What to do after 5 years of

Bisphosphonates?

David M Reid

Consultant Rheumatologist

Emeritus Professor of Rheumatology

University of Aberdeen

Volunteer Ambassador, National Osteoporosis

Society, UK

Questions to be answered?

What are the adverse effects of long-term bisphosphonate?

What might cause the adverse effects?

How might we predict the adverse effects?

What do Guidelines advise?

What post-bisphosphonate treatment options are available?

Are there any forthcoming options?

What are the adverse effects of

long-term bisphosphonates?

Osteonecrosis of the jaw

Estimated rates 1-90 per 100,000 patient years of

exposure in OP patients

Rates in the regimes used in cancer up to 18%1

Atypical femoral fractures

Absolute risk is low: 3.2 to 50 cases per 100,000

person-years.

Long-term use may be associated with higher risk

(∼100 per 100,000 person-years)2

References

1. Osteoporos Int. 2016 Mar;27(3):853-859. doi: 10.1007/s00198-015-3335-3. Epub 2015 Oct 22.

2. Journal of Bone and Mineral Research, Vol. 29, No. 1, January 2014, pp 1–23 DOI: 10.1002/jbmr.1998

How important is skeletal retention vs bone suppression?

Definition:

Exposed bone in the maxofacial region which does not heal within 8 weeks

Risk Factors:

Periodontal disease, oral surgical procedures with extractions or implants, radiation therapy, chemotherapy, diabetes, glucocorticoid use, and smoking

Bisphosphonate and denosumab therapy

Pathogenesis poorly understood but includes:

Suppressed bone resorption

Anti-angiogenic effect of bisphosphonates (not denosumab)

Genetic predisposition

Osteonecrosis of the Jaw

Definition of Atypical Femoral Fractures1

Major features

• Located anywhere along the femur from just distal to the lesser trochanter to just

proximal to the supracondylar flare

• Associated with no trauma or minimal trauma, as in a fall from a standing height or

less

• Transverse or short oblique configuration

• Noncomminuted

• Complete fractures extend through both cortices and may be associated with a

medial spike; incomplete fractures involve only the lateral cortex

Minor features

• Localized periosteal reaction of the lateral cortexb

• Generalized increase in cortical thickness of the diaphysis

• Prodromal symptoms such as dull or aching pain in the groin or thigh

• Bilateral fractures and symptoms

• Delayed healing

• Comorbid conditions (eg, vitamin D deficiency, rheumatoid arthritis,

hypophosphatasia)

• Use of pharmaceutical agents (eg, BPs, glucocorticoids, proton pump inhibitors)

Journal of Bone and Mineral Research, Vol. 29, No. 1, January 2014, pp 1–23

“Flaring or Beaking”

can be measured?

4 Major Features must be present to make the diagnosis

New thoughts on Pathogenesis

• Mutation determined by whole

genome sequencing in 3 sisters

• Affects Isoprenoid and

mevalonate metabolic pathways

Roca-Ayats N. et al N Engl j Med 376;18

nejm.org May 4, 2017

Ma S. et al. Scientific

Reports | 7:43399 | DOI:

10.1038/srep43399

How important is skeletal retention

Atypical Femoral Fractures – can we

predict them?

Hologic GE Lunar

So how do we prevent ONJ and AFFs?

Dental check-ups before starting bisphosphonates

Delay use of bisphosphonates?

Should we re-consider the use of HRT in women aged 50-60?

Use denosumab instead?

No long-term skeletal retention of the drug but strong (but intermittent) suppression of bone resorption

ONJ and AFF have both been reported in case reports and trials

Drug “Holidays”?

What do guidelines tell us?

Published March 2017

Oral Health

Management of

Patients at Risk of

Medication-related

Osteonecrosis of the

Jaw

Classification of Patient Risk

Published March 2015

Scottish Integrated Guideline Network 141March 2015

• Alendronic acid may be continued for up to 10 years in postmenopausal

women with osteoporosis, especially those that are at high risk of vertebral

fracture.

• Risedronate may be continued for up to 7 years in postmenopausal women

with osteoporosis

• Zoledronic acid may be continued for 3 years in postmenopausal women with

osteoporosis.

• After an interval of at least 3 years without treatment, fracture risk may

be reassessed to determine the need for further therapy.

Drug Holidays

No evidence was identified from randomised trials to suggest that drug

holidays were effective in reducing the risk of skeletal adverse effects.

Published March 2017

1. Bisphosphonates are retained in bone for varying periods of time, beneficial

effects may persist for some time after cessation of treatment.

2. NICE 2016 advises treatment review in patients taking bisphosphonates is

therefore important.

3. Trials are mostly been limited to a duration of three years, recommendations for

longer term use and for drug holidays are this based on limited evidence from

extension studies in postmenopausal women [Adler et al, 2016].

4. There is currently no evidence on which to base recommendations for men.

5. Withdrawal of treatment is associated with decreases in BMD and increased

bone turnover after 2-3 years for alendronate1,2 and 1-2 years for ibandronate

and risedronate3,4. Zoledronic acid, withdrawal after 3 years’ treatment was

associated with only a very small decrease in BMD after a further 3 years

without treatment5 [Black et al 2012a].

