Osteoporosis Diagnosis and Management:

Current Strategies

Normal Bone Physiology• Workhorses of the Bone Remodeling

World– Osteoblasts

• Bone formation/mineralization• Receives endocrine signaling, directs

osteoclasts

– Osteoclasts• Differentiation linked to RANKL ligand signalling

(on) vs. osteoprotegerin (off) decoy signalling• Cytokines can enhance activation or lifespan

– **blocked by Estrogen• Bone resorption

– Secrete HCl to chew up bone, dissolve collagen

– Osteocytes• Mechanosensors of bone (increased wt-bearing,

muscle-contractionsincreased bone strength)

Graphic of Bone Remodelling

Normal Calcium Regulation• PTH

– increases Ca resorption from bone– decreases renal tubular Ca / increases Phos excretion– stimulates 1,25OH vitamin D– enhances osteoblastic bone formation (pulsatile)– stimulates osteoblasts to activate osteoclastic bone

resorption (high continuous)• 1,25-Dihydroxyvitamin D

– increases gut resorption of both Ca and Phos– feedback inhibits PTH and renal 1-alpha-hydroxylase– stimulates osteoclast maturation to mobilized Ca from

bone (at high levels)– provides substrate for osteoblast bone formation (at

normal levels)– Requires intact liver, renal (1-alpha-hydroxylase), and

peripheral sunlight exposure

• Calcitonin – from thyroid parafollicular c-cells

(minor player—no problems post-thyroidectomy)

– inhibits osteoclast bone resorption– inhibits Ca and Phos gut absorption– inhibits renal tubular Ca and Phos

rebsorption• Estrogens/Testosterone

– enhance bone formation (weak anabolic), inhibit bone resorption by downregulating cytokine-mediation

– E2 causes mild suppression of Ca – Decreases calciuria

Types of Bone• Cortical—shafts of long bones, outer edge of all

other bones– Only 3% renewed per year– Forearm>Hip– Hyperparathyroidism, Hypogonadism may affect this

preferentially

• Trabecular (cancellous)—inner core of bones of the central skeleton– 25% renewed per year (much more metabolically active)– Accounts for 80% of the total skeleton surface area– Spine>Hip>Forearm– May see changes in spine earlier than hip or forearm

• After initiation of bisphosphonate tx• After onset of menopause without HRT• Can be confounded by osteophytes or prior compression

fractures

Peak Bone Mass

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

bone massbone resorptionbone formation

Osteoporosis: Definitions• Compromised bone strength due to

decreased bone mass and quality of micro-architecture

• due to marked imbalance in bone resorption vs. bone formation (“uncoupling”)

• fracture risk correlates well with decline in bone density by DXA– most commonly vertebral, hip, and distal radius

• Often a wrist fracture is the first sign– Earlier, more trauma required– Younger women fall forward, older fall to side or back

• Prior vertebral fx predisposes significantly to future fx– RR 4.4 for having more vertebral fxs – RR 2.5 for progressing to hip fx

– decrease in bone density by 1 SD = 2x fracture risk!

Bone Densitometry

• Principle: When a beam of ionized radiation passes through bone, amount of radiation reaching the detector is inversely proportional to the mineral content of the measured bone. This is then divided by a measured area of bone to give a density.

Dual Energy X-ray Absorptiometry• DEXA is preferred method b/c…

• Dual energy is better able to penetrate through soft tissue

• best correlated with fracture risk• high precision, low radiation exposure

• HOWEVER, DEXA can be falsely normal if…• aortic calcifications • spine/hip hardware• osteoarthritis (osteophytes)• compression fxs (decr bone area)—can be seen on

images provided with the DEXA results; falsely improve results

• Serial DEXAs must be done on same machine/location

• differences in individual machine calibration do NOT allow accurate comparisons!!

