Www.uc-osteoporosis.com SECONDARY CAUSES OF OSTEOPOROSIS Nelson B. Watts, MD Bone Health and...

www.uc-osteoporosis.com

SECONDARY CAUSES OF OSTEOPOROSIS

Nelson B. Watts, MD

Bone Health and Osteoporosis CenterMetabolic Bone Diseases and Mineral Disorders


• Use of bone densitometry• Secondary causes of bone loss• Laboratory evaluation• Calcium and vitamin D• Bone turnover markers• Lateral spine imaging with DXA



2000 NIH Consensus Development Conference

DEFINITION OF OSTEOPOROSIS

Normal Bone

Osteoporotic Bone

• A skeletal disorder characterized by– compromised bone strength

predisposing to– an increased risk of fracture.

• Bone strength reflects the integration of two main features: – bone density and – bone quality.


WHO CRITERIA FORPOSTMENOPAUSAL

OSTEOPOROSISThe T-score compares an individual’s BMD with the

mean value for young normal individuals and expressesthe difference as a standard deviation score.

Kanis JA et al, J Bone Miner Res 1994;9:1137-1141

-2.5 and belowOsteoporosis

Between -1.0 to -2.5Low bone mass (osteopenia)

-1.0 and aboveNormal

T-scoreCategory


• "When measurements are made at the hip alone, …the prevalence [of osteoporosis] is about one in five white women, comparable to the lifetime risk of a single osteoporotic fracture, such as a hip fracture.“

• "Such a cutoff value identifies approximately 30% of postmenopausal women as having osteoporosis using measurements made at the spine, hip, or forearm. This is approximately equivalent to the lifetime risk of fracture at these sites."

WHY THE WHO CHOSE T = -2.5

Kanis JA, et al. J Bone Miner Res 1994; 9:1137-1141


BONE DENSITY MEASUREMENTS AT PERIPHERAL SITES

LIMITATIONS• Less predictive for hip fracture than

hip measurement• Cannot be used for diagnosis with

WHO criteria• Cannot be used for monitoring (sites

less likely to change)

ADVANTAGES• Portable• Less expensive than central DXA• Ultrasound does not involve

radiation

QUS DXA pQCT


PREVALENCE OF OSTEOPOROSIS ANDLIFETIME FRACTURE RISK IN WHITE WOMEN

05

1015202530354045

Hip Spine Forearm Any

T -2.5 or below

Lifetime risk of fracture

1. Melton LJ III, et al. J Bone Miner Res 1995;10:1752. Melton LJ III, et al. J Bone Miner Res 1992;7:1005

Percent

1

2


0

5

10

15

20

25

30

35

EstimatedSpine+Hip*

Finger DXA ForearmDXA

Heel SXA Heel QUS

PREVALENCE OF OSTEOPOROSIS VARIES BY SITE AND METHOD

Siris E et al, JAMA 2001;286:2815-2822

Percent of subjects 2.5 SD or

more below young

adult mean

NORA Study, 200,160 ambulatory women age 50 and older

*Estimated from NAHNES III

Missed

55% 66% 84% 90%


-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

30 35 40 45 50 55 60 65 70 75 80 85 90 95

Forearm

PA Spine

Total Hip

Heel

Lat DXA

QCT

AGE DEPENDENCE OF T-SCORES

Age (years)

T-score

Data from manufacturers' data bases

Faulkner KG et al. J Clin Densitom 1999;2:343


WHO CRITERIA

• Apply only to postmenopausal Caucasian women – not men, younger women, other ethnic groups

• Apply only PA spine, hip and forearm DXA– not lateral spine, heel, finger, etc

• Apply only for central DXA– not peripheral DXA, QCT, QUS, etc.


