Once a Year? New Approaches to Osteoporosis Treatment

Once a Year? New Approaches to Osteoporosis Treatment
Bruce R. Troen, M.D. Geriatrics Institute Division of Gerontology and Geriatrics Medicine Geriatric Research, Education, and Clinical Center Miami VA Medical Center 1

To better understand and act upon:
Learning Objectives To better understand and act upon: New and forthcoming approaches to the treatment of osteoporosis. The significant prevalence and importance of vitamin D insufficiency. Learning Objectives After participating in this educational program, healthcare professionals will be better able to communicate: The lack of awareness of vitamin D insufficiency. The importance of vitamin D, calcium, and parathyroid hormone (PTH) in maintaining bone health. The definition of vitamin D insufficiency and how to recognize risk factors for it. How to interpret data regarding reduction in osteoporotic fracture risk with antiresorptive therapy. How to use evidence from clinical trials to support clinical decision making in the treatment of osteoporosis. Healthcare specialists can have an important impact on strengthening their community’s approach to managing osteoporosis. This program provides a conceptual framework to help facilitate communication of key issues and highlights recent clinical trial results.

Osteoporosis Rx Treat all with a history of fragility fractures. Rx benefits women with a fracture; less so women with osteopenia or men. ALN, RIS, IBN, raloxifene, PTH, and strontium reduce vertebral fractures. ALN, RIS, and HRT reduce hip fractures in community-dwelling women. Calcium + vit D reduce hip fractures in the community and in institutions.

Male Osteoporosis 2 million men 13-25% lifetime fracture risk
exponential increase with age, occurs ~10 years later in men than in women 1/5 of all hip fractures; by age 90, 1/6 of men suffer hip fracture vertebral fracture incidence: 12% (same as in women)

> 50% of hip fractures occur in pts. with T-scores > –2.5
No. of hip fracture cases No. of participants 60 50 40 30 20 10 Total Hip T-Score 1800 1600 1400 1200 1000 800 600 400 200 Hip Fracture Cases All Participants BMD is not the whole story! Wainwright SA 2005

BMD Contribution to Fracture Risk Reduction
Alendronate 16 % Cummings AMJ 112:281, 2002 Risedronate 28 % Eastell JBMR 18: 1051, 2003 Raloxifene 4 % Sarkar JBMR 17:1, 2002 18 % Watts J Clin Dens 7:255, 2004 Teriparatide 40 % Chen JBMR 21:1785, 2006 BMD is not the whole story!

Both age and BMD alter fracture risk
Age and BMD are the strongest predictors for hip fracture. Over age 50, 3 to 7 fold increase in hip/spine fracture risk, depending on T-score. Over a 4 SD interval of BMD (+1 to –3) the risk of fracture increases 14 fold at age 80. Might not apply to all populations, this is study from Norway. Also, there are problems with T-score: discrepancies across multiple sites of assessment and multiple technologies. Kanis et al. Osteoporos Int 2001

Osteoporosis - What’s New?
Ibandronate IV every 3 months ONJ - how much of a problem is it? Bisphosphonate wars - is one better? PTH - when should it be used? Under-diagnosis/treatment and poor compliance Zoledronate 5 mg IV once a year Denosumab 60 mg SQ twice a year Vitamin D insufficiency is widespread Vitamin D 600,000 IU once a year

Ibandronate IV every 3 months
Osteoporosis - What’s New? Ibandronate IV every 3 months

Ibandronate reduces vertebral fractures
Placebo Daily IBN Intermittent IBN 12 10 8 6 4 2 Vertebral fracture rate Overall North America Europe Chesnut et al., Curr Med Res Opin 3/05

Quarterly IV IBN is superior to daily oral IBN
2.5 mg daily 2 mg q 2 months 3 mg q 3 months 6 5 4 3 2 1 Change from baseline (%) Lumbar spine Total hip Femoral neck Trochanter Delmas et al. Arthritis & Rheumatism 54(6): 1838–

ONJ - how much of a problem is it?
Osteoporosis - What’s New? ONJ - how much of a problem is it?

