Monoclonal gammopathy of undetermined significance,multiple myeloma,and osteoporosis

The finding of monoclonal gammopathy of undetermined significance (MGUS) is not infrequent during an evaluation for osteoporosis or a fracture. In most cases, the diagnosis is MGUS, whose prevalence increases with age. Although the impact of MGUS on bone mineral density, bone remodeling, and the fracture risk remains unclear, this asymptomatic hematological disorder may constitute a risk factor for osteoporosis. Furthermore, each year, 1% of patients with MGUS progress to multiple myeloma, a disease whose pathophysiology and association with bone loss and pathological fractures are increasingly well understood. Osteoporotic fractures, although probably common in myeloma patients, are less likely to be recognized. Here, we discuss the pathophysiology of myeloma and MGUS and their impact in terms of bone mineral density, osteoporotic fractures, and bone turnover markers.     

Fracture risk among patients with Paget's disease: a population-based cohort study.

Localized disruption of bone architecture leads to an increased risk of pathological fractures in patients with Paget's disease, but the impact of the disease on overall fracture risk is unknown. We addressed this issue among 236 Olmsted County, Minnesota residents (107 women and 129 men) first diagnosed with Paget's disease from 1950 through 1994. These subjects (mean +/- SD age at diagnosis, 69.6+/-12.2 years) were followed subsequently for 2798 person-years. During this period of observation, 33 pathological fractures were attributed to Paget's disease (1 skull, 11 vertebra, 1 shaft/distal humerus, 1 pelvis, 6 proximal femur, 2 shaft/distal femur, and 11 tibia/fibula). Excluding the fractures through pagetic bone, there was no increase in overall fracture risk in this cohort (standardized incidence ratio [SIR], 1.2; 95% CI, 0.9-1.4). However, there was a statistically significant increase in the risk of subsequent vertebra (SIR, 3.0; 95% CI, 2.2-4.1) and rib fractures (SIR, 1.7; 95% CI, 1.1-2.4) but not fractures of the proximal femur (SIR, 0.6; 95% CI, 0.3-1.1) or distal forearm (SIR, 1.4; 95% CI, 0.7-2.5). Thus, unselected patients with Paget's disease in the community, who mostly have mild disease, have a significantly increased risk of vertebral fractures, although this may relate partly to increased surveillance. Additional work is needed to clarify the relationship between Paget's disease and vertebral fractures and to identify individuals at increased risk for more aggressive therapy.     

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.     

Fracture risk after surgery for peptic ulcer disease: a population-based cohort study.

In the 30-year period from 1956 to 1985, 471 Rochester, MN residents had an initial operation for peptic ulcer disease, 438 of whom were followed for at least 30 days (median 14.8 years per subject). In this population-based cohort, risk was elevated for all of the fracture sites traditionally associated with osteoporosis, including the proximal femur (standardized incidence ratio [SIR] 2.5, 95% CI 1.9-3.3), vertebra (SIR 4.7, 95% CI 3.8-5.7), and distal forearm (SIR 2.2, 95% CI 1.5-3.1). Fracture risk rose with age and was greater among women than men, but there was no influence on overall fracture risk of ulcer type or nature of the operation. In multivariate analyses, the independent predictors of vertebral fractures were age (hazard ratio [HR] per 10-year increase 1.8, 95% CI 1.6-2.0), use of corticosteroids (HR 2.3, 95% CI 1.01-5.2), thyroid replacement (HR 2.5, 95% CI 1.4-4.6), chronic anticoagulation (HR 2.3, 95% CI 1.1-4.6), and the presence of one or more conditions associated with secondary osteoporosis (HR 1.6, 95% CI 1.2-2.1). Gastrectomy with Billroth II reconstruction appeared to be relatively protective (HR 0.5, 95% CI 0.3-0.9), but such patients still had an increased risk of vertebral fractures compared with community residents generally (SIR 3.6, 95% CI 2.4-5.4). The independent predictors of hip fracture risk in this cohort were age (HR 2.7, 95% CI 2.1-3.5) and use of corticosteroids (HR 5.8, 95% CI 2.2-15.3) or anticonvulsants (HR 4.6, 95% CI 1.8-12.0), while higher body mass index was protective (HR 0.9, 95% CI 0.8-0.96). The independent predictors of distal forearm fractures were female gender (HR 4.7, 95% CI 2.2-10.1) and chronic anticoagulant use (HR 2.8, 95% CI 1.1-7.3). Thus, while the risk of osteoporotic fractures was significantly increased among patients operated for peptic ulcers, this appeared to be due more to specific characteristics of the cohort than to adverse effects of particular surgical procedures.     