RISK FACTORS FOR OSTEOPOROSIS

FEMALE

OLDER AGE

EARLY MENOPAUSE

FAMILY HISTORY

FAIR SKIN

NULLIPARITY

SLENDER BUILD

LOW CALCIUM INTAKE

SMOKING

INACTIVITY


RISK FACTORS AND LOW BMD

IMPACT Trial• ~7,000 women in 21

countries without known osteoporosis had BMD testing and risk factor assessment

64% did not haveosteoporosis

67% had no risk factors

33% had one or more risk factors

36% did haveosteoporosis

48% had no risk factors

52% had one or more risk factors

~50% of patients with osteoporosis ..did not have risk factors

~50% of patients with risk factors did ..not have osteoporosis

Watts NB et al, Arthritis Rheum 2001;44:S256


WHO SHOULD HAVE ABONE DENSITY TEST?

U.S. Preventive Services Task Force• Women 65 years of age and older [should] be screened

routinely for osteoporosis• Routine screening [should] begin at 60 years of age for

women at increased risk for osteoporotic fractures– Low body weight (<70 kg)– Lack of estrogen– Possibly other risk factors

• No recommendation for or against screening younger women at high risk

US PSTF, Ann Intern Med 2002;137:526-528



0

1000

2000

3000

4000

5000

6000

7000

8000

50-54 55-59 60-64 65-69 70-74 75-79

Hip

Vertebra

Nelson HD et al, Ann Intern Med 2002;137;529-541

0

100

200

300

50-54 55-59 60-64 65-69 70-74 75-79

Hip

Vertebra

Number Needed to Screen Number Needed to Treat

Age Age

Fracture Type Fracture Type



ISCD OsteoFLASH, www.iscd.org

Society Providing Recommendation

Patient category US PSTF NOF AACE ISCD

Women age 65 Yes Yes Yes Yes

Women 60-65 with risk factors Yes Yes Yes Yes

Women 60 with risk factorsInsufficient

data Yes Yes Yes

Men age 70 Not addressed Yes Not

addressed Yes

Younger men with risk factors Not addressed Yes Not

addressed Yes


FDA-APPROVED MEDICATIONSINDICATIONS

Postmenopausal Osteoporosis

Glucocorticoid-induced Osteoporosis

Men

Drug Prevention Treatment Prevention Treatment

Estrogen Calcitonin

(Miacalcin®, Fortical®)

Raloxifene

(Evista®)

Ibandronate

(Boniva®)

Alendronate (Fosamax®)

Risedronate

(Actonel®)

Zoledronic acid

(Reclast®)

Teriparatide

(Forteo®)


DrugVertebral Fracture

Nonvertebral Fracture

Hip

Fracture

Calcitonin

(Miacalcin®, Fortical®)

No effect demonstrated


Raloxifene

(Evista®)



Ibandronate

(Boniva®)



Alendronate

(Fosamax®)

Risedronate

(Actonel®)

Zoledronic acid

(Reclast®)

Teriparatide

(Forteo®)


FDA-APPROVED MEDICATIONSEVIDENCE FOR FRACTURE REDUCTION

Evidence for effect but not an FDA-approved indication


NOF TREATMENT GUIDELINES 2008

www.nof.org


NOF GUIDE -- 2008

Postmenopausal women and men age 50 and older presenting with the following should be treated:

• A hip or vertebral (clinical or morphometric) fracture• BMD T-score ≤ -2.5 at the femoral neck, total hip or spine

after appropriate evaluation to exclude secondary causes• Low bone mass (T-score between -1.0 and -2.5 at the

femoral neck, total hip or spine) AND– 10-year probability of hip fracture ≥3% or – 10-year probability of any major osteoporosis-related

fracture* ≥20% based on the US-adapted WHO algorithm

*Hip, humerus, forearm or clinical vertebral fracture


10-year risk ≥3% for hip fracture or ≥20% for major osteoporotic fractures

based on FRAX™ model

T-scores between -1.0 and -2.5

NOF GUIDELINES 2008

After exclusion of secondary cause, treat postmenopausal women and men age 50 and older who have…

T-score -2.5 or below in the femoral neck,

total hip or spine

A fracture of the hip or vertebra (clinical or morphometric)

www.uc-osteoporosis.com www.shef.ac.uk/FRAX

www.uc-osteoporosis.com www.shef.ac.uk/FRAX

Mary Smith, 66.8 years oldWt. 140 lbs., Ht 64 in.