Osteonecrosis of the Jaw
Ruggiero SL. J Oral Maxillofac Surg. 2004;62:

Osteonecrosis of the Jaw (ONJ)
Osteonecrosis of the Jaw is a rare condition that involves the loss, or breakdown of the jaw bone1 Occurs usually after tooth extraction Rather than healing post extraction, indolent infection of the bone occurs (osteomyelitis) This is background information on ONJ. 1National Cancer Institute. Oral complications of chemotherapy and head/neck radiation (PDQ).2004

ONJ with oral BP None seen in all clinical trial data (>100,000 patients ≥ 3 years) Postmarketing anecdotal reports: ALN ~75 cases, RIS ~10 FDA labeling on ONJ caution (especially for oral BPs) is not based on any sound science Oral BP cumulative ONJ may be ≤ % of all persons taking oral BPs (10 x more oral BP exposure than IV BPs) ONJ would never have been detected without high-dose IV BP use Dr. Paul Miller

ONJ Comparative Risks M. Lewiecki 2007
(1) Women age (from Swedish National Bureau of Statistics and database of Olmsted County, MN, USA.) Kanis JA et al. Osteoporos Int. 2001;12: Pharmcoepidemiol Drug Saf. 2003;12: National Center for Health Statistics. JADA. 2006;137: M. Lewiecki 2007

Bisphosphonate wars - is one better?
Osteoporosis - What’s New? Bisphosphonate wars - is one better?

BMD Increases With Alendronate and Risedronate at 24 Months in FACT
Total Hip Alendronate (N=375) Risedronate (N=375) p < .001 3.0 % 1.3 % Bonnick et al. JCEM 91(7): , 2006

BMD Increases With Alendronate and Risedronate at 24 Months in FACT
Lumbar Spine Alendronate (N=372) Risedronate (N=379) 5.2 % 3.4 % p < .001 Bonnick et al. JCEM 91(7): , 2006

Percent of Patients With Response by BMD Gains/Losses at 12 Months in FACT
Total Hip Percent of patients who lost BMD at 24 months Percent of patients who maintained or gained BMD at 24 months 16% 84% P≤0.002 P≤0.002 41% 59% Percent of Patients With Response by BMD Gains/Losses at 12 Months in FACT1 The percent of patients who responded at ≥0% change from baseline at 12 months at the hip trochanter was 84.5% and 67.8% for alendronate and risedronate, respectively. The treatment difference between alendronate and risedronate was 16.7% (95% CI: 11.4% to 22.0%, P<0.001). The percent of patients who responded at <0% change from baseline was 15.5% and 32.2% for alendronate and actonel, respectively. The treatment difference between alendronate and risedronate was –16.7% (95% CI: –22% to –11.4%, P<0.001). In the US study, alendronate 70 mg once-weekly produced significantly greater increases in BMD at 6 months at the following sites compared with risedronate 35 mg once-a-week: lumbar spine: 2.8% vs 2.1% P = 0.002; total hip: 1.6% vs 0.8%, P<0.001; femoral neck: 1.4% vs 0.9%, P = In the international study, alendronate 70 mg once-weekly produced significantly greater increases in BMD at 6 months compared with risedronate 35 mg once-a-week at hip trochanter: 2.6% vs 1.9%, P = 0.013; and total hip: 1.8% vs 1.3%, P = Nonsignificant increases were seen in BMD at 6 months between alendronate 70 mg once-weekly and risedronate 35 mg once-a-week at lumbar spine: 3.2% vs 2.9%, P = and femoral neck: 1.5% vs 1.5%, P = In the international study, patients taking alendronate experienced significant increases in BMD at 12 months compared with risedronate at the following sites: hip trochanter 3.6% (n = 435) vs 2.7% (n = 434), P = 0.008; lumbar spine 4.6% (n = 435) vs 3.8% (n = 437), P = 0.002; total hip 2.7% (n = 435) vs 2.0% (n = 435), P<0.001; femoral neck 2.3% (n = 435) vs 1.7% (n = 435), P = Similar results were observed in the international study, with the exception that the percent of patients who responded at ≥ 0% change from baseline was 83.4% and 76.7% for alendronate and risedronate, respectively. The treatment difference was 6.7% (95% CI: 1.4% to 12.0%, P = 0.013). 0% 40% 60% 80% 100% 20% ALN 70 mg once-weekly RIS 35 mg once-a-week Bonnick et al. JCEM 91(7): , 2006 Reference: 1. Sebba AI, Bonnick SL, Kagan R, et al, for the FOSAMAX Actonel Comparison Trial (FACT) Investigators. Response to therapy with once-weekly alendronate 70 mg compared to once-weekly risedronate 35 mg in the treatment of postmenopausal osteoporosis. Curr Med Res Opin. 2004;20:2031–2041.

