Adverse Skeletal Effects Research Articles

The skeletal effects of glucocorticoid excess override those of orchidectomy in mice.

Hypogonadism has been implicated as a contributing factor in glucocorticoid-induced osteoporosis, but evidence for this is limited. Hypogonadism and glucocorticoid excess both cause bone loss, but the cellular mechanisms responsible are distinct. Loss of gonadal steroids causes an increase in bone remodeling by up-regulating osteoblastogenesis and osteoclastogenesis. Glucocorticoid excess, conversely, suppresses remodeling by down-regulating osteoblastogenesis and osteoclastogenesis. Nonetheless, both conditions increase osteoblast apoptosis and decrease osteoclast apoptosis, and both cause bone loss due to an undersupply of osteoblasts relative to the need for cavity repair. To investigate their interactions, we compared the effects of orchidectomy, glucocorticoid excess, or both combined in mice. After 28 d, serum unbound testosterone concentration and seminal vesicle weight were not diminished when prednisolone was administered alone. Vertebral bone mineral density and compression strength decreased to the same extent in animals receiving prednisolone or after orchidectomy, but the changes were not additive. Orchidectomy induced the expected up-regulation of osteoblast and osteoclast progenitors, but these changes were prevented in orchidectomized mice simultaneously receiving glucocorticoids. Likewise, the increase in cancellous osteoid, osteoblasts, osteoclasts, bone formation, and activation frequency caused by orchidectomy were prevented by prednisolone. The prevalence of osteoblast apoptosis increased in the mice receiving prednisolone or after orchidectomy, but the increases were not additive. These data demonstrate that hypogonadism does not occur in or contribute to glucocorticoid-induced osteoporosis and that the adverse skeletal effects of glucocorticoid excess override those of orchidectomy.

Bone is a target for the antidiabetic compound rosiglitazone.

Rosiglitazone is an FDA-approved oral antidiabetic agent for the treatment of type 2 diabetes. This compound improves insulin sensitivity through the activation of the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPAR-gamma). In addition to sensitizing cells to insulin, the PPAR-gamma2 isoform appears to be critical for the regulation of osteoblast and adipocyte differentiation from common mesenchymal bone marrow progenitors. We have demonstrated previously that PPAR-gamma2 activated with rosiglitazone acts as a dominant inhibitor of osteoblastogenesis in murine bone marrow in vitro. Here, we show that in vivo, rosiglitazone administration results in significant bone loss. When rosiglitazone (20 microg/g body weight/d) was given to 6-month-old, nondiabetic C57BL/6 mice for 7 wk, a significant decrease in total body bone mineral density was observed. Analysis of bone microarchitecture, using micro-computed tomography, demonstrated a decrease in bone volume, trabecular width, and trabecular number and an increase in trabecular spacing. Histomorphometric analysis showed a decrease in bone formation rate, with a simultaneous increase in fat content in the bone marrow. Changes in bone morphology and structure were accompanied by changes in the expression of osteoblast- and adipocyte-specific marker genes; the expression of the osteoblast-specific genes Runx2/Cbfa1, Dlx5, and alpha1(I)collagen were decreased, whereas the expression of the adipocyte-specific fatty acid binding protein aP2, was increased. These in vivo data suggest that rosiglitazone therapy may pose a significant risk of adverse skeletal effects in humans.

Fracture risk after bilateral oophorectomy in elderly women.

