Beatriz Oliveri

Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures

Dual‐energy X‐ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient‐level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T‐score < −2.5 and not < −4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time‐dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%–61%] and 51% [95% CI: 39%–66%] accounted for by percent change at month 36 and change in time‐dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% – >100%] and 72% [95% CI: 24% – >100%], respectively). Previous patient‐level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab.

Effect of intravenous pamidronate on bone markers and local bone mineral density in fibrous dysplasia

Bisphosphonates have proven to be effective in patients with fibrous dysplasia of the bone (FD) as shown by their effect on bone pain, markers of bone turnover, or radiological changes. The aim of this study was to evaluate the usefulness of measuring bone mineral density (BMD) of affected bones to assess the efficacy of bisphosphonate treatment. Seven patients (mean age 26 years) received courses of 180 mg intravenous infusion of pamidronate every 6 months (60 mg/day during 3 days). Clinical symptoms, serum alkaline phosphatase, and urinary C-terminal cross-linking telopeptide of type I collagen were assessed every 3 months. BMD of total skeleton and X-rays of FD areas (FDa) were performed at baseline and at 12 months. BMD of FDa was compared with the contralateral side (CL) using the region of interest program on the total skeleton scan. BMD of total skeleton was normal at baseline. Average BMD of FDa was -11.4% compared with CL, a significantly greater difference than that observed between the left and right sides in healthy controls, -0.7% (P < 0.02). At 12 months bone pain diminished in all patients. Bone turnover markers decreased. Mean total skeleton BMD increased 3.3% (P < 0.02). Subregions of the total skeleton scan presenting FD lesions augmented: arms +9.6% (P < 0.02), legs +4.2%, and pelvis +3.5% (P < 0.05). The increase in mean BMD of FDa was +6.8% compared with +2.6% in CL. No changes were observed on the X-ray. These results indicate that simultaneous determination of markers of bone turnover and BMD of FDa is useful in short-term follow-up to determine the efficacy of intravenous pamidronate.

Vitamin D2 dose required to rapidly increase 25OHD levels in osteoporotic women.

Objective:Assessment of the effectiveness and safety of high daily 125 μg (5000 IU) or 250 μg (10 000IU) doses of vitamin D2 during 3 months, in rapidly obtaining adequate 25 hydroxyvitamin D (25OHD) levels.Design:Longitudinal study.Subjects:Postmenopausal osteopenic/osteoporotic women (n=38) were studied during winter and spring. Median age (25–75th percentile) was 61.5 (57.00–66.25) years, and mean bone mineral density (BMD) was 0.902 (0.800–1.042)g/cm2. Subjects were randomly divided into three groups: control group (n=13): no vitamin D2, 125 μg/day (n=13) and 250 μg/day (n=12) of vitamin D2 groups, all receiving 500 mg calcium/day. Serum calcium, phosphate, bone alkaline phosphatase (BAP), C-telopeptide (CTX), 25OHD, mid-molecule parathyroid hormone (mmPTH), daily urinary calcium and creatinine excretion were determined at baseline and monthly.Results:For all subjects (n=38), the median baseline 25 hydroxyvitamin D (25OHD) level was 36.25 (27.5–48.12) nmol/l. After 3 months, 8% of the patients in the control group, 50% in the 125 μg/day group and 75% in the 250 μg/day group had 25OHD values above 85 nmol/l (34 ng/ml). Considering both vitamin D2 groups together, mmPTH and BAP levels diminished significantly after 3 months (P<0.02), unlike those of CTX. Serum calcium remained within normal range during the follow-up.Conclusions:The oral dose of vitamin D2 required to rapidly achieve adequate levels of 25OHD is seemingly much higher than the usual recommended vitamin D3 dose (20 μg/day). During 3 months, 250 μg/day of vitamin D2 most effectively raised 25OHD levels to 85 nmol/l in 75% of the postmenopausal osteopenic/osteoporotic women treated.

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.

CHAPTER 24 – Densitometric Manifestations in Age-Related Bone Loss

This chapter considers various methodologies by which bone density is monitored, and the data that reveals the universal loss of bone mass associated with aging. The physical basis of densitometry is the differential attenuation of radiation by bone mineral from the soft tissues that surround the bone. The single photon absorptiometry (SPA) technique assumes that the soft tissue around the bone has a constant thickness. Total body scans can be done in approximately 10 to 15 minutes using dual-energy X-ray absorptiometry (DXA). They provide not only bone mineral density (BMD) of the total skeleton and its subregions, but also a very accurate measurement of soft tissue composition (fat and lean tissue). Bone densitometry provides essentially two measurements: bone mineral content (BMC, in grams) and bone area (in cm 2 ). BMC/area is called bone mineral density (in g/cm 2 ). BMD is strongly correlated with bone strength and therefore, is a powerful indicator of fracture risk. Bone densitometry, now a widely used and an essential element in clinical evaluation, can assess the skeletal status of patients with different metabolic bone diseases, monitor the effect of the disease itself or its treatment on the bone, and establish the risk for future osteoporotic fractures. Quantitative computed tomography (QCT) is another technique that provides a volumetric measurement of bone density in the vertebral body.