Responses to Alendronate and Risedronate at 24 Months in FACT
BMD (site) ALN RIS Hip Trochanter: 4.6% 2.5% Total Hip: 3.0% 1.3% Femoral Neck: 2.8% 1.0% Lumbar Spine: 5.2% 3.4% Bone markers ALN RIS BSAP: -40% -29% P1NP: -62% -46% NTX: -57% -44% CTX: -73% -53% Bonnick et al. JCEM 91(7): , 2006

RIS more effectively reduces non-vertebral fx’s than ALN or CT
Patients (%) Time to Fracture (Days) 6 5 4 3 2 1 Calcitonin Alendronate Risedronate RR = 0.41 Watts et al., JMCP (2):

RIS more effectively reduces hip fractures than ALN
0.58 0.50 0.40 0.30 0.20 0.10 0.00 Alendronate % of cohort with a hip fracture Risedronate RR = 0.57 Baseline month 3 month 6 month 12 month 24 Silverman et al., Osteoporos Int (2007) 18:25–34

RIS more effectively reduces fractures than ALN
Silverman et al., Osteoporos Int (2007) 18:25–34

PTH - when should it be used?
Osteoporosis - What’s New? PTH - when should it be used?

PTH + concurrent bisphosphonate?
NO Finkelstein et al., NEJM 9/03

Treatment / Prevention of Osteoporosis - PTH
those who continue to fracture or lose BMD after bisphosphonates x 2 years severe loss of BMD (T ≤ -3.5) prevalent fractures and T ≤ -2.5 20 µg subcutaneously daily treat for no longer than two years do NOT combine with anti-resorptive treat with anti-resorptive after PTH

Fracture Risk Reduction in Women with PMO No effect demonstrated
Agent Vertebral Fx New First Hip Fracture Nonvertebral Fracture Ca+2/Vit D  Calcitonin No effect demonstrated Raloxifene Ibandronate Alendronate Risedronate Teriparatide

Under-diagnosis, Under-treatment, and Non-compliance
Osteoporosis - What’s New? Under-diagnosis, Under-treatment, and Non-compliance

Osteoporosis: underdetected and undertreated
14/16 studies on fragility fractures < 32% had a BMD test 8-62% (median 18%) were on calcium or vitamin D 0.5-38% were on bisphosphonates Elliot-Gibson et al., Osteoporosis Int 15: , 2004

Osteoporotic nonvertebral fractures are often not diagnosed or treated

Bisphosphonate Persistence: Weekly vs. Daily (newly started)
Ettinger et al., Arthritis & Rheumatism 2004

Bisphosphonate Persistence: Weekly vs. Daily (previous)
Ettinger et al., Arthritis & Rheumatism 2004

All-cause hospitalization rate in osteoporosis pts. by adherence level
1.60 1.50 1.40 1.30 1.20 1.10 1.00 0.90 Relative Rate of Hospitalization > 90% 80-90% 50-80% < 50% Adherence (medication possession over time) Danese et al. ASBMR, Philadelphia, 2006

IBN vs. RIS: ?compliance Preference (depends how you ask!)
monthly > weekly weekly > monthly Persistence (depends on the study!) RIS vs. IBN: vs days IBN vs. RIS: 57% vs. 39% Adherence RIS: 72.7 ± 26.4% (p < ) IBN: 52.8 ± 31.5% Gold et al., Current Medical Research and Opinion 12(22): , 2006 Cooper et al. Int. J. Clinical Practice 2006

Osteoporosis: Bottom Line
Any treatment is better than no treatment! How can we improve treatment compliance and persistence?

