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Bisphosphonates Maintain BMD after Sequential Teriparatide and Denosumab in

Premenopausal Women with Idiopathic Osteoporosis

Mafo Kamanda-Kosseh

, Stephanie Shiau

, Sanchita Agarwal

, Ananya Kondapalli

, Ivelisse

Colon

, Nayoung Kil

, Mariana Bucovsky

, Joan M. Lappe

, Julie Stubby

, Elizabeth Shane

, Adi

Cohen

Columbia University Irving Medical Center, New York, New York, USA

Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ,

USA

Creighton University Medical Center, Omaha, Nebraska, USA

Keywords (< 6): Premenopausal osteoporosis, teriparatide, denosumab, bisphosphonate,

alendronate, zoledronic acid, bone density, HR-pQCT, bone turnover markers

Adi Cohen MD, MHS

https://orcid.org/0000-0002-0641-5747

Columbia University, College of Physicians & Surgeons

Department of Medicine, Division of Endocrinology

180 Fort Washington Avenue, HP9-910

New York, NY 10032

Telephone: 212-305-7225 Telefax: 212-342-4161

Email: ac1044@columbia.edu

The extension study was supported by Amgen, as an Investigator Initiated Study (ISS

#20177429). The parent studies of teriparatide and sequential denosumab were funded by the

United States Food and Drug Administration (FDA) Orphan Products Clinical Trials Grants

Program (R01 FD003902; R01005114). These studies were also supported by the National

Institutes of Health / National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24

AR052665; R03 AR064016), Thomas L. Kempner, Jr. and Katheryn C. Patterson and the

Simon-Strauss Foundation.

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Disclosure summary: AC, ES, and JML receive research support from Amgen.

Trial Registration

ClinicalTrials.gov NCT

03396315

ABSTRACT

Context:

We previously reported that sequential teriparatide followed by denosumab

substantially increases BMD in premenopausal idiopathic osteoporosis (PremenIOP).

Objective:

To determine whether administration of bisphosphonates after denosumab cessation

is associated with stable BMD in PremenIOP

Design:

Open-label extension study

Participants:

24 PremenIOP Teriparatide-Denosumab Study participants

Interventions

: Oral alendronate (ALN), 70mg weekly, or IV zoledronic acid (ZOL), 5mg once

(patient choice), was administered 7 months (M) after final denosumab dose.

Outcomes:

BMD by DXA and serum C-telopeptide (CTX) q6M; vertebral fracture assessment

(VFA) and HR-pQCT q12M.

Results:

24 women with PremenIOP (aged 43±8 years), severely affected with low trauma adult

fractures (range 0-12; 9 with vertebral fractures) and/or very low BMD, had large BMD increases

on sequential teriparatide-denosumab (spine: 25±9%; total hip: 11±6%). During the

Bisphosphonate Extension, mean BMD and CTX changes in the entire group were small and

not statistically significant at 6 or 12M.

Women choosing ZOL (n=6) versus ALN (n=18) did not differ by baseline age, BMI, fractures,

BMD, or CTX. On ZOL, there were small LSBMD declines and CTX increases, particularly

between 6M and 12M, while greater stability was observed on ALN.

Changes in BMD and CTX did not differ by duration of denosumab (36M vs <36M) or between

20 women who remained premenopausal and 4 who transitioned into menopause. Higher pre-

teriparatide CTX, likely reflecting baseline remodeling status, predicted more spine and hip bone

loss. No new vertebral (clinical or VFA screening) or non-vertebral fractures occurred.

Conclusion:

BMD remained stable in women with PremenIOP who received bisphosphonates

after sequential teriparatide-denosumab therapy.

Introduction

Premenopausal women with early onset osteoporosis and no known cause of bone loss or bone

fragility are considered to have idiopathic osteoporosis (IOP). Premenopausal women with IOP

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have deficits in bone density and microarchitecture

1-3

and variable bone remodeling activity as

assessed by serum bone formation markers

and tissue level bone formation rate (BFR/BS) on

tetracycline-labelled transiliac biopsies

We recently reported that a sequential protocol of teriparatide for two years followed by

denosumab for two to three years markedly increased areal BMD by dual energy x -ray

absorptiometry (DXA) at the spine and hip in premenopausal women with IOP

5,6

. On

teriparatide, serum bone turnover markers (BTMs), N-terminal propeptides of procollagen type 1

(P1NP), osteocalcin (OCN) and C-telopeptide (CTx), increased significantly by three months

and remained above baseline by 24 months

. On denosumab, serum P1NP, OCN and CTx

decreased by approximately 75-85% by three months after the first dose of denosumab and

remained suppressed

Denosumab cessation without additional treatment is known to result in increased BTMs, rapid

bone loss and increased vertebral fracture risk

7-9

in postmenopausal women. The risk of bone

loss and fracture with denosumab cessation in premenopausal women with IOP is unknown.

