________________________________________CGH Pharmacy & Therapeutics Committee__


ALENDRONATE / COLECALCIFEROL (FOSAMAX PLUS , MERCK & CO.)

This drug monograph is for Fosamax Plus 70 mg / 2800 units oral tablets, as officially applied for by Assoc
Prof Lam Khee Sien (Senior Consultant, Dept of Orthopaedic Surgery)

INTRODUCTION

Osteoporosis is a disease affecting many millions of people around the world. It is characterized
by low bone mass and micro-architectural deterioration of bone tissue, leading to bone fragility
and a consequent increase in risk of fracture.1

Osteoporosis is likely to increase as the population of Singapore is aging rapidly. In 1990 only
6% of the population was above the age of 65, but by 2030, this figure is projected to rise to
19%.2 Hence, it is important to consistently strive for more effective management of
osteoporosis, to decrease the related morbidity.

Fosamax Plus is a combination product of alendronate and colecalciferol. Alendronate is
available in CGH as a once-weekly 70 mg-tablet and a once-daily 10 mg-tablet. Vitamin D is
available mainly in combination with calcium carbonate.

PHARMACOKINETICS3-7

Oral bioavailability of alendronate is poor. Only about 0.64% of the dose is absorbed even after
an overnight fast and 2 hours before a standardised meal. Bioavailabilty decreases with food, but
in osteoporosis studies, alendronate was effective when administered at least 30 minutes before
the first food or beverage of the day. Colecalciferol (Vitamin D3) is well absorbed with or without
food. Absorption is impaired in the presence of biliary or hepatic dysfunction or fat malabsorption
syndromes.5

Alendronate transiently distributes to soft tissues but is then rapidly redistributed to bone or
excreted in the urine. It adheres to bone surface, with preferential localisation at resorptive sites
of active bone turnover. Protein binding is approximately 78%. Vitamin D3 distributed rapidly
mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage
form. Circulating Vitamin D3 is bound to vitamin D-binding protein.

There is no evidence that alendronate is metabolised. Colecalciferol is converted to 25-

hydroxyvitamin D3 in the liver. Further conversion to its active form, calcitriol (1,25-
dihydroxyvitamin D3) takes place in the kidney. Patients with impaired renal function and hepatic
function may exhibit a decreased ability to form the active metabolite.

Alendronate that is not retained in bones is renally cleared. Elimination half-life is up to 10 years
for alendronate bound to bones. Colecalciferol is excreted in the urine and faeces as metabolites.
Storage and slow release of colecalciferol from tissues occurs, and the terminal half-life may
exceed 3 weeks.

There is no published pharmacokinetic equivalence study done on Fosamax Plus . However,
data on file shows that oral bioavailability of alendronate and colecalciferol in combination are
similar to when they are administered separately.3,6,8

MECHANISM OF ACTION/PHARMACODYNAMICS

Alendronate sodium is a bisphosphonate that acts as a potent, specific inhibitor of osteoclast-

mediated bone resorption. Bisphosphonates are synthetic analogues of pyrophosphate that bind
to the hydroxyapatite found in bone.3 It decreases bone turnover and does not seem to impair
bone quality in post-menopausal women with osteoporosis. Moreover, increases in bone mineral
density (BMD) and bone strength associated with alendronate appear to be caused by increased
bone mineralisation rather than increased bone volume.6

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Colecalciferol is a secosterol that is the natural precursor of the calcium–regulating hormone

calcitriol (1,25-dihydroxyvitamin D3).3 Colecalciferol is converted to 25-hydroxyvitamin D3 in the
liver. Further conversion to its active form, calcitriol, takes place in the kidney. Conversion to
calcitriol is stimulated by PTH, oestrogen, hypocalcemia, and hypophosphatemia, and is
regulated via negative feedback. Calcitriol increases intestinal absorption and renal reabsorption
of both calcium and phosphorous, increasing their serum concentration. To a smaller extent, this
may inhibit parathyroid hormone (PTH) secretion, thus inducing bone formation and reducing
bone resorption.3,6 It had also been reported that Vitamin D increases lower-extremity
neuromuscular function, thereby reducing the risk of falling.4

CLINICAL EFFICACY

In randomised controlled trials, alendronate demonstrates greater fracture risk reduction versus
placebo.9,10 For postmenopausal women with and without fractures at baseline, there was a 63%
(p= 0.014) reduction in risk of hip fracture at 18 months, a 59% (p= 0.03) reduction in risk of
clinical vertebral fractures at 12 months, and a 90% (p<0.001) reduction in risk of multiple
vertebral fractures at three years.