Why other modalities exist and will continue to be sought…

• Peripheral ultrasound (ie, heel, finger, etc.)– More portable/widely available– Cheaper for widespread population screening– Sensitive screening tool, but not specific for osteoporosis; no

data on efficacy as tx guide

• Qualitative CT– 3D (vs. 2D DXA)actual vs. calculated bone area– Relatively high radiation exposure– Expensive– Better for short-statured, small-boned subjects– No good fracture data

• Tetracycline-labeled bone biopsy– Only current method of assessing full bone quality (ie, micro-

architecture)– Too invasive for other than experimental use in most cases

Beyond Bone Mineral Density• Clear that BMD is only one factor contributing to overall risk of fx

• Bone quality measurements are elusive• Residronate studies shed some light on this…

– Watts et al, J Bone Min Res, 2005• Fx reduction of 32% largely independent of BMD

changes over 3 yrs (only 12% benefit correlated with LS BMD changes, only 7% with FN BMD changes); same fx rate even if BMD decreased!

– Bauer et al, J Bone Min Res, 2006 (FIT)• High pre-tx bone turnover markers greatest benefit

from Residronate• BUT, even those with normal or low bone turnover

markers often have reduction of fractures on Residronate

Quick Primer on Central DXA interpretation of BMD

WHO Definition of Osteoporosis

• T-score = comparison to 25-30 y.o. white, postmenopausal women or young men

T-score Definition0 Mean BMD for

young normals> -1.0 SD Normal bone

mass-1.1 to -2.5 SD Low bone mass

(osteopenia)< -2.5 SD Osteoporosis

• Z-score– Less than or equal to –2.0

suggests secondary cause of osteoporosis

– USE ONLY THE Z-SCORE cut-off of of -2.0 or less when assessing children or young adults (pre-menopausal women or men <50 yrs)•t-scores were not designed for

interpretation within these age groups since they presume achievement of peak bone mass already and fracture risk generally associated with older patients

“Osteopenia”

• Low Bone Mass is the current favored term by the International Society of Clinical Densitometry

• Osteopenia implies fracture risk, which is very hard to predict in premenopausal women or in men (esp. < age 70)term coined to describe post-menopausal women’s bones only!

• Men naturally have bigger bones, which imparts significant fracture protection regardless of BMD

• Men and younger women often have better muscle tone/balanceless prone to falls

• Endogenous estrogens are very protective

Sample Study • Adequate image shows L1-L4 with minimal curvature from AP view and symmetric visualization of iliac crests

• Must have at least 2 interpretable of the 4

• Can only use the AVERAGE of the t-scores and z-scores of the interpretable VBs (not the worst VB alone!)

• DJD or compression fx can falsely increase bone density of 1 or more VB significantly

Sample Study

• Adequate hip image shows no more than a hint of lesser trochanter

• Only use FEMORAL NECK and TOTAL HIP scores– Best fracture correlation– Dx = worst site overall

• Ideally need to measure two interpretable sites to be conclusive– Use forearm and AP

spine if both hips have hardware, etc.

Sample Study

• Only use 1/3 forearm– Best fx data

• Best site for measure of cortical bone (hyperparathyroidism or vit D deficiency?)

• In this example, the hip and forearm show low bone mass, but the AP spine has avg t-score of –2.5– Pt has overall dx of

osteoporosis• Remember: if pt is pre-

menopausal or <30 yrs old, use z-score only– Less than –2.0 is “lower bone

mass than expected for age”

Osteoporosis Risk Factors• Modifiable

– Low Ca or vitamin D intake

– Estrogen/testosterone deficiency

– Sedentary lifestyle– Tobacco– EtOH > 2 drinks/d– Caffeine > 2 drinks/d– Meds (steroids,

excess thyroid hormone)

• Non-modifiable– Age– Race (Caucasian,

Asian)– Female gender– Early menopause– Slender build

(“small- boned”)– + FamHx

Who would WHO screen?• Women > 65 yrs• Postmenopausal women < 65 with RFs or

recent fragility (fall < standing height) fractures– ***Remember: clinically confirmed fragility fracture

trumps any bone density measurementthe patient still has osteoporosis!

