Learning ObjectivesThis activity is designed for physicians who treat postmenopausal women or other patients at risk for osteoporosis. There are no prerequisites for this activity. At the conclusion of this activity, participants should be able to:

• Weigh the risks and benefi ts of nutritional supplementation in the setting of osteoporosis prevention and treatment.• Address fracture risk and the need for treatment of osteoporosis in men.• Discuss new targets and novel agents in development for treatment of osteoporosis.• Maximize outcomes by employing evidence-based approaches to care with current agents and novel approaches.• Recognize the role of parathyroid hormone in skeletal health and its use to treat patients at high fracture risk.• Use a coherent risk:benefi t analysis to support clinical decision making related to bisphosphonate therapy.• Maximize the clinical utility of FRAX by recognizing its value and limitations.• Manage complex cases by recognizing the various factors that inhibit or contribute to skeletal health.

CME InformationRelease Date: November 15, 2011.Valid for credit through November 14, 2012.

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Indiana University School of Medicine, Osteoporosis Foundation of New Mexico, and Heath Focus, Inc. Indiana University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Indiana University School of Medicine designates this enduring activity for a maximum of 3 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

To receive credit, participants must read this newsletter and submit the activity evaluation form and posttest (passing score = 75% or higher). Access the evaluation and posttest forms at www.2011santafebonesymposium.com.

Length of time to complete the activity: 3 hours

Faculty DisclosureIn accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational pro-grams sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientifi c rigor. All faculty, authors, editors, and planning committee members participating in an IUSM-sponsored activity are required to disclose any relevant fi nancial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity.

Dr. Bilezikian reported that he has received consulting fees and/or hono-raria from Amgen Inc, Eli Lilly and Company, Merck & Co Inc, Novartis, and Warner Chilcott. Dr. Lewiecki reported that he has received grant support from, or served as a consultant and/or speaker for Amgen Inc, Eli Lilly and Company, Genentech Inc, GlaxoSmithKline, Merck & Co Inc, Novartis, Roche/GSK, Teva Pharmaceutical Industries Ltd, Upsher-Smith Laboratories Inc, Warner Chilcott, and Wyeth. Dr. McCloskey reported that he has received speaker fees and grant support from Alliance for Better Bone Health, Amgen Inc, Bayer AG, Hologic Inc, MSD (Merck & Co Inc), Pfi zer Inc, and Servier Laboratories. Dr. Morgan reported that she has received consulting fees from Amgen Inc. Dr. Miller reported that he has received grants, hono-raria, and served on scientifi c boards for Amgen Inc, Eli Lilly and Company, Genentech Inc, and Novartis. Dr. Orwoll reported that he has received consulting fees and/or research support from Amgen Inc, Eli Lilly and Company, Merck & Co Inc, and Wright Medical Technology Inc. Dr. Potts disclosed that he has no potential or actual confl icts of interest.

CME Reviewer: Statements of disclosure of relevant fi nancial relationships have been obtained from Julie Vannerson, MD. She has disclosed that she has no potential or actual confl icts of interest.

Staff : Hassan Danesh, PhD, Monica Armin, and Dr. Deborah Teplow have disclosed that they have no potential or actual confl icts of interest.

Note: Although it off ers CME credits, this activity is not intended to provide extensive training or certifi cation in the fi eld.

November 2011

As our knowledge of the biology of osteoporosis evolves, recommendations for prevention and treat-ment have also evolved, although many aspects are still unresolved or controversial. Long-standing research efforts are yielding new insights of clinical relevance regarding risk factors and osteoporosis in nontraditional populations, notably men. At the same time, research is refi ning our understanding of the mechanisms, risks, and benefi ts of established therapies, and discovering potential new therapeutic approaches. During the 2011 Santa Fe Bone Sympo-sium, a distinguished panel of experts addressed the current state of many of these advances and con-troversies, with emphasis on their clinical relevance. These presentations offer valuable insights into the complex clinical environment of osteoporosis care, and can help improve efforts to prevent, recognize, and treat osteoporosis.

FACULTYChair

E. Michael Lewiecki, MD Director New Mexico Clinical Research & Osteoporosis Center Clinical Assistant Professor of MedicineUniversity of New Mexico School of MedicineAlbuquerque, NM

Faculty

John P. Bilezikian, MD Professor of Medicine and PharmacologyChief of EndocrinologyColumbia University College of Physicians and SurgeonsDirectorMetabolic Bone Diseases ProgramColumbia University Medical CenterNew York, NY

Eugene V. McCloskey, MD Professor in Adult Bone DiseaseThe University of Sheffi eldHonorary Consultant Physician in Metabolic Bone DiseaseNIHR Biomedical Research Unit for Musculoskeletal DiseaseSheffi eld Teaching Hospitals NHS TrustSheffi eld, UK

Paul D. Miller, MDDistinguished Clinical Professor of MedicineUniversity of Colorado Health Sciences CenterDenver, CODirector Colorado Center for Bone ResearchLakewood, CO

Sarah L. Morgan, MDMedical DirectorThe University of Alabama at Birmingham Osteoporosis Prevention and Treatment Clinic and Center for Metabolic Bone DiseaseBirmingham, AL

Eric S. Orwoll, MDProfessor of Medicine Attending PhysicianDivision of Endocrinology, Diabetes, and Clinical Nutrition Bone and Mineral SectionOregon Health and Science UniversityPortland, OR

John T. Potts Jr, MD Distinguished Jackson Professor of Clinical MedicineMassachusetts General Hospital and Harvard Medical SchoolBoston, MA

CME posttest and meeting slides, transcripts & podcasts available at: www.2011santafebonesymposium.com

Fresh Perspectives in Osteoporosis and Metabolic Bone Disease

Highlights of the 2011 Santa Fe Bone Symposium

Controversies in Nutrition and OsteoporosisSarah L. Morgan, MD

Recommendations on Vitamin D Intake

Recommended Intake

The Institute of Medicine (IOM) report Dietary Intakes for Calcium and Vitamin D1 released at the end of 2010 has been rather controversial. Some of that controversy may have arisen because the IOM panel that created the recommendations relied only on randomized controlled trials and excluded evidence from epidemiologic and case-control studies that are familiar to many people.

The IOM panel had numerous charges, but I will focus on 3: (1) to recommend calcium and vitamin D intakes necessary for desirable health outcomes, (2) to identify upper limits for calcium and vitamin D intakes, and (3) to assess what health outcomes are infl uenced by calcium and vitamin D intake.

For calcium, the IOM recommendations did not change substantially from previous reports. For most adults aged 19 years to 50 years, the recom-mended dietary allowance of calcium is 1000 mg per day, but it is higher for women older than 50 years (1200 mg/day) and men older than 70 years (1200 mg/day). The recommendations for vitamin D intake, which increased modestly from previous reports, were more controversial. The new recommendations are 600 IU per day for most individuals, except those older than 70 years in whom the recommended dietary allowance is 800 IU per day.

2

One of the controversies surrounding the IOM report is whether the target levels for serum 25-hydroxyvitamin D (25-OH vitamin D) are adequate. The IOM report states that serum levels of 16 ng/mL (40 nmol/L) are adequate for approximately 50% of people and levels of 20 ng/mL (50 nmol/L) are adequate for approximately 95% of people. However, as noted by Heaney and Holick,2 the recommenda-tions from the IOM panel are directed at healthy people and are not applicable for people with disease or at risk for disease. Furthermore, determining acceptable vitamin D levels by sampling the range of serum levels in people, many of whom are deficient, is not a good way to deter-mine optimal levels for the prevention of disease.

Several lines of evidence suggest that vitamin D intake of 600 IU per day may be inadequate, especially if the goal is fracture prevention in at-risk persons. For example, a study conducted during the winter months in Nebraska found that a dosage of 1000 IU per day was only sufficient to maintain serum 25-OH vitamin D levels.3 Furthermore, several meta-analyses of fracture prevention in at-risk populations have found that vitamin D intake of 700 IU to 800 IU per day or higher and serum 25-OH vitamin D levels of greater than 16 ng/mL (40 nmol/L) are required for significant reductions in the risk of hip and nonvertebral fractures.4-6 An autopsy study found that bone mineralization de-fects consistent with vitamin D deficiency were not present in bones from people with circulating 25-OH vitamin D levels of greater than 30 ng/mL (75 nmol/L), suggesting that this circulating level should be a minimum for maintaining bone health.7 Finally, studies in people who are exposed to a large amount of sunlight show average serum 25-OH vita-min D levels of approximately 36 ng/mL (90 nmol/L) or higher.8-10

Many of us who treat patients for the pre-vention of osteoporosis try to maintain serum 25-OH vitamin D levels of greater than 40 ng/mL (100 nmol/L) using whatever dietary intake is required to maintain that level.11 Unfortunately, there is considerable variability in currently available assays of 25-OH vitamin D, and physicians need to be aware of this variability and try to use a reliable assay.12 The Endocrine Society currently recommends vitamin D intake of at least 600 IU per day for adults aged 50 years to 70 years and 800 IU per day for those older than 70 years.12 Special popu-lations may require 2- to 3-fold higher intakes of vitamin D, including obese individuals, and those taking anticonvul-sants; glucocorticoids; antifungals, such as ketoconazole; and medications for AIDS.12

