[Show abstract][Hide abstract] ABSTRACT: In men, idiopathic osteoporosis (IOP) is often associated with low serum insulin-like growth factor (IGF-1) and reduced bone formation. The characteristics of premenopausal women with IOP are not well defined. We aimed to define the clinical, reproductive, and biochemical characteristics of premenopausal women with unexplained osteoporosis.
This is a cross-sectional study of 64 women with unexplained osteoporosis, 45 with fragility fractures, 19 with low bone mineral density (BMD; Z-score less than or equal to -2.0) and 40 normal controls. The following are the main outcome measures: clinical and anthropometric characteristics, reproductive history, BMD, gonadal and calciotropic hormones, IGF-1, and bone turnover markers (BTMs).
Subjects had lower BMI and BMD than controls, but serum and urinary calcium, serum estradiol, vitamin D metabolites, IGF-1, and most BTMs were similar. Serum parathyroid hormone (PTH) and the resorption marker, tartrate-resistant acid phosphatase (TRAP5b), were significantly higher in both groups of subjects than controls and directly associated in all groups. Serum IGF-1 and all BTMs were directly associated in controls, but the association was not significant after controlling for age. There was no relationship between serum IGF-1 and BTMs in subjects. There were few differences between women with fractures and low BMD.
Higher serum TRAP5b and PTH suggest that increased bone turnover, possibly related to subclinical secondary hyperparathyroidism could contribute to the pathogenesis of IOP. The absence of differences between women with fractures and those with very low BMD indicates that this distinction may not be clinically useful to categorize young women with osteoporosis.
Osteoporosis International 03/2011; 23(1):171-82. DOI:10.1007/s00198-011-1560-y · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Data on the presence, extent, and reversibility of cardiovascular disease in primary hyperparathyroidism (PHPT) are conflicting.
To evaluate the heart in PHPT, we assessed cardiac structure and diastolic function in patients with mild PHPT compared with age- and sex-matched controls.
This was a case-control study.
The study was conducted in a university hospital Metabolic Bone Diseases Unit.
Fifty-four men and women with PHPT and 76 controls without PHPT participated in the study.
We measured left ventricular mass index (LVMI), the presence of mitral annular calcification, the ratio of early to late diastolic mitral inflow velocities (E/A), and early diastolic velocity of the lateral mitral annulus using Doppler tissue imaging (tissue Doppler e').
Patients had mild disease with mean (+/-sd) serum calcium 10.5 +/- 0.5 mg/dl and PTH 96 +/- 45 pg/ml. LVMI and diastolic function were normal in PHPT. There was no difference in LVMI (98 +/- 23 vs. 96 +/- 24 g/m(2), P = 0.69) or the frequency of mitral annular calcification between PHPT cases and controls. Diastolic function variables (E/A and tissue Doppler e') were higher (better) in cases compared with controls, although both were within the reference range. PHPT patients with low E/A had higher serum PTH (121 +/- 36 vs. 89 +/- 46 pg/ml, P = 0.03) and calcium (10.8 +/- 0.4 vs. 10.5 +/- 0.5 mg/dl, P = 0.05) than those with normal values. Finally, we found LVMI to be inversely associated with serum 25-hydroxyvitamin D in PHPT (r = -0.29, P < 0.05). All findings persisted after adjustment for group differences in cardiovascular risk factors.
Patients with biochemically mild PHPT do not have evidence of increased left ventricular mass, diastolic dysfunction, or increased valvular calcifications. However, the data support an association between low vitamin D levels and the development of left ventricular hypertrophy in this disorder. Finally, the increased serum calcium and PTH levels in those with diastolic dysfunction suggest that disease severity may determine the presence of cardiac manifestations in PHPT.
The Journal of Clinical Endocrinology and Metabolism 03/2010; 95(5):2172-9. DOI:10.1210/jc.2009-2072 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Data on the presence, extent, and reversibility of cardiovascular disease in primary hyperparathyroidism (PHPT) are conflicting.
This study evaluated carotid structure and function in PHPT patients compared with population-based controls.
This is a case-control study.
The study was conducted in a university hospital metabolic bone disease unit.
Forty-nine men and women with PHPT and 991 controls without PHPT were studied.
We measured carotid intima-media thickness (IMT), carotid plaque presence and thickness, and carotid stiffness, strain, and distensibility.
