Assessment of the healing process in distal radius fractures by high resolution peripheral quantitative computed tomography

In clinical practice, fracture healing is evaluated by clinical judgment in combination with conventional radiography. Due to limited resolution, radiographs don't provide detailed information regarding the bone micro-architecture and bone strength. Recently, assessment of in vivo bone density, architectural and mechanical properties at the microscale became possible using high resolution peripheral quantitative computed tomography (HR-pQCT) in combination with micro finite element analysis (μFEA). So far, such techniques have been used mainly to study intact bone. The aim of this study was to explore whether these techniques can also be used to assess changes in bone density, micro-architecture and bone stiffness during fracture healing. Therefore, the fracture region in eighteen women, aged 50 years or older with a stable distal radius fracture, was scanned using HR-pQCT at 1–2 (baseline), 3–4, 6–8 and 12 weeks post-fracture. At 1–2 and 12 weeks post-fracture the distal radius at the contra-lateral side was also scanned as control. Standard bone density, micro-architectural and geometric parameters were calculated and bone stiffness in compression, torsion and bending was assessed using μFEA. A linear mixed effect model with time post-fracture as fixed effect was used to detect significant (p-value ≤ 0.05) changes from baseline. Wrist pain and function were scored using the patient-rated wrist evaluation (PRWE) questionnaire. Correlations between the bone parameters and the PRWE score were calculated by Spearman's correlation coefficient. At the fracture site, total and trabecular bone density increased by 11% and 20%, respectively, at 6–8 weeks, whereas cortical density was decreased by 4%. Trabecular thickness increased by 23–31% at 6–8 and 12 weeks and the intertrabecular area became blurred, indicating intertrabecular bone formation. Compared to baseline, calculated bone stiffness in compression, torsion and bending was increased by 31% after 12 weeks. A moderate negative correlation was found between the stiffness and the PRWE score. No changes were observed at the contra-lateral side. The results demonstrate that it is feasible to assess clinically relevant and significant longitudinal changes in bone density, micro-architecture and mechanical properties at the fracture region during the healing process of stable distal radius fractures using HR-pQCT.     

Fracture Repair in the Distal Radius in Postmenopausal Women: A Follow‐Up 2 Years Postfracture Using HRpQCT

Fracture healing is characterized by an intense increase in modeling and remodeling of bone, which allows removal of the cast after a stable distal radius fracture within 3 to 5 weeks. However, at that time, bone strength has not recovered yet. We studied the changes in bone mineral density (BMD), microarchitecture, and bone stiffness after a distal radius fracture during a 2‐year follow‐up in comparison to the contralateral side and the association between the 2‐year stiffness and baseline BMD, microarchitecture, and early changes in these parameters. The fractured side of 14 postmenopausal women (mean age 64 ± 8 years) with a conservatively treated distal radius fracture was scanned by high‐resolution peripheral quantitative computed tomography (HRpQCT) at 1 to 2, 3 to 4, 6 to 8, and 12 weeks and 2 years postfracture. The same region contralaterally was scanned as well at the 2‐year visit. BMD, microarchitecture, and stiffness parameters were determined and the fracture side was compared with the contralateral side using a linear mixed‐effect model. Spearman's correlation was used to correlate the 2‐year bone stiffness with baseline BMD, microarchitecture, and early 3‐month changes in these parameters. Two years postfracture, cortical and trabecular thickness and torsional and bending stiffness were significantly higher at the fractured side compared with the nonfractured side (21%, 55%, 31%, and 29%, respectively, p < 0.05), whereas BMD was similar. Two‐year torsional and bending stiffness correlated significantly with baseline BMD and cortical perimeter (|rho| ≥ 0.63, p < 0.016) but not with early changes in bone parameters. Using HRpQCT, this study illustrates that fracture healing is not completed by the time the cast is removed. We showed that from 6 weeks to 2 years postfracture, large changes occur in BMD, microarchitecture, and biomechanical parameters at the fractured side, which were fully recovered after 2 years in comparison to the nonfractured contralateral side. Interestingly, higher 2‐year torsional and bending stiffness were associated with lower BMD and higher cortical perimeter at baseline. © 2015 American Society for Bone and Mineral Research.     

