Seminal Events For Bone Health And An Overview Of Guidelines

Educational Objectives

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

1. Evaluate treatments for osteoporosis and osteopenia according findings in recent literature.

2. Weigh the advantages and disadvantages of romosozumab for treatment of postmenopausal osteoporosis.

3. Elaborate on recent clinical guidelines for treatment of postmenopausal osteoporosis and Paget disease.

4. Identify the potential value of biomarkers for bone turnover and bone mineral density as surrogates for fracture risk.

5. Assess risk for fracture in patients with osteopenia to identify appropriate candidates for therapy.

Summary

Seminal event: event that strongly influences subsequent events

Romosozumab

Approval: likely most important event in past year; romosozumab anti-sclerostin antibody approved for treatment of postmenopausal osteoporosis in patients at high risk for fracture; indications similar to parathyroid hormone (PTH) receptor analogues and denosumab; black box warning — romosozumab potentially associated with increase in risk for serious cardiovascular events (eg, cardiovascular death, stroke, myocardial infarction)

Benefits: risk for important osteoporotic fractures reduced compared with placebo (FRAME study; Cosman et al 2016) and alendronate (ARCH study; Saag et al 2017); treatment benefit achieved with 1 yr of romosozumab persists for ≥2 yr after transition to antiresorptive agent (Lewiecki et al 2019b)

Safety: general safety profile unremarkable except for higher incidence of mild reactions at injection site compared with placebo or alendronate; serious cardiac events — chief issue; at 12 mo in ARCH study, incidence in romosozumab arm 2.5% compared with alendronate arm 1.9%; difference attenuated over remainder of study; over entire ARCH study, incidence in romosozumab arm 6.5% compared with alendronate arm 6.1%; data from trials submitted to Duke Cardiovascular Research Center for adjudication; hazard ratio for major adverse cardiac events (cardiovascular death, nonfatal stroke, and nonfatal MI) 1.87 for romosozumab compared with alendronate over first 12 mo; difference statistically significant; in FRAME study, cardiovascular signal lacking; disparity in cardiovascular signal between studies discussed extensively at US Food and Drug Administration (FDA) Advisory Committee meeting; efficacy of romosozumab not disputed; clear explanation for disparity lacking

Approval (continued): romosozumab approved in Japan in early 2019; in United States in April 2019; not approved in Europe (decision under appeal; approval anticipated in several countries); approved only for treatment of women with postmenopausal osteoporosis; BRIDGE study (Lewiecki et al 2018) found efficacy in men with osteoporosis high (study not yet submitted to FDA)

Sequential use: romosozumab given for only 1 yr at a time in sequence of treatments; ARCH study — found increases in bone mineral density (BMD) after 1 yr of treatment with romosozumab maintained after transition to alendronate; fracture benefit also maintained; FRAME study — found that romosozumab followed by denosumab resulted in progressive increase in BMD and maintenance of benefit in protection against fractures; anabolic agents — information about sequential use in either direction lacking; STRUCTURE study (Langdahl et al 2017) — participants who took bisphosphonates for ≥3 yr and alendronate for 1 yr before study transitioned to teriparatide or romosozumab; found romosozumab associated with progressive increase in areal and volumetric BMD; unpublished data — suggest that discontinuation of romosozumab after 1 yr of therapy resulted in loss of gains in BMD and return to baseline 1 yr after discontinuation; BMD regained after retreatment with romosozumab for 1 yr; BMD gains maintained in spine and hip for 2 yr after transition from romosozumab to single dose of zoledronic acid; in another arm of study, patients given romosozumab for 2 yr, transitioned to denosumab for third year, and retreated with romosozumab; very little change in BMD with retreatment found (rapid decrease in BMD typically expected with discontinuation of romosozumab or denosumab); in patients who received romosozumab for 2 yr and did not receive zoledronic acid on its discontinuation, all benefit lost over 2 yr

Clinical implications: phase II or III clinical trials of other drugs for osteoporosis lacking; appropriate treatment of patients with osteoporosis sequential use of different drugs (as opposed to maintenance with single drug for long time); data suggest that patients at very high risk for fracture should begin therapy with anabolic drug, followed by antiremodeling drug

Burosumab: approved for treatment of X-linked hypophosphatemia (vitamin D-resistant rickets) in children and adults

Endocrine Society’s first set of guidelines for postmenopausal osteoporosis (Eastell et al 2019): development guided by 4 principles of management; (1) in postmenopausal women, risk for fracture should be determined using country-specific assessment tools to guide decision making; (2) preferences of patient should be incorporated into plan for treatment; (3) nutritional and lifestyle interventions and prevention of falls should accompany all pharmacologic regimens to reduce risk for fracture; (4) in at-risk postmenopausal women with acceptable risk-benefit and safety profiles, multiple pharmacologic therapies are capable of reducing rates of fracture

