1. Osteoporosis Management: Translating Research Into Optimal Fracture Protection

2. Number of hospital bed days (thousands)
Osteoporosis in Women Accounts for More Disability and Direct Hospital Costs Than Many Other Diseases
600
548,615
500
400
353,654
352,062
Number of hospital bed days (thousands)
300
200,669
200
131,331
Lippuner K, von Overbeck J, Perrelet R, et al. Incidence and direct medical costs of hospitalizations due to osteoporotic fractures in Switzerland. Osteoporos Int 1997;7:414–425.
100
Osteoporosis
COPD
Stroke
Breast MI
carcinoma
Lippuner K, et al. Osteoporos Int 1997;7:414–425

3. The Incidence of Osteoporotic Vertebral and Hip Fractures is Higher in Women Than in Men and Increases With Age
Men
Women
400
400
Hip
Radiographic vertebral
300
300
Wrist
Rate per 10,000 per Year
200
200
100
100
>85
>85
50–54
55–59
60–64
65–69
70–74
75–79
80–84
50–54
55–59
60–64
65–69
70–74
75–79
80–84
Age (Years)
Age (Years)
Data from Europe 1988–1998
Sambrook P, Cooper C. Lancet 2006;367:2010–2018

4. Risk Factors for Osteoporotic fractures
Genetic/Non-modifiable
Age
Female sex
Asian or white ethnicity
Previous fragility fracture
Family history of hip fracture or osteoporosis
Small frame
Potentially Modifiable
Menopause-related estrogen deficiency
Low body weight
Calcium/vitamin D deficiency
Inadequate physical activity
Excessive alcohol intake
Cigarette smoking
Long-term steroid therapy (secondary osteoporosis)
Slide 12: Risk Factors for Osteoporotic Fractures
Genetic or nonmodifiable risk factors for osteoporotic fractures include:
Age
Female sex
Asian or white ethnic origin
Previous fragility fracture
Family history of hip fracture
Small frame
Major risk factors for osteoporosis that are potentially modifiable include:
Menopause-related estrogen deficiency
Low body weight
Calcium and vitamin D deficiency
Inadequate physical activity
Excessive alcohol intake
Cigarette smoking
Long-term glucocorticoid use
Factors demonstrated to confer additional fracture risk independent of BMD include age, previous fragility fracture, family history of hip fracture, neuromuscular disorders, low body weight, poor visual acuity, cigarette smoking, and long-term glucocorticoid use.
Reference
National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed August 31, 2007.
National Osteoporosis Foundation (NOF). Available at: Accessed August 31, 2007. 4

5. Diagnosis of Osteoporosis
Patient history, for detection of etiology and risk factors of osteoporosis.
Initial physical examination, signs of dorsal kyphosis could be the consequence of vertebral compression fractures.
X-rays or other medical imaging techniques to detect skeletal pathology and fractures.
Measurement of BMD to assess low bone mass
Laboratory tests measuring biochemical markers of bone turnover.
[NIAMS Osteoporosis Diagnosis, p1].

6. Recommendations for Bone Mineral Density Testing
All women aged 65 years or older, regardless of other risk factors for osteoporosis.
Postmenopausal women younger than 65 years who have at least 1 risk factor for osteoporosis other than menopause, eg:
Family history of osteoporosis.
Personal history of low trauma fracture at age >45.
Current smoking.
Low body weight (< 127 lb).
All postmenopausal women who have experienced a fragility fracture.
According to NOF guidelines, Delaney 2006, pS13

7. WHO Bone Density Criteria for Osteoporosis
Diagnosis
BMD T-Score
Normal
Low bone mass [osteopenia]
Osteoporosis
Severe osteoporosis
No lower than −1
Between −1 and −2.5
−2.5 or less
−2.5 or less with fragility fractures
T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip.
Reduction by 1 SD equals a 10%–12% decrease in BMD.
1 SD change increases fracture risk by 1.5- to 2.5-fold.
Slide 14: WHO Bone Density Criteria for Osteoporosis
Four general diagnostic categories for women are generally recognized, based on the results of bone mineral density scanning.1
The BMD is categorized as normal when the BMD value is within 1 standard deviation (SD) of the young adult reference mean, denoted as a T-score ≥−1.
A patient is said to have osteopenia, or low bone mass, if the BMD is more than 1 SD below the young adult mean but less than 2 SDs below this value, denoted as a T-score of < 1 and > 2.5.
Osteoporosis is diagnosed when a BMD value of 2.5 SD or more below the young adult mean is present, denoted as T-score < 2.5.
Severe, or established, osteoporosis, is the diagnosis when a patient has a BMD of 2.5 SD or more below the young adult mean and one or more fragility fractures.
Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD
Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold.
Reference
Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003.
Adapted from WHO Technical Report Series 921. Geneva: World Health Organization; 2003. 7

8. Real-World Obstacles in the Management of Osteoporosis
Silent disease; some fractures may initially go unnoticed.
Insufficient rates of diagnosis and treatment.
Poor adherence to prescribed doses:
Low persistence over time
Lack of compliance with dosing instructions
Southern Medical Journal • Volume 99, Number 6, June 2006
The Journal of Family Practice, Vol 59, No 6 | JUNE 2010

