOLERATE BISPHOSPHONATES.

2. PATIENT MAY NEED TO BE RE-ASSURED REGARDING ITS USE. MOST HAVE NO TROUBLE WITH IT.

3. DOCTOR NEED NOT MONITOR LABS-RELATIVELY EASY TO PRESCRIBE. EASE OF USE FAVORABLE, SIDE EFFECTS LOW, COST HIGH.

CASE TP

63 Y/O MALE COMPLAINING OF FATIGUE, GENERALIZED MYALGIA, ARTHRALGIA IN SHOULDER AND HIP GIRDLE REGIONS. ONSET A FEW WEEKS AGO. NO OTHER COMPLAINTS. EXAM UNREMARKABLE. NO OP RISK FACTORS. ESR 55, OTHER LABS ALL NORMAL, INCLUDING B 12, 25-OH VIT D AND TESTOSTERONE.

REMEMBERING YOUR EXTENSIVE RHEUMATOLOGY ROTATIONS DURING RESIDENCY, YOU DIAGNOSE PMR AND GIVE PREDNISONE 15 mg/day. 3 DAYS LATER HE RETURNS SINGING YOUR PRAISES, BECAUSE ALL OF HIS SYMPTOMS VANISHED 12 HOURS AFTER THE FIRST PREDNISONE DOSE. HE CONSIDERS YOU A DEITY. YOU THANK HIM AND SEND HIM HOME WITH THE USUAL TAPERING AND ESR SCHEDULE.

CASE TP

CASE TP

NICE WORK DOC, GOOD DIAGNOSIS AND TREATMENT PLAN.

HOWEVER, YOU LOST YOUR DEITY STATUS BY FAILING TO GET DEXA AND STARTING HIM ON A BISPHOSPHONATE.

CASE TP TEACHING POINT 1

STEROID-INDUCED BONE LOSS OCCURS RAPIDLY AND EARLY IN THE TREATMENT COURSE, THUS IF HE IS TO BE ON STEROIDS LONGER THAN 3 MONTHS (very likely with PMR), YOU NEED TO ADDRESS THIS ISSUE. YOU NEED BASELINE DEXA PLUS A BISPHOSPHONATE.


STEROIDS CAUSE THINNING, BUT NOT BREAKING OF TRABECULAE, SO BONE MASS LOSS DUE TO STEROIDS IS MORE RAPIDLY REVERSIBLE THAN THAT FROM AGE-RELATED OP.


IF BONE MASS CONTINUES TO DECREASE DESPITE USE OF BISPHOSPHONATE OR PATIENT CANNOT TOLERATE ORAL OR IV BISPHOSPHONATE, SWITCH TO TERIPARATIDE, AS IT HAS BEEN SHOWN SUPERIOR (BMD AND FRACTURE REDUCTION) TO BISPHOSPHONATES IN STEROID INDUCED OP1.

1K. SAAG ET AL. ASBMR MEETING 2007

1. PRESCRIBE BISPHOSPHONATE FOR ANY PATIENT WHO YOU THINK WILL BE ON STEROIDS LONGER THAN 3 MONTHS.

2. STEROID-INDUCED TRABECULAR CHANGES EASIER TO REVERSE THAN AGE/HORMONAL-INDUCED CHANGES.

3. USE TERIPARATIDE IF PT INTOLERANT OF BISPHOSPHONATES, OR BISPHOSPHONATES FAIL (supporting data exist)

CASE TP TEACHING POINT SUMMARY

CASE FA

53 Y/O MALE WITH ALPHA-1 ANTI-TRYPSIN DEFICIENCY. ON LUNG XPLANT LIST. OTHERWISE GOOD HEALTH. NO H/O FX. NEVER TOOK STEROIDS. FINALLY ADMITS TO BEING AN ALCOHOLIC. BMD SHOWS T SCORE OF –3.1 IN VERTEBRAE AND –2.7 IN HIPS. LABS UNREMARKABLE.

HE ALREADY HAS OSTEOPOROSIS & DEXA SHOWS AN 8-FOLD INCREASED FRACTURE RISK. IN THE NEAR FUTURE HE WILL START LONG-TERM STEROIDS AND CYCLOSPORIN FOR REJECTION SUPPRESSION. THESE DRUGS WILL ACCELERATE LOSS OF BONE MINERAL.

