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What’s New in Osteoporosis and Fragility Fractures

2022; Wolters Kluwer; Volume: 104; Issue: 17 Linguagem: Inglês

10.2106/jbjs.22.00530

1535-1386

Derek Hansen, Teerapat Tutaworn, Joseph M. Lane,

Bone Metabolism and Diseases

In this article, we establish a baseline status of clinical and basic research in the area of osteoporosis and fragility fractures, focused primarily on research published within the past 12 to 24 months. This topic will be an addition to the JBJS annual list of Guest Editorial topics. Bone Density Osteoporosis is characterized by decreased bone strength. Both bone mass and bone quality contribute to bone strength. Decreased strength leads to fragility fractures. The World Health Organization defines these fractures as caused by an injury that would be insufficient to fracture a normal bone. These fractures are the result of the reduced compressive and/or torsional strength of bone1. The fractures occur as a result of a minimal trauma, such as a fall from a standing height or less, or no identifiable trauma2. Pathological fractures from lesions are not included in this definition. The 2 main components of bone strength are bone mass and bone quality. Bone density measures bone mass and only accounts for 30% to 50% of the fracture risk. The FRAX (Fracture Risk Assessment Tool) incorporates bone density but includes age, low-energy fracture history, smoking, corticosteroid use, sex, autoimmune disease, height, and weight, among other critical elements. Universally, dual x-ray absorptiometry (DXA) is utilized to determine bone density. It measures the areal bone density adjusted for height and width but not depth in the lumbar spine, hip, and wrist. A number of situations compromise the measurements, including scoliosis, prior fracture, and degenerative arthritis. To compensate for these circumstances, volumetric measurements of a set volume of cancellous bone can be determined in the midst of the vertebral body using quantitative computed tomography (CT). The Hounsfield units in that volume are determined and converted to mg/cm3 of mineral. There is no universal agreement on the categories of osteoporosis, osteopenia, and normal bone density. Pinto et al.3 performed a systemic review of Hounsfield units measured by lumbar CT compared with bone density determined by DXA. They identified 18 articles comparing the 2 methods in 5,307 patients, most of whom had spine issues and were considered for spine surgery. There was variability across the articles, in part due to the study population, the site of analysis, the CT image machine, and the calibration. Hence, the ranges for each category are broad at this time. The International Society for Clinical Densitometry is well aware of this issue, and the clinical application should take this concept into consideration. Pinto et al. provided ranges, but solid cutoff values could not be established. The recommended volumetric bone mineral density (BMD) cutoff value for osteoporosis determined by CT is <80 mg/cm3. However, this is at the low end of the range found by Pinto et al. and may miss some patients who have osteoporosis according to other measurements. BMD as determined by DXA is a critical element in the diagnosis of osteoporosis and electing the appropriate care pathway. Once performed, the patient is begun on a pharmacologic treatment. Leslie et al.4 utilized a registry-based cohort from the Province of Manitoba to examine the association of bone density monitoring in routine clinical practice with anti-osteoporotic medication use and incident fractures in a matched cohort study. Whether the patient needs monitoring during the initial 5 years of treatment is still controversial. BMD testing with DXA has been managed as an integrated program since 1997 in the province4. The BMD Database has completeness and accuracy in excess of 99%. The authors identified 4,559 women who were ≥40 years of age and were receiving anti-osteoporotic therapy with serial bone densities for a mean interval of 3.2 years and 4,559 propensity score-matched women who did not have BMD monitoring. The monitored women had significantly better survival free from a major osteoporotic fracture (p = 0.04); the 10-year cumulative risk was 1.9% lower. The hip fracture rate in the monitored women was also better (p = 0.001); the 10-year cumulative risk was 1.8% lower. The medication persistence ratio, days of medication use, and treatment switching were greater in the monitored women. Treatment switching occurred in those individuals who lost bone mass while receiving treatment. The women who underwent bone density monitoring appeared to have superior clinical results. This article from a large, controlled database study demonstrated the added advantage, beyond diagnosis, of serial bone densities in individuals receiving anti-osteoporotic treatment. Periodic evaluation reinforces the