Elderly women with the lowest serum estrogen levels are at the greatest risk of bone loss and fractures, but it is controversial whether the ovaries contribute to estrogen production after menopause, and therefore, whether bilateral oophorectomy in postmenopausal women might have adverse skeletal effects. To address this potential problem, we estimated long-term fracture risk among 340 postmenopausal Olmsted County, MN, women who underwent bilateral oophorectomy for a benign ovarian condition in 1950-1987. In over 5632 person-years of follow-up (median, 16 years per subject), 194 women experienced 516 fractures (72% from moderate trauma). Compared with expected rates, there was a significant increase in the risk of any osteoporotic fracture (moderate trauma fractures of the hip, spine, or distal forearm; standardized incidence ratio [SIR], 1.54; 95% CI, 1.29-1.82) but almost as large an increase in fractures at other sites (SIR, 1.35; 95% CI, 1.13-1.59). In multivariate analyses, the independent predictors of overall fracture risk were age, anticonvulsant or anticoagulant use for > or = 6 months, and a history of alcoholism or prior osteoporotic fracture; obesity was protective. Estrogen replacement therapy was associated with a 10% reduction in overall fracture risk (hazard ratio [HR], 0.90; 95% CI, 0.64-1.28) and a 20% reduction in osteoporotic fractures (HR, 0.80; 95% CI, 0.52-1.23), but neither was statistically significant. The increase in fracture risk among women who underwent bilateral oophorectomy after natural menopause is consistent with the hypothesis that androgens produced by the postmenopausal ovary are important for endogenous estrogen production that protects against fractures.

Dissatisfaction with thyroxine therapy - could the patients be right?

In some patients with hypothyroidism, symptoms of ill health persist despite thyroxine treatment. It is unclear whether this arises from comorbidity or because standard thyroxine replacement is in some way inadequate for some individuals. Some patients feel better if they take a slightly excessive dose of thyroxine, but this carries a potential risk of adverse cardiac and skeletal effects. There are conflicting data on whether combined thyroxine/triiodothyronine treatment is preferable to thyroxine alone in dissatisfied patients.

Short-Term Vitamin A Supplementation Does Not Affect Bone Turnover in Men

Limited data in humans and animals indicate that excess vitamin A stimulates bone resorption and inhibits bone formation, effects that over time might lead to bone loss and fracture. Thus, it is possible that vitamin A supplementation is a currently unrecognized risk factor for the development of osteoporosis. To further evaluate this possibility, a prospective, randomized, single-blind study of vitamin A supplementation was conducted in 80 healthy men age 18-58 y. One half received 7576 microg (25,000 IU) of retinol palmitate daily with their evening meal; the others took a placebo. Blood was collected from fasting subjects and serum prepared at baseline and after 2, 4 and 6 wk of supplementation. Serum bone specific alkaline phosphatase (BSAP) and N-Telopeptide of type 1 collagen (NTx) were measured at all time points. Serum osteocalcin (Oc) was measured at baseline and after 6 wk of supplementation. BSAP, NTx and Oc did not differ between the supplemented and placebo-treated groups over the course of the study. In conclusion, short-term vitamin A supplementation at this dosage in healthy men does not alter serum markers of skeletal turnover. Thus, it is unlikely that short-term administration of vitamin A would contribute to the development of osteoporosis. Whether long-term vitamin A supplementation might have adverse skeletal effects remains to be determined.

In vivo NMR microscopy allows short-term serial assessment of multiple skeletal implications of corticosteroid exposure.

Corticosteroids are in widespread clinical use but are known to have adverse skeletal side effects. Moreover, it is not known how soon these effects become apparent. Here, we describe a longitudinal approach to evaluate the short-term implications of excess corticosteroid exposure by quantitative in vivo magnetic resonance imaging and spectroscopy in conjunction with digital image processing and analysis in a rabbit model. Two-week treatment with dexamethasone induced a significant reduction in trabecular bone volume, which occurred at the expense of uniform trabecular thinning without affecting network architecture. Paralleling the loss in bone volume was conversion of hematopoietic to yellow marrow in the femoral metaphysis and atrophy of the femoral epiphyseal growth plate. This work demonstrates that detailed quantitative morphometric and physiological information can be obtained noninvasively at multiple skeletal locations. The method is likely to eventually replace invasive histomorphometry in that it obviates the need to sacrifice groups of animals at multiple time points. Finally, this work, which was performed on a clinical scanner, has implications for evaluating patients on high-dose steroid treatment.

Vitamin A intake and hip fractures among postmenopausal women.

