Osteoporosis

1. Osteoporosis Armed Forces Academy of Medical Sciences

2. Interpreting DXAs • 56 y/o F with hyperparathyroidism • Need to follow DXA on regular basis • Pt on alendronate—is it working? • How do we interpret changes in BMD?

3. Interpreting DXAs DXA from 30 JAN 08 • DENSITY T-SCORE Z-SCORE • (gm/cm2) • Lumbar spine L1-L4: 0.903 -2.4 -1.3 • Left femoral neck: 0.823 -1.5 -0.3 • Total left proximal femur: 0.850 -1.3 -0.4 DENSITY T-SCORE Z-SCORE (gm/cm2) The lumbar spine (L1,L2,L3,L4) 0.921 -2.2 -1.2 The left femoral neck 0.820 -1.6 -0.4 Total Left Proximal Femur 0.851 -1.2 -0.4 DXA from 14 APR 06

4. Interpreting DXAs • First, make sure the study was done on the same machine • Next, make sure you are comparing same anatomic regions • Will compare BMD, not T or Z scores • Know what is a significant change for your center. This used to be included on reports but is not anymore

5. Least Significant Change • Get by scanning 30 pts twice and calculating technician’s standard deviation • Recently done at our center: • Spine: 0.008 gm/cm2 • Total Hip: 0.006 gm/cm2 • This is very good—too good?

6. Interpreting DXAs • 2008:Lumbar spine L1-L4: 0.903 • 2006: The lumbar spine (L1-L4) 0.921 • Difference: - 0.018 or about 2% Change at femoral neck is 0.003

7. Interpreting DXAs • DXA report stated: “A baseline DEXA scan was performed on 4/14/06. The change in bone mineral density (BMD) in the lumbar spine was calculated based on L1-L4. Change in BMD in the lumbar spine: -7.5%, which corresponds to 1.2% per year. Change in BMD in the total left femoral neck: -6.8%, which corresponds to -1.1% per year.”

8. So who’s right? • Other DXAs • 2004 2001 2000 • Spine .924 .976 1.086 • Change from 2008 • 0.021 0.073 0.183 • 2.3% 8% 20% • So what can we say about her BMD?

9. Interpreting DXAs • Over the past 4 yrs, BMD has been stable at the hip and slightly decreased at the spine • Has been on alendronate since 2001 • What do you expect to see happen to BMD on serial DXAs when on a bisphosphonate

10. FLEX trial Black et al, JAMA DEC 2006: 296:2927-2938

11. Markers of Bone Turnover Black et al, JAMA DEC 2006: 296:2927-2938

12. FLEX Trial • In women who discontinued therapy after 5 years, BMD remained at or above baseline values 10 years earlier and bone turnover was still somewhat reduced. • Discontinuation did not increase the risk of nonvertebral fractures or x-ray detected vertebral fractures over the next 5 years, but the risk of clinically diagnosed vertebral fractures was significantly increased among those who discontinued • These results suggest that for many women, discontinuation of alendronate after 5 years for up to 5 more years does not significantly increase fracture risk, but women at high risk of clinical vertebral fractures, such as those with vertebral fracture or very low BMD, may benefit by continuing beyond 5 years.

13. Evaluating Bisphosphonate Therapy • How often do you need to do DXAs? • Is it OK to stop therapy? • What about side effects? • Osteonecrosis of the jaw • Whom should you treat?

17. FRAX website • http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=2 • If 10 yr risk is >20% for a major osteoporotic fracture, or >3% for hip fracture, should consider treating. • Most helpful to risk stratify and avoid treating pts who are at low risk for fx. • Someday this may be incorporated into DXA reports

18. Limitations • Does not take into account spine BMD • Does not take into account other predisposing medical conditions such as other medications

19. New Player • Receptor activator of nuclear factor-kappaB ligand (RANKL) is a cytokine member of the tumour necrosis factor family that is the principal final mediator of osteoclastic bone resorption. It plays a major role in the pathogenesis of postmenopausal osteoporosis, as well as bone loss associated with rheumatoid arthritis, metastatic cancer, multiple myeloma, aromatase inhibitor therapy and androgen deprivation therapy. • Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for RANKL. By inhibiting the action of RANKL, denosumab reduces the differentiation, activity and survival of osteoclasts, thereby slowing the rate of bone resorption. • Denosumab has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with low BMD. Denosumab is a potential treatment for osteoporosis and other skeletal disorders

20. Denosumab • In a double-blind, head-to-head study with alendronate in post-menopausal women with low bone mineral density (BMD), denosumab achieved significantly greater BMD gains at the total hip, hip trochanter, and distal radius. BMD improvement at the total hip was approximately 40% greater in the denosumab treatment arm compared with those receiving alendronate (primary endpoint). • Twice-yearly injections of denosumab also achieved significant increases in BMD in a pivotal 332-patient study, in which it was compared with placebo. • At the end of the two-year study period, denosumab-treated patients had a significantly greater increase in lumbar spine BMD compared with placebo recipients (6.5 vs -0.6%; p<0.001). • Similar significant differences were observed between active treatment and placebo with respect to BMD at the total hip (3.4 vs -1.1%; p <0.0001), wrist (1.4 vs -2.1%; p<0.0001) and total body (2.4 vs -1.4%; p<0.0001). • Treatment with denosumab appeared well tolerated by patients enrolled in clinical trials performed to date.

21. Secondary Causes of Osteoporosis • When do you look for secondary causes? • What is the usefulness of the Z score?

22. Secondary Causes • Hyperthyroidism • Hyperparathyroidism • Cushings • Hypogonadism • Vit D defic • Medications: Steroids, heparin, dilantin • Hypercaciuria • Chronic renal failure • Multiple myeloma

23. Work-up • Serum and 24 hr urine calcium • TFTs • PTH • Testosterone • 25-Vit D • SPEP/UPEP • ?Cushings eval