STOP ALCOHOL, START TERIPARATIDE, VIT D AND Ca++ NOW, BEFORE XPLANT.

CASE FA

CASE FA TEACHING POINT 1

ALCOHOL CESSATION IS CRUCIAL, BECAUSE WITH CONTINUED ALCOHOL ABUSE NO THERAPY WILL WORK.

TERIPARATIDE IS PROBABLY THE BEST AGENT IN THIS CASE, AS IT HAS BEEN SHOWN IN TO BE SUPERIOR (BMD and FRACTURE PREVENTION) FOR STEROID-INDUCED OP.

CASE FA TEACHING POINT 2

CITE ASBMR ABSTRACT OR PUBLISHED ARTICLE

PATIENT QUITS ETOH AND GOES ON TERIPARATIDE. YOU RE-DO DEXA 1 YEAR LATER. IT SHOWS INCREASE IN VERTEBRAE BMD OF 20% AND IN HIP OF 12%. CONTINUE TERIPARATIDE FOR ANOTHER YEAR, THEN OFFER BISPHOSPHONATE.

CASE FA

CASE FA TEACHING POINT SUMMARY

1. REMOVE UNDERLYING CAUSES

2. AFTER TERIPARATIDE, MAINTAIN MINERAL CONTENT WITH ANTI-RESORPTIVE AGENT.

CASE EC80 Y/O FEMALE WHO DOES NOT BELIEVE IN DOCTORS BECAUSE “NONE OF ‘EM KNOW NOTHIN’.” PROUD OF THE FACT THAT SHE HAS NOT BEEN TO A DOCTOR IN 45 YEARS, WHEN SHE GAVE BIRTH TO HER YOUNGEST DAUGHTER, WHO NOW DRAGS HER IN TO SEE YOU. THE TWO OLDER DAUGHTERS HAVE OP AND THE THREE DAUGHTERS CONSPIRED TO GET MOM WORKED UP FOR IT AS WELL.

DEXA SCAN, WHICH IS PROPERLY DONE AND READ, SHOWS T-SCORES OF -4.5 IN HIPS AND VERTEBRAE. TOTAL 25-OH VITAMIN D 8 ng/ml, Ca++ 9.4 (9.4-10.3). PATIENT ANXIOUS TO GET BACK TO HER MILKING AND FIELD WORK ON TRACTORS, AND HER DANCING. SHE TAKES NO MEDS.

“I FEEL GREAT, DO YOU KNOW WHAT YOU’RE DOIN’?”

CASE EC

CASE EC

DUE TO HER T-SCORES AND HER LIFE STYLE HER RISK FOR FRACTURE IS VERY HIGH. SHE IS A TERIPARATIDE CANDIDATE. YOU TALK UNTIL ONSET OF CYANOSIS (your face-not hers), BUT YOU CANNOT CONVINCE HER TO TAKE IT.

“ONLY NURSES SHOULD GIVE SHOTS, AND I AIN’T NO NURSE, SO I AIN’T TAKIN’ NO SHOTS.”

YOU INFORM HER THAT THE NEXT BEST TREATMENT IS A BISPHOSPHONATE, SO YOU DISCUSS WITH HER BISPHOSPHONATE OPTIONS.

CASE EC

“SONNY, YOU MUST BE NUTS IF YOU THINK I’M TAKIN’ SOME PILL ONCE A WEEK THAT’S GONNA GIVE ME AN UPSET STOMACH, AND I CANT HAVE MY MORNING COFFEE BEFORE I TAKE IT OR FOR AN HOUR AFTER, AND I CAN’T LIE DOWN! BESIDES, THIS DRUG AIN’T GONNA DO NO GOOD IF I ONLY TAKE IT ONCE A WEEK. FORGIT IT.”

CASE EC

YOU REMIND HER THAT SHE CAN GET A BISPHOSPHONATE IV. FINALLY SHE CONSENTS TO GET ZOLEDRONATE 5 mg IV ONCE A YEAR.

