Longitudinal Effects of Denosumab on Trabecular Bone Score and Femur Strength Index

Bone fractures are a major cause of morbidity and health care expense among patients with
osteoporosis.The goal of osteoporosis therapy is to reduce fracture risk. The administration
of denosumab 60 mg subcutaneously (SC) every six months has been shown to limit bone
turnover, increase bone mineral density (BMD), and reduce the risk for new vertebral,
non-vertebral, and hip fractures among postmenopausal women with osteoporosis (Cummings,
2009). Although BMD is an important factor for fracture risk, it does not describe bone
microarchitecture, which is related to bone quality and mechanical bone strength. Trabecular
bone score (TBS) is an index for bone microarchitecture extracted from anterior-posterior
spine dual-energy X-ray absorptiometry (DXA). Previous research has shown TBS to
differentiate between women with and without fractures as well as predict future fracture
even after adjustment for BMD (Simonelli, Leib, Winzenrieth, & Hans, 2012). In a study of
29,407 Canadian women age 50 years and older at the time of baseline hip and spine DXA,
health service records were assessed to determine the incidence of non-traumatic osteoporotic
fractures subsequent to BMD testing. Lumbar spine TBS was derived for each DXA examination
and blinded to clinical parameters and outcomes. Osteoporotic fractures were identified in
1668 (5.7%) women, including 439 (1.5%) spine and 293 (1.0%) hip fractures. Significantly
lower spine TBS and BMD were found in women with major osteoporotic, spine, and hip fractures
(p<0.0001). The results of this study suggest that spine TBS is predictive of osteoporotic
fractures and provides additional clinical information independent of spine and hip BMD;
therefore, combining TBS trabecular texture index with BMD incrementally improves fracture
prediction in postmenopausal women (Hans, Goertzen, Krieg, & Leslie, 2011).

Clinical research has demonstrated the positive effect of denosumab on TBS over time. In a
randomized, double-blind, placebo-controlled trial of 215 postmenopausal women with low BMD
at the spine or total hip, denosumab (60mg SC every 6 months) was found to increase lumbar
spine QCT, DXA, and TBS at 12 months compared to placebo or alendronate (Thomas, 2013). In
another study conducted by McClung et al, postmenopausal women with osteoporosis who received
denosumab were found to have significant increases in TBS, independent of BMD, at 36 months
compared to baseline and placebo (McClung, Lippuner, Brandi, Kaufman, Zanchetta, & Krieg,
2012).

Femur strength index (FSI), which is a measure of femoral bone density, structure, and
strength, has also been shown to predict hip fracture independent of bone density and hip
axis length. In a study which compared FSI in a group of women age 50 years and older with
and without hip fracture (365 with prior hip fracture and 2,141 controls), FSI was found to
be significantly lower in the fracture group, after adjusting for T score and hip axis length
(Faulkner, et al., 2006). Like TBS, FSI can be obtained from femur DXA measurements using
modern software.

This is a single-site, open-label, non-randomized, observational study designed to assess the
change in TBS and FSI at 36 months. among post-menopausal women with osteoporosis taking
denosumab. All patients included in this study are under the medical care of the principal
investigator. Subjects will enter the study once they have completed 36 months of treatment
with denosumab and have evaluable DXA scans. Medical records will be retrospectively reviewed
and percent change in TBS and FSI scores will be calculated.

Inclusion Criteria:

- Subjects must meet the following inclusion criteria to be eligible for study entry:

- Post-menopausal female with diagnosed osteoporosis

- Age 40-90 years

- Completed 36 months of denosumab therapy (SQ; 60mg every 6 months) but not yet
received the 42 month injection

- Availability of DXA scans at the study-required time points, including the
willingness of subjects to undergo a DXA evaluation at 36 months, if required

- Provided written informed consent

Exclusion Criteria:

- Patients will be excluded from this study for any of the following reasons:

- Received denosumab injections for less than 36 months

- Patients who have missed more than 1 dose of denosumab in a 36 month period

- Contra-indicated for treatment with denosumab

- History of rheumatoid arthritis

- Current diagnosis of hyperparathyroidism; hyperthyroidism; osteomalacia, or other
known diseases that can affect bone

- In the opinion of the investigator, have any kind of disorder that may compromise
the ability of the subject to provide written informed consent