Fractures following thyroidectomy in women: a population-based cohort study

Hip fracture risk has been associated with hyperthyroidism and thyroidectomy in men and with hyperthyroidism in women, but the influence of thyroidectomy on fracture risk in women has not been adequately addressed. The 630 Rochester, MN women who underwent thyroidectomy in 1950-1974 were followed subsequently for 12,804 person-years (retrospective cohort study) during which 601 fractures were observed. Relative to incidence rates in the community, there was no increase in overall fracture risk (standardized incidence ratio [SIR] 0.9; 95% confidence interval [CI] 0.8-1.00). No increase was seen in limb fractures generally or in distal forearm fractures specifically (SIR 1.1, 95% CI 0.8-1.4). There was a modest but statistically significant increase in the risk of hip fractures following thyroidectomy (SIR 1.3, 95% CI 1.01-1.8), but much greater increases were apparent in the risk of subsequent fractures of the ribs, spine, and pelvis. There was almost a threefold increase in vertebral fractures (SIR 2.8, 95% CI 2.3-3.3), but the excess was mostly observed long after the original operation and may be attributable to ascertainment bias. Fracture risk was associated with advancing age and with the presence of one or more of the diseases that have been associated with secondary osteoporosis but not with a history of hyperthyroidism, extent of thyroid surgery, or subsequent use of thyroid replacement therapy. Thus, with the exception of some fractures of the axial skeleton, which might have been more completely diagnosed among affected women, there was no increase in fracture risk among women following thyroidectomy performed mainly for adenoma or goiter.     

Long-term fracture risk following adult-onset asthma: a population-based study

There are few data on skeletal outcomes in the growing population of patients with adult-onset asthma. We conducted a population-based retrospective (historical) cohort study among 226 residents of Rochester, Minnesota, USA, who were 35 years of age or older when first diagnosed with asthma. Fractures were ascertained by review of comprehensive community medical records, and observed fractures were compared with expected numbers based on incidence rates in the local population (standardized incidence ratios, SIR). During 4,022 person-years of follow-up, 100 patients experienced 211 fractures, for an actuarially estimated cumulative incidence of 63% after 30 years compared with 59% expected (p=0.004). Statistically significant increases were seen for moderate trauma fractures of the vertebrae (SIR, 2.9; 95% CI, 2.1 to 3.8) and ribs (SIR, 2.0; 95% CI, 1.2 to 3.2), as well as the proximal femur (SIR, 1.8; 95% CI, 1.02 to 2.8). As assessed by proportional hazards models, the only independent predictors of any subsequent moderate trauma fracture were age (hazard ratio [HR] per 10-year increase, 1.7; 95% CI, 1.5 to 2.1) and cumulative corticosteroid dose greater than the median of 1,775 mg (HR, 1.8; 95% CI, 1.1 to 3.0). In another multivariate analysis, the predictors of a moderate trauma vertebral fracture were older age (HR, 1.6; 95% CI, 1.3 to 2.1), concomitant chronic obstructive pulmonary disease (HR, 2.4; 95% CI, 1.2 to 4.9), cigarette smoking (HR, 2.3; 95% CI, 1.2 to 4.8), and cumulative corticosteroid dose greater than the median (HR, 2.6; 95% CI, 1.4 to 5.0). Other asthma therapies did not contribute significantly to these models. Thus, a 70% increase in overall fracture risk among unselected community patients with adult onset asthma was mainly confined to the subset who also had chronic obstructive pulmonary disease and was influenced by substantial corticosteroid use.     

