Bisphosphonates for osteoporosis where do we go from here? is bisphosphonates road to block...

Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!

Is Bisphosphonates Road To Block Osteoporosis Safe ?

Bisphosphonates for Osteoporosis — Where Do We Go from Here?

Dr.Sandeep Agrawal Consultant Orthopedic Surgeon

MS,DNB

Agrasen Hospital Gondia

Maharashtra

India [email protected]

www.agrasenortho.com

09960122234

OsteoblastsOsteoclast

Lining cells

Inhibitors of RANKL

Cathepsin K

THE BISPHOSPHONATES “DRUG HOLIDAY”

http://www.agrasenortho.com


PHARMACOKINETICS

Inverse relation between pharmacologic activity & oral bioavailability!

!Absorption by passive diffusion from gut!

!Milk & dairy products, orange juice, coffee and calcium and iron

products reduce absorption (Form insoluble complexes)!!

Bound to plasma proteins!!

20-80% of the absorbed dose is rapidly taken up by bone. !

Remainder is rapidly excreted in urine!!

Long skeletal retention (half life up to 10 years)



TYPES OF BISPHOSPHONATES

NON-NITROGENOUS

Olpadronate

NITROGENOUS

Tiludronate

Clodronate

Etidronate

Alendronate

Neridronate

Pamidronate

Risedronate

Ibandronate

Zoledronate



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Bisphosphonates – Antiresorptive Agents

FDA-approved for: Prevention and treatment of osteoporosis in

postmenopausal women !

Treatment to increase bone mass in men with osteoporosis

!

Treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids

!

Treatment of Paget’s disease of bone in men and women



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7

Bisphosphonates – Dosing

Alendronate* Prevention

5 mg PO daily 35 mg PO weekly

Treatment 10 mg PO daily

70 mg PO weekly 70 mg/2,800 IU vitamin D PO

weekly Risedronate

Prevention/Treatment 5 mg PO daily

35 mg PO weekly

Ibandronate Prevention/Treatment

2.5 mg PO daily 150 mg PO monthly

Treatment 3 mg IV every 3 months



High attraction for hydroxyapatite crystals and thus rapidly included into all parts of

skeleton !

Used as inhibitors of osteoclastic activity to alleviate bone pain that results from release of biochemical mediators in

metastatic bone disease



Anti-resorptive

Anabolic

‘Dual action’

!Alendronate inhibits the osteoclastic bone resorption!without inhibiting the osteoblastic bone formation –!

increase in bone mass

Mode Of Action



10

Osteoporotic bone remodelling



!Hwang and Wang, 2007



12

Bone Remodelling With Alendronate

Gets preferentially bound under osteoclasts. !

Osteoclasts ingest the attached alendronate. Released alendronate inactivates the osteoclasts.

!Bone resorption inhibited.

Alendronate may reduce the number of remodelling sites



OVERALL EFFECT:!!

Less trabecular thinning !

Decreased number of trabecular perforations

!

Smaller erosion of cortex !

Slowing down decrease in bone strength and occurrence of fractures



MECHANISM OF ACTION



Bone marrow precursors

OsteoblastsOsteoclast

Lining cells

Stimulators of Bone Formation Fluoride PTH analogs Sr Ranelate (?)

Inhibitors of Bone Resorption Estrogen, SERMs Bisphosphonates Calcitonin

Inhibitors of RANKL

Cathepsin K

Therapeutic strategies



19

Bisphosphonates – Administration

Must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only

(1 hour prior for monthly ibandronate) !

Should only be taken upon arising for the day !

Tablet should be swallowed with a full glass of water (8 oz) and patients should remain upright, walking, standing, or sitting for at

least 30 minutes (60 minutes for monthly ibandronate)

!Should supplement with calcium/vitamin D if dietary intake

inadequate



20

Bisphosphonates – Missed Dose

Once weekly alendronate, risedronate Take on morning after remembering, then resume

once weekly on regularly chosen day !

Once monthly ibandronate If next dose > 7 days away, take dose the morning

following the date remembered Then return to original schedule

If next dose < 7 days away, wait until next scheduled dose

Must not take two 150 mg tablets within the same week



21

Bisphosphonates – Adverse Effects

Hypocalcemia (18%) !

Hypophosphatemia (10%)

!Musculoskeletal pain, cramps – recent FDA

warning

Gastrointestinal Abdominal pain

Acid reflux Dypepsia

Esophageal ulcer Gastritis

!Osteonecrosis of the jaw (IV

bisphosphonates) Visual disturbances (rare)



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Contraindications/Precautions

!Abnormalities of the esophagus which delay

esophageal emptying, such as stricture or achalasia !

