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Bonviva : the Novel Therapeutic Drug for Osteoporosis

(A Highly Efficacious and Well Tolerated Ibandronate-150mg Once Monthly)

2008
11-752
Askandar Tjokroprawiro
Diabetes and Nutrition Center Dr.Soetomo Teaching Hospital
Airlangga University School of Medicine, Surabaya
AN OVERVIEW : FOCUS ON ONCE MONTHLY ORAL IBANDRONATE
In clinical practice, the most frequent types of osteoporosis can be categorized
into 3 types, such as: type I- osteoporosis (postmenopausal osteoporosis or PMO), type
II- osteoporosis (age-related osteoporosis or ARO), and type III-osteoporosis
(corticosteroid-induced osteoporosis or CIO).
Diabetic osteopenia and osteoporosis become major issues in daily clinical
experiences. Recent studies indicated that the probable causes of diabetic osteopenia can
be suggested and can be explained follows: AGE-modified collagen affected osteoblastic
cell differentiation and function, and this process could be responsible for osteopenia-
osteoporosis (especially in postmenopouse) in patients with diabetes mellitus.
The Treatment Update of osteoporosis can also be grouped into three
interventions: Healthy Lifestyle for osteoporosis. Prevention: Calcium Supplement 1-
1.5 g/day, and Drugs: Estrogen, Bisphosphonates, Calcitonin, Growth Hormone, SERMs,
Strontium Ranelate (SR), Vitamin D, Fluoride, PTH-PTHRP, and Symptomatic (Lumbar
Support etc).
Bisphosphonates continue to be used in treating Pagets disease and
hypercalcemia in malignancy, but new uses of drugs include prevention of
postmenopause osteoporosis, age-related osteoporosis, corticosteroid-induced
osteoporosis, and post-transplantation bone loss, and to decrease bone pain and to inhibit
of bone metastases in cancer patients. The bisphosphonates investigated in humans,
numbered in increasing order of potency can be abbreviated as E-TCP-NAORIZ-MICE:
Etidronate Tiludronate, Clodronate, Pamidronate Neridronate, Alendronate,
Olpadronate, Risedronate, Ibandronate, Zoledronate Minodronate, Incadronate,
Cimadronate, EB-1053.
Abbreviations: ACE = annual cumulative response; BALTO = bonviva alendronate trial in osteoporosis; BMD = bone
mineral density; BMF = bone marker feedback; BMS = bone material and structure; BonAdAsia = Bonviva Adherence
in Asia; BONE = ibandronate Osteoporosis in vertebral fractures in North America and Europe; BonAdAsia = BTO =
bone turn over; DIVA = dosing intra venous administration; E-TCP-NAORIZ-MICE = Etidronate Tiludronate,
Clodronate, Pamidronate Neridronate, Aledronate, Olpadronate, Risedronate, Ibandronate, Zoledronate
Minodronate, Incadronate, Cimadronate, EB-1053; FIT = fracture intervention trial; MOBILE-LTE = Monthly Oral
ibandronate In LadiEs Long Term Extension; NVFs = non-vertebral fractures; PERSIST = PERsistance Study of
Ibandronate versus alendronaTe; sCTX = serum C-telopeptide of the -chain type-1 collagen; VERT-NA = vertebral
efficacy with risedronate therapy North American; VFs = vertebral fractures.

MORNING SYMPOSIUM ON OSTEOPOROSIS

Annual Meeting of Rheumatology & Indonesian Autoimmunity Course
Jakarta, 17-20 April 2008
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Alendronate, Risedronate and Ibandronate (most recently) have been available in