“OK SONNY. I CAN DO 15 MINUTES ONCE A YEAR. IT’S PROBABLY STRONG ENOUGH BECAUSE I GET IT RIGHT INTO MY BLOOD. SEE, I TOLD YOU ONLY NURSES SHOULD BE GIVIN’ THIS STUFF!”

CASE EC TEACHING POINT 1

AVAILABLE BISPHOSPHONATES:

RISEDRONATE (ACTONEL)

ALENDRONATE (FOSAMAX AND GENERICS)

TILUDRONATE (SKELID)

ZOLEDRONATE (RECLAST)

IBANDRONATE (BONIVA)

PAMIDRONATE (AREDIA)

ETIDRONATE (DIDRONEL)

CASE EC TEACHING POINT 2

IV BISPHOSPHONATES ARE AN ATTRACTIVE ALTERNATIVE TO ORAL

BISPHOSPHONATES.

•COMPLIANCE ASSURED

•PATIENT CONVENIENCE

•NO GI SIDE EFFECTS

•NO ABSORPTION PROBLEMS

•HOWEVER, MORE EXPENSIVE

YOU HAVE OPTIONS GIVING IT:

CASE EC

1. GIVE IT IN YOUR OFFICE OR CLINIC

2. SEND HER TO OSTEOPOROSIS CLINIC

3. SEND HER TO THE INFUSION CENTER

YOU CHOOSE YOUR OFFICE, SINCE “THEM GUYS IN OP CLINIC DON’T KNOW NOTHIN’ EITHER.”

THE INFUSION GOES WELL. YOU GET A CALL 4 HOURS LATER. SHE IS IN THE ER WITH DIFFUSE CRAMPING, AN ABNORMAL ECG, AND CHVOSTEK’S SIGN. SERUM CALCIUM IS 7.0. PATIENT IS NOT PLEASED. REITERATES HER OPINION ABOUT DOCTORS.

WHAT HAPPENED?

CASE EC

THE PATIENT BECAME PROFOUNDLY HYPOCALCEMIC BECAUSE YOU GAVE HER A POTENT BISPHOSPHONATE WITHOUT CORRECTING HER LOW VITAMIN D AND BORDERLINE LOW CALCIUM

CASE EC TEACHING POINT 3ALWAYS CHECK CREATININE, TOTAL 25-OH VITAMIN D AND CALCIUM PRIOR TO GIVING IV

BISPHOSPHONATE!

CASE EC TEACHING POINT SUMMARY

1. DISCUSS ALL BISPHOSPHONATES WITH PATIENT-ORAL AND IV.

2. IV A GOOD ALTERNATIVE TO ORAL, AND THERE IS NO REASON TO PREFER ORAL OVER IV AGENTS

3. NEVER GIVE IV BISPHOSPHONATE UNTIL TOTAL 25-OH VITAMIN D IS NORMALIZED, CALCIUM INTAKE OPTIMIZED AND CrCl BETTER THAN 25.

45 YEAR OLD MALE SMOKER C/O SEVERAL YEARS OF LOW ENERGY, FATIGUE, LOSS OF STRENGTH, GENERAL MALAISE, DEPRESSION, LOW LIBIDO. NO HX OF OTHER MEDICAL PROBLEMS. IS HERE BECAUSE HIS PRIMARY DID A CHEST FILM AND RADIOLOGIST NOTED OSTEOPENIA OF THORACIC SPINE.

EXAM: GYNECOMASTIA, SPARSE BEARD GROWTH. DEXA: -3.8 IN SPINE AND HIPS. WHAT NEXT?

CASE HL

1. OSTEOPOROSIS CAN HAVE ANY OF SEVERAL UNDERLYING CAUSES.

2. BEFORE DECIDING ON TREATMENT, IT IS NECESSARY TO DETERMINE IF THERE IS AN UNDERLYING CAUSE OF THE OSTEOPOROSIS, BECAUSE IF MISSED, THERAPY FOR OSTEOPOROSIS WILL PROBABLY FAIL.