9. Months of Continuous Persistence 2
Compliance and persistence with Oral Bisphosphonates are poor and suboptimal in clinical practice1 10 20 30 40 50 60 70 80 90
100 1 2 3 4 5 6 7 8 9 11 12
Months of Continuous Persistence 2
Daily
Weekly
% of Patients
Slide 28: Real-World Persistence to Daily and Weekly Bisphosphonate Therapies
This study utilized data from a large, geographically diverse managed care plan to evaluate adherence to and persistence with alendronate, risedronate, or raloxifene therapy in 10,566 women newly diagnosed with osteoporosis
All three oral therapies were associated with low adherence (54 to 61%) and persistence (16 to 21%) rates, with weekly bisphosphonate regimens resulting in slightly higher rates than those of daily regimens
Persistency curves for daily and weekly users of antiresorptive therapies show a similar pattern, with a quick decline over the first 3 months followed by a slower, consistent decline over the remaining 12-month period
The mean time to discontinuation for daily and weekly users was 2.44 months and 2.55 months, respectively
Patients ≥65 years of age had adherence and persistence rates similar to those of the entire cohort (data not shown)
The poor adherence and persistence associated with oral osteoporosis therapies may compromise the effectiveness related to chronic administration of these agents
Reference
Downey TW, Foltz SH, Boccuzzi SJ, Omar MA, Kahler KH. Adherence and persistence associated with the pharmacologic treatment of osteoporosis in a managed care setting. South Med J 2006;99:
P = NS
1. Véronique Rabenda , Poor adherence to oral bisphosphonate treatment and its consequences:
a review of the evidence, Expert Opin. Pharmacother. (2009) 10(14):
2. Downey TW, et al. South Med J 2006;99: 9

10. Determinants of Poor Persistence
Poor persistence is particularly associated with complex administration and frequent dosing1,2
To improve persistence, eliminate the causes of poor persistence.
Poor persistence
Gastrointestinal intolerability3–5
Complexity of administration3–5
Frequency of dosing3–5
Burden of polypharmacy (multiple medications)3
1. Emkey RD, Ettinger M. Am J Med. 2006;119:S18–S Cramer JA, Silverman S. Am J Med Downey TW, et al. South Med J. 2006;99:570– Gold DT, et al. Ann Pharmacother Sambrook P. Aust Fam Physician. 2006;35:135–137. 10 10

11. Rationale for Less-Frequent and Easier-to-Follow Dosing Regimens
Poor adherence to daily, weekly, and monthly regimens of oral bisphosphonates may result in compromised effectiveness. 1
A once-yearly IV bisphosphonate therapy can deliver real-world effectiveness by assuring adherence for the entire annual dosing interval 2
Slide 30: Rationale for Less-Frequent and Easier-to-Follow Dosing Regimens
For many clinicians, bisphosphonates are the standard of care in osteoporosis because of their rapid efficacy and long-term safety.
Poor adherence to daily and weekly oral bisphosphonates may result in compromised effectiveness.
Once-yearly IV bisphosphonate therapy can deliver real-world effectiveness by assuring adherence for the entire annual dosing interval.
1-The Journal of Family Practice, Vol 59, No 6 | JUNE 2010
2- Black DM, et al. N Engl J Med. 2007;356: 11

12. Summary of FDA Approved Indications for Osteoporotic Therapies
Supplement to Journal of Managed Care Pharmacy JMCP May 2012 Vol. 18, No. 4-b

13. Pharmacologic Agents for the Treatment and Prevention of Osteoporosis
Mechanism of Action
Antiresorptive agents
Bisphosphonates (Gold standard)
Inhibits osteoclast-mediated bone resorption1–4
Calcitonin
Inhibits resorptive activity of osteoclasts1,5
Denosumab
Inhibits RANK-L to prevent RANK-L/RANK interaction thereby inhibiting osteoclast formation, function and survival6
HRT
Act as an agonist on bone, mediated through high-affinity binding to oestrogen receptors and regulation of gene expression1,7
SERMs
Anabolic agents (Severe disease)
Teriparatide [rhPTH(1-34)]
Stimulates bone formation by direct effects on osteoblasts and indirect effects on intestinal absorption and tubular re-absorption of calcium, and excretion of phosphate by kidney8
Other
Calcitriol; vitamin D
Aid calcium absorption and mineralization of the skeleton1
Calcium
Substrate for bone mineralization; suppresses circulating PTH1
Strontium ranelate
Increases bone formation, osteoblast precursor replication and collagen synthesis; reduces bone resorption by decreasing osteoclast differentiation and resorption9
1. NOF. Clinicians’ guide to prevention and treatment of osteoporosis. Washington, DC: NOF; Accessed August 24, 2011; 2. Zoledronic acid (Aclasta®) SmPC. London, UK: EMA; 2011; 3. Alendronate (Fosamax®) SmPC. London, UK: EMA; 2011; 4. Risedronate (Actonel) SmPC. London, UK: EMA; 2011; 5. Calcitonin (Miacalcic®) SmPC. London, UK: EMA; 2010; 6. Denosumab (Prolia®) SmPC. London, UK: EMA; 2011; 7. Raloxifene (Evista®) mPC. London, UK: EMA; 2010; 8. Teriparatide (Forteo®) SmPC. London, UK: EMA; 2011; 9. Strontium ranelate (Protelos®) SmPC. London, UK: EMA; 2011.