Maximum Intake

The upper limit of daily vitamin D intake has also been controversial. The new IOM report set the upper limit at 4000 IU per day,1 and there is evidence that that level is safe. In a group of 40 breast cancer pa-tients with bone metastases and without comorbid conditions causing hypersensi-tivity to vitamin D, 10,000 IU per day of vitamin D3 for 4 months was found to be safe.13 Serum 25-OH vitamin D3 reached a plateau after approximately 4 months, reduced inappropriately high parathyroid hormone [PTH] levels, and was not associ-ated with any cases of direct toxicity.13 At least 2 other studies have found that prolonged intake of vitamin D dosages of 4000 IU per day were associated with no adverse effects.14,15

Extraskeletal Benefits of Vitamin D

The IOM panel noted that there was not sufficient evidence to know whether there were benefits of vitamin D in addition to bone health and muscle strength, but also concluded that most people in North America are obtaining sufficient amounts of the vitamin. As pointed out by Heaney and Holick, however, we do not know whether higher intakes would have addi-tional benefits beyond those seen in bone2 (see also Shapses and Manson16). Further-more, a recent systematic review concluded that vitamin D supplementation was asso-ciated with a 17% reduction in the relative risk of falling in older adults.17

Calcium Supplementation

Risk of Cardiovascular Disease

The IOM recommendations for calcium intake are 1000 mg per day to 1200 mg per day for adults,1 but many Americans are not achieving those levels either by diet or through supplementation.18 Con-troversy has arisen regarding the use of calcium supplements, especially from a secondary analysis of vascular events in a randomized trial of calcium supplements (without vitamin D supplements) for frac-ture prevention in 1471 postmenopausal women.19 This study found that the self-reported incidence of myocardial infarc-tion (MI) and the composite outcome of MI, stroke, or sudden death were signifi-cantly increased in women who took a calcium supplement as compared with women who took a placebo (relative risk [RR] = 2.24; 95% CI, 1.20-4.17; P = .0099 for MI; RR = 1.66; 95% CI, 1.15-2.40; P = .0075 for the composite end point).19 However, the authors noted that an independent re-view of events resulted in a weaker effect of calcium on cardiovascular end points, although the effect remained marginally significant.

Analyses of other studies have found ei-ther no effects of calcium supplements on the risk of cardiovascular end points or much weaker effects. In the Women’s Health Initiative trial with 7 years of follow-up, there was no increase or decrease in the risk of MI or stroke in postmenopausal women randomly assigned to calcium supplements plus vitamin D versus placebo (n > 18,000 in each group).20 A recent meta-analysis of 12 studies found a small, but significant, increase in the risk of MI asso-ciated with the use calcium supplements, such that an excess event would affect 1 patient in 210 treated for 5 years.21 Many of the trials included in this meta-analysis, however, had limitations. For example, none of the trials studied calcium plus vitamin D, and none had cardiovascular events as a primary end point. Further-more, data on cardiovascular events were not collected in a standardized way and were adjudicated in a masked manner in only 2 of the trials. Indeed, another sys-tematic review concluded that there was no increased risk of cardiovascular events associated with either calcium supple-mentation, vitamin D supplementation, or the combination.22

The most recent evidence regarding the risk of cardiovascular disease associated with calcium supplementation is from a randomized controlled trial including 1460 women (average age = 75.1 years at enrollment). Participants were random-ized to receive 1200 mg per day calcium carbonate or placebo for 5 years. There was no increase in risk of atherosclerotic vascular disease associated with calcium supplementation during the trial (hazard ratio [HR] = 0.938; 95% CI, 0.690-1.274) or during an additional 4.5 years of follow-up.23 This study also found evidence suggesting that calcium supplementation reduced the risk of hospitalization and mortality in patients with atherosclerotic vascular disease.23

Although some of the studies reporting an increase in risk associated with the use of calcium supplements have caused alarm among our patients, at this time it is premature for patients to stop taking calcium and vitamin D supplements be-cause of concern about the risk of cardio-vascular disease.

Choosing a Calcium Supplement

Calcium supplements come in several forms, including calcium carbonate, calcium citrate, and calcium citrate malate. A crossover study in older people found that calcium carbonate supplements and orange juice fortified with calcium citrate malate were equivalent to skim milk in terms of calcium bioavailability and postprandial suppres-sion of intact PTH.24 Two studies have

CME posttest and meeting slides, transcripts & podcasts available at: www.2011santafebonesymposium.com

3

reported that calcium citrate has better bioavailability than calcium carbonate,25,26 but more detailed studies using more sensitive assays found that the 2 forms taken with meals were equivalent in terms of absorption, increases in serum calcium, and suppression of intact PTH levels.27,28 Thus, it is recommended that calcium carbonate be taken with meals.

Some medical conditions or treatments may affect calcium absorption. For example, some, but not all, studies have found that concurrent use of proton pump inhibitors reduces calcium absorption from calcium carbonate, with one group of authors speculating that the different results may be related to other food components.29 An-other study found that calcium citrate was absorbed better than calcium carbonate in patients with achlorhydria; although calcium carbonate absorption was normal when it was taken as part of a normal breakfast.30 A recent study also suggests that calcium citrate may exhibit better absorption after Roux-en-Y gastric bypass surgery.31 Over-all, however, studies suggest that calcium citrate and calcium carbonate exhibit similar absorption in most patients when the calcium carbonate supplements are taken with meals.

Kidney Stones

Kidney stones are a common problem, and the incidence of kidney stones appears to be increasing.32 The majority of kidney stones are calcium stones, and the majority of those are calcium oxalate.32 Observational studies have drawn confl icting conclusions about whether calcium supplementation increases or decreases the risk of kidney stones.33,34 However, prospective clinical trials have generally found no increase or decrease in the risk of kidney stones in people taking calcium supplements.35-37

Put It Into Practice• When recommending dosages of vitamin D for the prevention of osteoporosis, choose dosages that maintain serum 25- OH vitamin D levels of 40 ng/mL (100 nmol/L) or higher. • Higher dosages of vitamin D may be required in some patients, including obese individuals and those using anticonvulsants; glucocorticoids; antifungals, such as ketoconazole; and medications for AIDS.• Assure patients that either calcium carbonate or calcium citrate is an acceptable supplement in most cases. Calcium carbonate is cheaper and, when taken with meals, is equivalent to calcium citrate.

Osteoporosis in Men

Eric S. Orwoll, MD

Identifying Men at Risk of Fracture

Independent Risk Factors

The Osteoporotic Fractures in Men Study (MrOS) is a large, multicenter, observational study of musculoskeletal health and fracture in older men.38 The study enrolled 5994 men aged 65 years or older from 6 communities in the United States between the years 2000 and 2002. Because MrOS was intended to represent the general population, there were few exclusion criteria for enrollment. The average age of participants was 74 years at the time of enrollment and 89% were white. The participants were extensively characterized at baseline and have been regularly followed up since then. The average follow-up duration is now more than 8 years.

Selected independent risk factors for nonspinal fracture in men from the MrOS study are shown in the Table. Men who had 3 or more risk factors were at 5-fold higher risk of fracture than men who had no risk factors, independent of bone mineral den-sity (BMD).38 Having 3 or more risk factors and being in the lowest tertile of BMD was associated with a 15-fold increase in risk compared with men having no risk factors and who were in the highest tertile of BMD.38 It is notable that increasing age was an in-dependent risk factor and that height and body weight were not identified as risk factors in this analysis.

Rate of Bone Loss

Traditional depictions of bone loss during aging show a fairly constant rate of BMD decline after approximately 50 years of age in both men and women, with an ad-ditional rapid phase of bone loss imme-diately after menopause in women. Data from MrOS, to the contrary, clearly show that the rate of bone loss increases with increasing age.39 Furthermore, rates of

bone loss were heterogeneous, with 24% of men exhibiting no loss of BMD, and 13% exhibiting an accelerated rate of BMD loss (at least 1 standard deviation greater than the mean rate). Interestingly, those with the lowest BMD at baseline also had the highest rate of BMD loss. 39

The increased rate of BMD loss during aging likely has clinical implications inde-pendent of low BMD itself. Cawthon and colleagues measured change in femoral neck BMD in MrOS participants over an average of 4.6 years and then used a mul-tivariate model (adjusted for age, diabetes, physical activity at baseline, change in physical activity, weight, change in weight, and self-rated health) to assess the rela-tionship between rate of bone loss and subsequent fracture risk.40 Men who had an accelerated rate of BMD loss had a 1.8-fold higher risk of subsequent nonspinal fractures and 5.8-fold higher risk of sub-sequent hip fracture compared with men who maintained BMD. These increases in risk were independent of baseline BMD, such that men who had both accelerated BMD loss and low baseline BMD had an approximately 9-fold higher risk of subse-quent fracture compared with men who maintained BMD. These results raise the question of whether we should be mea-suring BMD longitudinally to assess the rate of BMD loss, especially in men with BMD in the low-normal range who would not be treated on the basis of low BMD alone. The follow-up question is whether men with accelerated BMD loss should be treated earlier than they would be on the basis of BMD alone.

