Osteoporosis Update

Educational Objectives

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

1. List guidelines of the International Society for Clinical Densitometry regarding assessment of bone density in women.
2. Optimize administration of alendronate in patients when indicated.
3. Use indicated medications in patients with osteoporosis who are at very high risk for fracture.
4. Optimize management of osteoporosis in patients with primary hyperparathyroidism.

Summary

Assessment of osteoporosis: bone strength depends on bone density (BD) and the quality of its structure; clinically, dual-energy X-ray absorptiometry (DEXA) is used to measure BD; though other methods exist, DEXA forms the basis for clinical definitions and diagnostic criteria; the results of DEXA are reported as T- and Z-scores, which represent the number of standard deviations from the mean; T-scores compare with a healthy premenopausal White female population, while Z-scores consider an age-, sex-, and ethnicity-matched population; diagnosis using DEXA relies on the lowest T-score from the spine, total hip, femoral neck, or occasionally the distal radius

Indications for assessment: the International Society for Clinical Densitometry (2023) provides testing guidelines that align with most standards; women ≥65 yr of age and younger postmenopausal women with risk factors are primary candidates for assessment; the Endocrine Society also recommends fracture risk (FR) assessments, including BD tests, for all postmenopausal women; while men can also experience osteoporosis, the US Preventive Services Task Force does not recommend screening for men; the T-score can be misleading; if the DEXA report appears contrary to the clinical presentation, consult with the interpreting specialist and verify the input data of the patient (eg, age, sex, weight, height)

Assessment of FR: the FR Assessment Tool (FRAX) estimates FR using patient demographics and clinical risk factors, with or without T-scores; treatment is advised for individuals with a history of hip or vertebral fractures (VF), T-scores in the osteoporotic range at the femoral neck or spine, or a significant 10-yr FR (eg, at the hip ≥3%, any major osteoporotic fracture ≥20%) based on FRAX criteria; while FRAX is helpful, clinical judgment and patient preferences guide treatment decisions

Follow-up BD assessment: is driven by the likelihood of influencing management decisions; routine 2-yr intervals, often covered by insurance, are not always necessary; these follow-ups are useful for monitoring treatment response; a lack of density increase with antiresorptive therapy does not indicate treatment failure; significant decreases or ≥2 fractures despite therapy suggest failure; monitoring frequency depends on initial T-scores, with patients at higher risk requiring more frequent evaluations; consistency in DEXA equipment is crucial for reliable comparisons in serial BD tests; ideally, patients should return to the same facility for follow-ups

Other tests for osteoporosis: Trabecular Bone Score (TBS) — assesses bone quality by analyzing pixel intensity patterns in lumbar spine DEXA images; TBS is an independent risk factor for fractures and is especially useful in older patients, where osteoarthritis compromises lumbar spine BD reliability; although TBS does not independently guide clinical decisions, it can enhance FRAX calculations for borderline cases; imaging of the spine — is valuable in identifying VFs, which significantly increase future FR independent of BD; VF can sometimes be asymptomatic; imaging (eg, plain films, VF assessment through DEXA) is important for high-risk patients; VF assessment offers convenience and lower radiation doses compared with traditional imaging; biomarkers — bone remodeling involves continuous communication between osteoblasts and osteoclasts; blood or urine biomarkers help measure bone formation and resorption, reflecting the remodeling process; these markers decrease with antiresorptive therapies and increase with anabolic treatments; elevated markers can predict rapid bone loss and higher FR but are not diagnostic for osteoporosis; their use in treatment monitoring is limited to specialized centers because of potential inaccuracies; laboratory tests are important for identifying secondary causes of bone loss, especially in cases with Z-scores less than -2

Management of osteoporosis: various treatment options exist, including bisphosphonates, denosumab, and anabolic agents; ibandronate, raloxifene, and calcitonin do not reduce hip or nonvertebral fracture (NVF) risk; hormone therapies (eg, estrogen), though beneficial for bone health, are no longer considered primary treatments for osteoporosis

Nutrition: the recommended daily calcium intake (eg, dietary sources, supplements) is ≈500 mg for postmenopausal women; clinical trials on osteoporosis drugs incorporate adequate calcium and vitamin D as baseline requirements; optimal vitamin D levels are ≥20 ng/mL, though not all patients require supplementation; it is advisable to check vitamin D levels for patients with osteoporosis prior to treatment initiation; adequate protein intake is also critical, particularly for elderly individuals at risk for falls