CASE HL

SOME CAUSES OF OSTEOPOROSIS

1. GENETIC PREDISPOSITION2. ORAL STEROIDS FOR LONGER THAN 3 MONTHS3. MALABSORPTION DISORDERS/POOR NUTRITION4. HYPERPARATHYROIDISM, 1º, 2º OR 3 º5. HYPERTHYROIDISM6. MENOPAUSE + FAILURE TO TREAT7. INFLAMMATORY ILLNESSES 8. TESTOSTERONE DEFICIENCY IN MALES, ? FEMALES8. ALCOHOL AND TOBACCO ABUSE9. INACTIVITY (BEDRIDDEN PATIENTS)10.DRUGS e.g. CYCLOSPORIN, HEPARIN, ANTI-

CONVULSANTS



25-OH VIT D--HYPOVITAMINOSIS D, MALABSORPTION

VIT B12--------MALABSORPTION CBC-------------MALABSORPTION

ESR-------------INFLAMMATORY ILLNESSES, MYELOMA

Ca++ ------------HYPERPARATHYROIDISM

PO4 -------------OSTEOMALACIA

CREATININE-2º/3º HYPERPARATHYROIDISM

ALK PHOS----OSTEOMALACIA, BASELINE

INTACT PTH--HYPERPARATHYROIDISM

8 AM TESTOSTERONE (MALES)- HYPOGONADISM

ALBUMIN------CALCIUM INTERPRETATION

URINE NTx----BASELINE FOR ANTI-RESORPTIVE

LABS TO BE ACQUIRED BEFORE Rx DECISION

LABS SHOW VERY LOW TOTAL AND FREE TESTOSTERONE. NO OTHER ABNORMALITY

CASE HL-CONTINUED

CASE HL

WORKUP DISCLOSED NO SECONDARY CAUSE FOR THE HYPOGONADISM. START TESTOSTERONE REPLACEMENT, ADD CALCIUM 1500 mg/DAY, PLUS VITAMIN D AT DOSE SUFFICIENT TO MAINTAIN LEVEL >32 ng/ml, ENCOURAGE EXERCISE, AND RECHECK DEXA IN ONE YEAR. IF DEXA SHOWS NO IMPROVEMENT, CAN CONSIDER DRUG Rx.

YOU MUST INSURE THAT THE PATIENT’S 25-OH VITAMIN D LEVEL IS >32 ng/ml), OR ALL THERAPIES FOR OSTEOPOROSIS WILL FAIL.


CASE HLTEACHING POINT SUMMARY

1. LOOK FOR UNDERLYING CAUSES OF OP

2. DO SCREENING LABS

3. KEEP VITAMIN D >32 ng/ml

OSTEOPOROSIS IS A SYSTEMIC SKELETAL DISEASE

CHARACTERIZED BY:

1---LOW BONE MASS2---MICROARCHITECTURAL DETERIORATION OF BONE

THIS RESULTS IN INCREASED BONE FRAGILITY AND SUSCEPTIBILITY TO

FRACTURE.

1. J Bone Miner Res . 2003;18:1932-1941.

BONE QUALITY, WHICH IS CLOSELY RELATED TO BONE MICROARCHITECTURE, IS A CRUCIAL DETERMINANT OF FRACTURE RESISTANCE

FRACTURE RISK FACTORS

LOW T-SCORES*

H/O PREVIOUS LOW TRAUMA FRACTURE*

PROLONGED USE OF CORTICOSTEROIDS

ADVANCED AGE

POOR VISION

TENDENCY TO FALL / NEUROLOGIC DYSFUNCTION


HOW DO WE DETERMINE RISK FOR FRACTURE?

(THERE IS NO PERFECT TOOL, NOT EVEN DEXA)

X-RAYS

DEXA

CLINICAL--HX/PX EXAMINATION/LABS

BONE BIOPSY/DIRECT VIS. AT SURGERY

LIMITATIONS OF DEXA

DEXA IS AN IMPERFECT TOOL FOR ASSESSING FRACTURE RISK, BUT IT

IS THE BEST WE HAVE THUS FAR

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

1 10

20

30

H2N-

1. Proc Natl Acad Sci USA 1974;71:384-388.

INTACT PTH IS hPTH (1-84)

