Introduction
Study design
Overview of study design
Inclusion criteria | ||||
Participant: | ||||
1) Is a woman at least 65 years of age | ||||
2) Meets one of the following criteria: | ||||
Criterion | Femoral neck or total hip BMD | Femoral neck and total hip BMD | Prior vertebral fracture1
| Suitable candidate for available osteoporosis therapy |
A | ≤−1.5 | ≥−4.0 | 1 | Yes |
B | ≤−2.5 | ≥−4.0 | 0 | Yes |
C | ≤−1.5 | No restriction | ≥1 | No |
D | ≤−2.5 | No restriction | 0 | No |
3) May not be a suitable candidate for commercially available osteoporosis therapy, e.g., due to contraindication, established intolerance, physician’s judgment, or participant’s unwillingness | ||||
4) Has at least one hip that is evaluable by DXA | ||||
5) Postmenopausal for at least 5 years | ||||
6) Understands the study procedures, alternative treatments available, and voluntarily agrees to participate by giving written informed consent | ||||
7) Is ambulatory | ||||
8) Is able to read, understand, and complete questionnaires and diaries | ||||
Exclusion criteria | ||||
Participant: | ||||
1) Has chosen treatment with agents demonstrated to reduce the risk of hip fracture | ||||
2) Has prior fragility hip fracture and is a suitable candidate for osteoporosis therapy (i.e., bisphosphonates, strontium ranelate, or PTH) | ||||
3) Has experienced a clinical fragility fracture (including a clinical vertebral fracture) within the prior 24 months | ||||
4) Had more than one prior vertebral fracture, as defined in inclusion criterion 2 above and is a suitable candidate for osteoporosis therapy | ||||
5) Has evidence of a metabolic bone disorder other than osteoporosis | ||||
6) Has a history of renal stones and serum calcium, serum 25-hydroxyvitamin D, and serum PTH are not all within normal limits. Serum 25-hydroxyvitamin D levels below 20 ng/mL (50 nmol/L) were considered abnormal | ||||
7) Has active parathyroid disease | ||||
8) Has a history of thyroid disease not adequately controlled by medication | ||||
9) Has serum creatinine >1.6 mg/dL and is considered to have severe renal insufficiency defined as calculated creatinine clearance ≤29 mL/min2
| ||||
10) Has received treatment with an agent that has an effect on bone including | ||||
Bisphosphonates | ||||
• Use of any oral bisphosphonate in the 6 months prior to screening | ||||
• Use of any oral bisphosphonate for more than 3 months within the prior 2 years | ||||
• Lifetime use of more than 6 months total; any lifetime use of IV zoledronate3
| ||||
Within the prior 12 months, use of | ||||
• PTH (1–34 or 1–84) | ||||
Within the prior 6 months, use of | ||||
• Estrogen with or without progestin | ||||
• Raloxifene or other SERM, tibolone or an aromatase inhibitor | ||||
• Subcutaneous calcitonin4
| ||||
Within the prior 6 months, use for more than 2 weeks of | ||||
• Systemic glucocorticoids (≥5 mg/day of prednisone or equivalent) | ||||
• Cyclosporin | ||||
Within the prior 3 months, use of | ||||
• Activated vitamin D (e.g., alphacalcidol) | ||||
At any time, use of | ||||
• Any anabolic steroid | ||||
• Fluoride treatment at a dose greater than 1 mg/day for more than 2 weeks | ||||
• Growth hormone | ||||
• Any cathepsin K inhibitor | ||||
• RANK ligand inhibitor | ||||
• Strontium-containing products | ||||
• Protease inhibitors for HIV treatment | ||||
Current use | ||||
• Chemotherapy or heparin | ||||
• Vitamin A >10,000 IU daily | ||||
• Vitamin D supplement >1200 IU daily and is unwilling to limit vitamin D supplement | ||||
• Anti-seizure medication and indices of calcium metabolism are not within normal limits | ||||
• Systemically administered azole antifungals | ||||
11) Has a daily calcium intake of <1200 mg and is unwilling to take study-prescribed calcium supplements | ||||
12) Has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s participation for the full duration of the study | ||||
13) Has a history of malignancy ≤5 years prior to signing informed consent | ||||
14) Is >80 years old and has a history of recurrent falls (≥2 falls in 1 year) | ||||
15) Is currently participating in a study with an investigational compound or device | ||||
16) Is a user of recreational or illicit drugs or has a recent history (within the last year) of drug or alcohol abuse or dependence | ||||
17) Demonstrates hepatic dysfunction defined as Elevation in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × upper limit of normal (ULN) and
Elevation in total bilirubin >2 × upper limit of normal (ULN) | ||||
18) Is considered to be at excessive risk of incident fracture according to local Ethics Committee and/or local regulatory agency |
-
Women with a prior radiographic vertebral fracture were required to have a BMD T-score ≤−1.5 at either the femoral neck (FN) or total hip (TH).