Meta-analyses of alendronate indicate that alendronate provides risk reductions for both
vertebral and non-vertebral fractures, at 48% and 49%, respectively (p<0.01).10 Superiority over
risedronate and raloxifene in reductions in bone resorption and BMD increases at the hip and
spine was further demonstrated in the FACT and EFFECT trials respectively. There was no
significant difference in the overall tolerability profiles between the drugs in comparison.12-13
There was sustained improvement in BMD and reduced bone turnover to the premenopausal
range over 10 years of treatment with alendronate. Its safety profile compared against placebo
was similar.14

1. Improved Vitamin D status in Postmenopausal Osteoporosis3,15

A 15-week randomised, double-blind, double-dummy, active-controlled, multi-center trial

was conducted during fall when 25-hydroxyvitamin D3 (25-OHD) levels are declining due
to the decreased UV synthesis of colecalciferol. Patients with osteoporosis and 25-OHD
levels of more than 9 ng/ml were randomised to receive once-weekly alendronate and
colecalciferol combination tablet (ALN + D) or alendronate alone (ALN). Patients were
also required to avoid sunlight and vitamin D supplements for the whole study period. All
of them also received 500-600 mg/day of elemental calcium as carbonate. Subjects
included men and women who were at least 6 months post-menopausal, and ranged
from 35 to 89 years of age. Subjects enrolled had serum 25-OHD levels more than 9
ng/ml, and were required to have normal serum PTH and total alkaline phosphatase if
their levels fell between 9 and 15 ng/ml.

The primary endpoint was set as the proportion of patients with serum 25-OHD levels of
less than 15 ng/ml (the level below which serum PTH rises rapidly, resulting in increased
bone turnover and bone loss). Secondary end points included the proportion of patients
with serum 25-OHD levels of less 9 ng/ml (the level below which overt deficiency and
osteomalacia are observed), bone resorption markers, urine N-Telopeptides of type 1
collagen (NTX) levels, and bone formation markers, serum bone-specific alkaline
phosphatase (BSAP).

At week 15, there was a significantly smaller proportion of patients with serum 25-OHD
levels of less than 15 ng/ml and 9 ng/ml in the ALN + D group, as compared to the ALN
group. Effects on urine NTX, serum BSAP, serum calcium and phosphorus lowering for
both treatment groups were similar, but there was a significantly greater rise in PTH
levels for the ALN group. Hypercalciuria was observed at the same low incidence in both
treatment groups. There were no cases of hypercalcemia.

Results from the study suggest that Fosamax Plus will be efficacious in improving
vitamin D status and suppressing increases in serum PTH levels in patients with

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osteoporosis who are home-bound or who are inadequately exposed to sunlight. This is
done without changing the anti-resorptive effects of once-weekly alendronate. These
beneficial effects may be more prominent for patients with serum 25-OHD of more than 9
ng/ml at baseline, normal serum PTH and total alkaline phosphatase levels, and who are
taking daily calcium supplements.

TOLERABILITY3,6-7,15

The adverse effect profile of Fosamax Plus comprises those observed with its individual
components. The incidence of treatment-related GI adverse events and discontinuation due to
treatment-related adverse events were similar for patients taking the combination product or
alendronate alone. Treatment-related upper GI adverse events were reported in 8.3% of
recipients of the combination product as compared to 9.2% in those taking alendronate alone.

Local irritation of the upper GI mucosa and esophageal adverse experiences are possible side
effects related to the alendronate component, especially if full administration instructions are not
followed. Other safety concerns are localised osteonecrosis of the jaw that has been reported
rarely with oral bisphosphonates, and bone, joint, and/or muscle pain that have rarely been
severe and/or incapacitating, that may set in from one day to several months after starting
treatment.