Background to Recommendations (1)

1. Ensrud KE et al. J Bone Miner Res 2004;19:1259-69.

2. Black DM et al. JAMA 2006;296:2927-38.

3. Ravn P et al. Bone 1998;22:559-64.

4. Watts NB et al. Osteoporos Int 2008;19:365-72.

5. Black DM et al. J Bone Miner Res 2012a;7:243-54.

Background to Recommendations (2)

1. In the Fracture Intervention Trial Long-term extension study of alendronate (FLEX)

significantly fewer clinical vertebral fractures in women previously treated with

alendronate for 5 years who continued with alendronate for five more years than in those

assigned to placebo after 5 years of alendronate1

2. In the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly

(HORIZON) study extension, the risk of morphometric vertebral fractures was

significantly lower in women continuing on zoledronic acid for 3 years after three years

therapy when compared to those switched to placebo, but the risk of non-vertebral

fractures was similar in the treatment and placebo groups2.

3. Post-hoc analyses from the alendronate and zoledronic acid extension studies suggest

that women most likely to benefit from long-term bisphosphonate therapy are those with

low hip BMD (T-score <-2.0 in FLEX and ≤-2.5 in HORIZON), those with a prevalent

vertebral fracture and those who sustained one or more incident fractures during the

initial 3 or 5 years of treatment3,4. Evidence level IIb

4. Older age was also associated with increased fracture risk after discontinuation of

alendronate therapy5.

1. Black DM et al. JAMA 2006;296:2927-38.

2. Black DM, Reid IR, Boonen S et al. J Bone Miner Res 2012a;7:243-54.

3. Black DM et al. N Engl J Med 2012b;366:2051-3.

4. Cosman F, et al. J Clin Endocrinol Metab 2014:99:4546-54.

5. Bauer DC et al. JAMA Intern Med 2014;174:1126-34.

Who should continue with treatment

after 5 years?

Continuation of bisphosphonate treatment beyond 3-5 years (3 years for zoledronic acid and 5 years for alendronate, ibandronate and risedronate) can generally be recommended in the following situations:

Age 75 years or more

Previous history of a hip or vertebral fracture

Occurrence of one or more low trauma fractures during treatment, after exclusion of poor adherence to treatment (for example less than 80% of treatment has been taken) and after causes of secondary osteoporosis have been excluded

Current treatment with oral glucocorticoids ≥7.5 mg prednisolone/day or equivalent

What to do at 5 years or before

Fracture risk should be reassessed:

After a new fracture regardless of when this occurs

If no new fracture occurs, after 18 months to 3 years

(Grade C recommendation)

Treatment review (FRAX + BMD) should be performed after 5 years of

treatment with alendronate, risedronate or ibandronate and after 3

years of treatment with zoledronic acid

(Grade C recommendation)

Reassessment of fracture risk in treated individuals can be performed

using FRAX with femoral neck BMD1

(Grade B recommendation)

NOGG intervention thresholds can then be used to guide the decision

as to whether treatment can be stopped for a period of time.

1. Leslie WD et al. J Bone Miner Res 2012;27:1243-51.

What to do at post “drug holiday”

reassessment

Reassess fracture risk using FRAX with femoral neck BMD1

NOGG intervention thresholds can then be used to guide the decision

as to whether treatment can be reinstituted for a period of time.

If the hip BMD T-score is ≤-2.5, resumption of treatment should be

considered regardless of FRAX-derived fracture probability.

If biochemical markers of bone turnover indicate relapse from

suppressed bone turnover and BMD has decreased following

withdrawal, resumption of treatment should be considered

(Grade C recommendation)

There is no evidence base to guide decisions about treatment beyond 10

years and management of such patients should be considered on an

individual basis.

Should these guidelines apply to denosumab?

BMD falls precipitously even after 8 years of denosumab

Eight of the 82 patients (9.8%) experienced one or more osteoporotic fractures during the 1-year observation study after stopping denosumab therapy.

The incidence of osteoporotic fracture was 4.9% in patients who were receiving denosumab during years 5–8 of the phase 2 study.

A bespoke method of treatment withdrawal may be required!

McLung MR et al. Osteoporos Int (2017) 28:1723–1732

Options for treatment beyond current guidelines

Alternative treatments beyond 5-years & post drug holiday?

Denosumab

In those with high risk of AFF as no long-term skeletal retention

In those requiring scheduled invasive dental treatment

Pre-treatment serum CTx to show bone no longer suppressed?

Teriparatide

In those with high risk of vertebral fractures or very low BMD

In those with impending AFF as detected by DXA software?

Any new options on the horizon?

Anti-sclerostin antibodies

A bone formation agent – Romosozumab

Given monthly by s/c route for 12 months

Lancet 2017; 390: 1585–94

Published Online

July 26, 2017

http://dx.doi.org/10.1016/

S0140-6736(17)31613-6

Romosozumab v Teriparatide in patients

treated with bisphosphonates for ≥ 3 years

Bone Markers

Hip Strength Analysis

Conclusions

There is increasing evidence of the rare adverse effects of ONJ

and AFF influencing decisions on long-term treatment for

osteoporosis

Although pathogenesis is not clear AFF in particular seems to be

become more common if bisphosphonate treatment is continued

beyond 5 years

The concept of a “drug holiday” has come to the fore in an

attempt to reduce the incidence

Recent guidelines give some indication as to how to manage the

“drug holiday” but are lacking detail on what to do next

Newer anabolic therapies may lead to a new post-

bisphosphonate treatment paradigm in the next few years.