Restoration of Stiffness During Fracture Healing at the Distal Radius,Using HR-pQCT and Finite Element Methods

Finite element analysis (FE) coupled with high-resolution peripheral quantitative computed tomography (HR-pQCT) allows for noninvasive in vivo assessment of fracture stiffness at peripheral locations including the distal radius. Previous studies have reported the ability of FE analysis to capture significant longitudinal changes in fracture stiffness. We hypothesized that continuum-based FE methods are necessary to capture significant changes in FE-estimated stiffness in men and women, with closed reductions and casting, over the course of their fracture healing process. The primary aim of the study was to evaluate the performance of 3 micro-FE (μFE) methods, 2 density-based (continuum) methods, and a homogeneous method. A total of 30 participants with stable distal radius fractures completed follow-ups at 2, 4, 6, 8, 12, and 26 weeks postfracture. Participants had their fractured wrist scanned using HR-pQCT at each follow-up; the contralateral wrist was also scanned at the initial assessment to represent baseline conditions. Images were used to generate continuum and homogeneous µFE models. Uniaxial compression and torsional tests were completed, with apparent stiffness determined as the primary outcome measure. Stiffness of the fractured wrist was compared to stiffness of the uninjured contralateral wrist to quantify the change in stiffness. Days since fracture significantly predicted change in stiffness for continuum and homogeneous µFE methods (p < 0.05). Continuum µFE methods appeared to account for partially mineralized tissues, resulting in a graduated recovery of stiffness (1% per week). Homogeneous µFE methods were more sensitive to stages of healing progression, resulting in a faster recovery of stiffness (3% per week). Our findings demonstrate the capability of µFE to capture the restoration of stiffness at the fractured side to prefracture stiffness in men and women, up to 6 months postfracture.     

The Effect of Calcium and Vitamin D<Subscript>3</Subscript> Supplementation on the Healing of the Proximal Humerus Fracture: A Randomized Placebo-Controlled Study

The purpose of this study was to (1) quantify the healing process of the human osteoporotic proximal humerus fracture (PHF) expressed in terms of callus formation over the fracture region using BMD scanning, and (2) quantify the impact of medical intervention with vitamin D₃ and calcium on the healing process of the human osteoporotic fracture. The conservatively treated PHF was chosen in order to follow the genuine fracture healing without influence of osteosynthetic materials or casts. Thirty women (mean age = 78 years; range = 58–88) with a PHF, osteoporosis or osteopenia (based on a hip scan, WHO criteria), and not taking any drugs related to bone formation, including calcium or vitamin D supplementation, were randomly assigned to either oral 800 IU vitamin D₃ plus 1 g calcium or placebo, in a double-blind prospective study. We measured biochemical, radiographic, and bone mineral density effect parameters to evaluate the impact on the healing process. Scanning procedures of the fractured shoulder included use of a fixation device to obtain the highest possible precision. Double scans of the fractured shoulder revealed a coefficient of variation (CV) on BMD measurements that improved from 2.8% immediately after fracture occurrence to 1.7% at 12 weeks (P = 0.003) approaching the 1.2% levels observed over the healthy shoulder. BMD was similar in the two groups at baseline (active 0.534 g/cm² vs. placebo 0.518 g/cm²), and both increased over the 12-week observation period, with peak levels in week 6. By week 6 BMD levels were higher in the active group (0.623 g/cm²) compared with the placebo group (0.570 g/cm², P = 0.006). Thirty seven percent of the patients presented with vitamin D levels below 30 nmol/l, indicative of mild vitamin D insufficiency. In conclusion, we have demonstrated that it is possible to quantify callus formation of the PHF with sufficiently high precision to demonstrate the positive influence of vitamin D₃ and calcium over the first 6 weeks after fracture. Whether this results in more stable fractures, extends to other fracture types, or applies to other osteogenic bone agents such as bisphosphonates remains to be examined.     

Assessment of Bone Microarchitecture in Chronic Kidney Disease: A Comparison of 2D Bone Texture Analysis and High-Resolution Peripheral Quantitative Computed Tomography at the Radius and Tibia

Bone microarchitecture can be studied noninvasively using high-resolution peripheral quantitative computed tomography (HR-pQCT). However, this technique is not widely available, so more simple techniques may be useful. BMA is a new 2D high-resolution digital X-ray device, allowing for bone texture analysis with a fractal parameter (H_mean). The aims of this study were (1) to evaluate the reproducibility of BMA at two novel sites (radius and tibia) in addition to the conventional site (calcaneus), (2) to compare the results obtained with BMA at all of those sites, and (3) to study the relationship between H_mean and trabecular microarchitecture measured with an in vivo 3D device (HR-pQCT) at the distal tibia and radius. BMA measurements were performed at three sites (calcaneus, distal tibia, and radius) in 14 healthy volunteers to measure the short-term reproducibility and in a group of 77 patients with chronic kidney disease to compare BMA results to HR-pQCT results. The coefficient of variation of H_mean was 1.2, 2.1, and 4.7% at the calcaneus, radius, and tibia, respectively. We found significant associations between trabecular volumetric bone mineral density and microarchitectural variables measured by HR-pQCT and H_mean at the three sites (e.g., Pearson correlation between radial trabecular number and radial H_mean r = 0.472, P < 0.001). This study demonstrated a significant but moderate relationship between 2D bone texture and 3D trabecular microarchitecture. BMA is a new reproducible technique with few technical constraints. Thus, it may represent an interesting tool for evaluating bone structure, in association with biological parameters and DXA.     

