Osteoporosis Medications:

When to Continue and When to Stop?

Sonali Khandelwal MD
Associate Professor
Director Rush Osteoporosis Center
Rush University Medical Center
Chicago, Illinois
Disclosures

I have no relevant financial relationships with ineligible

companies to disclose.
 Review Current Treatment guidelines for the
management of Osteoporosis based on Risk Factor
Stratification

Review key trials which provide evidence-based

guidance on therapeutic length of the most
common medications used to treat osteoporosis

Understand patient characteristics to consider drug

holidays

Discuss how to monitor drug holidays and when to

consider sequential therapy
 Bone health and Osteoporosis
Foundation (NOF) Guidelines for
Treatment

• For postmenopausal women and men

50 and older after appropriate
evaluation for secondary causes
• Osteoporosis by T- score
• T score -2.5 or less at Femoral Neck, Total hip ,
Lumbar spine or 1/3 Distal Radius
• Clinical Osteoporosis
• T- scores above -2.5 but with Hip or
Vertebral(Morphometric/Clinical) fractures
• Low BMD + High fracture risk
• T score between -1.0 and -2.5 at FN, TH or LS
• FRAX 10- year probability of Hip Fracture(HF) ≥
3% or Major Osteoporotic Fracture (MOF) ≥
20%

Leboff et al. Osteoporos Int 2022; 33: 2049-2102.

Pharmacological Therapy Options
Inhibit Bone Resorption Stimulate Bone Formation
(Antiresorptive, Antiremodeling) (Anabolic, Bone Forming)

• Alendronate (ALN) (Fosamax) • Teriparatide (TPT) (Forteo)

• Risedronate (RIS) (Actonel) • Abaloparatide (ABL) (Tymlos)
• Ibandronate (Boniva) • Romosozumab (Romo)
• Zoledronic acid (Reclast) (Evenity)
• Denosumab (Dmab) (Prolia)
• Raloxifene (Evista)
• Salmon Calcitonin (Miacalcin) Which One to
• Estrogen (Various) use?
• CE/Bazedoxifene (Duavee) For How long?
 Level of Risk Examples Treatment
Low T score > -1.0 and no hip or vertebral Non-pharmacological
(ES, AACE) fracture and FRAX MOF/Hip <20%/3%
Moderate T score -1.1 to -2.5 and no hip or Non-pharmacological or Bisphosphonate
(ES) vertebral fracture and FRAX MOF/HF
<20%/3%
High T score ≤ -2.5 or prior hip or vertebral Bisphosphonate
(ES, AACE) fracture, or FRAX MOF/HF ≥ 20%/3% DMAB
SERM

Very High T score ≤ -2.5 and fractures or multiple Anabolic

(ES) vertebral fractures or severe vertebral Bisphosphonate
fracture (>40% vertebral height loss) DMAB

Very High T score ≤ -3 and fracture in the last 12 Anabolic

(AACE) months, fracture on treatment, multiple Bisphosphonate
fractures, high fall risk multiple vertebral DMAB
fractures or severe vertebral fracture
(>40% vertebral height loss)
FRAX> 30%/4.5%

Adapted from Camacho PM et al., Endoc Pract. 2020; 26: 1-40.

Shoback D et al. , Clin Endocrinol Metabol. 2020; 105; 587-594.
 Oral Bisphosphonate therapy: Alendronate
• Fracture Intervention Trial (FIT):
• 3,658 women with Postmenopausal osteoporosis
• Primary End Points: Effect of Alendronate on BMD and Fracture risk
• Mean Follow up 3.8 years with open-label continuation

• Long term Extension FIT (FLEX):

• 1,099 women with Postmenopausal Osteoporosis
• Alendronate x 5 years --> Alendronate (A10) or Placebo (A5P5)
• Primary End Points: Total Hip BMD
• Secondary End Points: BMD at other sites and biochemical markers of bone
turnover with exploratory outcome measure of fracture incidence

Black et al. JAMA 2006; 296: 2927-2938.

