Dinaz Irani

Zoledronic Acid Prevents Bone Loss in Premenopausal Women Undergoing Adjuvant Chemotherapy for Early-Stage Breast Cancer

PURPOSE Adjuvant chemotherapy for breast cancer (BC) may be associated with increased rates of bone loss and decreased bone mineral density (BMD) and may lead to premature osteoporosis and increased fracture risk. We examined whether zoledronic acid (ZA) prevents bone loss in premenopausal women receiving chemotherapy for early-stage BC. PATIENTS AND METHODS This study is a randomized, double-blind, multicenter, phase III trial comparing ZA (4 mg intravenously every 3 months) versus placebo for 1 year. Premenopausal women underwent serial BMD measurements before initiating chemotherapy and at 6 and 12 months. The primary outcome was percent change in lumbar spine (LS) BMD at 6 months. Secondary outcomes were percent change at any BMD site and markers of bone turnover at 12 months. Linear mixed model analysis for repeated measures was performed. RESULTS Of 101 women who were randomly assigned and completed baseline evaluation, 96 completed the 6-month evaluation, and 85 completed the 12-month evaluation. Baseline characteristics were comparable between the groups. Mean age was 42 years. Placebo was associated with significant decline in LS BMD at both 6 (2.4%) and 12 (4.1%) months. Similarly, total hip BMD declined by 0.8% at 6 months and 2.6% at 12 months. In contrast, BMD remained stable in ZA patients (P < .0001 compared with placebo). CONCLUSION Premenopausal women receiving chemotherapy for BC sustained significant bone loss at the LS and hip, whereas BMD remained stable in women who received ZA. Administration of ZA during the first year of chemotherapy is an effective and well-tolerated strategy for preventing bone loss.

High Prevalence of Vitamin D Deficiency Despite Supplementation in Premenopausal Women With Breast Cancer Undergoing Adjuvant Chemotherapy

PURPOSE Vitamin D deficiency is associated with increased breast cancer risk and decreased breast cancer survival. The purpose of this study was to determine the prevalence of vitamin D deficiency, as measured by serum 25-hydroxyvitamin D (25-OHD), in premenopausal women at initiation of adjuvant chemotherapy for breast cancer and after 1 year of vitamin D supplementation. PATIENTS AND METHODS The study included 103 premenopausal women from the northeastern United States with stages I to III breast cancer who received adjuvant chemotherapy and participated in a 1-year zoledronate intervention trial. All patients were prescribed vitamin D(3) (cholecalciferol) 400 IU and calcium carbonate 1,000 mg daily. At baseline and at 6 and 12 months, bone mineral density (BMD) measurements were obtained and blood was collected and analyzed in batches for serum 25-OHD. Vitamin D deficiency was defined as serum 25-OHD less than 20 ng/mL, insufficiency as 20 to 29 ng/mL, and sufficiency as 30 ng/mL or greater. RESULTS At baseline, 74% of women were vitamin D deficient (median, 17 ng/mL). Vitamin D deficiency was slightly less common in white women (66%) compared with black (80%) and Hispanic (84%) women. After vitamin D supplementation for 1 year, less than 15% of white and Hispanic women, and no black women, achieved sufficient 25-OHD levels. Vitamin D levels did not correlate with baseline BMD and were not altered by chemotherapy or bisphosphonate use. CONCLUSION Vitamin D deficiency is highly prevalent in women with breast cancer. The current recommended dietary allowance of vitamin D is too low to increase serum 25-OHD greater than 30 ng/mL. Optimal dosing for bone health and, possibly, improved survival has yet to be determined.

Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women.

Typically, in the milder form of primary hyperparathyroidism (PHPT), now seen in most countries, bone density by dual‐energy X‐ray absorptiometry (DXA) and detailed analyses of iliac crest bone biopsies by histomorphometry and micro–computed tomography (µCT) show detrimental effects in cortical bone, whereas the trabecular site (lumbar spine by DXA) and the trabecular compartment (by bone biopsy) appear to be relatively well preserved. Despite these findings, fracture risk at both vertebral and nonvertebral sites is increased in PHPT. Emerging technologies, such as high‐resolution peripheral quantitative computed tomography (HRpQCT), may provide additional insight into microstructural features at sites such as the forearm and tibia that have heretofore not been easily accessible. Using HRpQCT, we determined cortical and trabecular microstructure at the radius and tibia in 51 postmenopausal women with PHPT and 120 controls. Individual trabecula segmentation (ITS) and micro–finite element (µFE) analyses of the HRpQCT images were also performed to further understand how the abnormalities seen by HRpQCT might translate into effects on bone strength. Women with PHPT showed, at both sites, decreased volumetric densities at trabecular and cortical compartments, thinner cortices, and more widely spaced and heterogeneously distributed trabeculae. At the radius, trabeculae were thinner and fewer in PHPT. The radius was affected to a greater extent in the trabecular compartment than the tibia. ITS analyses revealed, at both sites, that plate‐like trabeculae were depleted, with a resultant reduction in the plate/rod ratio. Microarchitectural abnormalities were evident by decreased plate‐rod and plate‐plate junctions at the radius and tibia, and rod‐rod junctions at the radius. These trabecular and cortical abnormalities resulted in decreased whole‐bone stiffness and trabecular stiffness. These results provide evidence that in PHPT, microstructural abnormalities are pervasive and not limited to the cortical compartment, which may help to account for increased global fracture risk in PHPT.