Body Composition

Low body mass is widely accepted as a risk factor for fractures, but a more careful examination of this issue reveals that the situation is more complex. De Laet and colleagues showed, using data from a meta-analysis, that the decrease in fracture risk associated with increasing body mass index (BMI) is attenuated when the data are corrected for BMD.41 Indeed, there was evidence that fracture risk began to

To earn CME credit, complete the posttest and evaluation at www.2011santafebonesymposium.com/posttest.html

bone loss were heterogeneous, with 24% of men exhibiting no loss of BMD, and

loss (at least 1 standard deviation greater than the mean rate). Interestingly, those with the lowest BMD at baseline also had the highest rate of BMD loss.

The increased rate of BMD loss during aging likely has clinical implications inde-

Characteristic Hazard Ratio (95% CI)

Fracture when ≥ 50 years of age 2.07 (1.62-2.65)

Age ≥ 80 years 1.33 (1.01-1.76)

Low total hip BMD (per standard deviation) 1.53 (1.34-1.74)

Any fall in the preceding year 1.59 (1.23-2.05)

Unable to complete narrow walk trial 1.70 (1.23-2.34)

Table. Independent Risk Factors for Nonspinal Fracture in Men from MrOS.38

BMD denotes bone mineral density.

4

increase again in people with high BMI. However, most of the data for this analysis came from studies of women.

The relationship between BMI and fracture risk in older men has been re-examined in MrOS.42 When participants were subdivided into groups according to BMI, the incidences of nonvertebral and hip fractures per 1000 person-years were lowest in men in the obese I category (BMI 30-34.9) and increased as BMI either decreased or increased. Men in the obese II category (BMI 35-39.9) had essentially the same fracture incidence as men in the normal weight category (BMI 18.5-24.9). In this study population, which was typical of the United States population, 27% of men were in the normal weight category. They accounted for 32% and 38% of the nonvertebral and hip fractures, re-spectively. Nevertheless, overweight (BMI 25-29.9) and obese men together accounted for the majority of fractures overall—68% and 62% of nonvertebral and hip fractures, respectively.42 Thus, even though very thin men are at higher fracture risk, most fractures occur in overweight and obese individuals.

To address the question of why men with high BMI continue to experience fractures, data from MrOS were used to examine the relationship between BMI and BMD. This analysis revealed that increasing BMI is associated with increasing BMD, but the correlation is weak (Pearson’s correlation coeffi cient r = 0.35).42 Indeed, many over-weight and obese men still have low BMD and remain at higher risk for fracture. Thus, screening recommendations that empha-size screening in people with low BMI may miss a lot of men who have low BMD because they are overweight or obese.

Another factor affecting the risk of fracture in obese men was hinted at by adjustment of the multivariate risk model for BMD. After making this adjustment, overweight and obese men had higher odds of fracture than normal-weight men, such that men in the obese II category had 5-fold higher risk of hip fracture and 1.9-fold higher risk of nonvertebral fracture.42 Further adjust-ments to the model to account for the risk of falls attenuated this increased risk, sug-gesting that obese men had poorer physi-cal function and increased incidence of falls compared with normal-weight men.42

Adiposity itself may also affect BMD. An analysis of change in total hip BMD as a function of both weight loss and change in adiposity over time, showed that both weight loss and increased adiposity were independently associated with a higher rate of BMD loss.42

In summary, low body mass is a risk fac-tor for fractures in older men, but because

underweight men are uncommon in west-ern cultures, most nonvertebral and hip fractures occur in overweight and obese men. Furthermore, among men with the same BMD, increased body mass is not protective against fracture risk. Thus, assessment of BMD should be considered in overweight men, especially if other risk factors are present. Treatment of osteopo-rosis should be considered in overweight men at risk of fracture, if appropriate. Development of clinical algorithms to assess fall risk may add value to efforts to prevent fractures in older men. It is not entirely clear whether we should recom-mend weight loss to reduce the risk of fracture, but recent evidence indicates that weight loss accompanied by exercise can be achieved without loss of bone mass,43 making this approach a potentially valu-able option.

Put It Into Practice• Remember that the rate of bone loss increases with increasing age in men (and women), and that the rate of bone loss is a risk factor for fractures independent of baseline BMD.• Men who are overweight or modestly obese have somewhat lower risk of fracture than men of normal weight, but some overweight and obese men remain at high risk of fracture. Risk assessment should not be limited to underweight or normal weight men.

New and Emerging Therapies for Osteoporosis John P. Bilezikian, MD

New Therapies

The most recent FDA-approved therapy for osteoporosis is denosumab, an inhibitor of the RANK/RANKL/OPG system that is critical for intercellular bone signaling. Receptor acti-vator of nuclear factor ĸB ligand (RANKL) is expressed by osteoblasts and binds to its cognate receptor (RANK) on the surface of osteoclasts and osteoclast progenitor cells. By activating RANK, RANKL is a power-ful stimulator of osteoclastogenesis and osteoclast action.44 Osteoprotegerin (OPG) functions as an important regulator of this system by acting as a decoy receptor for RANKL, making RANKL unavailable for binding to RANK.45 The balance between RANKL and OPG may be a critical element in the mechanism by which bone remodel-ing is controlled. Denosumab is a human immunoglobulin G (IgG) that acts in a

manner similar to OPG. Denosumab binds to RANKL, preventing it from binding to RANK, thereby reducing the activation and development of osteoclasts.46

Phase 2 trials of denosumab demonstrated substantial and sustained increases in bone density in the spine, hip, and distal radius.47,48 The extension of the phase 2 trial, now well beyond 6 years, documents continuing, linear accrual of BMD,49 a result that is distinctly different from the action of bisphosphonates in which the major increment in BMD occurs within the fi rst 3 years of treatment.50 The phase 2 trial has also given insight into the revers-ibility of denosumab.51 During treatment, denosumab markedly suppressed bone turnover markers, but the markers rapidly increased after discontinuation, even overshooting pretreatment levels. There-after, they returned to baseline. BMD also falls when denosumab is discontinued. The rapid reversibility of denosumab is another feature that distinguishes this drug from the bisphosphonates. Although this property can be viewed as a positive feature of denosumab, it also indicates that good compliance is necessary to achieve optimal therapeutic outcomes.

Administration of denosumab is associated with substantial, but transient, increas-es in intact PTH levels, which persist for approximately 3 months.48 This effect is paradoxical in that denosumab increases intact PTH and cortical BMD concurrently; whereas, primary hyperparathyroidism (in which intact PTH is increased) leads to a decrease in cortical BMD. To explain this paradox, it is possible that denosumab shifts the action of endogenous PTH from primarily catabolic action at cortical sites to anabolic action, which may involve fa-voring the inhibition of sclerostin by PTH.

The pivotal trial of denosumab randomized7808 postmenopausal women with osteo-porosis to receive denosumab 60 mg or placebo subcutaneously every 6 months for 36 months.52 The results demonstrated a significantly lower risk of vertebral fractures in the denosumab arm compared with the placebo arm (2.3% vs 7.2%; risk ratio = 0.32; 95% CI, 0.26-0.41; P < .001). Patients in the denosumab arm also experienced significantly lower rates of hip fracture (0.7% vs 1.2%; HR = 0.60; 95% CI, 0.37–0.97; P = .04) and nonvertebral fracture (6.5% vs 8.0%; HR = 0.80; 95% CI, 0.67–0.95; P = .01).

The approval of denosumab by the FDA came with several cautionary notes. One relates to an association with skin infections (cellulitis) or skin conditions (eczema) during the pivotal trial. However, increases in the incidence of these adverse effects have not been observed in the fourth year

CME posttest and meeting slides, transcripts & podcasts available at: www.2011santafebonesymposium.com

RANKL/OPG system that is critical for

5

of treatment in patients in the FREEDOM extension study.53 Another concern of the FDA is the possibility of “oversuppression” of bone turnover, a concept that is not clearly defined or understood for any os-teoporosis treatment. Nevertheless, bone biopsies from the pivotal clinical trial of denosumab showed marked suppression of bone turnover and a paucity of osteo-clasts.54 However, recent bone biopsy data showed that indices of bone remodeling rapidly returned to normal in patients who discontinued denosumab.55 Deno-sumab is not contraindicated in patients with impaired renal function.

