Osteoporosis

Clinical cases and literature review Clinical cases and literature review

Catherine Bakewell, MDCatherine Bakewell, MD

Quick overview

Definition—(per WHO) normal bone density is a Definition—(per WHO) normal bone density is a value within one standard deviation of the mean value within one standard deviation of the mean value in young adults of the same sex and race. value in young adults of the same sex and race.

BMD btw 1 and 2.5 standard deviations below the BMD btw 1 and 2.5 standard deviations below the mean is defined as osteopenia,mean is defined as osteopenia,

BMD > or = 2.5 standard deviations below the BMD > or = 2.5 standard deviations below the mean is defined as osteoporosis (and is associated mean is defined as osteoporosis (and is associated with skeletal fragility)with skeletal fragility)

Risk Factors History of fragility fracture in a first-degree relative History of fragility fracture in a first-degree relative Low body weight (less than 58 kg [127 lb]) Low body weight (less than 58 kg [127 lb]) Current cigarette smoking Current cigarette smoking Female sex Female sex Estrogen deficiency at an early age (menopause before age 45 years or bilateral ovariectomy, Estrogen deficiency at an early age (menopause before age 45 years or bilateral ovariectomy,

prolonged premenopausal amenorrhea [greater than one year]) prolonged premenopausal amenorrhea [greater than one year]) White race White race Advanced age Advanced age Lifelong low calcium intake Lifelong low calcium intake Alcoholism Alcoholism Inadequate physical activity Inadequate physical activity Recurrent falls Recurrent falls Dementia Dementia Impaired eyesight despite adequate correction Impaired eyesight despite adequate correction Poor health/frailty Poor health/frailty Medical conditions: chronic obstructive pulmonary disease, gastrectomy, hyperparathyroidism, Medical conditions: chronic obstructive pulmonary disease, gastrectomy, hyperparathyroidism,

hypogonadism, multiple myeloma, celiac disease hypogonadism, multiple myeloma, celiac disease Glucocorticoid therapy for more than three months Glucocorticoid therapy for more than three months Other drugs: anticonvulsants, GnRH agonists, lithium, excessiveOther drugs: anticonvulsants, GnRH agonists, lithium, excessive doses of thyroid hormonedoses of thyroid hormone

Screening

BMD should be measured in all BMD should be measured in all postmenopausal women < 65 y.o. who postmenopausal women < 65 y.o. who have one or more risk factors for have one or more risk factors for osteoporosis.osteoporosis.

Measurement of BMD is also recommended Measurement of BMD is also recommended for all women 65 years and older.for all women 65 years and older.

Mrs. T

A 53 year old woman presents to your A 53 year old woman presents to your clinic with concerns about osteoporosis, and clinic with concerns about osteoporosis, and she is requesting screening.she is requesting screening.

What do you want to know?What do you want to know?

Mrs T. (cont)

You decide to get a DXA scan, which You decide to get a DXA scan, which shows:shows:

A total T score of –2.0 at the hip, and –1.7 A total T score of –2.0 at the hip, and –1.7 at the spine.at the spine.

She complains of some height loss, but a She complains of some height loss, but a chest X-ray is negative for compression chest X-ray is negative for compression fractures.fractures.

Treatment of Osteopenia

You tell her she should take calcium and You tell her she should take calcium and vitamin D supplementation.vitamin D supplementation.

She asks “didn’t they just do a study that She asks “didn’t they just do a study that showed that that didn’t work? I thought I showed that that didn’t work? I thought I read something about that in the paper.”read something about that in the paper.”

EBM

Jackson et al, N Engl J Med. 2006. Jackson et al, N Engl J Med. 2006. “Calcium plus Vitamin D supplementation “Calcium plus Vitamin D supplementation and the risk of fractures.”and the risk of fractures.”

Design: Randomized, placebo-controlled trial, 36K women at 40 different sites, healthy, postmenopausal aged 50 – 70 Design: Randomized, placebo-controlled trial, 36K women at 40 different sites, healthy, postmenopausal aged 50 – 70 years (of note, corticosteriod use was an exclusion criteria). Mean follow up period: 7 years.years (of note, corticosteriod use was an exclusion criteria). Mean follow up period: 7 years.

Intervention: CaCO3 1000mg plus Vitamin D 400 IU daily. Personal use of calcium, vitamin D, bisphosphonates, and Intervention: CaCO3 1000mg plus Vitamin D 400 IU daily. Personal use of calcium, vitamin D, bisphosphonates, and calcitonin was allowed. 52% of women were taking HT at baseline.calcitonin was allowed. 52% of women were taking HT at baseline.