Our prior study has shown that premenopausal women with IOP lose bone mass after stopping

teriparatide

. In that context, and, since raloxifene, a selective estrogen receptor modulator, has

been ineffective in preventing bone loss after denosumab in postmenopausal women

, and

bone loss and vertebral fracture has been reported with denosumab cessation in a men with

IOP

and nonmetastatic prostate cancer

, we considered this premenopausal group, many

with vertebral fractures, to be at risk for bone loss without antiresorptive after denosumab

cessation. Additionally, current denosumab package labeling and current guidelines recommend

bisphosphonate or other antiresorptive therapy after completing a course of denosumab

8,14,15

Therefore, we enrolled participants who had completed teriparatide followed by denosumab in

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an open label study in which they received 12 months of oral or IV bisphosphonate treatment

(patient centered choice) followed by 12 months of observation.

The primary goal of the study was to assess whether consolidation therapy with oral or

intravenous bisphosphonate would prevent bone loss expected with denosumab cessation.

Additional goals were to assess the effects of consolidation therapy on CTX and on bone quality

as assessed by high resolution peripheral quantitative computed tomography (HR-pQCT), as

well as on incident fractures and other adverse events. We hypothesized that both oral and IV

bisphosphonate would prevent bone loss after denosumab cessation in premenopausal women

with IOP. Herein, we present results of the first 12 months of this Bisphosphonate Extension

Study.

Methods

Premenopausal women with IOP who had completed teriparatide treatment under FD003902

and sequential denosumab under FD005114

were eligible to participate in this open label

bisphosphonate extension study conducted at Columbia University Irving Medical Center

(CUIMC), New York, NY and Creighton University Medical Center, Omaha, NE.

Because of the young age of the participants, the risks of long term antiresorptive therapy, the

plan for post-denosumab bisphosphonate transition that would lengthen the treatment course,

and pregnancy planning considerations for some participants, FD005114 planned a limited

course denosumab. FD005114 offered 2-3 years of denosumab therapy based on patient

choice after discussion of individual factors including disease severity, response history, and

future pregnancy planning. Six patients were treated for 2 years, while 18 were treated for 3

years.

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Bisphosphonate treatment was initiated 7 months after the last denosumab dose. We designed

a protocol initiating bisphosphonate 7 months after the last denosumab dose because it had

been hypothesized that treatment with IV bisphosphonate while denosumab remains fully active

on bone may limit bone uptake and efficacy in this setting

. Participants chose either

alendronate (ALN) 70 mg po weekly for 12 months or one dose of zoledronate (ZOL) 5 mg IV,

after discussion of benefits, risks, potential side effects and administration method associated

with each medication.

Participants were assessed for habitual dietary calcium intake and provided with calcium

supplements that contained 315 mg of elemental calcium (as the citrate salt) and 250

international units (IU) of vitamin D; they were instructed to take two tablets daily as well as a

multivitamin with 400 IU of vitamin D, for a total of 630 mg calcium and 900 IU vitamin D.

The Columbia University Irving Medical Center Institutional Review Board (IRB) reviewed and

approved the study (IRB AAAN0161); the Creighton University Medical Center IRB approved

the study after it was approved by Columbia. All participants provided their written informed

consent. A Data and Safety Monitoring Committee met annually throughout the study.

Inclusion and exclusion criteria were those of the parent studies

5,6

. Eligible participants were

required to have regular menses, early follicular phase follicle stimulating hormone levels less

than 20 mIU/mL, no historical or biochemical secondary cause of osteoporosis, and no clinical

features of known monogenetic forms of osteoporosis (e.g., osteogenesis imperfecta). Prior to

enrollment in FD003902, all had radiographically documented adult, low-trauma fractures and/or

T-

scores that were ≤ -2.5 or Z-scores ≤ -2.0 at the lumbar spine (LS), femoral neck (FN) or total

hip (TH). Low trauma was defined as equivalent to a fall from a standing height or less; skull

and digit fractures were excluded. Women with secondary causes of osteoporosis (estrogen

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deficiency, eating disorders, celiac or gastrointestinal disease), osteomalacia, renal insufficiency,

abnormal liver function tests, hyperparathyroidism, urinary calcium above 300 mg/g creatinine,

serum 25-hydroxyvitamin D (25-OHD) levels below 20 ng/ml, specific drug exposures

(glucocorticoids, anticonvulsants, methotrexate, depot medroxyprogesterone acetate,

gonadotrophin releasing hormone agonists for suppression of menstrual cycles) were excluded.

If serum 25-OHD levels were < 30 ng/ml at baseline, additional vitamin D was prescribed as

clinically appropriate to maintain levels > 30 ng/ml. Normal serum calcium and renal function

were required. Participants were counseled regarding the need for effective contraception and

negative urine pregnancy tests were required at each visit.

Fasting morning serum was collected at the Bisphosphonate Extension Study baseline (7

months after the last denosumab dose), six and 12 months and stored at -80

C for batch

analyses of CTX performed in the Biomarkers Core of the Irving Institute for Clinical and

Translational Research at Columbia University. CTX was assessed by ELISA (RRID:

AB_2923399; IDS, Boldon, UK).

Fasting serum calcium and serum 25-OH vitamin D were

measured at baseline and fasting serum calcium was measured for each visit (Quest

Diagnostics).

Areal BMD was measured by DXA (Discovery, Hologic Inc., Waltham, MA) at baseline, 6 and 12

months at the LS, TH, FN and distal radius (DR)

. For 22 subjects, all scans were obtained on

the same machine at Columbia or Creighton over the course of all studies. Due to COVID

related travel restrictions, for 2 subjects (ALN group), scans obtained on the same outside

facility Hologic machine over the entire course of the Bisphosphonate Extension Study were

included in analyses. Short-term coefficient of variation is 0.7% (LS) and 1.4% (FN) at Columbia

and 1.5% (LS and FN) at Creighton. Phantoms were circulated between the study sites

(Columbia and Creighton). T- and Z-

scores were generated using the manufacturer’s database.

