Study Description

One in three women and one in five men will experience an osteoporotic fracture during their lifetime. Currently, available medications reduce fracture risk but are unable to fully restore skeletal integrity. Thus, there remains an urgent need for osteoporosis treatments that rapidly and effectively restore bone strength. Unlike most chronic conditions, osteoporosis has historically been treated with only one drug at a time. Attempts to combine anabolic agents with the most commonly used antiresorptive agents (bisphosphonates) did not prove efficacious. In contrast, we recently reported that the combination of teriparatide and the receptor activator of nuclear factor-κB ligand (RANKL) inhibitor, denosumab, increases bone density and improves bone microarchitecture and estimated strength more than either drug alone and more than any available therapy.

The study team has hypothesized that the efficacy of this combination is dependent on denosumab’s capacity to fully block teriparatide’s stimulation of bone resorption while allowing for teriparatide-induced stimulation of bone formation (modeling-based bone formation). In this proposal, the study team will directly assess the ability of teriparatide to stimulate modeling-based bone formation when bone resorption is blocked by denosumab. Furthermore, the study team will define the cellular and molecular mechanisms by which this combination achieves its efficacy.

To accomplish these aims, the study team will perform a short-term clinical trial in which postmenopausal osteoporotic women are randomized to receive three-months of teriparatide, denosumab or both medications. Iliac crest bone biopsy specimens will then be sampled from all subjects after quadruple-labeling, an innovative technique that is able to assess the effects of short-term interventions on bone resorption and formation without requiring “paired” biopsies in a single subject. With this technique, the study team is also able to evaluate treatment-induced changes in both static and dynamic indices of bone metabolism in each bone envelope separately (cancellous, endocortical, intra-cortical, and periosteal) and thus calculate the proportion of remodeling versus modeling- based bone formation in each skeletal compartment. This new understanding, in turn, will provide the framework for the design of studies with the potential to fundamentally advance osteoporosis treatment.

ELIGIBILITY CRITERIA:

Ages Eligible for Study:           45 Years and older   (Adult, Older Adult)

Sexes Eligible for Study:          Female

Accepts Healthy Volunteers:  Yes

Inclusion Criteria:

• Women aged 45+
• Postmenopausal
• Osteoporotic with high risk of fracture

Exclusion Criteria:

• Significant previous use of bone health modifying treatments
• Known congenital or acquired bone disease other than osteoporosis
• Significant renal disease, liver disease, cardiopulmonary disease, or psychiatric disease
• Abnormal calcium or parathyroid hormone level
• Serum vitamin D <20 ng/mL or >60ng/mL
• Serum alkaline phosphatase above upper normal limit with no explanation
• Anemia (hematocrit <32%)
• History of malignancy (except non-melanoma skin carcinoma), radiation therapy, or gouty arthritis
• History of urolithiasis within the last one year
• Excessive alcohol use or substance abuse
• Use of oral or parenteral glucocorticoids for more than 14 days within the past 6 months
• Extensive dental work involving extraction or dental implant within the past or upcoming 2 months
• Known sensitivity to mammalian cell-derived drug products
• Known contraindications to denosumab, teriparatide, or any of their excipients
• Known contraindications to tetracycline, demeclocycline, or other antibiotics in this drug class
• Continuous use of tetracycline for >1-month duration within the last 10 years

Study Design:

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: None (Open Label)

Primary Purpose: Treatment

Study Location(s):

Massachusetts General Hospital, Boston, Massachusetts, United States, 02114

Study Website:

https://www.clinicaltrials.gov/ct2/show/NCT04026256?term=NCT04026256&draw=2&rank=1