FN T-score -2.4, no risk factors


EVALUATION OF PATIENTS WITH OSTEOPOROSIS

• Just because a woman is postmenopausal and has osteoporosis doesn’t mean that she has postmenopausal osteoporosis

• Failure to identify underlying disorders may result in inadequate or inappropriate treatment


SOME CAUSES OF SECONDARY OSTEOPOROSIS IN ADULTS

Endocrine Disease or Metabolic Causes

Nutritional Conditions DrugsDisorders of

Collagen Metabolism

Other

Hypogonadism

Hypercalciuria

Hyperthyroidism

Hyperparathyroidism

Cushing’s syndrome

Acromegaly

Growth hormone deficiency

Vitamin D deficiency

Calcium deficiency

Vit. B12 deficiency

Weight loss

Malabsorption

Gastric surgery

Anorexia nervosa

Chronic liver disease

Alcoholism

Malnutrition

Prolonged TPN

Glucocorticoids

Anti-epilepsy drugs

Excess thyroid hormone

Depo-Provera

GnRH agonists

Aromatase inhibitors

Heparin

Osteogenesis imperfecta

Homocystinuria

Ehlers-Danlos syndrome

Marfan syndrome

Rheumatoid arthritis

Inflammatory bowel disease

COPD

Organ transplantation

Immobilization

Multiple myeloma

Some cancers

Renal tubular acidosis

Gaucher’s disease

Mastocytosis

Thalassemia

Adapted from Hodgson SF and Watts NB, AACE Guidelines on Osteoporosis, www.aace.com


ENDOCRINE AND METABOLIC DISEASES ASSOCIATED WITH OSTEOPOROSIS

• Hypogonadism• Hypercalciuria• Hyperthyroidism• Hyperparathyroidism• Cushing’s syndrome• Acromegaly• Growth hormone deficiency


NUTRITIONAL CONDITIONSASSOCIATED WITH OSTEOPOROSIS

• Vitamin D deficiency• Calcium deficiency• Vitamin B12 deficiency• Weight loss• Malabsorption• Gastric surgery• Anorexia nervosa• Chronic liver disease• Alcoholism• Malnutrition• Prolonged TPN


DRUGS ASSOCIATED WITH OSTEOPOROSIS

• Glucocorticoids

• Anti-epilepsy drugs

• Thyroid hormone (supraphysiologic doses)

• Depo-Provera

• GnRH agonists

• Aromatase inhibitors

• TZDs

• SSRIs

• PPIs


DISORDERS OF COLLAGEN METABOLISM

• Osteogenesis imperfecta

• Homocystinuria

• Ehlers-Danlos syndrome

• Marfan syndrome


OSTEOGENESIS IMPERFECTA

Type I• Autosomal dominant inheritance• Decreased production of type I

procollagen; substitution for glycine in triple helix of 1(I)

• Normal stature• Little or no deformity• Blue sclerae• Hearing loss in 50%• Teeth are usually normal• Histomorphometry: increased

cortical osteocytes, woven bone, thin collagen bundles


OSTEOGENESIS IMPERFECTA

Type IV• Autosomal dominant inheritance• Point mutation in 2(I) chain• Normal sclerae• Mild to moderate deformity• Variable short stature• Hearing loss in some• Dentogenesis imperfecta is common


OTHER CAUSES OF LOW BONE MASS

• Rheumatoid arthritis• Inflammatory bowel disease• COPD• Organ transplantation• Immobilization• Multiple myeloma • Some cancers• Renal tubular acidosis• Gaucher’s disease• Mastocytosis• Thalassemia


How often are secondary causes found?