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Trabecular Bone Score (TBS), a textural analysis of LS BMD images, was assessed at L1-L4

using TBS iNsight software version 3.1.2.

Prespecified retreatment criteria were applied at the 6-month timepoint for participants who had

chosen ALN treatment: the option to change to IV zoledronate 5mg was offered if there was

significant bone loss defined as greater than the manufacturer specified least significant change

at the spine, total hip or femoral neck resulting in a T score ≤ -2.5. There were no per protocol

retreatment criteria for the ZOL group.

Screening for moderate and severe vertebral fractures was performed by Vertebral Fracture

Assessment (VFA) on lateral spine images (evaluable vertebrae T4 to L5) using Hologic QDR

Physician Viewer software at baseline and 12 months of bisphosphonate treatment. Participants

were categorized as having vertebral fractures based on an International Society for Clinical

Densitometry (ISCD)-

certified densitometrist’s (AC) reading of the interpretable image using the

Genant semi-quantitative method, the currently recommended clinical technique. For the

diagnosis of moderate (25-40% reduction in vertebral height) or severe (>40% reduction in

vertebral height) fractures, sensitivity and specificity of VFA are comparable to spine

radiographs

HR-pQCT scans were performed at CUIMC at baseline and after 12 months of bisphosphonate

treatment using the second-generation scanner (XtremeCT II; XCT2, Scanco Medical,

Brüttisellen, Switzerland; 68 kVp voltage, 1460

μA current, 43 sec integration time) with an

isotropic voxel size of 60.7 μm. Scans of the non-dominant distal radius and tibia were acquired

unless there was a contraindication (prior fracture or metal implant), in which case the

contralateral limb was scanned. Briefly, a reference line was placed at the distal endplate on a

2-D scout view and scans were acquired using a standard fixed offset of 9 mm and 22 mm from

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the reference line at the radius and tibia, respectively generating a 10.2 mm long scan region in

the axial direction. Attenuation data were converted to equivalent hydroxyapatite (HA) densities.

The analytic methods have been described

18-20

, validated

21-23

and applied in various clinical

studies

24-27

. The manufacturer’s phantom was scanned daily for quality control.

In vivo

short

‐

term reproducibility (CV) for HR-pQCT measures at CUIMC is less than 1.5% for all

density measurements and less than 5.0 % for structural parameters except cortical porosity. All

scans were visually inspected for motion; scans with a motion score >3 were excluded from

analyses

Bone strength was estimated from the HR-pQCT images using micro-finite element analysis

(μFEA) based on a voxel conversion approach

29,30

. We simulated axial compression on each

radius and tibia model up to 1% strain using a homogeneous Young's modulus of 10 GPa and

Poisson's ratio of 0.3 to estimate stiffness (kN/mm)

. Failure load (N) was estimated based on

criterion by Pistoia et al.

. We used a commercial μFEA solver (FAIM, v8.0, Numerics88,

Calgary AB, Canada) to solve the models as previously described

Data Handling Procedures and Statistical Analysis

All data, including data collected on case report forms were entered into Microsoft Excel

(Microsoft Corporation, Redmond, WA) and imported to SAS (SAS Institute, Cary, NC). Missing

data were not imputed.

Given the non-randomized study design, the primary objective was to estimate the within-group

change in BMD by DXA at the lumbar spine (primary), total hip and femoral neck (secondary)

after stopping denosumab treatment. A one-sample two-tailed T-test against the null hypothesis

of no change was used to assess whether bisphosphonate treated patients differ on DXA

outcomes relative to the measurements acquired at the end of the denosumab treatment period,

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(7 months after the final dose of denosumab). The primary outcome was the within-group

difference (percent change) in LS BMD between the baseline bisphosphonate visit (which

coincided with the final denosumab study visit) and the 12-month bisphosphonate visit.

Secondary outcomes included the within-group difference (percent change) in (1) LS BMD at

6M, (2) TH, FN and DR BMD between the baseline bisphosphonate visit and the 6 and 12-

month visits, (3) change in HRpQCT parameters at 12 months, and (4) change in serum CTX at

6 and 12 months.

For this analysis method, assuming the largest SD (4.30%) for change in spine aBMD that we

had observed both in our historical cohort of women with IOP who discontinued teriparatide

and a 3% margin, we estimated that we would have >90% power to estimate the confidence

interval for an absolute change in aBMD at the spine (primary outcome), total hip and femoral

neck (exploratory outcomes) with a sample size of 25-30.

Pre-planned exploratory analyses compared DXA BMD and CTX change between the ALN and

ZOL treated groups and assessed relationships between remodeling parameters and BMD

change. No adjustments were made for multiple comparisons.

As this was a small, non-randomized study, we were not able to compare incidence of adverse

events or incident fractures in oral vs IV bisphosphonate subjects. However, we prospectively

captured all serious and nonserious adverse events, with particular emphasis on incident

vertebral fractures (by VFA scans at baseline and 12 months and radiographs of incident clinical

vertebral fractures) and non-vertebral fractures (verified by review of radiographs or radiograph

reports). All data are presented ± SD, excepting the Figures which are presented ± SE.