Outcomes: no difference in number of hip, wrist, vertebral, or total fractures. At year 6, Calcium plus vitamin D did Outcomes: no difference in number of hip, wrist, vertebral, or total fractures. At year 6, Calcium plus vitamin D did increase BMD by 0.9% at the hip but not at the spine.increase BMD by 0.9% at the hip but not at the spine.

Conclusions: No significant benefit, slight increase in risk of kidney stonesConclusions: No significant benefit, slight increase in risk of kidney stones

Problems? Flaws?

Study limitations Although not statistically significant, treated women did have 12% fewer hip fractures, Although not statistically significant, treated women did have 12% fewer hip fractures,

the type of fracture associated with the largest morbidity and mortality. Plus bone the type of fracture associated with the largest morbidity and mortality. Plus bone density at the hip increased slightly. density at the hip increased slightly.

Women in this trial were also at low risk; many had already had the benefits of taking Women in this trial were also at low risk; many had already had the benefits of taking large amounts of calcium and vitamin D, and more than half were taking hormone large amounts of calcium and vitamin D, and more than half were taking hormone therapy.therapy.

Vitamin D dosing was potentially inadequate (further discussion to follow)Vitamin D dosing was potentially inadequate (further discussion to follow)

40% of women in the intervention group did not take the supplements40% of women in the intervention group did not take the supplements

What doses do you recommend?

Vitamin D

Bishoff-Ferrari et al. performed meta-Bishoff-Ferrari et al. performed meta-analysis (JAMA 2005) analysis (JAMA 2005)

12 studies included: examined efficacy of 12 studies included: examined efficacy of different doses of Vitamin D different doses of Vitamin D

Conlusion: oral Vit D btw 700-800 IU/d Conlusion: oral Vit D btw 700-800 IU/d reduces risk of non-vertebral fractures; 400 reduces risk of non-vertebral fractures; 400 IU/d is not sufficient.IU/d is not sufficient.

Calcium To maintain neutral calcium balance:To maintain neutral calcium balance: 1,000mg/d for premenopausal women1,000mg/d for premenopausal women 1,500 mg/d for postmenopausal women1,500 mg/d for postmenopausal women

Counselling

Mrs. T needs to be counselled re:Mrs. T needs to be counselled re:

Bisphosphonates for Osteopenia

Should Mrs. T be started on Fosamax?Should Mrs. T be started on Fosamax?

Physiologic effects

* * Decreased bone resorption Decreased bone resorption

* Decreased bone formation by 70-95% * Decreased bone formation by 70-95%

* Increased mineralization density * Increased mineralization density

* Slight increase in bone volume * Slight increase in bone volume

* Increase bone strength first 5 years * Increase bone strength first 5 years

* Decreased fracture rate first 5 years,* Decreased fracture rate first 5 years,compared to placebo compared to placebo

* Half-life in bone greater than 10 years * Half-life in bone greater than 10 years

* Long-term effects on bone unknown * Long-term effects on bone unknown

Guidelines

National Osteoporosis Foundation National Osteoporosis Foundation recommends tx for women with T < -2.0 or recommends tx for women with T < -2.0 or < -1.5 with risk factors. < -1.5 with risk factors.

Schousboe et al, 2005

Modeled cost-effectiveness of treating Modeled cost-effectiveness of treating osteopenic women with alendronate for 5 osteopenic women with alendronate for 5 years.years.

Compared cost per quality-adjusted life-Compared cost per quality-adjusted life-year (QALY) of tx vs not tx women aged year (QALY) of tx vs not tx women aged 55 - 75, femoral neck scores of – 1.5 to – 55 - 75, femoral neck scores of – 1.5 to – 2.4. 2.4.

Costs ranged from 74 K to 322K per QALY Costs ranged from 74 K to 322K per QALY gained. gained.

Conclusions

Therapy only deemed cost effective in Therapy only deemed cost effective in women who had risk factors unrelated to women who had risk factors unrelated to BMD, such as dementia, visual impairment, BMD, such as dementia, visual impairment, or frequent falls.or frequent falls.

Current recommendation is to reserve Current recommendation is to reserve bisphosphonates for women with T scores bisphosphonates for women with T scores of –2.5, or those with osteopenia and of –2.5, or those with osteopenia and pathologic fracture.pathologic fracture.