Indonesia. The novel bisphosphonate, ibandronate, shows 2-fold more potent than
risedronate, and 10.000 fold than etidronate.
Bisphosphonates have been reported successfully in preventing (prevention
effects) the bone loss in osteoporosis and have resulted in lowered fracture incidence
(treatment effects). Ibandronate is a potent nitrogen-containing bisphosphonates. It has a
strong affinity for bone mineral and potently inhibits osteoclast-mediated bone resorption.
Ibandronate is effective for the treatment of hypercalcemia of malignancy, metastatic
bone disease, postmenopausal osteoporosis, corticosteroid-induced osteoporosis, and
Pagets disease.
The target of osteoporosis treatment in the prevention of all fracture types
including both vertebral fractures (VFs) and non-vertebral fractures (NVFs). While VF is
the most common osteoporotic fracture type, NVFs, such as those of the hip, can be the
most debiliting and costly.
Several clinical trials oral bisphosphonates (including alendronate, risedronate
and ibandronate) have shown that daily bisphosphonate therapy increases bone mineral
density (BMD), reduces bone turnover (BTO), and reduces the risk of fractures in women
with postmenopause osteoporosis. The 3 (three) main components of bone strength are
BMD, BTO, and micro architecture and collagen of the bone (BMS).
To date, however, there are no prospective studies investigating the antifracture
efficacy of approved weekly, monthly, or quarterly bisphosphonate treatment.
The results of meta-analysis (included 8710 patients) of phase-III studies on
ibandronate (BONE, IV Fracture Prevention, MOBILE, and DIVA) and the risk of NVFs
and clinical fractures in women with postmenopausal osteoporosis were recently reported
in 2008. The marketed doses of ibandronate, 150mg once-monthly oral (Bonviva) and 3
mg quarterly intravenous (IV) injection, produce greater increases in lumbar spine BMD
than treatment with the 2.5mg oral daily dose. This meta-analysis assessed whether such
doses also reduce fracture risk relative to placebo.
Monthly oral ibandronate (Bonviva) reduces bone resorption (sCTX) within 3
months, and significantly increases lumbar spine and proximal femur BMD. Thus,
monthly oral ibandronate significantly increases BMD and significantly suppresses BTO.
Intermittent bisphosphonate regimens require higher cumulative doses in order to
achieve equal effect on BMD and BTO markers (annual cumulative response = ACE of
Bonviva : 10.8 mg, whereas for I.V 3 mg ibandronate: 12 mg).
Intermittent oral and I.V injection in doses of ibandronate have demonstrated
significant gains in BMD and similar reductions in BTO markers versus daily
ibandronate. Once-150mg monthly and 3mg I.V quarterly ibandronate show ACE 10.8mg
and ACE 12mg, respectively; both regimens have been investigated. Total dose concept :
lessons from studies with ibandronate showed that ACE of an intermittent ibandronate
regimen should be approximately 11mg.
Recent studies concluded that antifracture efficacy is highly predicted by BMD
and BTO, and also BMS (bone material and structure). BONE study demonstrated that
monthly oral ibandronate preserves trabecular micro-architecture (BMS).
Conclusions Once-monthly oral ibandronate (Bonviva) shows 3 (three)
important functions (BMD, BTO, BMS) which favor bone strength to increase
antifracture efficacy or fracture resistance.
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Based on annual cumulative exposure (ACE) such 4 (four) studies previously