Safety of osteoanabolic therapy: A decade of experience

Osteoporosis is a prevalent disease that affects more than 10million Americans. The lifetime risk of an osteoporosisrelated fracture is 50% for Caucasian women and 25% for men. Hip fractures carry a 10% to 20% increase in mortality rate within the first year after fracture. The burden of the hip and other fractures can result in chronic pain, disability and other indices of reduced quality of life. Amidst these sobering statistics is the welcome advent over the past two decades of effective pharmacological therapies that reduce fracture risk. The therapies approved for the management of osteoporosis include bisphosphonates, raloxifene (a selective estrogen-receptor modulator), calcitonin, denosumab, strontium ranelate, and parathyroid hormone [teriparatide (recombinant PTH(1–34) and PTH(1–84)]. The fulllength PTH molecule and its foreshortened amino-terminal fragment (teriparatide) are currently the only osteoanabolic agents approved for use. PTH(1–84) is not available in the United States. In November, 2002, teriparatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis and, later, in men. The approval camewith restrictions in duration of therapy (18–24months) and was limited to individuals with advanced osteoporosis at high risk for fracture. Reasons for these limitations relate, at least in part, to the unexpected occurrence of osteosarcoma and other bone neoplasms in Fischer 344 rat toxicity studies. In fact, the pivotal phase 3 trial of teriparatide was suspended when these rat toxicity data became available. The effects on rats was doseand duration-dependent, with rats being treated for approximately 80% of their lifetime and at doses three to 58 times the currently approved human dose. Similar toxicity was seen for PTH(1–84) Given the clear-cut efficacy data when the results of the abbreviated clinical trial results for teriparatide were analyzed, the FDA and equivalent other agencies in Europe and elsewhere granted approval of teriparatide with the stipulations that it should be used for no longer than 2 years. In the United States, the drug carries a ‘‘black box warning’’ and contraindicates its use in patients with existing risk factors for osteosarcoma, including Paget’s disease of bone, prior skeletal radiation, and children with open epiphyses. Teriparatide has now been used in the United States for 10 years. With a decade of experience, it is timely to review the efficacy and safety profile of this medication. PTH(1–84) will also be reviewed. This perspective will be limited to PTH formulations that are available for the treatment of osteoporosis; we will not be discussing other anabolic agents that are currently being studied but are not yet approved, such as the sclerostin antibody (http://clinicaltrials.gov/ct2/results?term1⁄4 sclerostinþ antiþ antibody).

Higher Rates of Bone Loss in Postmenopausal HIV-Infected Women: A Longitudinal Study

CONTEXT AND OBJECTIVE The objective of the study was to assess the effects of HIV infection and antiretroviral therapy on change in bone mineral density (BMD) in postmenopausal minority women. DESIGN, SETTING, AND PATIENTS We report a longitudinal analysis of change in BMD with a median duration of 15.4 (interquartile range 13.1, 20.7) months in a prospective cohort study of 128 (73 HIV+, 55 HIV-) postmenopausal Hispanic and African-American women. MAIN OUTCOME MEASURES Annualized change in BMD by dual-energy x-ray absorptiometry and correlation with baseline markers of bone turnover and serum levels of inflammatory cytokines were measured. RESULTS HIV+ women were younger (56 ± 1 vs. 59 ± 1 yr, P < 0.05) and had lower body mass index (BMI; 28 ± 1 vs. 31 ± 1 kg/m(2), P < 0.01). The majority of HIV+ women were on established antiretroviral therapy for more than 3 yr. At baseline, BMD, adjusted for age, race, and BMI, was lower in HIV+ women at the lumbar spine (LS), total hip, and radius and serum C-telopeptide was higher. Annualized rates of bone loss adjusted for baseline BMD were higher in HIV+ women by 2.4-fold at the LS (-1.2 ± 0.3% vs. -0.5 ± 0.3%, P = 0.0009), 3.7-fold at the one third radius (-1.1 ± 0.2% vs. -0.3 ± 0.2, P = 0.006) and 1.7-fold at the ultradistal radius (-1.2 ± 0.2% vs. -0.7 ± 0.2%, P = 0.02). In multivariate analysis, HIV+ status predicted bone loss at the LS, total hip, and ultradistal radius. Among HIV+ women, lower BMI, higher markers of bone turnover levels, and tenofovir were associated with more bone loss. CONCLUSION HIV+ postmenopausal minority women had lower BMD, increased bone turnover, and higher rates of bone loss than HIV- women. These features may place these women at increased risk for fracture as they age.