Mrs T. Goes Home

So you decide that Mrs. T should start with So you decide that Mrs. T should start with supplementation and lifestyle modification, supplementation and lifestyle modification, and and undergo repeat DEXA scanundergo repeat DEXA scan in 2 years in 2 years time.time.

What about other therapies?

CalcitoninCalcitonin SERMsSERMs EstrogenEstrogen Intermittant PTHIntermittant PTH

Calcitonin

produced by cells in the thyroid gland produced by cells in the thyroid gland acts directly on osteoclasts acts directly on osteoclasts to stop bone to stop bone

resorptionresorption Taken as a nasal spray (Miacalcin), dose Taken as a nasal spray (Miacalcin), dose

200 units per spray (per day) 200 units per spray (per day) More expensive than bisphosphonateMore expensive than bisphosphonate Very safe, moderately effectiveVery safe, moderately effective

Estrogen

Reasonable to start under age 60 (or for first Reasonable to start under age 60 (or for first ten post-menopausal years).ten post-menopausal years).

Most physicians only recommend for Most physicians only recommend for treatment of post menopausal symptoms.treatment of post menopausal symptoms.

Excellent at maintaining bone mineral Excellent at maintaining bone mineral density.density.

Consider switching to SERM after 5 – 10 Consider switching to SERM after 5 – 10 years.years.

Selective Estrogen Receptor Modulators (ex:Raloxifene)

PPreventreventss vertebral osteoporotic fractures in vertebral osteoporotic fractures in women with osteoporosis, and stabilizes women with osteoporosis, and stabilizes bone density. bone density.

PPhysiological substitute for estrogen at the hysiological substitute for estrogen at the bone.bone.

Increased risk of thrombosis.Increased risk of thrombosis. Can worsen menopausal symptomsCan worsen menopausal symptoms. .

Ms. B

Ms B is a 67Ms B is a 67 yr old woman with yr old woman with a a T-score T-score of of –3–3. You have had her on Ca, Vit D, and . You have had her on Ca, Vit D, and BonivaBoniva (due to her awful GERD) for 2 (due to her awful GERD) for 2 years now. She develops the acute onset of years now. She develops the acute onset of thoracic back pain, and CXR reveals a new thoracic back pain, and CXR reveals a new compression fracture.compression fracture.

What are you going to do?!What are you going to do?!

Intermittent PTH

Recombinant (1-34) variant FDA approved in 2002, Recombinant (1-34) variant FDA approved in 2002, stimulates both osteoclasts and osteoblasts.stimulates both osteoclasts and osteoblasts.

Intermittent spikes of PTH stimulate more bone formation Intermittent spikes of PTH stimulate more bone formation than resorption.than resorption.

Administered at a dose of Administered at a dose of 20 mcg/day20 mcg/day SC for SC for 18 to 24 18 to 24 months.months.

After discontAfter discontinuationinuation,, patients should be treated for the patients should be treated for the next two years with an anti-resorping medication; next two years with an anti-resorping medication; otherwise the bone density will decreaseotherwise the bone density will decrease..

Other doses, durations are being experimented with, but Other doses, durations are being experimented with, but not officially approved. not officially approved.

Mrs. S

Mrs. S is a 78 year old woman with Mrs. S is a 78 year old woman with osteoporosis (T score –2.6 at the hip by osteoporosis (T score –2.6 at the hip by DEXA 2 years ago) on Fosamax 70 mg DEXA 2 years ago) on Fosamax 70 mg weekly.weekly.

She is concerned because she has heard She is concerned because she has heard about reports of dead jaw bone in people on about reports of dead jaw bone in people on this medication.this medication.

What do you say to her? What do you say to her?

Woo et al, Annals, 2006

Systematic review– Bisphosphonates and Systematic review– Bisphosphonates and Osteonecrosis of the JawsOsteonecrosis of the Jaws

368 patient cases368 patient cases Strongly assoc with use of aminobisphosphonates Strongly assoc with use of aminobisphosphonates

(IV preparation), for people with malignancy, (IV preparation), for people with malignancy, related to severe suppression of bone turnoverrelated to severe suppression of bone turnover

94% of pts tx with pamidronate or zoledronic acid 94% of pts tx with pamidronate or zoledronic acid or bothor both

Osteonecrosis, cont

85% of affected patients have metatstatic breast 85% of affected patients have metatstatic breast cancer or multiple myeloma. Only 4% have cancer or multiple myeloma. Only 4% have osteoporosis.osteoporosis.

