PRESENTER: DR.LEMAYIAN PETERSUPERVISOR: DR. OMBACHI

METABOLIC DISEASE OF SPINE-OSTEOPOROSIS

Skeletal d’se characterised by:

Low bone massMicro-achitectural breakdown of bone

tissue

“silent killer”Preventable d’se Devastating physical, psychosocial and

economical consequenceIncreasingly becoming a global problem-

most common metabolic bone d’se afflicting approx. 200m worldwide.

WHO DEFINITION:

DEFINITION BMD MEASUREMENT

T-SCORE

NORMAL Within 1SD of mean BMD for young adult women

T-score >-1

OSTEOPAENIA BMD 1-2.5 SD below the mean for young adult women

T-Score btn -1 and -2.5

OSTEOPOROSIS BMD >2.5 SD below mean for young adult women

T-Score <-2.5

SEVERE OSTEOPOROSIS

BMD >2.5 SD below mean for young adult women in a patient who has already experienced >1 fractures

T-Score <-2.5 with fragility fractures

This definition applies to postmenopausal women and men >50yrs

T-Score= patient’s BMD BMD of control subjects who are

at their peak BMDZ-Score=patient’s BMD BMD of patients matched for age

and sexZ-Scores used in premenopausal women,

children and men<50yrs

PATHOPHYSIOLOGY

HALLMARK: reduced skeletal mass due to imbalance btn bone resorption and formation

Failure to build bone reserve from childhoodBone lossAging with loss of gonadal functionBone loss accelerates rapidly in women

during the first years after menopause

a) Estrogen deficiency leads to…

↑ expression of RANKL by osteoblasts↓ release of OPG↑recruitment of pre-

osteoclasts→↑differentiation and prolonged survival of osteoclasts via IL-1,IL-6,TNFᾳ.

T-Cells inhibit osteoblastic differentiation and activity with premature apoptosis of osteoblasts through cytokines e.g. IL-7

Increased sensitization of bone to the effects of PTH

↑osteoclastic apoptotic activity via ↑production of TGFᵝ

b) Aging

Progressive ↓ in supply of osteoblasts Reduced Ca2+ uptake from GITBone resorption exceeds bone formation from

3rd decadeWomen lose-30-40% of cortical bone -50% of trabecular boneMen lose-15-20% of cortical bone -25-30% of trabecular bone

c) Ca²⁺deficiency

→2° hyperPTH -↓ renal excretion of Ca2+ -↑ renal production of 1,25-

(OH)2-D (calcitriol)→↑ca2+ absorption from the gut

→↑bone resorption

d) Vit D Deficiency

Impaired absorption of Ca2+ from gutCompensatory mechanism:-Leads to

hyperPTH→↑production of calcitriol from the kidneys

PTH and vit.D have their effect on bone being mediated via binding to osteoblasts and stimulating RANK/RANKL pathway

Osteoclasts do not have receptors for Vit.D or PTH

Osteoporotic Fractures

Aka Insufficiency/ fragility fracturesMostly from low-energy trauma/minor loadsVertebral bodies-1rly cancellous with

interconnected horizontal and vertical trabeculae.

In osteoporosis there’s ↓ in both bone mass and this internal interconnectivity(BUT preferentially disruption is in the horizontal trabeculae)→? Reason→?overaggresive osteoclastic resorption

Rosen and Tenenhouse cadaveric study:

As many as 200-450 horizontal trabeculae fractures per vertebral body in various stages of healing→cumulatively leads to weakening of cancellous bony structure

Osteoporosis Vs Osteomalacia

Normal human skeleton→60% mineral 40% organic material

(collagen)Osteoporosis-mineral: collagen ratio within

normal tho’ both are significantly ↓; bone is porous and brittle

Osteomalacia-mineral is reduced relative to organic content; bone is soft.

