Bone strength and surrogate markers: The first, second, and third fiddle

This study aims to quantify bone mineral density (BMD) changes following surgery in patients with primary hyperparathyroidism (PHPT) and to assess their relationship with clinical and biochemical variables. A historic cohort of 236 PHPT patients with DXA scans pre- and 1-year postoperatively, clinical data, and biochemical data was analyzed. The mean age was 60 years (range 19-86) and 81 % of the patients were women. A significant postoperative 2.6 % (95 % CI, 2.1; 3.1) increase in lumbar spine BMD was seen. The increase in BMD was positively associated with preoperative plasma PTH (p = 0.002), Ca(2+) (p < 0.001), and alkaline phosphatase (p = 0.014). Hip BMD increased 1.5 % (1.1; 1.9). The increase in BMD was positively associated with preoperative plasma PTH (p = 0.005) and Ca(2+) (p < 0.001) and inversely associated with plasma creatinine (p = 0.004) and age (p = 0.018). Total forearm BMD did not change significantly (-0.2 % (-0.5; 0.1)). An increase in forearm BMD was seen in 38 % of all patients, and the changes were positively associated with plasma PTH (p < 0.001) and Ca(2+) (p = 0.009). In all 91 patients with mild PHPT (plasma Ca(2+) < 1.45 mmol/l), there was a significant postoperative increase in spine BMD (1.9 % (1.2; 2.7)) and in hip BMD (1.0 % (0.4; 1.6)), but not in the forearm BMD (-0.3 % (-0.7; 0.2)). The postoperative BMD gain was higher in the hip and forearm in patients operated for adenomas compared with patients treated for hyperplasia. We found significant postoperative BMD improvements both at the hip and the spine. BMD improvements were also significant in mild cases. At all scan sites, there were positive associations between preoperative plasma PTH levels and postoperative BMD increases. The measured BMD changes may mainly be due to a decrease in PTH-induced bone turnover with refilling of the remodeling space.

Objective:To determine the safety and efficacy of full-length parathyroid hormone, PTH(1–84), treatment for up to 36 months by evaluating bone mineral density (BMD) changes, bone histomorphometric indices, and clinical fracture incidence in postmenopausal women with osteoporosis.Background:The TOP trial demonstrated increased lumbar spine BMD (6.9%) versus placebo after 18 months of PTH(1–84) treatment and reduced the incidence of new vertebral fractures (61%; p = 0.001). The therapeutic benefits of long-term treatment of postmenopausal women with PTH(1–84) are unknown.Methods:The safety and efficacy of 36 months of once-daily dosing with 100 µg PTH(1–84) in postmenopausal women with osteoporosis were assessed. Women receiving placebo during the TOP trial were eligible for PTH(1–84) in the extension study.Clinical trial registration:NCT00172120.Results:Lumbar spine BMD increased by 8.5% above baseline (p < 0.001) at 36 months of PTH(1–84) treatment, remaining stable during the last 12 months of treatment. Increases in total hip and femoral neck BMD occurred more slowly, reaching 3.2% and 3.4%, respectively above baseline at 36 months (p < 0.001). The total hip BMD showed no signs of reaching a limiting value although the femoral neck plateaued from months 24 to 36. Seven patients had vertebral fractures during the placebo phase of the TOP trial and before entering the extension study, but this rate decreased with the introduction of PTH(1–84) therapy, resulting in a single worsened vertebral fracture in the first 6 months and no further vertebral fractures from months 6 to 36. Treatment over 36 months with PTH(1–84) was well-tolerated and iliac crest biopsies showed no adverse effects on bone.Limitations:There was no placebo group for BMD comparisons. The number of patients assessed for fracture incidence was small.Conclusions:PTH(1–84) treatment for 36 months resulted in significant increases in BMD at the lumbar spine and hip, was associated with a lower incidence of vertebral fracture when compared to before therapy initiation, and was well-tolerated. The continuous increases in total hip BMD suggest that prolonged PTH(1–84) treatment may be beneficial for postmenopausal osteoporosis. Increased BMD at the femoral neck and lumbar spine also showed favourable changes but plateaued between 24 and 36 months. Long-term treatment was not associated with abnormalities in bone biopsies.