Ingestion of toxic amounts of vitamin A affects bone remodeling and can have adverse skeletal effects in animals. The possibility has been raised that long-term high vitamin A intake could contribute to fracture risk in humans. To assess the relationship between high vitamin A intake from foods and supplements and risk of hip fracture among postmenopausal women. Prospective analysis begun in 1980 with 18 years of follow-up within the Nurses' Health Study. General community of registered nurses within 11 US states. A total of 72 337 postmenopausal women aged 34 to 77 years. Incident hip fractures resulting from low or moderate trauma, analyzed by quintiles of vitamin A intake and by use of multivitamins and vitamin A supplements, assessed at baseline and updated during follow-up. From 1980 to 1998, 603 incident hip fractures resulting from low or moderate trauma were identified. After controlling for confounding factors, women in the highest quintile of total vitamin A intake (>/=3000 microgram/d of retinol equivalents [RE]) had a significantly elevated relative risk (RR) of hip fracture (RR, 1.48; 95% confidence interval [CI], 1.05-2.07; P for trend =.003) compared with women in the lowest quintile of intake (<1250 microgram/d of RE). This increased risk was attributable primarily to retinol (RR, 1.89; 95% CI, 1.33-2.68; P for trend <.001 comparing >/=2000 microgram/d vs <500 microgram/d). The association of high retinol intake with hip fracture was attenuated among women using postmenopausal estrogens. Beta carotene did not contribute significantly to fracture risk (RR, 1.22; 95% CI, 0.90-1.66; P for trend =.10 comparing >/=6300 microgram/d vs <2550 microgram/d). Women currently taking a specific vitamin A supplement had a nonsignificant 40% increased risk of hip fracture (RR, 1.40; 95% CI, 0.99-1.99) compared with those not taking that supplement, and, among women not taking supplemental vitamin A, retinol from food was significantly associated with fracture risk (RR, 1.69; 95% CI, 1.05-2.74; P for trend =.05 comparing >/=1000 microgram/d vs <400 microgram/d). Long-term intake of a diet high in retinol may promote the development of osteoporotic hip fractures in women. The amounts of retinol in fortified foods and vitamin supplements may need to be reassessed.

Long-term fracture risk among infertile women: a population-based cohort study.

Nulliparity has been linked to bone loss and fractures, but the contribution of infertility is unclear. The purpose of this study was to assess the long-term risk of fractures among infertile women. In a population-based retrospective cohort study, all 658 Olmsted County, Minnesota, women with infertility (failure to conceive after 1 year despite intercourse without contraception) first diagnosed at Mayo Clinic in 1935-1964 were followed for fractures. Risk was assessed by comparing new fractures of each type to the number expected from sex-specific and age-specific fracture rates in the general population (standardized incidence ratios [SIR]). During 18,130 person-years of follow-up, 184 women experienced at least one fracture when 291 would have been expected on the basis of fracture incidence rates in the general population (SIR 0.6, 95% CI 0.5-0.7). There was no increase in proximal femur fractures (SIR 1.0, 95% CI 0.6-1.6) and a statistically significant decrease in the risk of distal forearm fractures (SIR 0.7, 95% CI 0.5-0.97), two of the three sites traditionally associated with osteoporosis. By contrast, there was a significant increase in subsequent vertebral fractures (SIR 1.9, 95% CI 1.4-2.4) that was consistent across divergent causes of infertility and reported menstrual patterns. Although an apparent increase in the risk of vertebral fractures requires further investigation, we saw no indication of an increase in limb fractures, suggesting that infertility does not have long-term adverse skeletal effects like those reported for athletes and dieters with irregular menses.

Oral corticosteroids and fracture risk: relationship to daily and cumulative doses.