For pts with cancer receiving IV bisphosphonate, For pts with cancer receiving IV bisphosphonate, prevalence 6 – 10%.prevalence 6 – 10%.

In pts on alendronate for osteoporosis, prevalence In pts on alendronate for osteoporosis, prevalence unknown.unknown.

60% of all cases occur after dental surgery (such 60% of all cases occur after dental surgery (such as tooth extraction), the remaining 40% are assoc as tooth extraction), the remaining 40% are assoc with denture or physical trauma.with denture or physical trauma.

Osteonecrosis, cont

Osteonecrosis, cont

Osteonecrosis, cont

Mrs S.

You can reassure Mrs. S that her chances of You can reassure Mrs. S that her chances of osteonecrosis are very, very low.osteonecrosis are very, very low.

However, (for other patients) it is However, (for other patients) it is reasonable to hold off on initation of reasonable to hold off on initation of bisphosphonate until after necessary dental bisphosphonate until after necessary dental procedures.procedures.

Ms. W

Ms W is a charming 45 year old woman Ms W is a charming 45 year old woman with rheumatoid arthritis, who has been on with rheumatoid arthritis, who has been on low dose prednisone (5mg/day) for 10 years low dose prednisone (5mg/day) for 10 years now. now.

What is her risk of osteoporosis?What is her risk of osteoporosis?

Glucocorticoid induced bone loss

Unlike other agents that increase bone loss Unlike other agents that increase bone loss (thyroxine, sustained PTH), glucocorticoids (thyroxine, sustained PTH), glucocorticoids accelerate resorption while inhibiting bone accelerate resorption while inhibiting bone formation.formation.

Patients beginning on high dose prednisone (mean Patients beginning on high dose prednisone (mean 21mg/day) lost a mean of 27% of their L-spine in 21mg/day) lost a mean of 27% of their L-spine in one year one year (Reid et al, 1990)(Reid et al, 1990)..

Luckily, the decline in BMD slows thereafter.Luckily, the decline in BMD slows thereafter.

Mechanisms for glucocorticoid induced osteoporosis

General guidelines

Keep duration of therapy as short as Keep duration of therapy as short as possiblepossible

Consider high dose pulse therapy rather Consider high dose pulse therapy rather than tx for weeks or monthsthan tx for weeks or months

Don’t forget the basics (weight bearing Don’t forget the basics (weight bearing exercise, smoking cessation, minimize exercise, smoking cessation, minimize alcohol)alcohol)

Screening

Measure baseline BMD if it is anticipated Measure baseline BMD if it is anticipated that a patient will be on glucocorticoids for that a patient will be on glucocorticoids for > 3 mo. > 3 mo.

DEXA repeated yearly if on preventative DEXA repeated yearly if on preventative therapy.therapy.

Supplementation

Adequate Calcium and vitamin D supplementation Adequate Calcium and vitamin D supplementation appear to largely negate the effects of low dose appear to largely negate the effects of low dose (up to 10mg/day) steroid administration. (up to 10mg/day) steroid administration. (Buckley et al, 1996; (Buckley et al, 1996;

Saag et al, 1998).Saag et al, 1998). Recommended supplemenation doses that for Recommended supplemenation doses that for

postmenopausal women: 1500mg Calcium plus postmenopausal women: 1500mg Calcium plus 800IU of Vitamin D.800IU of Vitamin D.

HRT

For premenopausal women with oligo or For premenopausal women with oligo or amenorrhea on steroids, the ACR amenorrhea on steroids, the ACR recommends addition of oral contraceptive.recommends addition of oral contraceptive.

For men with testosterone deficiency For men with testosterone deficiency (decreased libido, fatigue) consider (decreased libido, fatigue) consider testosterone supplementation.testosterone supplementation.

Bisphosphonates

Should be initiated on essentially everyone Should be initiated on essentially everyone initiating long-term glucocorticoid therapy initiating long-term glucocorticoid therapy (>5mg/day for >3 months) except those on (>5mg/day for >3 months) except those on HRT (unless pt has fxr on HRT) or HRT (unless pt has fxr on HRT) or premenopausal women who may become premenopausal women who may become pregnant.pregnant.

ACR Recommendations (2001 Update)ACR Recommendations (2001 Update)

What would Schousboe say?