Fracture Risk in Type 2 Diabetes: Update of a Population‐Based Study

We found no significant excess of fractures among Rochester, MN, residents with diabetes mellitus initially recognized in 1950–1969, but more recent studies elsewhere have documented an apparent increase in hip fracture risk. To explore potential explanations for any increase in fractures, we performed an historical cohort study among 1964 Rochester residents who first met glycemic criteria for diabetes in 1970–1994 (mean age, 61.7 ± 14.0 yr; 51% men). Fracture risk was estimated by standardized incidence ratios (SIRs), and risk factors were evaluated in Andersen‐Gill time‐to‐fracture regression models. In 23,236 person‐years of follow‐up, 700 diabetic residents experienced 1369 fractures documented by medical record review. Overall fracture risk was elevated (SIR, 1.3; 95% CI, 1.2–1.4), but hip fractures were increased only in follow‐up beyond 10 yr (SIR, 1.5; 95% CI, 1.1–1.9). As expected, fracture risk factors included age, prior fracture, secondary osteoporosis, and corticosteroid use, whereas higher physical activity and body mass index were protective. Additionally, fractures were increased among patients with neuropathy (hazard ratio [HR], 1.3; 95% CI, 1.1–1.6) and those on insulin (HR, 1.3; 95% CI, 1.1–1.5); risk was reduced among users of biquanides (HR, 0.7; 95% CI, 0.6–0.96), and no significant influence on fracture risk was seen with sulfonylurea or thiazolidinedione use. Thus, contrary to our earlier study, the risk of fractures overall (and hip fractures specifically) was increased among Rochester residents with diabetes, but there was no evidence that the rise was caused by greater levels of obesity or newer treatments for diabetes.     

Fracture risk following bilateral orchiectomy

PURPOSE: Bone loss has been reported in patients with prostate cancer treated with androgen deprivation therapy. We assess fracture risk following bilateral orchiectomy. MATERIALS AND METHODS: Through the Rochester Epidemiology Project we identified 429 Olmsted County, Minnesota men who underwent bilateral orchiectomy in 1956 to 2000, almost all for prostate cancer. Fractures were ascertained from comprehensive medical records and compared with expected numbers based on local incidence rates (standardized incidence ratio, SIR). Potential risk factors were assessed with proportional hazards models. RESULTS: During 1961 person-years of followup 161 men experienced 267 fractures, for a cumulative incidence after 15 years of 40% compared to 19% expected (p <0.001). However, 42 were pathological fractures and 82 were found incidentally on radiological surveys for metastasis. Overall fracture risk was increased (SIR 3.42, 95% CI 2.91-3.99) but was reduced by excluding the pathological and incidental fractures (SIR 2.04, 95% CI 1.66-2.47). The increase was largely accounted for by the moderate trauma fractures of the hip, spine and distal forearm traditionally linked with osteoporosis (SIR 3.50, 95% CI 2.71-4.43). In multivariate analyses risk factors for fractures generally included patient age, inactivity, prior radiological diagnosis of osteoporosis, chemotherapy and use of nonsteroidal antiandrogens, while independent risk factors for the traditional osteoporotic fractures included age, inactivity and diagnosis of osteoporosis. CONCLUSIONS: Fractures are common in men with prostate cancer due to advanced age, occurrence of pathological fractures and enhanced skeletal surveillance but there remains a significant increase in osteoporotic fracture risk following bilateral orchiectomy.     

Unveiling Skeletal Fragility in Patients Diagnosed With MGUS: No Longer a Condition of Undetermined Significance?

