Aromatase inhibitors (AI) stimulate resorption-mediated bone loss

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Aromatase inhibitors (AI) stimulate
resorption-mediated bone loss

• Lower endogenous estrogen levels (eg, E2 lt10
  pg/ml) during postmenopause are related to
• - higher biochemical indices of bone resorption
• - lower BMD at spine, proximal femur, distal
  radius
• - greater decrease in BMD over 36-39 months
• - more fractures??
• AI cause a decrease in circulating estrogen
  levels (E1gtE2), thereby increasing bone
  resorption indices and BMD loss

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Effect of 6 months of treatment with placebo or
letrozole on urinary total deoxypyridinoline, a
marker of bone resorption, in late postmenopausal
women
J Bone Miner Res 2002 17 176
3
 Lumbar spine (A) and total hip (B) bone mineral
density change () after 1 year in
anastrozole-treated breast cancer patients either
on risedronate 35 mg/wk (n  11) or no
bone-specific treatment (n  90), vs. a control
population (n  114).
Confavreux et al, Bone 2007 41 346-52
4
Prevention and treatment of AI-induced bone loss
should focus on resorption-inhibition

• Available antiresorptive (anticatabolic)
  therapies
• Calcium and vitamin D
• Estrogen not an option in AI-treated women
• SERMs not a logical option in AI-treated women
• Bisphosphonates

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The need for calcium and vitamin D

• Why do postmenopausal women need extra calcium
  and vitamin D?
• ? because many women on a Western style diet
  are relatively calcium- and vitamin D-deficient
• What is the mechanism to explain the
  antiresorptive effects of calcium and vitamin D?
• ? because both calcium- and vitamin D-deficiency
  cause secondary hyperparathyroidism
• ? continuous hypersecretion (unlike
  discontinuous administration) of PTH stimulates
  bone resorption and bone loss

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Vitamin D status in osteoporotic women results
of a multinational study
Lips et al, J Intern Med 2006 260 245-54
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Current calcium intake is below the recommended
allowance in Belgian women

• Comparison with late Stone Age1
• - Ca intake derived from uncultivated plant
  foods (90 mg Ca/100 g, for 1000Kcal ?907 mg Ca)
  and insects (up to 129 mg Ca/100 g, for 1000Kcal
  ?up to 714 mg Ca)
• - wild game contains little Ca (14 mg Ca/100 g,
  for 1000Kcal ?107 mg Ca)
• Current Ca intake depends
• - almost entirely on dairy products
• - on (perceived) health factors lactose
  intolerance
• - on cultural factors milk(-derived products)
  as an accepted drink
• - on use of nutritional supplements
• On average, Ca intake in Belgian women is 600-700
  mg/day
• Recommended daily allowance 1200 (1500) mg Ca
  for postmenopausal women

1Am J Clin Nutr 1991 54 281-7S
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Vitamin D deficiency no sun, no fish

• Level of insufficiency is defined by 25(OH)D
  level
• 30 ng/ml (75 nmol/l) sufficient
• 20-29 ng/ml (50-74 nmol/l) suboptimal or
  insufficient
• lt20 ng/ml deficient (lt10 severely deficient
  10-19 mildly deficient)
• Groups among adults at special risk include
• - age 70 years (less time in sun, less skin
  synthesis)
• - obesity, previous bypass surgery
• - immigrant women (traditional clothing, less
  time in sun, skin pigmentation, poor vitamin D
  intake)
• Vitamin D deficiency is no argument against safe
  sun practices!
• Vitamin D intake fatty fish (salmon, sardines,
  mackerel, tuna)
• egg yolk

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Vitamin D status in osteoporotic women results
of a multinational study
Lips et al, J Intern Med 2006 260 245-54
12
Effect of calcium or calciumvitaminD on fracture
risk in people aged 50 y a meta-analysis
Tang et al, Lancet 2007 370 657-66
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No difference between calcium alone vs.
calciumvitaminD on fracture risk in people aged
50 y a meta-analysis
Tang et al, Lancet 2007 370 657-66
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Meta-analysis on effect of calcium and vitamin D
supplementation on fracture risk subgroup
effects

• Age (y) 50-69 (n36640) RR 0.97(0.92-1.02) NS
• 70-79 (n12481) RR 0.89(0.82-0.96)
• 80 (n3504) RR 0.76(0.67-0.87)
• Setting community (n49223) RR
  0.94(0.90-0.99)
• institutionalized(n3392) RR 0.76(0.66-0.88)
• Compliance 80 (n4508) RR 0.76(0.67-0.86)
• 60-69 (n3511) RR 0.92(0.71-1.19) NS
• 50-59 (n44494) RR 0.96(0.91-1.01) NS
• Ca intake lt700mg/d (n7272) RR
  0.80(0.71-0.89)
• 700mg/d (n45241) RR 0.95(0.91-1.00)
• Ca dose lt1200mg (n47359) RR 0.94(0.89-0.99)
• 1200mg (n5266) RR 0.80(0.72-0.89)
• VitD dose lt800 IU (n 36671) RR
  0.87(0.71-1.05) NS
• 800 IU (n 9437) RR 0.84(0.75-0.94)

