Management of Osteoporosis After Initial Treatment

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 treatment indications for drug therapy in osteoporosis.
2. Optimize intake of calcium and vitamin D in patients with osteoporosis.
3. Use alendronate in patients with osteoporosis.
4. Compare effects of zoledronic acid in oncologic settings with regimens in osteoporosis.
5. Contrast use of denosumab with bisphosphonates.

Summary

Introduction: ≈1 in 2 women and ≤1 in 4 men >50 yr of age experience fragility fractures; osteoporosis is associated with 2 million fractures annually; the impact is pronounced in older patients, with hip fractures carrying substantial morbidity and a mortality rate of ≤20% within 1 yr; men face a higher mortality risk compared with women; after a hip fracture, ≈80% of individuals experience substantial permanent disability, including difficulties in walking and the inability to perform at ≥1 activities of daily living

Definition: the World Health Organization defines osteoporosis as a progressive systemic skeletal disease marked by microarchitectural deterioration, leading to increased bone fragility and susceptibility to fractures; it is typically asymptomatic until a fracture occurs; diagnosis can be established through a bone density test with a T-score of <-2.5 or if an individual has experienced a fragility fracture; fracture risk is influenced by declining bone density and advancing age

Risk assessment: various factors are considered, including peak bone density accrual, influenced by factors (eg, childhood illnesses, estrogen exposure, menopausal age, family history), negative exposures (eg, medications, smoking, excess alcohol), current stability vs frailty (eg, falling, vision problems, weight loss), and comorbid conditions (eg, endocrine disorders, malabsorptive conditions, inflammatory conditions, kidney disease, liver disease, type 2 diabetes mellitus, obesity); combining these factors provides a comprehensive assessment of fracture risk, with specific attention to prior fractures, age, and bone density score

Prior fractures: especially those occurring in the last 2 yr, are significant prognostic factors for assessing fracture risk, with incident spine and hip fractures carrying higher hazard ratios; other fragility fractures also contribute to risk, albeit to a lesser extent than hip and spine fractures; the cumulative number of fractures correlates with a substantial increase in the relative risk for subsequent fractures; age is a recognized risk factor for fractures as bone density naturally declines, and various factors like comorbidities, frailty, and falls accumulate over time; hospitalization rates for fractures increase with age, with childhood fractures exhibiting a longer duration for boys compared with girls; in adulthood, fracture rates remain relatively stable until a noticeable surge in the late 60s or early 70s

The fracture risk assessment (FRAX) tool: includes the option to input a trabecular bone score (TBS) value, aimed at addressing the challenge of lower bone density in the spine compared with the hip in postmenopausal women because of estrogen deficiency; estrogen deficiency causes more bone loss at trabecular sites than cortical sites; FRAX traditionally relies on the femoral neck T-score, as the spine T-score may be affected by issues, eg, osteoarthritis; by incorporating TBS, FRAX can recalculate fracture risk; however, the adoption of this feature depends on a software update for existing bone density machines; the clinician considers a patient's overall fracture risk by assessing prior fractures, age, bone density, and FRAX scores; where patients may not disclose prior fractures, the possibility of incident vertebral fractures is explored through indicators, eg, chronic back pain or significant height loss, prompting additional diagnostic measures, eg, spine imaging, vertebral morphometric assay along with bone density testing

Treatment indications: for drug therapy in osteoporosis includes a diagnosis based on T-score or prior fractures; patients with osteopenia may also qualify if their FRAX scores surpass the specified thresholds (>20% for any fracture, and >3% for hip fracture) because of factors, eg, comorbid illness or parental hip fracture; lifestyle measures, calcium, and vitamin D are discussed with patients; maintaining healthy, stable body weight, quitting smoking, engaging in weight-bearing activities (eg, walking or resistance training), and assessing fall risks while implementing fall prevention strategies are emphasized; physical therapy and resources, eg, better bones and balance videos or Tai Chi are recommended

Calcium and vitamin D: dietary calcium is more effective than supplements; the serum calcium level alone does not indicate adequate intake; the 24-hr urine calcium test is utilized to assess absorption, especially in cases of malabsorption, eg, post-bariatric surgery patients; for supplementation, limit the total daily intake to 1200 to 1500 mg from food and pills; calcium carbonate should be taken with food because it needs acid for absorption; calcium citrate does not require acid and is recommended for patients taking proton pump inhibitors (PPIs) or after bariatric surgery; 25-hydroxy vitamin D levels should be maintained at >30 ng/mL, as levels below this threshold can lead to secondary hyperparathyroidism, posing risks to bone health