-
Those without a prior vertebral fracture were required to have a BMD T-score ≤−2.5 at the FN or TH, using the NHANES III 1998 database (reference values are those for Caucasian young adult women).
Rationale for study design
Recruitment, follow-up, and assessments
Recruitment
Randomization and stratification
Blinding
Assessments
Radiographic vertebral fracture assessment
BMD measurements
Laboratory assessments
Bone biopsy
Clinical fracture end point assessment
Adverse event reporting and adjudication
Adverse event | Rationale for adjudication | Data collected for adjudication1
| Attributes adjudicated |
---|---|---|---|
Morphea-like skin lesions | Reported in phase IIb study of balicatib | Photographs, serology, pathology report, or slides for skin biopsy The investigators were provided with specific instructions regarding the evaluation of cutaneous adverse events reported at clinic study visits or telephone visits. Specific questions were asked at each visit, about the appearance and texture of the skin, and relevant additional information obtained. There were provisions for dermatologic assessment and biopsy when appropriate, as well as provision for rheumatologic consultation in instances of new or worsening morphea | Confirm morphea |
Systemic sclerosis | Monitored as a precaution because of the finding of morphea-like skin lesions in the balicatib trial | Photographs, serology, pathology report, or slides for skin biopsy | Confirm systemic sclerosis |
Serious respiratory infection | Dose-related increased incidence in phase IIb study of balicatib | Chest X-ray, CT scan, spirometry, laboratory tests, culture and sensitivity | Confirm that event is primarily respiratory and has an infectious component, determine etiology if possible |
Osteonecrosis of the jaw | Reported in participants treated with bisphosphonates and denosumab, although a causal relationship has not been conclusively established | Radiographs | Confirm diagnosis and location, assess for risk factors |
Atypical femoral shaft fracture2
| Femur shaft fractures with less common (i.e., atypical) radiographic and clinical features have been reported with both bisphosphonates and denosumab. Standardized review of both femur fracture radiographs and clinical history is required to identify the major and minor features of atypical fractures according to ASBMR Task Force criteria [33, 34] | Radiographs | Confirm diagnosis |
Delayed fracture union2
| Rule out adverse effect for a drug used for the treatment of osteoporosis and fracture prevention | Radiographs | Confirm diagnosis, assess for risk factors |
Atrial fibrillation3
| Reports of an excess incidence of serious atrial fibrillation in placebo-controlled trials of zoledronic acid | ECG, cardiac diagnostic procedure reports | Confirm diagnosis, assess for risk factors |
Cardiovascular events3
| Observation of plaque stabilization in an animal model of accelerated atherosclerosis with cathepsin K deletion. Test hypothesis of a potential beneficial effect with cathepsin K inhibition in reducing the incidence of thrombotic cardiovascular and cerebrovascular events | ECG, cardiac diagnostic procedure reports, cardiac enzymes | Confirm diagnosis (myocardial infarction, unstable angina, cardiac thrombus), assess for risk factors |
Cerebrovascular events | ECG, cardiac diagnostic procedure reports, cerebrovascular imaging | Confirm diagnosis of stroke, determine etiology (thrombotic vs. hemorrhagic) if possible, assess for risk factors |