Role of the funding source

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This study was supported as an Investigator Initiated Study by Amgen Inc. while the two parent

studies were supported by the United States Food and Drug Administration (FDA) Orphan

Products Clinical Trials Grants Program. The principal investigators, Dr. Cohen and Dr. Shane,

designed and conducted the study. Amgen Inc. had no role in collection, analysis, and

interpretation of data, writing of the report, or decision to submit for publication. Statisticians at

Rutgers University performed all analyses. These studies were also supported by R03

AR064016 (Cohen), K24 AR052665 (Shane) and K23 AR054127 (Cohen), Thomas L. Kempner,

Jr. and Katheryn C. Patterson and the Simon-Strauss Foundation. Dr. Cohen and Dr. Shane had

full access to all study data and had final responsibility for the decision to submit for publication.

Results

From 4/2018 to 5/2021, 32 eligible women who had completed the Teriparatide and Denosumab

Studies were offered enrollment in the Bisphosphonate Extension Study and 27 women enrolled

(Figure 1). Of the 27, one was lost to follow up and two women were not able to travel for DXA

scanning at the study sites due to COVID travel restrictions. Therefore, 24 participants are

included in Table 1. At entry into the Teriparatide Study, mean age was 37.7 ± 8.1 years; at

entry into the Bisphosphonate Extension Study, mean age was 43.2 ± 8.0 years. At entry to the

Teriparatide Study, participants were severely affected with low trauma adult fractures (range 0-

12) and/or very low BMD. Nine women had a history of vertebral fractures. Six women had

previously presented with fractures during pregnancy or lactation and were considered to have

pregnancy and lactation associated osteoporosis (PLO) in addition to idiopathic osteoporosis.

Of these six, four had sustained vertebral fractures, while two had hip fractures. Additional

fractures sustained during the Teriparatide Study (in 3 participants: metatarsal, rib, (recurrent)

vertebral) and Denosumab Study (in 2 participants: radius, femur/tibia stress reaction) have

been previously reported

5,6

; the five subjects involved all enrolled in this Bisphosphonate

Extension Study (2 in the ZOL group, 3 in ALN).

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Per protocol, bisphosphonate initiation (oral or IV) was planned at 7 months after the last

denosumab dose. Bisphosphonate therapy was initiated at a mean of 7.3 ± 0.5 months after last

denosumab dose (range 7-9 months after last denosumab). Three women who initiated

bisphosphonate treatment 8-9 months after the last denosumab dose are included in these

analyses.

After completing sequential teriparatide-denosumab, participants demonstrated large increases

in BMD: 25 ± 9% at lumbar spine (LS), 11 ± 6% at the total hip (TH), and 14 ± 7% at the femoral

neck (FN). Pretreatment baseline LS BMD Z score was -2.0 ± 0.9, increasing to -0.1 ± 1.0 after

teriparatide-denosumab. Mean CTX was 342 ± 166 pg/mL before starting teriparatide and 173 ±

203 pg/mL after completing denosumab (Table 1).

Changes in BMD and CTX in All Participants

During bisphosphonate treatment, on average, there was no significant bone loss at the LS, TH,

FN, or forearm at 6 or 12 months. Mean CTX changes were also small and not statistically

significant at 6 or 12M (Figure 2).

We investigated potential predictors of spine and hip BMD percent change at 6 and 12 months

(Table 2). Participant age, height and weight were not related to spine and hip BMD change at

any timepoint. Bone remodeling rate at the time of bisphosphonate initiation, assessed by

fasting morning serum CTX level, was variably and inconsistently related to BMD changes. CTX

at this timepoint was significantly and inversely related to spine BMD change at 6 and 12

months, suggesting that higher CTX at bisphosphonate initiation predicted more spine bone

loss. In contrast, the opposite relationship with CTX was seen for total hip change at 6 months.

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TH BMD trended upward at the 6-month timepoint, and higher CTX was associated with more

favorable BMD change at the total hip.

We also examined relationships between baseline bone remodeling status at entry to the

Teriparatide Study (assessed by serum CTX and tissue level bone remodeling rate on transiliac

crest bone biopsies) and changes in BMD on bisphosphonate therapy. Higher pre-teriparatide

CTX was associated with more spine bone loss at 6 and 12 months and with more femoral neck

BMD change at 12 months of bisphosphonate therapy. Higher tissue level bone remodeling rate

was associated with more femoral neck loss at 6 but not at 12 months. Those with particularly

high remodeling states tended to drive these relationships. The two subjects (one on

alendronate and one on zoledronic acid) with the highest pretreatment CTX (both > 500 pg/mL)

also had the most spine/hip bone loss (both > 5%).