Classification of osteoporosis:

Localised 1°

Generalised 2°

1° Osteoporosis

(A) JUVENILEChildren/young adults; both sexes8-14 yrsNormal gonadal functionHallmark: abrupt bone pain/ fracture

following minor trauma

(B) IDIOPATHIC

a)PMO(TYPE 1)-high-turnover osteoporosisWomen>50-65yrsPhase of accelerated bone loss primarily

trabecular bonePredorminantly increased osteoclastic activityFracture vertebrae and distal forearm

commonVertebral # occur more often in the 7th decade

of life.

b) age-related/senile osteoporosis(TYPE 2)

-Low-turnover osteoporosis-gradual slow down in osteoblastic activity.Men and women >70 yrs Fractures in cortical and trabecular boneWrist, vertebrae and hip fractures common

2° Osteoporosis

CAUSE EXAMPLES

GENETIC/CONGENITAL Renal hypercalciuria, cystic fibrosis, ehler’s danlos, gauchers, marfans sx,osteogenesis imperfecta, hypoPO4²

ENDOCRINOPATHIES Cushing’s sx, DM,adrenal insuff., prolactinomas, hyperthyroidism, hyper-PTH, Hypogonadism, panhypopituitarism, klinefelter’s, turner’s sx

DEFICIENCY STATES Ca2+, Mg2+, Vit. D def, protein def., celiac d’se, malabsorption, malnutrition, parenteral nutrition

INFLAMMATORY CONDITIONS IBD, R.A., SLE, Ankylosing spondylitis

HAEMATOLOGICAL/ NEOPLASTIC DISORDERS

Haemophilia,, haemochromatosis, leukaemia, lymphoma, multiple myeloma, SCD, Thalassaemia, metastases

MEDICATIONS Anticonvulsants(Rx-induced Vit D def), antipsychotics, ARVS, Aromatase inhibitors(Anastrozole), anticancer drugs, Frusemide, Glucorcoticoids( PDN>5mg OD for >3/12), longterm Heparin, Li, SSRI, Hormonal therapies-Thyroxine, LHRH analogues

MISCELLANEOUS Pregnancy, lactation, alcoholism, depression, HIV/AIDS, CRD, CCF, Chronic liver disease, amyloidosis, prolonged immobility/disuse, Multiple sclerosis

STAGES

STAGE 1: loss of horizontal trabeculationsSTAGE 2: loss of vertical trabeculaeSTAGE 3: loss of both horizontal and vertical

trabeculae with resultant cavitation of the vertebral body

RISK FACTORS

National Osteoporosis Foundation (NOF) classifies them into:

a)Modifiable: physical inactivitydrugs, alcohol, cigarette smokingdeficiency statesThin build/small stature(body wght

<127lbs/ BMI<20-25 kg/m² in men), >10% body weight loss in menAndrogen deprivation therapy in menPrevious fragility fracture

b) Non-modifiable:

age (>50yrs)sex(F:M=4:1)race(caucasian/asian)genetics(+ve family history)amenorrhoea, late menarche, early

menopausepost-hysterectomy and oophorectomy,androgen/ estrogen def.

Pneumonic=OSTEOPOROSIS

O=lOw ca2+S=Seizure drugsT=Thin buildE=Ethanol intakeO=hypOgonadismP=Previous fracture0=thyrOid excessR=RaceO=Other realtives with osteoporosisS=SteroidsI=InactivityS=Smoking

EPIDEMIOLOGY

10m Americans affected(80% women)-NOF34M have ↓ bone mass with ↑ risk for

osteoporosis1.5m-2m osteoporotic fractures/yr (700,000

spinal #; 300,000 hip #; 200,000 wrist #)1 in every 2 women and 1 in every 5 men will

eventually experience osteoporotic #Men have a higher prevalence of 2°

osteoporosis

RACIAL DEMOGRAPHICS

RACE SEX(AGE>50YRS)

% ESTIMATED TO HAVE OSTEOPOROSIS

% ESTIMATED TO HAVE LOW BONE MASS

NON-HISPANIC WHITE;ASIAN

WOMEN 20 52

MEN 7 35

NON-HISPANIC BLACK

WOMEN 5

MEN 4 19

HISPANIC WOMEN 10 49

MEN 3 23

Osteoporosis-related fractures result in annual direct expenditure of $12.2b-17.9b