This study examined the effects of daily and cumulative oral corticosteroid doses on the risk of fractures. Information was obtained from the General Practice Research Database, which contains medical records of general practitioners in England and Wales. The study included 244 235 oral corticosteroid users and 244 235 controls. Patients taking higher doses (at least 7. 5 mg daily of prednisolone or equivalent) had significantly increased risks of non-vertebral fracture [relative rate (RR)=1.44, 95% confidence interval (CI) 1.34-1.54], hip fracture (RR=2.21, 95% CI 1.85-2.64) and vertebral fracture (RR=2.83, 95% CI 2.35-2.40) relative to patients using oral corticosteroids at lower doses (less than 2.5 mg per day). Fracture risk was also elevated among people with higher cumulative exposure to oral corticosteroids over the study period, but this effect was almost wholly removed by adjustment for daily dose, age, gender and other confounding variables. These findings suggest that the adverse skeletal effects of oral corticosteroids manifest rapidly and are related to daily dose. The level of previous exposure to oral corticosteroids was not a strong determinant of the risk of fracture. Preventive measures against corticosteroid-induced osteoporosis should therefore be instituted as soon after the commencement of glucocorticoid therapy as possible.

Does estrogen adequately protect postmenopausal women against osteoporosis: an iconoclastic perspective.

In sum, the skeletal benefits provided by hormone replacement therapy are important, and estrogen should be justifiably considered one of the fundamentals of menopausal management. However, its efficacy in the prevention of osteoporotic fractures should not be overstated. Low bone mass and fractures remain serious threats in older postmenopausal women, even in the presence of hormone replacement. With the recognition of that reality comes a variety of challenges to clinicians and investigators. Clinicians should use estrogen to its best advantage, though, at the same time, remain vigilant of its limitations. Older postmenopausal women who are, or who have been, taking estrogen should not be a priori considered adequately protected against fracture. The same careful clinical evaluation recommended for the protection of those at increased fracture risk, including bone mass measures, should be available to estrogen-taking women in the later postmenopausal period. Recognizing this need, the National Osteoporosis Foundation has recently recommended bone mineral density testing in older women, regardless of estrogen status, and HCFA reimbursement has become available for this indication. In the presence of low bone density, estrogen-taking women should be afforded appropriate levels of diagnostic and therapeutic attention, with the intent to further reduce fracture risk. Once estrogen therapy has been elected, patients and their clinicians should be aware that bone loss can still be expected in the later postmenopausal years. Periodic reevaluations of bone density and other risks for fracture (e.g. falls) may be appropriate. In the face of continued good health, those reevaluations can be infrequent, but women who have medical conditions associated with adverse skeletal effects should be followed more closely despite their estrogen therapy. If we are to build on the value of estrogen to improve our approach to osteoporosis, additional data are needed. When fracture risk has been considered in complex models that adjust for account other medical and lifestyle variables, a greater protective effect of estrogen has emerged (12), suggesting that there are factors whose actions attenuate those of estrogen. Prominent candidates include genetics, tobacco and alcohol use, medications, body composition, and propensity to fall. There are undoubtedly others yet unidentified. These should be further defined, and the basic mechanisms for interactions between them and estrogen should be examined. It would be clinically advantageous to use these factors to accurately identify not only the women who would benefit from estrogen replacement but also those who would not. Because estrogen has important beneficial effects, an essential research objective should be the development of therapeutic strategies that combine the advantages of estrogen with other modalities (pharmacological or otherwise), to maximally protect the many estrogen-taking women who may be considered at continued risk for fracture. To whit, the initial reports of combination therapy with bisphosphonates are encouraging (13, 14). Other important skeletal agents can be anticipated to interact with estrogen in as-of-yet unforeseen ways. On another front, it can be anticipated that selective estrogen receptor modulators will be subject to estrogen-like limitations when used for osteoporosis prevention/therapy, and their effects will be influenced by a similar, but distinct, array of covariates. Our vision of the role of hormone replacement in the reduction of osteoporotic fracture risk should be considerably sharpened. At one time, estrogen was the lone best hope for the avoidance of fracture, but no longer should we be satisfied with that imperfect solution. The development of much more efficient and effective methods for osteoporosis risk assessment, prevention, and treatment now provides a chance to surpass previous expectations. (ABSTRACT TRUNCATED)

Warfarin: no adverse skeletal effects in postmenopausal women

Warfarin: no adverse skeletal effects in postmenopausal women