Eligible subjectsComplete battery of

laboratory tests available(n=173)

Ineligible subjectsIncomplete laboratory testing

(n=136)

No previous known contributors toosteoporosis based on past medical history

(n=309)

History of known medications or diseasesaffecting bone and mineral metabolism

(n=355)

Post-menopausal women over age 65BMD T-score -2.5 or below

(n=664)

Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437




Patients with at least 1 new diagnosis (n=84) 48.6%Vitamin D deficiency, <20 ng/mL (n=35) 20.2%Hypercalciuria 9.8% Renal (n=7) Idiopathic (n=6) Undefined (n=4)Malabsorption 8.1% Relative calcium malabsorption (n=11) Celiac sprue (n=3)Hyperparathyroidism 6.9% Primary (n=1) Secondary (n=11)Exogenous hyperthyroidism (n=4) 2.3%Cushing’s disease (n=1) 0.6%Hypocalciuric hypercalcemia (n=1) 0.6%


LABORATORY EVALUATION FOR OSTEOPOROSIS

Abnormal

24-h urine calcium for all 39/173

Serum 25-OH vitamin D for all 35/173

Serum calcium for all 3/173

Serum TSH for all on replacement 4/25


This strategy finds 98% of cases, costs $116 per patient screened,

$332 per case found


VITAMIN D STATUS

• Best reflected by serum 25-hydroxyvitamin D levels

• Lab reference range is 20-100 ng/mL• Minimum desirable level is 30 ng/mL (80 nmol/L)• Reasonable range is 30 to 60 ng/mL (80 to 150

nmol/L)


VITAMIN D REDUCES RISK OF FALLING

Bischoff-Ferrari HA et al. JAMA 2004;291:1999-2006

Meta-Analysis


VITAMIN D REDUCES FRACTURESAND MAY REDUCE MORTALITY

Trivedi DP et al, BMJ 2003;326-469-475

Fractures (hip, wrist, forearm, vertebra)

Survival

Vitamin D 100,000 IU Q 4 months or placeboN=2037 men and 649 women ages 65-85

OR 0.78 (0.61,0.99) OR 0.88 (0.74,1.06))


MOST OF US WILL BENEFIT FROM A VITAMIN D SUPPLEMENT

• Vitamin D has important skeletal and extra-skeletal effects• Adequate 25-hydroxyvitamin D level is ≥30 ng/dL• Vitamin D deficiency is common• Most patients require 1,000-2,000 IU vitamin D per day to

achieve an adequate level• “Safe upper limit” is 2,000 IU per day• Supplements of 1,000 IU tablets are now widely available

(1,000-2,000 IU daily• Rx 50,000 IU ergocalciferol may be required (weekly, every

other week)


OPTIMAL CALCIUM INTAKE

1200 mg daily for adults age 50 and olderTOTAL FROM ALL SOURCES

Average calcium from diet:Women 50 and older : ~500 mg daily

Men 50 and older: ~600 mg daily

Most people need a calcium supplement of 700 to 1000 mg daily.

Many people are taking too much.


24-HOUR URINE CALCIUM

• Lab reference range 100-300 mg/day• Typical is 2-3 mg/kg/day• Upper limit of “normal” is 4 mg/kg/day

– Wt 100 kg, normal up to 400 mg/day– Wt 50 kg, normal up to 200 mg/day

• Low urine calcium = low intake or malabsorption• High urine calcium = high intake or calcium wasting

Must be collected when vitamin D is adequate and calcium intake is within target of 1200-1500 mg daily


LABORATORY EVALUATION FOR OSTEOPOROSIS

• CBC• Chemistry panel and phosphorus• 25-hydroxyvitamin D• 24-hour urine for calcium and creatinine• If patient is male, serum testosterone (total

and free)• Other studies if indicated by history, physical

findings or initial laboratory results


BIOCHEMICAL MARKERS OF BONE TURNOVER

• Enzymes (alkaline phosphatase, acid phosphatase)

• Degradation products (hydroxyproline, collagen cross links)

• Byproducts (osteocalcin, procollagen I extension peptides)