Strontium Is Incorporated into the Fracture Callus but Does Not Influence the Mechanical Strength of Healing Rat Fractures

Strontium ranelate (SrR) is a new agent used in the treatment of osteoporosis and is suggested to reduce bone resorption and increase bone formation. We investigated whether SrR influences the macro- and nanomechnical properties of healing fractures in rats. A closed tibia fracture model was used to study fracture healing in rats after 3 and 8 weeks of healing. Two groups of rats were treated with SrR (900 mg/kg/day) mixed into the food, while two groups served as control animals. The healing fractures were investigated by three-point bending, dual energy X-ray absorptiometry, energy-dispersive X-ray spectroscopy (EDX), and nanoindentation. There was a 100-fold increase (P < 0.001) in serum Sr after 3 and 8 weeks of SrR treatment. The callus volume was significantly higher in the SrR-treated group than in control animals (P < 0.01) after 3 weeks of healing. This was accompanied by a significant increase in callus bone mineral content (P < 0.05). However, after 8 weeks of healing, no difference was found in either callus volume or bone mineral content. SrR did not influence maximum load or stiffness of the fractures after either 3 or 8 weeks of healing. EDX showed that Sr was incorporated into the callus; however, this did not influence the nanomechanical properties. In conclusion, SrR stimulates callus formation but has no effect on callus remodeling. Sr is incorporated into the newly formed callus tissue, but this has no deteriorating effect on the mechanical properties of rat tibial fractures at either the macroscopic or nanoscopic level after 3 or 8 weeks of healing.     

Rapid correction of low vitamin D status in nursing home residents

Summary  This prospective study finds that ergocalciferol 50,000 IU three times weekly for four weeks effectively and safely corrects vitamin D inadequacy in nursing home residents. Introduction  Low vitamin D status is common among nursing home residents and contributes to bone loss, falls and fractures. The objective of this study was to evaluate the efficacy and safety of short course, high dose, oral vitamin D₂ (ergocalciferol) treatment. Methods  This prospective study included 63 nursing home residents. The 25 with low vitamin D status (serum 25(OH)D ≤ 25 ng/ml) received oral ergocalciferol 50,000 IU three times weekly for four weeks; the others received no change to their routine care. Serum total 25(OH)D, 25(OH)D₂, 25(OH)D₃, calcium, parathyroid hormone (PTH), bone turnover markers and neuro-cognitive assessments were obtained at baseline and four weeks. Results  Mean total 25(OH)D concentration increased (p < 0.0001) from 17.3 to 63.8 ng/ml in the treated group and remained unchanged in the comparison group. Serum 25(OH)D₃ remained stable in the comparison group, but declined (p < 0.0001) with D₂ treatment from 15.4 to 9.1 ng/ml. Serum PTH trended down in the treatment group (p = 0.06). No treatment-induced improvement in ambulation, cognition or behavior was observed. No hypercalcemia or other adverse effects were observed with ergocalciferol treatment. Conclusion  Four weeks of oral vitamin D₂ supplementation effectively and safely normalizes serum 25(OH)D in nursing home residents.     

Determinants of the mechanical behavior of human lumbar vertebrae after simulated mild fracture