Monoclonal gammopathy of undetermined significance (MGUS) is a common finding in clinical practice, affecting greater than 3% of adults aged 50 years and older. As originally described, the term MGUS reflected the inherent clinical uncertainty of distinguishing patients with a benign stable monoclonal plasma cell disorder from subjects destined to progress to malignancy. There is now clear epidemiologic evidence, however, that patients with MGUS suffer from a significantly increased fracture risk and that the prevalence of MGUS is increased in patients with osteoporosis. Despite this relationship, no clinical care guidelines exist for the routine evaluation or treatment of the skeletal health of patients with MGUS. Recent work has demonstrated that circulating levels of at least two cytokines (CCL3/MIP‐1α and DKK1) with well‐recognized roles in bone disease in the related monoclonal gammopathy multiple myeloma are also increased in patients with MGUS. Further, recent imaging studies using high‐resolution peripheral quantitative CT have documented that patients with MGUS have substantial skeletal microarchitectural deterioration and deficits in biomechanical bone strength that likely underlie the increased skeletal fragility in these patients. Accordingly, this Perspective provides evidence that the “undetermined significance” portion of the MGUS acronym may be best replaced in favor of the term “monoclonal gammopathy of skeletal significance” (MGSS) in order to more accurately reflect the enhanced skeletal risks inherent in this condition. © 2014 American Society for Bone and Mineral Research.     

Primary hyperparathyroidism and the risk of fracture: a population-based study.

While severe primary hyperparathyroidism (HPT) is clearly associated with osteitis fibrosa cystica, it remains uncertain whether mild, asymptomatic primary HPT adversely affects the skeleton. Thus, we assessed the incidence of age-related fractures in a large, population-based inception cohort of 407 cases of primary HPT (93 men and 314 women) recognized during the 28-year period, 1965-1992. Fracture risk was assessed by comparing new fractures at each site to the number expected from gender- and age-specific fracture incidence rates for the general population (standardized incidence ratios, SIRs). These community patients with primary HPT mostly had mild disease (mean +/- SD serum calcium, 10.9 +/- 0.6 mg/dl). Altogether, 471 fractures occurred during 5766 person-years of follow-up. Overall fracture risk was significantly increased in these patients (SIR 1.3, 95% confidence interval [CI] 1.1-1.5). Primary HPT was associated with an increased risk of vertebral (SIR 3.2, 95% CI 2.5-4.0), distal forearm (SIR 2.2, 95% CI 1.6-2.9), rib (SIR 2.7, 95% CI 2.1-3.5), and pelvic fractures (SIR 2.1, 95% CI 1. 1-3.5). The risk of proximal femur fractures was only marginally increased (SIR 1.4, 95% CI 1.0-2.0). By univariate analysis, increasing age and female gender were significant predictors of fracture risk, although higher serum calcium levels were also associated with increased fracture risk, and parathyroid surgery may have had a protective effect. By multivariate analysis, however, only age (relative hazard [RH] per 10-year increase, 1.6, 95% CI 1. 4-1.9) and female gender (RH 2.3, 95% CI 1.2-4.1) remained significant independent predictors of fracture risk. Thus, primary HPT among unselected patients in the community is associated with a significant increase in the risk of vertebral, Colles', rib, and pelvic fractures. These data have important implications for the current trend to recommend nonsurgical management for patients with mild primary HPT.     

More broken bones: a 4-year double cohort study of young girls with and without distal forearm fractures.

Predictors of childhood fractures have not been investigated previously. This study was undertaken to determine whether a previous history of forearm fracture, low bone mineral density (BMD; both areal bone mineral density [aBMD, g/cm2] and volumetric bone mineral apparent density [BMAD, g/cm3]), or anthropometry, influence fracture risk in young girls. At baseline, two cohorts of girls, aged 3-15 years, were evaluated: 100 had recently broken a forearm (group 1) and 100 were fracture free (group 2). Four years later we restudied 170 of these girls (82 from group 1 and 88 from group 2). We now report the relationships of previous fracture history, baseline BMD (measured by dual-energy X-ray absorptiometry), baseline weight, and height to risk of new fracture. More new fractures occurred in group 1 (37 fractures in 24 girls) than in group 2 (8 fractures in 7 girls; p = 0.0007). The independent predictors for occurrence of a new fracture at any skeletal site in a multivariate model adjusting for age, weight, total body aBMD, and fracture history were previous fracture (hazard ratio [HR], 3.28; 95% CI, 1.41-7.64); age (HR per 1-year increase, 0.91; 95% CI, 0.84-0.99); total body aBMD (HR per 1 SD decrease, 1.92; 95% CI, 1.31-2.81); and body weight (HR per 1 SD increase, 1.49; 95% CI, 1.06-2.08). Girls with two risk factors together had substantially greater fracture risk: previous fracture and low spinal BMAD (HR, 9.4; 95% CI, 2.8-32.0), previous fracture and high body weight (HR, 10.2; 95% CI, 2.8-37.6), or previous fracture and low total body aBMD (HR, 13.0; 95% CI, 3.9-43.1). We conclude that previous forearm fracture, low total body aBMD, low spinal BMAD, and high body weight each increase risk of new fractures within 4 years in young girls. Interventions to reduce the risk of fractures, particularly forearm fractures, in girls warrant further study.     