Adverse events due to colecalciferol are mainly GI in nature (nausea, diarrhoea, and epigastric
pain). Hypercalciuria and hypercalcemia related to the vitamin D3 component was rare.
Nevertheless, urine and serum calcium should be monitored in patients with diseases associated
with unregulated overproduction of calcitriol. Circulating vitamin D-binding protein levels are
about 20 times higher than concentrations of vitamin D compounds, and thus limit the possibility
of vitamin D toxicity. No toxicity has been associated with daily doses of colecalciferol as high as
10000 units.

DRUG INTERACTIONS3


Specific interaction studies have not been done for Fosamax Plus . If taken at the same time, it is
likely that calcium supplements, antacids, and other oral medications will interfere with the
absorption of alendronate. Alendronate has also been used in studies with a wide range of
commonly prescribed drugs without evidence of clinical adverse interactions.

Olestra, mineral oils, orlistat, and bile acids sequestrants may impair the absorption of vitamin D.
Administration of enzyme inducers and thiazides may increase the catabolism of vitamin D.

DOSAGE AND ADMINISTRATION3

Recommended dosage is one 70 mg/2800 units tablet once weekly. No dosage adjustment is

necessary for the elderly or for patients with mild-to-moderate renal insufficiency. Fosamax Plus
is not recommended for patients with moderate-to-severe renal insufficiency with creatinine
clearance of less than 35 ml/min.

Patients should receive supplemental calcium and/or vitamin D if intake is inadequate, especially
in cases of gastrointestinal malabsorption syndromes.

Fosamax Plus has not been studied in pregnant women, nursing mothers, and in children.

Fosamax Plus must be taken at least 30 minutes before the first food, beverage, or medication
of the day with plain water only. It is to be swallowed whole upon rising for the day with a full
glass of water, and patients should be instructed not to lie down for at least 30 minutes and until
after their first food of the day.

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ROLE IN THERAPY

The anti-resorptive effect of Fosamax Plus seems to be due to the alendronate component. The
vitamin D component, serves to enhance the GI absorption and renal reabsorption of calcium,
thus helping in calcium homeostasis. The MOH recommended daily intake of vitamin D for adults

above 65 years old is 800 units. The main advantage that Fosamax Plus offers is improving
vitamin D status and suppressing increases in serum PTH levels in patients with osteoporosis
who are home-bound or who are inadequately exposed to sunlight.

Because of the long binding of alendronate to osteoclasts and the storage of 25-OHD in the
tissues, there is no need for daily administration of alendronate nor colecalciferol.4,7 Fosamax

Plus incorporates the recommended weekly requirement of Vitamin D3, with the weekly dose of
alendronate in one tablet, allowing a convenient regimen for patients, without changing the anti-
resorptive effects nor adverse effect profile of alendronate.15 It is also safe for use in patients with

normal vitamin D levels, as the amount of vitamin D in Fosamax Plus will not cause vitamin D
toxicity if given with usual doses of calcium and vitamin D supplements.
  
Currently, Fosamax Plus is priced at parity with Fosamax . Therefore, Fosamax Plus may be an

alternative to replace once-weekly Fosamax , especially for patients who need the extra vitamin

D. However, it should be noted that Fosamax Plus is formulated mainly to extend the patent of
MSD’s alendronate products as generic alendronate may soon be available in European
markets.

COST

Drug Cost per Cost per 4 Usage Usage – DDE*

dosage weeks of (Nov 05-Oct (Nov 05-Oct
form therapy 06) 06)
Calcitonin nasal spray $63.27/bottle $126.54 1162 sprays 2324 pt-weeks
[200 units x 14 doses] (200 units/day)

(Miacalcic , Novartis)
Raloxifene 60 mg tab $3.47/tab $97.16 14311 tabs 2044 pt-weeks

(Evista , Eli Lily) (60 mg/day)
Etidronate 200 mg tab $0.80/tab $22.40** 752 tabs 322 pt-weeks

(Difosfen , Zyfas) (400 mg/day for
first 14 days)
Risedronate 35 mg tab $16.75/tab $67 9176 tabs 9176 pt-weeks