Tang et al, Lancet 2007 370 657-66
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Threshold curves for adults showing
diagrammatically why, in studies testing the
hypothesis that augmented calcium intakes will
improve calcium retention (or its concomitants,
bone mass and bone strength), one of the contrast
groups must have an intake below the threshold
value
Heaney, Am J Clin Nutr 2007 84(Suppl) 300-3S
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Bone health derived from Ca and vitD in
postmenopausal women using AI

• Anti-fracture effect of Ca and vitD is likely
  small in the 50-69 y age group, but nonetheless
  clinically worthwhile and recommended in this
  high-risk population
• VitD without calcium very likely has no benefit
  on fractures1
• Minimum dose 1000 mg Ca 800 IU vitD
• Risk of kidney stones is slightly increased (RR
  1.17, 1.02-1.34), watch out for excessive Ca
  intake (2.5 g/day)
• The 800 IU vitD dose is very safe, yet watch out
  for vitamin D intoxication (25 OH D 150 ng/ml)
• Compliance is of utmost importance to improve
  compliance,
• - perform bone densitometry and discuss results
  with patient (women with osteopenia/osteoporosis
  are more likely to increase Ca intake2)
• - nutritional intervention/counseling is more
  effective than prescribing calcium
  supplementation

1Boonen et al, J Clin Endocrinol Metab 2007 92
1415-23 2McLeod et al, J Nutr 2007 137 1968-73
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Nutritional intervention is more effective than
providing a calcium supplement

• Greek trial1 in 101 postmenopausal women with
  baseline Ca intake of 500-700 mg/d 1) control
  2) 600-mg calcium supplement 3) nutritional
  intervention (milk and yogurt fortified with Ca
  and vit D biweekly education sessions)
• ?Modified Ca intake was similar by 2
  interventions (1100-1200 mg), and energy intake
  was similar, but dairy intervention also
  increased P, vitamin D and protein intake
• ?Dairy intervention increased IGF-I levels
• ?Dairy intervention, but not calcium
  supplementation, increased BMD at the spine,
  pelvis and whole body after 12 months, and was
  more effective than Ca supplementation

1Manios et al, Am J Clin Nutr 2007 86 781-9
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Potential benefits of calcium and vitamin D other
than its anti-osteoporotic effect

• Early postmenopausal women with a low Ca intake
  are more likely to be overweight1
• Postmenopausal women on adequate Ca and vitamin D
  experience less weight gain (WHI randomized
  trial2)
• Possibly decreased incidence of cancer in
  postmenopausal women on calcium and vitamin D
• (randomized trial3 in Nebraska, USA, in 1179
  women 66 y old on average with no known cancers,
  assigned to placebo, Ca alone, or CavitD)
• Meta-analysis of randomized trials4 shows
  slightly decreased mortality with vitamin D
  supplementation (RR 0.93, 0.87-0.99)

1Varenna et al, Am J Clin Nutr 2007 86
639-44 2Caan et al, Arch Intern Med 2007 167
893-902 3Lappe et al, Am J Clin Nutr 2007 85
1586-91 4Autier Gandini, Arch Intern Med 2007
1671730-7
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Weight change by age in the Womens Health
Initiative trial (n 36 282 women, 50-79 y at
baseline)
Caan et al. Arch Intern Med 2007167893-902
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• Weight change in placebo or calciumvitamin D
  treated postmenopausal women according to
  baseline total calcium intake of lt1200 mg (left)
  vs. 1200 mg (right) in the Womens Health
  Initiative trial

• Caan et al. Arch Intern Med 2007167893-902

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Calcium and vitamin D supplementation reduces
cancer risk results of a randomized trial
(Nebraska, USA)

• Kaplan-Meier survival curves (ie, free of cancer)
  for the 3 treatment groups randomly assigned in
  the entire cohort of 1179 women (mean age 66 y)

Lappe et al. Am J Clin Nutr 2007851586-1591
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Meta-analysis of data on all-cause mortality in
18 randomized controlled trials with vitamin D
(both sexes)
Autier et al. Arch Intern Med 20071671730-7
23
Metabolism of 25-Hydroxyvitamin D to
1,25-Dihydroxyvitamin D for Nonskeletal Functions
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Bisphosphonates in AI-treated women

• When? ?In case of osteoporosis (history of
  fractures, RX diagnosis of fractures, T-score
  lt-2.5 SD at lumbar spine, femoral neck or total
  proximal femur)
• Why use bisphosphonates?
• ?effective to suppress bone remodeling and
  increase BMD in AI-treated women
• ?no known interference with estrogen metabolism
• ?established anti-fracture efficacy in
  postmenopausal osteoporosis
• ?acceptable tolerance, easy intake schedule
• What is their mechanism of action?
• ?bind avidly to hydroxyapatite, incorporate
  during remodeling
• ?reduce osteoclast activity and accelerate
  osteoclast apoptosis
• ?are very poorly absorbed, not at all in
  presence of Ca2 or dairy products

