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Osteoporosis. Clinical cases and literature review Catherine Bakewell, MD. Quick overview. Definition—(per WHO) normal bone density is a value within one standard deviation of the mean value in young adults of the same sex and race.

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Osteoporosis l.jpg

Osteoporosis

Clinical cases and literature review

Catherine Bakewell, MD


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Quick overview

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

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

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


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Risk Factors

  • History of fragility fracture in a first-degree relative

  • Low body weight (less than 58 kg [127 lb])

  • Current cigarette smoking

  • Female sex

  • Estrogen deficiency at an early age (menopause before age 45 years or bilateral ovariectomy, prolonged premenopausal amenorrhea [greater than one year])

  • White race

  • Advanced age

  • Lifelong low calcium intake

  • Alcoholism

  • Inadequate physical activity

  • Recurrent falls

  • Dementia

  • Impaired eyesight despite adequate correction

  • Poor health/frailty

  • Medical conditions: chronic obstructive pulmonary disease, gastrectomy, hyperparathyroidism, hypogonadism, multiple myeloma, celiac disease

  • Glucocorticoid therapy for more than three months

  • Other drugs: anticonvulsants, GnRH agonists, lithium, excessivedoses of thyroid hormone


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Screening

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

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


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Mrs. T

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

  • What do you want to know?


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Mrs T. (cont)

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

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

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


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Treatment of Osteopenia

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

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


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EBM

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

  • 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.

  • 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.

  • 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.

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


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Problems? Flaws?


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Study limitations

  • 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 density at the hip increased slightly.

  • 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 therapy.

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

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


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What doses do you recommend?


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Vitamin D

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

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

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


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Calcium

  • To maintain neutral calcium balance:

  • 1,000mg/d for premenopausal women

  • 1,500 mg/d for postmenopausal women


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Counselling

  • Mrs. T needs to be counselled re:


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Bisphosphonates for Osteopenia

  • Should Mrs. T be started on Fosamax?


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Physiologic effects

  • * Decreased bone resorption * Decreased bone formation by 70-95% * Increased mineralization density * Slight increase in bone volume * Increase bone strength first 5 years * Decreased fracture rate first 5 years,compared to placebo * Half-life in bone greater than 10 years * Long-term effects on bone unknown


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Guidelines

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


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Schousboe et al, 2005

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

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

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


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Conclusions

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

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


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Mrs T. Goes Home

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


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What about other therapies?

  • Calcitonin

  • SERMs

  • Estrogen

  • Intermittant PTH


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Calcitonin

  • produced by cells in the thyroid gland

  • acts directly on osteoclasts to stop bone resorption

  • Taken as a nasal spray (Miacalcin), dose 200 units per spray (per day)

  • More expensive than bisphosphonate

  • Very safe, moderately effective


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Estrogen

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

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

  • Excellent at maintaining bone mineral density.

  • Consider switching to SERM after 5 – 10 years.


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Selective Estrogen Receptor Modulators (ex:Raloxifene)

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

  • Physiological substitute for estrogen at the bone.

  • Increased risk of thrombosis.

  • Can worsen menopausal symptoms.


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Ms. B

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

  • What are you going to do?!


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Intermittent PTH

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

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

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

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

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


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Mrs. S

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

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

  • What do you say to her?


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Woo et al, Annals, 2006

  • Systematic review– Bisphosphonates and Osteonecrosis of the Jaws

  • 368 patient cases

  • Strongly assoc with use of aminobisphosphonates (IV preparation), for people with malignancy, related to severe suppression of bone turnover

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


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Osteonecrosis, cont

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

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

  • In pts on alendronate for osteoporosis, prevalence unknown.

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


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Osteonecrosis, cont


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Osteonecrosis, cont


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Osteonecrosis, cont


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Mrs S.

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

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


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Ms. W

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

  • What is her risk of osteoporosis?


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Glucocorticoid induced bone loss

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

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

  • Luckily, the decline in BMD slows thereafter.


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Mechanisms for glucocorticoid induced osteoporosis


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General guidelines

  • Keep duration of therapy as short as possible

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

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


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Screening

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

  • DEXA repeated yearly if on preventative therapy.


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Supplementation

  • Adequate Calcium and vitamin D supplementation appear to largely negate the effects of low dose (up to 10mg/day) steroid administration. (Buckley et al, 1996; Saag et al, 1998).

  • Recommended supplemenation doses that for postmenopausal women: 1500mg Calcium plus 800IU of Vitamin D.


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HRT

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

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


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Bisphosphonates

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

  • ACR Recommendations (2001 Update)


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What would Schousboe say?

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

  • DEXA at baseline and yearly

  • Start bisphosphonate tx only if BMD is abnormal (T score < -1.0).

  • Alendronate 35mg weekly for prevention, and 70mg weekly for treatment.


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Calcitonin

  • Consider calcitonin if bisphosphonate contraindicated or not tolerated.

  • May also reduce pain from prior fractures.


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Thiazides

  • Measure urinary calcium excretion.

  • Thiazide diuretics (and salt restriction) shown to decrease calcium excretion.

  • Enthusiasm tempered by lack of evidence that thiazides increase BMD in pts on corticosteriods.


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Ms W.

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

  • Should be on Calcium and Vit D.

  • Add bisphosphonate if T score < -1.0.

  • Consider addition of thiazide, especially if hypertensive or she has elevated urinary calcium excretion.

  • Evaluate for estrogen deficiency.


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References

  • Bischoff-Ferrari HA, Wellet WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randonized controlled trials. JAMA 2005; 293:2257-64.

  • 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. Ann Intern Med. 1996; 125: 961.

  • Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 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 patients with rheumatoid arthritis. Ann Intern Med 1993; 119:963

  • Ott S. Osteoporosis and bone physiology: description, diagnosis, treatment, and explanation of underlying physiology. Retrieved on September 26th, 2006 from University of Washington Web Site: http://courses.washington.edu/bonephys/

  • Primer on the Rheumatic Diseases. 12th Ed. Atlanta, GA: Arthritis Foundation; 2001: 511-27; 596.

  • Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001; 44:1496.

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

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

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

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


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