18F‐fluoride PET as a noninvasive imaging biomarker for determining treatment efficacy of bone active agents at the hip: A prospective,randomized, controlled clinical study

The functional imaging technique of ¹⁸F‐fluoride positron emission tomography (¹⁸F‐PET) allows the noninvasive quantitative assessment of regional bone formation at any skeletal site, including the spine and hip. The aim of this study was to determine if ¹⁸F‐PET can be used as an early biomarker of treatment efficacy at the hip. Twenty‐seven treatment‐naive postmenopausal women with osteopenia were randomized to receive teriparatide and calcium and vitamin D (TPT group, n = 13) or calcium and vitamin D only (control group, n = 14). Subjects in the TPT group were treated with 20 µg/day teriparatide for 12 weeks. ¹⁸F‐PET scans of the proximal femur, pelvis, and lumbar spine were performed at baseline and 12 weeks. The plasma clearance of ¹⁸F‐fluoride to bone, K_i, a validated measurement of bone formation, was measured at four regions of the hip, lumbar spine, and pelvis. A significant increase in K_i was observed at all regions of interest (ROIs), including the total hip (+27%, p = 0.002), femoral neck (+25%, p = 0.040), hip trabecular ROI (+21%, p = 0.017), and hip cortical ROI (+51%, p = 0.001) in the TPT group. Significant increases in K_i in response to TPT were also observed at the lumbar spine (+18%, p = 0.001) and pelvis (+42%, p = 0.001). No significant changes in K_i were observed for the control group. Changes in BMD and bone turnover markers were consistent with previous trials of teriparatide. In conclusion, this is the first study to our knowledge to demonstrate that ¹⁸F‐PET can be used as an imaging biomarker for determining treatment efficacy at the hip as early as 12 weeks after initiation of therapy.     

Differences in regional bone perfusion and turnover between lumbar spine and distal humerus: F-fluoride PET study of treatment-naïve and treated postmenopausal women

The functional imaging technique of ¹⁸F-fluoride positron emission tomography (¹⁸F-PET) allows the non-invasive assessment of regional bone blood perfusion and turnover. Bone perfusion and turnover measured using ¹⁸F-PET correlate closely with those obtained experimentally and so they can be readily applied in clinical research studies. The aim of this study was to compare bone perfusion and turnover between the lumbar spine and humerus in both treatment naïve postmenopausal women (n = 11) and those on stable antiresorptive therapy (n = 12). All women had a BMD T-score of less than − 2 at the spine and/or hip. Each woman had a dynamic PET scan of the lumbar spine and distal humerus after injection of 90 MBq ¹⁸F-fluoride. Using a three-compartmental model bone perfusion (K₁), the net plasma clearance of tracer to bone mineral (K_i) reflecting regional bone turnover and the rate constants k₂–k₄ describing the transport of fluoride between plasma, an extravascular bone compartment and bone mineral compartment were calculated. Mean bone perfusion (K₁) and bone turnover (K_i) were significantly higher at the lumbar spine compared to the humerus for both treatment-naïve and antiresorptive groups. K₁ values were on average 3 times greater while K_i was approximately 50% greater at the lumbar spine. The rate constant k₂, the reverse transport of fluoride from the extravascular compartment to plasma, was significantly lower at the humerus compared to the lumbar spine in both groups. The ratio K_i/K₁ describing the unidirectional extraction efficiency to bone mineral was significantly greater at the humerus compared to the lumbar spine for both study groups. No significant differences between skeletal sites were observed for k₃ or k₄. In conclusion a significant skeletal heterogeneity was observed in terms of bone perfusion and turnover between the lumbar spine and humerus. ¹⁸F-PET may aid in our understanding of the importance of bone perfusion in osteoporosis and differences in regional bone turnover with disease and in response to therapy.     

Regional bone metabolism at the lumbar spine and hip following discontinuation of alendronate and risedronate treatment in postmenopausal women

Summary

The aim of this study was to examine the effects of bisphosphonate discontinuation on bone metabolism at the spine and hip measured using ¹⁸?F-fluoride PET. Bone metabolism at the spine remained stable following discontinuation of alendronate and risedronate at 1?year but increased in the hip in the alendronate group only.