Emerging Therapies

Cathepsin K, an enzyme that is expressed in abundance in osteoclasts, is secreted during the process of bone resorption. It helps to excavate the resorption pits that become bone remodeling units.56 Inhibition of cathepsin K or deletion of the cathepsin K gene leads to shallower resorption pits and greater bone mass in animal models; although osteoclasts remain present and functional in other capacities, including osteoblast signaling.57

To date, only 1 cathepsin K inhibitor, odanacatib, has advanced to the stage of a major pivotal clinical trial. Results of a phase 2 trial of odanacatib are consistent with observations from animal models, indicat-ing that it inhibits bone resorption in a dose- dependent manner.58 Furthermore, bone resorption was inhibited to a much greater degree than bone formation, a feature that differentiates odanacatib from the bis- phosphonates and denosumab.58,59 Another cathepsin K inhibitor, ONO-5334, is in development.60

Future Therapeutic Approaches

An ideal osteoporosis treatment will restore the microarchitectural deficits that are characteristic of osteoporotic bone. The class of drugs that shows potential in this regard is described as osteoanabolic. Two drugs that belong to this class are PTH(1-84) and its amino terminal fragment PTH(1-34), known as teriparatide. When PTH or teriparatide is administered in low doses and intermittently (once daily, which leads to a pulsatile delivery of drug), anabolic properties of PTH pre-dominate.61 Indeed, several clinical trials using either teriparatide or PTH(1-84) have shown reductions in vertebral and nonvertebral fractures and associated im-provements in skeletal microstructure.61-66

Drawbacks to the use of teriparatide or PTH(1-84) include the need for daily subcutaneous injections and its expense. Concerns because animal studies show a risk of osteosarcoma have not been

substantiated in humans after almost a decade of use.62 Several approaches are be-ing pursued in an attempt to improve the delivery of PTH or to take advantage of endogenous PTH secretory mechanisms. One approach relies on the use of calcilyt-ics, which are inhibitors of the calcium-sensing receptor. One such agent, ronacal-eret, appeared to have promise by being associated with increases in endogenous PTH and concomitant increases in bone turnover markers. However, further ex-perience with ronacaleret has not fulfilled the promise that it would be associated with increases in BMD.67

One approach to improving PTH-based therapy is the use of an amino terminal fragment of human parathyroid hormone-related peptide (PTHrP). PTHrP is an endogenous protein with sequence homol-ogy to PTH at the amino-terminal end. It is produced by numerous tissues in the body, including some cancers, and is im-plicated in hypercalcemia associated with malignancy.68 Studies by Horwitz and colleagues found PTHrP to be associated with increases in bone formation markers with little or no change in bone resorption markers in postmenopausal women with osteoporosis.69 Using a PTHrP analog, O’Dea and coworkers found that bone resorption markers eventually increase.70 In this regard, PTHrP-derived molecules do not appear to be different than PTH-derived molecules.

Another approach for optimizing PTH-based therapy has focused on improving delivery of PTH using a transdermal patch. This approach was studied in a phase 2 trial of 165 postmenopausal women with osteoporosis.71 The study found that trans-dermal administration of teriparatide for 6 months increased lumbar spine and total hip BMD significantly more than placebo or subcutaneous teriparatide. Notably, the pharmacokinetics of transdermal teriparatide appeared to be more favorable than those of the subcutaneously admin-istered drug.71

Combination and Sequential Administration

From advances in our understanding of PTH as an anabolic agent, a kinetic model has arisen suggesting the existence of an “anabolic window” during which time PTH increases bone formation markers without significantly increasing bone resorption markers. Eventually, bone resorption markers also increase. The increase in bone resorption markers signals a switch from a modeling-based to a remodeling-based mechanism of PTH action. It is currently thought that the osteoanabolic actions of PTH are 30% modeling based and 70% remodeling based. During the remodeling

phase, bone formation exceeds bone resorption for the duration of the efficacy period of PTH action. The anabolic win-dow concept has led to various strategies to combine bisphosphonates with PTH-based therapies, administering the drugs either concurrently or sequentially.

Many patients who are given PTH(1-84) or teriparatide have been treated previously with a bisphosphonate. In some cases, there is a delay of up to 6 months before the anabolic actions of the PTH analog are apparent. Eventually, however, patients invariably respond. After anabolic treat-ment for the recommended 2-year period is complete, it is important to follow with an antiresorptive drug so that the gains with anabolic therapy can be maintained. Simultaneous combination therapy with an anabolic agent and an antiresorptive agent has been proposed because of the different mechanisms of action. However, this approach has been controversial, and it is still not clear that simultaneous combination therapy offers any advantage over sequential monotherapy.72

The Wnt Signaling Pathway

The Wnt signaling pathway, a complex and ubiquitous system, is involved in numerous physiological processes, as well as embryo-genesis, neurogenesis, and cancer. It is also a key pathway in regulating the differentia-tion and activity of osteoblasts.73 Activity of the Wnt pathway and, hence, bone forma-tion are controlled by sclerostin, a product of osteocytes.73 In this manner, sclerostin is thought to serve as an endogenous brake on bone formation (Figure 1).74 Indeed, studies of osteoporosis in animal models have shown that an antibody against scle-rostin increases bone formation and bone mass.75 Drugs targeting other components of the Wnt pathway may also be attractive targets for development as treatments of osteoporosis.

Serotonin

Serotonin is produced in the brain as well as in the gastrointestinal tract. There is evidence that excess free serotonin in pe-ripheral tissues, mostly derived from the gastrointestinal tract, reduces bone mass.76 Yadav and colleagues presented results from genetic studies suggesting that in-hibition of gastrointestinal production of serotonin can promote activity of osteo-blasts, leading to bone formation.77 These findings have led to studies of LP533401, an inhibitor of tryptophan hydroxylase 1, the enzyme responsible for serotonin synthesis in the gastrointestinal tract (but not in the brain). In a proof-of-principle study in ovariectomized mice, LP533401 prevented and reversed osteoporosis and improved bone quality.78,79 These results

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6

have been questioned in more recent studies.78,80

Summary

The future looks bright for the treatment and prevention of osteoporosis with many new pharmacologic candidates, including several that target novel mechanisms or signaling pathways. Many challenges remain, however, in demonstrating the efficacy and maintaining the safety and bone specifi city of these potential new therapies.

Put It Into Practice• Stress the importance of good compliance with denosumab therapy when counseling patients who are currently using or considering denosumab therapy for osteoporosis.

• After a 2-year course of PTH or teriparatide for osteoporosis, begin treatment with antiresorptive therapy so the gains achieved during anabolic therapy can be maintained.

Parathyroid Hormone in the Assessment and Treatment of Osteoporosis

John T. Potts Jr, MD

Parathyroid Hormone Function: Historical Perspective

Some of the biological ac-tions of PTH are paradoxical. Constant PTH excess causes bone loss in individuals with primary hyperpara-thyroidism. The paradox is that if given intermittently, PTH is very effective in building bone. It is, in fact, the only cur-rently FDA-approved anabolic therapy for osteoporosis. A historical overview of the biology of PTH will help to explain this paradox.

During the fi rst 25 years of the twentieth century, the functional role of the para-thyroid glands was highly controversial. It was known that removal or destruction of the glands in humans or animals caused tetany,81,82 but competing theories were presented to explain the cause of tetany. The controversy arose because the usual aqueous extracts of the glands were not effective at restoring blood calcium levels or curing tetany in parathyroidectomized animals. The controversy was resolved in 1925 when James Bertram Collip used hot acid extraction to release the active form of PTH from gland tissue. This extract

of the parathyroid glands restored blood calcium levels and controlled tetany in para-thyroidectomized dogs, thus confi rming that tetany is indeed due to hypocalcemia.83 The role of PTH in regulating blood calcium, and links between PTH, blood calcium, and bone disease were elucidated soon after. Much of this history is described in a book by Fuller Albright, another pioneer in parathyroid studies, which was published posthumously in 1990.84

Parathyroid Hormone in Diagnosis

Before 1970 the diagnosis of hyperpara-thyroidism was accepted only after parathyroidectomy cured patients with hypercalcemia and other symptoms of hyperparathyroidism. With the develop-ment of fi rst-generation assays for PTH and then more sensitive second- and third-generation assays, hyperparathy-roidism can now be diagnosed from clini-cal laboratory assays. More patients with the disease can be detected; therefore, the characteristics of patients with hyper-parathyroidism have changed. Nephro-lithiasis and overt skeletal disease, which were once fairly common, are now much less common, and approximately 80% of patients diagnosed with hyperparathy-roidism are asymptomatic, at least in the United States. Optimal management of patients with asymptomatic hyperpara-thyroidism is still being evaluated, but it appears that some patients can be man-aged without surgery.85

Parathyroid Hormone as an Anabolic Agent

If excess PTH is the cause of bone loss in hyperparathyroidism, how can it be use-

ful as an anabolic agent in bone? The fi rst evidence for the anabolic actions of PTH was obtained by Albright and colleagues in 1929.86 They used injections of PTH to release lead from the bones of patients with lead poisoning. They then tested such injections in rats and were surprised to observe that it caused increases in bone mass. Although this report was confi rmed by Hans Selye,81 there were no further studies of the anabolic actions of PTH for 40 years, largely because patients with hyperparathyroidism seen in those days had bone loss.