Zoledronic acid 5 mg IV once a year
Osteoporosis - What’s New? Zoledronic acid 5 mg IV once a year

Once Yearly Zoledronic Acid Reduces Fractures
HORIZON Pivotal Fracture Trial multi-national, multi-center, RCT 7,736 women age with T-score < -2.5 or fracture plus T-score < -1.5 calcium mg/day vit D ( IU/day) zoledronic acid IV infusion 5 mg Black et al. NEJM 356: , 2007

ZOL reduces hip fracture
3 Placebo (n = 3861) ZOL 5 mg (n = 3875) 41%* (17%, 58%) P = .0024 2 Cumulative Incidence (%) 1 Cumulative Risk of Hip Fracture (Strata I & II) ZOL 5 mg reduced the relative risk of incurring a hip fracture over time by 41% compared with placebo (hazard ratio=0.59; P = .0024). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. 3 6 9 12 15 18 21 24 27 30 33 36 Time to First Hip Fracture (months) *Relative risk reduction (95% confidence interval) vs placebo Black et al. NEJM 356: , 2007

ZOL reduces vertebral fx
3 Placebo (n = 3861) ZOL 5 mg (n = 3875) 77% (63%, 86%) P < .0001 2 Cumulative Incidence (%) 1 Cumulative Risk of Clinical Vertebral Fracture (Strata I & II) Assessment of number of clinical fractures (painful fractures that led to an office evaluation) occurring over 3 years revealed that a single annual infusion of ZOL 5 mg reduced the risk of clinical vertebral fractures by 77% compared with placebo over 3 years (P < .0001). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. 3 6 9 12 15 18 21 24 27 30 33 36 Time to First Clinical Vertebral Fracture (months) *Relative risk reduction (95% confidence interval) vs placebo Black et al. NEJM 356: , 2007

ZOL reduces non-vertebral fx
P = .0002 Time to First Clinical Non-vertebral Fracture (months) 2 4 6 8 10 12 3 9 15 18 21 24 27 30 33 36 25% (13%, 36%) Placebo (n = 3861) ZOL 5 mg (n = 3875) Cumulative Incidence (%) Cumulative Risk of Clinical Non-vertebral Fracture (Strata I & II) Incidence of clinical non-vertebral fractures was significantly reduced (approximately 25%) over 3 years with ZOL 5 mg treatment compared with placebo (P = .0002; estimated hazard ratio of 0.75). The most frequent fracture locations were wrist, hip, arm, and rib. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. *Relative risk reduction (95% confidence interval) vs placebo Black et al. NEJM 356: , 2007

Once Yearly Zoledronic Acid Reduces Fractures
side effects: fever (15%), myalgia (8%), flu-like symptoms, headache, and bone pain - majority resolved within 3 days ONJ - 1 Rx, 1 placebo (resolved w/ RX) atrial fibrillation 1.2% Rx, 0.4% placebo bone markers: decreased CTX, BSAP, and P1NP (to mid premenopausal range) Black et al. NEJM 356: , 2007

Denosumab 60 mg SQ twice a year
Osteoporosis - What’s New? Denosumab 60 mg SQ twice a year

RANK Ligand (RANKL) is a Key Mediator of Osteoclast Activity
(receptor activator of NFkB ligand) OPG RANKL Vit D PTH PGE2 IL-11 Osteoclast (mature) CTSK Stromal cells Osteoblasts RANK Osteoclast precursor

The RANKL / OPG Balance OPG RANKL growth factors hormones PTH
cytokines drugs vitamins gravity aging OPG RANKL

RANKL Expression Is Increased in Postmenopausal Women
60 Marrow stromal cells 90 P<0.001 30 B cells T cells P=0.003 Total * *† Normalized fluorescence intensity for OPG-Fc-labeled FITC Premenopausal Untreated postmenopausal Postmenopausal + ERT (n=12/group) *vs postmenopausal + ERT; †vs premenopausal. ERT = estrogen replacement therapy. Eghbali-Fatourechi et al. J Clin Invest. 2003;111:1221.