Discussions with patients: about normal bone homeostasis and osteoporosis, the explanation often simplifies the concept by highlighting that healthy bone undergoes constant breakdown and rebuilding; postmenopause or in conditions, eg, male hypogonadism, this cycle accelerates, resulting in a net bone loss; antiresorptive medications, eg, bisphosphonates, denosumab, slow down this turnover by inhibiting osteoclasts, allowing the body more time to rebuild bone; while these medications do not actively build bone, they allow the body to do so; anabolic agents, eg, parathyroid hormone agonists, romosozumab stimulate bone formation

Current therapies for osteoporosis: include antiresorptives, eg, estrogen and selective estrogen receptor modulator (SERM), oral and intravenous (IV) bisphosphonates (alendronate and zoledronic acid), and the receptor activator of nuclear factor kappa beta (RANK) ligand inhibitors (eg, denosumab); anabolic agents eg, teriparatide, mixed antiresorptive-anabolic agent romosozumab are also available; evaluating their efficacy, the focus is on relative risk reduction for vertebral and hip fractures; alendronate shows a 45% to 48% relative risk reduction for vertebral fractures, slightly higher for parenteral therapies; hip fractures exhibit ≈40% reduction for alendronate, zoledronic acid, and denosumab; teriparatide lacks sufficient data for hip fractures in landmark trials, but subsequent head-to-head trials suggest comparable or superior results against antiresorptive agents; notably, alendronate may be slightly more efficacious than risedronate, while ibandronate's weaker antiresorptive effects limit its use

Endocrine Society guidelines 2009: provide a comprehensive roadmap for managing osteoporosis, categorizing individuals into low, moderate, high, and very high risk; low-risk individuals, with normal bone density and low FRAX scores, may not require further consideration; moderate-risk individuals have osteopenia, no fractures, and low FRAX scores; high-risk individuals exhibit prior fractures or osteoporosis T-scores; very high-risk individuals have multiple spine fractures or very low T-scores

Initial therapy: in the majority of patients, bisphosphonates (oral or intravenous) are recommended, considering patient preference and contraindications, eg, severe esophageal disease, bariatric surgery, or an inability to sit upright; these medications are generally safe with a glomerular filtration rate (GFR) down to 30 to 35 mL/min; denosumab, anabolic therapy, or estrogen may also be considered based on individual patient characteristics

Clinical trials: 2 extension trials, the FLEX study for alendronate (Dennis et al [2006]) and an extension trial for zoledronic acid (Bauer et al [2014]), explored the concept of drug holidays in osteoporosis treatment; in the alendronate trial, women initially treated with alendronate were re-randomized to receive another 5 yr of alendronate or 5 yr of placebo; those on placebo experienced a slight increase in clinical spine fractures but no change in morphometric spine fractures or nonvertebral fractures; a post hoc analysis revealed that those with lower baseline femoral neck T-scores had a higher risk for nonspine fractures during the placebo period; the zoledronic acid trial, with a 3-yr course followed by another 3 yr of drug or placebo, showed fewer asymptomatic vertebral fractures but no difference in clinical spine fractures or nonvertebral fractures; both trials formed the basis for understanding bisphosphonate holidays, demonstrating continued fracture protection during the holiday, with some increase in some spine fractures, particularly for those with lower baseline bone density; the rationale for drug holidays is to mitigate the risk for atypical femoral fractures and osteonecrosis of the jaw (ONJ)

