Zoledronic acid to prevent bone loss in the first 6 months after renal transplantation

BACKGROUND: Bisphosphonates can prevent bone mineral density loss after renal transplantation, but their effect on trabecular mineralization and bone morphology, two key factors of bone stability, remains unknown. METHODS: In a 6-month, randomized, placebo-controlled study, 20 kidney transplant recipients received either 4 mg zoledronic acid or placebo twice within 3 months after engraftment. At transplantation and after 6 months, mean trabecular calcium concentration and trabecular morphometry were measured in bone biopsies. Bone mineral density (BMD) of the femoral neck and the lumbar spine were evaluated by dual-energy x-ray absorptiometry, and serum biochemical markers of bone metabolism were determined monthly. RESULTS: Trabecular calcium content increased significantly in the zoledronic acid group, but remained unchanged in the placebo group. BMD at femoral neck showed no change in the zoledronic acid group, but decreased in the placebo group. BMD of the lumbar spine was increased in the zoledronic acid group without change in the placebo group. High-turnover bone disease resolved similarly in both groups, as evidenced by a significant decrease of eroded bone surface, osteoclast and osteoblast surface. Serologic markers of bone formation and resorption were significantly lower in zoledronic acid-treated patients throughout the study. Kidney transplant function was stable after zoledronic acid therapy. CONCLUSIONS: Our results show that administration of zoledronic acid improves the calcium content of cancellous bone after kidney transplantation. The beneficial effect of bisphosphonate therapy is further evidenced by an increase of lumbar spine BMD, and stabilization of femur BMD.     

PINP as an aid for monitoring patients treated with teriparatide

Biochemical markers of bone turnover may be useful aids for managing patients with osteoporosis. A 12-month, phase 3, multicenter trial of Japanese patients at high risk of fracture was conducted to assess the effects of teriparatide 20 μg/day on BMD, serum markers of bone turnover, and safety. Two-hundred and seven subjects (93% female; median age 70 years) were randomized in double-blind fashion 2:1 to teriparatide versus placebo. Bone turnover markers including procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (bone ALP) and type I collagen cross-linked C-telopeptide (CTX) were collected at baseline, 1, 3, 6, and 12 months. Lumbar spine, femoral neck, and total hip BMD were measured at baseline, 3, 6, and 12 months. Increases in PINP at 1 month correlated best with increases in lumbar spine BMD at 12 months (r=0.76; P<0.01). The proportions of patients with an increase from baseline in PINP >10 μg/L at 1, 3, and 6 months were 3%, 0%, and 2% in the placebo, and 93%, 87%, and 83% in the teriparatide group. The proportions of patients with an increase in PINP >10 μg/L at either 1 or 3 months were 3% in the placebo and 95% in the teriparatide group (P<0.001). The proportions of patients with a significant increase in lumbar spine BMD (increase from baseline ≥3%) at 12 months were 20% in the placebo and 94% in the teriparatide group. The proportions of patients with an increase in PINP >10 μg/L at 1 or 3 months and an increase in lumbar spine BMD ≥3% at 12 months was 0% of placebo group patients and 92% of teriparatide group patients (P<0.001). These data confirm a strong relationship between early change in PINP and later change in lumbar spine BMD during teriparatide therapy. Also, these results suggest that monitoring with PINP and lumbar spine BMD successfully identifies positive responses in most patients taking teriparatide and negative responses in most patients not taking teriparatide. PINP monitoring may be a useful aid in the management of patients with osteoporosis during teriparatide treatment.     

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.     

Age at Transplant—One of the Factors Affecting Bone Mineral Density in Kidney Recipients—A Single-Center Retrospective Study

Abstract

Background: Osteoporosis/osteopenia after kidney transplantation is multifactorial, and the mechanism responsible for this condition is unclear. A cumulative steroid dose and female gender are two likely major risk factors for osteoporosis/osteopenia after transplantation, but there is no consensus as to which risk factors are most strongly associated with reduced bone mineral density (BMD). Methods: We assessed 84 kidney recipients who had received transplants at least 5 months prior to enrollment in the study. BMD at the lumbar spine, hip, and femoral neck was evaluated by dual-energy X-ray absorptiometry. We used the average BMD (BMDa), defined as the average of the sum of the lumbar spine, hip, and femoral neck mineral density values, as representative of body BMD. Results: This retrospective study revealed inverse correlations between the BMDa and creatinine level and age at transplant as well as a positive correlation with male gender. Osteoporosis occurred in transplantations where the duration since transplantation was longer. Conclusion: This retrospective study demonstrated that a decrease in BMD, reflecting a bone condition tending toward osteoporosis/osteopenia, is inversely correlated with male gender, creatinine level, and age at transplant in kidney recipients. Nonetheless, the time since transplant is higher in the osteoporosis group than in the osteopenia group.     

