I have financial relationships with the following companies:

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 Osteoporosis
Osteoporosis is characterized by reduced bone mass and impaired microstructure.
Normal Osteoporosis

Anabolic agents repair the microscopic architecture of bone tissue whereas

antiresorptive agents prevent further degradation.
David Dempster; 2000
 Anabolic Agents: Differences in
Mechanism of Action at the Tissue Level
• All anabolic agents stimulate bone formation, but mechanism differs
–With PTH Receptor Agonists (teriparatide and abaloparatide),
predominant bone formation is remodeling-based
–With sclerostin antibody (romosozumab), predominant bone
formation is modeling-based
• Agents have very different effects on bone resorption
–Teriparatide and abaloparatide stimulate bone resorption
–Romosozumab reduces bone resorption

Cosman F and Dempster DW. Current Osteoporosis Reports 2021

https://doi.org/10.1007/s11914-021-00663-1
 Serum Bone Turnover Marker Changes with
Teriparatide and Abaloparatide (ACTIVE Trial)
Serum PINP Serum CTX

Note
difference
in Y Axis for
PINP vs CTX

PTH Receptor Agonists Increase Formation and Resorption

Miller et al. JAMA. 2016;316:722-733 Non-Amgen

 Serum Bone Turnover Marker Changes with
Romosozumab Relative to Placebo (FRAME Trial)

PINP β-CTX
200
Change from baseline vs placebo (%)

150

100

50

–50

–100
0 1 3 6 9 12
+2 weeks +2 weeks +2 weeks
Time (months)

Sclerostin antibody: promotes formation and suppresses resorption

Cosman F, et al. N Engl J Med. 2016;375:1532–43.

 Very High Risk Patients (AACE)1
• Recent fracture
• History of multiple fractures
• Fractures on approved osteoporosis medications
• Fractures on medications known to cause skeletal harm
• Very low T-scores (e.g. < −3.0)
• High falling risk or history of injurious falls
• Very high fracture probability (e.g. FRAX >30% MOF, >4.5% hip fx)

Many of these patients are also at imminent risk:

fracture risk of >10% over next 2 years2

1. Camacho PM et al. Endocrine Practice 2020. AACE/ACE Guidelines 2020 Update.

2. Ferrari S et al. Swiss Med Wkly. 2020;150:w20352
 Imminent Risk: ≥ 10% in 2 Years1
• Recent clinical fracture: recurrent fracture risk in 1 year by site of first fracture2
Spine
Pelvis
Clavicle
Hip
Humerus
Femur Average risk for
Radius/Ulna recurrent fracture
Tibia/Fibula is 10% in 1 year
Ankle
0 2 4 6 8 10 12 14 16

• Radiographic incident vertebral fractures: recurrent vertebral fracture risk 20% in 1 year3
• Multiple prior clinical fractures (regardless of timing)4
– 2 prior fractures: recurrent risk 16% over 2 years
– 3 or more prior fractures: recurrent risk 25% over 2 years
1. Ferrari S, et al. Swiss Med Wkly. 2020;150:w20352. 2. Balasubarmanian A et al. Osteoporos Int. 2019;30:79–92.
3. Lindsay R et al. JAMA. 2001;285:320–3. 4. Gehlbach SH, et al. Osteoporos Int. 2007;18:805–10.
 Treatment for Very High Risk Patients

• Treatment goals for very high risk women, especially at imminent risk:
– Reduce fracture risk rapidly and potently
– Increase BMD rapidly and potently
• How do anabolic agents (teriparatide, abaloparatide and romosozumab)
compare with antiresorptive agents toward these goals?
– Speed of antifracture effect
– Magnitude of antifracture effect
– BMD and Microstructure

Cosman F. Endo Practice 2020; 26:777-786

Antiresorptive Agents Work Slowly
They gradually reduce risk with little or no effect against
nonvertebral fractures in the first 18 months.
 Antiresorptives Do Not Reduce Nonvertebral
Fracture Risk in the Imminent Risk Period
Reductions in nonvertebral fracture start at about 18 months.
Reductions not significant until 3 years.