Effect of one year residence in Antarctica on bone mineral metabolism and body composition.

Objective:To evaluate the changes of the biochemical parameters of mineral metabolism and to assess the effect of these changes on the bone mass of young healthy men who voluntarily lived in the Antarctic Continent for one year.Design:Lumbar spine and whole body bone mineral density (BMD) were measured pre- and post-campaign (14 months later). Serum and urinary biochemical parameters were measured every two months. Serum levels of calcium, phosphate, total alkaline phosphatase, parathormone (PTH) and 25-hydroxyvitamin D (250HD) were determined in blood fasting samples; and hydroxyproline, calcium and creatinine in 2 h fasting urine. The subjects received a dose of 100 IU/d of vitamin D during May after obtaining the samples and then an average of 125 IU/d from July to January.Subjects: Seventeen healthy volunteers, who left Buenos Aires during the 1992 summer: ten arrived in the Belgrano II Base at the end of January and the other seven arrived in San Martín in March and stayed there up to summer 1993.Results:BMD increased in lumbar spine (L2–L4), total body and the subarea of the legs but there were no differences between the pre- and post-campaign values in arms and pelvis. The percentage of fat mass decreased significantly after 1 y of residence in Antarctica, in comparison to the basal values. Most biochemical parameters remained unaltered and within the normal range during the whole study. PTH showed a nadir in March (end of the summer) when compared to initial levels (73.0±28.2 vs 39.9±32.7 pg/ml, P<0.05), and recovered its initial value in spring. Calcium levels showed a significant decrease in March (9.5±0.4 vs 8.5±1.0 mg%, P<0.01). 25OHD levels began to decrease in March (24.7±6.4 vs 18.7±5.3 ng/ml), reaching a minimum value whose difference approached statistical significance during the winter period (July: 16.4±8.2  ml, 0.05<P<0.06). No significant changes in serum phosphate, total alkaline phosphatase, urinary hydroxyproline/creatinine and calcium/creatinine ratios were found through the year.Conclusions:25OHD levels decreased in autumn and winter (nadir in July) and recovered the initial levels by the end of the campaign. An unexplained marked diminution in PTH and serum calcium was found at the beginning of the campaign. In spite of the low vitamin D levels, bone mass in this group of young healthy men increased, probably because of their intense physical activity.Sponsorship:Fundación Argentina de Osteología e Instituto Antártico Argentino.

Long-Term Pamidronate Treatment of Polyostotic Fibrous Dysplasia of Bone: A Case Series in Young Adults

BACKGROUND Limited information is available about long-term pamidronate treatment in adults with fibrous dysplasia (FD) of bone. OBJECTIVE The aim of this case series was to report the clinical outcomes and the biochemical and densitometric findings in a group of young adult patients with polyostotic FD treated for ≥3 years with IV pamidronate. METHODS Pamidronate was administered every 6 months (60 mg/d for 3 days) for 2 years. Thereafter, treatment was individualized. Pamidronate was administered at shorter or longer intervals based on response. Bone pain, radiography, serum bone alkaline phosphatase (BALP) activity, and urinary C-terminal cross-linking telopep-tide of type I collagen (CTX-I) concentration were assessed for a mean of 7 years. Bone mineral density (BMD) of FD areas (FDas) and contralateral areas (CLas) were measured at baseline and at 12 and 24 months. Data were collected prospectively. RESULTS Seven patients (5 women, 2 men; mean [SD] age, 31.0 [7.2] years [range, 22-43 years]) were included in the study. Patients received IV pamidronate for a mean of 6.9 years (median, 7.1 years [range, 3.7-10.9 years]). Pamidronate was associated with a reduction in bone pain and a significant reduction in BALP in all patients at the end of follow-up (P < 0.02). The mean reduction from baseline in CTX-I concentration (measured in 3 patients) was 56%; this difference was not significant. Mean BMD values of FDas were significantly increased at 12 months (by 5.9%; P < 0.05) compared with baseline; but was not significantly increased at 24 months (7.3%), probably reflecting a higher dispersion of values due to individual responses to treatment. No significant changes were observed in CLa BMDs. Mean BMD of FDa had a numerically lower decrease of 15.3% compared with CLa at baseline; these decreases with pamidronate were 10.8% at 12 months (P = NS) and 9.3% at 24 months (P < 0.05). Refilling of osteolytic lesions was not observed. CONCLUSIONS These patients with FD of bone treated with IV pamidronate long term had improvement in bone pain and BMD. The effectiveness of individualized pamidronate administration in the long-term treatment of FD in adult patients should be investigated in blinded controlled trials.

