SRI SIDDHARTHA MEDICAL COLLEGE,TUMKUR DEPARTMENT OF ORTHOPAEDICS

Topic:

USE OF BISPHOSPHONATES IN ORTHOPAEDIC SURGERY

Pearls and PitfallsModerator:

Dr. J.K ReddyHOD & ProfessorDept. of Orthopaedics

Presenter:Dr. Jaipalsinh MahidaJr. Resident M.S Ortho Dept. of Orthopaedics

INTRODUCTION

• Significant number of skeletal disorders affecting bone mineral densityAre product of increased osteoclastic activityMore frequent- osteoporosis, skeletal metastatic diseaseLess frequent- paget disease, osteogenesis imperfect

• BPNs are most clinically important & widely used antiresorptive medicationThey are syntheticMetabolically stable analogues of inorganic pyrophosphate

P-O-P bond replaced by nonhydrolyzable P-C-P diphosphate configuration of this molecule facilitates binding of calcium molecules

Initially used as bone scanning markers when combined with radioisotopes.

• Bisphosphonates are class of drugs that prevent the loss of bone mass• Used in treatment of many skeletal disorders:

Bone metastasesOsteoporosisPaget’s disease, etc

• The prefix “BIS” is a term indicating 2 phosphonate groups, attached to a common carbon atom• They are structurally similar to natural pyrophosphate, which is a

normal product of human metabolism that has a calcium chelating property

• These drugs have high attraction for hydroxyapatite crystals & thus rapidly included into all parts of skeleton.

• They are used as inhibitors of osteoclastic activity to alleviate bone pain that results from the release of biochemical mediators in metastatic bone disease.

• In last decadeBPNs- widely researched, specially in osteoporosisEfficacy- proved by many investigations in fracture preventionCost-effective & safe to use

• Several BPNs approved by FDA for treatment of orthopedic conditionsIncreased osteoclastic activityDecreased bone mineral density

• Orthopedic surgeons need to be familiar with use of BPNs & current indications• This article reviews use of BPNs in orthopedic surgery

HISTORY

• In 1897, von Baeyer & Hoffman reported the synthesis of 1st bisphosphonates

• Initially used in chemical industry as anticorrosive & anti scaling agent by virtue of their ability to inhibit formation of calcium on surfaces.

• In 1960, fleisch et al. 1st reported their ability to inhibit hydroxyapatite dissolution in bone

• 1st human use of bisphosphonates, Etidronate, was reported by Bassett et al. in 1969 for treatment of myositis ossificans progressive

• Smith et al in 1971 were 1st to repot the evidence of effectiveness of bisphosphonates for treatment of paget’s disease of bone

TYPES

NON-NITROGENOUS

ETIDRONATECLODRONATETILUDRONATE

NITROGENOUS

PAMIDRONATENERIDRONATEOLPADRONATEALENDRONATEIBANDRONATERISEDRONATEZOLENDRONATE

GENERATIONS

1ST GENERATION ORAL BISPHOSPHONATES1. ETIDRONATE2. MEDRONATE3. CLODRONATE4. TILUDRONATE

Mainly modified side chains (R1 R2) contains a chlorophenyl groupMetabolized into non-hydrolysable ATP analog that accumulates within

osteoclasts and induces apoptosis, which accounts for antiresorptive effect.Least potent

2nd GENERATION ORAL/IV BISPHOSPHONATES1. ALENDRONATE-oral2. PAMIDRONATE-IV3. IBANDRONATE-oral / IV

Contains nitrogen group (amino terminal) in side chainPrimarily inhibits bone resorptionAntiresorptive activity involves inhibition of multiple steps in the pathway

from mevalonate to cholesterol & isoprenoid lipids that are required for prenylation of protenis that are important for osteoclast function

10-100 times more potent than 1st generation BPNs

3rd GENERATION ORAL / IV BISPHOSPHONATES1. RISEDRONATE- oral2. ZOLEDRONATE - IV

Contains nitrogen atom within heterocylic ringUp to 10,000 times more potent than 1st generation BPNs