HORIZON1 FREEDOM2

1. Black DM et al. N Eng J Med 2007;356:1809

2. Cummings SR et al. N Engl J Med 2009;361:756-65
 Anabolic Agents Act Fast
Rapidly reduce risk in the first 18 months.
Rapid action is particularly important in patients with
severe osteoporosis at imminent risk of fracture.
 Teriparatide Reduces Vertebral and
Nonvertebral Fractures over 19 Months
Vertebral fracture Nonvertebral fractures
RRR 35%; p<0.05
16
Placebo PTH, 20 µg
14 12 Placebo
Percentage of women

12 PTH, 20 µg/day

Nonvertebral fractures
10
10

(% of women)
8
8
6
6
4
4
2 2

0 0
≥ 1 fracture > 1 fracture ≥ moderate or 0 2 4 6 8 10 12 14 16 18 20
severe fracture Months after randomization

Neer RM, et al. N Engl J Med 2001;344:1434-41.

 Abaloparatide and Teriparatide Reduce
Fractures in 18 Months (ACTIVE Trial)
Vertebral Fractures Nonvertebral Fractures

Miller PD et al. JAMA 2016;316:722-33

 Romosozumab Reduces Fractures
in 12 Months (FRAME Trial)1
Nonvertebral Fracture Year 1: Nonvertebral Fracture Year 1:
Vertebral Fracture Year 1 Total FRAME population Rest of World (Higher Risk)1-2
Subject Incidence (%)

1.Cosman F et al. N Engl J Med 2016;375:1532–43

2.Cosman F, et al. J Bone Miner Res 2018;33:1219-1226.
Romosozumab Effect Against Nonvertebral Fracture
is Dependent on Baseline Fracture Risk
Nonvertebral Fracture Risk Reduction in 1 Year
2.0

1.5
Hazard ratio p = 0.046
1.0

0.5

0.0
0 10 20 30 40
Probability of a major osteoporotic fracture (%) by FRAX

Romosozumab vs placebo on nonvertebral fracture:

HR with 95% CI by baseline FRAX probability for MOF

McCloskey EV et al. Osteoporos Int 2021;32:1601-08.

 Very High Risk Non-fracture
Patients from FRAME
• AACE definition of very high risk includes T-Score <-3 or very high FRAX (> 30%
MOF, > 4.5% hip fracture)
• 2825 women from FRAME who had no prior fracture met at least 1 of these
very high risk criteria
– 68% had T-score < -3
– 52% had 10 year hip fracture probability (FRAX) > 4.5%
• In these very high risk patients, we evaluated efficacy of romosozumab
followed by denosumab vs placebo followed by denosumab over 2 years

McClung MR, McClung MR, Betah D, Deignan C, Shi Y, Timoshanko J, Cosman F.

Presented at ASBMR September 2022.
Non-Amgen
 Very High Risk Nonfracture Subgroup
from FRAME: Fracture Rates over 24 Months
Placebo (N = 1385) Placebo-to-denosumab (N = 1385)
Romosozumab (N = 1440) Romosozumab-to-denosumab (N = 1440)

6
New Vertebral Fracture 6 Nonvertebral Fracture
Fracture Incidence (%)

Fracture Incidence (%)

5
RRR = 46%
4 RRR = 77%
4 P = 0.015
P < 0.001 RRR = 54%
RRR = 76%
P = 0.020 3.0%
3 P = 0.002 3
2.2%
1.9%
2 1.5% 2 1.6%
0.9%
1 0.5% 1
0.4%
0 0
12 24 12 24
Month Month
Numbers below bars = number of women with fracture/number of women with values at that time point. Data were analyzed based on the Mantel-Haenszel
method and logistic regression for new vertebral fracture and Cox proportional-hazards model for clinical and nonvertebral fracture adjusted for baseline
covariates, without multiplicity adjustment. RRR = relative risk reduction.

McClung MR, Betah D, Deignan C, Shi Y, Timoshanko J, Cosman F.

Presented at ASBMR Annual Meeting September 2022. 18
 Anabolic Agents Reduce Nonvertebral Fractures
Faster and to a Greater Extent than Antiresorptives
Denosumab
vs Placebo
18 Months

These are not head-to-head trials.

