Osteoporosis: Osteoporosis: Definitions, Risk, and Definitions, Risk, and

Treatment Treatment

"It's better for people to do "It's better for people to do the wrong thing or not the wrong thing or not

optimal thing than to do optimal thing than to do nothing.”nothing.”

-Dennis Black, statistician, principal investigator for -Dennis Black, statistician, principal investigator for FIT: alendronate trials, defending use of t-scores in FIT: alendronate trials, defending use of t-scores in

defining osteoporosisdefining osteoporosis

What is Osteoporosis?What is Osteoporosis?

““Osteoporosis is a systemic skeletal Osteoporosis is a systemic skeletal disorderdisorder characterized by decreased characterized by decreased bone mass and deterioration of bony bone mass and deterioration of bony microarchitecture.” microarchitecture.”

www.mrc-hnr.cam.ac.uk

Primary and Secondary Primary and Secondary OsteoporosisOsteoporosis

• PrimaryPrimary• Type 1: Postmenopausal Type 1: Postmenopausal

womenwomen– Thought to be due to Thought to be due to

estrogen or testosterone estrogen or testosterone deficiencydeficiency

– Estrogen increasing Estrogen increasing sensitivity to PTH?sensitivity to PTH?

• Type 2: Older men and Type 2: Older men and womenwomen– Due to decreased vitamin Due to decreased vitamin

D3?D3?

• SecondarySecondary– Chronic thyrotoxicosisChronic thyrotoxicosis– HyperparathyroidismHyperparathyroidism– Malabsorption/Malabsorption/

Calcium/Vitamin D Calcium/Vitamin D deficiencydeficiency

– Alcohol/SmokingAlcohol/Smoking– MedicationsMedications

• GlucocorticoidsGlucocorticoids• AnticonvulsantsAnticonvulsants• HeparinHeparin• Chemotherapy agentsChemotherapy agents• Antacids with aluminumAntacids with aluminum

Importance of Importance of OsteoporosisOsteoporosis

• The theoretical concern regarding The theoretical concern regarding decreased bone mass is the increased risk of decreased bone mass is the increased risk of fracture with minimal trauma. fracture with minimal trauma.

• Fractures: 1.5 million “osteoporotic” fractures in Fractures: 1.5 million “osteoporotic” fractures in US per year.US per year.– 700,000 vertebral700,000 vertebral– 300,000 hip fractures, over 37,000 patients die per year 300,000 hip fractures, over 37,000 patients die per year

due to complications.due to complications.

• Often associated with high morbidity and mortality Often associated with high morbidity and mortality with only 1/3 of patients with hip fractures with only 1/3 of patients with hip fractures returning to their prior level of functioning,. returning to their prior level of functioning,.

Prevalence of Prevalence of OsteoporosisOsteoporosis

• Silent Disease or Normal Aging?Silent Disease or Normal Aging?• ““Osteoporosis is a Osteoporosis is a major public healthmajor public health

threat for an estimated 44 million threat for an estimated 44 million Americans, or 55 percent of the people Americans, or 55 percent of the people 50 years of age and older. 10 Million 50 years of age and older. 10 Million people in the U.S. already have the people in the U.S. already have the disease”disease”– National Osteoporosis Foundation National Osteoporosis Foundation

• How to create criteria to give the How to create criteria to give the majoritymajority of women age 50 and older a of women age 50 and older a disease…disease…

Clinical Criteria for Clinical Criteria for Osteoporosis: What is a T Osteoporosis: What is a T

score? score? The DefinitionThe Definition• The diagnostic criteria of osteoporosis is based The diagnostic criteria of osteoporosis is based

on measurements of bone mineral density on measurements of bone mineral density (BMD).(BMD).

• A T-score is derived using a frequency A T-score is derived using a frequency distribution curve created with a population of distribution curve created with a population of healthy premenopausal young women at peak of healthy premenopausal young women at peak of bone mass. The t score is the number of bone mass. The t score is the number of standard deviations the patient is from the mean standard deviations the patient is from the mean of this “healthy normal” young population. of this “healthy normal” young population.

• A T-score of -1 to -2.5 SD = osteopenia A T-score of -1 to -2.5 SD = osteopenia • A T-score of less than -2.5 SD = osteoporosisA T-score of less than -2.5 SD = osteoporosis

Why use -2.5 standard Why use -2.5 standard deviations?deviations?