Inability to stand or sit upright for at least 30 minutes !

Patients at increased risk of aspiration !

Hypocalcemia: Should be corrected prior to initiating therapy

!Renal insufficiency (Not recommended if CrCl <

30-35 ml/min)



Contraindications



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Zolendronic Acid

Approved for osteoporosis treatment in postmenopausal women in August 2007

!Single 5 mg infusion given IV over > 15 minutes, once

yearly !

Should still supplement with calcium/vitamin D !

May be ideal for those with GI contraindications to the oral formulations



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Bisphosphonates – Clinical Efficacy

Controlled clinical trials indicate over 3-4 year period, alendronate ↑ bone mass and ↓ incidence of vertebral, hip, and all non-

vertebral fractures by 50%!!

Controlled clinical trials indicate risedronate ↑ bone mass and ↓ risk of vertebral fractures by 40% and non-vertebral fractures by

30% over 3-year period!!

Ibandronate has been shown in controlled clinical trials to ↑ BMD and reduce the risk of vertebral fracture by 50% over 3-year period!

!Alendronate appears to be well tolerated and effective for at least

ten years



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Bisphosphonate Therapy - Risks

Initial studies taken to the FDA to gain approval for these drugs identified a lower than expected

risk of GI side effects No unexpected side effects were seen in these

studies However, about 15 years ago, cases of

osteonecrosis of the jaw which dentists had not seen for a least a century, began to appear

Subsequently, the possibility of an increased risk of atypical femur fractures in patients treated

with these drugs was proposed.



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Osteonecrosis Of Jaw

Exposed necrotic bone in the maxillo-facial region

Not healing after 6-8 weeks in patients with no hx of craniofacial radiation

Exposed yellow-white hard bone with smooth or ragged borders, often in the site of dental extraction or other invasive dental procedure

with poorly fitting dentures Over 90% of reported cases in cancer

patients receiving BP doses 10X higher than used to treat osteoporosis Estimated incidence in OP:

1:10,000-1:100,000

Khosla et al. ASBMR Rask Force, JBMR 2008;23:159. Woo S-B et al, Ann Intern Med 2006;144:753-761.



BISPHOSPHONATE RELATEDOSTEONECROSIS OF THE JAW (BRONJ)

!

Patients may be considered to have BONJ if they have exposed bone in

the maxillofacial region for at least 8 weeks, are currently on or have

taken bisphosphonates and have no history of radiotherapy to the jaws

(AAOMS )



WHY DOES BONJ ONLY AFFECT THE MAXILLOFACIAL SKELETON

BPs accumulate in high turnover areas like mandible than elsewhere.!

!As a result of trauma or infection bone

cannot respond adequately.!!

Masticatory Forces!Chronic Low Grade Trauma!

Unable to repair micro-fractures!Necrotic Bone!

Bony sequestrum



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Femoral Shaft Fractures

In 2005, Odvina et al reported a series of nine patients with spontaneous, atypical fractures, all on bisphosphonate therapy for a period of

time ranging from 3 to 8 years. Four with fractures in the subtrochanteric region and one each with fractures of the

sacrum, rib, ischium, pubic rami and lumbar spine.

6/9 had delayed or absent healing during management.

Histology revealed over suppression of bone turnover, possibly linked to bisphosphonate usage, but other factors, i.e.. estrogens and

glucocorticoid use left much room for debate.

Odvina et al JCEM2005;90:1294–1301



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Atypical Fractures of the Femoral Diaphysis in Postmenopausal Women Taking Alendronate. Lenart, Brett; Lorich, Dean; Lane, Joseph !New England Journal of Medicine. 358(12):1304-1306, March 20, 2008.

Radiographs of Fractures of the Femoral Shaft Showing the"Simple with Thick Cortices”

!Pattern Panel A shows a fracture of the femoral shaft

in an 83-year-old woman with a 9-year history of alendronate use. Panel B shows a similar fracture in a

77-year-old woman with a 5-year history of alendronate use.



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Femoral Shaft Fractures

Usually occur in the proximal third of the femoral shaft !

May have a prodrome of thigh pain !

Often bilateral or sequential !

X-rays prior to fracture may reveal some beaking of the cortex and cortical thickening of the proximal femoral

shaft !

Early identification may require intervention – but exactly what is unclear



34

Atypical Femoral Fracture

Shane et al, JBMR 25:2010;25:2267–2294.