Assessment: guidelines provide no new insight into management; major differences between guidelines of Endocrine Society and those of National Osteoporosis Foundation, American Association of Clinical Endocrinologists, and North American Menopause Society lacking; guidelines include specific comments about PTH receptor analogues, but algorithm includes PTH receptor analogues in same line as bisphosphonates and denosumab, and guidance for selection of candidates for each initial therapy lacking; lack of inclusion of romosozumab important limitation (drug approved shortly before publication); guidelines include special reference to selective estrogen receptor modulators, calcitonin, and tibolone (not available in United States)

Guidelines on Paget disease (Ralston et al 2019): bisphosphonates recommended for treatment of bone pain associated with Paget disease; zoledronic acid bisphosphonate of choice; evidence sufficient to make recommendation about treatment of Paget disease to prevent fractures lacking; evidence for statement about effect of treatment of Paget disease with bisphosphonates on progression or development of osteoarthritis insufficient; editorial by Langdahl (2019) argued that guidelines closer to review than clinically relevant guidelines

Review of corticosteroid-induced osteoporosis (Buckley et al 2018): concluded that screening for risk for fracture indicated when corticosteroids started; pharmacologic treatment recommended in patients at high risk; bisphosphonates recommended as first-line treatment; speaker states that recommendations ignore data suggesting that teriparatide more effective in improving BMD and reducing vertebral fractures than alendronate, and ignore availability of denosumab (found more effective than risedronate for improving BMD in patients taking or beginning to take corticosteroids); review published by Adami et al (2019)

2 reports from Foundation for the National Institutes of Health: evaluated relationship between treatment-induced changes in biochemical markers of bone turnover or BMD and risk for fracture; data on bone markers published by Bauer et al (2018) suggested that treatment-related changes in bone-specific alkaline phosphatase and procollagen type 1 N-terminal propeptide (P1NP) levels strongly predicted efficacy of treatment of vertebral fractures, but not of nonvertebral or hip fractures; resorption markers not effective in predicting rates of fracture; Bouxsein et al (2019) found that larger improvements in BMD as assessed by dual-energy x-ray absorptiometry (DXA) associated with greater reductions in risk for fracture; expressed hope for acceptance of improvements in BMD as surrogate end point for fractures in trials of new treatments; 2 recent studies of individual patient data found that changes in BMD of hip with treatment related to incidence of nonvertebral fractures over following year; data suggest that in patient receiving treatment with denosumab, alendronate, or romosozumab, BMD of hip good predictor of risk for fracture over following year; BMD of hip while receiving treatment potential surrogate outcome in clinical trials of new agents; adoption of BMD of hip as target of treatment gaining momentum

Effect of zoledronate on reduction of risk for fracture in women with osteopenia (Reid et al 2018): 6-yr double-blind trial included 2000 women aged ≥65 yr with osteopenia defined by DXA BMD at either total hip or femoral neck on either side; ≈20% of participants had osteoporosis by BMD criteria at another site, but one site met criteria for osteopenia; participants randomized to zoledronate 5 mg or saline every 18 mo; at entry into study, rate of prevalent nonvertebral fracture 24%; of prevalent vertebral fracture 13%; study found zoledronate associated with statistically significant reduction in rate of clinical fractures and nonvertebral fractures for all end points except fracture of hip; rate of fracture of hip reduced, but did not achieve statistical significance; post hoc analysis excluding patients who met criteria for osteoporosis by BMD or vertebral fracture found same results; reduction in mortality rate 35% and reduction in overall rate of cardiovascular events 24% (not statistically significant); reduction in incidence of cancer 33% (statistically significant); cases of osteonecrosis of jaw or atypical femoral fracture lacking; study found that therapy with zoledronate effective in reduction of risk for fracture in patients at moderate risk who did not meet usual criteria for osteoporosis; treatment not indicated for every patient with osteopenia; study provides justification for treatment of patients at moderate risk; annual administration of zoledronate not required for effectiveness

Treated osteoporosis (Lewiecki et al 2019a): once T-score above-2.5, obtaining reimbursement for subsequent treatment often difficult; reimbursement should be available for long-term treatment of osteoporosis after normalization of end points and markers for disease activity (similar to long-term treatment of diabetes mellitus and hypertension); drugs can improve BMD, but osteoporosis cannot be cured by any available drug

Audience Questions

Evidence of cardiovascular protection by bisphosphonates: studies with strongest evidence involved zoledronate; placebo-controlled trials found cardioprotective signal with oral bisphosphonates lacking; epidemiologic and observational studies from Australia and Europe suggest protection against death mostly driven by cardiovascular disease with oral bisphosphonate therapy; clear evidence that alendronate cardioprotective lacking; if alendronate cardioprotective, negative inflection point in cumulative incidence of cardiac events in romosozumab-to-alendronate arm of ARCH study would be expected; such negative inflection point not found; disparity in data involved unusual nonlinear curve for alendronate

