Harold N. Rosen

Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial.

Although the antiresorptive agent alendronate has been shown to increase bone mineral density (BMD) at the hip and spine and decrease the incidence of osteoporotic fractures in older women, few data are available regarding early prediction of long‐term response to therapy, particularly with regard to increases in hip BMD. Examining short‐term changes in biochemical markers incorporates physiologic response with therapeutic compliance and should provide useful prognostic information for patients. The objective of this study was to examine whether early changes in biochemical markers of bone turnover predict long‐term changes in hip BMD in elderly women. The study was a double‐blind, placebo‐controlled, randomized clinical trial which took place in a community‐based academic hospital. One hundred and twenty community‐dwelling, ambulatory women 65 years of age and older participated in the study. Intervention consisted of alendronate versus placebo for 2.5 years. All patients received appropriate calcium and vitamin D supplementation. The principal outcome measures included BMD of the hip (total hip, femoral neck, trochanter, and intertrochanter), spine (posteroanterior [PA] and lateral), total body, and radius. Biochemical markers of bone resorption included urinary N‐telopeptide cross‐linked collagen type I and free deoxypyridinoline; markers of bone formation included serum osteocalcin and bone‐specific alkaline phosphatase. Long‐term alendronate therapy was associated with increased BMD at the total hip (4.0%), femoral neck (3.1%), trochanter (5.5%), intertrochanter (3.8%), PA spine (7.8%), lateral spine (10.6%), total body (2.2%), and one‐third distal radius (1.3%) in elderly women (all p < 0.01). In the placebo group, bone density increased 1.9–2.1% at the spine (p < 0.05) and remained stable at all other sites. At 6 months, there were significant decreases in all markers of bone turnover (–10% to –53%, p < 0.01) in women on alendronate. The changes in urinary cross‐linked collagen at 6 months correlated with long‐term bone density changes at the hip (r = –0.35, p < 0.01), trochanter (r = –0.36, p < 0.01), PA spine (r = –0.41, p < 0.01), and total body (r = –0.34, p < 0.05). At 6 months, patients with the greatest drop in urinary cross‐linked collagen (65% or more) demonstrated the greatest gains in total hip, trochanteric, and vertebral bone density (all p < 0.05). A 30% decrease in urinary cross‐linked collagen at 6 months predicted a bone density increase of 2.8–4.1% for the hip regions and 5.8–6.9% for the spine views at the 2.5‐year time point (p < 0.05). There were no substantive associations between changes in biochemical markers and bone density in the placebo group. Alendronate therapy was associated with significant long‐term gains in BMD at all clinically relevant sites, including the hip, in elderly women. Moreover, these improvements were associated with early decreases in biochemical markers of bone turnover. Early dynamic decreases in urinary cross‐linked collagen can be used to monitor and predict long‐term response to bisphosphonate therapy in elderly women. Future studies are needed to determine if early assessment improves long‐term patient compliance or uncovers poor compliance, thereby aiding the physician in maximizing the benefits of therapy.

Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy.

Abstract: Serum CrossLaps is a new assay for measuring carboxy-terminal collagen crosslinks (CTX) in serum. This measurement is reported to be more specific to bone resorption than other measurements. However, the utility of this and other markers in monitoring patients on antiresorptive therapy depends on how often changes anticipated with therapy exceed changes attributable to random variability. In a study where subjects received either placebo or pamidronate, we calculated the minimum significant change (MSC), that is, the change that was sufficiently large that it was unlikely to be due to spontaneous variability. We also examined the changes in markers of bone turnover in subjects treated with pamidronate (APD) (30 mg I.V. in 500 ml D5W over 4 hours) to see how often observed changes in turnover after treatment exceeded the MSC. The MSC for serum CTX was 30.2%, and was significantly (P < 0.05) lower than the MSC for urinary NTX (54.0%), and not significantly different from the MSC of urinary DPD (20.6%). Ninety percent of subjects treated with APD had a decline in serum CTX that exceeded the MSC, compared with 74% for bone-specific alkaline phophatase (BSAP), 57% for urinary N-telopeptide cross-links (NTX), and 48% for free deoxypyridinoline. Changes in serum CTX correlated reasonably well with changes in spine BMD after 2 years (r = 0.47), but this correlation did not quite reach statistical significance because of the small number of subjects. In conclusion, the serum CTX assay shows greater utility for assessing efficacy of antiresorptive treatment than some previously described markers.