In 1975 interest in the clinical use of PTH resumed, and purifi ed hormone became available for the fi rst time. Improvements in imaging techniques also made it possible to accurately measure bone mass without the need for repeated bone biopsies. Even-tually, international trials of PTH in pa-tients with osteoporosis were conducted, and it was found to be highly effi cacious.87 It wasn’t until 2002 that a PTH analog was approved by the FDA for the treatment of osteoporosis. PTH induces a more rapid and greater increase in BMD than other available therapies and a greater reduction in fracture rate, but it does not cure osteo-porosis. PTH requires parental adminis-tration and is expensive; thus, it is only approved for use in individuals at high risk of fracture.

The explanation for how PTH can have both catabolic and anabolic effects in bone is incompletely understood. It is known, however, that administering PTH in brief pulses is crucial for obtaining the anabolic effects; whereas, continuous administration yields a catabolic effect.

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tions of PTH are paradoxical.

Figure 1. Simplifi ed Diagram of the Role of the Wnt Signaling Pathway in Bone Formation, and Its Inhibition by Sclerostin.

7

Future Directions

Several approaches are being studied to improve the utility or effectiveness of PTH or PTH analogs. Approaches include combination therapy with antiresorptive agents, such as bisphosphonates or deno-sumab; the development of better PTH analogs; alternative methods of admin-istration; and agents that target down-stream components of the PTH signaling system in bone cells.

One promising area of research has arisen from studies of PTHrP and how PTH and PTHrP interact with the PTH receptor (PTH1R). PTHrP is made in many tissues of the body and participates in the para-crine/autocrine signaling involved in breast development, as well as in the development of bone and many other tis-sues. It binds to the same receptor as PTH, which has only 1 isoform, but has bio-logical effects that are quite distinct from those of PTH.85,88 Thus, a major enigma is how PTH and PTHrP can perform differ-ent biological functions while acting on the same receptor.

To investigate this enigma, we investigat-ed the binding of PTH and PTHrP to the receptor PTH1R. We found that PTH(1-34) binds to PTH1R to form a high-affinity state that is essentially irreversible. In contrast, PTHrP binds and then is quickly released from the receptor in the tradi-tional manner in which G protein–linked receptors are believed to be activated. The PTH-PTH1R complex is internalized within the target cell, leading to forma-tion of intracellular vesicles that continue to activate intracellular signaling.89,90 In contrast, PTHrP was not internalized and produced only transient activation of cell signaling pathways.

To examine the biological ramifi cations of this effect, we constructed more potent analogs of PTH. The most potent of these analogs, known as LA-PTH, increased blood calcium levels for at least 24 hours after a single administration in experi-mental animals; in contrast, PTH(1-34) increased calcium levels for only approxi-mately 2 hours.89

Such long-acting analogs would not be predicted to be useful for the treatment of osteoporosis, but should be useful for the treatment of hypoparathyroidism, for which PTH has not proven efficacious because of its rapid clearance. There is evidence that delivery systems, such as intradermal delivery, that exhibit more rapid pharmacokinetics result in better efficacy than when the same compound is delivered subcutaneously.91 Efforts to develop potent and more rapidly acting PTH analogs are, therefore, ongoing.

Put It Into Practice• The existence of normal calcemic hyperparathyroidism suggests the value of screening all patients with osteoporosis with a PTH assay. • There is no clinical difference between second- and third-generation PTH assays in clinical practice; they are both more sensitive than fi rst- generation assays. • Be alert to new developments in PTH analog design either as a better agent for osteoporosis or as a superior treatment for hypoparathyroidism.

Benefits and Risks of Bisphosphonate Therapy for OsteoporosisPaul D. Miller, MD

During the last 40 years, bisphosphonates have yielded enormous benefi ts in several clinical condi-tions, including Paget’s disease, myositis ossifi cans progressiva, osteoporosis, drug-induced bone loss, post-transplantation medicine, heterotopic ossifi cation, primary hyper-parathyroidism, aseptic necrosis, metastatic cancer to bone, and multiple myeloma. With this success has also come controversy, often fueled by media, litigation, and the use of buzzwords, such as “frozen bone” and “oversuppression.” Many of these contro-versies have led to patients stopping bisphosphonate therapy, often without good justification.

The evidence for most of these controversies is anecdotal, sometimes even hypothetical. Some of the controversies may stem from the pharmacokinetic/pharmacodynamic properties of bisphosphonates, especially the fact that they are taken up and stored in bone for prolonged periods and re-leased in their still-active form during bone remodeling.92-94 Although these properties may engender fear, they may also account for many of the established benefi ts of bisphosphonates.

Frozen Bone and Oversuppre ssion of Bone Turnover

The concept of frozen bone, meant to describe metabolically inactive bone, has been ascribed to the use of bisphospho-nates. However, there are no good-quality scientific studies that have shown the presence of frozen bone in patients using bisphosphonates at approved doses. When bone turnover markers are used to monitor

the effects of bisphosphonates, the drugs induce a rapid decline in serum N-telopep-tide cross-links (NTx) of approximately 50% to 60%, but the NTx levels then remain at a constant level despite continued admin-istration of bisphosphonate. Furthermore, in biopsy specimens from patients treated with long-term bisphosphonate therapy, double-labeling studies have shown continued bone turnover.95,96 Other studies have shown that osteoclasts may be sup-pressed, but are not absent in bone from patients treated with bisphosphonates.97 Finally, none of the bisphosphonate clinical trials have found sustained suppression of NTx below the lower limit of the premeno-pausal normal range. Thus, bisphosphonates do not completely suppress bone turn-over, and the rate of bone turnover does not continue to decline during extended treatment.98-104

Osteonecrosis of the Jaw

On June 2, 2006, The New York Times pub-lished an article titled “Drug for Bones Is Newly Linked to Jaw Disease,” which created signifi cant alarm among patients. In 2008, an expert panel representing the American Society for Bone and Mineral Research (ASBMR) defi ned osteonecrosis of the jaw (ONJ) as “exposed necrotic bone in the maxillofacial region, not healing after 6-8 weeks, and in patients with no history of craniofacial radiation.”105 Ac-cording to a study published in 2006, only approximately 4.1% of cases occur in patients receiving bisphosphonates for osteoporosis; whereas, about 94% of cases occur in patients receiving frequent doses of the drugs for bone metastases.106 Several risk factors for ONJ have been identified, including dental extraction and other invasive dental procedures, as well as dosage, potency, and dura-tion of bisphosphonate exposure; cancer; chemotherapy; and other factors.105,107 As of 2011, there have been a total of 141 validated cases of ONJ reported in osteoporosis patients.108 Estimates of the incidence of ONJ among patients receiv-ing bisphosphonates have varied widely, but range from 1 in 10,000 (0.01%) to 1 in 160,000 (0.000625%).105 In comparison with hip fracture risk used to initiate bisphos-phonate therapy (3%) and considering the severe consequences of hip fractures, the risk of ONJ is very low compared with its benefi ts. Although some experts have sug-gested that low levels of carboxy-terminal collagen cross-links can be used to predict the risk of ONJ in patients receiving bisphosphonates,109 examination of clinical trial data do not support this conclusion.109

The American Dental Association has con-cluded that “routine dental treatment gener-ally should not be modifi ed solely on the basis of oral bisphosphonate therapy.”110

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progressiva, osteoporosis, drug-induced

Very good information for counseling patients on this issue is available from the American Dental Association (http://www.ada.org/3045.aspx).

Atypical Fracture of the Femur

In July of 2008, The New York Times published another article about bispho-sphonates, citing a series of case reports describing an “unusual fracture pattern” in people who used bisphosphonates for 5 years or more. This issue was revived again in March 2010 when ABC News televised a report on the same issue. Two days later the FDA issued a press release stating that the case reports involved too few patients to prove an association with bisphosphonates, that patients should not stop taking bisphosphonates, and that healthcare providers should recognize a potential risk but continue to follow the approved labeling when prescribing oral bisphosphonates.