To investigate whether the incidence of vertebral fractures is related to the magnitude of change in bone mineral density (BMD) during alendronate treatment. Women in this study were age 55-81 years (n = 2,984). While participating in the Fracture Intervention Trial, they received 5 mg/day of alendronate for 2 years followed by 10 mg/day for the remaining 12-30 months of the study. Their BMD was measured at baseline and at 12 and 24 months, and spine radiographs were obtained at baseline and again at 36 or 48 months to identify new vertebral fractures. After 12 months of alendronate treatment, 35% of participants had increases of > or =3% in total hip BMD, and 21% had either decreased total hip BMD or no change. Women who had larger increases in total hip BMD during the first 12 months had a lower incidence of new vertebral fractures during the entire followup period. Only 3.2% of women with increases of > or =3% in total hip BMD experienced new vertebral fractures, whereas twice as many women (6.3%) whose BMD declined or stayed the same experienced new fractures (adjusted odds ratio 0.45, 95% confidence interval 0.27-0.72). Similar patterns were observed for spine BMD at 12 months, and for both sites using change in BMD at 24 months. Women with increases of > or =3% in BMD during the first 1 or 2 years of alendronate treatment had the lowest incidence of new vertebral fractures. These findings suggest that, among women taking antiresorptive agents, greater increases in BMD are associated with lower risk of new vertebral fractures.

We sought to examine the association between shorter-term changes in markers of bone turnover and longer-term changes in bone mineral density (BMD) and microstructure in a cohort of frail elderly women with multiple comorbid conditions including osteoporosis. We performed a secondary analysis of a 2-year zoledronic acid trial for osteoporosis in 155 women residents of long-term care communities (mean age 86.9 years). We examined the association of the 6-month change in serum C-terminal crosslinking telopeptide of type I collagen (CTX) and serum intact procollagen type I N propeptide (PINP) with the 12- and 24-month changes in BMD at the spine and hip and the trabecular bone score (TBS), an indirect measure of bone microstructure. For every 0.2-ng/ml 6-month CTX decrease, the corresponding increase in spine BMD at 12 and 24 months was 0.2% (p = 0.7210) and 1.1% (p = 0.0396), respectively; total hip BMD 1.1% (p = 0.0279) and 0.9% (p = 0.0716); and femoral neck BMD 1.7% (p = 0.0079) and 0.9% (p = 0.1698). Similarly, for every 20-ng/ml 6-month PINP decrease, the corresponding increase in spine BMD at 12 and 24 months was 0.9% (p = 0.0286) and 1.4% (p = 0.0012), respectively; total hip BMD 1.4% (p = 0.0005) and 1.4% (p = 0.0006); and femoral neck BMD 2.3% (p < 0.0001) and 2.0% (p < 0.0001). Bone marker changes were not consistently associated with TBS changes. Shorter-term 6-month changes in bone turnover markers are associated with the long-term changes in BMD over 1-2 years in the spine and hip but not with TBS.

Surrogate markers in clinical medicine provide a useful means to assess therapeutic response to pharmacologic therapy in a wide range of chronic disease states. In the area of osteoporosis, the surrogate markers of change in bone mineral density (BMD) and bone turnover markers (BTM) provide the clinician with a means of assessing the biologic response to osteoporosis-specific pharmacologic agents. Increases in BMD and/or reductions in BTM can independently be correlated to reductions in vertebral and nonvertebral fracture risk. In managing osteoporosis patients, the BTM change at an earlier point of time after initiation of therapy and a change in BTM can provide earlier feed-back to the patient and clinician regarding issues such as compliance and a bone biologic response. An increase in BMD at 12 or 24 months after initiation of therapy is also evidence of an improvement in bone strength though with antiresorptive agents no change in BMD may also be associated with risk reduction within clinical trial sets. In this regard, changes in BMD and BTM are complimentary in their application to patient management.