Leading cause of fractures in the elderlyWomen>50yrs have about 50% lifetime

fracture rate due to osteoporosis and about 80% of all fractures in pple aged >50yrs.

prognosis

Good if bone loss is detected early Incase of #→ may lead to chronic pain,

disability, prolonged immobilisation, death

Vertebral compression fractures

2/3 are asymptomatic and occur slowlyAssociated with ↑morbidity and mortalityMortality also correlates with number of

vertebral #Often occurs with minimal stressMostly affected-middle/lower thoracic and

upper lumbar

As posture worsens and kyphosis progresses→difficulty with balance, back pains, resp. compromise,↑ risk of pneumonia

↓ QOL

Presence of a # at one vertebral level→5-fold ↑ risk of getting another

CLINICAL PRESENTATIONS

Episode of acute back pain after bending, coughing,lifting, a fall, minor trauma

Pain-sharp, nugging, dull; exacerbated by movt; may radiate to the abdomen

Progressive kyphosis with loss of height+/- localised painParavertebral muscle spasm exacerbated by

activity/ reduced by lying supine.

Complications:

Chronic pain↑morbidity and mortality↓ QOLProlonged immobilitySevere kyphosisSpinal deformities→”dowager’s hump”→loss

of 1-2’ of height by 7th decade of lifeLoss of self-esteem→depression

PHYSICAL EXAM

InspectionPalpationHeight measurementActive/passive ROMNeurological exam

Signs esp in the elderly that may indicate ↑risk of a fall-gait problems, orthostatic hypotn, LL weakness, cognitive impairment

Findings of subtle collagen defects:-short 5th digit, dentinogenesis imperfecta, hyperlaxity, hearing loss, pes planus, bunions, blue sclera

DDX

Osteomalacia Tumors(osteolytic) Infections Osteonecrosis Other bone-softening metabolic disorders Mets Leukaemia/lymphoma Osteogenesis imperfecta Renal osteodystrophy Multiple myeloma Scurvy Paget’s disease Sickle cell anaemia Homocystinuria/homocystinaemia

WHO-Fracture-Risk algorithm(FRAX)

Developed to calculate 10yr probability of any major osteoporotic # in a given patient

Take into a/c BMD and other clinical risk fxtrs

NOF recommends RX for patients with WHO-10yr-probability of major osteoporosis-related # of >20% (or >30% for hip #)

This algorithm is useful in identifying patients most likely to benefit from Rx.

SCREENING

Women >50yrs of ageFor men, not carried out routinelyUS preventive Services Task Force(USPSTF)/

American College of Physicians(ACP) recommendations:

Indications for screening in menThose with 10yr risk for osteoporotic # equal

to or greater than that for 65yr old women who have no additional risk factors

INVESTIGATIONS

i) LAB WORKUPa) To establish baseline conditions:-CBC-Serum Ca²⁺,mg²⁺,po4-,Fe2+/ferritin levels-LFTs-TFTs-Vit. D levels-Cr/BUN

b) To exclude 2° causes

24 hr-urinary Ca2+ levelsPTH levelTestosterone/gonadotropin levelESR/ CRPUrinary free cortisol levels/ dexamethasone

suppression testBMASerum/Urinary protein electrophoresis

ii) Biochemical markers of bone turnover

Reflect bone formation and resorption

Maybe ↑in high-bone turnover states and may also be useful in some patients for monitoring early response to treatment

SERUM MARKERS OF BONE FORMATION

Bone specific alkaline phosphatase(BSAP)Osteocalcin(OC)-if high, indicates a high

turnover osteoporosisCarboxyterminal propeptide of type 1

collagen(PICP)Aminoterminal propeptide of type 1

collagen(PINP)

SERUM MARKERS OF BONE RESORPTION

Cross-linked C-Telopeptide of type 1 collagen(ICTP)

Tartrate-resisitant acid phosphataseN-Telopeptide of collagen cross-links(NTx)C-telopeptide of collagen cross-links(CTx)

URINARY MARKERS OF BONE RESORPTION

HydroxyprolineFree and total pyridinolines(Pyd)Free and total deoxypyridinolines(Dpd)NTxCTx

iii) IMAGING

(a) Plain radiography-to assess overall skeletal intergrity-suspected #-if patient has lost>1½” of height Can suggest presence of osteopaenia or

bone loss though cannot diagnose osteoporosis

Osteoporosis predorminantly affects trabecular bone rather than cortical bone

Cortical bone not affected by osteoporosis until >30% of bone loss has occurred

30-80% of bone mineral must be lost before radiographic lucency becomes apparent.