Is ultrasound of bone relevant for corticosteroid-treated patients? A comparative study with bone densitometry measured by DEXA

Corticosteroid treatment diminishes bone mass and alters bone quality. The objective was to evaluate bone in corticosteroid-treated patients and controls and in fractured and non-fractured patients treated with corticosteroids using both X-ray densitometry (DEXA) and ultrasound. We evaluated 34 women aged 58 +/- 14 years (X +/- SD), who had been on long-term low dose prednisone therapy for at least 6 months, and who had never received specific treatment for osteoporosis. Bone mineral density of total skeleton (TS), lumbar spine (LS), femoral neck (FN), and vertebral morphometry (MXA) were measured by DEXA. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness were measured using an Achilles Plus system. Forty-two healthy women served as controls. Both densitometric and ultrasound parameters in the patients were significantly diminished compared with controls: TS: P < 0.002, LS: P < 0.025, FS: P < 0.005, Stiffness: P < 0.001, BUA: P < 0.002 and SOS: P < 0.002. The percentage of patients with a Z score below -2 was higher in Stiffness and BUA: 38% and 47%, respectively, compared with a range of 16-24% in the other parameters (P < 0.05 BUA vs. DEXA measurements). Eleven patients with previous bone fracture had values lower than the non-fractured patients, both according to DEXA and ultrasound measurements, but the difference was only significant for BUA (P < 0.02). BUA of the calcaneus was more effective in detecting the specific skeletal alterations and fracture risk of the group of patients receiving chronic corticosteroid treatment.

Increase in android fat mass with age in healthy women with normal body mass index.

Body fat distribution is gender specific: men tend to accumulate adipose tissue in the android region, whereas women tend to do so in the gynoid region. The aim of the study was to assess total fat mass (TFM), android fat (AF), and gynoid fat (GF) mass in a selected group of healthy adult women with normal body mass index (BMI) to evaluate variations in fat distribution. Seventy-seven women (20--69yr of age) with BMI values between ≥18.5 and ≤24.9kg/m(2) were included. TMF, AF, GF, and the AF to GF ratio (A:G) were assessed using dual-energy X-ray absorptiometry. Results showed an increase in AF after the fifth decade of life (D), which reached statistical significance in the sixth and seventh decades (p<0.05--0.008), a 33% increase in kg of AF between the fourth and seventh and a 20% increase in A:G between the third and the seventh, with no significant changes in TFM and GF. In normal BMI women, age appears to be associated with changes in fat mass distribution with an increase in AF, which might have potential deleterious health consequences, after the fifth D.

Daily rhythm in bone resorption in humans: preliminary observations on the effect of hypoparathyroidism or blindness

Abstract While 24-hour rhythmicity of bone formation is largely dependent on serum cortisol, the physiological basis for daily changes in bone resorption remains uncertain. The present study was carried out to assess the effect of a chronic lack of PTH or blindness on overall daily bone resorption in a small group of human subjects. Three groups of subjects were examined: (a) hypoparathyroid (n = 6, 4 female); (b) congenitally blind (n = 6, 2 female); (c) control (n = 6, 6 female). All individuals were admitted to the hospital at 0600 h and stayed there for 26 h with normal day/night activity. Urine samples were obtained every 4 h, starting at 0800 h. Urinary cross-linked N-telopeptide of type I collagen (NTX) was measured by ELISA and expressed as the ratio with urinary creatinine levels. Mean 24-h concentration of urinary NTX was lower in hypoparathyroid and blind subjects as compared to controls (p < 0.001). Significant 24-h profiles of urinary NTX/creatinine concentration (expressed as % of change of the mean 24 h level) were observed in the three groups. While control and hypoparathyroid individuals showed maximal levels at early morning and a minimum at late afternoon (2000 h), blind subjects exhibited a minimum at early afternoon (1600 h). The results suggest that neither the lack of PTH nor the lack of vision suppress the circadian rhythmicity of urinary NTX in humans. Further studies comprising larger amounts of subjects are needed to support this conclusion.