PHARMACOKINETICS

• Inverse relation exists between pharmacologic activity & oral bioavailability• Absorption by passive diffusion from gut• Milk & other products, orange juice, coffee ,calcium, iron product;

reduces absorption• Bound to plasma proteins• 20-80% of absorbed dose is rapidly taken up by bones• Remainder is rapidly excreted in urine• Long skeletal retention (half life up to 10 yrs)

MECHANISM OF ACTION

BPNs are used to inhibit bone resorption & they act through different mode of action

1. Inhibits development of osteoclasts2. Induction of osteoclast apoptosis3. Reduction of osteoclast activity4. Prevention of development of osteoclast from hematopoietic precursors5. Stimulation of production of an osteoclast inhibitory factor

Non-nitrogen containing BPNs are taken up by osteoclasts & causes cell apoptosis through activation of caspase pathway

Nitrogen containing BPNs are not metabolized & affects protein prenylation of osteoclasts by inhibiting farnesyl disphosphate synthase, a key enzyme of mevalonate pathway

CALCIFICATION

• The physicochemical effect are very similar to pyrophosphate.

• Inhibits the formation & aggregation of calcium phosphate crystals, even at very low concentrations.

• Block the transformation of amorphous calcium phosphate into hydroxyapatite, & delay the aggregation of apetite crystals.

• BPNs also delays the dissolution of calcium phosphate crystals.

• All these effects are related to the marked affinity of BPNs for the surface of calcium phosphate where they bind onto the calcium by chemisorption.

• BPNs chiefly act as a crystal poison on both growth & dissolution.

BONE RESORPTION

• The inhibition of bone resorption can be explained largely by cellular mechanism

• Can be considered at 3 levels TISSUE LEVELSCELLULAR LEVELSMOLECULAR LEVELS

• The effect may be directly on the osteoclasts & may be mediated, via other cells such as osteoblastic lineage cells & macrophages.

TISSUE LEVELS:At this level, the action of active BPNs appears to be same of all, i.e: a

reduction in bone turnover

This is shown by decrease in both bone resorption & bone formation, as assessed in humans by calcium-45 kinetics, biochemical markers & morphology.

Under normal conditions, destroyed bone is replaced by bone formation

In adults this occurs mostly at trabeculae & cortex.

Morphological dynamic unit of turnover is BMU(basic multicellular unit)

The remodeling process in this unit starts with erosion of certain amount of bone through osteoclasts on the surface or interior of cortex.

Resorption follows a linear path, forming a canal within the cortex & a trench on the surface

Destruction is followed by a refilling of excavation by osteoblasts

The final morphological entity is called bone structural unit(BSU)It corresponds to an osteon within cortex & has been termed a hemiosteon when

it is at the surface of bone

Total bone resorption & formation will therefore depends upon number of BMUs present at any time which in turn will depend upon both number of BMUs formed & length of time they are active.

Under normal conditions, the amount of bone formed in each BMU equals amount destroyed, so that balance is zero.

In osteoporosis however, a greater amount of bone is resorbed than formed, leading to a negative balance.

BPNs act at the individual BMU level by decreasing depth of resorption site.

Since mount of new bone formed in BMU is not decreased, but possibly even Increased.

The local & consequently the whole body bone balance will be less negative or might even be positive.

The effect both on general turnover & local balance will lead to:Less trabecular thinningDecreased number of trabecular perforationsSmaller erosion of cortexThus slowing down the decrease in bone strength & occurrence of fractures

• Reason to accept that BPNs can lead to positive calcium & bone balance, both in animals & in humans.

1. Inherent to bone turnoverA decrease in bone resorption is not immediately followed by diminution of formation, so

that a temporary increase in balance through a reduction in the remodeling.

2. After decrease in turnover, new BSU formed will be remodeled later than it would be normally. It therefore has more time to finish lengthy process of mineralizationThis will lead to higher calcium content and therefore a higher bone mineral density &

content.