Within the Denosumab Study, denosumab treatment was offered for 2-3 years

. Upon entering

the bisphosphonate extension study, 18 participants had received 3 years of denosumab, while

6 had received less than 3 years of denosumab therapy. Among these 6, one had received 18

months and the rest had received 24 months of denosumab therapy. Changes in BMD and CTX

did not differ by duration of denosumab (36M vs <36M; Supplementary Table

As noted, all participants were premenopausal when they started the Teriparatide Study. Based

on menstrual history, menopausal symptoms, and serum FSH levels, 20 women remained

premenopausal and four women transitioned into menopause before/during the 12-month

bisphosphonate extension study. Participants who entered menopause reviewed options for

therapy with their primary care team, outside of the study. Of the four (all in the ALN group) who

entered menopause over the course of the study, two chose transdermal hormone therapy,

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while two remained off therapy. Changes in BMD and CTX did not differ between those who

remained premenopausal and those who transitioned to menopause (Supplementary Table

Prespecified retreatment criteria (see Methods) were applied at the 6-month timepoint for

participants who had chosen ALN treatment. No subject met retreatment criteria at the 6-month

timepoint.

In the subset of women (n=19) who started bisphosphonate < 8 months after the last

denosumab dose, completed a full year of bisphosphonate treatment, and remained

premenopausal during the study period, results were not substantively changed; mean BMD

and CTX changes were small and not statistically significant at 6 or 12 months (data not

shown).

Comparisons between ZOL and ALN groups

Of the 24 participants, 6 selected IV ZOL and 18 chose weekly oral ALN. Those who selected

ZOL or ALN did not differ at baseline by age, BMI, fractures, BMD, calciotropic hormones or

CTX (Table 1). The groups did not differ in terms of timing of bisphosphonate start. All

participants in the ZOL group received the infusion at the 7-month timepoint.

In the ZOL group, there were small declines in BMD and increases in CTX, particularly between

6M and 12M, while greater stability was observed in the ALN group (Figure 3). In the ZOL group

by 12 months, BMD declined by -2.4 ± 1.0% at the spine (p=0.04 vs baseline), -3.0 ± 4.3% at

the total hip (p=0.3 vs baseline) and -2.7 ± 3.4% (p=0.2 vs baseline) at the femoral neck and

CTX increased by 300 ± 190 pg/mL (p=0.02 vs baseline), on average. Changes on alendronate

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at 12 months were more favorable: -1.1 ± 4.8% at the lumbar spine, +0.4 ± 2.2 at the total hip

and +0.1 ± 3.3 at the femoral neck, and an increase in CTX of 7 ± 200 pg/mL (all NS vs

baseline). The ZOL group had significantly greater increases in CTX and decreases in TH BMD

than the ALN group (Figures 3B & 3D).

HR-pQCT

Thirteen women completed 12 months of bisphosphonate treatment and had HR-pQCT scans

at both baseline and 12-month time points. In the 13 patients, 12 tibia and 11 radius scans were

analyzable at both time points. After 12 months of treatment, at the tibia (Table 3), cortical

density decreased by 0.6% (p=0.002) and porosity increased by 9.9% with an absolute increase

of 0.17% (p=0.05). No significant changes were seen at the radius, although there was a trend

towards increase in total density and trabecular thickness by 0.7% (both p=0.08; data not

shown).

Adverse Events

Both oral and IV bisphosphonate were well tolerated. One subject stopped ALN treatment after

one month of treatment due to exacerbation of pre-existing dermatitis/hives; this subject was

followed off additional bisphosphonate therapy and results are included in the final dataset.

Another subject stopped oral alendronate after 6 months for personal reasons and is included in

the final dataset. Symptoms of acid reflux were reported in two women on ALN but did not lead

to discontinuation. Joint pain was reported in one woman on ZOL and four women on ALN.

Symptoms of acute phase reaction after ZOL infusion were reported by three women: two

women reported two days of joint pain and fatigue and one woman reported two days of

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abdominal pain. No episodes of hypo- or hypercalcemia occurred. No new vertebral (clinical or

VFA) or non-vertebral fractures occurred on bisphosphonate therapy.

Discussion

In 24 women with premenopausal idiopathic osteoporosis who experienced large increases in

BMD after sequential therapy with teriparatide and 24 to 36 months of denosumab, the gains

were maintained during a 12-month bisphosphonate transition year. High bone remodeling prior

to treatment (pre-teriparatide) predicted more bone loss during the bisphosphonate transition

year. Although not a randomized study, our data suggest that 12 months of weekly alendronate

provided greater suppression of CTX and stability of BMD than a single IV dose of zoledronic

acid, particularly at the hip sites and between the 6- and 12-month time points.

Our results are consistent with data from several reports that oral alendronate

34-36

and IV

zoledronic acid

35-40

maintain BMD in postmenopausal women after being treated with

denosumab for a similar amount of time. In two studies of approximately 100 postmenopausal

women who had received 1 year of denosumab, BMD remained stable on weekly

alendronate

34,41

. Similarly, BMD was maintained after a single dose of zoledronate in 27 women

who had received approximately 2 years of denosumab therapy

. These data contrast with

studies of risedronate and raloxifene, neither of which appear to prevent post-denosumab bone

loss

11,36,42

Zoledronic acid has been shown to have more potent suppressive effects on bone remodeling

than alendronate

. Thus, our findings that weekly alendronate provided greater suppression of

CTX and greater stability of BMD than a single dose of IV zoledronic acid could be considered

unexpected. We hypothesize that the differences seen between oral and IV bisphosphonate

may be related to the difference in the opportunity for skeletal uptake provided by the