Utility of biochemical markers of bone turnover in the follow-up of patients treated with bisphosphonates.

Abstract. Biochemical markers of bone turnover are often measured in patients treated with antiresorptive agents to monitor the effects of therapy. In order for a change in these markers to clearly indicate treatment effect, the change in the markers must exceed the amount of spontaneous variation typically seen with no treatment. Based on the measured long-term variability of markers in untreated patients, we defined a minimum significant change (MSC), that is, a change that was sufficiently large that it was unlikely to be due to spontaneous variability. We also examined the changes in markers of bone turnover in subjects treated with pamidronate to see how often observed changes in turnover after treatment exceeded the MSC. We found that urinary markers of bone resorption are best measured on 2-hour fasting samples, because results on random urine showed poor precision and less decline with therapy. We also found that of all the markers, urinary N-telopeptide cross-links (NTX) had the greatest decline after therapy (58%), although it also had the highest long-term variability (29.5%). The marker that most often showed a decline with treatment that exceeded the MSC was serum bone-specific alkaline phosphatase where 74% of observed changes exceeded the MSC. Other markers that often showed a decline with treatment that exceeded the MSC were 2-hour fasting urine NTX and free deoxypyridinoline, where 57% and 48%, respectively, of changes in therapy exceeded the MSC. The ideal marker would combine the large decline after treatment characteristic of NTX (60–70%) with the good precision of bone-specific alkaline phosphatase.

Vitamin K and maintenance of skeletal integrity in adults.

PURPOSE To determine the role of vitamin K status in the maintenance of skeletal integrity in adults. PATIENTS AND METHODS 1. Bone mineral density (BMD) was measured by quantitative digital radiography (QDR) in 50 patients taking a vitamin K antagonist (warfarin) who were recruited from a large urban cardiology practice, and 50 age-, sex- and race-matched controls recruited from the community. 2. The relationship of BMD versus indices of vitamin K status (determined by measuring levels of vitamin K and descarboxyprothrombin in the plasma) in 113 nonanticoagulated adults was assessed. RESULTS Measurements of BMD in the hip and spine were similar in anticoagulated subjects and matched controls. Multivariate analysis revealed that use of warfarin was not associated with a lower BMD. Ninety-five percent confidence intervals excluded a 0.06 g/cm2 reduction in BMD associated with the use of warfarin. Indices of vitamin K status did not correlate with BMD in normal subjects. CONCLUSIONS Patients receiving long-term maintenance therapy with a vitamin K antagonist have normal bone density. BMD is unrelated to vitamin K status in nonanticoagulated subjects. These data suggest that vitamin K does not have a major role in maintenance of skeletal integrity in adults.

The Official Positions of the International Society for Clinical Densitometry: Vertebral Fracture Assessment

Vertebral fracture assessment (VFA) is a low-cost method of accurately identifying individuals who have clinically unrecognized or undocumented vertebral fractures at the time of bone density test. Because prevalent vertebral fractures predict subsequent fractures independent of bone mineral density and other clinical risk factors, their recognition is an important part of strategies to identify those who are at high risk of fracture, so that prevention therapies for those individuals can be implemented. The 2007 Position Development Conference developed detailed guidelines regarding the indications for acquisition of, and interpretation and reporting of densitometric VFA tests. The purpose of the 2013 VFA Task Force was to simplify the indications for VFA yet keep them evidence based. The Task Force reviewed the literature published since the 2007 Position Development Conference and developed prediction models based on 2 large cohort studies (the Study of Osteoporotic Fractures and the Osteoporotic Fractures in Men Study) and the densitometry database of the University of Chicago. Based on these prediction models, indications for VFA were reduced to a simplified set of criteria based on age, historical height loss, use of systemic glucocorticoid therapy, and self-reported but undocumented prior vertebral fracture.