(b) Densitometry1)Dual-Energy X-Ray

Absorptiometry(DXA)-quantifies bone loss-standard for evaluation of BMD-not as sensitive as QCT for detecting early

trabecular bone loss, but it provides rapid scanning times, is less costly and precise

-used to calculate BMD at the lumbar spine, hip,prox. Femur and wrist

-data is reported as T and Z-scores

2) Single-photon Absorptiometry(SPA)

-precise and with low- radiation exposure

-relatively insensitive for detecting early-stage osteoporosis coz it measures cortical rather than trabecular bone.

3) Dual-Photon Absorptiometry(DPA)

-Can measure BMD in the spine and prox. Femur

-limited by poor reproducibility, prolonged scanning times and artifacts caused by vascular calcifications.

4) Computed Tomography

Quantitative CT Scanning(QCT)-assesses BMD only at the spine-can be used in both adults and children-is the most sensitive method for diagnosing

osteoporosis coz it measures trabecular bone within the vertebral body.

-cf with DXA, is more expensive, poor reproducibility, possible interference by osteophytes, higher radiation dose

Single-Photon Emission CT Scanning(SPECT)

-CT-Like bone imaging technique that offers better image contrast and more accurate lesion localisation

-increases sensitivity and specificity of bone scanning for detection of lumbar spine lesions by 20-50% over planar techniques

-visualise bony structures that would overlap on planar images e.g. facet joints, pars interarticularis, pedicles

5) U/S

Quantitative U/S of the Calcaneus(QUS)

-The heel is the only validated skeletal site for clinical use of QUS in osteoporosis mx.

-low cost, no radiation

-not as accurate.

6) MRI-Useful in discriminating btn acute and

chronic fractures of the vertebrae and occult fractures of the proximal femur.

7) Bone Scanning(99m Tc)

8) Bone biopsy and histology

MANAGEMENT

Approach considerationsRx is aimed at # prevention and rehabilitation.-lifestyle modification-pharmacotherapy-Rx of potentially-treatable 2° causes-surgical Mx of vertebral compression #-rehabilitation to control pain.

PHARMACOTHERAPY

NOF Recommendations:Pharmacotherapy should be reserved for

postmenopausal women and men >50yrs presenting with:

hip/vertebral #T-score of -2.5 or less at the femoral neck or

spinelow bone mass(T-score of btn -1.0 and -2.5 at

the femoral neck or spine)

10yr probability of a hip # of >3% or

10yr probability of a major osteoporosis-related # of >20% based on FRAX

ADVISABLE THAT ALL RX SHOULD BE GIVEN WITH CA2+ AND VITAMIN D SUPPLEMENTS

1. BIPHOSPHONATES

Most commonly usedFor Rx and prevention Oral and I.V. formulationsMOABinds to the hydroxyarpatite crystalls at active

bone resorption sites thereby inhibiting osteoclastic resorption.

S/E

Overtime, it ↓bone turnoverAt very high levels, ↓bone strength and

resilienceOsteonecrosis of the jawAtypical femur fractures(transverse subtroch

and shaft #)

Bone turnover markers should be monitored and if they become significantly ↓, the treatment holidays instituted until return to normal levels

i. Alendronate(Fosamax)

-dose : 70mg/wk PO

-↓ fracture rate of the spine, hip and wrist by 50%

-can be combined with Vit. D(Fosamax-Plus D)

ii) Risendronate(Actonel)-↓ vertebral fractures by 41% and non-

vertebral fractures by 39% over 3 yrs

-can be combined with Ca2+

iii) Ibandronate

-PO once monthly or IV 3-monthly

iv) Zolendronic Acid(Reclast)-most potent-↑ BMD at the spine by 4.3-5.1% and hip by