need for continued treatment for both the patient and the physician. Calcium and Vitamin D The concept of normalizing calcium and vitamin D is key to the treatment of osteoporosis. Controversy still remains as to whether vitamin D alone or in combination with calcium lowers fracture risk and enhances fracture healing. Yao et al.5 utilized a systemic review and meta-analysis of databases until December 2018. They included observational studies of ≥200 patients and randomized controlled trials (RCTs) involving at least 500 patients. RCTs tested vitamin D alone or vitamin D combined with calcium. The main outcomes were any fracture and hip fracture. In the 11 observational studies of 39,141 participants, there were 6,278 fractures and 2,367 hip fractures. Each increase of 10 ng/mL in 25(OH)D was associated with a relative risk for hip fracture of 0.80 (95% confidence interval [CI], 0.75 to 0.86) and a relative risk for any fracture of 0.93 (95% CI, 0.89 to 0.96). In the 11 RCTs of 34,243 participants, 2,843 fractures, and 740 hip fractures, vitamin D supplementation alone either intermittently or daily (400 to 30,000 IU), compared with no supplementation, did not reduce the risk of all fractures or hip fractures. Conversely, in an additional analysis of 6 RCTs with 49,282 participants, 5,449 fractures, and 730 hip fractures, supplementation with both vitamin D (400 to 800 IU) and calcium (1,000 to 1,200 mg/day) resulted in an increase of 9.2 ng/mL in 25(OH)D concentration, a 6% reduced risk of any fracture, and a 16% reduced risk of a hip fracture. This study concluded that vitamin D treatment alone is not beneficial but, when combined with calcium, it significantly lowers the risk of fragility fractures, most notably those of the hip. Enhancement of fracture healing was not addressed in this study. Controversy still remains as to the role of vitamin D and fracture healing. There are some data to support elevating vitamin D in patients with profound deficiency (<15 ng/mL), but, for patients with normal values, there is little evidence to support enhanced fracture-healing with further supplementation and attainment of vitamin D levels higher than the normal range. Heyer et al.6 addressed the use of vitamin D bolus therapy for distal radial fractures. Three groups of conservatively treated distal radial fractures were randomized into treatments with no vitamin D, a low bolus of D3 equivalent to 700 IU per day, and a high bolus of D3 equivalent to 1,800 IU per day. The fractures were examined by high-resolution peripheral quantitative CT for cortical and trabecular bone density and micro-finite element analysis-derived torsion. The control and low-dose vitamin D groups were similar in all comparisons. The high-dose vitamin D bolus group resulted in a decreased trabecular number (p < 0.01) and lower compression stiffness (p < 0.05). Low-dose vitamin D did not enhance fracture healing and the high-dose vitamin D was significantly detrimental. The association between calcium and vitamin D utilization and arthroplasty survival is poorly understood. Kong et al.7 performed a nationwide population-based cohort study of patients who underwent a total knee arthroplasty between 2009 and 2018, utilizing the Korean National Health Insurance Database. Of 142,000 patients, 28,403 took calcium and vitamin D and were compared with 113,744 patients who had never taken calcium and vitamin D. Implant survival was significantly improved in the patients who took calcium and vitamin D for >11 years compared with the patients who did not (log-rank p < 0.001). In addition, for both patients who did not have periprosthetic joint infections and those who did, implant survival was superior for the patients who took calcium and vitamin D. Thus, a combination of calcium and vitamin D (<800 IU) significantly enhanced total knee arthroplasty survival in a large cohort database. Medical Management Currently, there are multiple medications that prevent bone loss and/or increase bone mass and effectively reduce fracture risk8-20. Bisphosphonates The oldest category of medications for the treatment of osteoporosis is the bisphosphonates, which are diphosphate analogs that incorporate into the mineralized component of bone and inhibit osteoclast activity. They have had overemphasis in the lay press in the past with respect to side effects, namely, atypical femoral fractures and osteonecrosis of the jaw. A recent analysis performed from the data of 196,129 women demonstrated both the effectiveness of fracture prevention and the rarity of atypical fractures. In their analysis, the treatment of 10,000 Caucasian women with zoledronic acid for 3 years prevented 149 hip fractures and 541 clinical fractures and resulted in only 2 atypical femoral fractures21. The authors also demonstrated, as others have, that the duration of treatment is a risk factor for developing atypical fractures, and shorter stature, higher weight, and