Need for national survey to assess use of guidelines by medical professionals: majority of individuals in multiple organizations involved in creation of guidelines support idea of harmonized guidelines; executives and boards of organizations not supportive (each group prefers having own guidelines)

Evidence to suggest whether PTH receptor analogue or romosozumab more appropriate in patients with severe osteoporosis for whom secondary causes ruled out: lacking; 2 studies involved head-to-head comparison; phase II trial of romosozumab (McClung et al 2014) included only 1 yr of teriparatide; BMD responses greater in patients who received romosozumab compared with teriparatide; similar results found in STRUCTURE trial (Langdahl et al 2017); patients taking bisphosphonates transitioned to romosozumab or teriparatide; neither study evaluated fracture end points; both drugs dramatically effective in reducing rate of vertebral fractures; data from studies of abaloparatide and teriparatide also suggest dramatic reduction of risk for nonvertebral fractures; in overall FRAME study, romosozumab not found to result in statistically significant reduction in rate of nonvertebral fractures compared with placebo; romosozumab found to reduce risk for hip fracture by ≈38% compared with alendronate; romosozumab and PTH analogues appear very effective in treatment of entire spectrum of fractures; which agent more appropriate can be only inferred from changes in BMD in 2 cited studies

Role of Fracture Risk Assessment Tool (FRAX) in treatment of osteopenia: FRAX can divide patients with osteopenia into low and high risk; Reid et al (2018) provided evidence supporting treatment of patients with osteopenia and high FRAX scores

Execution of guidelines by primary care physicians and concept of severe osteoporosis as different disease with different method of treatment: studies provide evidence supporting beginning therapy with bone-building drug; effective transmission of information to primary care physicians necessary

Adjustment of dosing of medication in patients with osteoporosis and improving BMD: defining treatment target appropriate; in patients who achieve target, final consolidating step administration of dose of zoledronate (may maintain target BMD for long time)

Readings

Adami G et al: Glucocorticoid-induced osteoporosis: 2019 concise clinical review. Osteoporos Int 2019 Jun;30(6):1145-56; Bauer DC et al: Treatment-related changes in bone turnover and fracture risk reduction in clinical trials of anti-resorptive drugs: a meta-regression. J Bone Miner Res 2018 Apr;33(4):634-42; Bouxsein ML et al: Change in bone density and reduction in fracture risk: a meta-regression of published trials. J Bone Miner Res 2019 Apr;34(4):632-42; Buckley L et al: Glucocorticoid-induced osteoporosis. N Engl J Med 2018 Dec 27;379(26):2547-56; Cosman F et al: Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016 Oct 20;375(16):1532-43; Eastell R et al: Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society* clinical practice guideline. J Clin Endocrinol Metab 2019 May 1;104(5):1595-622; Langdahl BL: A clinical guideline on Paget’s disease of bone-a guideline or a review? J Bone Miner Res 2019 Apr;34(4):577-8; Langdahl BL et al: Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet 2017 Sep 30;390(10102):1585-94; Lewiecki EM et al: Treated osteoporosis is still osteoporosis. J Bone Miner Res 2019a Apr;34(4):605-6; Lewiecki EM et al: One year of romosozumab followed by two years of denosumab maintains fracture risk reductions: results of the FRAME extension study. J Bone Miner Res 2019b Mar;34(3):419-28; Lewiecki EM et al: A phase III randomized placebo-controlled trial to evaluate efficacy and safety of romosozumab in men with osteoporosis. J Clin Endocrinol Metab 2018 Sep 1;103(9):3183-93; McClung MR et al: Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014 Jan 30;370(5):412-20; Ralston SH et al: Diagnosis and management of Paget’s disease of bone in adults: a clinical guideline. J Bone Miner Res 2019 Apr;34(4):579-604; Reid IR et al: Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med 2018 Dec 20;379(25):2407-16; Saag KG et al: Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 2017 Oct 12;377(15):1417-27; United States Food and Drug Administration: Biologics license application 761062: romosozumab injection. https://www.fda.gov/media/121259/download. Accessed October 14, 2019.

Disclosures

For this program, the following has been disclosed: Dr. McClung is a consultant for Amgen and is on the Speakers’ Bureaus for Amgen and Radius Health. The planning committee reported nothing to disclose.

Acknowledgements

Dr. McClung was recorded at the 20th Annual Santa Fe Bone Symposium, held August 9-10, 2019, in Santa Fe, NM, and presented by the Osteoporosis Foundation of New Mexico. For information about upcoming CME opportunities from the Osteoporosis Foundation of New Mexico, please visit ofnm.org. The Audio Digest Foundation thanks Dr. McClung and the Osteoporosis Foundation of New Mexico for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

OR422401

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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