A 2010 report from a task force of the ASBMR concluded that there is no definite relationship between the use of bisphos-phonates and atypical fractures of the femur.111 Of the 310 cases reported world-wide at that time, 286 were in patients taking bisphosphonates. Recent cohort studies have obtained risk estimates, as exemplified by a Swedish study of 59 cases of atypical fractures among 12,777 women aged 55 years or older who had a fracture of the femur.112 In that study, the increase in absolute risk of atypical frac-tures associated with bisphosphonate use was 5 cases per 10,000 patient-years. A to-tal of 91 patients needed to be treated for 3 years to prevent 1 hip fracture, 14 patients needed to be treated for 3 years to prevent 1 morphometric vertebral fracture, but 667 needed to be treated for 3 years to cause 1 case of atypical femoral fracture. Thus, the benefit strongly outweighed the risk. As with other studies, the risk may be increased with increasing duration of bisphosphonate therapy.112

The clinical pattern of atypical femur fractures in patients taking bisphospho-nates has been described by Nieves and Cosman.113 Most atypical femur fractures were in patients using long-term bisphos-phonate therapy (> 4 years), the fractures usually present with unilateral or bilat-eral anterior thigh ache that progresses over several months, and they usually occur in the absence of trauma. Initial x-rays may be negative, after which time there may be cortical thickening 4 inches to 5 inches below the lesser trochanter. The use of computed tomography or magnetic resonance imaging may allow earlier detection.113

Atrial Fibrillation

The issue of atrial fibrillation (AF) as a potential side effect of bisphosphonates arose from the pivotal trial of zoledronic acid for fracture prevention.104 In that trial, the rates of AF as an adverse event were comparable in the zoledronic acid and placebo arms (2.4% vs 1.9%, respectively), but rates of AF as a serious adverse event (leading to hospitalization, prolongation of hospitalization, or leading to disability) were higher in the zoledronic acid arm (50 patients [1.3%] vs 20 patients [0.5%]; P < .01). There was no relation between the occurrence of AF and the time of admin-istration or cumulative dose of zoledronic acid. Furthermore, the overall incidence of AF was lower than expected for patients in the same age range. There was no dif-ference in AF or serious AF rates in the trial of zoledronic acid for recurrent fracture,114 or in trials of the drug in cancer patients, some of which used much more frequent administration of the drug (eg, 4 mg every 3 to 4 weeks in patients with bone metastases).115-117

In light of the increased rate of serious adverse events in the trial of zoledronic acid for fracture prevention, retrospective reviews of alendronate and risedronate clinical trials were performed. There was a nonsignificant trend toward higher rates of AF in the pivotal trial of alendronate (1.5% vs 1% for placebo; P = .07)118 and no difference versus placebo for risedronate.119 In the extension study of zoledronic acid for fracture prevention, there was no significant increase in AF after 6 years of therapy. Ultimately, in 2008, the FDA is-sued an updated safety review regarding this matter and concluded that healthcare professionals should not alter their prescribing patterns for bisphosphonates, and patients should not stop taking their bisphosphonate medications.120 In my practice, I discuss the potential for cardiac arrhythmias only with patients who have a history of heart arrhythmia being considered for treatment with intravenous zoledronic acid.

Esophageal Cancer

In January of 2009, The New England Journal of Medicine published a letter to the editor from Dr. Diane Wysowski, an employee of the FDA.121 The letter described 23 patients in the United States who were given a diag-nosis of esophageal cancer while taking alendronate between 1995 and 2008. Unfortunately, no comparative data were presented and no denominator was given with which the reader could gauge the percentage of alendronate patients represent-ed, the percentage of esophageal cancers, or how the rate compares with the rate of

esophageal cancer in the general population or in patients receiving other drug therapies. In a letter issued in July 2011,122 the FDA noted that they have not determined that taking an oral bisphosphonate increases the risk of esophageal cancer, with conflicting results from various studies. Furthermore, the incidence of esophageal cancer is very low even in patients taking bisphosphonates. The FDA also concluded that there are insufficient data to recommend endoscopic screening of asymptomatic patients.122

Renal Safety

Bisphosphonates are excreted by the kid-neys and secreted by the kidney tubules, and, therefore, have the potential to cause kidney damage at high doses. Early in the history of bisphosphonates, data suggested that intravenous pamidronate and clodronate were associated with acute renal failure or focal glomerular sclerosis. We have limited data on the use of modern bisphospho-nates in patients with impaired kidney function because most clinical trials excluded patients with poor kidney function based on serum creatinine levels. A post-hoc analysis of data from a multinational trial of zoledronic acid for fracture prevention found that infusions were associated with a transient (measured 9 to 11 days after infusion), but significant, increase in serum creatinine concentration in a small percentage of patients.123 Serum creatinine levels had returned to baseline within 12 months, and there was no evidence of long-term reductions in renal clearance in patients receiving zoledronic acid com-pared with those receiving placebo.123

Several steps can be taken to minimize the risk of renal damage during zoledronic acid infusion.124 Slowing the rate of infu-sion may reduce the risk, as a higher incidence of elevated serum creatinine has been seen in patients whose infusions were completed in less than 15 minutes.125, 126 In patients with stage 1, stage 2, or stage 3 chronic kidney disease (CKD), a 30-minute infusion duration has been recommend-ed.125 In addition, patients should be well- hydrated and should avoid taking diuretics and nonsteroidal anti-inflammatory drugs for several days before the infusion.127

Conclusion

Osteoporosis is a serious disease with a high risk of fracture and mortality in un-treated patients. Prevention and treatment can significantly reduce these risks. In ap-propriately selected patients, the benefits of bisphosphonates strongly outweigh the risks. Discuss the benefits and risks with patients and come to a shared decision based on accurate information about the benefits and risks for each patient.

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Put It Into Practice• Reassure patients who are taking bisphosphonates that they do not completely suppress bone turnover, even during long-term therapy.• The benefi ts of bisphosphonates far outweigh the risks of ONJ or atypical fractures of the femur. Longer duration of therapy (> 4 years) may be associated with an increased risk of atypical fractures, so reevaluate the benefi ts and risks of therapy after approximately 4 years of treatment.• Discuss the benefi ts and risks of bisphosphonates with patients and come to a shared decision on their use based on accurate information.• If considering off-label use of zoledronic acid in fracturing patients with established osteoporosis and impaired renal function (stage 4 to 5 CKD), slow the rate of administration of zoledronic acid from 15 minutes to 30 or 60 minutes.

Update on FRAX: The ISCD/IOF FRAX Initiative and the ISCD Position Development ConferenceEugene V. McCloskey, MD

The FRAX fracture risk assessment tool was developed to help clini-cians recognize patients at risk of fracture and to take steps to reduce that risk. The development of the FRAX algorithm involved a 2-stage process. The fi rst stage involved assessment of risk factors to determine the risk of fracture and mortal-ity. In the second stage of FRAX, risk was superimposed on the epidemiology of fracture and mortality in each country to give recommendations on treatment thresholds. Although FRAX is valuable to specialists treating osteoporosis, most cli-nicians treating this disease are primary care physicians who are not experts in the assessment of fracture risk. It is the primary care audience for whom FRAX was primarily designed.

Because of the intended worldwide scope of FRAX, risk factors selected for the model had to be widely assessed in previous studiesand amenable to easy assessment in the clinic. Furthermore, the overall utility of FRAX rests on the ability to modify risk with pharmacologic therapy. Thus, the risk factors incorporated into FRAX include

age, sex, height, weight, prior fracture, parental history of hip fracture, current smoking status, use of glucocorticoids, rheumatoid arthritis, secondary osteopo-rosis, alcohol consumption, and femoral neck BMD. These risk factors behave similarly throughout the world. However, because BMD may not be available in all areas, it is an optional part of FRAX, even though it is known to improve the sensitivity of the FRAX model without reducing specifi city. Thus, in areas where resources for measuring BMD are limited, the use of such tests should be targeted to patients who are closest to the threshold for intervention on the basis of other assessments.

FRAX has a number of limitations. For ex-ample, it does not incorporate all known risk factors, such as falls and biochemical markers, and it lacks detail on some other risk factors, such as glucocorticoid use, smoking, and prior fractures. To address some of these limitations, the Interna-tional Society for Clinical Densitometry (ISCD) and the International Osteoporosis Foundation (IOF) embarked on a joint ini-tiative to address the clinical interpretation of FRAX and produce position statements about some of the limitations and con-troversial issues surrounding the use of FRAX. For the purpose of this discussion, I will focus on the issues that affect the use of FRAX in the clinic. These issues should be considered part of the clinical judgment that is a necessary part of the decision to initiate osteoporosis therapy.

Rheumatoid Arthritis

The presence of rheumatoid arthritis (RA) is included in the FRAX model because it is known to be an independent risk factor for fracture, but it is included only as a simple dichotomous (yes/no) question. Evidence from several studies indicates that increasing severity of RA increases fracture risk, even though different stud-ies have used different scales to assess RA severity.128 Data from the UK’s General Practice Research Database (GPRD) con-fi rmed that use of oral glucocorticoids for RA increases fracture risk in a dose-dependent manner, but they also showed that disease-modifying therapies in wide-spread use before 2006 did not signifi cantly increase fracture risk.129 Furthermore, in-dividual studies of the disease-modifying therapies methotrexate, cyclosporine, and azathioprine have not found consistent evidence that they are associated with increased fracture risk.128 Studies of anti-tumor necrosis factor therapies have pro-vided evidence that these agents stabilize or increase BMD130 and decrease fracture risk.131 The ISCD/IOF panel concluded that FRAX may underestimate fracture risk in patients who have functional impairment

due to RA and that there is no consistent evidence that nonglucocorticoid medications for RA increase risk.

