Clinical trial NCT03396315: Bisphosphonates for Prevention of Post-Denosumab Bone Loss
Official title: Bisphosphonates for Prevention of Post-Denosumab Bone Loss in Premenopausal Women With Idiopathic Osteoporosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: IOP
Osteoporosis
Keywords: premenopausal women
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Amgen
First posted: 2018-01-10
Enrollment: 24
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Difference in BMD at the Lumbar Spine (L1-4) Within Group
timeFrame: Baseline, 12 month
Secondary outcomes:
Other outcomes:
Locations:
city: Omaha
country: United States
facility: Creighton University
state: Nebraska
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Elizabeth Shane, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cohen A, Recker RR, Lappe J, Dempster DW, Cremers S, McMahon DJ, Stein EM, Fleischer J, Rosen CJ, Rogers H, Staron RB, Lemaster J, Shane E. Premenopausal women with idiopathic low-trauma fractures and/or low bone mineral density. Osteoporos Int. 2012 Jan;23(1):171-82. doi: 10.1007/s00198-011-1560-y. Epub 2011 Mar 2.
citation: Cohen A, Dempster DW, Recker RR, Stein EM, Lappe JM, Zhou H, Wirth AJ, van Lenthe GH, Kohler T, Zwahlen A, Muller R, Rosen CJ, Cremers S, Nickolas TL, McMahon DJ, Rogers H, Staron RB, LeMaster J, Shane E. Abnormal bone microarchitecture and evidence of osteoblast dysfunction in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab. 2011 Oct;96(10):3095-105. doi: 10.1210/jc.2011-1387. Epub 2011 Aug 10.
citation: Cohen A, Lang TF, McMahon DJ, Liu XS, Guo XE, Zhang C, Stein EM, Dempster DW, Young P, Saeed I, Lappe JM, Recker RR, Shane E. Central QCT reveals lower volumetric BMD and stiffness in premenopausal women with idiopathic osteoporosis, regardless of fracture history. J Clin Endocrinol Metab. 2012 Nov;97(11):4244-52. doi: 10.1210/jc.2012-2099. Epub 2012 Sep 7.
citation: Cohen A, Liu XS, Stein EM, McMahon DJ, Rogers HF, Lemaster J, Recker RR, Lappe JM, Guo XE, Shane E. Bone microarchitecture and stiffness in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab. 2009 Nov;94(11):4351-60. doi: 10.1210/jc.2009-0996. Epub 2009 Oct 16.
citation: Cohen A, Stein EM, Recker RR, Lappe JM, Dempster DW, Zhou H, Cremers S, McMahon DJ, Nickolas TL, Muller R, Zwahlen A, Young P, Stubby J, Shane E. Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study. J Clin Endocrinol Metab. 2013 May;98(5):1971-81. doi: 10.1210/jc.2013-1172. Epub 2013 Mar 29.
citation: Nishiyama K, Wang J, Young P, et al. Teriparatide Is Associated with Improved Microarchitecture and Estimated Bone Strength in Premenopausal Women with Idiopathic Osteoporosis: An HR-pQCT Study. American Society for Bone and Mineral Research Annual Meeting; 2013; Baltimore, MD: American Society for Bone and Mineral Research
citation: Cosman F, Nieves J, Woelfert L, Formica C, Gordon S, Shen V, Lindsay R. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res. 2001 May;16(5):925-31. doi: 10.1359/jbmr.2001.16.5.925.
citation: Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest. 1998 Oct 15;102(8):1627-33. doi: 10.1172/JCI3914.
citation: Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: results of a randomized controlled clinical trial. J Bone Miner Res. 2000 May;15(5):944-51. doi: 10.1359/jbmr.2000.15.5.944.
citation: Finkelstein JS, Arnold AL. Increases in bone mineral density after discontinuation of daily human parathyroid hormone and gonadotropin-releasing hormone analog administration in women with endometriosis. J Clin Endocrinol Metab. 1999 Apr;84(4):1214-9. doi: 10.1210/jcem.84.4.5643.
citation: Cohen A, Kamanda-Kosseh M, Recker RR, Lappe JM, Dempster DW, Zhou H, Cremers S, Bucovsky M, Stubby J, Shane E. Bone Density After Teriparatide Discontinuation in Premenopausal Idiopathic Osteoporosis. J Clin Endocrinol Metab. 2015 Nov;100(11):4208-14. doi: 10.1210/jc.2015-2829. Epub 2015 Sep 10.
citation: Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, Grazette L, San Martin J, Gallagher JC. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011 Apr;96(4):972-80. doi: 10.1210/jc.2010-1502. Epub 2011 Feb 2.
citation: Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-229. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26.
citation: Anastasilakis AD, Makras P. Multiple clinical vertebral fractures following denosumab discontinuation. Osteoporos Int. 2016 May;27(5):1929-30. doi: 10.1007/s00198-015-3459-5. Epub 2015 Dec 22. No abstract available.
citation: Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical Features of 24 Patients With Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases. J Bone Miner Res. 2017 Jun;32(6):1291-1296. doi: 10.1002/jbmr.3110. Epub 2017 Mar 13.
citation: Anastasilakis AD, Yavropoulou MP, Makras P. Bisphosphonates or denosumab discontinuation and risk of fractures. Maturitas. 2017 Aug;102:75. doi: 10.1016/j.maturitas.2017.04.016. Epub 2017 Apr 27. No abstract available.
citation: Anastasilakis AD, Yavropoulou MP, Makras P, Sakellariou GT, Papadopoulou F, Gerou S, Papapoulos SE. Increased osteoclastogenesis in patients with vertebral fractures following discontinuation of denosumab treatment. Eur J Endocrinol. 2017 Jun;176(6):677-683. doi: 10.1530/EJE-16-1027. Epub 2017 Mar 10.
citation: Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O. Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int. 2016 May;27(5):1923-5. doi: 10.1007/s00198-015-3380-y. Epub 2015 Oct 28.
citation: Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B. Severe Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: 9 Clinical Cases Report. J Clin Endocrinol Metab. 2017 Feb 1;102(2):354-358. doi: 10.1210/jc.2016-3170.
citation: Popp AW, Zysset PK, Lippuner K. Rebound-associated vertebral fractures after discontinuation of denosumab-from clinic and biomechanics. Osteoporos Int. 2016 May;27(5):1917-21. doi: 10.1007/s00198-015-3458-6. Epub 2015 Dec 22.
citation: Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios D, Siddhanti S, Borenstein J, Kendler DL; DAPS Investigators. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. 2012 Jan;23(1):317-26. doi: 10.1007/s00198-011-1780-1. Epub 2011 Sep 17.
citation: Reid IR, Horne AM, Mihov B, Gamble GD. Bone Loss After Denosumab: Only Partial Protection with Zoledronate. Calcif Tissue Int. 2017 Oct;101(4):371-374. doi: 10.1007/s00223-017-0288-x. Epub 2017 May 13.