• Criteria developed by the World Health Criteria developed by the World Health Organization and partner, the International Organization and partner, the International Osteoporosis Foundation in 1992Osteoporosis Foundation in 1992

• The committee cited studies indicating that The committee cited studies indicating that 16% of women in Rochester, MN would 16% of women in Rochester, MN would experience a hip fracture in their lifetime. experience a hip fracture in their lifetime. They also noted that when pooling several They also noted that when pooling several years of BMD data, 16% of postmenopausal years of BMD data, 16% of postmenopausal women were at -2.5 sd below the mean BMD women were at -2.5 sd below the mean BMD of a healthy young woman. There was no of a healthy young woman. There was no concrete data to link the 16% at -2.5 SD and concrete data to link the 16% at -2.5 SD and the 16% with hip fractures. (We won’t even the 16% with hip fractures. (We won’t even go into osteopenia)go into osteopenia)

• Incidentally, the IOF’s board is composed of Incidentally, the IOF’s board is composed of 30+ drug and medical equipment companies.30+ drug and medical equipment companies.

Bone Mineral Density and t-Bone Mineral Density and t-scores and the DEXA scanscores and the DEXA scan

Using DEXA for t-scoresUsing DEXA for t-scores

• Not all machines use same standard Not all machines use same standard healthy patienthealthy patient

• Variations in calibration depending on Variations in calibration depending on manufacturermanufacturer

• More than just bone mineral density can More than just bone mineral density can be used to predict future risk of be used to predict future risk of fractures.fractures.

• BUT the controversy surrounding T-BUT the controversy surrounding T-scores and bone mineral density scans scores and bone mineral density scans could take up several presentations….so could take up several presentations….so onto prevention of fractures.onto prevention of fractures.

Finding the population at Finding the population at risk of fracture? risk of fracture?

Does the current osteoporosis criteria Does the current osteoporosis criteria really identify those at risk for really identify those at risk for fracture or should treatment be fracture or should treatment be based on other risk factors?based on other risk factors?– Other studies have found risks such as Other studies have found risks such as

family history of fracture, lower weight, family history of fracture, lower weight, greater height, hyperthyroidism history, greater height, hyperthyroidism history, and inability to rise from a chair were and inability to rise from a chair were more predictive of future fracture than more predictive of future fracture than bone mineral density (Cummings).bone mineral density (Cummings).

Goals of TreatmentGoals of Treatment

• Because fractures are the main cause of the Because fractures are the main cause of the morbidity and mortality associated with morbidity and mortality associated with “osteoporosis”, the goal of therapies should “osteoporosis”, the goal of therapies should be directed towards prevention of a fracture.be directed towards prevention of a fracture.

• Warning: Increases in bone mineral density Warning: Increases in bone mineral density are not directly correlated with decreases in are not directly correlated with decreases in fracturesfractures

• Treatments should be assessed and compared Treatments should be assessed and compared based on a decrease in fracture rate. Watch based on a decrease in fracture rate. Watch for studies that discusses changes in BMD for studies that discusses changes in BMD and do not mention fracture rate. and do not mention fracture rate.

Prevention of FracturesPrevention of Fractures

• A balanced diet rich in calcium and A balanced diet rich in calcium and vitamin D vitamin D

• Weight-bearing and resistance-Weight-bearing and resistance-training exercises training exercises

• A healthy lifestyle with no smoking A healthy lifestyle with no smoking or excessive alcohol intake or excessive alcohol intake

• Bone density testing and medication Bone density testing and medication when appropriate when appropriate – National Foundation of OsteoporosisNational Foundation of Osteoporosis

Reporting Relative RiskReporting Relative Risk

• Can often make treatment seem more Can often make treatment seem more beneficialbeneficial

• Example: A medication decreased the Example: A medication decreased the harmful outcome from 1% in the control harmful outcome from 1% in the control group to 0.5% in the treatment group. group to 0.5% in the treatment group. The relative risk reduction is 50% but The relative risk reduction is 50% but the absolute risk reduction is only 0.5%. the absolute risk reduction is only 0.5%.