14. Zoledronic acid: Key Pharmacological Characteristics
Binding to Hydroxyapatite1
High binding affinity for bone in vitro
Maximizes attachment
Minimizes detachment
Potent FPP synthase inhibition in vitro
Maximizes antiresorptive potential
Minimizes total amount of drug required
Allows single administration of total annual dose 4 3
KL (L/mol x 106) 2 1
CLO ETD RIS IBA ALN ZOL
FPP synthase2
0.0
0.1
0.2
0.3
0.4
0.5
Zoledronic Acid: Key Pharmacological Characteristics
The unique pharmacologic profile of zoledronic acid may explain why it is possible to achieve profound and sustained suppression of bone resorption with a single, low dose of bisphosphonate:
Zoledronic acid has a high binding affinity for bone mineral.1 This maximizes the amount of drug that binds to bone and is likely to minimize the amount of drug that diffuses from bone after binding.
Zoledronic acid is a potent inhibitor of FPP synthase.2 This maximizes the antiresorptive potential of the drug and minimizes the total amount of drug required in each dose.
Zoledronic acid has a high therapeutic ratio (resorption inhibition:mineralization inhibition)3 and good renal tolerability.4 This maximizes the safety of this bisphosphonate and allows the patient’s total annual dose to be delivered in a single administration.
References
1. Nancollas GH, Tang R, Phipps RJ, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone ,38:
2. Dunford JE, Thompson K, Coxon FP, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther ;296:
3. Widler L, Jaeggi KA, Glatt M, et al. Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). J Med Chem ;45:
4. Green JR, Seltenmeyer Y, Jaeggi KA, et al. Renal tolerability profile of novel, potent bisphosphonates in two short-term rat models. Pharmacol Toxicol. 1997;80:
IC50 (mM)
ALN IBA RIS ZOL
Nancollas GH, et al. Bone. 2006;38:
Dunford JE, et al. J Pharmacol Exp Ther. 2001;296: 14

15. Zoledronic Acid Clinical Trials: Past, Present and Future
HORIZON-PFT Study 2301 Core Slides
Zoledronic Acid Clinical Trials: Past, Present and Future
June-08
PUBLISHED
Zoledronic Acid For Paget’s Disease
PUBLISHED
HORIZON Pivotal Fracture Trial (PFT)
HORIZON Recurrent Fracture Trial (RFT)
PUBLISHED
HORIZON Pivotal Fracture Trial (PFT):
Bone remodeling
PUBLISHED
HORIZON
Glucocorticoid-induced Osteoporosis (GIO) Trial
HORIZON PFT Trial (Subgroup Analysis)
PUBLISHED
HORIZON
PFT extension
study
2005–6
2007
2008
2009–10
2012
CONFIDENTIAL

16. Long-term Treatment of Patients with Osteoporosis
Zoledronic Acid Extension Study

17. Journal of Bone and Mineral Research, 2012

18. HORIZON-PFT Extension: Objectives
A 3-year extension of the 3-year HORIZON-PFT study was performed to address whether increasing the duration of therapy beyond 3 years will:
Maintain BMD
Provide additional fracture protection
Reinforce the safety profile established for 3 years of ZOL therapy
It was planned to enroll approximately 2480 postmenopausal women with osteoporosis who had completed participation in the core study.
The following criteria were used to determine site eligibility for participation in the extension study:
A site must have had greater than or equal to 18 active patients participating in the core study 6 months prior to global “First Patient, First Visit” (FPFV) of the extension study as determined by the Novartis clinical team
A site must have had overall data quality in the core study (defined as the number of data queries issued by data management per CRF received from the site) of less than 0.2 per patient at 6 months prior to global FPFV of the extension study
A country must have had no less than 3 sites fulfilling both criteria above to allow that country to participate in the extension study
Countries and sites monitored by an outsourced vendor in the core study were limited to the United States and Canada in the extension study. Additional countries and sites monitored by an outsourced vendor in the core study could be added if needed to meet enrollment targets at the discretion of the Novartis clinical team. In the event that additional countries and sites were added at the discretion of the Novartis clinical team, additional criteria for participation might have applied
All sites with at least 6 patients at 6 months prior to global FPFV who had participated in the biomarker subset (with frozen shipments), QCT subset, or spine and distal radius DXA subset in the core study were allowed to continue in the extension study even if the above criteria were not met
PFT = pivotal fracture trial, Dennis Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

19. Patient Flow From Core Study to Extension
HORIZON-PFT core study (3 years)
Placebo N = 3,876
ZOL N = 3,889
1,221 assigned to ZOL
to maintain blinding
(follow up <3 years)
P3Z3
Randomized in extension
N = 1,233
Extension
(3 years)
It was planned to enroll approximately 2480 postmenopausal women with osteoporosis who had completed participation in the core study.
The following criteria were used to determine site eligibility for participation in the extension study:
A site must have had greater than or equal to 18 active patients participating in the core study 6 months prior to global “First Patient, First Visit” (FPFV) of the extension study as determined by the Novartis clinical team
A site must have had overall data quality in the core study (defined as the number of data queries issued by data management per CRF received from the site) of less than 0.2 per patient at 6 months prior to global FPFV of the extension study
A country must have had no less than 3 sites fulfilling both criteria above to allow that country to participate in the extension study
Countries and sites monitored by an outsourced vendor in the core study were limited to the United States and Canada in the extension study. Additional countries and sites monitored by an outsourced vendor in the core study could be added if needed to meet enrollment targets at the discretion of the Novartis clinical team. In the event that additional countries and sites were added at the discretion of the Novartis clinical team, additional criteria for participation might have applied
All sites with at least 6 patients at 6 months prior to global FPFV who had participated in the biomarker subset (with frozen shipments), QCT subset, or spine and distal radius DXA subset in the core study were allowed to continue in the extension study even if the above criteria were not met
Placebo
N = 616
Z3P3
ZOL
N = 617 Z6
Dennis Black, University of California, San Francisco, USA,
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to t
he HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 19