Sex steroids are important determinants of bone acquisition and bone homeostasis. Cross-sex hormonal treatment (CHT) in transgender persons can affect bone mineral density (BMD). The aim of this study was to investigate in a prospective observational multicenter study the first-year effects of CHT on BMD in transgender persons. A total of 231 transwomen and 199 transmen were included who completed the first year of CHT. Transwomen were treated with cyproterone acetate and oral or transdermal estradiol; transmen received transdermal or intramuscular testosterone. A dual-energy X-ray absorptiometry (DXA) was performed to measure lumbar spine (LS), total hip (TH), and femoral neck (FN) BMD before and after 1 year of CHT. In transwomen, an increase in LS (+3.67%, 95% confidence interval [CI] 3.20 to 4.13%, p < 0.001), TH (+0.97%, 95% CI 0.62 to 1.31%, p < 0.001), and FN (+1.86%, 95% CI 1.41 to 2.31%, p < 0.001) BMD was found. In transmen, TH BMD increased after 1 year of CHT (+1.04%, 95% CI 0.64 to 1.44%, p < 0.001). No changes were observed in FN BMD (-0.46%, 95% CI -1.07 to 0.16%, p = 0.144). The increase in LS BMD was larger in transmen aged ≥50 years (+4.32%, 95% CI 2.28 to 6.36%, p = 0.001) compared with transmen aged <50 years (+0.68%, 95% CI 0.19 to 1.17%, p = 0.007). In conclusion, BMD increased in transgender persons after 1 year of CHT. In transmen of postmenopausal age, the LS BMD increased more than in younger transmen, which may lead to the hypothesis that the increase in BMD in transmen is the result of the aromatization of testosterone to estradiol. © 2017 American Society for Bone and Mineral Research.

BackgroundStudies have shown increased prevalence of osteoporosis and increased risk for vertebral fractures in patients with ankylosing spondylitis (AS). Measurements of bone mineral density (BMD) in the lumbar spine anterior-posterior (AP) projection may be difficult to interpret due to the ligamentous calcifications, and the lateral projection might be a better measuring site. Our objectives were to investigate BMD changes after 5 years at different measuring sites in patients with AS and to evaluate disease-related variables and medications as predictors for BMD changes.MethodsIn a longitudinal study, BMD in Swedish AS patients, 50 ± 13 years old, was measured with dual-energy x-ray absorptiometry (DXA) at the hip, the lumbar spine AP and lateral projections, and the total radius at baseline and after 5 years. Patients were assessed with questionnaires, blood samples, and spinal radiographs for grading of AS-related alterations in the spine with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and assessment of vertebral fractures by the Genant score. Multiple linear regression analyses were used to investigate predictors for BMD changes.ResultsOf 204 patients included at baseline, 168 (82%) were re-examined after 5 years (92 men and 76 women). BMD decreased significantly at the femoral neck and radius and increased significantly at the lumbar spine, both for AP and lateral projections. Mean C-reactive protein during follow-up predicted a decrease in the femoral neck BMD (change in %, β = –0.15, p = 0.046). Use of bisphosphonates predicted an increase in BMD at all measuring sites (p < 0.001 to 0.013), except for the total radius. Use of tumor necrosis factor inhibitors (TNFi) predicted an increase in AP spinal BMD (β = 3.15, p = 0.012).ConclusionThe current study (which has a long follow-up, many measuring sites, and is the first to longitudinally assess the lateral projection of the spine in AS patients) surprisingly showed that lateral projection spinal BMD increased. This study suggests that the best site to assess bone loss in AS patients is the femoral neck and that inflammation has an adverse effect, and the use of bisphosphonates and TNFi has a positive effect, on BMD in AS patients.