Bone mineral density in long-term Chinese heart transplant recipients: a cross-sectional study

Osteoporosis, which usually peaks during 6 to 12 months after transplantation, remains an important concern after heart transplantation. Immunosuppressants contribute to this phenomenon. Glucocorticoids are well documented to cause bone loss, but the role of cyclosporine (CsA) remains controversial, especially among long-term recipients on low doses of steroid. We herein report a cross-sectional study of bone mineral density (BMD) among long-term Chinese heart transplant recipients. We enrolled 41 patients of mean age 50.15 +/- 13.58 years with a mean follow-up of 57.02 months. Lumbar spine and femoral neck BMD were measured by dual energy x-ray absorptiometry. Trough CsA levels (C(0)) and markers of mineral metabolism, including bone-specific alkaline phosphatase and urinary N-telopeptide, were determined by immunoassay. Sixty six percent of subjects showed bone loss at the femoral neck, significantly more than those in the lumbar spine. Those receiving a higher CsA dosage (<2.5 mg/kg/d) showed greater femoral neck BMD, but lower serum creatinine values. Our results demonstrated that bone loss remains long after transplantation, though bone markers are within normal limits.     

Prevention of Osteoporosis in Heart Transplant Recipients: A Comparison of Calcitriol with Calcitonin and Pamidronate

Bone loss and osteoporotic fractures are common in cardiac transplant recipients. To compare two prophylactic medical regimens after heart transplantation, 26 consecutive heart transplant recipients were randomized to receive either continuous oral calcitriol (0.5 μg/day) combined with nasal salmon calcitonin (200 U/day) for the first 3 months (group A) or intermittent intravenous pamidronate (0.5 mg/kg body weight) every third month (group B). Bone mineral density (BMD) and biochemical indices of bone turnover were measured at baseline and 3, 6, 12, and 18 months after transplantation. The mean pretransplant BMD, measured by dual energy X-ray absorptiometry (DXA) was significantly lower in the patients compared with age-matched healthy controls. During the first year of treatment, rates of bone loss at the lumbar spine and femoral neck were slightly but significantly slower in the patients treated with pamidronate, but there was no longer a significant difference between the two groups after 18 months of heart transplantation. Irrespective of the mode of osteoporosis prevention, osteocalcin levels increased whereas urinary deoxypyridinoline decreased after transplantation, and significant bone loss was observed in both treatment groups. We found no relationship between initial BMD, markers of bone turnover, cumulative glucocorticoid dose, or cyclosporine levels and the rate of bone loss after cardiac transplantation. In summary, we found that the rapid and severe bone loss following heart transplantation could be attenuated by two preventive measures, pamidronate or calcitriol with calcitonin. Received: 26 December 1997 / Accepted: 10 February 2000     

Outcomes of bisphosphonate therapy in kidney transplant recipients: a systematic review and meta‐analysis

Mineral and bone disorders that precede kidney transplantation are exacerbated in the post‐transplant setting by tertiary hyperparathyroidism and immunosuppressive regimens. Bone mineral density (BMD) decreases following transplantation, leading to increased fracture risk. The effect of bisphosphonates on fracture is unknown. The aim of this study was to update estimates of change in BMD and fracture rates in bisphosphonate‐treated kidney transplant recipients through meta‐analysis. Studies comparing bisphosphonate therapy to standard of care were included if follow‐up duration was more than 6 months. We performed random‐effects meta‐analysis to determine the effect of bisphosphonates on lumbar spine and femoral neck BMD and fracture rates. Bisphosphonates improved femoral neck and lumbar spine BMD compared with controls (0.055 g/cm², 95% CI 0.012–0.099 and 0.053 g/cm², 95% CI 0.032–0.074, respectively) without adversely affecting serum creatinine or calcium. This corresponded to an unweighted improvement in BMD of 6.0% and 7.4%, respectively. There was no difference in fracture incidence in the two groups. Bisphosphonate therapy in kidney transplant recipients is associated with a statistically significant improvement in BMD at the lumbar spine and femoral neck. There was no difference in fracture incidence. Bisphosphonates did not adversely affect allograft dysfunction or serum calcium levels.     