Teriparatide is hPTH (1-34)- synthetic- recombinant

FORTEO IS HUMAN PARATHYROID HORMONE 1-34

THE CHOICE OF AGENT DEPENDS ON THE RISK OF FUTURE FRACTURE

EQUALLY IMPORTANT IS THE MECHANISM OF ACTION OF THE DRUG CHOSEN

SAFETY ISSUES

FORTEO® (teriparatide [rDNA origin] injection) Important Safety Information

In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor), that was dependent on dose and treatment duration. The effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in humans given a 20-mcg dose. Because of the uncertain relevance of the rat osteosarcoma finding to humans, teriparatide should be prescribed only to patients for whom the potential benefits are considered to outweigh the potential risk. Teriparatide should not be prescribed for patients who are at increased baseline risk for osteosarcoma (including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, or prior external beam or implant radiation therapy involving the skeleton) (see WARNINGS and PRECAUTIONS, Carcinogenesis).

Warning

See Black Box Warning and Important Safety Information for FORTEO.See full Prescribing Information for FORTEO.

FORTEO® (teriparatide [rDNA origin] injection) Indications for FORTEO

FORTEO is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture

FORTEO is indicated to increase bone mass in men with primary osteoporosis or osteoporosis associated with hypogonadism, who are at high risk for fracture

Individuals at high risk for fracture include those who (based on physician assessment): Have a history of osteoporotic fracture, or Have multiple risk factors for fracture, or Failed previous osteoporosis therapy, or Are intolerant to previous osteoporosis therapy



The following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO:

Paget’s disease of bonePediatric populations and young adults with

open epiphysesPrior external beam or implant radiation therapy

involving the skeleton

Patients with any of the following conditions also should not receive FORTEO:

Bone metastases or a history of skeletalmalignancies

Metabolic bone diseases other than osteoporosis

Pre-existing hypercalcemiaPregnancy and lactation

Adverse Events Adverse events usually were mild

and generally did not require discontinuation of therapy

Early discontinuation due to adverse events occurred in 5.6% of patients assigned to placebo and 7.1% of patients assigned to FORTEO

Reported adverse events that appeared to be increased by FORTEO treatment were dizziness and leg cramps

Warnings



The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years is not recommended.

FORTEO should be used with caution in patients with active or recent urolithiasis or taking digitalis. Transient episodes of symptomatic orthostatic hypotension were observed infrequently in short-term

pharmacology studies. Limited information is available to evaluate safety in patients with hepatic, renal, and cardiac disease. In laboratory tests, FORTEO transiently increases serum calcium, with the maximal effect observed at

approximately 4 to 6 hours post-dose. By 16 hours post-dose, serum calcium generally has returned to, or near, baseline.

Persistent hypercalcemia was not observed in clinical trials with FORTEO. No clinical adverse events associated with increases in serum or urine calcium and serum uric acid

were observed. No clinically important adverse renal effects were observed in clinical studies.

Additional Safety Information

Contraindication: FORTEO should not be given to patients with hypersensitivity to teriparatide or to any of its excipients.

Precautions: General


FORTEO® (teriparatide [rDNA origin] injection) Dosage and Administration


The FORTEO Pen is a multidose, prefilled delivery device that can be used up to 4 weeks (28 daily doses), including the first injection from the pen

Dose: 20 mcg once a day

Do not transfer the contents of the pen into a syringe

Needle (29- to 31-gauge) must be changed after each use

Administered as a subcutaneous injection into the thigh or abdominal wall

Duration of therapy: 18-24 months

WARNING

IN MALE AND FEMALE RATS, TERIPARATIDE CAUSED AN INCREASE IN THE INCIDENCE OF OSTEOSARCOMA (A MALIGNANT BONE TUMOR), THAT WAS DEPENDENT ON DOSE AND TREATMENT DURATION. THE

EFFECT WAS OBSERVED AT SYSTEMIC EXPOSURES TO TERIPARATIDE RANGING FROM 3 TO 60 TIMES THE EXPOSURE IN HUMANS GIVEN A 20-MCG DOSE. BECAUSE OF THE UNCERTAIN

RELEVANCE OF THE RAT OSTEOSARCOMA FINDING TO HUMANS, TERIPARATIDE SHOULD BE PRESCRIBED ONLY TO PATIENTS FOR

WHOM THE POTENTIAL BENEFITS ARE CONSIDERED TO OUTWEIGH THE POTENTIAL RISK. TERIPARATIDE SHOULD NOT BE PRESCRIBED

FOR PATIENTS WHO ARE AT INCREASED BASELINE RISK FOR OSTEOSARCOMA (INCLUDING THOSE WITH PAGET’S DISEASE OF

BONE OR UNEXPLAINED ELEVATIONS OF ALKALINE PHOSPHATASE, OPEN EPIPHYSES, OR PRIOR RADIATION THERAPY INVOLVING THE

SKELETON) (SEE WARNINGS AND PRECAUTIONS, CARCINOGENESIS).

