Clinical cases and literature review Catherine Bakewell, MD 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. 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) Clinically osteopenia has referred more to T < = -1.5

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, excessive doses of thyroid hormone

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. The hip is the recommended site of screening, followed by the L-spine. Occasionally the wrist is done as well.

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? Risk factors: She weighs 115 pounds, is Caucasian, and smokes 1 PPD. She also enjoys at least two martinis after dinner. Menopausal status: average age—51.4 yrs old Calcium intake: minimal, drinks milk in her coffee every morning, no supplements

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. What do you tell her?

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.”

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

Problems? Flaws?

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

What doses do you recommend?

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.

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

Counselling Mrs. T needs to be counselled re: She also need to be counselled re: ETOH consumption

Bisphosphonates for Osteopenia Should Mrs. T be started on Fosamax?

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 bisphosphonates get deposited in the bone and will accumulate for years ? make bone more brittle or impair the ability to repair damage? Women off of alendronate after 5 years had similar fracture rates to those who continued taking it. Would discontinue bisphosphonates after 5 years of use.

http://courses.washington.edu/bonephys/opalgorithm1.gif Thanks to Dr. Ott!!!

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

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. 74K = 55yr old women with low T-scores (-2.4) 322K= 75 year old women with high T-scores (-1.5)

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. Cost effective = < $50,000 per QALY

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.

What about other therapies? Calcitonin SERMs Estrogen Intermittant PTH

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 This is the safest medicine that has benefits to the bones. Studies show some reduction in vertebral fractures. This might be a good choice for somebody with only moderate risk or somebody who has side effects with the other medications. There are no known serious side effects

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. Increased risk of stroke and dementia outweighs all other benefits after age 65.

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. Also equally costly as alendronate

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?! Boniva .. That new q monthly ibandronate 150mg po

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. PTH named Forteo For example ..--- studies mentioned above excluded people on bisphosphonates prior to initiation of therapy, and started them only after cessation. Newer studies have had good results with concomitant use. May ultimately be first line for people with T scores less than -3.5

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?

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 Pamidronte – Aredia, zoledronic acid--Zometa

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.

Osteonecrosis, cont Slightly different percentages, but good visual aid. Thx Dr. Ott.

Osteonecrosis, cont

Osteonecrosis, cont

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.

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?

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. T3 and PTH increase both resorption and formation, the latter to a lesser extent Loss appears closer to 7% in 20wks on low dose pred (10mg/d) without Ca+ supplementation (Laan, et al 1993)

Mechanisms for glucocorticoid induced osteoporosis Direct inhibitory effect on osteoblasts Increase in osteoblast and clast apoptosis (? Whether the mechanism of AVN as well) Decrease in serum estrogen and testosterone as mediated by inhibition of secretion of GnRH; increased PTH; Decreased formation of calcitriol 1,25 dihydroxyVitD, decreased intestinal absorption of Ca++ Increased excretion of Ca+ in urine, both due to increased serum levels (PTH) as well as direct effect on the kidney

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)

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. BMD screening : (or 6 mo. at low doses, ie < 10mg/day)

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.

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. Logical, since steriods reduce estrogen and testosterone production, why not replace it? ACR = American College of Rheumatology Estrogen replacement not considered first line therapy due to increased risks of stroke, breast cancer, MI, DVT, etc, Bottom line: hormone replacement should only be implemented when pt symptommatic from deficiency, NOT for bone health alone.

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) Note > should be greater than OR equal to

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.

Calcitonin Consider calcitonin if bisphosphonate contraindicated or not tolerated. May also reduce pain from prior fractures.

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.

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.

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.