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.     

Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis.

The relationship between early changes in biochemical markers of bone turnover and the subsequent BMD response to daily teriparatide therapy in women with postmenopausal osteoporosis was studied. Changes in five biochemical markers, obtained from a subset of women enrolled in the Fracture Prevention Trial, were examined. Early increases in the PICP and the PINP were the best predictors of BMD response to teriparatide in this analysis. INTRODUCTION: Early reductions in biochemical markers of bone turnover with antiresorptive therapy negatively correlate with subsequent increases in BMD. We undertook this analysis to determine if early changes in biochemical markers with teriparatide therapy predict subsequent increases in BMD. MATERIALS AND METHODS: In the Fracture Prevention Trial, 1637 postmenopausal women with osteoporosis were randomized to receive daily, self-administered, subcutaneous injections of placebo, teriparatide 20 microg/day, or teriparatide 40 microg/day. Serum concentrations of two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and the carboxy-terminal extension peptide of procollagen type 1 [PICP]) and urinary concentrations of two bone resorption markers (free deoxypyridinoline [DPD] and N-terminal telopeptide [NTX]) were assessed in a trial population subset (n = 520) at baseline and at 1, 3, 6, and 12 months. We also assessed serum concentrations of another bone formation marker, the amino-terminal extension peptide of procollagen type 1 (PINP), in a subset of 771 women at baseline and 3 months. Lumbar spine (LS) BMD was measured by DXA at baseline and 18 months. Femoral neck BMD was measured at baseline and 12 months. RESULTS AND CONCLUSION: Baseline bone turnover status correlated positively and significantly with BMD response. The highest correlations occurred for the LS BMD response to teriparatide 20 microg/day. Among all studied biochemical markers, increases in PICP at 1 month and PINP at 3 months correlated best with increases in LS BMD at 18 months (0.65 and 0.61, respectively; p < 0.05). The relationships between these two biochemical markers and the LS BMD response were stronger than the corresponding relationships for the femoral neck BMD response. Using receiver operator curve analysis, we determined that the increases in PICP at 1 month and PINP at 3 months were the most sensitive and accurate predictors of the LS BMD response.     

Once-weekly teriparatide reduces serum sclerostin levels in postmenopausal women with osteoprosis

Once-weekly teriparatide treatment is widely used in the treatment of osteoporosis in Japan but the mechanisms causing the increase in bone mineral density (BMD) of the lumbar spine remain unknown. Methods: This prospective study examined the effects of once-weekly teriparatide treatment on the serum levels of sclerostin, osteocalcin, and bone formation markers as well as BMD of the lumbar spine and femoral neck in 32 postmenopausal women with osteoporosis. Results: The mean age of subjects was 76.3 ± 7.0 years old. Teriparatide significantly reduced serum sclerostin levels at 12 and 18 months in postmenopausal women with osteoporosis, and significantly increased serum osteocalcin levels at 3,12 and 18 months and PINP levels at 1 and 3 months, respectively. Teriparatide treatment significantly increased BMD of the lumbar spine at 6, 12, and 18 months, but did not affect BMD of the femoral neck. Examination of the relationships between percent changes in bone metabolic indices and BMD of the lumbar spine during the teriparatide treatment showed serum sclerostin changes at 3 months were negatively correlated with BMD changes of the lumbar spine at 6, 12, and 18 months. Serum osteocalcin changes were not correlated with BMD changes in the lumbar spine at 12 months. Conclusions: The present study showed that once-weekly teriparatide treatment reduced serum sclerostin levels in postmenopausal women with osteoporosis. The effects of teriparatide on sclerostin may be associated with the response of the BMD of the lumbar spine.     

Changes in bone mineral density and selected metabolic parameters over 24 months following renal transplantation