Meta-analyses conducted >15 years ago reported that improvements in bone mineral density (BMD) were associated with reduction in vertebral and nonvertebral fractures in osteoporosis trials. Numerous studies have been conducted since then, incorporating new therapies with different mechanisms of action and enrolling many more subjects. To extend these prior analyses, we conducted a meta-regression of 38 placebo-controlled trials of 19 therapeutic agents to determine the association between improvements in BMD and reductions in fracture risk. We used a linear model to examine the relationship between mean percent difference in BMD change between treatment and placebo groups and the logarithm of the relative risk. We found that greater improvements in BMD were strongly associated with greater reductions in vertebral and hip fractures but not nonvertebral fractures. For vertebral fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.56, 0.54, and 0.63, respectively (p ≤ 0.0002). For a 2% or 6% improvement in total hip BMD, we might expect a 28% or 66% reduction, respectively, in vertebral fracture risk. For hip fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.48 (p = 0.01), 0.42 (p = 0.02), and 0.22 (ns), respectively. For a 2% or 6% improvement in total hip BMD, we might expect a 16% or 40% reduction in hip fracture risk. In conclusion, our results extend prior observations that larger improvements in dual-energy X-ray absorptiometry (DXA)-based BMD are associated with greater reductions in fracture risk, particularly for vertebral and hip fractures. Although these results cannot be directly applied to predict the treatment benefit in an individual patient, they provide compelling evidence that improvements in BMD with osteoporosis therapies may be useful surrogate endpoints for fracture in trials of new therapeutic agents. © 2019 American Society for Bone and Mineral Research.

OP0039 A Five Year Prospective Study of Bone Mineral Density in Ankylosing Spondylitis

Changes in Bone Mineral Density Following Treatment of Osteomalacia

Recent experience from different groups suggests that low fluoride doses resulting in moderate increases in bone mineral density (BMD) may be advantageous in terms of fracture-reducing potency. In a randomized prospective 3-year study we examined the therapeutic efficacy of different dosages of monofluorophosphate (MFP) plus calcium in comparison with calcium alone in 134 women with established postmenopausal osteoporosis (mean age 64.0 years, average vertebral fractures per patient 3.6). Group A received 1000 mg calcium/day and a low-dose intermittent MFP regimen (3 months on, 1 month off) corresponding to an average daily fluoride ion dose of 11.2 mg. Group B received 1000 mg calcium/day plus continuous MFP corresponding to 20 mg fluoride ions per day. Group C was treated with 1000 mg calcium alone throughout the study period. Bone density was measured with dual-energy X-ray absorptiometry at L2-4 and three proximal femur areas and with single photon absorptiometry at two radius sites. New vertebral fractures were identified from annual lateral radiographs of the spine. A significant reduction in subjective complaints as measured by a combined pain-mobility score (CPMS) was found in both fluoride groups in comparison with the calcium monotherapy group. Group A showed increases in BMD at all six measuring sites, reaching +12.6% at the spine after 3 years. In group B we found significant increases at the spine, Ward's triangle and distal radius, but slight decreases at the femoral neck and radius shaft. For the spine the average change amounted to +19.5% after 3 years. In group C losses of BMD were observed at all six sites, with an average loss of 1.6% for the spine at the end of the study. The incidence of new vertebral fractures per 100 patient-years was 8.6, 17.0 and 31.6 in groups A, B and C, respectively. In conclusion, both calcium-MFP regimens resulted in significantly lower vertebral fracture rates than calcium monotherapy. However, the low intermittent MFP regimen, leading to a mean annual increase in spinal BMD of only 4.2%, showed a clear trend to greater effectiveness in reducing vertebral fracture than the higher fluoride dosage that was followed by an average spinal BMD increase of 6.5% per year. Furthermore the rate of fluoride-specific side effects (lower-extremity pain syndrome) was 50% lower in patients receiving the lower fluoride dosage.