3. If the decrease in resorption depth at individual remodeling sites is not matched by a decrease in formation in the individual BMU, local bone balance in BMU will be positive

4. The last possibility is an increase in amount bone formed at the level of BMU.

CELLULAR LEVELS:At this level final target of BPNs action is ostroclast

4 mechanism appears to be involved:

1. Inhibition of osteoclast recruitment2. Inhibition of osteoclastic adhesion3. Shortening of life span of osteocalsts4. Inhibition of osteoclast avtivity

First three mechanism will lead to decrease in number of osteocalstsAll 4 effects could be either due to a direct action on osteoclast or its precursors

MOLECULAR LEVELS:Possible biochemical action of BPNs on osteoclast

o Binding to apatite crystalso Local release during bone resorptiono Preferential accumulation under osteoclasts

o Decrease in osteoclast activity• Altered cytoskeleton• Ruffled border decreased• Acid extrusion decreased• Enzyme activity decreased

o Decrease in osteoclast numbero Apoptosis increased

SIDE EFFECTS

• Upset stomach• Inflammation/ erosion of esophagus• Fever/ flu-like symptoms• Slight increased risk for electrolyte disturbance• Uveitis• Musculoskeletal joint pain• BPNs related osteonecrosis of JAW

INDICATIONS

• Multiple conditions for which BPNs are used1. Osteoporosis2. Metastatic disease to bone3. Paget disease4. Osteogenesis imperfecta 5. Osteolysis in arthroplasty6. Pediatric disorders

1. OSTEOPOROSIS:

One of the first indication for which BPNs received FDA approval75 million people affected in Europe, Japan & USAWHO defined it as mineral bone density that is 2.5 Standard Deviation less

than peak of young adult of same gender & raceThis value expressed as T score

When bone density value compared with normal individual of same age & gender

value expressed as Z scoreZ score < -2, reflects lowest 2.5%

It is Primary independent risk factor for fractures in elderlyCan be treated Risk can be reduced

Treated with many medicationHormone replacement therapy Selective estrogen receptor modulators (Raloxifene)Calcitonin therapyBisphosphonates

• Most important• Proved to reduce risk of hip fractures

Prospective, randomized, placebo-controlled, phase III regulatory trialsGave most data of fracture reduction efficacy & safety of BPNsConducted in postmenopausal womenAverage follow up- 3 YrsFewer than 50,000 participantsConcerns in long term effects of BPNs Scarce dataNo placebo-controlled data beyond 5 yrs

2 trials testing Alendronate-extended to 10 yrs• Showed increase in mineral density in lumbar spine (13.7%) & other skeletal

sites• Dose of 5mg showed modest increase in bone density• 70 mg/week is therapeutically as effective as 10mg/daily- Weekly dose

standard therapy• Confirmed direct relation of alendronate & increased bone density

o Discontinuation of treatment – gradual loss of bone density & increased N-telopeptide level

• Comparison with different dosages (not with placebo)• Efficacy of alendronate in terms of fracture reduction risk didn’t seem to

diminish with 10 yrs sustained therapy

10 trials evaluated efficacy of antifracture effect of BPNs in osteoporosis1st landmark study – Fracture intervention Trial (FIT)• Multicentered• Prospective study• 3658 women at risk of osteoporotic fractures• Blind & Randomized to receive alendronate or placebo for 3-4 yrs• Main end point- presence of vertebral fracture

o Clinically evident vertebral fracture or loss of >20% vertebral body on lateral x-ray• 8% presented radiographically evident vertebral fracture compared to 15% in placebo• Secondary end point- reduction in risk of developing any fracture in alendronate group

(2.3% Vs 5%)• Over all numbers of hip & wrist fractures decreased in alendronate group

These trials assessing antifracture effects of BPNs suggestsAlendronate, risedronte & zolendronic acid decrease fracture risk

• Spine• Non vertebral site• Hip

Ibandronate reduces risk only in vertebral fracturesGeneral observation of these investigations

Efficacy in fracture risk reduction depends on patient’s risk profile• Patient with higher Fracture risk presented a higher absolute risk reduction.

Benefits of BPNs in patients with osteoporosisIncidence of hip fracture in USA decreases when treated with BPNs(1996 -2007)Other investigations showed reduction in morbidity, reduced health care costs,

reduced mortalityUse of BPNs oral/IV upto 3 yrs

• Decreases mortality up to 28% in low energy hip fracturesAdjusted reduction risk of mortality in men & women using BPNs for 5 yrs is 27%Bolland et al.