Antibody to RANKL prevents OC precursor differentiation
denosumab Inhibition of mature OC formation X CTSK Vit D PTH PGE2 IL-11 Stromal cells Osteoblasts Osteoclast precursor

Denosumab increases BMD and decreases bone resorption
RCT, dose ranging 412 women, mean age 63 with T-scores: LS < -1.8 to -4.0 or FN/hip < -1.8 to -3.5 calcium 1000 mg/day, vit D 400 IU/day denosumab SC, q 3mo. & q 6 mo. McClung et al. N Engl J Med. 2006;354:821.

Denosumab SC q6mo enhances lumbar spine BMD
Months from baseline (%) Mean change -2 -1 1 2 3 4 5 6 8 10 12 Placebo Denosumab 60 mg Denosumab 100 mg ALN 70 mg/wk Denosumab 14 mg Denosumab 210 mg McClung et al. N Engl J Med. 2006;354:821.

Denosumab SC q6mo enhances total hip BMD
Months 1 2 3 4 5 6 7 8 9 10 11 12 -2 -1 from baseline (%) Mean change * Placebo Denosumab 60 mg Denosumab 100 mg ALN 70 mg/wk Denosumab 14 mg Denosumab 210 mg McClung et al. N Engl J Med. 2006;354:821.

Denosumab SC q6mo maintains distal third radius BMD
Placebo Denosumab 60 mg Denosumab 100 mg ALN 70 mg/wk Denosumab 14 mg Denosumab 210 mg Months -3 -2 1 2 3 -1 12 4 5 6 7 8 9 10 11 from baseline (%) Mean change McClung et al. N Engl J Med. 2006;354:821.

Denosumab suppresses serum c-telopeptide
Months -100 -80 -60 -40 -20 20 2 4 6 8 10 12 from baseline (%) Mean change Placebo Denosumab 60 mg Denosumab 100 mg ALN 70 mg/wk Denosumab 14 mg Denosumab 210 mg Adapted from McClung et al. N Engl J Med. 2006;354:821.

Osteoporosis - What’s New?
Vitamin D insufficiency is widespread and plays a critical role in fractures

The 25(OH)D Continuum: Controversy
“deficiency” “insufficiency” “normal” ng/ml The 25(OH)D Continuum Controversy The significance of serum levels of 25(OH)D is best expressed as a continuum, because there is controversy as to which level will bring about pathology. “Deficiency” is the level at which osteomalacia, a disease characterized by generalized accumulation of undermineralized bone matrix, occurs. It is manifested by rickets in children, and extreme bone pain and muscle weakness in adults, which generally occur at levels below 25 nmol/L (10 ng/mL).1 “Insufficiency” is the range of serum 25(OH)D at which there begins to be an inadequate absorption of calcium to maintain necessary physiologic circulating calcium levels. The low circulating levels of calcium begin to trigger the calcium-sensing receptor to stimulate the secretion of PTH. The elevated PTH secretion is the body’s physiologic response to restore plasma calcium, which it must do at the expense of bone. Calcium begins to be taken from bone when vitamin D levels are below about 75 nmol/L (30 ng/mL) of vitamin D, all the way to about 25 nmol/L (10 ng/mL), which leads to a steep rise in PTH, and thus development of osteomalacia. The controversy: deciding what level vitamin D is low enough (insufficient) to cause the PTH elevation to become critical. The range of controversy for insufficiency is shown by the shaded area covering the arrows.2 “Normal”: Above 75 nmol/L (30 ng/mL), the circulating level of 25(OH)D is high enough to keep PTH within normal circulating levels.3 References: 1. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001;22:477–501. 2. Boonen S, Rizzoli R, Meunier PJ, et al. The need for clinical guidance in the use of calcium and vitamin D in the management of osteoporosis: a consensus report. Osteoporos Int. 2004;15:511–519. 3. Heaney RP. Vitamin D: how much do we need, and how much is too much? Osteoporos Int. 2000;11:553–555. nmol/l 1. Boonen S et al. Osteoporos Int. 2004;15:511–519. 2. Lips P. Endocr Rev. 2001;22:477–501. 3. Heaney RP. Osteoporos Int. 2000;11:553–555. 4. Heaney RP. Am J Clin Nutr. 2004;80(suppl):1706S-1709S. 5. Thomas MK et al. N Engl J Med. 1998;338:777–783.