PTH(1–84) Is Associated With Improved Quality of Life in Hypoparathyroidism Through 5 Years of Therapy

CONTEXT In hypoparathyroidism, quality of life (QOL) is compromised as compared to normal subjects. We previously reported our results showing an association with recombinant human PTH(1-84) therapy in hypoparathyroidism and improvement in QOL measures for 1 year. OBJECTIVE We tested the hypothesis that PTH(1-84) therapy in hypoparathyroidism through 5 years would be associated with continued improvement in QOL measures. DESIGN Sixty-nine hypoparathyroid subjects received open-label PTH(1-84). Before and during therapy, subjects completed the RAND 36-Item Short Form (SF-36) Health Survey, a measure of health-related QOL covering eight domains of physical and mental health. RESULTS At baseline, subjects scored significantly lower than the normative reference range in all 8 domains (T-scores -1.4 to -0.9; P < .001 for all). With PTH therapy, intention-to-treat analysis showed significant improvement in the overall score at 2 months that persisted through 5 years (386 ± 19 to 482 ± 25; P < .0001). The mental component summary score improved at 2 months and was sustained through 5 years (199 ± 11 to 246 ± 14; P = .001), as did all four individual mental health domains and T-scores (vitality, social functioning, role emotional, mental health). The physical component summary score improved at 2 months and was sustained through 5 years (187 ± 10 to 237 ± 13; P < .0001), as did 3 physical health domains and T-scores (physical functioning, role physical, general health). CONCLUSIONS PTH(1-84) therapy is not only associated with improvement in biochemical and skeletal indices, previously well-documented, but also in mental and physical health as determined by the SF-36 metric.

The Effect of PTH(1–84) on Quality of Life in Hypoparathyroidism

CONTEXT Complaints from hypoparathyroid patients often reflect a reduction in quality of life (QOL), yet few data exist characterizing these complaints or the potential effects of PTH therapy to ameliorate them. OBJECTIVE We tested the hypothesis that PTH(1-84) therapy improves QOL in hypoparathyroidism. DESIGN Fifty-four hypoparathyroid subjects received open-label recombinant human PTH(1-84). Before and during PTH(1-84), subjects completed the RAND 36-Item Health Survey, a measure of health-related QOL covering 8 domains of physical and mental health. RESULTS At baseline, subjects scored significantly lower than the normative reference range in all 8 domains (T-scores -1.35 to -0.78; P < 0.001 for all). With PTH(1-84), the total score improved as early as month 1 and remained higher through 1 year (400 ± 200 to 478 ± 230; P = 0.001). The overall mental component summary score improved (204 ± 110 to 247 ± 130; P = 0.001), as did 3 mental health domains (vitality, social functioning, and mental health), all within 1 month (T-scores improving from -1.3 to -0.7, -1.0 to -0.6, and -0.9 to -0.3, respectively; P < 0.05 for all). The overall physical component summary score also increased by 1 month and remained higher at 1 year (196 ± 110 to 231 ± 130; P = 0.003) as did 2 physical health domains (physical functioning and general health: T-scores improving from -0.8 to -0.4, -1.2 to -0.8, respectively; P < 0.01 for both). CONCLUSIONS These data suggest that hypoparathyroidism is associated with compromised QOL. Along with improved biochemical control, these results indicate that PTH(1-84) treatment of hypoparathyroidism improves physical and mental functioning.

Clinical characteristics and medication use among premenopausal women with osteoporosis and low BMD: the experience of an osteoporosis referral center.