• Women considering tx for osteoporosis• Of note, Medicare allows DEXA for…

– E2 deficiency + one other RF– Vertebral osteopenia, deformity or fracture (on X-

ray)– 1oHPT– Steroid tx > physiologic dose for > 3mos.– Monitoring of osteoporosis tx

Who would WHO treat??

• T-score < -2.0 w/o risk factors• T-score < -1.5 with risk factors• Women >70 y.o. with multiple

risk factors regardless of bone density

• Men >50 y.o. with risk factors and t-score < -2.0; w/o risk factors and t-score </= -2.5

• Patients on high risk medications (ie, HD steroids >3 mos)

Osteoporosis: DDx

• Osteomalacia (vit D deficiency)– Malabsorption

• Hyperparathyroidism• Hyperthyroidism• Hypogonadism (premenopausal women,

or men)• Cushing’s syndrome• Multiple myeloma• Rheumatoid arthritis• ESRD• Osteogenesis imperfecta

Cost-effective Evaluation• CBC, bone panel, renal panel,

TSH• menstrual hx in pre-

menopausal female (if amenorrheic, can check E2, LH/FSH, bHCG)

• serum total testosterone in a male

• 24hr urine Ca, Phos, and Cr• 25-OH vitamin D (calcidiol)

level

Fracture Prevention

Treatment Options: Does change in bone density really translate into change in

rate of fractures?

Fracture Incidence

• Age alone doubles LS fx risk per decade, increases hip fx rate too– T-score of –2.5 in a 50 y.o. is not equivalent to t-score of –2.5 in a 70

y.o.• In fact, the 50 y.o. is 50% less likely to fracture!

• Women– Wrist fractures are a marker for future fxs

• Start at age 45-50, peak age 65• Fall onto outstretched hand (FOOSH)

– Vertebral fractures peak later• Start age 55-60, no peak (linear continuous rise)

– Hip fractures increase at age 65 • Exponential increase

– Average age of menopause is 52 yrs– Greatest BMD loss from E2 deficiency is within the first 1-2 yrs

• Men– No increased incidence of wrist fx– Vertebral fxs increase after age 55-60– Hip fxs after age 70-75

T-score Fracture Prediction vs. Age• Prediction of first forearm, symptomatic vertebral,

humerus, or hip fx in women in Malmo, Sweden (Kenis et al, Ost Int 2001)

0

10

20

30

40

50

1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0

Femoral Neck T-score

Ten Year Fracture

Probability (%)

Age

8070

60

50

Treatment Options for Osteoporosis

• Non-pharmacological– smoking and EtOH/caffeine

cessation(<3 glasses per day)– increased weight-bearing

activity– falls prevention– increase dairy and Ca-fortified

drinks– Increase high vitamin D foods

(fish, eggs, beans)

• Pharmacological– 1-1.2g of elemental Ca/day with meals– vitamin D 700-1000 IU/d– Antiresorptive agents

• Bisphosphonates• Estrogens• SERMs (Raloxifene)• (Denosumab)

– Anabolic agents (bone formation)• Testosterone—always do first in men if

hypogonadal• PTH (Teraparatide)• GH• Fluoride• Strontium (promising, but signif potential toxicities)

Benefits of Calcium and Vitamin D• Dawson-Hughes et al, NEJM, 1997

– 500mg calcium + 700 IU vitamin D3 (cholecalciferol) x 3 yrs

– 389 free-living, ambulatory patients >65 yrs

– Taking <1500mg of Ca++ per day at baseline

– Results: Ca/vitD group 5.9% non-vertebral fx rate vs. placebo group 12.9% (RR 0.5, CI 0.2-0.9)

– Similar to large French study of 3400 elderly women given 1200mg of Ca +800 IU vit D3/day

• Bischoff-Ferrari et al, JAMA, 2004– Vitamin D improves muscle

strength/prevents falls in the elderly

Cumulative Percentage of All 389 Subjects age 65 and older with a First Non-vertebral FractureDawson-Hughes et al,NEJM, 1997.