FORTEO® WARNINGS

• THE FOLLOWING CATEGORIES OF PATIENTS HAVE INCREASED BASELINE RISK OF OSTEOSARCOMA AND THEREFORE SHOULD NOT BE TREATED WITH FORTEO:

– PAGET’S DISEASE OF BONE– PEDIATRIC POPULATIONS– PRIOR RADIATION RX INVOLVING THE SKELETON

• PATIENTS WHO HAVE ANY OF THE FOLLOWING CONDITIONS ALSO SHOULD NOT RECEIVE FORTEO:

– BONE METASTASES OR A HISTORY OF SKELETAL MALIGNANCIES

– METABOLIC BONE DISEASES OTHER THAN OSTEOPOROSIS

– PRE-EXISTING HYPERCALCEMIA– PREGNANCY AND LACTATION

(FORTEO®) TERIPARATIDE (rDNA ORIGIN) INJECTION

PRECAUTIONS: GENERAL

• THE SAFETY AND EFFICACY OF FORTEO HAVE NOT BEEN EVALUATED BEYOND 2 YEARS OF TREATMENT. CONSEQUENTLY, USE OF THE DRUG FOR MORE THAN 2 YEARS IS NOT RECOMMENDED.

• FORTEO SHOULD BE USED WITH CAUTION IN PATIENTS

– WITH ACTIVE OR RECENT UROLITHIASIS

– TAKING DIGITALIS

• LIMITED INFORMATION IS AVAILABLE TO EVALUATE SAFETY IN PATIENTS WITH HEPATIC, RENAL, AND CARDIAC DISEASE.

TERIPARATIDE SUMMARY OF SIDE EFFECTS-LAB

• SAFETY EVALUATION: 24 CLINICAL TRIALS-OVER 2800 WOMEN AND MEN

• HYPERCALCEMIA WAS ABSENT OR MILD AND TRANSIENT (MAX 4 TO 6 HOURS POST-DOSE NORMAL AT 24 HOURS)-NO PERSISTENT HYPERCALCEMIA

• MEAN 24-HR Ur CA INCREASED 30 MG/DAY

• MEAN SERUM URIC ACID INCREASED 13-20% (NO SEQUELAE SUCH AS ACUTE GOUT)

• CHANGES REVERSED AFTER FORTEO WITHDRAWAL

• NO CLINICAL ADVERSE EVENTS WERE ASSOCIATED WITH INCREASES IN SERUM OR URINE CALCIUM

•ADVERSE EVENTS USUALLY WERE MILD AND GENERALLY DID NOT REQUIRE DISCONTINUATION OF THERAPY.

•EARLY DISCONTINUATION DUE TO ADVERSE EVENTS OCCURRED IN 5.6% OF PLACEBO PATIENTS AND 7.1% OF FORTEO PATIENTS.

•REPORTED ADVERSE EVENTS THAT APPEARED TO BE INCREASED BY FORTEO TREATMENT WERE DIZZINESS AND LEG CRAMPS.

•TRANSIENT EPISODES OF SYMPTOMATIC ORTHOSTATIC HYPOTENSION WERE OBSERVED INFREQUENTLY.