AIMS Osteoporosis is uncommon in premenopausal women, and most cases have a secondary cause. Women with osteoporosis and no known secondary cause are said to have idiopathic osteoporosis (IOP). We aimed to estimate the proportion of premenopausal women seen in our referral center with IOP as opposed to secondary osteoporosis, to describe their clinical characteristics, to compare women with a low-trauma fracture history with those with low bone mineral density (BMD) alone, and to estimate the frequency of bisphosphonate use. METHODS We reviewed medical records from all premenopausal women evaluated for osteoporosis or low BMD in our center during 2005. We included premenopausal women diagnosed on the basis of low-trauma fracture, low BMD or both (Z score < or= -2.0 or T score < or = -2.5), or both. RESULTS Among these patients (n = 61; mean age 37 +/- 8), 57 (93%) were Caucasian, 34 (57%) had a family history of osteoporosis, and 26 (43%) had used bisphosphonates. The most common secondary causes were amenorrhea (34%, n = 21), anorexia nervosa (16%, n = 10), and glucocorticoid exposure (13%, n = 8). After exclusion of secondary causes, 39% (24 of 61) of the entire group and 48% (14 of 29) of the fracture group were thought to have IOP. Women with a known secondary cause had lower BMD Z scores at the spine and hip than those with IOP. Women with low BMD and no fractures had shorter stature and weighed less than those with fractures, but overall differences between the groups were not statistically significant. Bisphosphonates had been prescribed for 38% (11 of 29) of women with a fracture history and 47% (15 of 32) of women with low BMD and no fractures. CONCLUSIONS Our findings suggest that IOP is common among premenopausal women with osteoporosis or low BMD evaluated at a referral center. The smaller stature of women diagnosed only on the basis of BMD criteria raises the question of whether their areal BMD measurements are spuriously low because of smaller bone size. The high proportion of premenopausal women who had been prescribed oral bisphosphonates for low BMD measurements is of concern, as such women are likely to be at low short-term risk of fracture, and a more conservative approach to therapy is preferable in this group.

Use of parathyroid hormone in hypoparathyroidism.

Hypoparathyroidism is a disorder characterized by hypocalcemia, deficient PTH, and abnormal bone remodeling. Standard treatment of hypoparathyroidism consists of oral calcium and vitamin D supplementation. However, maintaining serum calcium levels can be a challenge. In addition, concerns exist regarding hypercalciuria and ectopic calcifications that can be associated with such treatment. Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved treatment. This review focuses on the use of PTH in the treatment of hypoparathyroidism, in the form of teriparatide [PTH(1–34)] and the full-length molecule, PTH(1–84). Studies in hypoparathyroid subjects demonstrate that PTH(1–34) and PTH(1–84) lower or abolish supplemental calcium and vitamin D requirements as well as increase markers of bone turnover. Densitometric and histomorphometric studies in some subjects treated with PTH(1–34) and PTH(1–84) show an improvement in bone-remodeling dynamics and return of bone metabolism toward normal levels. Given the chronic nature of hypoparathyroidism, and the expectation that PTH will be used for extended periods of time in hypoparathyroidism, further studies are needed to determine the long-term safety of PTH therapy in this population.

Parathyroid hormone 1-84 alters circulating vascular endothelial growth factor levels in hypoparathyroidism.

CONTEXT We previously reported on four patients treated with PTH(1-84) who recovered from postoperative hypoparathyroidism many years after onset. Because vascular endothelial growth factor (VEGF) has been shown to be necessary for the induction of PTH-mediated angiogenesis, we postulated a possible role for VEGF in the recovery of parathyroid function in these subjects. OBJECTIVE Our objective was to measure VEGF levels in subjects with hypoparathyroidism who regained parathyroid gland function and matched controls. SETTING AND DESIGN Subjects with hypoparathyroidism who regained parathyroid gland function were each matched to two hypoparathyroid controls by postoperative etiology, age (within 5 y), menopausal status, and duration of hypoparathyroidism. We measured serum VEGF levels at baseline and through 48 months of PTH(1-84) therapy. RESULTS VEGF levels increased after the initiation of PTH(1-84) therapy for the entire cohort, from 309.7 ± 162 pg/ml at baseline to 380.2 ± 178 pg/ml at 12 months (P = .03). Levels trended downward thereafter. There were no significant differences in VEGF levels between the subjects with recovery of parathyroid function and the matched controls. CONCLUSIONS PTH(1-84) alters serum VEGF levels in subjects with hypoparathyroidism. Additional investigation is necessary to understand the mechanisms by which some subjects with postoperative hypoparathyroidism recover parathyroid gland function.