Calcium and Vitamin D• WHI brought controversy about usefulness of

Ca/vitD in OP prevention but consider…• Health-conscious, active population (low risk)

– Vs. nursing home/hospitalized populations with poorer nutrition and sun exposure

• Most had not reached age of greatest risk of hip fx by end of study

• Majority already taking more than recommended daily Ca intake even in placebo group (>1200 mg/d)

• Most were not vitamin D deficient to begin with, and those that were had only mild deficiency (25OHD >25-30)

• Vitamin D dose < 700-800 IU that has shown benefit in prior studies

• Only 60% were compliant with study med• Subgroup that was compliant had significant hip fx risk

reduction of 29%• RR of renal stones was increased by 17%

– Unclear clinical vs. subclinical; other risk factors not screened

Osteomalacia

• disorder of bone mineralization associated with insufficient vitamin D, calcium, and/or phosphate– ‘weak’ or ‘soft’ bone– known as rickets in childhood

• impaired growth, soft skull (craniotabes), rachitic rosary, bowed legs

– presents with • chronic diffuse bone pain (worse with movement or palpation) • +/- atraumatic fractures• muscle weakness/atrophy, increased risk of falls

– may present with symptomatic hypocalcemia

• Occult vitamin D deficiency is common!– Even seen at high frequency in Florida and CA– Goal are levels above 30, severe def. is <10-15 ng/mL

Radiographic Findings of Osteomalacia• Plain films

– Generalized osteopenia– Looser zones/Milkman fractures

(pseudofractures)• short perpendicular radiolucent lines• bilateral in femur, pelvis, hands/feet

– complete fractures

• Bone densitometry– osteopenia or osteoporosis

(diffuse)– cannot distinguish from regular

Osteoporosis

Bone sections are viewed under ultraviolet light to estimate mineralization activity by visualizing tetracycline labels. The normal bone reveals that the majority of the osteoid has crisp double tetracycline labels (white arrows), indicative of normal mineralization activity.

The osteomalacic bone, however, has smeared tetracycline labels without the double label (white arrows). Moreover, the tetracycline labels do not occupy the majority of the osteoid-bone interface. Such observations are representative of the abnormal mineralization that characterizes the osteomalacic bone disorder.

Vitamin D Metabolism

Treatment of Osteomalacia• ESRD (renal osteodystrophy) & VDDR

– high dose calcium and 1,25vitD (calcitriol)

• Vitamin D deficiency– 5-10,000 IU/d or 50,000-100,000/wk of

ergocalciferol (D2)check levels in 8-10 weeks to avoid toxicity

– Maintenance 700-2000 IU/d– 4000 IU/d recommended for breastfeeding women– 1gm elemental calcium/d

• Hypophosphatemic rickets– phosphate suppl, calcitriol

• Tumor-induced osteomalacia– find the tumor and remove it!

Estrogens/Progestins

WHI: Estrogen + Progestin and risk of Hip Fracture

• reduced the risk of hip fracture by 33% (HR, 0.67; 95% nCI, 0.47–0.96; 95% aCI, 0.41–1.10)

• subgroup analyses, decreased the risk of hip fracture by 60% among women who reported a baseline calcium intake of more than 1200 mg/d but not among women with lower calcium intake (P for interaction = .02).

• reduced the risk of hip fracture in women with a BMI of less than 25 (HR, 0.50; 95% nCI, 0.28–0.90) and with a BMI of 25 to less than 30 (HR, 0.67; 95% nCI, 0.37–1.20) but not in women with a BMI of 30 or more

• risk of hip fracture was reduced to a similar degree in women stratified by age, smoking, fall and fracture history, past use of HRT, parental fracture hx, years since menopause, and summary fracture risk score.

WHI Investigators, JAMA, 2003.