Bisphosphonates: are widely used for osteoporosis treatment, with options including oral agents (alendronate and risedronate) and intravenous (IV) agents (zoledronic acid); these drugs attach to bone remodeling surfaces, causing osteoclast apoptosis and reducing bone resorption; bisphosphonates also become incorporated into the bone matrix, providing prolonged efficacy; clinical trials demonstrate a 50% FR reduction with bisphosphonates; IV bisphosphonates are often preferred as first-line treatment because of higher adherence compared with oral alternatives; adverse effects (eg, flu-like symptoms, hypocalcemia, musculoskeletal pain) are generally transient; renal toxicity limits their use in patients with significant renal impairment; long-term bisphosphonate use raises concerns about over-suppression of bone remodeling, potentially leading to rare complications (eg, osteonecrosis of the jaw, atypical femoral fractures); drug holidays are considered for patients with stable BD, a femoral neck T-score greater than -2.5, and no history of hip or spine fracture after 3 yr of IV or 5 yr of oral bisphosphonate therapy; it is relatively safe to discontinue treatment, as the effect of FR reduction gradually decreases; reassessments of BD are advised at intervals of 2 to 4 yr to guide further management

Denosumab (Prolia): a monoclonal antibody targeting the RANK ligand, which functions similarly to osteoprotegerin to decrease the rate of bone resorption; it is administered as a subcutaneous injection every 6 mo; it is safe for patients with renal or hepatic impairment; it significantly reduces the rate of bone remodeling, which can lead to hypocalcemia in individuals with a history of or risk factors for hypocalcemia, including vitamin D deficiency; the US Food and Drug Administration (FDA) approved denosumab in 2010 following the FREEDOM trial by Cummings et al (2009), which demonstrated a significant reduction in FR, eg, a dramatic decrease in VF, ≈50% reduction in hip fractures, and a meaningful reduction in NVF; the rebound phenomenon — if denosumab is discontinued or a dose is missed, an increase in bone turnover and a decrease in BD is found, raising the risk of VF, particularly in the first year after stopping treatment; this phenomenon does not appear to increase the risk for other fractures but is a concern for patients who miss doses; so, adherence to the dosing schedule is essential; it is reasonable to continue treatment indefinitely for those at persistently high FR

Discontinuation: indicated for various reasons, eg, reduced FR after prolonged use, adverse effects, or administrative issues; when stopping denosumab, transitioning to a bisphosphonate, either a single dose of zoledronic acid or a 1-yr course of oral bisphosphonates, can mitigate the increased risk for VF; if denosumab proves ineffective or if FR remains high, transitioning to a stronger drug (eg, romosozumab) is advised, but teriparatide should not be used

Anabolic therapy: is indicated for patients at very high FR because of their rapid action in enhancing bone formation and they reduce FR; the American Association of Clinical Endocrinologists provides specific criteria to classify individuals as very high risk, including recent fractures, fractures during therapy, multiple fractures, glucocorticoid use, severe BD loss (T-score less than -3), high fall risk, or a very elevated FRAX score; after an osteoporosis-related fracture, the risk for another fracture within 1 yr increases 5 fold in postmenopausal women, emphasizing the importance of prompt treatment

Teriparatide (Forteo): is the first anabolic agent approved by the FDA in 2002; it comprises the first 34 amino acids of parathyroid hormone (PTH); while continuous stimulation of PTH receptors on osteoblasts is catabolic, intermittent low-dose PTH has an anabolic effect; teriparatide is given by daily subcutaneous injection and has a short half-life; daily injection is a drawback, especially for older patients who may resist self-administration; oral forms of PTH are currently under study, potentially offering a more patient-friendly alternative; teriparatide enhances bone architecture, cortical thickness, and trabecular connectivity

Abaloparatide (Tymlos): this PTH-related protein analog functions as a daily subcutaneous injection and has effects similar to teriparatide; it offers a longer duration of the osteoanabolic window, a period of maximal bone-building activity, compared with teriparatide (6-12 mo); the anabolic effects of both medications decline after a few years; the ACTIVE trial conducted by Miller et al (2016) compared abaloparatide with teriparatide and found ≈80% decrease in VF and a 30% to 45% decrease in NVF in the first 18 mo; abaloparatide was found to be more effective than teriparatide

Adverse effects of anabolic therapy: there is potential for increased urine or serum calcium; therefore, anabolic therapy is contraindicated in primary hyperparathyroidism and should be avoided in patients with kidney stones; risk for osteosarcoma is noted in high-dose rat studies with both anabolic drugs; while long-term human data have alleviated osteosarcoma concerns for teriparatide, abaloparatide is limited to 2 yr of use because of less extensive safety data; both drugs are contraindicated in individuals with risk factors for osteosarcoma (eg, Paget disease, radiation exposure, family history, metastatic bone cancer)

Romosozumab (Evenity): is a monoclonal antibody that targets sclerostin, a protein that inhibits bone formation; sclerostin suppresses osteoblast differentiation and function while promoting osteoclast function; by inhibiting sclerostin, romosozumab increases bone formation and decreases resorption; it was approved by the FDA in 2019 and is administered monthly for 1 yr (short anabolic window), followed by an antiresorptive drug; the FRAME trial by Cosman et al (2016) revealed that romosozumab demonstrated significant BD gains (13% at the spine and ≈7% at the total hip) and VF risk reduction, but no significant reductions in nonvertebral fractures; the ARCH trial by Saag et al (2017) demonstrated significant reductions in both VF and NVF; concerns about cardiovascular events, particularly in the ARCH trial, led to a black box warning contraindicating its use in patients with a recent history (≤1 yr) of myocardial infarction or stroke