Cummings SR et al. N Engl J Med 2009;361:756-65
Bone et al. JCEM 2018;103:2949-57
Anabolic Agents Reduce Fractures Earlier
and More than Antiresorptive Agents
in Head to Head Trials
 Teriparatide Reduces Vertebral Fractures
vs Risedronate (VERO Trial)
N = 1,360 women with least 2 moderate or 1 severe vertebral fracture at enrollment

Incidence of new vertebral fractures

Teriparatide Risedronate
14 RRR: 56% (95% CI: 0.29, 0.68)
Patients with new vertebral

p < 0.0001
12
10 12.0%
fractures (%)

RRR: 48% (95% CI: 0.30, 0.91) (64/533)

8 p = 0.019
6
4 6.0% 5.4%
(35/585)
(28/516)
2 3.1%
(18/574
0 )
12 months 24 months

Kendler DL, et al. Lancet 2018;391:230-40.

 Teriparatide Reduces Clinical and Nonvertebral
Fractures vs Risedronate (VERO Trial)
First clinical fracture 7 First nonvertebral fracture
12 Hazard ratio: 0.48 6 Hazard ratio: 0.66 Risedronate

Cumulative incidence (%)

(CI 0.32-0.74) Risedronate (CI 0.39-1.10)
10 5
Cumulative incidence (%)

p = 0.0009 p = 0.09

8 4

6 3 Teriparatide

4 2
Teriparatide
1
2
0
0
0 6 12 18 24 baseline 6 12 18 24
Number at risk
Teriparatide 680 623 589 561 508 680 625 592 565 513
Risedronate 680 616 584 553 502 680 622 595 570 518

Kendler DL et al. Lancet 2018;391:230-40.

 Romosozumab Reduces Vertebral Fractures
vs Alendronate (ARCH Study)
RRR = 48%‡
Risk ratio 0.52 (CI 0.40-0.66)
14 p < 0.001 Romosozumab
RRR = 37%†
Risk ratio 0.63 (CI 0.47-0.85) Alendronate
12 p = 0.003
11.9%
10 243/2047
Subjects (%)

8
6
6.3% 6.2%
4 128/2047 127/2046
4.0%
2 82/2046
0
12 Months* 24 Months*

Saag K, et al. N Engl J Med 2017;377:1417-1427.

 Romosozumab Reduces Nonvertebral
and Hip Fractures vs Alendronate (ARCH Study)
Nonvertebral fractures Hip fractures
20 6

5
Cumulative incidence (%)

Cumulative incidence (%)

15
4
RRR = 19% RRR = 38%
10 p = 0.037 3 p = 0.015

2
5
1

0 0
0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
n= Month Month
Romo-to-Aln 2,046 1,867 1,776 1,693 1,627 1,114 714 350 109 2,046 1,900 1,829 1,766 1,715 1,195 772 379 125
Aln-to-Aln 2,047 1,873 1,755 1,661 1,590 1,097 697 330 110 2,047 1,914 1,821 1,750 1,690 1,182 755 364 124

Alendronate Romosozumab Alendronate-to-alendronate Romosozumab-to-alendronate

Saag K, et al. N Engl J Med 2017;377:1417-27.

 Abaloparatide Reduces Fractures More than
Alendronate (ACTIVE/ACTIVExtend Trial)
New Vertebral Fracture Rates

• Vertebral Fracture rates

- Placebo: 2.5%
- Alendronate: 1.7%
- Abaloparatide: 0.5%
• Vertebral fracture rates lower with
abaloparatide vs alendronate (p<0.03)
• Trend toward reduced nonvertebral
fracture with abaloparatide versus
alendronate (reduced by 45%; P = .11)

Leder BZ et al JCEM 2020; 105: 938–943

 VERO and ARCH Compared Anabolic
Agents with Oral Bisphosphonates
What About Comparison with the more
Potent Agent Denosumab?
 Romo/Dmab vs Denosumab-Only Comparison
Study Design: FRAME and FRAME Extension
Romo/Dmab
• Women aged ≥ 55 to ≤ 90 years with T-
score > ‒3.5 to ≤ ‒2.5 at the total hip or
Romosozumab
210 mg SC QM Denosumab Denosumab femoral neck were included
n = 3589 60 mg SC Q6M 60 mg SC Q6M
• Patients randomized to Romo or
Randomized
N = 7180 Daily Calcium and Vitamin D placebo for 1 year followed by Dmab
for 2 years
Placebo
SC QM
Denosumab
60 mg SC Q6M
Denosumab
60 mg SC Q6M
• Here, our focus was on patients who
n = 3591
received:
Dmab/Dmab
– Romo/Dmab: Romo for 12
FRAME FRAME Extension
months followed by Dmab for 12
months in FRAME
Month 0
Double-blind
12
Open-label
24 36
– Dmab/Dmab: Dmab for 12
months in FRAME and for 12
months in the FRAME Extension
N = number of patients in the study. n = number of patients in each study arm. Dmab,
denosumab; Q6M, every 6 months; QM, monthly; Romo, romosozumab; SC, subcutaneously
trial