Our aim was to evaluate changes in serum levels of selected bone metabolism indicators and bone density over 24 months following renal transplant. A partial objective was assessment of the effectiveness of prophylactic administration of vitamin D and calcium preparations to prevent progression of osteopathy after kidney transplantation. Forty patients after kidney transplantation were prophylactically given vitamins A and D (800 IU) and calcium (1000 mg) a day. During monitoring, the serum creatinine in all recipients was <200 micromol/L (subgroup A with creatinine concentration < 120 micromol/L versus subgroup B with creatinine 120 to 200 micromol/L). The concentration of serum parathormone, serum level of bone fraction of alkaline phosphatase, serum concentrations of phosphorus and calcium urinary 24-hour excretion of phosphorus and calcium were examined at 2 weeks and 2 years after transplantation. In the same time period, radiographs of thoracic, lumbar spine, and hip joints were obtained. Bone density (BMD) of the lumbar (L) spine and the hip was determined by dual-energy X ray (Lunar Prodigy). Two years after transplantation in subgroup A, the BMD showed decrease in 80% of recipients in the L spine area but hip showed a 15% BMD increase. In subgroup B, the BMD decreased in 95% recipients in L and hip and only 25% showed a BMD increase. No clinical or radiographic sign of fracture was detected in this group. We conclude that prophylactic administration of vitamin D and calcium is not sufficient to prevent the progression of osteopathy after renal transplantation. Changes in bone density evaluated after the kidney transplantation are affected by graft function.     

Risk factors for changes in bone mineral density and the effect of antiosteoporosis management after renal transplantation

Using the pretransplant bone mineral density (BMD) data records of renal recipients, we retrospectively examined risk factors affecting posttransplant changes in BMD and the effect of antiosteoporosis management. For 294 kidney transplant recipients from January 1996 to September 2003, BMD values were expressed as spine and femur T-scores. Gender, age, pretransplant diabetes, blood type compatibility, mode and duration of dialysis, and previous transplantation were considered to be variables affecting BMD changes. T-test or ANOVA was used to compare risk factors. At the time of transplantation, mean spine T-scores were significantly lower among the retransplant group. Mean femur T-scores were significantly lower among the retransplant group, older patients (older than 45 years), and female recipients. Prolonged hemodialysis (>12 months) and retransplant were risk factors for BMD loss during the first year posttransplant. Early application of antiosteoporosis management was effective to ameliorate posttransplant BMD loss. However, antiosteoporosis management after 1 year posttransplant was relatively ineffective. Pretransplant evaluation of BMD and the possibility of significant BMD loss during the first posttransplant year should not be overlooked. Prophylaxis against bone loss and treatment should be started as soon as possible after transplantation for recipients with either normal or abnormal pretransplant BMD.     

Bone mineral density in pediatric transplant recipients

BACKGROUND: Reduced bone mass and fragility fractures are known complications after transplantation in adults. Far less is known about the skeletal effects of transplantation in children and adolescents. METHODS: This cross-sectional study examined the skeletal status of children (ages 9-18 years) who were at least 1 year post-cardiac (n=13), post-renal (n=8), or post-bone marrow (BMT; n=15) transplantation. Bone mass at total hip, femoral neck, spine (L2-4), and whole body (WB) was determined by dual energy x-ray absorptiometry and compared with age, sex, and ethnic-specific reference data. Standard deviations (z-scores) were calculated for both areal bone mineral density (BMD) and estimated volumetric bone density (bone mineral apparent density [BMAD]). RESULTS: Cardiac transplant patients had significantly lower BMD z-scores compared with the reference population at all skeletal sites. BMT recipients had significantly reduced BMD z-scores at total hip, spine, and WB. Kidney transplant patients had a significantly reduced WB BMD z-score only. Spine BMAD z-scores remained significantly reduced in cardiac and BMT subjects. Three of 36 patients had radiographic evidence of spinal fracture after transplantation. No correlation between steroid dosage and any measure of bone mass was observed. CONCLUSIONS: Cardiac and BMT recipients had reduced BMD at multiple skeletal sites, and renal transplant recipients had reduced WB BMD for age. Deficits in spine bone density persisted after correcting for small bone size using BMAD. Low bone density and the occurrence of vertebral fractures indicate that cardiac, renal, and bone marrow transplantation in children is associated with reduced bone health.     

Abnormally High and Heterogeneous Bone Matrix Mineralization After Childhood Solid Organ Transplantation: A Complex Pathology of Low Bone Turnover and Local Defects in Mineralization

