Enhancing Osteoporosis Therapy: Can We Open the Anabolic Window?
Condition: Osteoporosis
MeSH terms: Osteoporosis
Intervention: Teriparatide; Raloxifene
Intervention description: Teriparatide (TPD; Forteo) is supplied as a pre-filled syringe that dispenses 20 ug. The dose is one subcutaneous injection daily. Each pre-filled injection delivery device contains sufficient TPD for a 28-day supply of 20 mcg/day.; Raloxifene (RLX; Evista) is supplied as a 60 mg tablet. RLX is stored at room temperature.
Intervention MeSH terms: Teriparatide; Raloxifene Hydrochloride
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: Female
Minimum age: 60 Years
Maximum age: 89 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      Current osteoporosis therapies produce a prompt increase in bone mass, followed by only
      modest or no further subsequent gains. This limitation, known as the "remodeling transient,"
      reflects the "coupling" of bone resorption with formation such that interventions impacting
      either of these processes lead to compensatory changes of the other. For example, medications
      which increase bone formation promptly also stimulate bone resorption. Thus, given the need
      to dramatically increase bone mass in patients with osteoporosis, it is necessary to
      "uncouple" formation and resorption. The investigators believe this to be possible using
      currently existing FDA-approved therapeutic agents, by using a novel, sequential approach.

      This pilot project will obtain preliminary data essential to support future work. In this
      study, the investigators will begin to explore the use of sequential anabolic treatment with
      teriparatide followed by antiresorptive therapy with raloxifene. The investigators propose
      that such sequential treatment will allow opening of the "anabolic window," the brief period
      of time following initiation of teriparatide therapy in which bone formation exceeds
      resorption.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Generally healthy, community-dwelling ambulatory post-menopausal women.

          -  Able and willing to sign informed consent.

          -  Age 60 to 89.

          -  Have osteoporosis defined as follows:

          -  BMD T-score of the lumbar spine, femur neck, total proximal femur or .3 radius of -2.5
             to -4.0; note: the lumbar spine must include two vertebrae that are evaluable by DXA
             in the opinion of the investigator.

        OR

          -  BMD T-score of the lumbar spine, femur neck, total proximal femur or .3 radius of -1.5
             or lower and either an atraumatic (in the opinion of the investigator) nonvertebral
             fracture; [note: nonvertebral fracture sites include the wrist, hip, pelvis, ribs,
             humerus, clavicle, femur, tibia and fibula] or a minimum of two mild or one moderate
             or severe atraumatic vertebral fractures (defined using the Genant visual
             semi-quantitative scale).

          -  Baseline serum 25(OH)D concentration > 20 ng/ml and < 60 ng/ml.

          -  Able and willing to receive daily subcutaneous injections using a Forteo® pen.

        Exclusion Criteria:

          -  History of exposure to external beam or implant radiation therapy involving the
             skeleton.

          -  Paget's disease or unexplained elevations of alkaline phosphatase.

          -  Any history of venous thrombosis including deep vein thrombosis, pulmonary embolism,
             retinal vein thrombosis and superficial phlebitis.

          -  Documented atherosclerotic vascular disease, including but not limited to prior
             myocardial infarction, angina, atrial fibrillation, stroke and TIA.

          -  Marked hypertriglyceridemia (>500 mg/dl).

          -  History of prior treatment with estrogen resulting in hypertriglyceridemia (> 500
             mg/dl).

          -  Serum calcium, alkaline phosphatase, PTH or TSH outside the normal reference range.

          -  History of nephrolithiasis or urolithiasis within 10 years prior to enrollment; those
             with a history of nephro- or urolithiasis must have an appropriate radiology study
             (e.g., IVP or KUB) within six months documenting absence of stones.

          -  Baseline 24-hour urine calcium > 250 mg.

          -  Known risk factors for hypercalcemia, e.g., malignancy, tuberculosis, sarcoidosis.

          -  History of any form of cancer except adequately treated squamous cell or basal cell
             skin carcinoma.

          -  Use of active vitamin D analogs or high dose vitamin D (≥50,000 IU weekly) in the last
             year.

          -  Active or suspected diseases (within 1 year prior to enrollment) that affect bone
             metabolism, e.g., renal osteodystrophy, hyperthyroidism, osteomalacia,
             hyperparathyroidism.

          -  Known allergy, hypersensitivity, contraindication or intolerance to teriparatide or
             raloxifene.

          -  History of vaginal bleeding within the past year.

          -  Renal failure or substantial hepatic impairment. Note "renal failure" is defined as a
             calculated creatinine clearance (using the Cockroft-Gault formula) of ≤ 35 ml/minute.

          -  Severe disease, e.g., cardiac, hepatic, pulmonary, etc., which may limit ability to
             complete this study. Specifically, significantly impaired hepatic function (ALT or GGT
             3x the upper limit of normal.

          -  Known malabsorption syndromes, e.g., celiac disease, active inflammatory bowel
             disease, gastric bypass, etc.

          -  Use of anion exchange resins (e.g., cholestyramine) in the past month.

          -  Current use of warfarin (coumadin).

          -  Current use of highly protein-bound drugs including diazepam, diazoxide and lidocaine.

          -  Current use of digoxin.

          -  Any prior use of bisphosphonates, denosumab, strontium, fluoride, teriparatide or
             parathyroid hormone.

          -  Prior use of estrogen, raloxifene, calcitonin or testosterone will be allowed if
             discontinued more than six months previously. Low dose intra-vaginal estrogens (0.3 mg
             or less of conjugated equine estrogen or equivalent) may be continued throughout the
             study.

          -  Treatment with glucocorticoids in doses ≥ 5 mg prednisone daily for > 30 days in the
             prior year.

          -  Treatment with other drugs known to affect bone metabolism, e.g., anticonvulsants
             except benzodiazepines or gabapentin, within the prior year. Note: oral calcium
             supplementation, vitamin D supplementation or diuretic use that has been stable for
             six months are allowed).

          -  Treatment within the last 30 days with any drug that has not received regulatory
             approval.

          -  Metal in spine precluding spine QCT.

          -  Any condition that may interfere with evaluation of at least two lumbar vertebrae
             determined on VFA performed at time of screening. Examples include confluent aortic
             calcification, severe osteoarthritis, spinal fusion and lumbar spine fractures.