Black et al. Journal Clinc Endcri 2000; 85: 4118-4124.
 ss
❖ At 10 years:
A5P5:
❖ BMD maintenance at the spine
❖ BMD decline at all other sites but not to
pretreatment levels
❖ Gradual increase BTMs at 5 years but not to
baseline
A10:
❖ BMD at hip after 4-5 years was not further
increased
❖ BMD continued to increase at Spine

Black et al. JAMA 2006 (296)24: 2927-2938

 ❖ 55% reduction in new clinical
vertebral fractures lower in
A10 vs. A5P5
❖ Other sites had equal
fracture rate between A10
and A5P5

Black et al. JAMA 2006; 296: 2927-2938.

 IV Bisphosphonate therapy: Zoledronic Acid
• Horizon Pivotal Fracture Trial
• 1,233 postmenopausal Women
• Patients received 3 years ZOL then randomized to 3 more years IV ZOL (Z6) vs.
3 years placebo(Z3P3)
• Primary endpoints: Femoral neck (FN) BMD percentage change from year 3
to 6 in the intent-to-treat (ITT) population
• Secondary endpoints: Other BMD site changes, fractures, biochemical bone
turnover markers and safety profile.

Black et al. J Bone Miner Res. 2012;27: 243-254.

 Horizon- Pivotal Fracture Trial

Black et al. J Bone Miner Res. 2012;27: 243-254.

 • BMD at FN and TH constant in Z6 and
slight decrease Z3P3 (but not to
baseline)
• BMD maintenance at LS for Z6 vs. Z3P3
• BTMs remained constant in Z6 but rose
slightly in Z3P3, remaining well below
pretreatment levels in both

Black et al. J Bone Miner Res. 2012;27: 243-254.

Black et al. J Bone Miner Res. 2012;27: 243-254.
 ❖New Morphometric vertebral
fractures lower in Z6 vs. Z3
❖Though not a direct causal
relationship; VFs including
Morphometric VFs have been linked
to increased risk for other fractures
and increased morbidity over time

Black et al. J Bone Miner Res. 2012;27: 243-254.

Hasserius et al. Osteop Intern 2003; 14: 61-68.
Cosman et. al J Clin Endocrinol Metab, 2014, 99:4546 – 4554.
Conclusions: FLEX/FIT, Horizon and Extension
Studies
• BMD decline at all sites (except spine) (but not to pretreatment levels) in
those that pursued drug holiday
• Initial increases in BTMs after drug discontinuation but not to pretreatment
levels and these did not predict fracture risk
• Clinical Vertebral fractures (FIT/FLEX) and Morphometric vertebral fractures
(Horizon) higher in those individuals undergoing drug holiday
• Subjects who benefit the most from long-term ALN or ZOL are categorized
as high risk based on:
• Persistent T score (FN and TH) ≤ -2.5
• Incident Fractures while on therapy
• High vertebral fracture risk
 Bone Turn Over Markers
• The trials suggest there is a gradual increase in BTMs as BMD declines with
drug holidays, however based on limited evidence for how this increase in
BTMs affects fracture risks → limited evidence to support their use for
fracture risk prediction
• AACE and IOF endorse the use of BTMs in the following situations:
• Help to stratify patients with very high or very low bone turnover
• Useful short-term method to follow the response as well as adherence to therapy
• The IOF recommend Procollagen type 1 N-terminal peptide (P1NP) to
assess bone formation and C-terminal Crosslinking telopeptide (CTX) to
assess bone resorption

Vasikaran et. al Osteoporos Int. 2011; 22:391-420.

Camacho PM et al., Endoc Pract. 2020; 26 : 1-40.
 ASBMR Treatment Length Recommendations

Adler R et al. J Bone Mineral Res. 2016; 31(1):16-35

 Bisphosphonate Drug Holiday
• The rationale for a bisphosphonate holiday is the expectation that
prolonged skeletal retention of these medications will confer
antifracture benefits for some period of time, perhaps several years,
in appropriately selected patients.
• A period off the drug may reduce risk for Osteonecrosis of the Jaw
(ONJ) and Atypical Femoral Fracture (AFF)
• Drug holiday length can be variable based on the individual patient
clinical characteristics (age, demographics previous therapy) and
ongoing risk factors
• Not all holidays are equal
• Binding affinity for the bone is highest with ZOL > Alendronate > RIS

Leboff et al. Osteoporos Int 2022; 33: 2049-2102.

