Osteoporosis

Educational Objectives

The goal of this program is to improve the management of osteoporosis. After hearing and assimilating this program, the clinician will be better able to:

1.   Discuss and recommend osteoporosis prevention for patients at low risk for fracture.

2.   Use the World Health Organization’s fracture risk assessment tool (FRAX) to assess risk for fracture.

3.   Explain the concept of least significant change and its use in determining patients’ response to therapy for os­teoporosis and osteopenia.

4.   Determine which patients on antiresorptive therapy may be appropriate candidates for a “drug holiday.”

5.   List the advantages and disadvantages of estrogen therapy for prevention and treatment of osteoporosis  in postmenopausal women.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality of health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Mc­Dermott has received honoraria from Eli Lilly, Procter & Gamble, sanofi-aventis, and Novartis. Dr. Shaw is on the Speakers’ Bureau for Merck. The planning committee reported nothing to disclose.

Acknowledgments

Dr. McDermott spoke in Park City, UT, at Advances in Internal Medicine 2009, presented February 1-6, 2009, by the Uni­versity of Utah School of Medicine. Dr. Shaw spoke in Kiawah Island, SC, at the 20th Annual Conference on Focus on the Female Patient, presented July 26-30, 2009, by the Southern Medical Association. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Osteoporosis: Diagnosis and Management

Michael T. McDermott, MD, Professor of Medicine and Clinical Pharmacy, University of Colorado Denver, School of Medicine, and Director, Endocrinology and Diabetes Practice, University of Colorado Hospital, Au­rora, CO

Osteoporosis: compromised bone strength leading to increased risk for fragility fractures, defined as fracture with low trauma (ie, fall from standing height or less); causes significant morbidity; bone densitometry helps diagnose patients with high risk for fracture but no history of fractures; bone mineral density (BMD) T score  —  >-1 indicates normal condition; between -1 and -2.5 indicates osteopenia; <-2.5 indicates osteoporosis; diagnosis based on site with lowest T score; most important group to treat  —  patients with history of fragility fractures (eg, of vertebrae or hip); <20% of patients with hip or vertebral fractures treated; patients more often treated based on T score than on fractures

Fracture risk assessment tool (FRAX):  World Health Organization (WHO) fracture risk score; focuses on global risk for fracture; risk factors weighted and inserted into FRAX calculation to compute fracture risk score; recom­mended tool for evaluation of patients for osteoporosis; risk factors for fractures  —  age; sex; height and weight; previous fracture history; parental hip fracture; current smoking habits; glucocorticoid use; rheumatoid arthritis; secondary osteoporosis; alcohol use ≥3 units/day; low femoral neck BMD; bone densitometry  —  software devel­oped to compute FRAX directly on bone densitometry machines; WHO recommendations  —  treat for osteoporosis with ≥3% probability of hip fracture and ≥20% probability of major osteoporotic fracture; National Osteoporosis Foundation recommendations  —  treat patients with history of fragility fractures or T score <-2.5 in spine, hip, or femoral neck; if T score between -1 and -2.5, use FRAX to determine whether to treat; if T score >-1, evaluate in 1 to 2 yr

Fracture or low BMD: osteoporosis most common cause; evaluation for other causes  —  history and physical exam­ination; tests for calcium, phosphorus, and alkaline phosphatase to diagnose parathyroid or vitamin D disorders; measure 25-hydroxyvitamin D; obtain estimated glomerular filtration rate (GFR) and creatinine (data for osteopo­rotic agents invalid for GFR <30 mL/min and no adequate studies in patients with impaired renal function or stage 4 or stage 5 kidney disease); measure testosterone in men; measure calcium excretion and creatinine with 24-hr urine test; urinary calcium <100 mg/mL indicates poor calcium intake or absorption, due to intestinal disease or vi­tamin D deficiency; urinary calcium <500 mg/mL with history of kidney stones indicates idiopathic hypercalciuria; calcium excretion >1500 mg/day indicates use of calcium supplements, which increases risk for kidney stones; test for antibodies to tissue transglutaminase for celiac disease; measure thyrotropin for possibility of hyperthyroidism

Nonpharmacologic intervention: calcium intake of 1000 to 1500 mg/day recommended, based on age; 800 to 1200 U/day of vitamin D recommended; regular exercise (aerobic and resistance); fall prevention (most cost-effective)