20. HORIZON-PFT Extension: Study Overview
International, multicenter, double-blind, placebo controlled extension trial,
1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n.616) or placebo (Z3P3, n.617).
All patients received daily oral calcium (1000 to mg) and vitamin D (400 to 1200 IU).
*All patients received calcium 1000–1500 mg/d and vitamin D 400–1200 IU/d and follow-up telephone calls every 3 months.
FN: femoral neck, BTMs ;bone turn over markers, PBO = placebo, ZOL = zoledronic acid, Dennis Black, University of California, San Francisco, USA, The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

21. HORIZON-PFT Extension: End Points
Primary endpoint:
Percentage change in FN BMD at Year 6 vs. Year 3.
Secondary endpoints:
BMD at other sites, BTMs, fracture incidence & safety.
*All patients received calcium 1000–1500 mg/d and vitamin D 400–1200 IU/d and follow-up telephone calls every 3 months.
FN: femoral neck, BTMs ;bone turn over markers, PBO = placebo, ZOL = zoledronic acid, Dennis Black, University of California, San Francisco, USA, The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

22. HORIZON-PFT Extension: Inclusion and Exclusion Criteria
HORIZON-PFT Study 2301 Slide Library
V2 12-Mar-07
HORIZON-PFT Extension: Inclusion and Exclusion Criteria
Key inclusion criteria1
Postmenopausal women aged ≤ 93 years who received all 3 infusions of study drug in the Core study.
Randomized ≤ 13 weeks after completing the Core study.
Key exclusion criteria2
Pregnancy.
Prior use of IV bisphosphonate, strontium, sodium fluoride, PTH.
Use of oral bisphosphonate, systemic corticosteroid, anabolic steroid or growth hormone without sufficient washout.
Serum calcium < 2 or > 2.75 mmol/L at Core study last visit.
Renal insufficiency with CrCl < 30 mL/min or urine dipstick > 2+ protein.
Inclusion criteria
Women, under 93 years of age, inclusive (at the time of randomization in extension study)
who have completed 3 years of participation in the core study and who have received 3
infusions of study medication in the core study according to the guidelines and
instructions provided.
Signed written informed consent to participate in the extension study
Patients must be considered ambulatory. Patients can be included who are ambulatory
with an assistive device (cane, walker, etc)
Patients must have been taking the dosage of calcium and vitamin D required in the core
study (1000 to 1500 mg of elemental calcium and 400 to 1200 IU of vitamin D daily) for
at least 3 months prior to entry into the extension study
Patients must have DXA measurements of the hip performed at Visit 7 (final core study
visit).
Patients must be randomized into the extension study no longer than 13 weeks after
completing the core study.
Exclusion criteria
Patients who demonstrated a major protocol violation in the core study or patients for
whom the investigator feels participation in the extension study is not appropriate
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test (> 5 mIU/ml)
Women of child-bearing potential (WOCBP), defined as all women physiologically
capable of becoming pregnant, including women whose career, lifestyle, or sexual
orientation precludes intercourse with a male partner and women whose partners have
been sterilized by vasectomy or other means, UNLESS they meet the following definition
of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of
spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post surgical
bilateral oophorectomy with or without hysterectomy
Any prior use of iv bisphosphonate other than the study drug during the core study and
during the period after completion of the core study but prior to randomization in the
extension study
Any use of oral bisphosphonates for more than 1 month total during the core study and
Any prior use of PTH for more than 1 month during the core study and during the period
after completion of the core study but prior to randomization in the extension study
Use of systemic corticosteroids (oral or i.v.) at an average dose of greater than or equal to
7.5 mg per day of oral prednisone or equivalent for a period of three months just prior to
entering the extension. Note: Use of corticosteroids in forms such as topical creams, nasal or inhaled
formulations or those injected locally (intra-articularly) are NOT exclusionary
Any use of anabolic steroids or growth hormone for more than 3 months just prior to
entering the extension
Any prior use of strontium (all formulations)
Any use of sodium fluoride for osteoporosis during the core study and during the period
Serum calcium less than 8 mg/dL (2.0 mmol/L) at Visit 7 in the core study or at a
subsequent pre-dose laboratory test prior to randomization in the extension study
Serum calcium greater than 11.0 mg/dL (2.75 mmol/L) at Visit 7 in the core study or at a
Active primary hyperparathyroidism
Surgery to the thyroid or parathyroids resulting in partial or complete hypoparathyroidism
Uncontrolled seizure disorders associated with falls
Bilateral hip replacement or bilateral hip surgery with implantation of an appliance during
the core study
Cancer exclusions:
Patients with a new diagnosis or active treatment for cancer during the course of the core study.
Patients using tamoxifen or aromatase inhibitors for a recent or active cancer
Patients with metastases (or with a history of metastases)
Patients with the following may be included: basal cell or squamous cell carcinoma of the skin, colonic polyps with non-invasive malignancy which have been removed, Ductal Carcinoma in-situ (DCIS) that has been surgically removed, and Carcinoma in-situ (CIS) of the uterine cervix that has been surgically removed.
Multiple myeloma or Paget’s disease diagnosed or discovered during the core study
Occurrence of iritis or uveitis except when secondary to trauma during the core study and
History of diabetic nephropathy or retinopathy or uncontrolled diabetes (e.g. patients with
a history of HbA1c > 10%).
AST or ALT greater than twice the upper limit of normal at Visit 7 (final core study visit)
or at a subsequent pre-dose laboratory test prior to randomization in the extension study
Alkaline phosphatase greater than 1.5 times the upper limit of normal at Visit 7 (final core
study visit) or at a subsequent pre-dose laboratory test prior to randomization in the
Renal insufficiency with a calculated creatinine clearance less than 30.0 mL/min (0.5
mL/sec) or urine dipstick greater than 2+ protein without evidence of contamination or
bacteriuria at Visit 7 (final core study visit) or at a subsequent pre-dose laboratory test
prior to randomization in the extension study
Serum creatinine greater than 2.0 mg/dL (176.8 μmol/L) at Visit 7 (final core study visit)
A sustained increase in serum creatinine between Visit 6 and Visit 7 in the core study of
greater than 0.5 mg/dL (44.2 μmol/L)
History of hypersensitivity to bisphosphonates or any serious adverse reaction to the study
drug during the core study and during the period after completion of the core study but
Use of other investigational drugs within 3 months prior to randomization in the extension
study
Any medical or psychiatric condition which, in the Investigator’s opinion, would preclude
the participant from adhering to the Protocol or completing the trial per protocol.
A life expectancy of less than 3 years.
CrCl = creatinine clearance; IV = intravenous; PTH = parathyroid hormone; SCr = serum creatinine.
1. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243– Black DM, et al. N Engl J Med. 2007;356:1809–1822.
CONFIDENTIAL