Quantification of Human and Rodent Brown Adipose Tissue Function Using 99mTc-Methoxyisobutylisonitrile SPECT/CT and 18F-FDG PET/CT

For brown adipose tissue (BAT) to be effective at consuming calories, its blood flow must increase enough to provide sufficient fuel to sustain energy expenditure and also transfer the heat created to avoid thermal injury. Here we used a combination of human and rodent models to assess changes in BAT blood flow and glucose utilization. Methods: 99mTc-methoxyisobutylisonitrile (MIBI) SPECT (n = 7) and SPECT/CT (n = 74) scans done in adult humans for parathyroid imaging were reviewed for uptake in regions consistent with human BAT. Site-directed biopsies of subcutaneous and deep neck fat were obtained for electron microscopy and gene expression profiling. In mice, tissue perfusion was measured with 99mTc-MIBI (n = 16) and glucose uptake with 18F-FDG (n = 16). Animals were kept fasting overnight, anesthetized with pentobarbital, and given intraperitoneally either the β3-adrenergic receptor agonist CL-316,243, 1 mg/kg (n = 8), or saline (n = 8) followed by radiotracer injection 5 min later. After 120 min, the mice were imaged using SPECT/CT or PET/CT. Vital signs were recorded over 30 min during the imaging. BAT, white adipose tissue (WAT), muscle, liver, and heart were resected, and tissue uptake of both 99mTc-MIBI and 18F-FDG was quantified by percentage injected dose per gram of tissue and normalized to total body weight. Results: In 5.4% of patients (4/74), 99mTc-MIBI SPECT/CT showed increased retention in cervical and supraclavicular fat that displayed multilocular lipid droplets, dense capillary investment, and a high concentration of ovoid mitochondria. Expression levels of the tissue-specific uncoupling protein-1 were 180 times higher in BAT than in subcutaneous WAT (P < 0.001). In mice, BAT tissue perfusion increased by 61% (P < 0.01), with no significant changes in blood flow to WAT, muscle, heart, or liver. CL-316,243 increased glucose uptake in BAT even more, by 440% (P < 0.01). Conclusion: Pharmacologic activation of BAT requires increased blood flow to deliver glucose and oxygen for thermogenesis. However, the glucose consumption far exceeds the vascular response. These findings demonstrate that activated BAT increases glucose uptake beyond what might occur by increased blood flow alone and suggest that activated BAT likely uses glucose for nonthermogenic purposes.

The effect of PTH antagonist BIM-44002 on serum calcium and PTH levels in hypercalcemic hyperparathyroid patients.

Abstract. BIM-44002, a pure competitive antagonist of parathyroid hormone (PTH), has a high affinity for the PTH/PTHrP receptor in vitro, and can completely inhibit the actions of a PTH agonist in rats in vivo. Toxicology studies in rats and dogs showed BIM-44002 to be devoid of any adverse effects. Therefore we undertook an investigation to evaluate the potential utility of BIM-44002 in lowering elevated serum calcium in three patients with primary hyperparathyroidism. BIM-44002 was administered by continuous intravenous infusion at dosages of 100 μg/hour (370 nmol/hour) for 12 hours, followed by 200 μg/hour for 12 hours, followed by 400 μg/hour for 12 hours. Vital signs and serum ionized and total calcium were monitored hourly and for 3 hours after cessation of the infusion. Blood for PTH determinations was obtained at the same time points. Serum calcium and PTH did not change during and after the infusion of the antagonist. No subject experienced any adverse reactions to the infusion of the antagonist. We conclude that although the PTH antagonist BIM-44002 was effective both in vitro and in vivo in animals, and it was safe in humans, it was not able to lower serum calcium in patients with hyperparathyroidism. Possible reasons for lack of clinical efficacy are discussed.

