1. Bone Turnover Suppression Based on an ASBMR/ECTS Clincal Debate “Too Much Suppression of Turnover Is Bad for Bone” Co-Chairs: Socrates Papapoulos, Douglas C. Bauer Debaters: Richard Eastell, Ian R. Reid Friday, October 15, 2010 ASBMR 2010 Toronto, Ontario

2. In support of the statement that “too much suppression of bone turnover is bad for bone” Patients Treated with high-dose bisphosphonates (BPs) With adynamic bone disease Treated with glucocorticoids Patients undergoing radiotherapy for cancer therapy can have zero bone turnover at the site of irradiation and are at risk for fracture

3. Glucocorticosteroid Effects on Vertebral Fracture Patients on glucocorticoid therapy have a fivefold increase in vertebral fracture risk over controls within months of initiating treatment Dialysis patients with adynamic bone disease have 6x higher hip fracture risk, more 2x the vertebral fracture risk than dialysis patients without low bone turnover

4. Fractures in the ADOPT Study *P<0.01; †P<0.05 for the comparison with rosiglitazone (unadjusted, contingency chi-square test). Over 9% of women developed a fracture over 4 years compared with 5% of those on metformin and about 3% on glyburide Rosiglitazone decreases bone formation and can lead to a rapid and significant decrease in bone density Adapted from Kahn et al. N Engl J Med 2006;355:2427-43.

5. Bone Suppression/Low Bone Turnover Too much suppression should be defined as bone turnover markers below levels found in healthy people Bone markers in clinical use remain controversial but P1NP may be the most useful Various clinical trials indicate that many patients who receive standard treatment for osteoporosis have low bone turnover Atypical subtrochanteric fractures may be associated with long-term BP use although they can occur in treatment-naive patients as well Severe sustained suppression of bone turnover can lead to osteonecrosis of the jaw regardless of how bone turnover is suppressed Glycosylation of the bone matrix can impair the mechanical properties of bone

6. PINP levels showing density distribution of patients treated with alendronate 10 mg/day or raloxifene 60 mg/day for ≥12 months After treatment, most women had P1NP concentrations within the lower half of the premenopausal reference interval (3% below lower limit) After treatment, 60% of women had P1NP concentrations below the lower limit of the premenopausal reference interval 1.2, 1.9 on scale represent the lower and upper limits and 1.5 the geometric mean. Prior to treatment, P1NP concentrations were in the upper half of the reference interval. P1NP= procollagen type I N-terminal propeptide FACT=Forteo-Alendronate Comparator Trial; AAA=Anabolic After Antiresorptive; MORE=Multiple Outcomes of Raloxifene Evaluations; GHAH=A Randomized Double-Blind Trial to Compare the Efficacy of Teriparatide with Alendronate in Postmenopausal Women with Osteoporosis Adapted from Eastell et al. Osteoporos Int 2010;Epub ahead of print.

7. The majority of patients in the FREEDOM trial had P1NP levels below reference intervals for healthy young individuals Despite this, the incidence of vertebral fracture, hip and non-vertebral fracture risk in denosumab recipients was lower than in controls and there was no signal of bone harm

8. Summary Evidence linking BP use with osteonecrosis of the jaw is extremely weak Even in the setting of atypical fractures of the femur, research indicates there is considerable cellular activity near the femur There is no clear link between low bone turnover and AFFs The ASBMR Task Force recently stated that a causal association between BPs and AFFs has not been established