• Conducted meta-analysis in 2010• Showed use of antiresorptive therapies in osteoporosis including BPNs for at least 1 yr is

associated with decreased mortality in elderly patients at high risk of fracture

2. OSTEOPOROSIS IN MEN & GLUCOCORTICOID USE:High prevalence of hip fractures in men (25%- 30% of all hip fractures)

• Significant because 1- year mortality doubles after hip fracture 2 trials focused on male population showed

• Increased bone density• Reduction in bone turnover markers & fracture events• Difficulties still exist in treatment

o Evidence is scarceo Lack of agreement about definition of disease & best time to start therapy

Patients taking glucocorticoids therapy• known to develop osteoporosis as direct secondary effect• Fracture incidence- 1.3 50 2.6 times higher • Alendronate & risedronate- FDA approved for this clinical indication• Data are scarce but 2PCRTs proved risedronate’s efficacy with 70%

reduction in vertebral fractures • Data for alendronate also comes from 2 PCRTs• Increased bone mineral density & decreased fracture risk are significant

only when combining data from both studies• Recommended to start early treatment as prevention plan

3. METASTATIC DISEASE OF BONE40% -90% of patients with carcinoma (breast, lung, kidney, prostate, thyroid)

develop skeletal metastasisMetastatic tumors more common than primary (25:1)Skeleton is 3rd most common place for metastesisBPNs included in standard care

Effective in inhibition of osteoclastic activity correlated with trends of increased survivalReduction in local release of growth factor

Pain & pathological fractures in Oncologic Patients

Cochran Breast Cancer Group reported review in 2012assessed effect of BPNs & other agents in terms of

• Skeletal events• Bone pain• Quality of life• Recurrence• Survival in women with breast cancer without clinical evidence of bone metastasis

34 PCRTs comparing BPNs with placebo, other BPNs & donesumab, & early versus delayed treatment in the scenarios described earlier included• Total sample of 2865 patients with breast cancer with bone metastasis • BPNs reduced risk of skeletal events by 15% compared to placebo • Most beneficial were IV- zoledronic acid, pamidronate, ibadronate

BPNs reduced risk of skeletal events in 12 studies(median reduction-28%)Significant improvement of bone pain with BPNs use(611 studies)2 studies showed improvement in quality of life

20 trials done involving 6692 patients with multiple myeloma• BPNs reduce risk of vertebral fractures & bone pain• Zolendronate proved to be better than etidronate & placebo

o Not superior to pamidronate or clodronate for survival increase, vertebral/ non vertebral fracture

The American society of clinical oncology published guidelines in 2011 for breast cancer states• “bone-modifying agent therapy is only recommended for patients with breast cancer with

evidence of bone metastasiso Denosumab 120mg S/C every 4 weekso IV pamidronate 90mg over no less than 2 hrs or zoledronic acid 4mg over no less than 15

mins every 3-4 weekso This is insufficient to demonstrate greater efficacy of one bone-modifying agent over

another”

Current recommendation• No use of BPNs in patients without metastatic disease• New evidence from trials using clodronate in lymph node positive & bone marrow

involvement showso Reduction in skeletal / nonskeletal metastasiso Prolongation of disease free periodo Increase overall survival

Several recent publication reported benefit of BPNs in bony metastasis• Increased bone density• Fracture risk reduction• Decreased bone pain

Neoplastic Hypercalcemi:

Hypercalcemia of malignanvcy-Most common complication of advanced cancerAffects 20% patientsMost common in patient with

Multiple myelomaMetastatic carcinoma of lung, breast, kidney

Main mediators of this processParathyroid related hormone related peptideCytokines produced by tumors

Mediators increase production of receptor activator of nuclear factor kappa-B ligand in osteoblasts

Ligand attaches to RANK receptor of osteoclast

Activates c-Fos & TRAF6 cascades

Triggers osteoclastic bone resorptionOsteoblasts produce osteoprotegerin(OPG) Inhibits RANK receptor activation by

binding to RANK ligandThis regulations system is affected as malignant cells overstimulate osteoblasts (PTHrP) with