Asian ethnicity also increase the risk. A recent analysis of osteonecrosis of the jaw incidence comparing the 2 antiresorptive treatments from a Swedish patient registry demonstrated markedly higher rates in patients taking denosumab than had been previously reported and similar rates in patients receiving bisphosphonates, with an incidence of osteonecrosis of the jaw per 10,000 patient-years of 28.3 for patients taking denosumab and 4.5 for patients taking bisphosphonates22. For bisphosphonates, a rate of 2.53 per 10,000 patient-years has been reported previously23. Disparate from the Swedish registry data, the extension of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial found the incidence of osteonecrosis of the jaw in patients taking denosumab to be 5.2 per 10,000 patient-years24. Controversy has existed as to whether or not bisphosphonates inhibit fracture healing and the timing of treatment in patients with osteoporosis. Some have gone as far as to stop these medications in scenarios in which bone healing is required. The American Society for Bone and Mineral Research (ASBMR) Task Force has released a consensus statement that there is no evidence to support impaired fracture healing in patients taking bisphosphonate medications25. Furthermore, a recent RCT evaluated this notion in a distal radial fracture model. Patients who were ≥50 years of age and had a distal radial fracture treated with immobilization or a surgical procedure were randomized to receive 70 mg of alendronate weekly within 14 days of fracture (n = 215) or placebo (n = 206). The authors found no differences in radiographic union rates and functional outcomes and concluded that bisphosphonate therapy can be commenced early after fracture if clinically indicated26. Romosozumab Romosozumab is a monoclonal antibody that binds to sclerostin, an inhibitor of the wnt signaling pathway involved in bone formation. With the inhibition removed, bone formation predominates. Further evidence regarding sclerostin as a potential target comes from a genetic condition of sclerostin deficiency characterized by high bone mass and low fracture incidence. There is also an anti-osteoclastogenic benefit as evidenced by decreases in bone turnover markers. Romosozumab was approved by the U.S. Food and Drug Administration (FDA) in 2019 for the treatment of women with postmenopausal osteoporosis. It has not yet been approved for osteoporosis treatment in men. In the ARCH (Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk) trial, 4,093 postmenopausal women with osteoporosis were randomized to receive either 210 mg of romosozumab subcutaneously monthly or 70 mg of alendronate orally weekly over 12 months followed by open-label alendronate in both groups. There was a 48% reduction in vertebral fractures, a 38% reduction in hip fractures, and a 19% reduction in nonvertebral fractures favoring the romosozumab group27. In the FRAME (Fracture Study in Postmenopausal Women with Osteoporosis) study, 7,180 postmenopausal women with osteoporosis were randomized to 210 mg of romosozumab subcutaneously monthly for 12 months compared with placebo, and then all patients received 60 mg of denosumab subcutaneously every 6 months. At 12 months, there was a 73% lower risk of vertebral fracture in the treatment group, and this continued at 24 months, with the romosozumab group having a 75% lower risk after both groups had transitioned to denosumab28. During clinical trials, there was growing concern about possible major cardiovascular events, including myocardial infarction, stroke, and cardiovascular-related deaths. The FRAME study, a placebo-controlled trial for the first year followed by open-label denosumab, did not show any difference in adjudicated cases of serious cardiovascular events or cardiovascular-related deaths28. However, in the ARCH study, there were significant differences in adjudicated serious cardiovascular events between the romosozumab group (2.5%) and the alendronate group (1.9%). This difference stabilized after the first 12 months when all patients were taking alendronate, with the suggestion by some that alendronate may have a cardioprotective benefit27. Others have analyzed the data in the 2 main clinical trials and surmised that the difference in cardiovascular risk may be related to chance and also cited poor evidence of a cardioprotective effect with alendronate29. At present, there is a black box warning for romosozumab following its 2019 approval by the FDA warning that it may increase the risk of myocardial infarction, stroke, and cardiovascular death. Patients with histories of such events should not take the drug, and further research continues to explore if patients with multiple comorbidities predisposing patients to cardiovascular events, such as hypertension, hypercholesterolemia, and diabetes, may also be at increased risk. Genant et al. examined postmenopausal women with low bone mass and