(Actonel , Sanofi-Aventis) (35 mg/week)
Strontium ranelate 2 g $3.81/sachet $106.68 1049 sachets 150 pt-weeks

sachet (Protos , Servier)# (2g/day)
Teriparatide 750 mcg/3 mL $993.70/pen $993.70 0 0
multidose injection pen (20 mcg/day)

(Forteo , Eli Lily)##
Alendronate 10 mg tab $2.30/tab $64.40 12126 tab 1732 pt-weeks

(Fosamax , MSD) (10 mg/day)
Alendronate 70 mg tab $17.27/tab $69.08 42390 tabs 42390 pt-weeks

(Fosamax , MSD) (70 mg /week)
Alendronate 70 mg/ $17.27/tab $69.08 N.A. N.A.
Colecalciferol 2800 units (70 mg/ 2800 units

tab (Fosamax Plus , MSD) /week)
* Daily dose equivalents (DDE) – a representation of the number of defined doses prescribed for
patients within a given time scale (e.g., patient-days, patient-year, etc); value acts as a common
denominator when comparing the usage volume of 2 or more drugs with varying dosage
requirement.
** Based on cyclical quarterly treatment schedule: 400 mg/day for 14 days followed by calcium & vitamin
D for the next 2 and a half months.
#
Approved in Sept’ 06. Usage shown is from approval date.
##
Approved in Apr’ 06.

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________________________________________CGH Pharmacy & Therapeutics Committee__

REFERENCES

Anonymous. Osteoporosis. World Health Organisation.

http://www.who.int/dietphysicalactivity/publications/trs916/en/gsfao_osteo.pdf (Last accessed
5th December 2006).
1. Ministry of Health, Singapore. Osteoporosis. MOH Clinical Practice Guidelines 02/2002.
http://www.moh.gov.sg/cmaweb/attachments/publication/osteo_pdf.pdf (Last accessed 5th December
2006).
2. Fosamax Plus. Alendronate/Colecalciferol. Local product circular. Merck & Co., Inc., Whitehouse
Station, New Jersey, USA.
3. Heaney RP. Alendronate plus colecaciferol for the treatment of osteoporosis. Women’s Health 2006;
2(1): 23-27.
4. Colecalciferol (Drug evaluation). In: Klasco RK (Ed): DRUGDEX System. Thomson Micromedex,
Greenwood Village, Colorado (Edition expires 31 Dec 2006).
5. Reynolds NA, Curran MP. Alendronate/colecalciferol. Treat Endocrinol 2005; 4(6): 371-377.
6. Epstein S. The problem of low levels of vitamin D and osteoporosis: Use of combination therapy with
alendronic acid and colecalciferol (vitamin D3). Drugs Aging 2006; 23(8): 617-625.
7. Data on file, MSD Singapore.
8. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with
osteoporosis: The fracture intervention trial (FIT). J Clin Endocrinol Metab 2000; 85(1): 231-236.
9. Black DM, Thompson DE, Bauer DC, et al. Randomised trial of effect of alendronate on risk of fracture
in women with existing vertebral fractures. Lancet 1996; 348: 1535-1541.
10. Cranney A, Guyatt G, Wells G, et al. Summary of meta-analyses of therapies for postmenopausal
osteoporosis. Endocr Rev 2002; 23(4): 570-578.
11. Rosen CJ, Hochberg MC, Bonnick SL, et al. Treatment with once weekly alendronate 70 mg compared
with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis. J Bone Miner Res
2005; 20(1): 141-151.
12. Sambrook PN, Geusens P, Ribot C, et al. Alendronate produces greater effects than raloxifene on
bone density and bone turnover in postmenopausal women with low bone density: Results from
EFFECT. J Intern Med 2004; 255:503-511.
13. Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for the treatment of
osteoporosis in postmenopausal women. N Engl J Med March 18, 2004; 350:11-21.
14. Recker R, Lips P, Felsenberg D, et al. Alendronate with and without colecalciferol for osteoporosis:
Results of a 15-week randomised controlled trial. Curr Med Res Opin 2006; 22(9): 1745-1755.

Monograph prepared by:

Cordelia Chen, B Sc (Pharm) (Hons)

Pre-Registration Pharmacist

9th Dec 2006