3.1-3.5%-↓ spine # by 70% and hip by 41%-given IV once yearly

2. SELECTIVE ESTROGEN RECEPTOR MODULATORS( SERM)

RALOXIFENE(Evista)-↓ risk of vertebral fractures by 35%

3. PTH

TERIPARATIDE(human recombinant PTH)MOA: ?stimulation of angiogenesis→vascular

endothelial stem cells differentiated to become osteoblasts

indications Rx of osteoporosis where other Rx has failed

or intolerance has developed

Finkelstein et al: combination therapy with biphosphonates has ↓benefits

Cosman et al: 3/12-on followed by 3/12-off pulses of teriparatide in pts on weekly Alendronate→BMD increased above that of either Rx alone.

4. CALCITONIN

MOA: ↓osteoclastic activity-reserved for those intolerant to estrogens

-Formulations: Inj or Intranasal spray (200i.u. OD)

5. DENOSUMAB

Humanised monoclonal Ab against RANKLDOSE: 60mg SQ every 6/12May become 1st line of Rx for patients with

autoimmune and inflammatory disorders coz overactivity of RANKL is a major factor in bone loss in such pts.

6. HRT

Currently not recommended coz of S/E(ca breast, MI, CVA, DVT)

i) Estrogen Derivatives-premarin, Estradiol, Estropipate

ii)Estrogen-Progestin combinations:-Estradiol-Levonorgesterol-conjugated Estrogen/medroxyprogesterone

acetate

7. OTHERS

Vitamin-D formulations:ergocalciferol(Vit D2), cholecalciferol(Vit D3)

Ca2+ salts: ca-citrate, ca-carbonate

Strontium ranelate

Daily nitroglycerin ointment

American association of clinical endocrinologists

1st line: alendronate, risendronate, zolendronic acid, denosumab

2nd line: ibandronate3rd line: raloxifeneTreatment failure: teriparatide

SURGICAL THERAPY

OBJECTIVE: early mobilisation and return to normal or near normal function

INDICATIONS: incapacitating/ persistent severe focal back pain related to vertebral collapse

i) Anterior and posterior decompression and stabilisation with pedicle screws, rods, plates, cages +/- bone grafting to achieve fusion

ii) KYPHOPLASTY Reduces amount of kyphosis and restores

vertebral body height Minimally invasive

iii) VERTEBROPLASTY

-Useful to control pain associated with vertebral #

-fuses fracture fragments into one block using acrylic cement, preventing painful mvt of individual fragments.

-also reduces pain by heat produced by polymerization process as the cement hardens

-does not restore height of compressed vertebral body

DIETARY MEASURES

Oral Vit. D and Ca2+ supplements daily intake for osteoporotic patients:

-Ca2+: 1200-1500mg-Vit. D: 400-800i.uSources of Ca2+ : dairy products, nuts,

sunflower seeds, vegsVit D sources: eggs, liver, fatty fish, milk

OTHER RX MODALITIES

PHYSIOTHERAPY-to strengthen back extensor muscles to

↓kyphosis-orthotics: -Thoracolumbosacral

orthotics(TLSO) -Jewett brace -Cruciform ant spinal

hyperext(CASH) brace

OCCUPATIONAL THERAPY-training in performance of activities of daily

living

EXERCISES-aerobic, low-impact exercise(3-5 sessions/wk

each 45-60min)

PREVENTION OF OSTEOPOROSIS

Starts in childhoodAdequate ca2+/vit D intake/ weight-bearing

exercises2-pronged:i) Behaviour modification-cigarette smoking -physical

inactivity -intake of

alcohol,caffeine, animal protein

ii) Pharmacological

-regular periodic bone densitometry(every 2 yrs for postmenopausal women)

-Longterm monitoring-DXA repeated every 2-3 yrs if baseline is normal and every 1-2yrs in osteoporotic patients undergoing Rx.

END!