Given the high costs of bisphosphonate for Given the high costs of bisphosphonate for prevention, perhaps a better strategy would prevention, perhaps a better strategy would be:be:

DEXA at baseline and yearlyDEXA at baseline and yearly Start bisphosphonate tx only if BMD is Start bisphosphonate tx only if BMD is

abnormal (T score < -1.0).abnormal (T score < -1.0). Alendronate 35mg weekly for prevention, Alendronate 35mg weekly for prevention,

and 70mg weekly for treatment.and 70mg weekly for treatment.

Calcitonin

Consider calcitonin if bisphosphonate Consider calcitonin if bisphosphonate contraindicated or not tolerated.contraindicated or not tolerated.

May also reduce pain from prior fractures.May also reduce pain from prior fractures.

Thiazides

Measure urinary calcium excretion.Measure urinary calcium excretion. Thiazide diuretics (and salt restriction) Thiazide diuretics (and salt restriction)

shown to decrease calcium excretion.shown to decrease calcium excretion. Enthusiasm tempered by lack of evidence Enthusiasm tempered by lack of evidence

that thiazides increase BMD in pts on that thiazides increase BMD in pts on corticosteriods.corticosteriods.

Ms W.

Should have a DEXA scan at the hip and Should have a DEXA scan at the hip and lumbar spine.lumbar spine.

Should be on Calcium and Vit D.Should be on Calcium and Vit D. Add bisphosphonate if T score < -1.0.Add bisphosphonate if T score < -1.0. Consider addition of thiazide, especially if Consider addition of thiazide, especially if

hypertensive or she has elevated urinary hypertensive or she has elevated urinary calcium excretion.calcium excretion.

Evaluate for estrogen deficiency.Evaluate for estrogen deficiency.

References Bischoff-Ferrari HA, Wellet WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-Bischoff-Ferrari HA, Wellet WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-

analysis of randonized controlled trials. analysis of randonized controlled trials. JAMAJAMA 2005; 293:2257-64. 2005; 293:2257-64. Buckley LM, Leib ES, Cartularo KS, et al. Calcium and Vitamin D3 supplementation prevents loss in the spine Buckley LM, Leib ES, Cartularo KS, et al. Calcium and Vitamin D3 supplementation prevents loss in the spine

secondary to low-dose corticosteroids in patients with rheumatoid arthritis. secondary to low-dose corticosteroids in patients with rheumatoid arthritis. Ann Intern MedAnn Intern Med. 1996; 125: 961.. 1996; 125: 961. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J N Engl J

MedMed. 2006;354:669-83.. 2006;354:669-83. Laan, RF, Van Riel, PL, Van de Putte, LB, et al. Low-dose prednisone induces rapid reversible axial bone loss in Laan, RF, Van Riel, PL, Van de Putte, LB, et al. Low-dose prednisone induces rapid reversible axial bone loss in

patients with rheumatoid arthritis. patients with rheumatoid arthritis. Ann Intern MedAnn Intern Med 1993; 119:963 1993; 119:963 Ott S. Ott S. Osteoporosis and bone physiologyOsteoporosis and bone physiology: description, diagnosis, treatment, and explanation of underlying physiology. : description, diagnosis, treatment, and explanation of underlying physiology.

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Primer on the Rheumatic DiseasesPrimer on the Rheumatic Diseases. 12. 12thth Ed. Atlanta, GA: Arthritis Foundation; 2001: 511-27; 596. Ed. Atlanta, GA: Arthritis Foundation; 2001: 511-27; 596. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American

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Reid, IR, Heap, SW. Determinants of vertebral mineral density in patients receiving long-term glucocorticoid therapy. Reid, IR, Heap, SW. Determinants of vertebral mineral density in patients receiving long-term glucocorticoid therapy. Arch Intern MedArch Intern Med 1990; 150:2545. 1990; 150:2545.

Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucocorticoid-induced Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. osteoporosis. N Engl J MedN Engl J Med. 1998; 339: 292.. 1998; 339: 292.

Schousboe JT, Nyman JA, Kane RL, et al. Cost-effectiveness of aldenronate therapy for osteopenic postmenopausal Schousboe JT, Nyman JA, Kane RL, et al. Cost-effectiveness of aldenronate therapy for osteopenic postmenopausal women. women. Ann Intern MedAnn Intern Med. 2005;142: 734 – 41.. 2005;142: 734 – 41.

Woo SB, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and Osteonecrosis of the Jaws. Woo SB, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and Osteonecrosis of the Jaws. Ann Intern Ann Intern MedMed. 2006;144:753-761.. 2006;144:753-761.