Bisphosphonates for osteoporosis where do we go from here? is bisphosphonates road to block osteoporosis safe dr.sandeep c agrawal agrasen hospital gondia india www.agrasenortho.com

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
drsandeep123@gmail.com
www.agrasenortho.com
09960122234
Osteoblasts
Osteoclast
Lining cells
Inhibitors of
RANKL
Cathepsin K
THE BISPHOSPHONATES “DRUG HOLIDAY”

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

5
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

6
6

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
Osteoblasts
Osteoclast
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)

22
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

24
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

25
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

26
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.

27
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 RELATED 
OSTEONECROSIS 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

31
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

32
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.

33
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

35
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

37
— 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
or
T 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)

42
*
*Use FRAX to estimate risk

43
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

44
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.

45
Hot topics

46
- 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

47
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

50
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

51
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 illness
Headache Arthralgia
1 2 3 1 2 3 1 2 3 1 2 3 1 2 3
Incidence(%)
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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