Indications of DXA in Women Younger Than 65 yr and Men Younger Than 70 yr: The 2013 Official Positions

Dual-energy X-ray absorptiometry (DXA) is the method of choice to assess fracture risk for women 65 yr and older and men 70 yr and older. The 2007 International Society for Clinical Densitometry Official Positions had developed guidelines for assessing bone density in younger women during and after the menopausal transition and in men 50-69 yr and the 2008 National Osteoporosis Foundation (NOF) guidelines recommended testing in postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors. The purpose of the 2013 DXA Task Force was to reassess the NOF guidelines for ordering DXA in postmenopausal women younger than 65 yr and men 50-69 yr. The Task Force reviewed the literature published since the 2007 Position Development Conference and 2008 NOF, reviewing clinical decision rules such as the Osteoporosis Screening Tool and FRAX and sought to keep recommendations simple to remember and implement. Based on this assessment, the NOF guidelines were endorsed; DXA was recommended in those postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors for low bone mass, such as low body weight, prior fracture, high-risk medication use, or a disease or condition associated with bone loss.

Subregion analysis of the rat femur: A sensitive indicator of changes in bone density following treatment with thyroid hormone or bisphosphonates

Measurement of bone mineral density (BMD) by dual X-ray absorptiometry (DXA) is a precise and accurate way to assess changes in BMD due to a variety of causes. However, the degree of bone loss may vary depending on the skeletal site examined. We postulated that interventions that change bone density would have a different effect on an area rich in trabecular bone, such as the distal femur, than on other subregions of the femur. Male Sprague-Dawley rats (325–350 g) were treated with triiodothyronine (T3), a bisphosphonate (pamidronate), or placebo for 21 days and then sacrificed. Ex vivo BMD of the proximal, distal, mid and total femur were measured by DXA. We found that mean BMD of hyperthyroid rats was significantly lower than controls at all femoral subregions. However, the difference in mean BMD between hyperthyroid and control rats was greatest at the distal femur (8.6%). In rats treated with bisphosphonate, mean BMD was significantly higher than controls at the proximal, distal, and total femur. The difference in mean BMD between controls and rats treated with bisphosphonate was greatest at the distal femur (31.8%). Furthermore, pamidronate (APD)-treated rats had lower mean mid-femur BMD than controls. We conclude that changes in BMD after treatment with bisphosphonate or T3 are greatest at the distal femur subregion, and that treatment with bisphosphonate may cause a slight reduction in midfemur BMD. Future studies examining changes in BMD in the rat femur after interventions that alter mineral metabolism should include subregion analysis.

Effect of Clothing on Measurement of Bone Mineral Density

It is unknown whether allowing patients to have BMD (bone mineral density) studies acquired while wearing radiolucent clothing adlib contributes appreciably to the measurement error seen. To examine this question, a spine phantom was scanned 30 times without any clothing, while draped with a gown, and while draped with heavy winter clothing. The effect on mean BMD and on SD (standard deviation) was assessed. The effect of clothing on mean or SD of the area was not significant. The effect of clothing on mean and SD for BMD was small but significant and was around 1.6% for the mean. However, the effect on BMD precision was much more clinically important. Without clothing the spine phantom had an least significant change of 0.0077 gm/cm(2), while when introducing variability of clothing the least significant change rose as high as 0.0305 gm/cm(2). We conclude that, adding clothing to the spine phantom had a small but statistically significant effect on the mean BMD and on variance of the measurement. It is unlikely that the effect on mean BMD has any clinical significance, but the effect on the reproducibility (precision) of the result is likely clinically significant.