Introduction

Bisphosphonates such as alendronate (ALN) or risedronate (RIS) have persistent effects on spine BMD following discontinuation.

Methods

Positron emission tomography (PET) was used to examine regional bone metabolism in 20 postmenopausal women treated with ALN (n?=?11) or RIS (n?=?9) for a minimum of 3?years at screening (range 3–9?years, mean 5?years for both groups). Subjects underwent a dynamic scan of the lumbar spine and a static scan of both hips at baseline and 6 and 12?months following treatment discontinuation. ¹⁸?F-fluoride plasma clearance (K_i) at the spine was calculated using a three-compartment model. Standardised uptake values (SUV) were calculated for the spine, total hip, femoral neck and femoral shaft. Measurements of BMD and biochemical markers of bone turnover were also performed.

Results

With the exception of a significant decrease in spine BMD in the ALN group, BMD remained stable. Bone turnover markers increased significantly from baseline by 12?months for both study groups. Measurements of K_i and SUV at the spine and femoral neck did not change significantly in either group. SUV at the femoral shaft and total hip increased significantly but in the ALN group only, increasing by 33.8% (p?=?0.028) and 24.0% (p?=?0.013), respectively.

Conclusions

Bone metabolism at the spine remained suppressed following treatment discontinuation. A significant increase in SUV at the femoral shaft and total hip after 12?months was observed but for the ALN group only. This study was small, and further clinical studies are required to fully evaluate the persistence of BP treatment.     

Differences in regional bone metabolism at the spine and hip: a quantitative study using 18F-fluoride positron emission tomography

Summary

This study showed that regional bone blood flow and ¹⁸F-fluoride bone plasma clearance measured by positron emission tomography are three times lower at the hip than the lumbar spine.

Introduction

Measurements of effective bone plasma flow (K ₁), bone plasma clearance (K _i ) and standardised uptake values (SUV) using ¹⁸F-fluoride positron emission tomography (¹⁸F-PET) provide a useful means of studying regional bone metabolism at different sites in the skeleton. This study compares the regional ¹⁸F-fluoride kinetics and SUV at the hip and lumbar spine (LS).

Methods

Twelve healthy postmenopausal women with no history of metabolic bone disease apart from two with untreated osteoporosis were recruited. Each subject underwent 60-min dynamic ¹⁸F-PET scans at the LS and proximal femur two weeks apart. K ₁, K _i and SUV were measured at the LS (mean of L₁–L₄), femoral neck (FN), total hip (TH) and femoral shaft (FS). Differences between sites were assessed using the nonparametric Kruskal–Wallis test with a Bonferroni correction for multiple comparisons.

Results

Values of K ₁, K _i and SUV at the FN, TH and FS were three times lower than at the LS (p?=?0.003). Amongst the proximal femur sites, K _i and SUV were lower at the FS compared with the FN and TH, and SUV was lower at the TH compared with the FN (all p?<?0.05). The volume of distribution was lower at the TH and FS compared with the LS (p?<?0.05).

Conclusion

The lower values of K ₁, K _i and SUV at the hip suggest that lower bone blood flow in the proximal femur is an important factor explaining the principal reason for the differences in bone fluoride kinetics between the LS and hip sites.     

Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass

Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption, and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s.c. teriparatide (20 µg once daily), and s.c. romosozumab (210 mg once monthly). QCT measurements were performed at the lumbar spine (mean of L₁ and L₂ entire vertebral bodies, excluding posterior processes) and hip. One year of treatment with romosozumab significantly increased integral vBMD and BMC at the lumbar spine and total hip from baseline, and compared with placebo and teriparatide (all p < 0.05). Trabecular vertebral vBMD improved significantly and similarly from baseline (p < 0.05) with both romosozumab (18.3%) and teriparatide (20.1%), whereas cortical vertebral vBMD gains were larger with romosozumab compared with teriparatide (13.7% versus 5.7%, p < 0.0001). Trabecular hip vBMD gains were significantly larger with romosozumab than with teriparatide (10.8% versus 4.2%, p = 0.01), but were similar for cortical vBMD (1.1% versus –0.9%, p = 0.12). Cortical BMC gains were larger with romosozumab compared with teriparatide at both the spine (23.3% versus 10.9%, p < 0.0001) and hip (3.4% versus 0.0%, p = 0.03). These improvements are expected to result in strength gains and support the continued clinical investigation of romosozumab as a potential therapy to rapidly reduce fracture risk in ongoing phase 3 studies. © 2016 American Society for Bone and Mineral Research.     