1Cosman F, et al. N Engl J Med. 2016;375:1532-1543. 2Lewiecki EM, et al. J Bone Miner Res. 2019;34:419-428.
 Study Design: Propensity Score Matching
• Because the Dmab/Dmab cohort was on average 1 year older than the
Romo/Dmab cohort, cohorts were balanced using propensity score
matching
• Propensity score was calculated by logistic regression with all available
baseline covariates including age, prior fracture history, BMD at multiple
sites, demographic variables, lifestyle variables, lab results
• Propensity score matching created matched cohorts of 2772 women each
arm
• 2 year fracture incidence compared between matched cohorts receiving
Romo/Dmab vs Dmab/Dmab

Cosman F, Oates M, Betah D, Ferrari S, Timoshanko J, Wang Z, McClung MR.

Presented at ASBMR Annual Meeting September 11, 2022.
 Romo/Dmab vs Dmab/Dmab
2 Year Fracture Incidence in Matched Cohorts
Romo/Dmab Dmab/Dmab
HR: 0.80
95% CI: 0.59, 1.09 HR: 0.84
P = 0.16 95% CI: 0.61, 1.16
P = 0.29
4
3.68
3.5 3.39
Percent Incidence (%)

3 OR: 0.43 2.74 2.63

95% CI: 0.23, 0.78
2.5 HR: 0.69
P = 0.006
95% CI: 0.30, 1.62
2
P = 0.40
1.5 1.3
1
0.62 0.54
0.5 0.32
0
n1/N1 = 16/2579 35/2700 n1/N = 76/2772 102/2772 73/2772 94/2772 9/2772 15/2772

New Vertebral Clinical Nonvertebral Hip

Fracture Fracture Fracture Fracture
n1 = # subjects with fracture; N1 = # subjects in the PSM subset for new vertebral fracture analysis; N = Number of subjects who were
matched. For new vertebral fractures, missing values imputed by carrying forward the last nonmissing postbaseline

Cosman F et al. Presented at ASBMR Annual Meeting September 11, 2022.

Fracture Risk Reduction Achieved with
Anabolic Treatment is Sustained During
Antiresorptive Therapy
 Abaloparatide: Sustained Vertebral Fracture
Risk Reduction (ACTIVE/ACTIVExtend)

Bone et al. JCEM 2018;103:2949-57

Abaloparatide: Sustained Nonvertebral Fracture
Risk Reduction (ACTIVE/ACTIVExtend)
Time to first nonvertebral fracture
12

Patients with ≥ 1 nonvertebral fracture (%)

10 ALN monotherapy
began at 19 PBO/ALN
8 months

4 ABL/ALN
39% RR; P = 0.038
2

Number of
0 0 4 8 12 16 20 24 28 32 36 40 44
patients at
risk Months
PBO/ALN: 581 574 571 568 563 550 531 511 488 482 467 19
ABL/ALN: 558 557 553 551 548 541 525 511 503 499 483 25

Bone et al. JCEM 2018;103:2949-57

 Romosozumab: Sustained Vertebral
Fracture Risk Reduction (FRAME Extension)
Placebo Romosozumab Placebo-to-denosumab Romosozumab-to-denosumab

Month 12 Month 24 Month 36

4% RRR = 66%
HR 0.34 (95% CI 0.23-0.51)
RRR = 75%
Subject incidence

p < 0.001
3% p < 0.001
RRR = 73% 2.8%
p < 0.001 2.5%
2%
1.8%
1%
1.0%
0.5% 0.6%
0%
New vertebral fracture
n/N1 = 59/3,322 16/3,321 84/3,327 21/3,325 94/3,327 32/3,327

n/N1 = number of subjects with fractures/number of subjects in the primary analysis set for vertebral fractures.
P-values for 12-month and 24-month periods are adjusted values based on a sequential testing procedure based on odds ratio. P-value for
month 36 is nominal, based on odds ratio. Data displayed for 12-month and 24-month periods are as reported for the primary analysis. CI,
confidence interval; HR, hazard ratio; RRR, relative risk reduction.