COLLAGEN CROSS LINKS

CTxNTx

N-TELOPEPTIDEREGION

HELICAL REGION C-TELOPEPTIDEREGION

PyrDpd

Watts NB. Clin Chem 1999;45:1359-1368


BMD AND MARKERS PREDICT HIP FRACTURETHE EPIDOS STUDY

0

1

2

3

4

5

6

OddsRatio

LowHip BMD

Garnero P et al, J Bone Miner Res 1996;11:1531

2.7

CTX

Free DPD

2.2 1.9

HighMarker

4.84.1

Both


0

20

40

60

80

100

0

5

10

15

20

25

30

0

50

100

150

200

250

300

NOT EVERYONE WITH OSTEOPOROSIS HAS ABNORMAL BONE TURNOVER

89 Elderly Women with Osteoporosis

Pyr Dpd NTx

Garnero P et al, J Clin Endocrinol Metab 1994;79:1693


URINE NTX

• Remodeling has diurnal variation: need second morning fasting urine or fasting blood

• Urine sample may be preferred for logistical reasons

Reference range Ostex Mayo Quest

Premenopausal women 5-65 0-64 10-110

Men 3-51 0-64 11-103

Postmenopausal women NA 0-130 NA

Target: at or below the median value for premenopausal women (30 nmol BCE/mmol creatinine)*

*de Papp AE et al, Bone 2007;40:1222-1230


CLINICAL USES FOR BONE TURNOVER MARKERS

• Patient with borderline low BMD who is not a treatment candidate: when to test again

• Patient with low BMD who has no other risk factors: when to treat

• Patient on antiresorptive treatment who has bone loss or fracture: is the medication being absorbed and is it working?

• Patient on anabolic therapy: is medication working?


Osteoporosis can be diagnosed based on the presence or history of an osteoporotic fracture; however, a fracture is not required for diagnosis

REMINDER


LATERAL SPINE IMAGING WITH DXA

• Done with current DXA equipment at time of DXA visit (convenient)

• Small amount of radiation

• Good at visualizing T4-L4 and identifying moderate and severe fractures

• Not good at visualizing upper thoracic vertebrae or mild compression fractures


IMPORTANCE OF RECOGNIZINGVERTEBRAL DEFORMITIES

Greenspan SL et al, J Clin Densitom 2001;4:373-380

26% of those with “osteoporosis” had T-scores above –2.5 but had one or more vertebral deformities

482 women being screened for osteoporosis studies.

All had BMD and lateral spine imaging.

Osteoporosis was defined as either T-2.5 or below OR a vertebral deformity.

32% T –2.5 or below

57% T above –2.5No vertebral deformity

11% T above -2.5 but

vertebral deformity


USING DXA EQUIPMENT FORVERTEBRAL FRACTURE ASSESSMENT

• CPT code 77082, reimbursement ~$30• Vertebral fracture assessment (VFA) with DXA

equipment is useful for screening patients with – “osteopenia” (to decide when to treat) or– osteoporosis (for selection of therapeutic agent)

• Utility for monitoring not clear• If vertebral fractures are strongly suspected, get x-

rays


FOR PATIENTS WITH FRACTURE

Remember: not all fractures aredue to osteoporosis.

• Consider bone scan if there is equivocal fracture or if fracture might be remote

• Consider MRI or biopsy if fracture might be due to metastatic carcinoma

• Consider MRI if there is question of lateral or posterior displacement


ILIAC CREST BONE BIOPSY

• Patients with unusual features of osteoporosis – men– young women– patients with very low bone mass– patients who have fragility fractures but

normal bone mass • Patients failing conventional therapy


EVALUATION OF PATIENTS WITH OSTEOPOROSIS

• Use central DXA for testing, women 65 and older without risk factors and younger postmenopausal women with risk factors

• All patients with osteoporosis should have lab workup for secondary causes

• Give the right amount of calcium and plenty of vitamin D

• Bone turnover markers have a limited role• Lateral spine imaging with DXA should be done in

selected patients


WILL YOUR BONES LAST AS LONG AS YOU DO?

Questionsor

comments?


Www.uc-osteoporosis.com SECONDARY CAUSES OF OSTEOPOROSIS Nelson B. Watts, MD Bone Health and...

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