Fracture risk following bariatric surgery: a population-based study

Summary

The effects of bariatric surgery on skeletal health are poorly understood. We found that bariatric surgery patients are more prone to fracture when compared to the general population. While further studies of fracture risk in this population are needed, bone health should be discussed in bariatric surgery clinics.

Introduction

Bariatric surgery is an increasingly common treatment for medically complicated obesity. Adverse skeletal changes after bariatric surgery have been reported, but their clinical importance remains unknown. We hypothesized that bariatric surgery patients are at increased risk of fracture.

Methods

We conducted a historical cohort study of fracture incidence among 258 Olmsted County, Minnesota, residents who underwent a first bariatric surgery in 1985–2004. Relative fracture risk was expressed as standardized incidence ratios (SIRs), while potential risk factors were evaluated by hazard ratios (HR) obtained from a time-to-fracture regression model.

Results

The mean (±SD) body mass index at bariatric surgery was 49.0?±?8.4 kg/m², with an average age of 44?±?10 years and 82 % (212) females. Gastric bypass surgery was performed in 94 % of cases. Median follow-up was 7.7 years (range, 6 days to 25 years), during which 79 subjects experienced 132 fractures. Relative risk for any fracture was increased 2.3-fold (95 % confidence interval (CI), 1.8–2.8) and was elevated for a first fracture at the hip, spine, wrist, or humerus (SIR, 1.9; 95 % CI, 1.1–2.9), as well as for a first fracture at any other site (SIR, 2.5; 95 % CI, 2.0–3.2). Better preoperative activity status was associated with a lower age-adjusted risk (HR, 0.4; 95 % CI, 0.2–0.8) while prior fracture history was not associated with postoperative fracture risk.

Conclusions

Bariatric surgery, which is accompanied by substantial biochemical, hormonal, and mechanical changes, is associated with an increased risk of fracture.     

Long-term fracture risk following renal transplantation: a population-based study

Abnormal bone metabolism is a recognized complication of end-stage renal disease, but fracture risk following renal transplantation has not been well quantified. We followed the 86 Olmsted County, Minnesota, residents who underwent initial renal transplantation in 1965–1995 for 911 person-years (median, 10.6 years per subject) in a retrospective cohort study. Fractures, and possible risk factors, were assessed through review of each subjects complete community medical records. Altogether, 117 fractures were observed during follow-up extending to 33 years. The cumulative incidence of any fracture at 15 years was 60% versus 20% expected (P<0.001). There was a significantly increased risk of fractures generally [standardized incidence ratio (SIR), 4.8; 95% CI, 3.6–6.4] and vertebral (SIR, 23.1; 95% CI, 12.3–39.6) and foot fractures (SIR, 8.4; 95% CI, 5.1–12.9) especially. Age at first transplantation, renal failure due to diabetes, pancreas transplantation, peripheral neuropathy, peripheral vascular disease and blindness were all associated with overall fracture risk. In a multivariate analysis, however, only age and diabetic nephropathy were independent predictors of fracture risk generally, while higher activity status was protective. Diabetes was the only independent predictor of lower limb fractures, whereas age and osteoporosis history predicted vertebral fractures. Cumulative corticosteroid dosage was not associated with increased fracture risk in this analysis. Despite the fact that our patients had few risk factors for preexisting bone disease attendant to postmenopausal osteoporosis, prior corticosteroid use or renal osteodystrophy, these data indicate that renal transplantation is associated with a significant increase in fracture risk among unselected patients in the community. Diabetic patients, particularly, experience excess lower limb fractures. Patients and their care providers should be aware of this elevated fracture risk, which continues long-term.Presented at the 24th Annual Meeting of the American Society of Bone and Mineral Research in San Antonio, Tex., USA.     