Greater Gains in Spine and Hip Strength for Romosozumab Compared With Teriparatide in Postmenopausal Women With Low Bone Mass

Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo‐controlled clinical trial of treatment‐naïve postmenopausal women with low bone mass, romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded romosozumab s.c. (210 mg monthly) or placebo, or open‐label teriparatide (20 μg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L₁ vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus –3.9%; p < 0.0001); changes in femoral strength for romosozumab showed similar but smaller changes, increasing more with romosozumab versus teriparatide (3.6% versus –0.7%; p = 0.027), and trending higher versus placebo (3.6% versus ?0.1%; p = 0.059). Compartmental analysis revealed that the bone‐strengthening effects for romosozumab were associated with positive contributions from both the cortical and trabecular bone compartments at both the lumbar spine and hip. Taken together, these findings suggest that romosozumab may offer patients with osteoporosis a new bone‐forming therapeutic option that increases both vertebral and femoral strength within 12 months. © 2017 American Society for Bone and Mineral Research.     

Osteoporosis assessment by whole body region vs. site-specific DXA

The ability of regional data from whole body scans to provide an accurate assessment of site-specific BMD, osteoporosis prevalence and fracture risk has not been fully explored. To address these issues, we measured total body (TBBD) and site-specific BMD in an age-stratified population sample of 351 women (21–93 years) and 348 men (22–90 years). We found an excellent correlation between AP lumbar spine and total body lumbar spine subregion BMD (r ²=0.92), but weaker ones for total hip compared to pelvis region (r ²=0.72) or between total wrist and left arm subregion from the whole body scan (r ²=0.83). The error in estimating site-specific BMD from total body regions ranged from 4.3% (lumbar spine) to 11.2% (femoral neck) in women and from 4.9 to 11.1%, respectively, in men. Site-specific versus regional measurements at the lumbar spine and total hip/pelvis provided comparable overall estimates of osteoporosis prevalence, but disagreed on the status of individuals; measurements at whole body regions underestimated osteoporosis as assessed at the femoral neck or total wrist. All measurements were associated with a history of various fractures [age adjusted odds ratios (OR), 1.3 to 2.1 in women and 1.2 to 1.5 in men] and were generally interchangeable, but femoral neck BMD provided the best estimate of osteoporotic fracture risk in women (OR, 2.9; 95% CI, 1.7–5.0). Although there are strong correlations between BMD from dedicated scans of the hip, spine and distal forearm and corresponding regions on the whole body scan, the measurements provide somewhat different estimates of osteoporosis prevalence and fracture risk.     

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1–34) (teriparatide) 20 µg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1‐year multicenter, multinational, randomized, partial double‐blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 ± 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 µg (n = 137), zoledronic acid alone (n = 137), or teriparatide alone (n = 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual‐energy X‐ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively (p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone (p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total‐hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks (p < .05), with final 52‐week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N‐terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum β‐C‐telopeptide of type I collagen [β‐CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone (p < .002). Limitations of the study included its short duration, lack of endpoints beyond DXA‐based BMD (e.g., quantitative computed tomography and finite‐element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered. © 2011 American Society for Bone and Mineral Research.     

[18F]‐Sodium Fluoride PET/MR Imaging for Bone–Cartilage Interactions in Hip Osteoarthritis: A Feasibility Study