Drug holiday monitoring ? When to Resume
therapy?
• BP DRUG holidays are not drug retirements- Osteoporosis is a chronic progressive
disease that tends to worsen with aging and needs continuous monitoring
• During a Drug HOLIDAY
• Continue Baseline recommendations (Exercise/Vitamins/ Fall prevention)
• Continue Assessment with DXA (Every 2 years)
• Continue Clinical risk factor assessment
• Consider Trend BTMs (However current data not fully suggestive for fracture risk prevention)
• Consider Reinitiation of Therapy:
• BMD T-score falls to ≤-2.5
• BMD decreases greater than 3-4% at monitored sites
• New fractures occur
• New/additional risk factors bone loss emerge
• Major increase in BTMs ??
Leboff et al. Osteoporos Int 2022; 33: 2049-2102.
Adler R et al. J Bone Mineral Res. 2016; 31(1):16-35
Atypical Femoral Fractures

❖ First reported in 2005 in patients

receiving oral BPs
❖ Occur with little or no trauma
❖ Age-adjusted incidence rates suggest
a duration related increase
2 year exposure : 1.8/100,000 per year
8-10 year exposure : 113/100,000 per
year

Le Blanc et al. J of Bone and Min

Res, 2017; 32: 2304–2314.
Dell RM et al. Bone Miner Res
2012;27:2544-50.
AFF risk vs. Fragility Fracture Prevention
❖Risk factors for AFF:
❖Asian race
❖Long duration of
therapy BP
❖Multiple antiresorptive
therapies
❖Glucocorticoid use
❖RA
❖Varus hip angle/bow-
leg deformity

Black et al. NEJM 2020; 383:743-53.

 Weighing the benefit of continued therapy to
potential risks

Wang et al. Journ Bone Min Res 2022;6:1-17.

 Weighing the benefit of continued therapy to
potential risks

Wang et al. Journ Bone Min Res 2022. 6:1-17

 Osteonecrosis of the Jaw
• First reported in 2003 in patients receiving high dose IV
bisphosphonate therapy for metastatic cancer
• Incidence 1/10,000 to 1/100,000 patient treatment years
• Appears to be a trend toward ONJ with duration of BP use but the quality of
data is poor
• The American Dental Association (ADA) reports that sound oral hygiene
practices and regular dental care may be the optimal method for lowering risk
of drug-related ONJ.

Khosla S, Burr D, Cauley J, et al. J Bone Miner Res. 2007;22:1479–91.

Adler R et al. J Bone mineral Res. 2016; 31:16-35.
Pharmacological Therapy Options
Inhibit Bone Resorption Stimulate Bone Formation
(Antiresorptive, Antiremodeling) (Anabolic, Bone Forming)

• Alendronate (ALN) (Fosamax) • Teriparatide (TPT) (Forteo)

• Risedronate (RIS) (Actonel) • Abaloparatide (ABL) (Tymlos)
• Ibandronate (Boniva) • Romosozumab (Romo)
• Zoledronic acid (Reclast) (Evenity)
• Denosumab (Dmab) (Prolia)
• Raloxifene (Evista)
• Salmon Calcitonin (Miacalcin)
• Estrogen (Various)
• CE/Bazedoxifene (Duavee)
 Denosumab
• Approved as a primary agent or secondary
agent to treat OP in high to very high-risk
patients
• Freedom trial
• 7,868 women aged 60-90 PMO
• 9% increase in Spinal BMD; 4-5% increase in hip
BMD
• Reduction in fracture risk:
• 68% decrease in New VFs
• 40% decrease in Hip Fracture
• 20% decrease in Non-Vertebral Fractures
• 10-year safety data
• Infection, cellulitis, malignancy remained low
• AFF (0.8 per 10,000 participant years)
• ONJ (5.2 per 10,000 participant years)
Cummings et al. N Engl J Med 2009; 361:756-765.
Bone et al. Lancet Diabetes Endocrinol 2017; 5: 513–23.
Miller et. Al Osteoporosis International (2020) 31:181–191
Miller et. Al Osteoporosis International 2020; 31:181–191.
Miller et al. J Clin Endocrinol Metab, 2016; 101(8):3163–3170
Miller et al. 2020 Osteoporosis International
31:181–191
 Denosumab Holiday
• Denosumab HOLIDAY is not recommended:
• Upon stopping denosumab there is notable rebound in remodeling rates to
values higher than pretreatment levels with rapid bone loss due to a brisk rise
in bone resorption markers
• Biochemically: Osteoclast precursors which have remained dormant during Dmab
treatment regain activity immediately
• The rapid bone loss and increase in bone markers has been associated with
an increased risk of multiple vertebral fractures