Hypovitaminosis D (<30 ng/mL) is prevalent across latitudes in North America
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● P = NS for test of trend. Holick et al. J Clin Endocrinol Metab. 2005;90:3215–3224.

Vitamin D deficiency in South Florida
25 (OH) D Winter Summer (N=212) (N=99) Men 24.9 ± ± % Women 22.4 ± ± % Vitamin D deficiency (< 20 ng/ml) Men 38 % Women 40 % 90% < 32 ng/ml Hypovitaminosis observed across age and racial groups, and independently of sunlight exposure or vitD/calcium supplementation Levis et al. J Clin Endocrinol Metab 2005;90:

Vitamin D and African Americans
<50 nmol/l: 53-76% NHB, 8-33% NHW many do not achieve optimal 25OHD at any time of the year median vitamin D intakes are low 6-31% lower than other groups decreased intake of dairy products and fortified cereals Harris, J. Nutrition 136: , 2006

Cutoff Points for Serum 25(OH)D, ng/mL
Prevalence of Low Vitamin D Levels in a Minimal Trauma Fracture Population Of 78 patients hospitalized with an osteoporotic fracture (76 hip fractures), 97% had vitamin D levels <30 ng/mL 20.5 52.5 80.8 96.2 97.4 N = 78 1 9 8 7 Patients, % 6 5 4 Prevalence of Low Vitamin D Levels in a Minimal Trauma Fracture Population This observational study assessed the prevalence of vitamin D levels less than 30 ng/mL, in 78 adults, aged 52 to 97 years (63% of the population was >80 years old). The sample consisted of patients consecutively hospitalized with hip and extremity fractures between August 2001 and January 2002 recruited from 2 St. Paul, Minnesota hospitals. Seventy-eight percent (78%) of the population were women, and 97% had a hip fracture.1 Only one half of the patients (n = 39) were reportedly taking at least 400 IU/day of vitamin D. Patients who reported vitamin D supplementation of at least 400 IU/day had greater mean 25(OH)D levels compared with those who used no supplement (16.4 vs 11.9 ng/mL; P = 0.002).1 All but 2 patients (97.4%) had 25(OH)D levels below 30 ng/mL.1 Reference: 1. Simonelli C, Weiss TW, Morancey J, Swanson L, Chen Y. A high prevalence of vitamin D inadequacy in a minimal trauma fracture population. Curr Med Res Opin.2005:21: 3 2 1 < 9 < 1 5 < 2 < 2 5 < 3 Cutoff Points for Serum 25(OH)D, ng/mL Simonelli et al. Curr Med Res Opin. 2005:21:

Vitamin D supplementation reduces falls
Primary analysis OR: 0.69 ( ) Secondary analysis OR: 0.84 ( ) Bischoff-Ferrari, H. A. et al. JAMA 2004;291:

Vitamin D reduces falls in older people in residential care
Mean age , 25(OH)D nmol/L 1767 assessed: 579 <25 nmol, 39 >90 nmol Ergocalciferol 10,000/week  1,000/day Falls OR ( ) Fall OR (compliant) ( ) NNT 12 (8 for first year) Fracture rates not reduced Flicker et al. JAGS 2005;53:

Calcium + vitamin D reduces non-vertebral fractures
Dawson-Hughes et al. NEJM 1997 500 mg Ca+2 & 700 IU vit D