Chronic renal, liver, and heart failure in children associates with multiple skeletal complications. Increased fracture incidence often persists after transplantation and could be related to alterations in bone material properties. In the present cohort study we evaluated bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging (qBEI) in 23 pediatric solid organ allograft recipients with suspected osteoporosis. We measured BMDD in the entire cross‐sectional area of transiliac bone biopsies obtained from kidney (n = 9), liver (n = 9), and heart (n = 5) transplant recipients (aged 7.6 to 19.7 years; 6.0 ± 5.6 years posttransplantation, patients with a history of clinical fractures: n = 14). The BMDD findings were compared with age‐appropriate references and with a previously presented cohort of children with chronic kidney disease on dialysis (CKD5D, n = 18). Furthermore, we related the BMDD parameters with patients’ clinical and bone histomorphometric outcomes. Compared to healthy children, qBEI results for cancellous and cortical bone in transplant recipients revealed an increase in the most frequently occurring calcium concentration (+2.9%, p = 0.001; +3.5%, p = 0.014), in the portion of fully mineralized bone (fivefold; 10‐fold, both p < 0.0001) and in heterogeneity of mineralization (+26,5% and +27.8%, both p < 0.0001), respectively. Moreover, the BMDD parameters were nonsignificantly distinct from CKD5D cohort except that the heterogeneity in mineralization was higher posttransplantation. There was a strong inverse correlation between the average calcium content of the bone matrix and patients’ biochemical ALP levels, histomorphometric indices of bone formation and resorption. The abnormally high bone matrix mineralization in transplant recipients, consistent with serum and histomorphometric outcomes, suggests a history of low bone turnover with accumulation of fully mineralized bone packets. Additionally, the increased heterogeneity of mineralization suggests local alterations in mineralization kinetics, which may be linked to dysfunctional osteocytes that were recently shown to accumulate within the bone matrix during organ failure and concomitant glucocorticoid and immunosuppressive medication. © 2017 American Society for Bone and Mineral Research.     

Bone disease in long-term adult kidney transplant patients with normal renal function

BACKGROUND: In successful renal transplantation, the degree of renal function recovery is usually incomplete and information is scarce about the abnormalities of mineral metabolism in long-term adult renal recipients with normal renal function. This study was designed to investigate bone mineral metabolism in patients with a long-term normal functioning kidney. METHODS: Twenty-nine adult asymptomatic renal transplant (RT) recipients with stable graft function for more than 10 years and serum creatinine <2 mg/dL were studied. They were classified into two groups according to glomerular filtration rate: Group A (N = 12; nine men, three women)>70 mL/min (x: 126 +/- 55 mL/min) and Group B (N = 17; nine men, eight women) <70 mL/min (x: 56 +/- 11 mL/min). Circulating biochemical markers of bone remodelling, bone histomorphometry, and densitometry (lumbar spine and hip) were obtained to investigate bone disease in these patients. RESULTS: Serum PTH was slightly elevated in 10 patients (83%) in group A. Serum PTH levels were positively related to serum calcium, osteocalcin, BAP, telopeptide, OH-proline, and creatinine. There was no histologic data to support overactivity on bone in this group of patients, with only one showing high bone turnover. Mineralization was prolonged in 34% of patients. Twenty-two patients (75%) exhibited normal bone turnover. In the group with GFR>70 mL/min the prevalence of mineralization defect in the presence of normal serum levels of calcitriol suggested vitamin D resistance. Lumbar and femoral neck osteoporosis was present in 25% and 33% of patients in group A, and 23% and 53% in group B, respectively. T-score at lumbar spine was negatively correlated with months since transplantation. Patients under treatment with cyclosporine (CsA) showed increased concentrations of osteocalcin and D-pyr and higher lumbar bone mineral density (BMD), but bone histomorphometry was not influenced by CsA. CONCLUSION: Patients with long-term renal transplantation with normal renal function frequently present with slight increases in PTH, but without an effect on bone histology. CsA did not induce changes in bone histology and delayed mineralization was frequently observed.     

Time-dependent changes in skeletal response to teriparatide: escalating vs. constant dose teriparatide (PTH 1-34) in osteoporotic women

Once-daily injections of teriparatide initially increase biochemical markers of bone formation and resorption, but markers peak after 6-12 months and then decline despite continued treatment. We sought to determine whether increasing teriparatide doses in a stepwise fashion could prolong skeletal responsiveness. We randomized 52 postmenopausal women with low spine and/or hip bone mineral density (BMD) to either a constant or an escalating subcutaneous teriparatide dose (30 μg daily for 18months or 20 μg daily for 6 months, then 30 μg daily for 6 months, and then 40 μg daily for 6 months). Serum procollagen I N-terminal propeptide, osteocalcin, and C-terminal telopeptide of type I collagen were assessed frequently. BMD of the spine, hip, radius, and total body was measured every 6 months. Acute changes in urinary cyclic AMP in response to teriparatide were examined in a subset of women in the constant dose group. All bone markers differed significantly between the two treatment groups. During the final six months, bone markers declined in the constant dose group but remained stable or increased in the escalating dose group (all markers, p<0.017). Nonetheless, mean area under the curve did not differ between treatments for any bone marker, and BMD increases were equivalent in both treatment groups. Acute renal response to teriparatide, as assessed by urinary cyclic AMP, did not change over 18 months of teriparatide administration. In conclusion, stepwise increases in teriparatide prevented the decline in bone turnover markers that is observed with chronic administration without altering BMD increases. The time-dependent waning of the response to teriparatide appears to be bone-specific.     