The ability of a vertebra to carry load after an initial deformation and the determinants of this postfracture load‐bearing capacity are critical but poorly understood. This study aimed to determine the mechanical behavior of vertebrae after simulated mild fracture and to identify the determinants of this postfracture behavior. Twenty‐one human L₃ vertebrae were analyzed for bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA) and for microarchitecture by micro–computed tomography (µCT). Mechanical testing was performed in two phases: initial compression of vertebra to 25% deformity, followed, after 30 minutes of relaxation, by a similar test to failure to determine postfracture behavior. We assessed (1) initial and postfracture mechanical parameters, (2) changes in mechanical parameters, (3) postfracture elastic behavior by recovery of vertebral height after relaxation, and (4) postfracture plastic behavior by residual strength and stiffness. Postfracture failure load and stiffness were 11% ± 19% and 53% ± 18% lower than initial values (p = .021 and p < .0001, respectively), with 29% to 69% of the variation in the postfracture mechanical behavior explained by the initial values. Both initial and postfracture mechanical behaviors were significantly correlated with bone mass and microarchitecture. Vertebral deformation recovery averaged 31% ± 7% and was associated with trabecular and cortical thickness (r = 0.47 and r = 0.64; p = .03 and p = .002, respectively). Residual strength and stiffness were independent of bone mass and initial mechanical behavior but were related to trabecular and cortical microarchitecture (|r| = 0.50 to 0.58; p = .02 to .006). In summary, we found marked variation in the postfracture load‐bearing capacity following simulated mild vertebral fractures. Bone microarchitecture, but not bone mass, was associated with postfracture mechanical behavior of vertebrae. © 2011 American Society for Bone and Mineral Research.     

Pharmacokinetics of oral vitamin D3 and calcifediol

AimLong-term pharmacokinetics after supplementation with vitamin D₃ or calcifediol (the 25-hydroxyvitamin D₃ metabolite) is not well studied. Additionally, it is unclear whether bolus doses of vitamin D₃ or calcifediol lead to 25(OH)D₃ plasma concentrations considered desirable for fracture prevention (30 ng/mL). We therefore investigated plasma pharmacokinetics of 25(OH)D₃ during different vitamin D₃ and calcifediol supplementation regimens.MethodsIn this seven-arm, randomized, double-blind, controlled parallel-group study, 35 healthy females aged 50–70 years (5 per group) received 20 μg calcifediol or vitaminD₃ daily, 140 μg calcifediol or vitaminD₃ weekly, for 15 weeks, or a single bolus of either 140 μg calcifediol, or vitaminD₃, or both. 25(OH)D₃ plasma concentrations were quantified using LC–MS/MS in 14 clinical visits among all participants.ResultsFor daily (weekly) dosing, the area under the concentration–time curve (AUC_0–24h), which is the measure for exposure, was 28% (67%) higher after the first dose of calcifediol than after the first dose of vitamin D₃. After 15 weeks, this difference was 123% (178%). All women in the daily and weekly calcifediol groups achieved 25(OH)D₃ concentrations > 30 ng/mL (mean, 16.8 days), but only 70% in the vitamin D₃ daily or weekly groups reached this concentration (mean, 68.4 days). A single dose of 140 μg calcifediol led to 117% higher 25(OH)D₃ AUC_0–96h values than 140 μg vitamin D₃, while the simultaneous intake of both did not further increase exposure.ConclusionsCalcifediol given daily, weekly, or as a single bolus is about 2–3 times more potent in increasing plasma 25(OH)D₃ concentrations than vitamin D₃. Plasma 25(OH)D₃ concentrations of 30 ng/mL were reached more rapidly and reliably with calcifediol.     

Teriparatide Followed by Denosumab in Premenopausal Idiopathic Osteoporosis: Bone Microstructure and Strength by HR-pQCT

Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in skeletal microstructure. We have reported that sequential treatment with teriparatide and denosumab improves central skeletal bone mineral density (BMD) by dual-energy X-ray absorptiometry and central QCT in PreMenIOP. We conducted preplanned analyses of high-resolution peripheral quantitative computed tomography (HR-pQCT) scans from teriparatide and denosumab extension studies to measure effects on volumetric BMD (vBMD), microarchitecture, and estimated strength at the distal radius and tibia. Of 41 women enrolled in the parent teriparatide study (20 mcg daily), 34 enrolled in the HR-pQCT study. HR-pQCT participants initially received teriparatide (N = 24) or placebo (N = 10) for 6 months; all then received teriparatide for 24 months. After teriparatide, 26 enrolled in the phase 2B denosumab extension (60 mg q6M) for 24 months. Primary outcomes were percentage change in vBMD, microstructure, and stiffness after teriparatide and after denosumab. Changes after sequential teriparatide and denosumab were secondary outcomes. After teriparatide, significant improvements were seen in tibial trabecular number (3.3%, p = 0.01), cortical area and thickness (both 2.7%, p < 0.001), and radial trabecular microarchitecture (number: 6.8%, thickness: 2.2%, separation: −5.1%, all p < 0.02). Despite increases in cortical porosity and decreases in cortical density, whole-bone stiffness and failure load increased at both sites. After denosumab, increases in total (3.5%, p < 0.001 and 3.3%, p = 0.02) and cortical vBMD (1.7% and 3.2%; both p < 0.01), and failure load (1.1% and 3.6%; both p < 0.05) were seen at tibia and radius, respectively. Trabecular density (3.5%, p < 0.001) and number (2.4%, p = 0.03) increased at the tibia, while thickness (3.0%, p = 0.02) increased at the radius. After 48 months of sequential treatment, significant increases in total vBMD (tibia: p < 0.001; radius: p = 0.01), trabecular microstructure (p < 0.05), cortical thickness (tibia: p < 0.001; radius: p = 0.02), and whole bone strength (p < 0.02) were seen at both sites. Significant increases in total vBMD and bone strength parameters after sequential treatment with teriparatide followed by denosumab support the use of this regimen in PreMenIOP. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Longitudinal study of vitamin D metabolites after long bone fracture

