Therapy of the Skeletal Disease of Type 2 Diabetes With Denosumab

Type 2 Diabetes Mellitus (T2DM) has become one of the most important diseases of our time.
Recent research shows that diabetes has negative effects on bones and that people with
diabetes might be more likely to break a bone. We don't know the reasons for this, but we
suspect that normal bone replacement is slowed down in diabetes and this could slow down the
growth of new bone. It is possible that the normal bone material becomes weaker because
sugar-related components ("Advanced Glycation Endproducts") are making the bone more brittle.
The investigators have shown in past research that people who have type 2 diabetes are more
likely to have both weaker bone with lower "bone material strength" and also higher levels of
sugar-related components ("Advanced Glycation Endproducts"). This study will focus on
attempting to lower the sugar-related components ("Advanced Glycation Endproducts") by
treating a group of patients with type 2 diabetes with a medication Prolia® or denosumab for
one year. The investigators will compare postmenopausal women both before and after denosumab
use and study them in terms of different bone features based on blood tests, bone imaging, a
bone indentation test and a measurement of sugar-related components in the skin. This study
will help to clarify if using this medication helps improve bone strength in women with
diabetes.

Inclusion Criteria:

1. An understanding, ability and willingness to fully comply with study procedures and
restrictions.

2. Ability to voluntarily provide written, signed and dated informed consent as
applicable to participate in the study.

3. Postmenopausal women age ≥ 55 and ≤ 75 years at time of consent.

4. Diagnosis of T2D for ≥ 10 years. Upon review of patient's medical history, patient
will be confirmed to currently have reasonably controlled T2D as assessed by the
investigator, with HbA1c ≤ 8.4%. If HbA1c is ≥ 8.5%, re-screening will be allowed
after approximately 3 months following adjustment of diabetes therapy.

5. Dual energy x-ray absorptiometry (DXA) T-score ≤ -1.5 at one or more sites (lumbar
spine, femoral neck, total hip or distal 1/3 radius).

6. Normal albumin-adjusted serum calcium level.

Exclusion Criteria:

1. Hormone replacement treatment use (to avoid the influence of estrogen).

2. Fractures (excluding skull, facial bones, metacarpals, fingers, toes, and fractures
associated with severe trauma) within 12 months.

3. A history of pathological fractures (eg, due to Paget's disease, myeloma, metastatic
malignancy).

4. Type 1 diabetes.

5. Disorders associated with altered skeletal structure or function (chronic renal
disease stage 4 or worse, chronic liver disease, malignancy, hypoparathyroidism or
hyperparathyroidism, acromegaly, Cushing's syndrome, hypopituitarism, chronic
obstructive pulmonary disease, alcohol intake > 3 units/day).

6. Treatment for blood clots or coagulopathy.

7. Treatment with any of the following drugs in past year: corticosteroids ≥ 5 mg/day (>3
mos. at any time or >10 days), anticonvulsant therapy, pharmacological doses of
thyroid hormone (TSH calcitonin, bisphosphonates, estrogen or selective estrogen receptor modulator, sodium
fluoride, denosumab, teriparatide, abaloparatide, strontium, fluoride,
thiazolidinediones (TZDs), SGLT2 inhibitors.

8. Serum 25(OH)D levels < 20 ng/ml. If 25(OH)D levels are < 20 ng/ml, rescreening will be
allowed following a vitamin D loading regimen of 50,000 IU/week for 4 weeks. If serum
25(OH)D levels are ≥ 20 ng/ml after supplementation, the subject will be allowed to
enroll.

9. Clinically significant hypersensitivity to denosumab or any components of denosumab 60
mg.

10. Known sensitivity to any of the products to be administered during the study (e.g.,
calcium or vitamin D).

11. Subject is pregnant or breast feeding, or planning to become pregnant within 5 months
after the end of treatment.

12. Female subject of child bearing potential and is not willing to use, in combination
with her partner, highly effective contraception during treatment and for 5 months
after the end of treatment.

13. Significant dental/oral disease, including prior history or current evidence of
osteonecrosis/osteomyelitis of the jaw, or the following:

- Active dental or jaw condition which requires oral surgery

- Non-healed dental/oral surgery

- Planned invasive dental procedures for the course of the study