Romosozumab/Denosumab Study for Premenopausal IOP

Inclusion Criteria:

• Premenopausal women, aged 18-48, with regular menses and no historical orbiochemical secondary cause of osteoporosis; the lower age limit is to ensureepiphyses are fused, the upper to make it less likely that women will entermenopause during the study. All subjects under age 25 will be screened (bone ageradiograph) prior to enrollment to rule out open epiphyses.

• Documented adult fractures judged to be low-trauma (equivalent to a fall from astanding height or less) and T-score or Z-score ≤ -1.5 at the LS, TH or FN.

• Must agree to use highly effective contraception throughout the period of studydrug administration.

Highly effective contraception includes methods considered by the CDC to be >99% effective (e.g. vasectomized partner, tubal ligation, hysterectomy, IUD) as well as a combination of barrier method (condoms) with hormonal contraception considered to be > 90% effective (oral contraceptive pill, patch or ring). Systemic progestin only methods (oral or implanted) are not included due to their effect on systemic estrogen levels and thus potential effects on bone health in this premenopausal population.

Exclusion Criteria:

• Any cardiovascular disease: history of myocardial infarction (MI) or stroke. Normalelectrocardiogram (ECG) or ECG with no clinically significant abnormality isrequired at study entry.

• Conditions requiring chronic anticoagulation (coumadin, heparins)

• Early follicular phase serum FSH>20 mIU/ml (to exclude perimenopausal women)

• Disorders of mineral metabolism: primary/secondary hyperparathyroidism, osteomalacia (including that associated with a diagnosis of hypophosphatasia), vitamin Ddeficiency

• Suspicion of osteomalacia (elevated alkaline phosphatase, bone pain exacerbatedby weight bearing, bone tenderness)

• Vitamin D deficiency (serum 25-OHD<30ng/ml). Women with levels of 10-29 ng/mlwill be eligible after treatment with vitamin D has resulted in levels ≥30ng/ml.

• Hypocalcemia

• Hypercalciuria: urinary calcium excretion over 300 mg/g Cr that can not beeffectively lowered with medical management (reduced calcium intake, thiazidediuretics). As in our prior studies, prevalent nephrolithiasis in the absenceof pretreatment hypercalciuria is not an exclusion.

• Current pregnancy or lactation

• Highly effective contraception is required, pregnancy testing is performed ateach visit

• Current active eating disorder, hypothalamic or exercise induced amenorrhea.Patients with past history of these disorders, resolved > 1 year ago, are eligibleto participate. The Eating Aptitude Test -Questionnaire is given to identify womenwith subclinical eating disorders

• Current malignancy

• Endocrinopathy: new onset untreated hyperthyroidism/hypothyroidism, Cushing'ssyndrome, prolactinoma

• Renal insufficiency (eGFR below 60 ml/min)

• Liver disease (AST, ALT, bilirubin, total alkaline phosphatase activity above uppernormal limit)

• Intestinal malabsorption disorders including but not limited to pancreaticinsufficiency, active Crohn Disease or untreated celiac disease.

• History/current GCs, anticonvulsants, anticoagulants, methotrexate, GnRH agonists tosuppress menstruation

• Oral glucocorticoid dose equivalent >5 mg prednisone for >3 months.

• Current use of specific anticonvulsants (carbamazepine, phenytoin, phenobarbital),methotrexate, GnRH agonists to suppress menstruation. Subjects who completedtreatment with these medications > 1 year ago are eligible to participate

• Current GCs (oral GC equivalent to 5mg prednisone or more). Subjects who completedtreatment with these medications for ≤ 3 months, > 1 year ago are eligible toparticipate.

• Current anticoagulant use; past use of warfarin (Coumadin) or low molecular weightheparin is not an exclusion, although known thrombotic disease is an exclusion

• Depo Provera (depot medroxyprogesterone acetate) unless taken after age 20, morethan 5 years ago

• Drugs for osteoporosis (raloxifene, bisphosphonates, denosumab, calcitonin,TPTD/abaloparatide): Subjects who discontinue these medications will be eligible:

• 3 months after stopping raloxifene or calcitonin

• 12 months after stopping abaloparatide, teriparatide, alendronate, risedronate,ibandronate, or pamidronate

• 24 months after the last dose of zoledronate

• 18 months after the last dose of denosumab. Subjects who have received ≤ 6months of teriparatide or abaloparatide will be eligible 2 months after thelast dose.

Subjects who have received ≤ 12 months of teriparatide or abaloparatide will be eligible 6 months after the last dose.

• Women with a history of dental extraction or other invasive dental work within 3months, or who require invasive dental work within the next two years, will beexcluded

• Hypersensitivity to romosozumab or denosumab