Animal models suggest a key role for dihydroxylated vitamin D metabolites in fracture healing, as evidenced by increases in serum concentration of 24R,25‐dihydroxyvitamin D (24R,25[OH]₂D) after long bone fracture. Human studies investigating the kinetics of serum concentrations of 24R,25[OH]₂D, 1,25‐dihydroxyvitamin D (1,25[OH]₂D) and their parent metabolite 25‐hydroxyvitamin D (25[OH]D) are lacking. We, therefore, conducted a longitudinal study to determine whether total, free, or bioavailable concentrations of these vitamin D metabolites fluctuate in humans after long bone fracture. Twenty‐eight patients with cross‐shaft (diaphyseal) long bone fracture presenting to an emergency department in London, UK, were studied. Serum concentrations of 25(OH)D, 24R,25(OH)₂D, 1,25(OH)₂D, vitamin D binding protein, albumin, and calcium were determined within 48 hours of fracture and again at 1 and 6 weeks postfracture. Concentrations of free and bioavailable vitamin D metabolites were calculated using standard equations. No changes in mean serum concentrations of 25(OH)D or 24R,25(OH)₂D were seen at either follow‐up time point versus baseline. In contrast, mean serum 1,25(OH)₂D concentration declined by 21% over the course of the study, from 68.5 pmol/L at baseline to 54.1 pmol/L at 6 weeks (p < 0.05). This decline was associated with an increase in mean serum corrected calcium concentration, from 2.32 mmol/L at baseline to 2.40 mmol/L at 1 week (p < 0.001) that was maintained at 6 weeks. No changes in free or bioavailable concentrations of any vitamin D metabolite investigated were seen over the course of the study. We conclude that serum 1,25(OH)₂D concentration declines after long bone fracture in humans but that the serum 24R,25(OH)₂D concentration does not fluctuate. The latter finding contrasts with those of animal models reporting increases in serum 24R,25(OH)₂D concentration after long bone fracture.     

Bone Impairment in a Large Cohort of Chinese Patients With Tumor-Induced Osteomalacia Assessed by HR-pQCT and TBS

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Previous studies have revealed generalized mineralization defects and low areal bone mineral density (aBMD) in TIO. However, data on the bone microarchitecture in TIO are limited. In this study, we evaluated the microarchitecture in the peripheral (distal radius and tibia) and axial (lumbar spine) skeleton using high-resolution peripheral quantitative computed tomography (HR-pQCT) and trabecular bone score (TBS) and investigated related factors in a large cohort of Chinese patients with TIO. A total of 186 patients with TIO who had undergone dual-energy X-ray absorptiometry (DXA) or HR-pQCT scans were enrolled. Compared with age-, sex-, and body mass index (BMI)-matched healthy controls, TIO patients (n = 113) had lower volumetric BMD, damaged microstructure, and reduced bone strength in the peripheral skeleton, especially at the tibia. The average TBS obtained from 173 patients was 1.15 ± 0.16. The proportion of patients with abnormal TBS (<1.35) was higher than that with low L₁ to L₄ aBMD Z-score (Z ≤ −2) (43.9% versus 89.6%, p < 0.001). Higher intact fibroblast growth factor 23 (iFGF23), intact parathyroid hormone (iPTH), alkaline phosphatase, and β-isomerized C-terminal telopeptide of type I collagen (β-CTx) levels, more severe mobility impairment, and a history of fracture were associated with poorer HR-pQCT parameters but not with lower TBS. However, greater height loss and longer disease duration were correlated with worse HR-pQCT parameters and TBS. Moreover, TBS was correlated with both trabecular and cortical HR-pQCT parameters in TIO. In conclusion, we revealed impaired bone microarchitecture in the axial and peripheral skeleton in a large cohort of Chinese TIO patients. HR-pQCT parameters and TBS showed promising advantages over aBMD for assessing bone impairment in patients with TIO. A longer follow-up period is needed to observe changes in bone microarchitecture after tumor resection. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Anticonvulsant drug-induced osteomalacia: Alterations in mineral metabolism and response to vitamin D3 administration

