Please select the eligibility criteria that correspond to the clinical trial below.
Title: Evaluation of Efficacy of Zoledronic Acid in Patients With Haemoglobin Syndromes (Thalassemia and Sicle Cell Anaemia) and Risk of Skeletal Events
Brief Summary: The evaluation of efficacy is performed by laboratory monitoring of bone density and resorption markers and clinical monitoring of bone density improvement. This is a prospective, randomized, parallel group, single blind study of one year treatment with zoledronic acid every 6 months as compared to one year treatment with zoledronic acid every 3 months and to placebo every 3 months in patients with hemoglobin syndromes and risk of skeletal complications.


Options:
A: Inclusion Criteria:

* Women who are 60 to 90 years of age may be eligible to participate
* Bone mineral density (BMD) T-Score at hip or spine must be less than -2.5

Exclusion Criteria:

* BMD T-Score at the hip or the spine of less than -4.0
* Patients with any severe or more than two moderate vertebral fractures on spinal x-ray at entry
B: Inclusion Criteria:

* Adults (\>30 years of age) described as skeletally mature subjects
* Thalassemia Major
* Low BMD (T-score \<-2.5) in one of the 3 studied sites (lumbar spine, femoral neck, wrist).
* Have signed the informed consent form (consent should be taken before any study-specific procedure is performed).

Exclusion Criteria:

* BMD T-score \< -4.0 in one of the 2 studied sites (lumbar spine, femoral neck).
* Previous administration of denosumab from clinical trials or others (e.g. commercial use).
* Current participation in another clinical trial or having received any investigational product within the last 3 months.
* Impaired renal function as determined by an estimated glomerular filtration rate (eGFR) of ≤ 30 mL/min (using the Chronic Kidney Disease-Epidemiology, ((CKD-EPI) formula).
* Patients with sickle cell disease.
* Known to have a liver failure or chronic hepatic disease e.g. cirrhosis, chronic hepatitis; or elevated transaminases defined as Alanine Transaminase (ALT) and/or Aspartate Transaminase (AST) \> 2 fold the upper limit of normal laboratory range.
* Heart failure (NYHA above 2).
* Patients with life expectancy of less than one year.
* Subject refuses to use a reliable contraceptive method (oral contraceptives, progesterone implants, intrauterine device, condoms) throughout the study by women of childbearing potential. Women of childbearing potential agree to use 2 highly effective forms of contraception and to continue this practice for 7 months after last injection of study medication.
* Pregnancy, planning a pregnancy or currently lactating
* Severe concurrent illness which in the investigator's opinion may confound patient evaluation, e.g. malignancy (except basal cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years.
* Known alcohol or drug abuse or any other condition associated with poor compliance
* Patients that have received oral bisphosphonates within 6 months of study enrollment or intravenous bisphosphonates, fluoride and strontium ranelate within 1 year of study enrollment.
* Parathormone (PTH), PTH derivatives, teriparatide, odanacatib, anabolic steroids, testosterone, glucocorticosteroids (\> 5 mg/day of prednisone equivalent for \> 10 days), systemic hormone-replacement therapy, selective estrogen receptor modulators (SERMs), raloxifene, tibolone, calcitonin or calcitriol use within the last 6 weeks.
* Evidence of hyper- or hypothyroidism; patients with an abnormal Thyroid stimulating hormone (TSH) level on thyroid treatment (patients on stable thyroid treatment with a normal TSH allowed); current hyper- or hypoparathyroidism; current hyper or hypocalcemia (hypocalcemia based on albumin adjusted serum calcium \< 8.5 mg/dL); vitamin D deficiency (25-hydroxy Vitamin D level \< 12 ng/mL; if repeat 12-20 ng/mL after repletion, subject will be allowed); rheumatoid arthritis; Paget's disease; bone disease that would interfere with interpretation of findings.
* Known sensitivity to mammalian cell-derived drug products.
* History of any Solid Organ or Bone Marrow Transplant
* History of osteonecrosis of the jaw, and/or recent tooth extraction or other dental surgery; or planned invasive dental work during the study.
* Intolerance to calcium supplements.
* Malabsorption syndrome; severe malabsorption including Celiac disease, Short Bowel Syndrome, Crohn's disease, Previous Gastric Bypass.
C: Inclusion Criteria:

* Patients with thalassaemia or sickle cell anaemia and bone density, z-scores \< -1.5, in at least one of the examined sites
* Normal renal function. Urea and creatinine should not exceed \> 2-fold the upper limit of normal (\< 2 x ULN).

Exclusion Criteria:

-

Other protocol-defined inclusion / exclusion criteria may apply.
D: Inclusion Criteria:

* 6 to 30 years of age
* thalassemia
* bone mineral density Z-score \< -1.0 (by DXA)

Exclusion Criteria:

* Bone marrow transplant recipient
* Currently prescribed treatment for low bone mass other than calcium or vitamin D (e.g. calcitonin, bisphosphonates)
* Currently prescribed zinc supplementation who are unable or unwilling to stop during this trial
* Currently participating in another trial with a medication known to affect bone mineral density.
* Chronic use of systemic corticosteroids
* Untreated hypogonadism or growth hormone deficiency
* Baseline serum copper \< 70 µg/dL
* Baseline vitamin D-25OH \< 11 ng/mL
* Pregnant or lactating at study entry

Answer: C