Lewiecki EM, et al. J Bone Miner Res 2019;34:419-428.

 Romosozumab: Sustained Nonvertebral Fracture
Risk Reduction (FRAME Extension)
Placebo Romosozumab Placebo-to-denosumab Romosozumab-to-denosumab

Nonvertebral fractures
Placebo vs Open-label Extension denosumab
6% romosozumab denosumab

5% RRR = 25%
p = 0.057

4%
RRR = 21%
HR 0.79
(95% CI 0.63-0.99)
3% RRR = 25% p = 0.039
p = 0.096

2%

1%

0%
0 6 12 18 24 30 36

Study month

3,591 3,144 2,956 2,750

3,589 3,149 2,959 2,738

Lewiecki EM, et al. J Bone Miner Res 2019;34:419-428.

 Rationale for Anabolic First
in Very High Risk Patients
• Anabolic agents reduce fracture risk faster and to a greater extent vs
antiresorptive treatment in head to head trials1.
• Fracture Risk reductions with anabolic agents are sustained during antiresorptive
treatment
• What about BMD?
– FNIH/SABRE project findings suggest that the magnitude of BMD gain with
osteoporosis treatment is associated with antifracture efficacy2-3
– Surrogate threshold BMD (total hip) effects associated with fracture risk
reduction at different skeletal sites
– 1.4% Significant RR for Vertebral Fracture
– 2.1 % Significant RR for Nonvertebral Fracture
– 3.2% Significant RR for Hip Fracture

1. Cosman F. Endo Practice 2020; 26:777-786 2. Bouxsein M, et al. JBMR 2019; 34: 632–642
3. Black DM, et al. Lancet Diab Endo 220; 8:672-682.
 Anabolic First is Best for BMD

BMD gains with anabolic agents as initial therapy

are larger than with antiresorptive agents .
BMD gains with anabolic agents as initial therapy
are larger than BMD gains seen after
antiresorptive agents.
 Total Hip BMD Gain with Abaloparatide and
Teriparatide for 18 Months (ACTIVE)1

Mean total hip BMD increase at 18

months1:
Teriparatide 3.3%
Abaloparatide 4.2%

Mean total hip BMD increase with

2 years alendronate in
ACTIVExtend2: 1.4%

1. Miller PD et al. JAMA 2016;316:722-33. 2. Bone et al. JCEM 2018;103:2949-57

 Total Hip BMD Gain with 1 Year Romosozumab
in Treatment Naïve Women (ARCH)
Total Hip BMD
Alendronate Romosozumab
Change from baseline (%)

8 7.1 7.0
6.2

3.4 3.6
4 2.8

0.0
0
0 12 24 36
Time (months)

Romozosumab (n = 1,826)
Alendronate (n = 1,829)

Saag K, et al. N Engl J Med. 2017;377:1417–27.

 Hip BMD Declines for at least 1 year
with Teriparatide After Bisphosphonates
Study Sample size Treatment Prior to Teriparatide Change in total hip during TPTD

6 mo 12 mo 18 mo 24 mo

Ettinger JBMR 2004 33 Alendronate (mean 29 mo) –1.8% –1.0% +0.3% –

Boonen JCEM 2008 107 Alendronate (median 29 mo) –1.2% –0.6% +0.6% +2.1%

Boonen JCEM 2008 59 Risedronate (mean 23 mo) –1.6% –0.4% +0.9% +2.9%

Miller JCEM 2008 158 Risedronate (mean 37 mo) –1.2% –0.3% –

Miller JCEM 2008 166 Alendronate (mean 38 mo) –1.9% –1.7% –

Cosman JCEM 2009 50 Alendronate (mean 46 mo) –0.8% – +0.9% –

Langdahl Lancet 2017 209 Alendronate (mean 66 mo) –0.8% –0.5 – –

Cosman F et al. J Bone Miner Res 2017;32:198-202

Langdahl BL et al. Lancet 2017;390:1585-94
 Hip BMD Declines with Denosumab First
Followed by Teriparatide
Change in Total Hip BMD vs Baseline
Switch
10
Mean (SEM) Percentage Change
in Total Hip BMD (%)

8
*
6.6%
6
Teriparatide

4 Denosumab
†
2.8%
2

0
0 6 12 18 24 30 36 42 48
Months

*p < 0.05 versus the other group. †p < 0.0005 versus the other group

Adapted from Leder BZ, et al. Lancet. 2015;386:1147-1155.