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administration timing and protocol (one dose vs repeated dosing). Several other authors have

hypothesized that inability of zoledronic acid to prevent post-denosumab bone loss in some

protocols could be related to suppression of bone turnover, and low bone uptake, at the time of

zoledronic acid administration

15,16,44

. It is possible that persistent remodeling suppression related

to the prior denosumab dose (even at 7±0 months after denosumab dose) inhibited optimal

uptake of the one-time dose of IV zoledronic acid at the time that it was given, while the

repeated dosing of the weekly alendronate allowed repeated opportunities for skeletal

medication uptake as the denosumab effects waned. A recent position statement by ECTS

published after our trial’s design, has proposed consideration of repeat dosing of zoledronic acid

in the first year after denosumab withdrawal. Further investigation will be needed to delineate

the optimal timing and dosing regimen for IV bisphosphonate after denosumab cessation.

Some studies of postmenopausal women who received one dose of zoledronic acid after

denosumab have documented an initial response followed by an increase in bone turnover

markers later in the transition year

15,44-46

. This has led several authors to recommend close

monitoring of bone turnover markers with consideration of early retreatment with zoledronic acid

in those who demonstrate a rise in bone turnover markers

15,45

. Our data also suggest that while

a single dose of IV zoledronic acid given 7 months after the last denosumab dose may suppress

bone turnover and prevent bone loss for 6 months, the effect may wane during the second half

of the year. Further studies are required to determine the utility of monitoring plans in all

populations.

Some studies suggest that the duration of denosumab treatment may affect the trajectory of

BMD after discontinuation, with more bone loss occurring after longer treatment

15,40,46

. A recent

review of 15 studies separated by short (< 2.5 years) vs long (> 2.5 years) duration of

denosumab reported that bisphosphonates were more effective in preventing bone loss in those

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treated for a shorter time

. All participants in our study were treated for only 2-3 years. The

relatively brief exposure to denosumab may explain why we found no effect of duration on BMD

maintenance.

The results of our study are novel because they pertain to the previously unstudied scenario of

denosumab withdrawal in premenopausal women with idiopathic osteoporosis. Postmenopausal

women

or patients with rheumatoid arthritis on glucocorticoids

are assumed to have a high

bone turnover state with increased drive for bone loss as an underlying etiology of their

osteoporosis. In contrast, we have documented that premenopausal women with idiopathic

osteoporosis have quite variable baseline bone remodeling status. Those with low bone

remodeling activity documented on transiliac crest biopsy have very disrupted bone

microstructure and osteoblast dysfunction. Those with high bone remodeling activity have

evidence of mild hypercalciuria and secondary hyperparathyroidism

. We hypothesized that

those with IOP and low bone formation would be less likely to lose bone during bisphosphonate

transition, while those with increased bone resorption at baseline would be more likely to

experience bone loss. The inverse relationship that we observed between BMD change and

bone remodeling before treatment (pre-teriparatide) generally supports our hypothesis. CTX

measured at denosumab end/bisphosphonate baseline was less consistently predictive of BMD

response and may be more reflective of individual duration of denosumab action than an

underlying state of bone metabolism that could affect the results during the bisphosphonate

transition year.

This study has several strengths. It is a long-term prospective study providing detailed bone

density, bone structure and bone turnover data in a well characterized albeit rare population of

premenopausal women with idiopathic osteoporosis treated with a sequential regimen of

anabolic (teriparatide) and antiresorptive (denosumab) osteoporosis therapy. Our study also has

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several limitations. The study is small because it was limited to those enrolled in the teriparatide

and denosumab studies. The small sample size limited subgroup analyses as well as our ability

to discern effects of treatment on fracture risk. The almost universal experience of rapid bone

loss and the risk of rebound vertebral fractures after denosumab cessation, and the current

product labeling made a placebo group design unethical, and the study population was too

small for a randomized study comparing zoledronic acid and alendronate. Limitations also

include the nonrandomized design which led to uneven group size and may have introduced

bias. The onset of the COVID pandemic during the study prevented travel for some participants

and delayed some study visits. The analyses presented here do not address the durability of the

effect of the one year of planned bisphosphonate therapy. Data from the year of follow up after

bisphosphonate cessation are undergoing analysis and will be presented in future.

In conclusion, in premenopausal women with idiopathic osteoporosis, bisphosphonate therapy

is associated with stable bone density in the first 12 months after sequential treatment with

teriparatide followed by up to three years of denosumab. Duration of denosumab therapy and

transition to menopause did not appear to affect the results. Some women with very high bone

remodeling rate prior to treatment, which may reflect underlying mechanisms of osteoporosis in

idiopathic osteoporosis, may be at greater risk for bone loss during the year of bisphosphonate

therapy after denosumab. Additionally, our results suggest that 12 months of weekly

alendronate may provide greater suppression of CTX and more stable BMD than a single dose

of IV zoledronate, particularly at the hip and during the second 6 months of the year. Future

studies are needed to determine the optimal individualized protocol for bisphosphonate

transition after denosumab therapy.

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Acknowledgements:

We would like to express our sincere gratitude to the study participants who contributed to this

research, to the organizations that provided funding for this research, and to Dr. Robert R.

Recker, who served as Site Principal Investigator at Creighton University, collaborator, and

coauthor over the course of the parent Teriparatide Study, Denosumab Extension Study, and

this Bisphosphonate Extension Study.