RANK ligand productionOsteoblasts can’t produce enough OPG increase in osteoclastic activity

BPNs therapy - most effective 2 prospective randomized trials

Pamidronate(90mg, 2hrs infusion) effective & safeZolendronic acid (4mg or 8mg, 5-minute infusion) More Trend of zoledronic acid use as administration more convenient

4. PAGET DISEASE (Osteitis deformans):Incidence of 3.3% in patients older than 40 yrsCause is unknownStrong family history as 40% of affected have 1st degree relative with diseaseIn study of single large family

Pattern of transmission- autosomal dominantRegion on chromosome 18 strongly associated

Viral infection- suggested as a causeParamyxovirus-like nuclear inclusions – identified in osteoclasts of patients

with disease

Paget disease characterized byLocalized & accelerated bone resorption

f/byIneffective & random dense bone matrix deposition

SymptomsBone painHeadacheNeurological symptoms secondary to peripheral & central nerve compression

Use of Calcitonin & BPNs – successful in treatmentBPNs used are

EtidronateAlendronateTiludronate oral BPNsRisedronatePamidronte – IV

Optimal dosage & treatment – controversialMild disease – 60mg infusion over 3-4 hrsModerate to severe –weekly/biweekly 60mg infusion with cumulative doses

up to 400mg Oral dose- alendronate 40mg daily for 6 months

• Clinical evaluation & measurement of Alkaline phosphatase

5. Osteogenesis Imperfecta:Affects type I collagenSymptoms

OsteopeniaLow-energy fractureProgressive deformityLoss of mobilityChronic bone pain

Traditionally 4 subtypes according to clinical presentation, genetics, severity

V – VII addedNo type 1 mutation

Past treatment Pain controlSurgical management of deformities

Recent publication showsBPNs use is effective in treatment

Landmark study by Glorieux et al (1998)Uncontrolled observational study in 30 childrenAge 3 to 16 yrsIV pamidronate

• Recommended dose- 0.5 – 1.5 mg/kg• Effective in maintain sustained reduction of S.alkaline phosphatase• Increased bone mineral density• Increased bone cortical thickness on X-ray• Decreased fracture rate & pain• Improved walking

Some patients may require osteotomies for associated deformitiesStudy by Munns et al

Retrospective studyModerate to severe OIEvaluated factors influencing fracture & osteotomy site healingPamidronate use

• delayed osteotomy healingo Older ageo Ostotomies at tibia

• No delay in fracture healing

BPNs are not curativeDo not alter/modify genetic defectOptimal doses & regime- unclear

6. Osteolysis in Arthroplasty:Recently increased number of arthroplastys

Increases complication• Loosening• Periprosthetic fractures

Failure of component is secondary to bone lossMechanism of bone loss

Wear- debries osteolysis• Macrophages that absorb small particle of wear debries activate osteoclasts to start bone

resorption through RANK/RANK ligand systemStress-shielding forcesimmobilization

Use of BPNs has shown to stop RANK/RANK ligand system (in primary results)Skoldenberg et al reported in 2011 (PCRT)

73 patients (age: 40-70 yrs)35mg Risedronate or placebo givenPrimary end point- change in bone mineral density (Gruen femoral zones 1-7)Patients evaluated at 2 days & at 3, 6, 12, 24 monthsSecondary end point-

• stem migration • Clinical outcomes

Result:• Higher mineral bone density at 6 months (7.2%) & 1 yr (9.2%) in zone 1 & 7 taking BPNs• Migration of femoral stem & clinical outcomes didn’t differ between groups.