IMT, carotid plaque thickness, carotid stiffness, and distensibility were abnormal in PHPT patients, and IMT was higher in patients than controls (0.959 vs. 0.907 mm, P < 0.0001). In PHPT, PTH levels, but not calcium concentration, predicted carotid stiffness (P = 0.04), strain (P = 0.06), and distensibility (P = 0.07). Patients with increased carotid stiffness had significantly higher PTH levels than did those with normal stiffness (141 +/- 48 vs. 94.9 +/- 44 pg/ml, P = 0.002), and odds of abnormal stiffness increased 1.91 (confidence interval = 1.09-3.35; P = 0.024) for every 10 pg/ml increase in PTH, adjusted for age, creatinine, and albumin-corrected calcium.
Mild PHPT is associated with subclinical carotid vascular manifestations. IMT, a predictor of cardiovascular outcomes, is increased. Measures of carotid stiffness are associated with extent of PTH elevation, suggesting that those with more severe PHPT may have impaired vascular compliance and that PTH, rather than calcium, is the mediator.
The Journal of Clinical Endocrinology and Metabolism 09/2009; 94(10):3849-56. DOI:10.1210/jc.2009-1086 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Journal of Women's Health 01/2009; 18(1):79-84. DOI:10.1089/jwh.2008.0887 · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bariatric surgery is common and may be associated with deleterious effects on the skeleton.
Our objective was to assess bone metabolism and bone mineral density (BMD) after Roux-en-Y gastric bypass.
We conducted a 1-yr prospective longitudinal study at a university hospital bariatric surgery practice and metabolic bone disease unit.
Participants included 23 obese (mean body mass index 47 kg/m(2)) men and women, aged 20-64 yr.
Serum PTH, 25-hydroxyvitamin D, osteocalcin, and urinary N-telopeptide, and BMD were assessed.
Patients lost 45 +/- 2 kg 1 yr postoperatively (P < 0.01). PTH increased early (3 months, 43-50 pg/ml; P < 0.001) and urinary calcium dropped (161-92 mg/24 h; P < 0.01), despite doubling of calcium intake (1318-2488 mg/d; P < 0.001). Serum 25-hydroxyvitamin D concentrations were unchanged (23-26 ng/ml), although vitamin D intake increased by 260% (658 IU/d at baseline to 1698 IU/d at 12 months; P < 0.05). Markers of bone remodeling rose (P < 0.01 for both urinary N-telopeptide and osteocalcin), whereas BMD decreased at the femoral neck (9.2%, P < 0.005) and at the total hip (8.0%, P < 0.005). These declines were strongly associated with the extent of weight loss (femoral neck: r = 0.90, P < 0.0001; and total hip: r = 0.65, P = 0.02). Lumbar spine and distal radius sites did not change.
After Roux-en-Y gastric bypass, there was evidence of calcium and vitamin D malabsorption. Bone turnover increased, and hip bone density rapidly declined. The decline in hip BMD was strongly associated with weight loss itself. Vigilance for nutritional deficiencies and bone loss in patients both before and after bariatric surgery is crucial.
[Show abstract][Hide abstract] ABSTRACT: Men undergoing heart transplantation during the early 1990s had declines in testosterone associated with rapid bone loss. It is unclear whether low testosterone still occurs in an era of lower prednisone doses, whether cyclosporine A (CsA) contributes, whether hypothalamic-pituitary-gonadal (HPG) suppression or direct testicular effects are responsible, and whether low testosterone influences bone loss in men receiving therapy to prevent osteoporosis.
Serum testosterone, estradiol, sex hormone binding globulin, gonadotropins, and bone density were measured and prednisone and CsA doses and levels for the first 2 years after transplantation were recorded in a more recently transplanted cohort of 108 participants in a trial comparing alendronate and calcitriol for prevention of posttransplant osteoporosis.
Total and free testosterone levels were lowest during the first month (257+/-131 and 6.2+/-3 ng/dL, respectively) and normalized by 2 months. Gonadotropins were low in the majority, suggesting HPG suppression. Low total testosterone persisted in 14% at 1 year and 18% at 2 years. Prednisone was the major predictor of serum testosterone. No adverse effect of CsA and no relationship between serum testosterone and bone density change were detected.
Low serum testosterone levels still occur in the early posttransplant period, probably related to HPG suppression by prednisone rather than direct testicular effects of CsA. They are not associated with bone loss in men receiving therapies to prevent osteoporosis. At later time points, low testosterone levels are common and apparently related to primary gonadal dysfunction, suggesting that long-term male heart transplant recipients should be evaluated for hypogonadism.