Figure Legends

Figure 1: Consort Diagram

Legend: N/A

Figure 2: Change in BMD and CTX on 12 months of bisphosphonate after denosumab

withdrawal in all subjects.

2A. Percent change in BMD at the Lumbar Spine

2B. Percent change in BMD at the Total Hip

2C. Percent change in BMD at the Femoral Neck

2D. Change in Serum CTX

Legend: There were no statistically significant changes in BMD or CTX at any timepoint.

Figure 3: Change in BMD and CTX on 12 months of bisphosphonate after denosumab

withdrawal in the alendronate and zoledronic acid groups.

3A. Percent change in BMD at the Lumbar Spine

3B. Percent change in BMD at the Total Hip

3C. Percent change in BMD at the Femoral Neck

3D. Change in Serum CTX

Legend: Alendronate group: solid line; Zoledronic acid group: dashed line.

# p<0.05 for within group change vs baseline; * p<0.05 for comparison of change in alendronate

vs zoledronic acid groups.

Table 1: Subject Characteristics
Mean ± SD unless otherwise
indicated

All Patients
(N=24)

Alendronate
(N=18)

Zoledronic
acid
(N=6)

P-value

Subject Characteristics at
Teriparatide Study Baseline (Parent
study baseline, prior to treatment)

Age (years)

37.7 ± 8.1

38.7 ± 8.6

34.7 ± 6.3

0.3

Weight (kg)

57.4 ± 10.7

56.1 ± 8.0

61.4 ± 16.8

0.3

Height (cm)

163.4 ± 8.0

162.3 ± 8.4

166.8 ± 6.1

0.2

Body mass index (BMI; kg/m

)

21.4 ± 3.3

21.3 ± 2.5

22.0 ± 5.2

0.7

BMD (g/cm

)

Lumbar spine

0.80 ± 0.10

0.78 ± 0.10

0.86 ± 0.08

0.1

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  Total hip
  Femoral neck
  Distal radius

0.74 ± 0.09
0.63 ± 0.11
0.67 ± 0.06

0.72 ± 0.09
0.61 ± 0.10
0.67 ± 0.06

0.78 ± 0.09
0.70 ± 0.12
0.68 ± 0.04

0.2
0.09
0.9

BMD Z-score
  Lumbar spine
  Total hip
  Femoral neck
  Distal radius

-2.01 ± 0.89
-1.52 ± 0.72
-1.68 ± 0.91
0.05 ± 0.99

-2.13 ± 0.88
-1.60 ± 0.71
-1.84 ± 0.83
0.04 ± 1.06

-1.65 ± 0.90
-1.21 ± 0.73
-1.13 ± 1.03
0.08 ± 0.85

0.3
0.3
0.1
0.95

BMD T-score
  Lumbar spine
  Total hip
  Femoral neck
  Distal radius

-2.26 ± 0.90
-1.69 ± 0.75
-1.96 ± 0.98
-0.28 ± 1.00

-2.43 ± 0.88
-1.80 ± 0.73
-2.15 ± 0.90
-0.33 ± 1.1

-1.79 ± 0.89
-1.30 ± 0.77
-1.31 ± 1.08
-0.16 ± 0.82

0.1
0.2
0.09
0.7

Serum parathyroid hormone
(pg/mL)

19.3 ± 6.4

20.0 ± 6.8

16.7 ± 4.5

0.3

Serum calcium (mg/dL)

9.3 ± 0.3

9.3 ± 0.4

9.3 ± 0.2

0.9

Serum 25-OHD (ng/mL)

39.5 ± 9.1

39.2 ± 9.3

40.3 ± 9.1

0.8

Serum C-telopeptide (CTX; pg/mL)

342 ± 166

342 ± 180

345 ± 122

0.97

Urinary calcium excretion (mg/g
creatinine)

144.0 ± 66.1

135.2 ± 66.8

174.0 ± 60.4

0.3

Cancellous Bone Formation Rate
(BFR; mm

/mm/yr) on tetracycline

labeled transiliac crest bone biopsy

0.011 ± 0.009 0.012 ± 0.010 0.009 ± 0.006 0.5

Subject Characteristics at
Bisphosphonate Extension Study
Baseline

Age (years)

43.2 ± 8.0

44.2 ± 8.4

40.3 ± 6.8

0.3

Weight (kg)

61.6 ± 12.3

61.2 ± 12.0

62.8 ± 14.7

0.8

Height (cm)

163.0 ± 8.0

162.2 ± 8.4

166.6 ± 6.3

0.3

Body mass index (BMI; kg/m

)

23.0 ± 3.8

23.2 ± 3.6

22.5 ± 4.6

0.7

Number of fractures
Median (IQR)
Range

3 (1, 4)
0, 14

2 (1, 4)
0, 14

3.5 (3, 6)
1, 9

0.3

Number of adult fractures
Median (IQR)
Range

2 (1, 3.5)
0, 12

2 (0, 3)
0, 12

2.5 (2, 5)
1, 9

0.3

Vertebral fractures [N(%)]

9 (37.5)

7 (38.9)

2 (33.3)

0.8

PLO Designation [N(%)]

6 (25.0)

4 (22.2)

2 (33.3)