TERIPARATIDE SUMMARY OF SIDE EFFECTS-CLINICAL

TERIPARATIDE INDICATION IN POSTMENOPAUSAL WOMEN

FORTEO IS INDICATED FOR THE TREATMENT OF POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS WHO ARE AT HIGH RISK FOR FRACTURE.THESE INCLUDE THOSE WHO (BASED ON PHYSICIAN ASSESSMENT) …

• HAVE A HISTORY OF OSTEOPOROTIC FRACTURE

• HAVE MULTIPLE RISK FACTORS FOR FRACTURE

• FAILED PREVIOUS OSTEOPOROSIS THERAPY

• ARE INTOLERANT TO PREVIOUS OSTEOPOROSIS THERAPY

TERIPARATIDE INDICATION IN MEN

FORTEO IS INDICATED TO INCREASE BONE MASS IN MEN WITH PRIMARY OSTEOPOROSIS OR OSTEOPOROSIS ASSOCIATED WITH HYPOGONADISM, WHO ARE AT HIGH RISK FOR FRACTURE.THESE INCLUDE THOSE WHO (BASED ON PHYSICIAN ASSESSMENT) …

• HAVE A HISTORY OF OSTEOPOROTIC FRACTURE

• HAVE MULTIPLE RISK FACTORS FOR FRACTURE

• FAILED PREVIOUS OSTEOPOROSIS THERAPY

• ARE INTOLERANT TO PREVIOUS OSTEOPOROSIS THERAPY

Copyright restrictions may apply.

McClung, M. R. et al. Arch Intern Med 2005;165:1762-1768.

PERCENTAGE CHANGE (MEAN {+/-} SE) FROM BASELINE IN LUMBAR SPINE BONE MINERAL DENSITY

MO

Copyright restrictions may apply.

McClung, M. R. et al. Arch Intern Med 2005;165:1762-1768.

PERCENTAGE CHANGE (MEAN {+/-} SE) FROM BASELINE TO MONTH 18 IN FEMORAL NECK BONE MINERAL DENSITY

RAT CARCINOGENICITY STUDY

• 2-YEAR RAT STUDY REQUIRED BY FDA RULES

– EXAGGERATED SKELETAL RESPONSE TO TPTD– DOSE-RELATED BONE PROLIFERATIVE LESIONS

INCLUDING OSTEOSARCOMA– NO INCREASE IN SOFT-TISSUE NEOPLASMS

• FOLLOW-UP RAT STUDY

– DOSE AND DURATION OF TREATMENT ARE PRIMARY FACTORS IN DEVELOPMENT OF RAT BONE TUMORS

– ROLE OF AGE AT INITIATION OF TREATMENT IS NOT CONCLUSIVE

Vahle JL, et al. Toxicologic Pathology 2002;30:312-321Vahle JL, et al. J Bone Miner Res 2002;17:Suppl 1

IS THIS A WORRY?THIS RAT STRAIN HAS ABOUT A 5% SPONTANEOUS INCIDENCE OF OS IN THEIR NATURAL STATE.

BONE STRUCTURE, GROWTH AND REMODELING IN RATS DIFFERS IN MANY IMPORTANT WAYS FROM HUMANS.

RAT BONES RESPOND TO RAT PTH VERY DIFFERENTLY THAN HUMAN BONES RESPOND TO HUMAN PTH. SO THE SIGNIFICANCE OF RESULTS USING HUMAN PTH IN RATS IS NOT CLEAR.

RATS GOT VERY HIGH DOSES OF PTH FOR MOST OF THEIR LIVES. THIS WILL NEVER OCCUR IN HUMANS TREATED WITH PTH.

IS THIS A WORRY?

EVEN IN CASES OF HUMAN HYPERPARATHYROIDISM, IN WHICH PTH LEVELS MAY BE CONTINUALLY HIGH FOR YEARS, THERE HAVE BEEN NO INCREASE IN EXPECTED CASE RATES OF OSTEOGENIC SARCOMA IDENTIFIED.

HOWEVER, OSTEOGENIC SARCOMA IS A VERY RARE TUMOR: 4 CASES PER MILLION, AND OF THOSE, 2 ARE ASSOCIATED WITH PAGET’S DISEASE.

THERE IS NO EVIDENCE THAT HUMAN PTH CAUSES OSTEOGENIC SARCOMA IN HUMANS.