Discontinuation criteria
Data monitoring committee
Ancillary studies
Population pharmacokinetics study
Special imaging sub-study
Sarcopenia end point sub-study
Statistical methods
Data analysis
Sample size considerations
Interim analyses
Planned subgroup analyses
Participant baseline characteristics
Geographic region | Number (%) of investigational sites | Number (%) of participants randomized |
---|---|---|
Fracture trial | ||
Asia | 110 (28.4) | 3151 (18.9) |
Latin America | 62 (16.0) | 5442 (32.6) |
Europe/US/others | 215 (55.6) | 8120 (48.6) |
Total | 387 | 16,7131
|
Special imaging sub-study | ||
South Africa | 3 (30.0) | 61 (37.2) |
Europe/US/others | 7 (70.0) | 103 (62.8) |
Total | 10 | 164 |
Sarcopenia end point sub-study | ||
Asia | 3 (8.8) | 73 (13.1) |
Latin America | 8 (23.5) | 263 (47.3) |
Europe/US/others | 23 (67.6) | 220 (39.6) |
Total | 34 | 556 |
Bone biopsy | ||
Asia | 2 (7.7) | 6 (2.2) |
Latin America | 9 (34.6) | 51 (18.6) |
Europe/US/others | 15 (57.7) | 215 (79.2) |
Total | 26 | 272 |
Evaluable participants (n = 16,071) | |
---|---|
Age (years), mean (SD) | 72.8 (5.3) |
>70 years old, n (%) | 11,004 (68.5) |
Race, n (%) | |
Caucasian | 9085 (56.5) |
Asian | 2832 (17.6) |
Multiracial | 3706 (23.1) |
Black/African American | 261 (1.6) |
Native American | 185 (1.2) |
Pacific Islander | 2 (0.001) |
BMD T-score, mean (SD) | |
Lumbar spine | −2.7 (1.2) |
Total hip | −2.4 (0.7) |
Femoral neck | −2.7 (0.5) |
Trochanter | −2.3 (0.8) |
Bone turnover markers, mean (SD)1
| |
uNTX/Cr (nmol/mmol Cr) | 47.4 (37.4) |
sCTX (ng/mL) | 0.44 (0.22) |
sBSAP (ng/mL) | 15.78 (6.50) |
sP1NP (ng/mL) | 58.62 (28.81) |
Clinical fracture history since menopause, n (%) | |
Any | 5552 (34.5) |
Hip | 224 (1.4) |
Spine | 1439 (9.0) |
Other | 4407 (27.4) |
Years since menopause, mean (SD) | 25.3 (7.7) |
Prior radiographically assessed vertebral fracture, n (%)2
| 7446 (46.4) |
Mild fracture (Genant grade 1) | 4414 (59.3) |
Moderate fracture (Genant grade 2) | 1858 (25.0) |
Severe fracture (Genant grade 3) | 1174 (15.8) |
Unreliable or missing data | 36 |
Extension study
Current status
Summary
Acknowledgments
Funding statement
Conflicts of interest
-
Henry Bone, Michigan Bone & Mineral Clinic, Detroit, MI, USA
-
David Dempster, Columbia University Medical Center, New York, NY, USA
-
John A Eisman, Garvan Institute of Medical Research, University of Notre Dame Australia, St Vincent’s Hospital and UNSW Australia, Sydney, Australia
-
Susan Greenspan, University of Pittsburgh, Pittsburgh, PA, USA
-
Michael McClung, Oregon Osteoporosis Center, Portland, Oregon, USA
-
Toshitaka Nakamura, University of Occupational and Environmental Health, Kitakyushu, Japan
-
Socrates Papapoulos, Leiden University Medical Center, Leiden, Netherlands
-
Weichung J. Shih, Robert Wood Johnson Medical School, Piscataway, NJ, USA
-
Robert Wallace (chairperson), University of Iowa College of Public Health, Iowa City, IA, USA
-
Cyrus Cooper, MRC Epidemiology Research Centre, Southampton General Hospital, Southampton, UK
-
Kristine Ensrud, Minneapolis Veteran Affairs Medical Center and University of Minnesota, Minneapolis, MN, USA
-
David Kendler, ProHealth Clinical Research, Vancouver, BC, Canada
-
Leonard Milstone, Yale University School of Medicine, New Haven, CT, USA
-
Stuart Ralston, Molecular Medicine Centre, Western General Hospital Edinburgh, UK
-
Bruce Turnbull, Cornell University School of Operations Research and Information Engineering, Ithaca, NY, USA