Long-term fracture risk among children with asthma: a population-based study.

Fracture risk among patients diagnosed with asthma in childhood is greater in males and oral corticosteroid users, but most fractures are of the appendicular skeleton and may relate to impaired skeletal development. INTRODUCTION: There are no population-based data on fracture outcomes among the growing number of patients with asthma diagnosed in childhood. MATERIALS AND METHODS: We conducted a population-based retrospective (historical) cohort study among 279 Rochester, Minnesota, residents who were <35 years of age (mean, 6.2 years) when first diagnosed with asthma. Fractures were ascertained by review of comprehensive community medical records, and cases were compared directly with age- and sex-matched controls in a stratified proportional hazards model. Risk factors for fractures among the asthma cases were assessed using Andersen-Gill time-to-fracture regression models. RESULTS: During 6649 person-years of follow-up (median, 24.3 years/subject), 107 asthma patients experienced 189 fractures, for a crude fracture incidence rate of 2.8 per 100 person-years. The actuarially estimated cumulative fracture incidence after 20 years was 40% compared with 34% among controls (p = 0.122). There was no significant increase in overall fracture risk among cases compared to their age- and sex-matched controls (hazard ratio [HR], 1.3; 95% CI, 0.9-1.9), but males with asthma had a 2.6-fold greater risk of hand and finger fractures than control males. The independent predictors of overall fracture risk among the asthma patients included male gender (HR, 2.2; 95% CI, 1.5-3.2) and use of oral corticosteroids (HR, 2.0; 95% CI, 1.2-3.1) or anti-cholinergic agents (HR, 3.9; 95% CI, 1.5-10). CONCLUSIONS: Rather than osteoporotic fractures of the axial skeleton, oral corticosteroid therapy was associated here with limb fractures, suggesting a relationship with impaired development of a biomechanically competent skeleton. Additional studies are needed to assess this possibility.     

Postmenopausal bilateral oophorectomy is not associated with increased fracture risk in older women.

We studied whether oophorectomy performed after menopause is associated with an increased risk of hip or vertebral fractures in 6295 Study of Osteoporotic Fractures participants. There was no association between postmenopausal oophorectomy and the risk of hip or vertebral fractures. INTRODUCTION: Bilateral oophorectomy after natural menopause has been associated with an increased risk of osteoporotic fractures, potentially because of a decline in serum estradiol and testosterone levels after the oophorectomy. We prospectively tested this hypothesis in the Study of Osteoporotic Fractures (SOF). MATERIALS AND METHODS: We studied 6295 white women 65 years of age participating in the SOF who were not taking estrogen therapy at baseline. Hip fracture analyses included 708 hip fractures; vertebral fracture analyses included 267 incident vertebral fractures. Baseline serum estradiol and free testosterone values were available in a small subset of participants. RESULTS AND CONCLUSION: There were no significant differences in age, weight, or BMD between the women who underwent postmenopausal oophorectomy (n = 583) and those who did not (n = 5712). Free testosterone levels were significantly lower among women who had a postmenopausal oophorectomy. A history of postmenopausal oophorectomy was not associated with an increased risk of hip (hazard ratio [HR] = 1.1; 95% CI = 0.9-1.5) or vertebral fracture (HR = 0.7; 95% CI = 0.5-1.2). The relationship between oophorectomy and hip fracture was not altered by adding serum estradiol level (HR = 1.3; 95% CI = 0.5-3.2) or serum free testosterone level (HR = 1.7; 95% CI = 0.8-3.7) to the model. In summary, postmenopausal oophorectomy was not associated with an increased risk of hip or vertebral fracture in this cohort. These results are in contrast to previous findings, suggesting that the relationship between postmenopausal oophorectomy and fractures is not fully elucidated and that incidental oophorectomy after menopause should still be considered carefully in each potential patient.     

Fracture risk with multiple myeloma: a population-based study.