WHI: fracture incidence

Million Women Study

• 1996-1998, post-menopausal women age 50-69 yrs in the UK

• Several different HRT formulations used• Stopping HRT negates benefits to fx

protection and BMD within the first 12 mos• Length of prior use makes no difference,

though effect of current use peaks at 5-9 yrs• Decreased wrist and hip fxs, but no clear

vertebral fx benefit• Same hip fx benefit (RR 0.62) as in WHI

study

Bisphosphonates in osteoporosis• Oral bisphosphonates (Alendronate, Risedronate)

– Best studied; most conclusive fx risk reduction (50-60%)– Well-tolerated – Extension of the FIT study from 5 to 10 yrs showed

spine BMD improved further but hip remained stable– Fx risk reduction stabilized in hip at 5 yrs, spine at 6-7

yrs– Low risk patients stopping Alendronate at 5 yrs only

showed slight decreases in BMD hip or spine 5 yrs later (Bone et al, NEJM, 2004)long-lasting incorp into skeleton; bone turnover markers still lower than baseline after 5 yrs off tx

Reasonable Alternatives to Oral Bisphosphonates• IV bisphosphonates

– Zoledronic acid now proven to decrease fracture risk in post-menopausal women by 60%(HORIZON trial, NEJM, 2008)

– Ibandronate only proven to decrease fx risk (MOBILE study, Ann Rheum Dis, 2006) in spine, GC-mediated

– Others (Pamidronate) have similar efficacy of BMD improvement to orals

– Bypasses GI absorption or intolerance issues

• Raloxifene (Evista)– Selective estrogen receptor modulator (SERM)– Significant improvements in BMD and fx risk (less than oral

bisphosphonates)– Better for pts with hyperlipidemia or h/o breast CA– Worsens hot flashes; equal to higher risk of VTE than E2– Same risk of thromboembolic events as estrogens

Alendronate and Osteopenia• Quandt et al., Mayo Clin Proc 2005

(Fracture Intervention Trial data)• Post-menopausal women 55-80 yrs• Mean f/u period 3.8 yrs• All had at least 1000mg Ca intake +250

IU VitD• FN osteopenia (t-score –1.6 to -2.5)

– Spine not used (concern about DJD confounding?)

• With or without baseline vertebral fx– Only those with clinical or radiographic prior

VF showed clear benefit of tx– W/o prior VF, baseline fx rate was too low to

see benefit from tx with Alendronate

Bisphosphonates: Emerging Concerns?

• Osteonecrosis of the jaws (ONJ)– Small retrospective case series

• Vast majority with high dose IV tx for malignant hyperCa/bone pain

• Extremely rare reports with oral bisphos tx– Direct association not established yet

• None of the large prospective oral bisphos studies have reported it

• Dentists recommending holding tx a 3-6 months prior and following extensive dental surgery, etc.

• Oversuppression of bone turnover, impaired microfracture repair over time?– No evidence of diminished mechanical strength in

high dose animal studies– Bone bx in postmenopausal women on Bisphos

have normal mineralization/histomorphometry

Antiresorptive Agents:Reduction in Fracture Incidence

Up to 50%Calcium and vitamin D

32-39%

Non-vertebral (hip, wrist)

0%33% (PROOF only)

Calcitonin

0%31-49%Raloxifene

33% (WHI only)

42%Estrogens

20-58%30-50%Risedronate

30-45%47-50%Alendronate

HipLS

A few words on PTH• Most promising anabolic agent to date• FDA approved in Nov 02• High pulsatile PTH favors bone formation• Relative contraindication in renal insufficiency • Absolute contraindication-HPT• daily SQ injections for 18-24 months• preliminary data suggests combo tx with

bisphosphonate reduces effectiveness of PTH in men and post-menopausal women

• Vertebral fx risk reported to decrease by up to 68%, non-vertebral by up to 53% (post-menopausal women)

• currently recommended when bisphosphonates failed or contraindicated– Though greatest benefit may be in bisphos-naïve pts!

Forteo (Teraparatide)Black et al, NEJM, Sep 2003

Newer agents on the Horizon...• Denusomab

– Monoclonal antibody against RANKL– Blocks signally to activate osteoclast – Similar improvements in total hip

BMD to alendronate– Well-tolerated– No fracture prevention data yet

• Wnt pathway agents– Pathway leading to osteoblast

enhancement– Potential targets for pharm

development identified

RANK-ligand and Osteoprotegerin

Questions?