• RRR=relative risk reductionRRR=relative risk reduction• ARR=absolute risk reductionARR=absolute risk reduction• NNT=Number needed to treatNNT=Number needed to treat

Comparing treatment Comparing treatment optionsoptions

Examined randomized controlled trials comparingExamined randomized controlled trials comparing1) Vitamin D and calcium to placebo1) Vitamin D and calcium to placebo2) Alendronate to placebo2) Alendronate to placebo– Trials involving alendronate were selected due to Trials involving alendronate were selected due to

the large number of trials and apparently most the large number of trials and apparently most beneficial compared to newer/other beneficial compared to newer/other bisphosphonatesbisphosphonates

3) Weight bearing exercise to placebo3) Weight bearing exercise to placeboThere were few RCTs on weight bearing exercise and There were few RCTs on weight bearing exercise and fractures. The benefit of exercise depended on the type of fractures. The benefit of exercise depended on the type of exercise. No RCTs compare exercise to bisphosphonates or exercise. No RCTs compare exercise to bisphosphonates or other medical treatment in reducing fractures other medical treatment in reducing fractures

The following slides examine the results of several trials for 1 The following slides examine the results of several trials for 1 and 2 above.and 2 above.

Calcium and Vitamin DCalcium and Vitamin DStudyStudy PopulationPopulation OutcomesOutcomes RRR/ARRRRR/ARR P-valueP-value

Chapuy 92Chapuy 92 Women in Women in nursing homes nursing homes with with osteoporosisosteoporosis

Hip fractures Hip fractures 1.5 yr1.5 yr

Nonvertebral fx Nonvertebral fx 1.51.5

ARR: 2.0% ARR: 2.0% RRR: 25% NNT: RRR: 25% NNT: 5050

ARR: 4% RRR: ARR: 4% RRR: 24% NNT: 26 24% NNT: 26

.004.004

<.001<.001

Dawson-Dawson-HughesHughes

19971997

Men and Men and women with women with osteoporosis > osteoporosis > age 65age 65

Nonvertebral fx Nonvertebral fx (3 years)(3 years)

ARR of 7%ARR of 7%

RRR of 54%RRR of 54%

NNT: 14NNT: 14

.02.02

Record 2005Record 2005 Men and Men and women >70 women >70 with low with low trauma trauma fracturesfractures

New fracture (2 New fracture (2 years)years)

Not significantNot significant

Porthouse 2005Porthouse 2005 Age > 70 with 1 Age > 70 with 1 risk factor for risk factor for hip fxhip fx

Hip fractures (2 Hip fractures (2 years)years)

Not significant: Not significant: hip fracture hip fracture rate was very rate was very low in this low in this group, even the group, even the controls at controls at 1.4% 1.4%

Patients had

fracture

14 NNT, relativel

y inexpens

ive

BisphosphonatesBisphosphonates

• Inhibitors of Bone resorption. May Inhibitors of Bone resorption. May disrupt the mevalonate pathway disrupt the mevalonate pathway leading to decreased osteoclast leading to decreased osteoclast activity but mechanism is not clearly activity but mechanism is not clearly understood. understood. Maybe we can use

statins for osteoporosis??

Site of Bisphosphona

te action

Proteins which increase

osteoclastic activity are reduced.

Prevention with Prevention with AlendronateAlendronate

StudyStudy Population-all Population-all postmenopausapostmenopausal womenl women

OutcomesOutcomes RRR/ARRRRR/ARR P-valueP-value

Liberman 1995, Liberman 1995, Sponsored by Sponsored by MerckMerck

Women with Women with osteoporosis. osteoporosis. Separate Separate analysis in pt analysis in pt with previous with previous fracture fracture

Vertebral fxVertebral fx

Nonvertebral fxNonvertebral fx

RRR: 48%RRR: 48%

ARR: 3.0%ARR: 3.0%

NNT: 33 NNT: 33

-NS-NS

.03.03

Black, 1996 Black, 1996 FIT1FIT1

Sponsored by Sponsored by MerckMerck

Low BMD and Low BMD and previous previous fracturefracture

Vertebral Vertebral fracturefracture

HipHip

RRR: 50% ARR: RRR: 50% ARR: 7.0% NNT 147.0% NNT 14

RRR: 49% ARR: RRR: 49% ARR: 1.1% NNT: 1001.1% NNT: 100

<.001<.001

Cummings, Cummings, 1998 FIT2 1998 FIT2 Sponsored by Sponsored by MerckMerck

Femoral neck t Femoral neck t score < -2.1 score < -2.1 and no hx of and no hx of fracturefracture