Pathologic fractures, especially of the axial skeleton, are extremely common in patients with multiple myeloma and cluster around the time of diagnosis. Osteoporotic fractures seem to be less of a problem in these patients. INTRODUCTION: It is generally believed that fractures are common in patients with multiple myeloma as a result of lytic bone lesions, generalized bone loss, and/or elevated bone turnover from excessive cytokine production, but the actual risk of pathologic versus osteoporotic fractures has not been quantified. MATERIALS AND METHODS: In a population-based retrospective cohort study, 165 Olmsted County, MN, residents with myeloma diagnosed from 1945 to 2001 (55% men; mean age, 70.7 +/- 11.1 years) were followed for 537 person-years. The relative risk of fractures was assessed by standardized incidence ratios (SIRs), and risk factors were evaluated in proportional hazards models. RESULTS: Altogether, 134 patients experienced 463 fractures. In the year before diagnosis, 16 times more fractures were observed than expected, mostly pathologic fractures of the vertebrae and ribs. Subsequently, there was a 9-fold increase in fracture risk. However, 69% of these fractures were pathologic, and another 11% were found incidentally on myeloma monitoring. With the latter two groups excluded, subsequent fracture risk was elevated 3-fold, with a 2-fold increase in the risk of an osteoporotic fracture. In multivariate analyses, the predictors of overall fracture risk were oral corticosteroid use and elevated serum calcium levels, whereas pathologic fractures were additionally predicted by use of chemotherapy. CONCLUSION: There is a dramatic increase in fractures around the time of diagnosis of myeloma, most of which are pathologic fractures. The most important predictor of overall fracture risk is oral corticosteroid use.     

Can BMD assessed by DXA at age 8 predict fracture risk in boys and girls during puberty?: an eight-year prospective study.

This study reports on the association between DXA at age 8 and subsequent fractures in both male and female children. Bone densitometry at the total body and spine (but not hip) is a strong predictor of fracture (especially upper limb) during puberty. INTRODUCTION: The aim of this study was to determine if prepubertal DXA can predict fracture risk during puberty. MATERIALS AND METHODS: We studied 183 children who were followed for 8 yr (1460 person-years). Bone densitometry was measured at the total body, hip, and spine by DXA and reported as BMC, BMD, and bone mineral apparent density (BMAD). Fractures were self-reported at age 16 with X-ray confirmation, RESULTS: There were a total of 63 fractures (43 upper limb). In unadjusted analysis, only total body BMD showed an inverse relationship with upper limb fracture risk (p = 0.03). However, after adjustment for height, weight, age (all at age 8), and sex, total body BMC (HR/SD, 2.47; 95% CI, 1.52-4.02), spine BMC (HR/SD, 1.97: 95% CI, 1.30-2.98), total body BMD (HR/SD, 1.67; 95% CI, 1.18-2.36), total body BMAD (HR/SD, 1.54; 95% CI, 1.01-2.37), and spine BMD (HR/SD, 1.53; 95% CI, 1.10, 2.22) were all significantly associated with upper limb fracture risk. Similar, but weaker associations were present for total fractures. There was a trend for overweight/obesity to be associated with increased upper limb fracture risk (HR, 1.53/category; p = 0.08). CONCLUSIONS: Measurement of bone mass by DXA is a good predictor of upper limb fracture risk during puberty. Although we did not measure true BMD, the constancy of fracture prediction after a single measure suggests bone strength remains relatively constant during puberty despite the large changes in bone size.     