Glucocorticoids

As expected, data from the GPRD confi rm that there is a dose relationship between glucocorticoid use and fracture risk.132 Unfortunately, the data used to construct FRAX did not include dose or cumula-tive exposure. However, the ISCD/IOF panel estimated that the average range of glucocorticoid exposure used to construct the FRAX model was 2.5 mg to 7.5 mg per day. The panel also concluded that FRAX underestimates fracture risk if the glucocorticoid dose is higher than that av-erage range, and overestimates risk if the glucocorticoid dose is below that average range.133 Suggested magnitudes of those adjustments has been estimated using data from the GPRD (Figure 2).134

The ISCD/IOF panel also concluded that frequent, but intermittent, use of higher doses of glucocorticoids increases fracture risk, but quantifying that risk is not pos-sible.133 Furthermore, the use of high-dose inhaled glucocorticoids may increase fracture risk, and FRAX may underes-timate fracture risk in patients who use those medications. However, patients using appropriate doses of glucocorticoids for adrenal insuffi ciency have not been shown to be at increased fracture risk, and should not be considered glucocorticoid users for the purposes of FRAX.133

Alcohol Consumption and Smoking

Alcohol consumption is also a dichoto-mous variable in FRAX, with a threshold of 3 or more units (24 g) per day. However, there is evidence that consumption of greater than 2 units per day of alcohol increases the risk of fracture relative to 1 unit per day in a dose-dependent manner.135,136 Although some studies have found no association, the studies with the largest number of heavy drinkers were more likely to demonstrate an increased risk. One meta-analysis also found evi-dence that modest alcohol consumption (0.5–1.0 drink/day) lowered the risk of hip fracture compared with no consump-tion.136 At this time, however, there is insuffi cient evidence to alter the alcohol consumption threshold used in FRAX.

Current smoking increases the risk of fracture, especially hip fracture, and that effect is captured within the current FRAX model.137 According to data from the Women’s Health Initiative, past smok-ing is not a risk factor for hip fracture.138 There is evidence for a trend toward high-er risk of fracture in those with higher levels of current smoking exposure, but the relationship is weak.139 The ISCD/IOF

The development of the FRAX algorithm

that is a necessary part of the decision to initiate osteoporosis therapy.

Rheumatoid Arthritis

The presence of rheumatoid arthritis (RA) is included in the FRAX model because it is known to be an independent risk factor for fracture, but it is included only as a simple dichotomous (yes/no) question.

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panel concluded that it was not possible to quantify the risk of fracture associated with smoking dose.140

Prior Fracture

Prior fracture is captured in FRAX, but the number of prior fractures and their severity is not. In many clinical scenarios, it is not necessary to adjust FRAX to account for the number of prior fractures. Clinical judg-ment will tell you that someone who has had 5 prior vertebral fractures is at high risk, and use of FRAX is not necessary in such cases. The ISCD/IOF panel recog-nized that FRAX underestimates fracture risk in persons with multiple prior fractures and with severe prior vertebral fractures.141 Clinical judgment should also play a role in factoring in fracture risk associated with parental history of fragility fractures in locations other than the hip.

Falls

Falls are an obvious risk for fracture, and a history of falls is one of the most common factors that clinicians would like to have included in FRAX. However, the risk of fracture associated with falling is infl uenced by many factors, including the position before falling and the reaction to falling. Thus, the ISCD/IOF panel concluded that FRAX may underestimate the risk of frac-ture in patients with a history of frequent falls, but that it is not possible to quantify the increase in risk at this time.142 Again, clinical judgment should be used to adjust treatment thresholds to account for a patient’s history of falls.

Biochemical Markers

A number of biochemical markers have been studied as predictors of fracture risk, but the methods used and the results

have been inconsistent.143 Furthermore, in many studies, bone turnover markers did not predict fracture independent of BMD. Thus, the ISCD/IOF panel concluded that there is not conclusive evidence that bone turnover markers predict the risk of frac-ture independent of BMD.144

BMD at Other Sites

FRAX can incorporate BMD measurements taken from the femoral neck. However, BMD measurements taken from other sites may be discordant with the results from the femoral neck. One recent study concluded that differences in BMD between the femo-ral neck and lumbar spine can be used to adjust the 10-year fracture probability ob-tained from FRAX, shifting some patients into higher-risk or lower-risk categories.145 Although these fi ndings were determined in only one cohort, they may inform clinical judgment about risk of fracture in some patients.

Summary

FRAX is both a clinical tool and an educa-tional tool, helping to disseminate infor-mation about the assessment of fracture risk. FRAX does not incorporate all known risk factors for fracture or their severity, and it does not replace good clinical judgment. Improvements to FRAX may be possible in the future with the availability of high-quality data.

Put It Into Practice• Use good clinical judgment to adjust an individual patient’s risk category on the basis of RA severity and functional impairment, glucocorticoid use, number and severity of prior fractures, and history of falling.• Be aware that heavy alcohol consumption may also increase the risk of fracture.

Figure 2. Percentage Adjustment of 10-year Probability of Hip Fracture or Major Osteoporotic Fracture According to Glucocorticoid Dose (Prednisone Equivalent) and Age. From an Analysis of GPRD Data. Modifi ed from Kanis et al.134