Summary Parameters of mineral metabolism were examined in 6 patients with moderately severe anticonvulsant drug-induced osteomalacia. Compared to 15 matched controls, the patients exhibited significantly reduced serum calcium, inorganic phosphate, and 25-hydroxyvitamin D concentration, elevated serum alkaline phosphatase and immunoreactive parathyroid hormone (iPTH) concentration, reduced intestinal⁴⁷Ca absorption, reduced urinary calcium and increased urinary hydroxyproline excretion, and reduced forearm bone mass. Intestinal absorption of vitamin D₃ was normal. Following 4 months of treatment with vitamin D₃ (4000 units/day), serum 25-OHD concentration was increased to 3 times mean normal values and all parameters except serum iPTH, urinary calcium excretion, and forearm bone mass were returned to levels not significantly different from normal. Serum iPTH concentration was reduced by 39% (P<0.05); 24-h urinary calcium excretion rose by 98% (P<0.001), and forearm bone mass increased by 5.6% (P<0.05). It is concluded that moderate-dose vitamin D₃ supplementation is effective in normalizing parameters of mineral metabolism in this disorder, despite evidence of resistance to the biologic effects of vitamin D.     

Vitamin D Binding Protein Genotype and Osteoporosis

Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF), which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1), Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased and decreased serum 25-(OH)D₃ for haplotype 1 (P = 3 × 10⁻⁴) and haplotype 2 (P = 3 × 10⁻⁶), respectively. Similar associations were observed for 1,25-(OH)₂D₃. The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers (P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06–2.05). All associations were independent of age and gender. Our study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic and environmental risk factors for bone metabolism.     

Association Between Muscle Mass Determined by D3-Creatine Dilution and Incident Fractures in a Prospective Cohort Study of Older Men

The relation between a novel measure of total skeletal muscle mass (assessed by D₃-creatine dilution [D₃Cr]) and incident fracture is unknown. In 1363 men (mean age 84.2 years), we determined D₃Cr muscle mass; Fracture Risk Assessment Tool (FRAX) 10-year probability of hip and major osteoporotic (hip, humerus, vertebral, forearm) fracture; and femoral neck bone mineral density (BMD) (by dual-energy X-ray absorptiometry [DXA]). Incident fractures were centrally adjudicated by review of radiology reports over 4.6 years. Correlations adjusted for weight and height were calculated between femoral neck BMD and D₃Cr muscle mass. Across quartiles of D₃Cr muscle mass/weight, proportional hazards models calculated hazard ratios (HRs) for any (n = 180); nonspine (n = 153); major osteoporotic fracture (n = 85); and hip fracture (n = 40) after adjustment for age, femoral neck BMD, recurrent fall history, and FRAX probability. Models were then adjusted to evaluate the mediating influence of physical performance (walking speed, chair stands, and grip strength). D₃Cr muscle mass was weakly correlated with femoral BMD (r = 0.10, p < 0.001). Compared to men in the highest quartile, those in the lowest quartile of D₃Cr muscle mass/weight had an increased risk of any clinical fracture (HR 1.8; 95% confidence interval [CI], 1.1–2.8); nonspine fracture (HR 1.8; 95% CI, 1.1–3.0), major osteoporotic fracture (HR 2.3; 95% CI, 1.2–4.6), and hip fracture (HR 5.9; 95% CI, 1.6–21.1). Results were attenuated after adjustment for physical performance, but associations remained borderline significant for hip and major osteoporotic fractures (p ≥ 0.05 to 0.10). Low D₃Cr muscle mass/weight is associated with a markedly high risk of hip and potentially other fractures in older men; this association is partially mediated by physical performance. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Effect of vitamin D3 treatment on bone density in neurofibromatosis 1 patients: A retrospective clinical study