Conventional AP radiograph of the pelvis (A) shows bilateral focal cortical thickening from periosteal new bone formation (arrows). Corresponding bone scintigraphy (B) demonstrates focal increased radionuclide uptake in the proximal lateral femoral cortices (arrows). MRI images of the femurs (C) demonstrate subtle decreased

signal on T1-weighted and increased signal on T2-weighted images only of the right femur on!

this section. Similar findings on AP DXA hip images (D) show focal bilateral cortical thickening consistent with early, evolving femoral insufficiency fractures.

A B

DC



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Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures

in Older Women

L. Park-Wyllie, PharmD, MS, M. Mamdani, PharmD, MA, MPH, D. Juurlink, MD, PhD, G. Hawker, MD, MSc, N. Gunraj, MPH, P. Austin, PhD, D. Whelan, MD, MSc, P. Weiler, MD, MASc, P Eng. Laupacis, MD, MSc

JAMA. 2011;305(8):783-789

Population-based, nested case-control study in a cohort of women aged 68 years or older from Ontario, Canada treated with oral bisphosphonate between April 1, 2002, and March 31, 2008. Primary analysis - association between hospitalization for a

subtrochanteric or femoral shaft fracture and duration of bisphosphonate exposure

Secondary analysis - association of bisphosphonate use and classic intertrochanteric or femoral neck fractures



36

Summary

716 (0.35%) suffered a subtrochanteric or femoral shaft fracture after receiving

bisphosphonate therapy. Cases were matched with 3580 controls

Bisphosphonate treatment to prevent typical femoral fractures should last at

least 5 years. Bisphosphonate treatment for more than 5

years begins to increase the risk for atypical femoral shaft fractures which are

still extremely rare.

JAMA. 2011;305(8):783-789



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Bisphosphonates for Osteoporosis — Where Do We Go from Here?

Available data do not identify patients likely to benefit from treatment

beyond 3-5 years. !!!

… decisions to continue treatment must be based on individual

assessment of risks and benefits and on patient preference.

NEJM 366:2048, 2012



38

How Long to Treat With Bisphosphonates?

1.Patients who did not need treatment in the first place Discontinue Treatment

!2.Lower risk patients, if DXA is stable/increasing

Consider a drug holiday after 3-5 years of treatment !

3.Higher risk patients (fractures, corticosteroid Rx, very low BMD)

Consider a drug holiday after 10 years of therapy !

4.May use teriparatide or raloxifene (but not another potent antiresorptive agent – ie. denosumab) during

the holiday from bisphosphonates

Watts and Diab JCEM, 2010 95:1555.


Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!39

Whom to treat ?

Prior h/o hip/vertebral #

or

T Score < -2.5

orT Score -1 to -2.5 & 10 yr risk (FRAX) :

HIP # > 3 % or major osteoporotic # > 20 %

Postmenopausal women /men > 50 yrs

with



40

Proposed Guidelines for Use of Bisphosphonates

1.Patients with bone density T-scores of -2.5 or lower at femoral neck after 3 to 5 years of treatment at highest risk for vertebral

fractures and appear to benefit most from continued therapy (for up to 10 years).

!2.Patients with an existing vertebral fracture and T-scores up to

−2.0 may also benefit from continued therapy. !

3.Patients with femoral neck T-scores above −2.0 have low risk of vertebral fractures and are unlikely to benefit from continued

treatment after 3-5 years.

Black et al. 2012, NEJM 366:2051



THE “DRUG HOLIDAY”

Suggested that cessation of the BPs allows regeneration of osteoclasts and some improvement in bone turnover.!

! For patient who has been taking an oral BP longer than

3years, it should be discontinued, 3 months before and 3 months after the surgical procedure, if approved by the

patient’s physician.! !

Serum C-telopeptide (CTx) levels should be greater than 150 pg/mL before any surgical procedure, and rechecked

at the time of surgery. ! (Lam DK, Sandor

GKB 2007)



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*

*Use FRAX to estimate risk



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NOF’s Clinician’s Guide

Applies the recently released algorithm on absolute fracture risk call FRAX® by the WHO!

!Also called 10-year fracture risk model and 10-year

fracture probability!!

Estimates the likelihood of a person to break a bone due to low bone mass over a period of 10 years!

!Most useful to determine if treatment needed for those

with low bone mass or osteopenia!!

http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=2

43


http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=2


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When Should the Holiday End?*

Arbitrary* - Longer for drugs with highest skeletal affinity (zoledronic acid), shorter for drugs with lowest

skeletal affinity (risedronate)? !