compared treatment with romosozumab and teriparatide. At 12 months, utilizing a quantitative CT scan, the romosozumab group demonstrated significantly improved hip and lumbar volumetric BMD and bone mineral content compared with both the teriparatide group and a placebo group30. Further analysis of this trial was performed to investigate if these increases also correlated with improved strength and fracture resistance using finite element analysis. Keaveny et al. found a 27.3% vertebral strength improvement in the romosozumab group that was significantly greater than the 18.5% improvement in the teriparatide group (p = 0.005), and significantly greater hip strength improvement in the romosozumab group at 3.6% compared with −0.7% in the teriparatide group (p = 0.027)31. In a large-scale RCT evaluating fracture healing in patients treated surgically for tibial shaft fractures, 299 of 402 patients were randomized to the romosozumab treatment group. There was no difference between the treatment group and the placebo group in terms of radiographic union (the primary outcome) and clinical healing (the secondary outcome)32. In this study, romosozumab dosing was different from that for patients with osteoporosis; patients were treated on day 1 and weeks 2, 6, and 12 with various doses totaling 70 to 210 mg. Another recent study randomized 243 patients (55 to 94 years of age) with a hip fracture to receive romosozumab and 89 patients to the placebo group33. Over the course of 20 weeks, there was no significant difference between groups with regard to the primary end point, the Timed Up and Go Test score, and the secondary end point of radiographic union. Similar to the study by Bhandari et al.32, osteoporosis dosing was not used. Despite its anabolic effect, there are no data in humans to suggest that romosozumab can augment or aid in fracture union and it should not be used with that goal in mind. However, it is a great option for patients with severe bone deficiency and has been shown to work well in patients with prior bisphosphonate therapies that have not responded well to the parathyroid hormone (PTH) analogs. Before considering treatment with romosozumab, patients should be screened for a history of stroke and cardiac events. Teriparatide Teriparatide, a PTH analog, was approved in 2002 by the FDA. In the article that presented the animal data concerning for osteogenic sarcoma development, the dosing and duration of treatment compared with the life span of the rats were extremely disproportionate to the human treatment experience, and the authors concluded that such events were not likely to occur in humans34. Following this animal study, the FDA and the pharmaceutical company that produced teriparatide performed surveillance to investigate if there was any potential harm to humans. The results from the 13 years of data collected by the Osteosarcoma Surveillance Study showed that the incidence of osteogenic sarcoma in patients treated with teriparatide was no different from the background incidence rate35. The FDA had a black box warning due to the theoretical risk of developing osteogenic sarcoma34, but, since 2021, the FDA no longer has a black box warning on the drug Forteo (teriparatide). The potential anabolic benefits of teriparatide have been used to enhance outcomes of spinal fusion, with reported success. Particularly in women with osteoporosis who undergo lumbar fusion, the use of teriparatide has been used to enhance fusion rates, with some reports utilizing 2 months of pretreatment and at least a 10-month course of the total treatment. Ohtori et al. have published extensively on the use of teriparatide for posterior lumbar fusion and have shown increased fusion rates compared with patients with osteoporosis receiving risedronate36-39. In 1 retrospective analysis of women with osteoporosis, 2 months of pretreatment followed by 8 months of postoperative treatment led to higher fusion rates of 82% in the teriparatide group compared with 68% in the risedronate group and a mean fusion time that was 2 months earlier (p < 0.05)36. In a randomized, placebo-controlled trial of women ≥50 years of age with low bone density undergoing single-level interbody lumbar fusion, the use of teriparatide administered once weekly over 6 months significantly improved fusion rates as assessed by CT scan40. Of note, this is a lower dose than that utilized for osteoporosis treatment. These studies have advocated for the routine screening of patients requiring lumbar spine fusion for a history of fragility fracture and bone density testing with referral for pretreatment of teriparatide in those with T scores of <−2 or a history of fragility fracture41. The literature consists of both retrospective reviews and several randomized studies to evaluate the benefits of teriparatide on fracture healing. Various outcome measures of radiographic union, pain scores, and functional tests have been