Calcium: dairy products  —  best source; 300 mg of absorbable calcium each serving; dairy products preferable over calcium supplements if patient does not have high cholesterol and can tolerate dairy (calcium supplements accept­able if ingesting dairy not possible); gastric acid required for calcium absorption  —  calcium citrate and calcium carbonate equally absorbed (»24%) without food; milk absorbed at »35% (gold standard); calcium citrate and cal­cium carbonate absorbed at »30% with food (gastric acid present); patients without gastric acid  —  calcium citrate absorbed better than calcium carbonate; proton pump inhibitors (PPIs) reduce calcium carbonate absorption by 60% and increase risk for hip fracture; in patients on PPIs, consider calcium citrate or doubling calcium carbonate dose; urinary calcium of 150 to 350 mg/day indicates proper calcium absorption

Vitamin D: precursor in skin converted to vitamin D₃ (cholecalciferol) after sun exposure; amounts of precursor di­minish significantly with age; in liver, vitamin D converted to 25-hydroxyvitamin D (storage form); to determine vitamin D deficiency or toxicity, measure 25-hydroxyvitamin D; in kidneys, 1-alpha-hydroxylase adds 1-hy­droxyl group and converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (active form); parathyroid hormone (PTH) catalyzes conversion; patients with hypoparathyroidism or renal failure cannot make conversion; calcitriol recommended for patients with hypoparathyroidism due to thyroidectomy; nutrition  —  Food and Nutrition Board recommends 1000 U/day; safe to take 2000 U/day of vitamin D₃; 30 to 1000 ng/mL of 25-hydroxyvitamin D rec­ommended serum concentration; vitamin D deficiency  —  <10 ng/mL, treat with 50,000 U of vitamin D twice weekly for 3 mo; 10 to 20 ng/mL, treat with 50,000 U once weekly for 3 mo; 20 to 30 ng/mL, treat with 1000 to 2000 U/day of vitamin D₃ 

Bone remodeling: removal of old bone and synthesis of new bone; osteoclasts remove bone by secreting acid and proteolytic enzymes, thus creating resorption pits; old bone excreted in urine as N-telopeptides of bone collagen; osteoblasts build new bone by filling resorption pits with osteoid (bone-specific collagen with high affinity for cal­cium phosphate crystals)

Receptor activator of nuclear factor kappa beta (RANK) RANK  —  on surface of osteoclasts; RANK ligand (RANKL)  —protein that binds to RANK; osteoprotegerin (OPG)  —  decoy receptor; mechanism  —  osteoblasts in bone marrow secrete RANKL, which stimulates osteoclasts to resorb bone after binding to RANK; cells in bone marrow secrete OPG, which binds RANKL and inhibits bone resorption; whether bone resorbed depends on bal­ance between RANKL and OPG

Classes of medication: antiresorptive agents  —  inhibit bone resorption by inhibiting osteoclasts; include bisphos­phonates, raloxifene, calcitonin, estrogen, and RANKL inhibitors; anabolic agents  —  stimulate bone formation by stimulating osteoblasts; include teriparatide

Antiresorptive therapy: oral bisphosphonates  —  risedronate (Actonel) given 5 mg daily, 35 mg weekly, or 150 mg monthly; alendronate given 10 mg daily or 70 mg weekly, alone or with 2800 or 5600 U of vitamin D; ibandronate (Boniva) given 150 mg monthly; risedronate, alendronate, and ibandronate provide adequate fracture reduction in spine; nonoral antiresorptive therapies (eg, IV bisphosphonates) recommended for oral intolerance, upper GI symp­toms, poor compliance, or lack of safety; zoledronic acid (Reclast)  —  5 mg in saline solution preparation, adminis­tered in office over 15 to 30 min once per year; ensures compliance; eliminates upper GI symptoms; ibandronate injection  —  3 mg preparation, administered over 15 to 30 sec every 3 mo; pamidronate injection  —  30 mg in 250 to 500 mL saline preparation, administered over 2 to 4 hr every 3 mo; not Food and Drug Administration (FDA)-ap­proved; positive response but no long-term efficacy or safety data; monoclonal antibody against RANKL (Denosumab)  —antiresorptive; eliminates RANKL from circulation by binding it; when given to postmenopausal women 60 to 90 yr of age with T scores between -2.5 and -4.0 as subcutaneous injection every 6 mo for 3 yr, BMD increased 9.2% in spine and 6.0% in hip, compared to placebo; vertebral fractures reduced by 68%, hip fractures by 40%, and nonvertebral fractures by 20%; currently seeking FDA approval; side effects unknown