Lewiecki et al. Ther Adv Musc Dis 2018; 10 (11) 209-233

McCLung Osteopros Int 2016; 27:1677-1682
Bone et al. J Clinc Endocrin 2011, 96:972-980.
 ❖ After discontinuation of therapy
with DMAb rate of fractures
increased by 7.1% per 100
participant years
❖ Of the participants that
developed one fracture, rate of
multiple fractures was higher
than placebo 4.2% vs. 3.2 %

Cummings et al. J Bone and Mineral Research 2018; 33: 190–198.

 ❖Vertebral fractures were
higher in individuals with
history of vertebral fracture
before therapy 9.4% vs. 7%

Cummings et al. J Bone and Mineral Research 2018, 33: 190–198.

Real world: Reasons Why Denosumab May be
stopped
• Safety concerns? Lack of safety data after 10 years
• Patient preference
• Noncompliance/missed doses
• Side effects:
• Hypocalcemia
• Serious infections
• ONJ/ Dental Procedures
• AFF
• Long-term ongoing bone suppression
❖3 RCTs, 2 Retrospective and 7
Observational studies
❖Existing data support treatment
for 10 years in high and very
high risk patients
❖Current data suggest that the
duration of DMAB therapy is an
important determinant of the
extent of the rebound effect
Tsourdi et al. The Journal of Clinical Endocrinology &
Metabolism, 2021; 106: 264-281.
Tsourdi et al. The Journal of Clinical Endocrinology &
Metabolism, 2021; 106: 264-281.
Tsourdi et al. The Journal of Clinical Endocrinology &
Metabolism, 2021; 106: 264-281.
 ❖ Treat to target in Osteoporosis is a
• Initial treatment should be selected according to the
concept notlikelihood
guideline of
achieving an acceptable level of fracture risk ❖ over a reasonable
Using T-score aloneperiod
may not be
of time possible in those high-risk
• A patient may respond to therapy but yet have patientsan ongoing highcurrent
with the risk
for fracture available therapies who T score
may never go above -2.5
• Goals of treatment ❖ Using T-score alone does not
• T-score ≥ -2.5 apply to patients who initiate
• Stable or improved baseline T-score with no fractures
medications due to HIGH FRAX
• Achieving absolute lower fracture risk

Cummings et al. J Bone Miner Res. 2017; 32: 3-10.

 Treat to Target Approach
OUTCOME BISPHOSPHONATE DENOSUMAB

Target is reached and no Consider Drug Continue treatment or

fractures Holiday after 3-5 consider switch to BIS
years

On pathway to target Continue Continue

Not on pathway to target Switch to DMAB or Consider Adding

ANABOLIC TPT/ABA or Switch to
ROMO
Adapted from Lewiecki et al. Endocrinol Metab 2021; 36: 270-278.
 Treat to Target Approach
OUTCOME BISPHOSPHONATE DENOSUMAB

Target is reached and no Consider Drug Continue treatment or

fractures Holiday after 3-5 consider switch to BIS
years

On pathway to target Continue Continue

Not on pathway to target Switch to DMAB or Consider Adding

ANABOLIC TPT/ABA or Switch to
ROMO
 Treat to Target Approach
OUTCOME BISPHOSPHONATE DENOSUMAB

Target is reached and Consider Drug Holiday Continue treatment or

no fractures after 3-5 years consider switch to BIS

On pathway to target Continue Continue

Not on pathway to Switch to DMAB or Consider Adding

target ANABOLIC TPT/ABA or Switch to
ROMO
Adapted from Lewiecki et al. Endocrinol Metab 2021; 36: 270-278.
 Treat to Target Approach
OUTCOME BISPHOSPHONATE DENOSUMAB

Target is reached and no Consider Drug Holiday Continue treatment or

fracture after 3-5 years consider switch to BIS

On pathway to target Continue Continue

Not on pathway to target Switch to DMAB or Consider Adding

ANABOLIC TPT/ABA or Switch to
ROMO
Adapted from Lewiecki et al. Endocrinol Metab 2021; 36: 270-278.
Thank you