used to assess success. A systematic review of patients with osteoporosis showed a significantly shorter healing time in the teriparatide-treated group42. A more rigorous meta-analysis of adults with surgically treated acute fractures randomized to teriparatide or placebo included 5 studies with a total of 380 patients and concluded that teriparatide lacked effectiveness for fracture healing. The meta-analysis also showed that teriparatide lacked effectiveness in reducing pain and time to radiographic union, but it did show that it yielded significant functional improvement43. A closer look at the RCTs is warranted. In 102 postmenopausal women treated with reduction and casting for a distal radial fracture, the teriparatide group had a significantly faster time to radiographic union of 7.4 weeks compared with 9.1 weeks in the placebo group. However, an additional group that received twice the typical dose, 40 μg of teriparatide daily, had no benefit when compared with the placebo group44. Among elderly patients treated surgically for pertrochanteric hip fractures, 224 patients were randomized to teriparatide or risedronate, 171 patients were ultimately analyzed, and patients who took teriparatide had significantly better Timed Up and Go Test scores at 6, 12, 18, and 26 weeks and visual analog scale (VAS) for pain score during the Timed Up and Go Test at 18 weeks45. Taken together, there is evidence for possible enhancement of functional recovery, and of radiographic union, that may be greater in the patient population with osteoporosis. We therefore consider all patients with acute fractures treated both operatively and nonoperatively who are indicated for osteoporosis treatment as potential candidates for treatment with teriparatide. Its usefulness as an adjuvant treatment for acute fracture healing is less clear and unsubstantiated. We have used it to do just that in limited patient-specific scenarios. Unfortunately, cost can be a limiting factor. Following atypical femoral fractures in patients undergoing pharmacologic treatment with denosumab or a bisphosphonate, it is recommended to stop treatment. If treatment is still warranted based on fracture risk and BMD, beginning a PTH analog medication should be considered. Although teriparatide and abaloparatide serve as treatments for the underlying osteoporosis, they may also be beneficial for increasing the odds of successful union of an atypical femoral fracture. The literature on union rates can be confusing, but it appears that a surgical procedure has a greater success rate in atypical fractures that are nondisplaced compared with those that are displaced. The union rates of surgically treated atypical fractures are dismal at 54%46. Although there is no good evidence-based literature to suggest that teriparatide can heal atypical fractures or is useful as an adjunct following surgical fixation of atypical femoral fractures, there are encouraging data from case reports47 and teriparatide serves as the best option for continued osteoporosis treatment in patients requiring continued therapy. Abaloparatide is a human recombinant parathyroid hormone-related peptide (PTHrP). It is approved for the treatment of postmenopausal osteoporosis in those at high risk of fracture. At this time, there are no fracture-healing or spinal fusion data in humans. However, in the realm of osteoporosis, abaloparatide is equal to or better than teriparatide in bone mass augmentation48. Denosumab Denosumab (Prolia) is a monoclonal antibody that binds to the receptor activator of nuclear factor kappa-B ligand (RANKL), thereby inhibiting osteoclast function and osteoclastogenesis. It was approved by the FDA in 2010 and has been used to treat men and women with osteoporosis. Recently, there has been concern about what are termed "rebound fractures." If a dose is missed or a patient discontinues the medication without starting another treatment, reported cases of contiguous vertebral compression fractures have been reported. Upon a review of the current literature, the rates of rebound fractures in the absence of bisphosphonate treatment at the end of denosumab treatment are between 1% and 10% and involve a median of 5 vertebral fractures at a median time of 11 months following the last denosumab injection49. The working theory is that immature preosteoclasts have increased in number and presence within the bone and, when denosumab is stopped or missed, the RANKL that is no longer quenched from the system stimulates the increased number of preosteoclastic cells to differentiate and resorb bone. When patients are unable to receive a dose of denosumab or are planned to discontinue treatment, starting a bisphosphonate medication is recommended to prevent the rebound phenomenon. At present, the exact timing, duration, and treatment option are unclear. Most recommend the use of a potent oral bisphosphonate or intravenous zoledronic acid for 1 year starting