Fracture reduction efficacy: alendronate, risedronate, zoledronic acid, ibandronate, raloxifene, calcitonin, and terip­aratide reduced vertebral fractures in 2- to 3-yr studies; FDA approved; alendronate, risedronate, and zoledronic acid shown to reduce hip and other nonvertebral fractures; efficacy of teriparatide also demonstrated for nonverte­bral fractures

Treatment decisions: nonfracture population  —  based on overall risk profile, including BMD; T score >-1, recom­mend prevention (eg, calcium, vitamin D, exercise); T score between -1 and -2.5, use FRAX tool to consider phar­macologic intervention (eg, bisphosphonates and raloxifene); bisphosphonates or raloxifene for upper-end osteoporosis; T score <-3, treat with bisphosphonates and teriparatide; fracture population  —  focus on fracture reduction; treat with bisphosphonates and teriparatide

Osteonecrosis of jaw (ONJ): majority of cases occur in cancer patients (eg, multiple myeloma, breast cancer, pros­tate cancer) with metastatic disease who had taken zoledronic acid (Zometa) 4 mg every 3 wk to 3 mo; of total ONJ cases, 35% had taken zoledronic acid in high doses, 31% pamidronate, and 28% both medications; minority of cases in patients on oral bisphosphonates; characteristics of patients at high risk for ONJ  —  history of high-dose in­travenous bisphosphonates; cancer patients on chemotherapy or radiation therapy; steroid use; previous jaw trauma; poor oral hygiene; periodontal disease; ONJ reported in patients who have never taken bisphosphonates, thus bisphosphonate causality not validated; when starting or continuing bisphosphonate therapy, discuss and fol­low appropriate dental guidelines; good oral hygiene and regular dental care required; for dental surgery, discon­tinue bisphosphonates for 3 mo (effects of bisphosphonates continue for 6 -12 mo after discontinuation)

Drug holidays after 5 yr: bisphosphonates reduce fracture risk for £5 yr by suppressing bone remodeling; due to ONJ and atypical femoral fractures reported in patients on bisphosphonates for >5 yr, drug holidays reasonable in low-risk patients after 5 yr (ie, can discontinue bisphosphonates for 1 yr in patients with osteopenia and no frac­tures); in high-risk patients (T score <-2.5 and history of fractures), not established whether drug holiday accept­able; speaker usually continues current therapy or switches to anabolic therapy (eg, teriparatide); if therapy changes, monitor BMD and biomarkers

Monitoring response to therapy  —  least significant change (LSC)  —  calculation available at www.iscd.org; estab­lish LSC for every densitometer; serial changes valid only if measured on same instrument; for new patients, estab­lish new baseline and measure change in 1 yr on same instrument; calculated for absolute BMD change, not T score change; T score compares patient to reference population (updated each year); therefore, T score can change while BMD remains same; percent change in BMD equals previous year’s BMD minus that of current year, and BMD di­vided by previous year’s BMD; clinical trials show LSCs of »2.7% in spine and »5.7% in hip; positive change sig­nificant only if it exceeds LSC (associated with >50% fracture reduction); BMD decreases without therapy, thus stable BMD considered response to therapy (20%-25% fracture reduction); response failure defined only by BMD decrease >LSC on same machine; for increased or unchanged BMD, International Society for Clinical Densitome­try recommends continuation of current therapy

Causes of failure to respond: poor compliance (most common); calcium or vitamin D deficiency; comorbid condi­tions (eg, myeloma, hyperthyroidism, hyperparathyroidism); glucocorticoids and anticonvulsants; incorrect dose or dose interval; lack of efficacy (least common)

Atypical femoral fractures: presentation  —  thigh pain, no history of trauma; transverse fracture to femoral shaft, possibly propagated from stress fracture; bilateral in two-thirds of patients; suppressed bone turnover (low bio­markers, eg, N-telopeptides and bone-specific alkaline phosphatases); delayed healing or nonhealing of fractures; all patients had taken bisphosphonates for ³5 yr

Using hormones to prevent osteoporosis

Howard A. Shaw, MD, MBA, Associate Professor of Obstetrics and Gynecology, University of Connecticut School of Medicine, and Chairman and Director, Department of Obstetrics and Gynecology, St. Francis Hospi­tal and Medical Center, Hartford, CT

Estrogen and osteoporosis: menopause occurs at mean age of 51 yr; due to estrogen deficiency and bone resorption, rapid bone loss occurs immediately after cessation of menses; estrogen usually given short-term (6 mo-5 yr) to treat menopause symptoms (eg, hot flushes, vaginal dryness, urinary symptoms); estrogen also prevents and treats osteo­porosis by reducing risk for fracture; estrogen performed better than calcium or placebo at preventing bone loss in forearm and whole body and at increasing BMD in spine