ObjectivesWe have previously demonstrated reduced bone density and an increased incidence of 25-hydroxy vitamin D₃ (25-OH D₃) deficiency in adults with neurofibromatosis 1 (NF1) compared to healthy controls. Vitamin D₃ is a cheap, safe, and effective supplement in the general population, but its value in NF1 patients has not been demonstrated. This study investigates the therapeutic potential of oral vitamin D₃ on bone mineral density (BMD) in NF1 patients with vitamin D₃ deficiency.MethodsWe measured serum 25-OH D₃, parathyroid hormone, calcium, and bone alkaline phosphatase concentrations, urinary deoxypyridinoline concentrations, and BMD in 35 adults with NF1. Nineteen patients received vitamin D₃ supplementation for 2 years, six patients received supplementation for 1 year and 10 patients received no supplementation. Supplementation was administered in a dose that maintained the serum 25-OH D₃ level above 30 μg/l. BMD was measured again at 1 and 2 years, and biochemical assessments of bone metabolism were measured at least every half year during therapy.ResultsTreated subjects had significantly reduced loss of BMD, as measured by T score at the hip (p = 0.011) and lumbar spine (p = 0.022). The effect on hip BMD was apparent at 1 year in comparison to baseline (p = 0.02) and was greater at 2 years in comparison to measurements at 1 year (p = 0.02).ConclusionsVitamin D₃ supplementation improves BMD in adult NF1 patients. Further studies are needed to elucidate the mechanisms responsible for reduced BMD in NF1 patients.     

Adverse Effects of High-Dose Vitamin D Supplementation on Volumetric Bone Density Are Greater in Females than Males

Three years of high-dose vitamin D supplementation (400 IU, 4000 IU, 10,000 IU) in healthy vitamin D–sufficient individuals aged 55 to 70 years (serum 25(OH)D 30–125 nmol/L at baseline), resulted in a negative dose-response relationship for bone density and strength. This study examined whether response differed between males and females. A total of 311 participants (53% male) were randomized to 400 IU (male = 61, female = 48), 4000 IU (male = 51, female = 49), or 10,000 IU (male = 53, female = 49) daily vitamin D₃. Participants were scanned with high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure total volumetric BMD (TtBMD) at baseline, 6, 12, 24, and 36 months. Finite element analysis estimated bone strength. Balance, physical function, and clinical biochemistry parameters were also assessed. Constrained linear mixed effects models determined time-by-treatment group-by-sex interactions. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L (400 IU); 81.3, 115.3, and 132.2 (4000 IU); and 78.4, 188.0, and 144.4 (10,000 IU), respectively. There were significant time-by-treatment group-by-sex interactions for TtBMD at the radius (p = .002) and tibia (p = .005). Treatment with 4000 IU or 10,000 IU compared to 400 IU resulted in TtBMD losses in females, but this was not observed with males. After 3 years, females lost 1.8% (400 IU), 3.8% (4000 IU), and 5.5% (10,000 IU), whereas males lost 0.9% (400 IU), 1.3% (4000 IU), and 1.9% (10,000 IU) at the radius. At the tibia, losses in TtBMD were smaller, but followed a similar trend. There were no significant bone strength interactions. Vitamin D supplementation with 4000 IU or 10,000 IU, compared with 400 IU daily, resulted in greater losses of TtBMD over 3 years in healthy vitamin D–sufficient females, but not males. These results are clinically relevant, because vitamin D supplementation is widely administered to postmenopausal females for osteoporosis prevention. Our findings do not support a benefit of high-dose vitamin D supplementation for bone health, and raise the possibility of harm for females. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Recovery of Bone Mineral Density in 126 Patients after Surgery for Primary Hyperparathyroidism

Primary hyperparathyroidism (pHPT) is associated with increased fracture risk and decreased bone mass. The recovery of bone mass after surgery varies; therefore tests that predict the increase in bone mass after parathyroidectomy would be desirable. Preoperatively and at 1 year after surgery bone mineral content (BMC) in the distal radius and bone mineral density (BMD) in the lumbar spine and hip, as well as biochemical variables, were measured in 126 pHPT patients (95 women, 31 men). The mean ± SD age of the patients was 63 ± 15 years. The mean ± SD serum calcium level was 2.78 ± 0.16 mmol/L. Altogether, 60% of the patients had a low oral calcium intake, and 18% had a 25-hydroxyvitamin D₃ deficiency. Preoperatively, postmenopausal women had lower Z-scores for BMD in the hip (p < 0.001) and lumbar spine (p < 0.05) than did premenopausal women. One year after surgery the bone density had increased in about 50% of the patients. The multiple logistic regression analysis showed that there was a weak association between the change in BMD in the hip, the serum 1,25-dihydroxyvitamin D₃ level (p < 0.05), and renal function (p < 0.05), respectively. We concluded that about 50% of patients have increased bone mass after pHPT surgery, but the increase in the bone density is difficult to predict for the individual patient. Because many pHPT patients have low oral calcium intake and a vitamin D deficiency, it would be of interest to evaluate the role of postoperative calcium/vitamin D supplements.     