Vertebral (4 yr)Vertebral (4 yr)

Hip/other (4yr)Hip/other (4yr)

RRR: 44% ARR: RRR: 44% ARR: 1.7% NNT: 591.7% NNT: 59

-NS-NS

.002.002

Pols 1999 Pols 1999 FOSIT FOSIT Sponsored by Sponsored by MerckMerck

Lumbar spine t Lumbar spine t score < -2.0score < -2.0

NonvertebralNonvertebral RRR: 45% RRR: 45% ARR: 2.0% ARR: 2.0% NNT: 50 NNT: 50

.021.021

Mostly beneficial in patients with

previous fracture

Large NNT for hip

fractures

No statistically significant

benefit on hip fractures

Cochrane Review of 11 Cochrane Review of 11 trials of alendronatetrials of alendronate

• Once daily dose in primary preventionOnce daily dose in primary prevention– RRR 45% ARR 2% NNT 50 for vertebral fracturesRRR 45% ARR 2% NNT 50 for vertebral fractures- - No significant difference in primary prevention of hip No significant difference in primary prevention of hip

fracturesfractures

• Once daily dose in secondary prevention, Once daily dose in secondary prevention, slightly slightly more effectivemore effective– RRR 45%, ARR 6%, NNT 16 for vertebral fracturesRRR 45%, ARR 6%, NNT 16 for vertebral fractures– RRR 53%, ARR 1% NNT 100 for hip fracturesRRR 53%, ARR 1% NNT 100 for hip fractures

Conclusion: Alendronate may be beneficial and cost effective in Conclusion: Alendronate may be beneficial and cost effective in preventing vertebral fractures in patients who have already preventing vertebral fractures in patients who have already experienced an osteoporotic fracture. Their benefit in experienced an osteoporotic fracture. Their benefit in preventing hip fractures is minimal and limited to patients preventing hip fractures is minimal and limited to patients who have already experienced a fracture.who have already experienced a fracture.

-Cochrane Review-Cochrane Review

And in the media…And in the media…

• Sounds much more effective and Sounds much more effective and promising!!promising!!

At least these

women look older.

Most advertise

ments show

women in their late 40s/early

50s

Other BisphosphonatesOther Bisphosphonates

• Most trials with alendronate.Most trials with alendronate.• Similar results (or less effective) Similar results (or less effective)

have been found in studies of other have been found in studies of other bisphosphonates and reduction of bisphosphonates and reduction of fractures.fractures.

• Side effect profiles vary based on Side effect profiles vary based on type of bisphosphonate.type of bisphosphonate.

Side EffectsSide Effects

• Esophageal UlcerationEsophageal Ulceration• GI Perforations, ulcerations and GI Perforations, ulcerations and

bleeds (depending on type of bleeds (depending on type of bisphosphonates)bisphosphonates)

• Musculoskeletal painMusculoskeletal pain• Renal Function disordersRenal Function disorders• HypocalcaemiaHypocalcaemia• Some reports of Atrial FibrillationSome reports of Atrial Fibrillation

GENERALIZAITON!!!GENERALIZAITON!!!

CAUTION in generalizing the results of CAUTION in generalizing the results of studies to larger populations.studies to larger populations.

• Most of the studies of bisphosphonates Most of the studies of bisphosphonates and fractures were done in:and fractures were done in:– Older women (mostly over age 65, some Older women (mostly over age 65, some

over age 80 most benefit)over age 80 most benefit)– Women withOUT GI problemsWomen withOUT GI problems– Patients who had already experience a Patients who had already experience a

fracturefracture

Conclusions on Conclusions on bisphosphonates….bisphosphonates….

• No benefit on hip fracture in patients whose bone No benefit on hip fracture in patients whose bone mineral density is close to “normal”mineral density is close to “normal”

• Some benefit in patients in preventing second Some benefit in patients in preventing second vertebral fracture if already have a fracture. vertebral fracture if already have a fracture. Could benefit patients on chronic steroids and Could benefit patients on chronic steroids and those with increased risk of falling from another those with increased risk of falling from another disease (although Vitamin D was similarly effective disease (although Vitamin D was similarly effective in these “fall-risk” populations)in these “fall-risk” populations)

• Cannot be generalized to patients with GERD, Cannot be generalized to patients with GERD, history of ulcers because risks may not outweigh history of ulcers because risks may not outweigh benefits and studies have not been done in this benefits and studies have not been done in this population.population.