23. Characteristics and Bone Parameters at Extension Study Baseline
HORIZON-PFT Study 2301 Slide Library
Characteristics and Bone Parameters at Extension Study Baseline
V2 12-Mar-07
Z6 (n = 616)
Z3P3 (n = 617)
Age, years
Mean
75.5
Femoral neck T-score, n (%)*
≤ –2.5
353 (57.3)
325 (52.7)
Prevalent vertebral fractures, n (%)
256 (41.6)
227 (36.8) 1
177 (28.7)
168 (27.2)
≥ 2
186 (29.7)
222 (36.0)
On average, patients were 75.5 years old, with >50% having femoral neck BMD T-scores lower than 2.5 and approximately 60% with at least one vertebral fracture.
Baseline characteristics between the Z3P3 and Z6 groups were similar.
*Missing values: Z6, n = 2;Z3P3, n = 2.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
CONFIDENTIAL

24. Efficacy Data from the HORIZON-PFT Extension Study

25. Change from Baseline (%)
6 Years of Continuous ZOL Treatment Resulted in Significant Gains in Femoral
Neck BMD Z6
Z3P3 5
1.36%
+4.5%
(0.58, 2.15)
P = 4 3
+3.1%
Change from Baseline (%) 2
Start of extension 1
Core Study
Extension Study 1 2 3 4 5 6
Time (Years from Core Study Baseline)
ITT = intention to treat.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

26. 6 Years of ZOL Treatment Maintained Increases in Femoral Neck BMD
Core Study1
Core + Extension Study2
Placebo Z3 Z6
Z3P3
1.36%
5.0
5.0
4.0
4.0
3.0
3.0
P < **
2.0
2.0
Change From Baseline (%)
1.0
5.06%*
1.0
Start of extension trial
0.0
0.0
–1.0
–1.0
–2.0
–2.0
–3.0
–3.0
0.5 1
1.5 2
2.5 3 1 2 3 4 5 6
Time (Years)
Time (Years from Core Study Baseline)
*P < , P value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables
**P value computed from 2-way ANOVA with treatment and region as explanatory variables.
1. Black DM, et al. N Engl J Med. 2007;356:1809– Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

27. Change from Baseline (%)
Change in Total Hip BMD at Year Relative to Core Baseline (ITT)* Z6
Z3P3 8 7 6 5
1.47%
P <
Change from Baseline (%) 4 3 2 1
Core Study
Extension Study 1 2 3 4 5 6
Time (Years)
* ITT = intention to treat.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

28. Change in Lumbar Spine BMD at Year 6 Relative to Core Baseline (ITT)*Z6
Z3P3 14 12 10
2.06% 8
Change from Baseline (%) 6 4 2
Start of extension
Core Study
Extension Study –2
Time (Years from Core Study Baseline)
*ITT = intention to treat.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254, P = 0.19

29. Change in Lumbar Spine BMD at Year 6 Relative to Core Baseline (ITT)*
Core Study Population1
Subset of Core Study Population
2.06%
P = 0.19 14
Placebo Z3 Z6
Z3P3 12 10 8
Change From Baseline (%) 6 4
6.71%*
Start of extension trial 2 -2 1 2 3 4 5 6
Time (Years)
Time (Years from Core Study Baseline)
*P <
Black DM, et al. N Engl J Med. 2007;356:1809–1822. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
* ITT = intention to treat.