Many patients will have been on more than one - complicating matters.

!Some use bone turnover markers (measure degree of active bone resorption) – but which ones and what cut

off values to use is unclear. !

There is no good evidence here. BMD – If significant decrease seen with annual testing

Watts and Diab JCEM, 2010 95:1555.

* To quote Dr. Watts himself, this is an evidence free zone.



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Hot topics



46

Bisphosphonates for Osteoporosis - Summary

Risk/Benefit Ratio – favorable for most high risk patients

!Length of treatment depends upon fracture risk

!Risks of ONJ and AFF (Atypical Femoral Fracture)

may increase after 5 years but risk is low !

What to do about ONJ and AFF? ONJ: Look in the mouth

!AFF: Instruct patient to report thigh/groin pain and

investigate if clinically indicated. Review films of any reported femur fracture



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www.hormone.org



48

No known Metabolism of the drug in Vivo!!

Remains in body for ever and goes for recycling?!!

Insufficiency fractures!!

Immediate Osteoclasts apoptosis!!

Osteoblastic activity continues!!

Mineralization and maturation take long time!!

Increased BMD is due to non absorption of hydroxyapatite and continued mineralization!

!Increased mineral content with diminished elasticity, increased

brittleness

Hidden Truth Of Alendronate



49

Bisphosphonate Therapy Benefits

Decreased risk of breast cancer !

Decreased risk of colorectal cancer !

Decreased risk of stroke !

Decreased risk of gastric cancer !

Decreased overall mortality

Nelson Watts – Endocrine Society National Meeting - 2012



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A single infusion of ZOLENDRONATE 5 mg reduced bone resorption marker rapidly than weekly oral ALN 70 mg

(Urine NTX) (Serum β-CTX )

* P<0.0001; †P<0.05, for relative change from baseline, ZOL vs ALN; NTX: urine N-telopeptide; β-CTX: Serum β-C-telopeptide of type I collagen



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Safety: Five most common Post-Dose Symptoms (≤ 3 Days After

Infusion) and declined markedly with subsequent infusions

0

2

4

6

8

10

12

14

16

Annual Infusion

Pyrexia

Myalgia

Flu-like illnessHeadache Arthralgia

1 2 3 1 2 3 1 2 3 1 2 3 1 2 3

Inci

den

ce (

%)

15%

2%

1%1% 2%

1%2%

1%2%

1%

8%7%

6% 5%

Placebo values cross-hatched

1%

Treatment with antipyretic analgesics appeared to mitigate these symptoms2 Acetaminophen four times/day for 3 days significantly reduced the incidence and

severity of post-dose symptoms following ZOL infusion3



Reduce frequent dosing with bisphosphonates may improve compliance as an important thing for the

success of osteoporosis treatment.!!

Six years of annual ZOL 5 mg infusion preserves bone mass and discontinuation after 3 years still provided residual benefit of fracture protection.!

!It may be beneficial for some women, particularly those at high vertebral fracture risk, to continue

ZOL for an additional 3 years

1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242



•Herbert Fleisch. Bisphosphonates: Mechanisms of Action. Endocrine Reviews 19(1): 80–100.

•M.D. Francis,D.J. Valent J. Historical perspectives on the clinical development of bisphosphonates in the treatment

of bone diseases. Musculoskelet Neuronal Interact 2007; 7(1):2-8.

•Angelo Mariotti. Bisphosphonates and Osteonecrosis of the Jaws.

•Carol Tekavec, CDA, RDH. Bisphosphonates. Journal of the American Dental Association in August 2006.

•Howard C Tenenbaum et al .Bisphosphonates and periodontics : potential applications for regulation of bone mass

in the periodontium and other therapeutic/ diagnostic uses. JOP 2002;73:813-822.

•R. G. G. Russell, N. B. Watts, F. H. Ebetino, M. J. Rogers. Mechanisms of action of bisphosphonates: similarities

and differences and their potential influence on clinical efficacy. Osteoporos Int (2008) 19:733–759.

•American Association of Oral and Maxillofacial Surgeons. Position Paper on Bisphosphonate-Related

Osteonecrosis of the Jaw—2009 Update.

!

REFERENCES



Thank you

Keep your bone healthy



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Bisphosphonates for osteoporosis where do we go from here? is bisphosphonates road to block...

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Transcript of Bisphosphonates for osteoporosis where do we go from here? is bisphosphonates road to block...