Atypical femoral fractures: present as low or no trauma fractures in the femoral shaft, first observed in 2007, coinciding with a decline in bisphosphonate use; these fractures typically manifest as a progressive ache in the upper thigh or groin over weeks to months, distinct from sudden occurrences; radiologic features aid in diagnosis; genetics, particularly femur shape, and ethnicity, with a higher risk in East Asians than Whites, are linked to the pathogenesis; the American Society of Bone and Mineral Research criteria include low or minimal trauma, prodromal symptoms for weeks to months, and use of certain pharmaceutical agents, eg, bisphosphonates, glucocorticoids, and PPIs; image the contralateral thigh, as changes may indicate an increased risk of developing a fracture; continued bisphosphonate use poses a clear risk for atypical femoral fractures, with cases per 100,000 person-years increasing with consecutive use; caution is advised in interpreting literature because of reliance on ICD codes without radiographic evidence, but 2 large registry-based studies using strict criteria support the association between bisphosphonate use and atypical femoral fractures; the data indicate that the risk for atypical femoral fractures increases with 3 to 5 yr of bisphosphonate use, but it remains considerably lower than the risk for typical fragility fractures; considering the substantial relative risk reduction (40%-70%) achieved by these drugs in preventing fragility fractures, the overall benefit outweighs the potential risk; a study estimates that for 1000 women with osteoporosis, 3 yr of bisphosphonate use prevents 100 fractures, including 11 hip fractures, with only 0.1 cases of atypical femoral fracture; limited data suggest that a 3-yr drug holiday can reduce the risk for atypical femoral fractures by 80%

Osteonecrosis of the jaw: a concerning condition characterized by a nonhealing wound with exposed bone in the oral mucosa lasting >8 wk; typically associated with invasive procedures, eg, tooth extraction, dental implantations; it can occasionally occur spontaneously; the absolute risk in osteoporosis ranges from 1 in 10,000 to 1 in 100,000, but is higher in oncology settings in which zoledronic acid is administered every 3 mo compared with the once-a-year regimen in osteoporosis; tooth extraction poses the highest trigger for ONJ

Society guidelines for management of osteonecrosis of the jaw: various medical societies provide guidelines with varying recommendations, but a common practice is to temporarily hold bisphosphonates for 2 mo before an invasive dental procedure; this precaution, while reassuring for patients and orthodontists, does not affect the presence of bisphosphonates in the bones, which persist for years after administration; getting routine dental care, tooth extractions, or implants before initiating bisphosphonate therapy is advisable

Patients at continued high risk on bisphosphonate therapy: counseling includes awareness of potential signs of an atypical femoral fracture, eg, a dull ache in the upper thigh or groin, prompting notification for further evaluation; in cases where an atypical femoral fracture is confirmed, imaging the contralateral leg is recommended

Treatment recommendations: for patients at low to moderate risk, without osteoporosis or fractures, treatment should not be initiated, with bone density reassessment scheduled for the future; the focus is mainly on patients at high or very high risk, often with osteoporosis with or without fractures, and usually initiation of bisphosphonate therapy recommended; after the initial course, consideration is given to a drug holiday after 3 to 5 yr if the patient transitions to low or moderate risk; continued therapy or a switch to an alternative treatment is considered if the patient remains in the high-risk category

Defining drug failures in osteoporosis: can be based on fractures or bone density results; while technically one fracture may not be considered a failure per guidelines, clinically relevant fractures, eg, symptomatic vertebral or hip fractures, might prompt a reevaluation of treatment; monitoring bone density during therapy may have benefits, eg, improving compliance, detecting secondary causes of osteoporosis; a significant decrease in bone density, beyond the machine's least significant change, could be viewed as a failure, although stability or a slight increase may be acceptable if the patient is not experiencing fractures; bone turnover markers, specifically serum carboxy-terminal collagen crosslinks, can be considered for assessing treatment efficacy, with a drop expected after treatment initiation; interpretation requires comparing values before and after treatment initiation; an isolated value during therapy is not helpful because of individual variability

Denosumab: an antiresorptive monoclonal antibody to RANK ligand; differs from bisphosphonates in its mechanism; the FREEDOM trial (Cummings et al [2009]) demonstrated fracture risk reduction; its extension trial showed continuous improvement in bone density through 10 yr without plateaus; denosumab provides benefits only while taken, so drug holidays are not recommended; adverse effects include increased infection risks; denosumab is approved by the Food and Drug Administration for stage 4 chronic kidney disease (CKD), but its use requires careful consideration because of potential complications in renal osteodystrophy and adynamic bone disease; there is no substantial evidence to assess changes in fracture rates for this population; the speaker uses denosumab only in patients with CKD if renal osteodystrophy has been optimized, the risk for adynamic bone disease is low, and the patient has experienced a fragility fracture; the speaker does not use denosumab for primary prevention in this population; denosumab is beneficial only while it is taken; after discontinuation, vertebral fractures and bone turnover markers rise within months; bone density returns to baseline within 2 yr; no proven exit strategy exists; bridging with bisphosphonates may not offer the same benefits as continuous denosumab use