30. Patients with New Vertebral Fracture (%) 1233 randomized to Extension
Significantly Fewer New Morphometric Vertebral Fractures in ZOL Continuation Than Discontinuation (ITT)**
PBO
ZOL Core Study (Yr 0–3)
Z3P3 Z6 15
70%†
For fractures, we saw 49% lower risk for morphometric vertebral fractures but no significant difference in clinically evident vertebral fractures or nonvertebral fractures. 10
Patients with New Vertebral Fracture (%)
49%* 5
For fractures, we saw 49% lower risk for morphometric vertebral fractures but no significant difference in clinically
evident vertebral fractures or nonvertebral fractures,
Hip fractures: Z6=1.33%, Z3P3=1.36%. HR 0.90, 95% CI 0.33 to 2.49, p=0.8424
Clinical vertebral fractures: Z6=1.22%, Z3P3=0.73. HR 1.81, 95% CI 0.53 to 6.19, p=0.3433
Core study new morphometric vertebral fracture rate, ZOL vs PBO:
Years 0-1: 3.7 vs 1.5%. Relative risk, 0.40; P<0.001
Years 0-2: 7.7 vs 2.2%. Relative risk, 0.29; P<0.001
Core Study1
Extension Study2
1233 randomized to Extension
** ITT = intention to treat.
Core study:†P < relative risk reduction vs. placebo (PBO).
*P = , relative risk reduction vs Z3P3; n = the number of patients in the analysis population with X-rays at Year 3 and Year 6 ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years.
1. Black DM, et al. N Engl J Med. 2007;356:1809– Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

31. Taken together, these efficacy results show that continuing ZOL for 6 years maintains early gains in BMD and, by implication, bone strength, but discontinuation after 3 years also maintains substantial residual benefit.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

32. Change in Serum PINP with 6 vs. 3 Years Zoledronic Acid (ITT)60 Z6
Z3P3
Time of infusion
Start of extension
Absolute difference at Year 6
3.0 ng/mL
(P = ) 40 *
28.8 *
Mean PINP (ng/mL) 20
25.8
Core Study
Extension Study 1 2 3 4 5 6
Time (Years)
Mean values remained within the premenopausal reference range throughout
PINP: Procollagen type I N-terminal propeptide, Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822) Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

33. Change in BSAP with 6 vs. 3 Years Zoledronic Acid (ITT)
Z3P3 20 15
Time of infusion
Z3P3
9.1%
Absolute difference
0.14 ng/mL
P =0.74
(Y0-Y6)
Mean level (ng/mL) 10 Z6
9.0% 5 1 2 3 4 5 6
Time (Years)
BSAP: Bone specific alkaline phosphatase , Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822). Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

34. Change in β-CTX with 6 vs. 3 Years Zoledronic Acid (ITT)
0.6 Z6
Z3P3
0.4
Start of extension
Time of infusion
Absolute difference Year 0–6
0.03 ng/mL
(P = 0.45)
0.4
Mean β-CTX (ng/mL)
0.3
0.18
0.2
0.16
0.1
Core Study
Extension Study 1 2 3 4 5 6
Time (Years)
Mean values remained within the premenopausal reference range throughout.
Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822) Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

35. Start of extension trial
6 Years of ZOL Treatment Maintains Reduction in β-CTX at a Lower Level Than 3 Years of Treatment (ITT)
0.8 Z6
Z3P3
0.6
Start of extension trial
0.4
Mean β-CTX (ng/mL)
0.3
0.2 *
0.1
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5 6
Time (years)
Mean values remained within the premenopausal reference range throughout.
ß-CTX :Beta C-terminal type 1 collagen telopeptide, *P < No significant difference at any other time point in the extension study. Horizontal dashed lines represent premenopausal reference range (Adapted from Black DM, et al. N Engl J Med. 2007;356: ).
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

36. Safety Data from the HORIZON-PFT Extension Study

37. Overall Safety Results of the Extension Study
HORIZON-PFT Study 2301 Slide Library
V2 12-Mar-07
Category
Z6, n = 613
n (%)
Z3P3, n = 616
P value
Total subjects with any AEs
552 (90.1)
552 (89.6)
0.85
Total subjects with any SAEs
191 (31.2)
168 (27.3)
0.15
Total deaths
26 (4.2)
18 (2.9)
0.22
Total discontinuations due to AEs
14 (2.3)
11 (1.8)
0.55
No increase in risk of AEs or SAEs with long-term (6-Year) ZOL treatment compared with 3 years of treatment
AE = adverse event; PMO = postmenopausal osteoporosis; SAE = serious adverse event.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
CONFIDENTIAL

38. Zoledronic Acid: Long-Term Safety
In general, safety was similar in those continuing ZOL compared with those who discontinued.
In the extension trail , rates of post dose symptoms were much lower than active group rates in the core study and not significantly different between randomized groups.
Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 38