This study characterized the distribution of [¹⁸F]‐sodium fluoride (NaF) uptake and blood flow in the femur and acetabulum in hip osteoarthritis (OA) patients to find associations between bone remodeling and cartilage composition in the presence of morphological abnormalities using simultaneous positron emission tomography and magnetic resonance imaging (PET/MR), quantitative magnetic resonance imaging (MRI) and femur shape modeling. Ten patients underwent a [¹⁸F]‐NaF PET/MR dynamic scan of the hip simultaneously with: (i) fast spin‐echo CUBE for morphology grading and (ii) T_1ρ/T₂ magnetization‐prepared angle‐modulated partitioned k‐space spoiled gradient echo snapshots for cartilage, bone segmentation, bone shape modeling, and T_1ρ/T₂ quantification. The standardized uptake values (SUVs) and Patlak kinetic parameter (K_pat) were calculated for each patient as PET outcomes, using an automated post‐processing pipeline. Shape modeling was performed to extract the variations in bone shapes in the patients. Pearson's correlation coefficients were used to study the associations between bone shapes, PET outcomes, and patient reported pain. Direct associations between quantitative MR and PET evidence of bone remodeling were established in the acetabulum and femur. Associations of shaft thickness with SUV in the femur (p = 0.07) and K_pat in the acetabulum (p = 0.02), cam deformity with acetabular score (p = 0.09), osteophytic growth on the femur head with K_pat (p = 0.01) were observed. Pain had increased correlations with SUV in the acetabulum (p = 0.14) and femur (p = 0.09) when shaft thickness was accounted for. This study demonstrated the ability of [¹⁸F]‐NaF PET‐MRI, 3D shape modeling, and quantitative MRI to investigate cartilage‐bone interactions and bone shape features in hip OA, providing potential investigative tools to diagnose OA. © 2019 The Authors. Journal of Orthopaedic Research^® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 37:2671–2680, 2019     

Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial.

We compared combination treatment with teriparatide plus raloxifene with teriparatide alone in women with postmenopausal osteoporosis in a 6-month double-blind, placebo-controlled trial that measured biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline. INTRODUCTION: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing teriparatide [rhPTH(1-34)] monotherapy with combination teriparatide and raloxifene therapy. MATERIALS AND METHODS: A 6-month randomized, double-blind trial comparing teriparatide plus raloxifene (n = 69) versus teriparatide plus placebo (n = 68) was conducted in postmenopausal women with osteoporosis. RESULTS: Bone formation (N-terminal propeptide of type 1 collagen [PINP]) increased similarly in both treatment groups. However, the increase in bone resorption (serum C-terminal telopeptide of type I collagen [CTx]) in the combination group was significantly smaller than in the teriparatide-alone group (p = 0.015). Lumbar spine BMD significantly increased 5.19 +/- 0.67% from baseline in the teriparatide-alone group. In the combination group, lumbar spine (6.19 +/- 0.65%), femoral neck (2.23 +/- 0.64%), and total hip (2.31 +/- 0.56%) BMD significantly increased from baseline to study endpoint, and the increase in total hip BMD was significantly greater than in the teriparatide-alone group (p = 0.04). In the teriparatide-alone group, mean serum calcium levels increased from baseline to endpoint (0.30 +/- 0.06 mg/dl, p < 0.001), whereas mean serum phosphate remained unchanged. In the combination group, mean serum calcium was unchanged, and mean serum phosphate decreased (-0.20 +/- 0.06 mg/dl, p < 0.001) from baseline to endpoint. Changes in serum calcium (p < 0.001) and phosphate (p < 0.004) were significantly different between treatment groups. The safety profile of combination therapy was similar to teriparatide alone. CONCLUSIONS: Combination therapy increased bone formation to a similar degree as teriparatide alone. However, the increase in bone resorption was significantly less and total hip BMD significantly increased for combination therapy compared with teriparatide alone. Combination treatment with raloxifene may thus enhance the bone forming effects of teriparatide. Further studies over longer treatment duration that include fracture endpoints are necessary to fully ascertain the clinical significance of combination raloxifene plus teriparatide therapy in postmenopausal osteoporosis.     