TERIPARATIDE (FORTEO) REDUCES THE RISK OF NEW VERTEBRAL FRACTURES

*p <.001

Placebo(n=448)

FORTEO(n=444)

N=64

N=22

Risk ReductionRelative: 65%*Absolute: 9.3%*

20

8

46

1012

14

16

Relative Risk 0.35 95% CI, 0.22 to 0.551

% WITH NEW

VERTEBRAL FRACTURE(S)

1. N Engl J Med. 2001;344:1434-1441.

FORTEO REDUCES THE RISK OF MULTIPLE NEW VERTEBRAL

FRACTURES

1. N Engl J Med. 2001;344:1434-1441.

Placebo(n=448)

FORTEO(n=444)

N=22

N=5

Risk ReductionRelative: 77%†

Absolute: 3.8%†

% WITH 2 OR MORE NEW

VERTEBRAL FRACTURES

0

2

1

3

4

5

6Relative Risk 0.23, 95% CI, 0.09 to 0.601

*p <.001

FORTEO REDUCES THE RISK OF NONVERTEBRAL FRAGILITY FRACTURES1

1 defined as occurring with minimal trauma

Neer RM, et al. N Engl J Med. 2001;344:1434-1441

Placebo(n-544)

FORTEO(n=541)

N=30

N=14

53%

0

1-

2-

3-

4-

5-

6-

% WITH NONVERTEBRAL

FRAGILITY FRACTURES

Risk ReductionRelative: 53%†

Absolute: 3.0%†

UNCOUPLES BUILDING AND RESPORPTION, IN FAVOR OF BUILDING,

SO NET EFFECT IS THAT BONE MASS AND STRENGTH INCREASE

0 0

BUILDING INCREASES

RESORPTIONDECREASES

STRONTIUM RANELATE

AMG 162

AMG 162 BLOCKS RANKL

IBANDRONATE (BONIVA) PO, IV

ZOLEDRONATE (ZOMETA) IV

STRONTIUM RANELATE

TERIPARATIDE (FORTEO) SQ

AMG 162 (RANKL INHIBITOR)

PTH

once-daily continuous

RANKL OPG

osteoclast

bone resorption

serum Ca++

osteoblast apoptosis

boneliningcells

cbfa1 (pre-OB)

osteoblast number/function

bone formation

bone mass/strength

MODE OF DELIVERY DETERMINES SKELETAL RESPONSE TO PTH

1. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;1999:257-259.

Age (Years)

An

nu

al I

nci

den

ce p

er

1000

Wo

men

Vertebrae

Hip

Wrist

Incidence of Osteoporotic Fractures in Women After Age 501

40

30

20

10

050 60 70 80

Months Since Randomization

FORTEO (n=541)

Placebo (n=544)

% o

f W

om

en*

2 4 1086 12 14 16 180 20

FORTEO® (teriparatide [rDNA origin] injection) Time Effect to New Nonvertebral Fragility Fracture1

*Percent of women who had one or more nonvertebral fragility fractures during the study.

1. N Engl J Med. 2001;344:1434-1441.

0

1

2

3

4

5

7

6


FORTEO® (teriparatide [rDNA origin] injection) Increased Lumbar Spine BMD in Postmenopausal Women With Osteoporosis*,1

Months since randomization

0

2

4

6

8

10

12

14

0 3 6 9 12 15 18

FORTEO (n=129)

Placebo (n=137)

BM

D (

Mea

n %

Ch

ang

e

± S

E)

3.9%†

6.9%†

9.4%†

11.8%†

*266 subjects treated for 18 months and with data available at all time points. †p<0.001 for FORTEO vs. placebo at each post-baseline time point.

1. FORTEO [Package insert]. Indianapolis, IN: Eli Lilly and Company; 2004. See Black Box Warning and Important Safety Information for FORTEO.

See full Prescribing Information for FORTEO.

FORTEO REDUCES THE RISK OFNEW NONVERTEBRAL FRAGILITY FRACTURES

0

1

2

3

4

5

6

% W/ NEW FRAGILITY

FRACTURES

RR 0.47 (0.25, 0.88), p<0.05

All Radius/Wrist

Ribs Hip Humerus Pelvis OtherFoot/Ankle

Neer RM, et al. N Engl J Med. 2001;344:1434-1441

osteoporosis for the generalist daniel g. malone md associate professor of medicine, rheumatology,...

Documents

case qe slide

oh vitamin d slide

ngml slide

young adult young adult

case qe total

oh vitamin d level

oh vitamin d2

case qe target