What’s New in Osteoporosis and Fragility Fractures

Abstract

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 may also be at risk. et al. examined postmenopausal women with low bone mass and compared treatment with romosozumab and At 12 months, utilizing a quantitative CT the romosozumab group demonstrated significantly improved hip and lumbar volumetric BMD and bone mineral compared with both the group and a placebo Further analysis of this trial was performed to if these also with improved strength and fracture using element et al. found a vertebral strength in the romosozumab group that was significantly greater than the in the group (p = and significantly greater hip strength in the romosozumab group at compared with in the group (p = In a RCT fracture healing in patients treated for fractures, of patients were randomized to the romosozumab treatment There was no difference between the treatment group and the placebo group in of radiographic union and clinical healing In this study, romosozumab was from that for patients with patients were treated on and and 12 with 70 to 210 recent study randomized patients to years of with a hip fracture to receive romosozumab and patients to the placebo the of there was no significant difference between groups with to the end the and and the end of radiographic to the study by et osteoporosis was not its there are no data in to that romosozumab can or in fracture union and it should not be with that in However, it is a for patients with bone deficiency and has been to well in patients with prior bisphosphonate that have not well to the treatment with patients should be for a of and a was approved in by the In the article that the data for the and duration of treatment compared with the of the were to the treatment and the authors concluded that such events were not to occur in this study, the FDA and the that performed to if there was any potential to The from the years of data by the Study that the incidence of in patients treated with was no from the incidence The FDA had a black box warning due to the risk of developing but, since the FDA no has a black box warning on the The potential of have been to enhance outcomes of with reported in women with osteoporosis who lumbar the use of has been to enhance with some utilizing 2 months of and at least a of the total treatment. et al. have published on the use of for lumbar and have rates compared with patients with osteoporosis receiving In analysis of women with osteoporosis, 2 months of followed by months of treatment to higher rates of in the group compared with in the group and a mean that was 2 months (p < In a placebo-controlled trial of women ≥50 years of age with low bone density lumbar the use of weekly over 6 months significantly improved rates as by CT Of this is a lower than that utilized for osteoporosis treatment. 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