0.6

BMD (g/cm

)

  Lumbar spine
  Total hip
  Femoral neck
  Distal radius

0.99 ± 0.1
0.83 ± 0.1
0.72 ± 0.1
0.66 ± 0.05

0.98 ± 0.1
0.82 ± 0.1
0.71 ± 0.1
0.66 ± 0.05

1.02 ± 0.1
0.85 ± 0.09
0.77 ± 0.1
0.67 ± 0.03

0.5
0.5
0.3
0.6

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Trabecular bone score

1.38 ± 0.09

1.391 ± 0.10

1.384 ± 0.07

0.9

BMD Z-score
  Lumbar spine
  Total hip
  Femoral neck
  Distal radius

-0.06 ± 1.0
-0.66 ± 0.7
-0.65 ± 0.9
0.05 ± 0.8

-0.06 ± 1.1
-0.68 ± 0.8
-0.70 ± 0.9
0.05 ± 0.8

-0.07 ± 0.6
-0.59 ± 0.7
-0.46 ± 0.9
0.05 ± 0.6

0.98
0.8
0.6
0.998

BMD T-score
  Lumbar spine
  Total hip
  Femoral neck
  Distal radius

-0.55 ± 1.1
-0.92 ± 0.9
-1.15 ± 1.0
-0.48 ± 0.8

-0.60 ± 1.2
-0.98 ± 1.0
-1.28 ± 1.1
-0.54 ± 0.8

-0.36 ± 0.7
-0.74 ± 0.73
-0.75 ± 0.9
-0.33 ± 0.5

0.7
0.6
0.3
0.6

Serum parathyroid hormone
(pg/mL)

23.1 ± 8.9

22.7 ± 9.9

24.3 ± 8.4

0.7

Serum calcium (mg/dL)

9.5 ± 0.4

9.5 ± 0.5

9.4 ± 0.4

0.6

Serum creatinine (mg/dL)

0.79 ± 0.11

0.78 ± 0.12

0.80 ± 0.11

0.8

Serum 25-OHD (ng/mL)

43.0 ± 10.9

43.2 ± 12.4

42.2 ± 5.3

0.8

Serum C-telopeptide (CTX; pg/mL)

173 ± 203

192 ± 210

124± 194

0.5

Table 2: Potential Predictors of Percent Change in BMD (Pearson Correlations, r,p)

Significant relationships are shown in

bold

, trends are shown in

Italics

LS BMD

6M change

LS BMD

12M change

TH BMD

6M change

TH BMD

12M change

FN BMD

6M change

FN BMD

12M change

Bisphosph
onate
Study
Baseline

Age

0.11, 0.6

0.33, 0.2

-0.06, 0.8

0.14, 0.5

0.08, 0.7

0.30, 0.2

Weight

-0.11, 0.6

-0.11, 0.7

0.18, 0.4

0.15, 0.5

0.28, 0.2

0.08, 0.7

Height

-0.33, 0.1

-0.29, 0.2

0.10, 0.7

-0.01, 0.96

0.21, 0.4

-0.11, 0.6

Serum CTX

-0.44, 0.05

-0.61, 0.006

0.58, 0.008

0.33, 0.2

0.35, 0.1

-0.12, 0.6

Teriparatid
e Study
Baseline
(prior to
sequential
treatment
course)

Serum CTX

-0.57, 0.009

-0.60, 0.005

0.42, 0.07

0.14, 0.6

-0.01, 0.98

-0.46, 0.04

Cancellous Bone
Formation Rate
on tetracycline
labeled transiliac
crest bone
biopsy

0.09, 0.7

0.16, 0.5

0.26, 0.3

-0.65, 0.003

-0.36, 0.1

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TABLE 3: Change in density, microstructure and estimated strength on 12 months of bisphosphonate

after denosumab cessation assessed by HR-pQCT at the distal tibia in 12 women (mean ± SD)

Baseline

12M % change

Tb.Area (mm

)

559 ± 119

-0.06 ± 0.25

0.7

Ct.Area (mm

)

107± 10

0.20 ± 1.34

0.7

Tot.vBMD (mgHA/ccm)

250 ± 42

-0.12 ± 1.45

1.0

Tb.vBMD (mgHA/ccm)

116 ± 21

0.61 ± 2.10

0.4

Tb.N (1/mm)

1.16 ± 0.15

-0.17 ± 2.75

0.5

Tb.Th (mm)

0.242 ± 0.021

-0.02 ± 0.58

0.9

Tb.Sp (mm)

0.85 ± 0.11

0.06 ± 2.15

0.2

Tb.1/N.SD (mm)

0.32 ± 0.06

-0.63 ± 1.99

0.5

Ct.vBMD (mgHA/ccm)

934 ± 43

-0.64 ± 0.65

0.002

Ct.Po (%)

1.79 ± 0.87

9.91 ± 13.25

0.05

Ct.Th (mm)

1.24 ± 0.18

0.03 ± 1.10

0.8

Stiffness (kN/mm)

140.9 ± 19.7

-0.10 ± 2.24

0.4

FL (N)

7252 ± 912

-0.34 ± 1.79

0.3

Data Availability Statement:

Some or all datasets generated during and/or analyzed during the current study are not publicly

available but are available from the corresponding author on reasonable request.

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