To assess the effectiveness and safety of zoledronate (ZOL) in preventing glucocorticoid therapy-associated bone loss in patients with acute flare of Crohn's disease (CD) in a randomized, double-blind, placebo-controlled trial. Forty CD patients starting a glucocorticoid therapy (60 mg prednisolone per day) for acute flare (CD activity index (CDAI) >220) were randomized to compare the effect of ZOL (4 mg intravenous, n=20) or placebo (n=20) on change in lumbar bone mineral density (BMD). All patients received calcium citrate (800 mg) and colecalciferol (1,000 IU) daily. Dual energy X-ray absorptiometry (DXA) of the lumbar spine (L1-L4) was performed at baseline and day 90. Follow-up examinations at day 1/7/14/30 and 90 included laboratory tests and adverse event/serious adverse events reports. Thirty-six patients were available for per-protocol analysis. With placebo (n=18), a decrease in BMD was seen (T-score: -0.98 ± 0.8, day 0 and -1.25 ± 0.77, day 90, P=0.06), with ZOL (n=18) BMD increased (-1.15 ± 1.02, day 0 and -0.74 ± 1.09, day 90, P=0.03). The change in BMD under placebo (-0.26 ± 0.21) vs. ZOL (+0.41 ± 0.19) was highly significant (P=0.006). In all, 14 out of 18 patients with ZOL had an increase in BMD (+0.64 ± 0.48), 12 of 18 with placebo a decrease (-0.50 ± 0.39). Changes of clinical findings and laboratory results of inflammation (leukocytes, platelets, and C-reactive protein) were the same in- and between-groups throughout the study. With ZOL, serum bone degradation marker β-Cross-Laps decreased. Study medication was safe and well tolerated. ZOL is effective in preventing glucocorticoid therapy-induced bone loss in patients with acute flare of CD and should be considered whenever a glucocorticoid therapy is started in CD patients.

Changes in long-term bone health in patients receiving avapritinib for the treatment of indolent systemic mastocytosis in the pioneer study

An ASBMR Task Force recommends a drug holiday for certain women treated for ≥5 years with oral alendronate or ≥3 years with intravenous zoledronic acid, with reassessment 2 to 3 years later. It is not known whether changes in bone mineral density (BMD) or bone turnover markers differ after oral or intravenous therapy. Our goal was to compare changes in BMD and procollagen type I N propeptide (PINP) after oral or intravenous bisphosphonate use. In the Fracture Intervention Trial Long-term Extension (FLEX), women who received a mean 5 years of alendronate were randomized to placebo or continued treatment. In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial Extension I (HORIZON-PFT E1), women who received 3 years of zoledronic acid were randomized to placebo or continued treatment. We examined the proportion of participants with BMD loss or PINP gain ≥ least significant change (LSC) and those whose values exceeded a threshold (T-score ≤-2.5 or PINP ≥36.0 ng/mL, a premenopausal median value). After 3 years of placebo, the FLEX group had greater mean total hip BMD decreases (-2.3% versus -1.2% in the HORIZON-PFT E1 group, p < 0.01) and greater rises in PINP (+11.6 ng/mL versus +6.7 ng/mL, p < 0.01). There was a greater proportion of individuals in FLEX with total hip BMD loss and PINP increases that exceeded LSC, and PINP values ≥36.0 ng/mL. In contrast, there were small changes in the proportion of women with femoral neck T-scores ≤-2.5 in both groups. In conclusion, 3 years after bisphosphonate discontinuation, a considerable proportion of former alendronate and zoledronic acid users had meaningful declines in total hip BMD and elevations in PINP. Despite a longer treatment course, alendronate may have a more rapid offset of drug effect than zoledronic acid. © 2018 American Society for Bone and Mineral Research.

Forty patients were enrolled in a prospective randomised study using conventional method or "Trabecular Metal Cone" (TM Cone) (Zimmer inc., Warsaw, USA) for reconstruction of bone loss of the proximal tibia during revision total knee arthroplasty (rTKA). The aim was to evaluate changes in bone mineral density (BMD) at the proximal tibia. Thirty-six patients [median 67 years (range: 40-85 years)] received rTKA with NexGen® (Zimmer Warsaw, USA) revision system. Knee Society´s Knee Scoring System and the Anderson Orthopaedic Research Institute (AORI) bone classification was used. Changes in BMD were measured by dual energy X-ray absorptiometry (DEXA). Knee and function score improved in both groups. No significant changes between the groups were found. Changes in BMD within the two groups were quite similar. Overall decreases in BMD of 0.1 - 5.4 % were found in both groups (ROI 1-6) postoperative to 12 months of follow-up, except that ROI 7 showed an increase in BMD (0.8 - 1.3 %). After 24 months of follow-up, an increase in BMD was found along the stem (ROI 2-5) of 1.9 - 6.3 % , with significant changes in the TM Cone Group (ROI 3, 4, 5) . No significant changes in BMD between the groups were found. The bone remodelling pattern was almost the same in the two groups after two years.