Goal-directed Treatment for Osteoporosis Also called “Treat to Target” Dennis M. Black, PhD UC San Francisco

Current status of Treat-to-Target Thinking Working group from ASBMR Initial report 2015. Cummings, Lewieki, Cosman, others Not yet published Just completed initial report, controversial Work in progress...setting up conceptual system for future Imagine it is 2020 ..better yet 2025

Purpose of Goals Anticipate how to use new treatments that have very potent effects on BMD and, perhaps, greater reductions in risk Improve follow-up of patients on treatment Improve the approach to selecting initial drug therapy for patients

Standard approach to treatment (current) Start with “1st line” drug, usually a bisphosphonate Follow up BMD in 1-2 years to see if she is ‘responding’ to the treatment If ‘responding’, continue If not responding, consider switching to another anti-resorptive drug or PTH

Goal-directed Treatment

General principles for drug treatments for osteoporosis Set a goal for patient Choose the treatment that has a reasonable chance of reaching that goal Follow-up periodically –> every 3 – 5 years to reassess the chance of reaching goal

1. Set a goal If the main reason is a low BMD, then the patient’s goal should be BMD If the main reason was a high fracture risk, then the goal should be an acceptably low risk Problematic for several reasons..

BMD T-score Goal If main reason for starting treatment is a T-score ≤ -2.5 at the femoral neck, total hip, or lumbar spine by DXA, then the goal of treatment should be T-score > -2.5 at that site.

Why a T-score > -2.5? Goal should be higher than the level for starting treatment: T-score ≤ -2.5

Why a T-score > -2.5? Goal should be higher than the level for starting treatment: T-score ≤ -2.5 Extension studies show: When hip T-score remains ≤ -2.5, continuing treatment reduces vertebral fracture risk When hip T-score becomes > -2.5, little benefit in continuing treatment, so consider a drug holiday1,2 1. Alendronate: Schwartz AV et al. J Bone Miner Res. 2010;25:976-982. 2. Zoledronate: Black DM et al. J Bone Miner Res. 2012;27:243-254.

Initial treatment

Choosing Initial Treatment Treatment should offer at least a 50% chance of achieving the goal within 3 to 5 years.

Low Probability of Achieving Goal with Alendronate Goal FN T-score > -2.5 Currently: T-score = -3.5 Typical gain with alendronate: 4-5% (1/2 t-score) Probability of reaching the goal: <5% in 3 years Alendronate Ms. S Unpublished data from FIT.

Follow-up

Follow-up Patients receiving treatment should be assessed within 3-5 years for achievement of the treatment goal* * May assess sooner for “response” and adherence

Principles of follow up for achievement of goals Has the patient adhered to treatment? Aim for at least 80% adherence If poor adherence persists, consider zoledronate (1/year) or denosumab (2x per year)

Principles of follow up for achievement of goals Has the patient adhered to treatment? Has the patient had a new fracture or lost BMD? If a patient has a fracture while on therapy or has had a large decrease in BMD (or is not near “goal”)..Consider switching to a more potent treatment

If BMD goal is achieved If target T-score >-2.5 achieved with a bisphosphonate (Alendronate or Zol) Stop treatment Reassess BMD periodically Restart no more than 5 years later

If BMD goal is achieved with non-bisphosphonate therapy For non-bisphosphonate treatments, like denosumab, teriparatide or SERM, BMD declines rapidly after treatment is stopped. After achieving the goal, treatment should be continued with an agent that maintains BMD Best a bisphosphonate

BMD goal is not achieved If T-score is still less than -2.5, what is the probability of achieving the goal with continued therapy? If <50%, switch to more potent agent However, switching to denosumab or PTH improves BMD only 1-2% in 12 months We need more potent treatments

Goal directed therapy: Controversies

Treat-to-target: Controversies* No evidence that achievement of BMD goal will reduce risk more than initial course of therapy We don’t have therapies that increase BMD very much No evidence about risk changes on therapy by FRAX. People are getting older: risk increasing over time *McCloskey, Harvey, Kanis. J. Clin Rheum 2015

Controversies continued: Many recommendations, little evidence Need trials comparing anti-fracture efficacy across drugs and combinations Little data comparing the chance of reaching BMD by starting alternative treatments Little data about switching treatment No algorithms for estimating fracture risk for patients taking or switching treatment An enhanced FRAX? *McCloskey, Harvey, Kanis. J. Clin Rheum 2015

Treat to Target: Summary Treat to target algorithm is: Aspirational A work in progress We need more evidence about various aspects of this approach including switching treatments We need more potent treatments

Goal-directed work.. Warriors 2015 season start: 23-0 23 Wins, no losses