Household Tobacco Smoke Exposure is Negatively Associated with Premenopausal Bone Mass

Subjects exposed to environmental tobacco smoke have been found to be at increased risk for several health problems. Whether exposure to passive tobacco smoke is associated with reduced bone mineral density (BMD) is unknown. In order to examine this, we measured BMD in 154 healthy premenopausal women (age range 40–45 years). BMD of the total hip, femoral neck, lumbar spine and total body was measured by dual-energy X-ray absorptiometry (DXA). Data were collected on exposure to household tobacco smoke from age 10 years to the present as well as on other lifestyle factors related to bone mass. We found that 67.5% of the subjects had a history of household tobacco smoke exposure. Subjects exposed to household tobacco smoke had a mean adjusted BMD that was significantly lower at the total hip (p= 0.021) and femoral neck (p= 0.018) compared with subjects who were not exposed. In addition, duration of household tobacco smoke exposure was negatively associated with BMD at the total hip (p = 0.010), femoral neck (p= 0.004), lumbar spine (p = 0.037) and total body (p = 0.031). Subjects exposed to household tobacco smoke for 15 years or more had mean adjusted BMD that was 4% lower at the total body, and more than 8% lower at the total hip, femoral neck and lumbar spine, compared with subjects who were not exposed. In conclusion, household tobacco smoke exposure during adolescence and young adulthood was found to be negatively associated with BMD at the total hip and femoral neck, and duration of exposure was negatively associated with BMD at the total hip, femoral neck, lumbar spine and total body in premenopausal women. Received: 17 December 2001 / Accepted: 16 February 2002     

Teriparatide’s effects on quantitative ultrasound parameters and bone density in women with established osteoporosis

This study aimed to evaluate the effects of teriparatide [hPTH (1–34)] on quantitative ultrasound (QUS) parameters and bone mineral density (BMD) at the axial and appendicular (hand) skeleton in women with established osteoporosis who had been previously treated with antiresorptive drugs. Sixty postmenopausal women (age 71.1±6.8 years) were randomly assigned to either receive once-daily 20-μg subcutaneous teriparatide (n=30) or continue the antiresorptive treatment (n=30). At baseline and at 2-month intervals we measured QUS parameters at the calcaneus using the Achilles Plus (GE, Lunar), measuring speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index; QUS parameters at the phalanxes using the Bone Profiler (IGEA), measuring amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), and fast wave amplitude (FWA); and BMD values at the right hand using dual x-ray absorptiometry. BMD at the lumbar spine, femur, and whole body were measured on a 6-monthly basis. After 1 year of teriparatide treatment, the changes in BMD were 7.1% at the lumbar spine, 2.6% at the femoral neck, −0.8% at the total hip, and −0.6% for the whole body. Teriparatide induced a significant and persistent decrease in BMD at the hand (−3.6% at month 6 and −2.7% at month 12). In the teriparatide group at month 12, AD-SoS was slightly increased (0.7%; not significant), whereas BTT significantly decreased (−16.4%, p<0.001) and FWA significantly increased (17.5%, p<0.001). The FWA/BTT ratio increased by 26.6% and 32.9% at months 6 and 12, respectively, in the teriparatide group and remained unchanged in the antiresorptive group. In women with established osteoporosis who had previously been treated with various antiresorptive drugs, 1 year of teriparatide treatment determined the expected increase in BMD at the axial skeleton and a significant and prolonged decrease in BMD at the hand. Moreover, teriparatide determined important changes in BTT and FWA, two parameters obtained from the analysis of ultrasonographic trace at the phalanxes, which could be considered in monitoring for the early effect of teriparatide on bone.     

Hip and spine strength effects of adding versus switching to teriparatide in postmenopausal women with osteoporosis treated with prior alendronate or raloxifene

Many postmenopausal women treated with teriparatide for osteoporosis have previously received antiresorptive therapy. In women treated with alendronate (ALN) or raloxifene (RLX), adding versus switching to teriparatide produced different responses in areal bone mineral density (aBMD) and biochemistry; the effects of these approaches on volumetric BMD (vBMD) and bone strength are unknown. In this study, postmenopausal women with osteoporosis receiving ALN 70 mg/week (n = 91) or RLX 60 mg/day (n = 77) for ≥18 months were randomly assigned to add or switch to teriparatide 20 µg/day. Quantitative computed tomography scans were performed at baseline, 6 months, and 18 months to assess changes in vBMD; strength was estimated by nonlinear finite element analysis. A statistical plan specifying analyses was approved before assessments were completed. At the spine, median vBMD and strength increased from baseline in all groups (13.2% to 17.5%, p < 0.01); there were no significant differences between the Add and Switch groups. In the RLX stratum, hip vBMD and strength increased at 6 and 18 months in the Add group but only at 18 months in the Switch group (Strength, Month 18: 2.7% Add group, p < 0.01 and 3.4% Switch group, p < 0.05). In the ALN stratum, hip vBMD increased in the Add but not in the Switch group (0.9% versus –0.5% at 6 months and 2.2% versus 0.0% at 18 months, both p ≤ 0.004 group difference). At 18 months, hip strength increased in the Add group (2.7%, p < 0.01) but not in the Switch group (0%); however, the difference between groups was not significant (p = 0.076). Adding or switching to teriparatide conferred similar benefits on spine strength in postmenopausal women with osteoporosis pretreated with ALN or RLX. Increases in hip strength were more variable. In RLX‐treated women, strength increased more quickly in the Add group; in ALN‐treated women, a significant increase in strength compared with baseline was seen only in the Add group.     