mentioned (BONE, I.V fracture prevention, MOBILE, and DIVA) were grouped into 3
(three) dose levels.
Annual cumulative response (ACE) was defined as the annual dose (mg) x
bioavailability (0.6%, oral; 100%, IV) or placebo.
Six key NVFs (clavicle, humerus, wrist, pelvis, hip, and leg), all NVFs, and all
clinical fractures were examined.
The meta-analysis revealed that the high-dose group (ACE > 10.8mg) showed
significant reductions in the adjusted RR of (relative to placebo): key NVFs 34.4%, p =
0.032; all NVFs 29.9%, p = 0.041; clinical fracture 28.8%, p = 0.010). The high-dose
group also had significantly longer time to fracture versus placebo for key NVFs (p =
0.031), all NVFs (p = 0.025), and clinical fractures (p = 0.002).
The most recent study on the adherence of patients to the Bonviva therapeutic
regimen in Asia (BonAdAsia Study 2008, n = 596) reported the results which can be
summarized and listed below.
1. Patients: 94.6% adherent and 5.7% non-adherent patients.
2. The sCTX levels decreased significantly over time (each with p < 0.0001) over
the 3-month (50.1%) and the 6-month (51.2%) study periods.
3. Study safety profile (n = 590) : 41.1% of the patients had adverse events (87.1%
were mild, with 36.6% gastrointestinal and 29.6% muscoluskeletal. Of its are non
serious adverse events.
Conclusions Bonviva significantly decreased the sCTX, with favorable safety profile.
Patients were adherent to Bonviva intake regardless of bone marker feedback (BMF)
On the basis of the results of several studies, such as BALTO, BONE, MOBILE,
MOBILE-LTE, PERSIST, BonAdAsia, and others, which provide the efficacy and the
safety of Bonviva (150 mg ibandronate, once-monthly) as the novel therapeutic
regimen in the treatment of osteoporosis, the conclusion below is made.
Besides, the results of the below listed studies and reports support the efficacy and
tolerability of monthly oral ibandronate (Bonviva) therapy.
1. Monthly oral 150 mg ibandronate provides consistent gains in BMD after 3 years
or treatment (2 years in MOBILE plus 1 year in MOBILE-LTE) with a tolerability
profile similar to the daily regimen.
2. The MOBILE-LTE study revealed progressive improvements in efficacy with oral
150mg ibandronate when administered monthly.
3. Rapid suppression of serum CTX (sCTX) within 3 (three) days of treatment
initiation with monthly oral 150 mg ibandronate.
4. MOBILE-LTE results: Median sCTX levels remained within the premenopausal
range after 3 years and were reduced by 52.0% (100mg arm) and 64.9% (150 mg
arm) compared with the MOBILE study baseline.
5. A meta-analysis of individual patients data showed significant reduction in non-
vertebral fracture will high-versus low-dose ibandronate.
6. Monthly oral ibandronate preserves trabecular micro-architecture: micro-
computed tomography findings from the BONE study.
7. Ibandronate-induced reduction of bone turnover marker predicts antifracture
efficacy. Bone strength = BMD + BTO + Bone microarchitecture structure.
8. Ibandronate-induced BMD gains are related to vertebral antifracture efficacy.
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9. The data show that 150 mg monthly ibandronate provides consistent gains in
BMD in postmenopausal women with osteoporosis. This evidence, plus the
favorable tolerability profile and greater persistence with monthly ibandronate
versus weekly regiments support the clinical benefits.
10. Conclusion of the BALTO study: significantly more women with PMO preferred
once-monthly 150 mg ibandronate therapy to once-weekly alendronate therapy,
and found the once-monthly regimen to be more convenient.

Taken together (not comparative study), RRR (%) for the new vertebral fracture at 3
years, Bonviva 2.5 mg/day (BONE study, RRR 62%) is superior than alendronate 5-10
mg/day (FIT, 47%) and risedronate 5 mg/day (VERT-NA, 41%). For non-vertebral
fracture efficacy in high-risk patients, ibandronate showed 69% RRR.
Conclusions Ibandronate is a potent 3rd generation nitrogen-containing
bisphosphonate. This novel bisphosphonate shows twice fold more potent than
risedronate, and ten fold more potent than alendronate. This drug has shown its high
efficacy to increase BMD, to reduce BTO, to improve BMS, and to reduce the risk of
vertebral fractures (RRR 62%) in PMO; for non-vertebral fracture, ibandronate showed
69% RRR. The MOBILE study long term extension (MOBILE-LTE) has demonstrated
the progressive improvements in efficacy with 150mg oral ibandronate (Bonviva) when
administered once monthly. Bonviva at dose level of ACE > 10.8 mg, the marketed 150
mg once-monthly oral, shows highly efficacious and well tolerated bisphosphonate.
Bonviva may provide significant vertebral and non-vertebral and clinical efficacy;
patients will be more convenience and have more quality of life while taking once
monthly ibandronate than daily or weekly bisphosphonate.

-oOo-