Sequential and combination therapies: current guidelines recommend initiating therapy with an anabolic agent followed by an antiresorptive drug for individuals at high FR; practical challenges (eg, cost, patient preferences, access) often influence treatment decisions; many high-risk patients have already been treated with bisphosphonates, and transitioning to an anabolic agent from these drugs presents unique challenges; the STRUCTURE study by Cosman et al (2022) demonstrated that women who had been treated with alendronate for 3 yr experienced increased BD across all sites when switched to romosozumab; in contrast, switching to teriparatide resulted in increased spine BD but decreased hip BD, which is particularly concerning for patients recovering from hip fractures; this issue is even more pronounced when transitioning from denosumab to teriparatide, where the decrease in hip BD is more significant and prolonged; adding an anabolic agent to ongoing antiresorptive therapy, rather than switching, is beneficial; studies indicate that adding teriparatide to ongoing alendronate increases BD more effectively than switching therapies; the DATA-Switch trial by Leder et al (2015) revealed that patients combining denosumab and teriparatide achieved substantial BD increases that were maintained after continuing denosumab alone

Readings

Adejuyigbe B, Kallini J, Chiou D, et al. Osteoporosis: Molecular pathology, diagnostics, and therapeutics. Int J Mol Sci. 2023;24(19):14583. doi:10.3390/ijms241914583; Ahmad A, Crawford CH 3rd, Glassman SD, et al. Correlation between bone density measurements on CT or MRI versus DEXA scan: A systematic review. N Am Spine Soc J. 2023;14:100204. doi:10.1016/j.xnsj.2023.100204; Clynes MA, Harvey NC, Curtis EM, et al. The epidemiology of osteoporosis. Br Med Bull. 2020;133(1):105-117. doi:10.1093/bmb/ldaa005; Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16):1532-1543. doi:10.1056/NEJMoa1607948; Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis [published correction appears in N Engl J Med. 2009;361(19):1914]. N Engl J Med. 2009;361(8):756-765. doi:10.1056/NEJMoa0809493; Dimai HP. Use of dual-energy X-ray absorptiometry (DXA) for diagnosis and fracture risk assessment; WHO-criteria, T- and Z-score, and reference databases. Bone. 2017;104:39-43. doi:10.1016/j.bone.2016.12.016; Farrah Z, Jawad AS. Optimising the management of osteoporosis. Clin Med (Lond). 2020;20(5):e196-e201. doi:10.7861/clinmed.2020-0131; Iolascon G, de Sire A, Curci C, et al. Osteoporosis guidelines from a rehabilitation perspective: Systematic analysis and quality appraisal using AGREE II. Eur J Phys Rehabil Med. 2021;57(2):273-279. doi:10.23736/S1973-9087.21.06581-3; Krueger D, Tanner SB, Szalat A, et al. DXA Reporting updates: 2023 official positions of the International Society for Clinical Densitometry. J Clin Densitom. 2024;27(1):101437. doi:10.1016/j.jocd.2023.101437; Leder BZ, Tsai JN, Uihlein AV, et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): Extension of a randomised controlled trial. Lancet. 2015;386(9999):1147-1155. doi:10.1016/S0140-6736(15)61120-5; Lončar Brzak B, Horvat Aleksijević L, Vindiš E, et al. Osteonecrosis of the Jaw. Dent J (Basel). 2023;11(1):23. doi:10.3390/dj11010023; Miller PD, Hattersley G, Riis BJ, et al. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: A randomized clinical trial [published correction appears in JAMA. 2017;317(4):442. doi: 10.1001/jama.2016.20139]. JAMA. 2016;316(7):722-733. doi:10.1001/jama.2016.11136; Morin SN, Feldman S, Funnell L, et al. Clinical practice guideline for management of osteoporosis and fracture prevention in Canada: 2023 update. CMAJ. 2023;195(39):E1333-E1348. doi:10.1503/cmaj.221647; Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417-1427. doi:10.1056/NEJMoa1708322; Yong EL, Logan S. Menopausal osteoporosis: Screening, prevention and treatment. Singapore Med J. 2021;62(4):159-166. doi:10.11622/smedj.2021036; Zou Y, Liu Z, Li H, et al. Evaluation of bone metabolism-associated biomarkers in Tibet, China. J Clin Lab Anal. 2021;35(12):e24068. doi:10.1002/jcla.24068.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Cook was recorded at the 36th Annual Recent Developments in Internal Medicine, held October 17-19, 2024, in Atlantic Beach, NC, and presented by Eastern Area Health Education Center. For information about upcoming CME activities from this presenter, please visit https://www.easternahec.net. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

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