Forearm Bone Mineral Densitometry Cannot be Used to Monitor Response to Alendronate Therapy in Postmenopausal Women

Alendronate significantly increases bone mass and reduces hip and spine fractures in postmenopausal women. To determine whether forearm densitometry could be used to monitor the efficacy of alendronate, we examined changes in bone mineral density (BMD) at the forearm (one-third distal, mid-distal, ultradistal radius) versus changes at the hip (femoral neck, total hip) and spine (posteroanterior and lateral) in a double-masked, randomized, placebo-controlled clinical trial of 120 elderly women (mean age 70 ± 4 years) treated with alendronate for 2.5 years. We found that among women in the treatment group, BMD increased by 4.0–12.2% at the hip and spine sites (all p<0.001), whereas BMD increased only nominally at the one-third distal radius (1.3%, p<0.001) and mid-radius (0.8%, p<0.05), and remained stable at the ultradistal radius. At baseline, forearm BMD correlated with that of the hip (r= 0.55–0.64, p<0.001), femoral neck (r= 0.54–0.61, p<0.001) and posteroanterior spine (r= 0.56–0.63, p<0.001). Changes in radial BMD after 1 year of therapy were not correlated with changes in hip and spine BMD after 2.5 years of therapy. In contrast, short-term changes in total hip and spine BMD were generally positively associated with long-term changes in total hip, femoral neck and spine BMD (r= 0.30–0.71, p<0.05). Furthermore, long-term BMD changes at the forearm did not correlate with long-term hip and spine BMD changes, in contrast to the moderate correlations seen between spine and hip BMD at 2.5 years (r= 0.38–0.45, p<0.01). We conclude that neither short- nor long-term changes in forearm BMD predict long-term changes in overall BMD for elderly women on alendronate therapy, suggesting that measurements of clinically relevant central sites (hip and spine) are necessary to assess therapeutic efficacy. Received: 18 February 1999 / Accepted: 20 May 1999     

Combination of bone mineral density and upper femur geometry improves the prediction of hip fracture

Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is the main determinant of the clinical evaluation of hip fracture risk. However, it has been shown that BMD is not the only predictive factor for hip fracture, but that bone geometry is also important. We studied whether the combination of bone geometry and BMD could further improve the determination of hip fracture risk and fracture type. Seventy-four postmenopausal females (mean age 74 years) with a non-pathologic cervical or trochanteric hip fracture without previous hip fracture or hip surgery constituted the study group. Forty-nine had a cervical fracture (mean age 73 years) and 25 had a trochanteric fracture (mean age 76 years). The control group consisted of 40 age-matched females (mean age 74 years). The geometrical parameters were defined from plain anteroposterior radiographs, and the potential sources of inaccuracy were eliminated as far as possible by using a standardized patient position and calibrated dimension measurements with digital image analysis. BMD was measured at the femoral neck (FEBMD), Wards triangle (WABMD), and the trochanter (TRBMD). Stepwise linear regression analysis showed that the best predictor of hip fracture was the combination of medial calcar femoral cortex width (CFC), TRBMD, neck/shaft angle (NSA), and WABMD (r=0.72, r²=0.52, P<0.001). The area under the receiver operating characteristic curve (ROC) for this model was 0.93, while the area under ROC for TRBMD alone was 0.81. At a specificity of 80%, sensitivity improved from 52.5% to 92.5% with this combination compared with TRBMD alone. The combined predictors of cervical and trochanteric fracture differed, being NSA, CFC, TRBMD, and WABMD for cervical and TRBMD and femoral shaft cortical thickness for trochanteric fracture. In addition, we found a statistically significant correlation between FEBMD and femoral shaft and femoral neck cortex width (r=0.40, P<0.01 and r=0.30, P<0.01, respectively). The results confirm that the combination of BMD and radiological measures of upper femur geometry improve the assessment of the risk of hip fracture and fracture type compared to BMD alone, and that bone geometry plays an important role in the evaluation of bone strength.     