Postmenopausal women treated with combination parathyroid hormone (1–84) and ibandronate demonstrate different microstructural changes at the radius vs. tibia: the PTH and Ibandronate Combination Study (PICS)

Summary

In postmenopausal women receiving combination parathyroid hormone (PTH) (1–84) therapy and ibandronate, we evaluated bone microarchitecture and biomechanics using high-resolution peripheral quantitative computed tomography (HR-pQCT). Cortical and trabecular changes were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia.

Introduction

PTH therapy and bisphosphonates decrease fracture risk in postmenopausal osteoporosis, but their effects on bone microstructure and strength have not been fully characterized, particularly during combination therapy. PTH increases trabecular bone mineral density (BMD) substantially but may decrease cortical BMD, possibly by stimulating intracortical remodeling. We evaluated bone microarchitecture and biomechanics with HR-pQCT at the radius (a nonweight-bearing site) and tibia (weight bearing) in women receiving combination PTH(1–84) and ibandronate.

Methods

Postmenopausal women with low bone mass (n?=?43) were treated with 6 months of PTH(1–84) (100 μg/day), either as one 6- or two 3-month courses, in combination with ibandronate (150 mg/month) over 2 years. HR-pQCT was performed before and after therapy.

Results

Because changes in HR-pQCT parameters did not differ between treatment arms, groups were pooled into one cohort for analysis. Trabecular BMD increased at both radius and tibia (p?<?0.01 for each). Cortical thickness and BMD decreased at the radius (p?<?0.01), consistent with changes in dual-energy X-ray absorptiometry, while these parameters did not change at the tibia (p?≤?0.02 for difference between radius and tibia). In contrast, cortical porosity increased at the tibia (p?<?0.01) but not radius. Stiffness and failure load decreased at the radius (p?<?0.0001) but did not change at the tibia.

Conclusions

Cortical and trabecular changes in response to the PTH/ibandronate treatment combinations utilized in this study were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. Our findings support the possibility that weight bearing may optimize the effects of osteoporosis therapy.     

Early Changes in Bone Density,Microarchitecture, Bone Resorption,and Inflammation Predict the Clinical Outcome 12 Weeks After Conservatively Treated Distal Radius Fractures: An Exploratory Study

Fracture healing is an active process with early changes in bone and inflammation. We performed an exploratory study evaluating the association between early changes in densitometric, structural, biomechanical, and biochemical bone parameters during the first weeks of fracture healing and wrist‐specific pain and disability at 12 weeks in postmenopausal women with a conservatively treated distal radius fracture. Eighteen patients (aged 64 ± 8 years) were evaluated at 1 to 2 and 3 to 4 weeks postfracture, using high‐resolution peripheral quantitative computed tomography (HR‐pQCT), micro‐finite element analysis, serum procollagen type‐I N‐terminal propeptide (P1NP), carboxy‐terminal telopeptide of type I collagen (ICTP), and high‐sensitive C‐reactive protein (hsCRP). After 12 weeks, patients rated their pain and disability using Patient Rated Wrist Evaluation (PRWE) questionnaire. Additionally, Quick Disability of the Arm Shoulder and Hand (QuickDASH) questionnaire and active wrist range of motion was evaluated. Linear regression models were used to study the relationship between changes in bone parameters and in hsCRP from visit 1 to 2 and PRWE score after 12 weeks. A lower PRWE outcome, indicating better outcome, was significantly related to an early increase in trabecular bone mineral density (BMD) (β ?0.96 [95% CI ?1.75 to ?0.16], R² = 0.37), in torsional stiffness (?0.14 [?0.28 to ?0.004], R² = 0.31), and to an early decrease in trabecular separation (209 [15 to 402], R² = 0.33) and in ICTP (12.1 [0.0 to 24.1], R² = 0.34). Similar results were found for QuickDASH. Higher total dorsal and palmar flexion range of motion was significantly related to early increase in hsCRP (9.62 [3.90 to 15.34], R² = 0.52). This exploratory study indicates that the assessment of early changes in trabecular BMD, trabecular separation, calculated torsional stiffness, bone resorption marker ICTP, and hsCRP after a distal radius fracture provides valuable information regarding the 12‐week clinical outcome in terms of pain, disability, and range of motion and validates its use in studies on the process of early fracture healing. © 2014 American Society for Bone and Mineral Research.