• Cannot be generalized to younger patients with Cannot be generalized to younger patients with osteopenia. Most studies focus on patients over osteopenia. Most studies focus on patients over 60, some with patients over 50.60, some with patients over 50.

General ConclusionsGeneral Conclusions

The measurement of osteoporosis should be The measurement of osteoporosis should be redefined to identify patients at highest risk of redefined to identify patients at highest risk of future fracture.future fracture.

Decreasing bone mineral density with age is Decreasing bone mineral density with age is normal. normal.

Calcium, vitamin D (in patients who are deficient) Calcium, vitamin D (in patients who are deficient) and weight-bearing exercise will help prevent and weight-bearing exercise will help prevent fractures (among other benefits)fractures (among other benefits)

Bisphosphonate research indicates modest Bisphosphonate research indicates modest reductions in fractures and have mostly been reductions in fractures and have mostly been studied in patients who are studied in patients who are -older, post menopausal women, many with -older, post menopausal women, many with previous fractures, and without any GI previous fractures, and without any GI problems.problems.

ReferencesReferences• Hamdy, R. et al. Review of Treatment Modalities for Postmenopausal Hamdy, R. et al. Review of Treatment Modalities for Postmenopausal

Osteoporosis. Southern Medical Journal. 98(10) Oct 2005.Osteoporosis. Southern Medical Journal. 98(10) Oct 2005.• National Osteoporosis Foundation. Disease statistics. National Osteoporosis Foundation. Disease statistics.

Http://www.nof.org/osteoporosis/Http://www.nof.org/osteoporosis/ Accessed February 15, 2008. Accessed February 15, 2008.• Chapuy MC et al. Vitamin D3 and calcium to prevent hip fractures in Chapuy MC et al. Vitamin D3 and calcium to prevent hip fractures in

elderly women. N England Journal of Medicine 1992; 327: 1637-elderly women. N England Journal of Medicine 1992; 327: 1637-1642.1642.

• Dawson-Hughes, B. et al. Effect of calcium and vitamin D Dawson-Hughes, B. et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age supplementation on bone density in men and women 65 years of age or older N Engl J Med 1997; 10: 670-676or older N Engl J Med 1997; 10: 670-676

• Grant et al. Oral Vitamin D3 and calcium for secondary prevention of Grant et al. Oral Vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (RECORD) Lancet 2005: 365 low-trauma fractures in elderly people (RECORD) Lancet 2005: 365 1621-16281621-1628

• Porthouse J, et al. Randomised controlled trial of calcium and Porthouse J, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol for prevention of fractures in supplementation with cholecalciferol for prevention of fractures in primary care. BMJ 2005:; 330: 1003.primary care. BMJ 2005:; 330: 1003.

• Susan Kelleher. Disease expands through marriage of marketing and Susan Kelleher. Disease expands through marriage of marketing and machines. The Seattle Times June 2005.machines. The Seattle Times June 2005.

• Moynihan, R et al. Selling sickness: the pharmaceutical industry and Moynihan, R et al. Selling sickness: the pharmaceutical industry and disease mongering. BMJ 2002; 324: 886-891.disease mongering. BMJ 2002; 324: 886-891.

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• Pols et al. Multinational, placebo controlled, randomized trial Pols et al. Multinational, placebo controlled, randomized trial of the effects of alendronate on bone density and fracture risk of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass results of the in postmenopausal women with low bone mass results of the ROSIT study. Fosamax International Trial Study Group. ROSIT study. Fosamax International Trial Study Group. Osteoporosis International. 1999;9 461-468.Osteoporosis International. 1999;9 461-468.

• Liberman, UA et al. Effect of oral alendronate on bone mineral Liberman, UA et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study. N ENgl J Med 1995; 333: 1437-1443Treatment Study. N ENgl J Med 1995; 333: 1437-1443

• Black, DM et al Randomized trial of effect of alendronate on Black, DM et al Randomized trial of effect of alendronate on risk of fractures in women with existing vertebral fractures. risk of fractures in women with existing vertebral fractures. FIT Lancet 12996 348: 1535-1541.FIT Lancet 12996 348: 1535-1541.

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