Teriparatide vs. calcitonin in the treatment of Asian postmenopausal women with established osteoporosis

This study compared the clinical efficacy, safety, and tolerability of daily subcutaneous injections of teriparatide and salmon calcitonin in the treatment of postmenopausal women with established osteoporosis in Taiwan. This 6-month, multicenter, randomized, controlled study enrolled 63 women with established osteoporosis. They were randomized to receive either teriparatide 20 μg or calcitonin 100 IU daily in an open-label fashion. Lumber spine, femoral neck, total hip bone mineral density (BMD), and biochemical markers of bone turnover were measured, and adverse events and tolerability were recorded. The results at 6 months showed that patients using teriparatide had larger mean increases in spinal BMD than those who used calcitonin (4.5% vs. 0.1%), but the BMD changes in these two groups at the femoral neck and the total hip were not significant. There were also larger mean increases in bone markers in the teriparatide group than in the calcitonin group (bone specific alkaline phosphatase 142% vs. 37%; osteocalcin 154% vs. 23%). We conclude that teriparatide has more positive effects on bone formation than salmon calcitonin, as shown by the larger increments of lumbar spine BMD and bone formation markers, and caused only mild adverse events and no significant change in liver, kidney or hematological parameters. Compared with the published global results, teriparatide seems to be equally effective and safe to use in this Asian population.     

18F-fluoride Positron Emission Tomography Measurements of Regional Bone Formation in Hemodialysis Patients with Suspected Adynamic Bone Disease

¹⁸F-fluoride positron emission tomography (¹⁸F-PET) allows the assessment of regional bone formation and could have a role in the diagnosis of adynamic bone disease (ABD) in patients with chronic kidney disease (CKD). The purpose of this study was to examine bone formation at multiple sites of the skeleton in hemodialysis patients (CKD5D) and assess the correlation with bone biopsy. Seven CKD5D patients with suspected ABD and 12 osteoporotic postmenopausal women underwent an ¹⁸F-PET scan, and bone plasma clearance, K _i, was measured at ten skeletal regions of interest (ROI). Fifteen subjects had a transiliac bone biopsy following double tetracycline labeling. Two CKD5D patients had ABD confirmed by biopsy. There was significant heterogeneity in K _i between skeletal sites, ranging from 0.008 at the forearm to 0.028 mL/min/mL at the spine in the CKD5D group. There were no significant differences in K _i between the two study groups or between the two subjects with ABD and the other CKD5D subjects at any skeletal ROI. Five biopsies from the CKD5D patients had single tetracycline labels only, including the two with ABD. Using an imputed value of 0.3 μm/day for mineral apposition rate (MAR) for biopsies with single labels, no significant correlations were observed between lumbar spine K _i corrected for BMAD (K _i/BMAD) and bone formation rate (BFR/BS), or MAR. When biopsies with single labels were excluded, a significant correlation was observed between K _i/BMAD and MAR (r = 0.81, p = 0.008) but not BFR/BS. Further studies are required to establish the sensitivity of ¹⁸F-PET as a diagnostic tool for identifying CKD patients with ABD.     

Efficacy and safety of teriparatide in bisphosphonate-pretreated and treatment-naive patients with osteoporosis at high risk of fracture: Post hoc analysis of a prospective observational study

Background

Teriparatide is the first anabolic agent shown to reduce the risk of fractures in patients with osteoporosis. In Japan, teriparatide is prescribed to treat patients at high risk of fracture. Given that bisphosphonates are commonly used prior to teriparatide as treatment for osteoporosis, information on the effectiveness and safety of teriparatide with or without previous bisphosphonate treatment is helpful for physicians in clinical practice. This study aims to report the effectiveness and safety of teriparatide in treatment-naive and bisphosphonate-pretreated patients in Japan as real-world evidence.