Calcium plus vitamin D reduces hip fractures
1200 mg Ca+2, 800 IU vit D3 3270 healthy ambulatory women 18 months & 36 months BMD: Rx-2.7%, C-4.6% (p=.001) non-vertebral fxs - 32 % (p=.015) hip fractures - 43 % (p=.043) 25(OH)D 162%, PTH 44% Chapuy et al. NEJM 1992 and BMJ 1994; Chapuy et al. Osteoporos Int. 2002

700-800 IU/d vitamin D reduces fractures, but 400 IU/d does not
Hip Fx Non-vert Fx 1.0 400 1.0 Bischoff-Ferrari et al. JAMA 2005;293:

Vitamin D and disease Bone - osteoporosis Neuromuscular - falls
Cancer - prostate, breast, ovary, colon Cardiovascular - BP, CHF Inflammation - CRP, TNF, IL-6 Autoimmune - multiple sclerosis Metabolic - glucose / insulin sensitivity

Once-yearly I.M. cholecalciferol (600000 IU) is effective therapy for vitamin D deficiency.
Test Baseline 4 months 12 months Calcium 2.40 ± 0.11 2.40 ± 0.12 2.45 ± 0.10 25(OH)D 32 ± 8.4 114 ± 35* 73 ± 13* Creatinine 0.08 ± 0.02 0.07 ± 0.02 0.08 ± 0.03 PTH 7.4 ± 4 6 ± 3 5.2 ± 3* 2° urine Ca+2/cr 0.24 ± 0.2 0.29 ± 0.3 0.40 ± 0.3* Diamond et al. MJA 2005; 183: 10-12

Vit D Supplementation Measure 25-OH D Many healthy: 800-1200 IU/day
diet (1-2 glasses milk) plus units Elderly / impaired mobilty / little sunlight: 1, ,000 IU per day ergocalciferol (D2): 50,000 each month cholecalciferol (D3): 2, ,000 per day No evidence of adverse effects at doses less than 10,000 IU/day Monitor 25-OH D every 3 months

Fall Prevention Checklist
Check glasses: correct prescription and worn correctly Check for factors that impair walking and balance: peripheral neuropathy, arthropathy Check for postural hypotension, arrhyrthmias Check for excessive use of tranquilizers, sedatives, hypnotics, & anti-depressants Pay attention to home environments: nonslip floors; good lighting; hand rails; no obstacles; beds/seating - easy in & out

WHI Trial “… we must conclude that calcium with vitamin D supplementation is not an effective means of preventing hip fracture in this population.” (Wrong!) Ca mg, vit D IU: BID >50% HRT, 64% placebo taking 800 mg Ca+2 & 400 IU vit D 25(OH)D levels: hip fracture 46.0±22.6 nmol, controls 48.4±23.5 nmol Hip fracture reduced in adherent subjects: OR (0.52 to 0.97)

“I had come to an entirely erroneous conclusion, which shows my dear Watson, how dangerous it always is to reason from insufficient data.” Sherlock Holmes in “The speckled band”

Monitoring treatment Total or bone specific alkaline phosphatase before initiating Rx, repeat 3-6 months later NTX or CTX before Rx, repeat 6-12 weeks Estradiol levels in women receiving replacement therapy Testosterone in men receiving replacement Vitamin D before initiating Rx, repeat in 3 months ?BMD infrequently needed, requires minimum 1 year interval

Selected References 1. Black, et al., Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis. N Engl J Med, 346(18): 2. McClung MR et al., Denosumab in Postmenopausal Women with Low Bone Mineral Density N Engl J Med 354;8: 3. Ott, S, Osteoporosis and Bone Physiology. 4. Silverman, SL, Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: The risedronate and alendronate (REAL) cohort study Osteoporos Int 18:25-34. 5. Sambrook, P, Olver, I, Goss, A, Bisphosphonates and osteonecrosis of the jaw Australian Family Physician 35(10), October 2006. 6. Troen, BR, Osteoporosis in older people: a tale of two studies (and three treatments). J Am Geriatr Soc (5):853-5.

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