 Treatment Sequences with Romosozumab
Change in Total Hip BMD1
1 Year Gains With Romosozumab Cumulative 2 Year Gains With Sequential Treatment

Romosozumab prior to antiresorptive

LS Mean (95% CI) Percentage

LS Mean (95% CI) Percentage

Change in Total Hip BMD (%)

Change in Total Hip BMD (%)

Romosozumab after alendronate ROMO/
12 Romosozumab after denosumab 12 ROMO/ DMAb
10 ALN
10 8.5 DMAb/
7.1 ROMO
8 6.2 6.0 After 8
ALN After 3.8
6 6
DMAb
2.9
4 4
0.9
2 2
N/A
0 0
n= 1773 3197 197 13 n= 1619 2903 13
ARCH2 FRAME3 STRUCTURE4 PHASE 25 ARCH2 FRAME3 STRUCTURE4 PHASE 25

1. Cosman F et al, Osteoporosis Int 2022;33:1243–1256

2. Saag KG et al. N Engl J Med 2017;377:1417–27.
3. Cosman F et al. N Engl J Med 2016;375:1532–43.
4. Langdahl BL et al. Lancet 2017;390:1585–94.
5. McClung MR, et al. JBMR Plus 2021; 5:1-9
 Anabolic Agents Improve Bone
Microarchitecture
In both Cancellous and Cortical Bone
“Teriparatide treatment stimulates both trabecular and cortical bone formation, resulting in increased
cortical thickness and cancellous bone volume, improved cancellous bone connectivity, and a shift
from rod-like to plate-like trabecular morphology. These changes constitute a reversal of osteoporotic
bone structural changes and explain the pronounced decrease in vertebral and nonvertebral fracture
rates observed after teriparatide treatment”.
Jiang Y et al JBMR 2003; 18: 1932-1941
 FRAME Iliac Crest Bone Biopsies:
Effects on Bone Volume and Structure
Representative Placebo and Romosozumab-Treated Patients Median Values: Placebo Versus Romosozumab at Month 12

Romosozumab
Median Placebo
210 mg QM P value
(Q1, Q3) (n = 32)
(n = 39)
15.97 22.04
Tb.BV/TV, % 0.006
(13.92, 21.13) (17.92, 28.61)
0.204 0.241
Tb.Th, mm 0.001
(0.180, 0.232) (0.215, 0.293)
3.99 3.24
TBPf, /mm 0.030
(3.25, 5.61) (2.11, 4.34)
0.661 0.786
Ct.Th, mm 0.056
(0.535, 0.837) (0.621, 0.977)
3.87 3.39
Ct.Po, % 0.47
(2.28, 5.74) (2.34, 4.93)

Tb.BV/TV, trabecular bone volume per tissue volume

Tb.Th, trabecular thickness
TBPf, trabecular bone pattern factor (lower indicates better microarchitecture)
Ct.Th, cortical thickness
Chavassieux P, et al. JBMR. 2019;34:1597–608. Ct.Po, cortical porosity
 Summary
• Beginning with anabolics provides a more rapid and larger fracture risk
reduction than beginning with antiresorptives
– Fracture risk reduction is maintained during antiresorptive treatment
• Anabolic agents increase BMD more than antiresorptives
• Beginning with anabolic agents and transitioning to antiresorptives
provides larger BMD gain than the inverse sequence
– BMD differences with anabolic first vs antiresorptive first regimens
should produce greater effects against fracture
• Anabolic agents repair bone structure and increase bone mass more than
antiresorptives
• Recent guidelines (AACE, Endocrine Society, NAMS) recommend anabolic
agents first for patients at very high risk for fracture