Rare EN1 Variants and Pediatric Bone Mass

A recent whole‐genome sequencing study in search of variation associated with adult areal bone mineral density (aBMD) identified rare variants near EN1, with markedly large effect sizes, and a common variant near SOX6. To understand the developmental effects of these loci, we sought to determine if they were associated with pediatric dual‐energy X‐ray absorptiometry–derived aBMD and bone mineral content (BMC) and if the associations were modified by sex. Our sample comprised 733 females and 685 males of European ancestry enrolled in the longitudinal Bone Mineral Density in Childhood Study (up to 7 annual study visits). Sex‐ and age‐specific Z‐scores, adjusted for height, were calculated for the total hip, femoral neck, spine, and distal radius. Total body less head (TBLH) BMC Z‐scores were also calculated. The previously reported single nucleotide polymorphisms (SNPs) near EN1 and SOX6 were derived from our imputed data set. Linear mixed‐effects models were used to test associations between each SNP and bone Z‐scores, plus interactions with sex were explored. The rare T allele of lead EN1 SNP rs11692564 was associated with higher aBMD Z‐score for total hip (beta = 0.62, p = 9.0 × 10^?4) and femoral neck (beta = 0.53, p = 0.010). In sex‐stratified analyses, this variant was associated with higher bone Z‐scores in females only, with the associations being strongest for total hip (sex interaction p = 1.9 × 10^?4; beta females = 0.86, p = 6.6 × 10^?6) and femoral neck (sex interaction p = 0.016; beta females = 0.73, p = 0.001). The common G allele of SOX6 SNP rs11024028 was associated with higher aBMD Z‐score for total hip (beta = 0.12, p = 0.009), femoral neck (beta = 0.13, p = 0.003), and TBLH‐BMC (beta = 0.09, p = 0.007); furthermore, this association strengthened in males in the sex‐stratified analyses. Our findings reveal that rare genetic variation near EN1 and common variation near SOX6 operates in childhood and has implications for the lifelong risk of osteoporosis and fracture. The sex differences observed need to be independently replicated. © 2016 American Society for Bone and Mineral Research.     

Efficacy of Zoledronic Acid in Maintaining Areal and Volumetric Bone Density After Combined Denosumab and Teriparatide Administration: DATA-HD Study Extension

Combined teriparatide and denosumab rapidly and substantially increases bone mineral density (BMD) at all anatomic sites. Discontinuation of denosumab however, results in high-turnover bone loss and increased fracture risk. The optimal way to prevent this bone loss remains undefined. This study is a preplanned extension of the DATA-HD study, where postmenopausal women with osteoporosis were randomized to receive 9 months of either 20 μg or 40 μg of teriparatide daily overlapping with denosumab (60 mg administered at months 3 and 9). At the completion of this 15-month study, women were invited to enroll in the DATA-HD Extension where they received a single dose of zoledronic acid (5 mg) 24 to 35 weeks after the last denosumab dose. Areal BMD and bone turnover markers were measured at month 27 and 42 (12 and 27 months after zoledronic acid, respectively) and spine and hip volumetric bone density by quantitative CT was measured at month 42. Fifty-three women enrolled in the DATA-HD Extension. At the femoral neck and total hip, the mean 5.6% and 5.1% gains in BMD achieved from month 0 to 15 were maintained both 12 and 27 months after zoledronic acid administration. At the spine, the mean 13.6% gain in BMD achieved from month 0 to 15 was maintained for the first 12 months but modestly decreased thereafter, resulting in a 3.0% reduction (95% CI, −4.0% to −2.0%, p < .0001) 27 months after zoledronic acid. The pattern of BMD changes between months 15 and 42 were qualitatively similar in the 20-μg and 40-μg groups. A single dose of zoledronic acid effectively maintains the large and rapid total hip and femoral neck BMD increases achieved with combination teriparatide/denosumab therapy for at least 27 months following the transition. Spine BMD was also largely, though not fully, maintained during this period. These data suggest that the DATA-HD Extension regimen may be an effective strategy in the long-term management of patients at high risk of fragility fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).