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References

1. National Academy of Sciences website. Available at: www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. 2. Heaney RP, et al. J Bone Miner Res. 2011;26(3):455-7. 3. Heaney RP, et al. Am J Clin Nutr. 2003;77(1):204-10. 4. Bischoff-Ferrari HA, et al. Arch Intern Med. 2009;169(6):551-61. 5. Bischoff-Ferrari HA, et al. JAMA. 2005;293(18):2257-64. 6. Tang BM, et al. Lancet. 2007;370(9588):657-66. 7. Priemel M, et al. J Bone Miner Res. 2010;25(2):305-12. 8. Barger-Lux MJ, et al. J Clin Endocrinol Metab. 2002;87(11):4952-6. 9. Binkley N, et al. Clin Chim Acta. 2010;411(23-24):1976-82. 10. Tangpricha V, et al. Am J Clin Nutr. 2004;80(6):1645-9. 11. Binkley N, et al. J Clin Densitom. 2011;14(2):95-9. 12. Holick MF, et al. J Clin Endocrinol Metab. 2011;96(7):1911-30. 13. Amir E, et al. Cancer. 2010;116(2):284-91. 14. Vieth R, et al. Am J Clin Nutr. 2001;73(2):288-94. 15. Vieth R. Am J Clin Nutr. 1999;69(5):842-56. 16. Shapses SA, et al. JAMA. 2011;305(24):2565-6. 17. Michael YL, et al. Ann Intern Med. 2010;153(12):815-25. 18. Mangano KM, et al. J Am Diet Assoc. 2011;111(5):687-95. 19. Bolland MJ, et al. BMJ. 2008;336(7638):262-6. 20. Hsia J, et al. Circulation. 2007;115(7):846-54. 21. Bolland MJ, et al. BMJ. 2010;341:c3691. 22. Wang L, et al. Ann Intern Med. 2010;152(5):315-23. 23. Lewis JR, et al. J Bone Miner Res. 2011;26(1):35-41. 24. Martini L, et al. Am J Clin Nutr. 2002;76(6):1345-50. 25. Heller HJ, et al. J Clin Pharmacol. 1999;39(11):1151-4. 26. Heller HJ, et al. J Clin Pharmacol. 2000;40(11):1237-44. 27. Heaney RP, et al. Osteoporos Int. 1999;9(1):19-23. 28. Heaney RP, et al. J Am Coll Nutr. 2001;20(3):239-46. 29. O’Connell MB, et al. Am J Med. 2005;118(7):778-81. 30. Recker RR. N Engl J Med. 1985;313(2):70-3. 31. Tondapu P, et al. Obes Surg. 2009;19(9):1256-61. 32. Brener ZZ, et al. South Med J. 2011;104(2):133-9. 33. Jackson RD, et al. N Engl J Med. 2006;354(7):669-83. 34. Curhan GC, et al. Arch Intern Med. 2004;164(8):885-91. 35. Curhan GC, et al. N Engl J Med. 1993;328(12):833-8. 36. Borghi L, et al. N Engl J Med. 2002;346(2):77-84. 37. Heaney RP. J Am Coll Nutr. 2008;27(5):519-27. 38. Lewis CE, et al. J Bone Miner Res. 2007;22(2):211-9. 39. Cawthon PM, et al. J Bone Miner Res. 2009;24(10):1728-35. 40. Cawthon P, et al. ASBMR 2010. Presentation SU0314. 41. De Laet C, et al. Osteoporos Int. 2005;16(11):1330-8. 42. Nielson CM, et al. J Bone Miner Res. 2011;26(3):496-502. 43. Villareal DT, et al. N Engl J Med. 2011;364(13):1218-29. 44. Boyle WJ, et al. Nature. 2003;423(6937):337-42. 45. Vega D, et al. J Clin Endocrinol Metab. 2007;92(12):4514-21. 46. Lewiecki EM. Expert Opin Biol Ther. 2006;6(10):1041-50. 47. Lewiecki EM, et al. J Bone Miner Res. 2007;22(12):1832-41. 48. McClung MR, et al. N Engl J Med. 2006;354(8):821-31. 49. Miller PD, et al. J Clin Endocrinol Metab. 2011;96(2):394-402. 50. Bilezikian JP. Am J Med. 2009;122(suppl 2):S14-21. 51. Miller PD, et al. Bone. 2008;43(2):222-9. 52. Cummings SR, et al. N Engl J Med. 2009;361(8):756-65. 53. Chapurlat R, et al. Arthritis Rheum. 2010;62 (suppl):S903. Abstract 2157. 54 Reid IR, et al. J Bone Miner Res. 2010;25(10):2256-65. 55. Brown JP, et al. J Bone Miner Res. 2011;26(11):2737-44. 56. Stoch SA, et al. Clin Pharmacol Ther. 2008;83(1):172-6. 57. Pennypacker B, et al. Bone. 2009;44(2):199-207. 58. McClung M, et al. Bone. 2009;44(suppl 2): S438. 59. Costa AG, et al. Nat Rev Rheumatol. 2011;7(8):447-56. 60. Eastell R, et al. J Bone Miner Res. 2011;26(6):1303-12. 61. Dobnig H, et al. Endocrinology. 1997;138(11):4607-12. 62. Bilezikian J. J Clin Rheumatol Musculoskelet Med. 2011;in press. 63. Chen P, et al. J Bone Miner Res. 2006;21(11):1785-90. 64. Gallagher JC, et al. J Clin Endocrinol Metab. 2005;90(3):1583-7. 65. Greenspan SL, et al. Ann Intern Med. 2007;146(5):326-39. 66. McClung MR, et al. Arch Intern Med. 2005;165(15):1762-8. 67. Fitzpatrick LA, et al. J Clin Endocrinol Metab. 2011;96(8):2441-9. 68. Rankin W, et al. Cancer. 1997;80(8 suppl):1564-71. 69. Horwitz MJ, et al. J Clin Endocrinol Metab. 2010;95(3):1279-87. 70. O’Dea L. ICE2010. Presentation 71365. 71. Cosman F, et al. J Clin Endocrinol Metab. 2010;95(1):151-8. 72. Cusano NE, et al. Curr Med Res Opin. 2011;27(9):1705-7. 73. Kubota T, et al. J Bone Miner Metab. 2009;27(3):265-71. 74. Hoeppner LH, et al. Expert Opin Ther Targets. 2009;13(4):485-96. 75. Li X, et al. J Bone Miner Res. 2009;24(4):578-88. 76. Richards JB, et al. Arch Intern Med. 2007;167(2):188-94. 77. Yadav VK, et al. Cell. 2008;135(5):825-37. 78. Ducy P. Curr Opin Pharmacol. 2011;11(1):34-8. 79. Yadav VK, et al. Nat Med. 2010;16(3):308-12. 80. Cui Y, et al. Nat Med. 2011;17(6):684-91. 81. Potts, JT. Available at: joe.endocrinology-journals.org/content/187/3/311.full. 82. Gley E. Comptes Rendus de la Société de Biologie. 1891;3:366-8. 83. Collip JB. J Biol Chem. 1925;63:395-438. 84. Albright F, et al. “Uncharted Seas.” Portland (OR): Kalmia Press; 1990. 85. Bilezikian JP, et al. J Clin Endocrinol Metab. 2009;94(2): 333-81. 86. Bauer W, et al. J Exp Med. 1929;49(1):145-62. 87. Neer RM, et al. N Engl J Med. 2001;344(19):1434-41. 88. Horwitz MJ, et al. J Clin Endocrinol Metab. 2003;88(4):1603-9. 89. Okazaki M, et al. Proc Natl Acad Sci USA. 2008;105: 16525-30 90. Ferrandon S, et al. Nat Chem Biol. 2009;5(10):734-42. 91. Cosman F, et al. J Clin Endocrinol Metab. 2010;95(1):151-8. 92. Rodan G, et al. Curr Med Res Opin. 2004;20(8):1291-300. 93. Green JR. Semin Oncol. 2002;29(6 suppl 21):3-11. 94. Nancollas GH, et al. Bone. 2006;38(5):617-27. 95. Black DM, et al. JAMA. 2006;296(24):2927-38. 96. Ste-Marie LG, et al. Calcif Tissue Int. 2004;75(6):469-76. 97. Weinstein RS, et al. N Engl J Med. 2009;360(1):53-62. 98. Black DM, et al. Lancet. 1996;348(9041):1535-41. 99. Ettinger B, et al. JAMA. 1999;282(7):637-45. 100. Harris ST, et al. JAMA. 1999;282(14):1344-52. 101. Reginster J, et al. Osteoporos Int. 2000;11(1):83-91. 102. McClung MR, et al. N Engl J Med. 2001;344(5):333-40. 103. Miller PD, et al. J Bone Miner Res. 2005;20(8):1315-22. 104. Black DM, et al. N Engl J Med. 2007;356(18):1809-22. 105. Silverman SL, et al. J Bone Miner Res. 2008;23(1):159-65. 106. Woo SB, et al. Ann Intern Med. 2006;144(10):753-61. 107. Khosla S, et al. J Oral Maxillofac Surg. 2008;66(6):1320-2. 108. U.S. FDA website. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM270958.pdf. 109. Sawatari Y, et al. Oral Maxillofac Surg Clin North Am. 2007;19(4):487-498, v-vi. 110. JADA website. Available at: http://jada.ada.org/content/137/8/1144.abstract. 111. Shane E, et al. J Bone Miner Res. 2010;25(11):2267-94. 112. Schilcher J, et al. N Engl J Med. 2011;364(18):1728-37. 113. Nieves JW, et al. Curr Osteoporos Rep. 2010;8(1):34-9. 114. Lyles KW, et al. N Engl J Med. 2007;357(18):1799-1809. 115. Carteni G, et al. Oncologist. 2006;11(7):841-8. 116. Rosen LS, et al. Cancer. 2004;100(12):2613-21. 117. Rosen LS, et al. J Clin Oncol. 2003;21(16):3150-7. 118. Cummings SR, et al. N Engl J Med. 2007;356(18):1895-6. 119. Karam R, et al. N Engl J Med. 2007;357(7):712-3. 120. U.S. FDA website. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136201.htm. 121. Wysowski DK. N Engl J Med. 2009;360(1):89-90. 122. U.S. FDA website. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm263320.htm. 123. Boonen S, et al. Kidney Int. 2008;74(5):641-8. 124. Miller PD. Bone. 2011;49(1):77-81. 125. Miller PD. Cleve Clin J Med. 2009;76(12):715-23. 126. Berenson J, et al. Oncologist. 2004;9(3):319-29. 127. Miller PD. Semin Nephrol. 2009;29(2):144-55. 128. Broy SB, et al. J Clin Densitom. 2011;14(3):184-9. 129. van Staa TP, et al. Arthritis Rheum. 2006;54(10):3104-12. 130. Barnabe C, et al. Semin Arthritis Rheum. 2009;39(2):116-22. 131. Coulson KA, et al. J Clin Rheumatol. 2009;15(4):155-60 132. van Staa TP, et al. Rheumatology (Oxford). 2000;39(12):1383-9. 133. Leib ES, et al. J Clin Densitom. 2011;14(3):212-9. 134. Kanis JA, et al. Osteoporos Int. 2011;22(3):809-16. 135. Kanis JA, et al. Osteoporos Int. 2005;16(7):737-42. 136. Berg KM, et al. Am J Med. 2008;121(5):406-18. 137. Kanis JA, et al. Osteoporos Int. 2005;16(2):155-62. 138. Robbins J, et al. JAMA. 2007;298(20):2389-98. 139. Høidrup S, et al. Int J Epidemiol. 2000;29(2):253-9. 140. Dimai HP, et al. J Clin Densitom. 2011;14(3):190-3. 141. Blank RD, et al J Clin Densitom. 2011;14(3):205-21. 142. Masud T, et al. J Clin Densitom. 2011;14(3):194-204. 143. Vasikaran S, et al. Osteoporos Int. 2011;22(2):391-420. 144. McCloskey EV, et al. J Clin Densitom. 2011;14(3):220-2. 145. Leslie WD, et al. Osteoporos Int. 2011;22(3):839-47.

E. Michael Lewiecki, MD John P. Bilezikian, MD Eugene V. McCloskey, MD Paul D. Miller, MD

Sarah L. Morgan, MD Eric S. Orwoll, MD John T. Potts Jr, MD

Highlights of the 2011 Santa Fe Bone Symposium

PresortedFirst Class

U.S. POSTAGEPAID

Elmwood Park, NJ Permit #99

Health Focus, Inc.PO Box 2090Mountain View, CA 94042-2090

Earn up to

16 hours

CME credit@

Eugene V. McCloskey, MD Paul D. Miller, MD E. Michael Lewiecki, MD John P. Bilezikian, MD

John T. Potts Jr, MD Sarah L. Morgan, MD Eric S. Orwoll, MD

Fresh Perspectives in Osteoporosis and Metabolic Bone Disease:

SAVE THE DATE! 2012 Santa Fe

Bone Symposium: August 10–11

www.2011santafebonesymposium.com