Bisphosphonates for Prevention of Post-Denosumab Bone Loss

Phase 2

Completed

Conditions: IOP
Osteoporosis

Interventions: Drug: Alendronate
Drug: Zoledronic Acid

Registration Number: NCT03396315

Lead Sponsor: Columbia University

Brief Summary: The primary goal of the study is to assess the extent to which bisphosphonate therapy will prevent decreases in bone mass that may occur after cessation of denosumab in premenopausal women with idiopathic osteoporosis (IOP) enrolled in AAAN0161 (FD05114) "Denosumab for the prevention of post-teriparatide bone loss in premenopausal women with idiopathic osteoporosis".

In addition, the investigator will observe participants for a second year off bisphosphonate therapy to assess duration of response.

The hypothesis is that bisphosphonate therapy with alendronate or zoledronic acid, initiated after recovery of bone remodeling activity, will prevent significant bone loss after discontinuing denosumab.

Detailed Description: Osteoporosis in premenopausal women with normal menstrual function and no specific cause is termed idiopathic osteoporosis (IOP). IOP is a rare disease with an estimated prevalence of \<200,000 affected premenopausal women in the United States.

Women with IOP completing at least one year and up to three years of denosumab (Protocol AAAN0161) will be offered participation in this open-label study in which they would choose whether to take oral alendronate 70 mg weekly for 12 months or a single intravenous dose of zoledronic acid 5 mg. Subjects and study personnel will be blinded to BMD outcomes until 12 months.

Discontinuation of denosumab is followed by substantial increases in bone turnover markers to well above baseline, bone resorption reaching twice baseline levels for about 6 months. Over the first 12 months off therapy, all the bone density gained on treatment is lost. Studies done at the institution has demonstrated the occurrence of multiple vertebral fractures in some patients who have stopped denosumab. Based upon these new fracture data, the Prolia label is currently recommending that consideration should be given to transition to another antiresorptive drug in patients stopping denosumab. The main goals of this extension study are to determine rates of bone loss and incidence of radiographic vertebral fractures during one year of bisphosphonate therapy (oral alendronate or intravenous zoledronic acid) initiated after completing denosumab.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 24

Inclusion Criteria

All women completing at least 12 months of Forteo treatment and at least 12 months of denosumab under previous research studies who remain without a diagnosis of an excluded medical condition and medication exposures as detailed below, will be offered enrollment into this study.

Exclusion Criteria

Known intolerance to calcium supplements
Contraindications to bisphosphonate treatment:
1. Hypocalcemia
2. Pregnancy
3. Known hypersensitivity to bisphosphonates
History of osteomalacia
History of osteonecrosis of the jaw
History of dental extraction or other invasive dental surgery within the prior 4 weeks
Invasive dental work planned in the next 12 months
Any condition or illness (acute, chronic, or history), which in the opinion of the Investigator might interfere with the evaluation of efficacy and safety during the study or may otherwise compromise the safety of the subject
Self-reported or known alcohol or drug abuse within the previous 12 months
Current or recent (within 1 year of enrollment) inflammatory bowel disease or malabsorption
Abnormal laboratory tests performed during Visit 1
1. Renal insufficiency or liver disease: estimated glomerular filtration rate (eGFR) < 35 ml/min, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >50% above upper limit of normal
2. Hypercalcemia, hypocalcemia
3. Vitamin D deficiency: 25-Hydroxyvitamin D (25-OHD) < 30 ng/mL
Subjects must be willing to participate voluntarily. Specifically excluded are the following: 1) women less than 20 (or 35 in the case of those who wish to participate because they have low BMD); 2) protected individuals (institutionalized); 3) prisoners; 4) any other prospective participant who, for any reason, might not be able to give voluntary informed consent.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
alendronate	Alendronate	Subjects will receive oral alendronate
zoledronic acid	Zoledronic Acid	Subjects will receive zoledronic acid

Primary Outcome Measures

Name	Time	Method
Difference in BMD at the Lumbar Spine (L1-4) Within Group	Baseline, 12 month	Within-group difference (percent change) in BMD at the lumbar spine (L1-4) will be measured by Dual-energy X-ray absorptiometry (DXA) and calculated.

Secondary Outcome Measures