25
Change in serum osteocalcin (A) and CTX (B) bone
turnover markers over 1 year in
anastrozole-treated breast cancer patients on
risedronate (n  11) vs. no bone-specific
treatment (n  88)
Confavreux et al, Bone 2007 41 346-52
26
 Lumbar spine (A) and total hip (B) bone mineral
density change () after 1 year in
anastrozole-treated breast cancer patients either
on risedronate 35 mg/wk (n  11) or no
bone-specific treatment (n  90), vs. a control
population (n  114).
Confavreux et al, Bone 2007 41 346-52
27
Several bisphosphonate compounds are effective in
postmenopausal osteoporosis

• Non-nitrogen-containing
• Etidronate Osteodidronel 400 mg 14d/90d
• Clodronate
• Tiludronate
• Nitrogen-containing
• Pamidronate
• Alendronate Fosamax, Fosavance, Alendronate
  Teva
• 5-10 mg/d po 70 mg/wk
• Risedronate Actonel 5 mg/d po 35 mg/wk po
• Ibandronate Bonviva 150 mg/month po
• Zoledronate Aclasta 5 mg/year iv

postmenopausal osteoporosis is not a valid
indication postmenopausal osteoporosis is a valid
indication
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Bisphoshonates are generally well tolerated

• Side-effects and inconvenience
• - oral compounds upper gastro-intestinal
  symptoms, no difference between alendronate 70
  mg/wk and risedronate 35 mg/wk
• - oral compounds must be taken in fasting
  state, with 8 oz of water, no food for 30-60
  min, no lying down
• - intravenous compounds acute phase reaction
  (fever, myalgia, etc.) in 10- 30 with first
  dose eye reactions
• Complications
• - osteonecrosis of the jaw (ONJ) very rare with
  oral anti-osteoporosis schedules risk factors
  are high-dose parenteral treatment, poor oral
  hygiene, diabetes, and smoking
• - atrial fibrillation (iv zoledronate) 1.3 vs.
  0.5 in placebo group
• - pancreatitis (alendronate po) very rare

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Are the bisphosphonate compounds equally
effective against fractures?

• Analyses of Belgian Bone Club1 HORIZON trial
  data2
• - Alendronate 10mg/d po antifracture effect at
  vertebral nonvertebral sites in osteoporotic
  women
• - Risedronate 5mg/d po similar antifracture
  effect as alendronate, evidence from preplanned
  analyses somewhat less robust
• - Ibandronate 2.5mg/d po antifracture effect at
  vertebral sites, at nonvertebral sites only in
  severe osteoporosis by post-hoc analysis
• - Zoledronate 5mg/y iv antifracture effect at
  vertebral nonvertebral sites in osteoporotic
  women
• From a clinical viewpoint, these compounds are
  largely comparable ibandronate may not be the
  first choice in women with osteoporosis at the
  hip

1Boonen et al, Osteoporos Int 2005 16
239-54 2Black et al, N Engl J Med 2007 356
1809-22
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For how long should bisphosphonates be given?

• BMD increase with alendronate is maintained for
  at least 10 y1
• Results of the FLEX trial2 alendronate-treated
  women (5-10 mg, 5y) were maintained on
  alendronate (5 or 10 mg) or switched to placebo
• ? placebo slow increase of bone resorption
  markers
• ? placebo BMD gain at lumbar spine is
  maintained, but BMD gain is gradually lost at
  the hip toward baseline BMD
• ? placebo twofold higher risk of clinical
  vertebral but not nonvertebral
• Conclusion of FLEX trial
• - established osteoporosis (with ) continue
  for 10y
• - (mild) densitometric osteoporosis consider
  drug holiday after 5y, follow-up by bone
  densitometry

1Bone et al, N Engl J Med 2004 350
1189-99 2Black et al, JAMA 20062962927-38
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BMD Change in FLEX Participants
Black et al. JAMA 20062962927-38
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Very long-term bisphosphonate treatment and bone
quality an unresolved issue

• Argument powerful suppression of bone remodeling
  ? frozen (dead) bone, unable to heal
  microscopic fractures ? decrease in intrinsic
  bone strength
• Clinically, no evidence for a diminution of the
  antifracture effect over a 10-y period (FLEX
  trial)
• Histomorphometry study (n 50) no association
  between microcracks and duration of BP treatment
  or activation frequency1
• However, in a dog model2, there is an increase in
  the number of microcracks with bisphosphonates,
  but this is counteracted by the increase in
  mineralized bone ? no decrease in bone strength
  after 1y
• Clinical trial data with gt10y treatment are
  needed to fully resolve this issue

1Chapurlat et al, J Bone Miner Res 2007 22
1502-9 2Allen et al, Bone 2006 39 872-9
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Relationship between activation frequency (Ac.f)
and crack surface density (Cr.S.Dn) on
histomorphometry of the lumbar vertebra in dogs
treated with vehicle or various and clinically
relevant doses of alendronate or risedronate.
Decreased activation frequency is associated
with an increase in microdamage accumulation by a
quadratic relationship (P lt 0.001).
Allen et al, Bone 2006 39 872-9