at 6 months from the last denosumab dose50. Improved spinal fixation has been demonstrated in women with osteoporosis who receive treatment with denosumab and require posterior spinal fusion. A prospective study utilized quantitative CT at baseline and 12 and 24 months in postmenopausal women with osteoporosis receiving denosumab and utilized finite element models of L4 to analyze bone strength and pedicle screw pullout. Their results showed improved BMD and pullout strength at 12 and 24 months compared with baseline51. Evidence-Based Orthopaedics The editorial staff of JBJS reviewed a large number of recently published studies related to the musculoskeletal system that received a higher Level of Evidence grade. In addition to articles cited already in this update, 3 other articles relevant to osteoporosis and fragility fractures are appended to this review after the standard bibliography, with a brief commentary about each article to help guide your further reading, in an evidence-based fashion, in this subspecialty area. Evidence-Based Orthopaedics Bhasin S, Gill TM, Reuben DB, Latham NK, Ganz DA, Greene EJ, et al.; STRIDE Trial Investigators. A randomized trial of a multifactorial strategy to prevent serious fall injuries. N Engl J Med. 2020 Jul 9;383(2):129-40. The authors conducted a pragmatic, cluster-randomized trial at 86 practices to evaluate the effectiveness of a multifactorial intervention by specially trained nurses to prevent falls compared with enhanced usual care. The rate of a first adjudicated serious fall injury did not differ significantly between groups; the number of events per 100 person-years of follow-up was 4.9 in the intervention group and 5.3 in the control group (hazard ratio, 0.92; p = 0.25). The rates of hospitalization or death were similar in both groups. This article is also consistent with fall prevention efforts in hospitalized patients. Nonmodifiable factors such as neurological status, rather than the activities at the time of the fall, may be more dominant in fall initiation. This is a high-level randomized study that demonstrated no improvement in fall risk among geriatric patients treated with individualized care plans aimed at fall prevention. This is important information for orthopaedists who treat geriatric patients and are instrumental in helping to prevent falls in at-risk patients. Li N, Hiligsmann M, Boonen A, van Oostwaard MM, de Bot RTAL, Wyers CE, Bours SPG, van den Bergh JP. The impact of fracture liaison services on subsequent fractures and mortality: a systematic literature review and meta-analysis. Osteoporos Int. 2021 Aug;32(8):1517-30. This systematic analysis utilized 16 of 955 published articles that examined the impact on subsequent fractures and mortality before and after a fracture liaison service was implemented. There were 18 comparisons performed, with a follow-up range of 6 months to 4 years. Excluding the influence of bias, 9 comparisons demonstrated that the fracture liaison service intervention led to lower subsequent fractures (odds ratio, 0.70 [95% CI, 0.52 to 0.93]; p = 0.01). The significant difference was only evident in studies with >2 years of follow-up. There was no significant difference in mortality. This meta-analysis demonstrates the benefit of a fracture liaison service in preventing subsequent low-energy fractures, but mortality appears to be related to issues beyond osteoporosis management. The results of this study should be considered by orthopaedic groups who treat geriatric patients with fracture, as orthopaedic surgeons are the clinicians who care for patients immediately following a fracture. Patients may benefit from having nurse practitioners who can specifically diagnose and treat osteoporosis in order to optimize patient care. This study shows improved treatment rates and outcomes. Negm AM, Lee J, Hamidian R, Jones CA, Khadaroo RG. Management of sarcopenia: a network meta-analysis of randomized controlled trials. J Am Med Dir Assoc. 2022 May;23(5):707-14. The authors examined 59 RCTs on the effectiveness of interventions in the treatment of sarcopenia, with the primary outcome of muscle mass and the secondary outcomes of muscle strength and physical function. The trials demonstrated that mixed exercises were the most effective in increasing muscle mass. Muscle strength was most improved by nutrition and physical activity. Aerobic exercises were most effective in enhancing physical performance. Most of the studies had a high risk of bias and more robust methodology is needed to ensure that the conclusions are correct. Sarcopenia is difficult to reverse. There are multiple methods to recognize the disorder. In spite of this difficulty, the most promising approach toward suspected sarcopenia should be improved nutrition and mixed exercises. This study is of particular importance for helping to advance fall prevention in geriatric patients with fracture and to maximize their care.