Anabolic therapies: less commonly used because of their expense and approval challenges; they show good fracture reduction data for spine and nonspine fractures, with less robust data for hip fractures; typically administered as a daily subcutaneous injection over a 2-yr course; patients require follow-up with an antiresorptive to maintain benefits; anabolic therapies are considered for severely low bone density or multiple vertebral fractures, potentially as first-line therapy or transitioning from bisphosphonates; Handel et al (2023) compared various drugs, favoring denosumab over bisphosphonates for vertebral fractures; all drugs show benefits over placebo; analyzing data for "all clinical fractures" can be challenging because of diverse fracture types; advancing age correlates with improved relative risk reduction, particularly for bisphosphonates; anabolic agents, administered in clinical settings, may enhance compliance compared with oral bisphosphonates

Optimal order for therapies: the most effective approach involves starting with an anabolic therapy to actively build bones, followed by transitioning to an antiresorptive, eg, bisphosphonate, denosumab to maintain and further enhance bone density; while transitioning from bisphosphonates to anabolic agents is possible, the benefit may be slightly reduced compared with starting de novo; switching from a bisphosphonate to denosumab is effective when indicated; patients on denosumab should continue on denosumab; switching from denosumab to anabolic agents is strongly discouraged because of decreased benefits from the anabolic agent and a significantly increased risk for vertebral fractures; if patients on long-term denosumab wish to discontinue, bridging with bisphosphonates is preferable to abruptly stopping; for very high-risk patients treated initially with teriparatide, there are options for switching to a bisphosphonate or denosumab; estrogen, hormone replacement therapy, or raloxifene can also be considered as a first-line choice, especially for patients <10 yr after menopause with vasomotor symptoms, primarily targeting lower vertebral fracture reduction; nonvertebral site data for these treatments are less robust

Cost of osteoporosis medications: alendronate and zoledronic acid are inexpensive; denosumab is more expensive but still reasonable; anabolic therapy, costing ≈$25,000 per yr, is considered very expensive

Readings

Bertoldo F, Cianferotti L, Di Monaco M, et al. Definition, assessment, and management of vitamin D inadequacy: suggestions, recommendations, and warnings from the Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS). Nutrients. 2022;14(19):4148. Published 2022 Oct 6. doi:10.3390/nu14194148; Carey JJ, Chih-Hsing Wu P, Bergin D. Risk assessment tools for osteoporosis and fractures in 2022. Best Pract Res Clin Rheumatol. 2022;36(3):101775. doi:10.1016/j.berh.2022.101775; Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–65; Deeks ED. Denosumab: A review in postmenopausal osteoporosis [published correction appears in Drugs Aging. 2018 Mar 9;:]. Drugs Aging. 2018;35(2):163-173. doi:10.1007/s40266-018-0525-7; Händel MN, Cardoso I, von Bülow C, et al. Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. BMJ. 2023;381:e068033. doi:10.1136/bmj-2021-068033; Johnston CB, Dagar M. Osteoporosis in older adults. Med Clin North Am. 2020;104(5):873-884. doi:10.1016/j.mcna.2020.06.004; Kawahara M, Kuroshima S, Sawase T. Clinical considerations for medication-related osteonecrosis of the jaw: a comprehensive literature review. Int J Implant Dent. 2021;7(1):47. Published 2021 May 14. doi:10.1186/s40729-021-00323-0; Langdahl BL. Overview of treatment approaches to osteoporosis. Br J Pharmacol. 2021;178(9):1891-1906. doi:10.1111/bph.15024; Uihlein AV, Leder BZ. Anabolic therapies for osteoporosis. Endocrinol Metab Clin North Am. 2012;41(3):507-525. doi:10.1016/j.ecl.2012.05.002.

Disclosures

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

Acknowledgements

Dr. Wolf was recorded at Riding the Waves of Primary Care 2023, held Nov 6-10, 2023, on Kohala Coast, HI, and presented by the Providence Regional Medical Center Everett and Amedco LLC. For information about upcoming CME activities from this presenter, please visit Cmetracker.net/prov. Audio Digest thanks Dr. Wolf and the presenters for their cooperation in the production of this program.

CME/CE INFO

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Lecture ID:

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