39. Renal Safety
There were significantly more short-term rises in serum creatinine 9 to 11 days after infusion in the Z6 versus the Z3P3 group, but these short-term increases quickly resolved;
There was no difference between treatment groups in mean change in creatinine clearance and there were no long-term differences in any aspect of renal function.
Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 39

40. Selected Cardiovascular Events
Category
Z6, n = 613
n (%)
Z3P3, n = 616
P value
Arrhythmia SAEs
20 (3.3)
11 (1.8)
0.11
Atrial fibrillation SAEs
12 (2.0)
7 (1.1)
0.26
Stroke-related AEs
26 (4.2)
19 (3.1)
0.29
Stroke SAEs
9 (1.5)
0.06
Stroke SAEs excluding TIA
13 (2.1)
0.18
Death from stroke
4 (0.7)
0 (0.0)
Myocardial infarction SAEs
5 (0.8)
4 (0.6)
0.75
Hypertension
48 (7.8)
93 (15.1)
0.0001
The difference in cardiovascular events in the Z6 (2.0%) versus Z3P3 (1.1%), was not statistically significant (P : 0.26).
TIA = transient ischaemic attack.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

41. Pivotal Fracture Trial,1, 2 Extension Study,*3 New Events, n
Bone Safety
Pivotal Fracture Trial,1, 2
Events, n
Extension Study,*3 New Events, n
Z3 (N = 3862)
PBO (N = 3852)
Z6 (N = 613)
Z3P3 (N = 616)
Osteonecrosis of the jaw (ONJ) 1
Subtrochanteric or diaphyseal femur fracture† 3 2
No cases of atypical femur fracture or hip or knee avascular necrosis.
One case of ONJ reported from a patient with risk factors in Z6 which was resolved with appropriate treatment.
In non-randomized group (P3Z3):
1 ONJ case with several ONJ risk factors.
1 Subtrochanteric fracture with no atypical features.
ONJ case in the Z6 group was in a 77-year-old Asian female. She was a smoker with a medical history of poor dental hygiene, anaemia, periodontal disease, and loss of a tooth. Her dental visits occurred on an emergency basis only. She presented with mandibular pain, swelling, pus discharge from the alveolar ridge, numbness of the lower lip, and weight loss. The patient made a complete recovery following treatment with antibiotics, wound debridement and sequesterectomy. The reported SAEs of osteomyelitis and osteonecrosis were both moderate in intensity and suspected to be related to study drug by the investigator.
*Events were new events that occurred during the extension trial. †Results for the Pivotal Fracture Trial are from a secondary analysis that reviewed fracture records and radiographs (when available) from all hip and femur fractures to identify those below the lesser trochanter and above the distal metaphyseal flare and to assess atypical features.
1. Grbic JT, et al. JADA. 2008;139:32–40; 2. Black DM, et al. N Engl J Med. 2010; 362:1761– Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

42. Summary of HORIZON-PFT Extension Study

43. HORIZON-PFT Extension Study: Efficacy Summary
HORIZON-PFT Study 2301 Slide Library
V2 12-Mar-07
HORIZON-PFT Extension Study: Efficacy Summary
Long-term efficacy results showed that 6 years of ZOL treatment led to:
Significantly greater increases from baseline in femoral neck and total hip BMD than discontinuation at 3 years.
Significant risk reduction in vertebral morphometric fracture risk vs. discontinuation at 3 years.
Maintenance of BTMs within reference range.
Losses in BMD and BTMs in discontinuation group were modest
Residual benefits after discontinuation suggests that some patients may discontinue infusions for up to 3 years.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the
HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
CONFIDENTIAL

44. HORIZON-PFT Extension Study: Safety Summary
HORIZON-PFT Study 2301 Slide Library
V2 12-Mar-07
Safety results were similar in those continuing ZOL vs. those who discontinued:
Rates of post-dose symptoms were similar and much lower than that in ZOL group in the Core study.
There is no significant increase in the risk of atrial fibrillation with ZOL treatment.
ZOL treatment for 6 years showed no overall impact on renal function:
Significantly more transient rises in SCr 9–11 days after infusion in patients who continued ZOL that quickly resolved.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the
HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
CONFIDENTIAL
HORIZON-PFT Slide Library - 44

45. Clinical Implications of the Extension Study: Who Should Remain on Treatment? Post hoc Analysis

46. Clinical Recommendation
6-year data support a positive benefit/risk for long-term ZOL therapy.
A post hoc analysis provides insights on which patients:
May benefit most from continued treatment beyond 3 years.
May be considered for treatment discontinuation for up to 3 years.
Decision to continue or interrupt ZOL therapy beyond 3 years should be made on an individual patient basis.
Current labeling recommends that the lower-risk population with osteopenia be
treated with Reclast infusion every other year and that the higher risk osteoporotic population
be treated with annual infusions of Reclast.
The most important predictors of
new morphometric fracture risk in the Z3P3 group were FN or total hip T-score at H2301E1
baseline <-2.5 [Odds Ratio (95% Confidence Interval [CI]) = 3.3 (1.4, 8.0), p=0.008; and 4.01
(1.8, 8.9), p=0.0007, respectively], and incident morphometric vertebral fracture during the
Core study (Odds Ratio 4.74 [1.3, 16.7], p=0.0156). Significant beneficial treatment effects
(absolute fracture risk reduction and lowest NNT) with continued Reclast in H2301E1 were
seen in these high risk subgroups. While it is acknowledged that the sample size for this
analysis is small and should be interpreted with caution, the findings are consistent with the
OP literature.
FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. Available at: AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM pdf 46