Heel ultrasonography is not a good screening tool for bone loss after kidney and pancreas transplantation

BACKGROUND: Solid organ transplant recipients, particularly simultaneous pancreas kidney recipients, are at high fracture risk. We tested whether quantitative ultrasonography (QUS) of the heel predicts bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) in solid organ transplant recipients. METHODS: Thirty-eight transplant recipients (22 Female/16 Male) were studied. Spine and hip BMD was measured with a Hologic DXA scanner. 'Stiffness' of the heel was measured with a Lunar Ultrasound densitometer and compared with BMD by DXA. Contributing factors to bone loss were also assessed. RESULTS: Mean age was 43.1 +/- 1.3 yr. Simultaneous pancreas-kidney, kidney, and pancreas alone transplant recipients were assessed. Mean time post-transplantation was 3.0 +/- 0.6 yr. Mean DXA spine T-score was -1.15 +/- 0.22 (mean +/- SEM) and hip T-score was -1.22 +/- 0.20. There was no difference in mean T-score between women and men at the hip or spine. Mean right heel stiffness T-score was -0.97 +/- 0.25. There was no correlation between QUS and DXA at either the hip or spine in women or men. QUS had a false negative rate for identifying osteopenia or osteoporosis of 17% compared with DXA. The false positive rate for identifying osteopenia was 61%. CONCLUSIONS: The QUS is an unacceptable tool for identifying those at risk for bone loss after kidney or pancreas transplantation.     

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.     

Timing and quantification of bone loss in cardiac transplant recipients

To evaluate osteopenic bone disease in heart transplant patients, we prospectively measured bone mineral density (BMD) in 33 consecutive male recipients before hospital discharge and 1 year later, using dual photon absorptiometry. At hospital discharge BMD measurement at the lumbar spine was only 90% of that expected in healthy age- and sex-matched controls (P=0.005). One year later BMD had further decreased by 8.5% at the lumbar spine and by 10.4% at the femoral neck (P=0.0001). Five patients suffered vertebral compression fractures during the 1st post-operative year. Our results indicate that osteopenia of the lumbar spine is already present at the time of hospital discharge after transplantation and that further bone loss occurs at a considerable rate during the 1st postoperative year at the lumbar spine and at the femoral neck.     

Nonsustained effect of short-term bisphosphonate therapy on bone turnover three years after renal transplantation

BACKGROUND: We recently showed that two doses of 4 mg of zoledronic acid (ZOL) ameliorated the bone loss and improved bone histology within the first six months after kidney transplantation. The aim of the present study was to evaluate whether this early short-term intervention exhibited a sustained bone-sparing effect. METHODS: A homogenous group of 20 de novo renal transplant recipients were equally randomized to two infusions of 4 mg of ZOL or placebo at two weeks and three months after engraftment. Patients were followed up for three years by sequential determination of bone densitometry and specific biochemical markers. RESULTS: From month six to three years after transplantation, both treatment groups exhibited an improvement of bone mineralization. Femoral neck bone mineral density z-scores increased statistically significantly from -1.3 (2.6) to -0.2 (3.6) in the placebo group and from -1.6 (2.9) to -1.2 (1.9) in the ZOL group (median, range). Biochemical parameters of osteoblast activity such as osteocalcin and bone-specific alkaline phosphatase did not increase significantly in both groups. Osteoprotegerin, a marker of osteoclast inhibition, was significantly elevated over the first six months in the ZOL group, but decreased to similar levels, as in the placebo group, over the next two and a half years. Other markers of osteoclast activity such as c-telopeptide of type 1 collagen, calcitonin, and intact parathyroid hormone were not different between six months and three years in either group. CONCLUSION: The early bone-sparing effect of short-term ZOL therapy confers no sustained benefit versus placebo at three year post-transplantation.