[Show abstract][Hide abstract] ABSTRACT: Tamoxifen has antiestrogenic effects in the breast and estrogenlike activity in the skeletons of postmenopausal women. We hypothesized that postmenopausal women with breast cancer would experience a rapid decline in bone mineral density (BMD) after stopping tamoxifen, similar to that seen with estrogen withdrawal. The objective of this study was to assess, in a randomized, double-blind, placebo-controlled trial, whether administration of alendronate (70 mg weekly) would prevent bone loss associated with tamoxifen discontinuation.
Postmenopausal women with breast cancer were randomly assigned to receive alendronate or placebo for 1 year within 3 months after withdrawal of tamoxifen therapy. We initiated a randomized, double-blind, placebo-controlled trial of alendronate (70 mg weekly) in an effort to prevent bone loss associated with discontinuation of tamoxifen therapy. Patients treated with aromatase inhibitors were excluded from the study. BMD at the spine, hip, and forearm was measured at baseline and at 12 months. Analyses employed repeated-measures analysis of variance.
Patient accrual was considerably limited by the substantial increase in use of aromatase inhibitors during the enrollment period. The study patients (N = 11) had similar baseline BMD T-scores in the alendronate (n = 6) and placebo (n = 5) subgroups. After 1 year, tamoxifen withdrawal was associated with a significant decline in BMD at the femoral neck, which appeared to be prevented by weekly administration of alendronate (-5.2% versus 0.1%; P = .02). Levels of urinary N-telopeptide, a marker of bone turnover, increased by 48% in study subjects in the placebo group (P < .01), whereas weekly alendronate treatment was associated with a 52% decline (P < .01) in this bone resorption marker.
Differences in BMD and bone turnover were evident despite the small sample size. These data suggest that postmenopausal women with breast cancer completing tamoxifen therapy warrant an evaluation of their skeletal health and that bisphosphonate therapy may be useful in preventing bone loss associated with discontinuation of tamoxifen.
Endocrine Practice 03/2008; 14(2):162-7. DOI:10.4158/EP.14.2.162 · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most young people with osteoporosis have an identifiable cause. Others have an idiopathic form for which no etiology can be found. We have reported that men with idiopathic osteoporosis (IOP) have histomorphometric evidence of decreased bone formation and osteoblast dysfunction. The pathogenesis of IOP in young women remains unclear. Our aim was to characterize the histomorphometry of IOP in healthy premenopausal women. We compared iliac crest bone biopsies from nine women with IOP to 18 healthy, age-, sex-, and race-matched controls. Compared with controls, differences in bone remodeling were identified, particularly in cancellous bone. Although cancellous bone volume did not differ, there was a trend toward lower trabecular number and increased separation in women with IOP. In cancellous bone, there was no increase in osteoid width or perimeter, but IOP patients had lower bone formation parameters, including a 10% reduction in wall width (P < 0.01), an 18% reduction in mineral apposition rate (P < 0.01), and a 42% reduction in mineralized perimeter (P < or = 0.02). Additionally, the bone formation rate was 52% lower (0.026 +/- 0.004 vs. 0.054 +/- 0.01 microm/microm(2).d; P < 0.01), and a trend toward decreased activation frequency was observed in IOP patients. Conversely, bone resorption was altered in IOP patients, reflected by a longer resorption period (134 +/- 35 vs. 38 +/- 6 d; P < or = 0.02) and increased eroded perimeter (5.5 +/- 0.7 vs. 4.1 +/- 0.4%; P = 0.05). Wall width and mineralized perimeter were similarly lower in endocortical bone. Resorption period and eroded perimeter were higher in intracortical bone. Women with IOP have uncoupling of resorption and formation and, like men with IOP, osteoblast dysfunction.
[Show abstract][Hide abstract] ABSTRACT: Functioning parathyroid adenomas of the oxyphil cell type are rare, and the clinical characteristics of patients with these tumors have not been well defined. We describe two cases of severe primary hyperparathyroidism (PHPT) caused by benign oxyphil parathyroid adenomas. The patients' clinical presentations mimicked parathyroid carcinoma. Both had very large tumors associated with marked elevations in PTH and serum calcium levels. Skeletal manifestations were also atypical for benign PHPT, with severe osteoporosis in one patient and osteitis fibrosa cystica in the other. These cases also highlight the remarkable capacity of the skeleton to recover after successful parathyroidectomy, previously reported in other forms of severe PHPT. Bone mineral density improved dramatically 1 yr after parathyroidectomy, with increases of 51% at the lumbar spine, 36% at the total hip, and 11% at the distal one third radius. Most of the increases occurred in the first postoperative months. Consistent with this early and accelerated skeletal response, markers of bone turnover were increased 2 months after surgery and normalized by 8 months postoperatively. In patients with PHPT who present with severe or atypical clinical features, oxyphil adenoma should be considered.