47. Clinical Recommendation
The existing data do not support a specific limitation on the duration of use of Aclasta for all osteoporosis patients.
However, based on the reduction in morphometric fractures, those who are at high fracture risk, ( existing vertebral fractures or with hip osteoporosis after an initial course of therapy), may benefit from continued annual infusions.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the
HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. Available at:

48. Consider IV Bisphosphonates for First-line Therapy
To avoid noncompliance problems and the associated increase in fracture risk, consider IV bisphosphonates for first-line therapy in women with postmenopausal osteoporosis.
The intermittent dosing regimens of IV bisphosphonates ensure 100% persistence throughout the dosing interval.
Slide 39: Conclusions
Osteoporosis is a major public health issue associated with significant morbidity, mortality, and health care costs
The prevalence is increasing as the population ages worldwide
Effective therapies are available, but treatment and adherence patterns are suboptimal in the real-world setting
Better diagnosis and longer-acting therapies with few adverse events that address obstacles to adherence may improve real-world outcomes
Adapted from The Journal of Family Practice, Vol 59, No 6 | JUNE 2010 , Postmenopausal osteoporosis: Another
approach to management 48

49. Zoledronic Acid Efficacy In Prevention Of Postmenopausal Osteoporosis
NEW
Zoledronic Acid Efficacy In Prevention Of Postmenopausal Osteoporosis

50. Preventing fragility fractures is an important public health objective
Fragility fractures are associated with increased morbidity and mortality, so an effective fracture prevention strategy would have a major impact on morbidity and a smaller but important impact on mortality in older adults.1–3
In the United States, approximately 10 million women have osteoporosis and another 34 million have low bone mass (osteopenia).4
1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785–95.
2. Miller RG. Osteoporosis in postmenopausal women. Therapy options across a wide range of risk for fracture. Geriatrics 2006;61:24–30.
3. Brown JP, Josse RG, 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada [published errata appear in CMAJ 2003;168:400, CMAJ 2003;168:676, and CMAJ 2003;168:544]. CMAJ. 2002;167 (10 Suppl): S1–34.
4. National Osteoporosis Foundation Available at: December06, 2009.
References 1-4 are stated in McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

51. Although women with low bone mass have a lower fracture risk compared with women of the same age with osteoporosis, they are at risk for developing osteoporosis unless bone loss is prevented.
Zoledronic acid has been evaluated for the prevention of PMO in a 2 year study.
The study compared a single ZOL acid infusion or two annual infusions with PBO (McClung 2009).

52. STUDY DESIGN
24 ‐ month, multicenter, randomised, double‐blind, placebo‐controlled, parallel group clinical trial in the prevention of bone loss in postmenopausal women with osteopenia.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

53. OBJECTIVES
To demonstrate that zoledronic acid given at randomization and at Month 12 or given at randomization only was superior to placebo in % change in lumbar spine BMD at Month 24 in women stratified by time since menopause(<5years or≥5years).
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

54. Population and methodology
581 female patients aged over 45 years with osteopenia.
Stratum I patients : less than 5 years since menopause.
Stratum II patients : 5 or more years since menopause.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

55. TREATMENT Regimen Zol 5mg infusion at randomization and Month 12 or,
Zol 5mg infusion at randomization and placebo infusion at Month 12 or,
Placebo infusion at randomization and Month 12.
All patients received calcium 500–1200 mg/d; vitamin D400–800 IU/d.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

56. Results
Significantly, both Zoledronic acid regimens were superior to placebo in increasing lumbar spine, total hip, femoral neck, trochanter and distal radius BMD at Month 24 and Month 12 in both subpopulations (Stratum I and II) of postmenopausal women.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

57. Zoledronic Acid Once per 2
Zoledronic Acid Once per 2* Years Results in Significant Increase in BMD of Lumber Spine and Femoral Neck at Months 12 and 24 Relative to Baseline
p ˂ 0.001
*The recommended regimen in prevention of postmenopausal osteoporosis is a single IV infusion of 5mg Aclasta administered once yearly. An annual assessment of patient’s risk of fracture and clinical response to treatment should guide the decision of when retreatment should occur, Aclasta BPI
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

58. RESULTS (Cont’d)
Both once‐yearly ACLASTA and ACLASTA given at the start of the study significantly decreased levels of serumβ‐CTx, serum P1NP and serum BSAP compared with placebo at all time points over 24 months in both subpopulations of postmenopausal women.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

59. Zoledronic Acid Once Per 2
Zoledronic Acid Once Per 2* Years Results in Significant Decrease in BTM** Levels Relative to Baseline at all Time Points
p ˂ 0.001
**Bone Turnover Markers.
* The recommended regimen in prevention of postmenopausal osteoporosis is a single IV infusion of 5mg Aclasta administered once yearly. An annual assessment of patient’s risk of fracture and clinical response to treatment should guide the decision of when retreatment should occur. Aclasta BPI
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

60. Conclusion
Both once-yearly dosing and a single dose of intravenous zoledronic acid 5 mg prevented bone loss for 2 years and were well- tolerated in postmenopausal women with low bone mass.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5):

61. Thank You