2 other PCRT showed similar findingsOne PCRT (10mg alendronate during 1 yr) showed:-

• Increased bone mineral density at 1 yr in distal femur & proximal tibia• Reduction in bone loss during immediate postoperative period in TKR

Second PCRT (90mg pamidronate IV- 5 days after THR) showed:• Reduction of markers of bone turnover in urine & serum

Insufficient data to support use of BPNs to prevent progression of osteolysis around implants, once identified

7. PEDIATRIC DISORDERS:Use of BPNs in pediatric group is controversialProlonged use of BPNs- associated with brittle bonesReport by Whyte et al (2003)

Patient with secondary osteopetrosis due to BPNs useReceived 60mg pamidronate every 3 weeks for 2.5 yrsResult

• Increased bone density • Persistent defective remodeling for > 18 months after treatment discontinued

Guidelines of treatment based on safe & well monitored clinical studies needed

Osteoporosis in childrenPrimary uncommonIdiopathic juvenile osteoporosis(primary)

Occurs in prepubertal childrenNo history of bone diseaseCharacterized Clinically by

recurrent low energy fracture in vertebral bodies or metaphysis Bone painkyphosis

formation of new osteoporotic bone without callus formationGradual remission after onset of puberty

BPNs useful forBone pain controlReduction of fractureIncreased bone mineral density

Sebestyen et al in 2012Treating idiopathic juvenile osteoporosis

• Associated with vertebral fractures• Depended on narcotic medication• Spine brace immobilization

IV zolendronic acid use successfully discontinued narcotic medication & Spinal brace use• No affect on fracture healing

Secondary osteoporosis More prevalenta) Glucocorticoid-induced

Increase osteoclastogenesisReduce intestinal calcium resorptionIncreased renal calcium excretionBone loss in 6-12 months of useVertebral fractures- most common

Reyes et al in 200755 children & 2 yr follow-upGlucocorticoid – induced osteoporosisShowed• High risk of osteoporosis

oNonambulatoryoGrowth-retarded oLong term methotrexate therapyoFamily history

Treated with alendronate in vertebral fracture for 2 years• Improved bone mineral density

b) Associated with immobilizationDevelops in

• Cerebral palsy• Condition confining to bed or wheelchair

Osteoporosis secondary to• Impaired weight-bearing ambulation• Lack of muscular forces of bone• Inadequate nutrition• Low calcium & Vit D intake• Use of anticonvulsant therapy

10 yr follow-up study showed• Reduced fractures rate at 1 year in nonambulatory patient with cerebral palsy

o Reduction maintained for 4 yearso Subset patients sustained fracture after discontinuation of BPNs

Randomized study with 13 adolescents with crohn diseaseRandomized to saline infusion or Zoledronic acid(1 dose of 0.066 mg/kg)At 6 months follow up

• Increase in lumbar spine bone mineral density in BPNs groupo Still present at 12 monthso Decreased urinary C telopeptide excrition

Fibrous Dysplasia & McCune-Albright Syndrome:Fibrous dysplasia:-

Production of fibrous tissue & woven bone at site where normal bone should developProne to fractures

Osteolytic lesions affecting ribs, craniofacial & long bonesCharacteristic defect is somatic mutation in gene coding for alpha subunit of G

protein that stimulates production of cAMPOver production of cAMP generates c-fos gene overexpression, which is an

important regulator in osteoblastic/ osteoclastic proliferation & differentiationExcessive osteoclastic activity is targated with BPNsClinical trials with IV pamidronate showed

Improvement in painIncreased N-telopeptide valuesOn radiograph- cortical thickening & progressive ossification seenResults in children less consistence

Legg- Calve-Perthes:Infant form of osteoporosis of femoral headIncidence- 8.5 to 21 per 100,00 per yearMost serious sequel

Femoral head deformity secondary to subchondral collapse, leading to early degenerative arthritis

Osteoclastic activity mediates subchondral collapseScarce literature

Only 3 level IV studies evaluating effect of BPNs Only 1 study used BPNs in precollapse stage

• Prevention of femoral head deformity obtained in 9 of 17 patients

SUMMARY

Bisphosphonates1st line of therapy in most patients with osteoporosis

• Use in orthopaedic condition increased in last decadedecrease risk of fracture in hip ,spine & other nonvertebral sites in osteoporotic patients cost-effective Effective in decreasing mortality & increasing survival in osteoporotic patientsProtective effect continues for long term therapy in osteoporotic patientsBenefits outweighs risk of adverse effect, which are uncommon but are becoming more

noticeable because of current widespread useIndications for use are increasing because good results are obtainedResults in treating increased osteoclastic activity & decreased bone mineral density are

promising

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