Studies of estrogen: reduced risk for fracture in combination estrogen-progestin and estrogen only treatment groups (0.7 hazard ratio); for all estrogen therapies, current users at lower risk for fracture than nonusers (relative risk 0.62); maximum bone protection increased when estrogen therapy began soon after menopause and continued in­definitely; higher BMD in women treated with estrogen and discontinued than in women never treated with estro­gen; lower BMD in women who discontinued estrogen than in women currently being treated

Estrogen as treatment: estrogen FDA-approved for prevention, not treatment; reduced risk for vertebral fractures by >50% and increased BMD in spine and proximal femur in women treated with transdermal estrogen patch and cal­cium; BMD in lumbar spine and hip increased compared to placebo (4.1% vs 0.4% in spine, 1.7% vs 0.1% in hip) in women >75 yr of age

Effects of low-dose estrogen: higher BMD in women with low estrogen than in women with no estrogen; in 3 groups of women given different estrogen doses (0.3 mg, 0.45 mg, and 0.625 mg), spine and hip BMD increased with dose; doses as low as transdermal patch (0.014 mg) and 0.15 mg prevent bone loss

Hormones vs bisphosphonates: estrogen-medroxyprogesterone acetate (MPA)  —  more protective against bone loss than either component alone in women 45 to 59 yr of age; however, combination suppressed bone turnover, which may increase risk for fracture; increased BMD over 3 yr (3.5%-5.0% in spine and 1.7% in hip); with placebo, BMD fell 1.8% in spine and 1.7% in hip; progestin  —  inhibits bone resorption; less protective than estrogen in bone loss; meta-analysis and systematic review (2008)  —  concluded that alendronate, risedronate, zoledronic acid, and estro­gen efficacious in reducing risk for vertebral, nonvertebral, and hip fractures; raloxifene, estrogen-progestin, and estrogen increased risk for thromboembolic effects; selective estrogen receptor modulators  —raloxifene (gold stan­dard) approved for prevention and treatment of osteoporosis; improves BMD and reduces fracture risk; tamoxifen also shown to prevent osteoporosis

Estrogen as first-line therapy: estrogen not considered first-line therapy for prevention of osteoporosis in perimeno­pausal women; useful to treat persistent menopausal symptoms or in women unable to take bisphosphonates or other pharmacologics; bisphosphonates and raloxifene first-line in prevention and treatment of osteoporosis

Suggested Reading

Bahtiar A et al: Identification of a novel L-serine that suppresses osteoclastogenesis in vitro and bone turnover in vivo. J Biol Chem 49:284, 2009; Bamias A et al: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: inci­dence and risk factors. J Clin Onc 23:34, 2005; Bell KJ et al: Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data. BMJ b2266: 338, 2009; Binkley N et al: 25-hydroxyvi­tamin D measurement, 2009: a review for clinicians. J Clin Densitom 4:12, 2009; Black DM et al: Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 24:296, 2006; Black DM et al: Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 18:356, 2007; Bonjour JP et al: Inhibition of markers of bone resorption by consumption of Vitamin D and calcium-fortified soft plain cheese by institutionalised elderly women. Br J Nutr 7:102, 2009; Cosman F et al: Effects of teriparatide in postmenopausal women with osteoporosis on prior alendronate or raloxifene: differences between stopping and continuing the antiresorptive agent. J Clin Endocrinol Metab 10:94, 2009; Cummings SR et al: Denosumab for pre­vention of fractures in postmenopausal women with osteoporosis. N Engl J Med 8:361, 2009; Davison KS et al: Assessing fracture risk and osteoporosis drugs: bone mineral density and beyond. Am J Med 11:122, 2009; Khan AA et al: Bisphos­phonate associated osteonecrosis of the jaw. J Rheumatol 3:36, 2009; Nakashima T, Takayanagi H: Osteoimmunology: crosstalk between the immune and bone systems. J Clin Immunol 5:29, 2009; Rabenda V et al: Low incidence of anti-os­teoporosis treatment after hip fracture. J Bone Joint Surg Am 10:90, 2009; Riches PL et al: Osteoporosis associated with neutralizing autoantibodies against osteoprotegerin. N Engl J Med 15:361, 2009; Smith MR et al: Denosumab in men re­ceiving androgen-deprivation therapy for prostate cancer. N Engl J Med 8:361, 2009.