Vertebral Fractures Predict Subsequent Fractures

This population-based study documents an increase in most types of fractures following the occurrence of a clinically recognized vertebral fracture among 820 Rochester, Minnesota, residents. During 4349 person-years of follow-up, 896 new fractures were observed. Relative to incidence rates in the community, there was a 2.8-fold increase in the risk of any fracture, which was greater in men (standardized incidence ratio (SIR), 4.2; 95% CI, 3.2–5.3) than women (SIR, 2.7; 95% CI, 2.4–3.0). The estimated cumulative incidence of any fracture after 10 years was 70%. The greatest increase in risk was for subsequent fractures of the axial skeleton, in particular a 12.6-fold increase (95% CI, 11–14) in additional vertebral fractures. There was a lesser increase in most limb fractures, including a 2.3-fold increase (95% CI, 1.8–2.9) in hip fractures and a 1.6-fold increase (95% CI, 1.01–2.4) in distal forearm fractures. There was a slightly greater association with distal forearm fractures among those whose first vertebral fracture occurred before age 70 years but a similar relationship with hip fractures, including cervical and intertrochanteric hip fractures separately, regardless of age at the initial vertebral fracture. There was also an equivalent increase in subsequent fracture risk whether the initial vertebral fracture was attributed to severe or moderate trauma. These data show that vertebral fractures represent an important risk factor for fractures in general, not just those of the spine and hip. Received: 2 September 1998 / Accepted: 9 February 1999     

Relative contributions of bone density, bone turnover, and clinical risk factors to long-term fracture prediction.

Long-term fracture prediction using bone mineral density remains controversial, as does the additional contribution from assessing bone turnover or clinical risk factors. We measured bone mineral density at various sites, along with biochemical markers of bone turnover, sex steroid levels, and over 100 clinical variables, at baseline on an age-stratified sample of 304 Rochester, MN women in 1980. The 225 postmenopausal women were subsequently followed for 3146 person-years (median, 16.2 years per subject), wherein they experienced 302 new fractures: 81% resulted from minimal or moderate trauma and 60% of these involved the proximal femur, thoracic or lumbar vertebrae, or distal forearm. Accounting for multiple fractures per subject, these osteoporotic fractures together were best predicted by baseline femoral neck bone mineral density (age-adjusted hazard ratio [HR] per SD decrease, 1.37; 95% CI, 1.10-1.70); 19 moderate trauma forearm fractures were best predicted by distal radius bone mineral content, whereas 28 hip fractures and 100 vertebral fractures were best predicted by femoral neck bone mineral density. Femoral neck bone mineral density performed comparably in predicting osteoporotic fracture risk within the first decade of follow-up (HR, 1.38; 95% CI, 1.10-1.74) as well as more than 10 years after baseline (HR, 1.39; 95% CI, 1.05-1.84). The older biochemical markers were not associated with fractures, but serum "free" estradiol index was independently predictive of short- and long-term fracture risk. Consistent clinical risk factors were not identified, but statistical power was limited. Identifying patients at increased long-term risk of fracture is challenging, but it is reassuring that femoral neck bone mineral density can predict osteoporotic fractures up to 20 years later.     

Fracture risk in women with breast cancer: a population-based study

A positive association has been reported between greater bone density and higher breast cancer risk, suggesting that these women could be at reduced risk of fracture. To estimate fracture risk among unselected community women with breast cancer and to systematically assess associations with various risk factors including breast cancer treatments, we conducted a population‐based historical cohort study of 608 Olmsted County, MN, USA, women with invasive breast cancer first diagnosed in 1990 to 1999 (mean age 61.6 ± 14.8 years), who were followed for 5776 person‐years. Altogether, 568 fractures were observed in 270 women (98 per 1000 person‐years). Overall fracture risk was elevated 1.8‐fold, but the absolute increase in risk was only 9%, and 56% of the women did not experience a fracture during follow‐up. Excluding pathologic fractures (15%) and those found incidentally (24%), to allow for ascertainment bias, the standardized incidence ratio was 1.2 (95% confidence interval [CI] 0.99 to 1.3) for total fracture risk and 0.9 (95% CI 0.7 to 1.2) for osteoporotic fracture risk alone. Various breast cancer treatments were associated with an increased risk of fracture, but those associations were strongest for pathologic fractures, which were relatively more common among the women who were premenopausal when their breast cancer was diagnosed. Moreover, underlying clinical characteristics prompting different treatments may have been partially responsible for the associated fracture outcomes (indication bias). These data thus demonstrate that breast cancer patients in general are not at greatly increased risk of fracture but neither are they protected from fractures despite any determinants that breast cancer and high bone density may have in common. © 2012 American Society for Bone and Mineral Research.