Progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy.

Atypical femur fracture (AFF) is an uncommon complication of long-term bisphosphonate use, but the risk declines substantially after treatment cessation. We report a case of a 70-year-old woman with osteopenia treated with alendronate for 9 years who presented with right mid-thigh pain and radiographic findings of focal lateral cortical thickening in the right mid-femur and lateral cortex irregularity in the proximal-mid left femur. Alendronate was discontinued, but she remained on estrogen for menopausal symptoms. Four years later, a horizontal linear translucent defect was seen in the right mid-femur area of cortical hypertrophy, consistent with an incomplete AFF. The patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Three years later (7 years after initial presentation), the cortical irregularities in the left femur were more prominent and three small horizontal linear translucent defects were now evident, consistent with early incomplete atypical fracture development. The patient also suffered a wrist fracture. She was treated with teriparatide for 1.5 years with resolution of the translucent defects in the left but not the right femur, although abnormal thickening of the lateral cortex persisted in both femurs. Our case demonstrates incomplete atypical femur fracture progression in a patient with long-term bisphosphonate exposure, even after treatment cessation. These findings highlight the importance of follow-up for patients who develop diaphyseal femur stress fractures and the potential for early healing with anabolic therapy. This case also demonstrates the challenge in managing older patients with incomplete AFF at risk for progression to complete AFF and osteoporotic fracture.

Atypical femur fracture incidence in women increases with duration of bisphosphonate exposure.

In a northern California population of older women who were treated with oral bisphosphonate drugs, the incidence of atypical femur fracture, a rare complication of treatment, increased with longer duration of bisphosphonate exposure. These findings align with those previously reported in an independent southern California population. INTRODUCTION: The age-adjusted incidence of atypical femur fracture (AFF) reported in southern California increased with bisphosphonate (BP) exposure, ranging up to 113 per 100,000 person-years for 8-10-year exposure. This study examines the incidence of AFF in a northern California population. METHODS: Women age 45-89 years who initiated oral BP during 2002-2014 in Kaiser Permanente Northern California were followed for AFF outcome, defined by a primarily transverse diaphyseal femur fracture through both cortices, with focal periosteal/endosteal hypertrophy, minimal trauma, and minimal/no comminution. Total BP exposure was determined from dispensed prescriptions. The incidence of AFF, calculated for 2-year BP categories ranging from < 2 to > 10 years, was age-adjusted using the 2000 US Census. RESULTS: Among 94,542 women, 107 experienced an AFF during or < 1 year after BP cessation (mean exposure 6.6 ± 3.0 years and total days' supply 5.7 ± 2.8 years at AFF). A strong relationship between AFF incidence and increasing BP exposure was seen, more than doubling for each 2-year category until 8-10 years. Among women with 2- to < 4-year BP, the crude and age-adjusted incidence was 18 and 9 per 100,000 person-years but increased over 2- and 5-fold for women with 4- to < 6- and 6- to < 8-year BP, respectively. For those receiving ≥ 8-year BP, the crude and age-adjusted incidence peaked at 196 and 112 per 100,000 person-years exposure. CONCLUSION: Incidence of AFF increases markedly after 4-6 years of BP. These trends align with southern California and confirm a strong BP duration-related risk of this rare but serious event.

Racial/ethnic differences in hip and diaphyseal femur fractures.

UNLABELLED: Contemporary femur fracture rates were examined in northern California women and compared by race/ethnicity. During 2006-2012, hip fracture rates declined, but diaphyseal fracture rates increased, especially in Asians. Women with diaphyseal fracture were younger and more likely to be bisphosphonate-treated. These disparities in femur fracture should be further examined. INTRODUCTION: The epidemiology of diaphyseal femur fracture differs from proximal femur (hip) fracture, although few studies have examined demographic variations in the current era. This study examines contemporary differences in low-energy femur fracture by race/ethnicity in a large, diverse integrated health-care delivery system. METHODS: The incidence of hip and diaphyseal fracture in northern California women aged ≥50 years old during 2006-2012 was examined. Hip (femoral neck and pertrochanteric) fractures were classified by hospital diagnosis codes, while diaphyseal (subtrochanteric and femoral shaft) fractures were further adjudicated based on radiologic findings. Demographic and clinical data were obtained from health plan databases. Fracture incidence was examined over time and by race/ethnicity. RESULTS: There were 10,648 (97.3 %) hip and 300 (2.7 %) diaphyseal fractures among 10,493 women. The age-adjusted incidence of hip fracture fell from 281 to 240 per 100,000 women and was highest for white women. However, diaphyseal fracture rates increased over time, with a significant upward trend in Asians (9 to 27 per 100,000) who also had the highest rate of diaphyseal fracture. Women with diaphyseal fracture were younger than women with hip fracture, more likely to be of Asian race and to have received bisphosphonate drugs. Women with longer bisphosphonate treatment duration were also more likely to have a diaphyseal fracture, especially younger Asian women. CONCLUSION: During 2006 to 2012, hip fracture rates declined, but diaphyseal fracture rates increased, particularly among Asian women. The association of diaphyseal fracture and bisphosphonate therapy should be further investigated with examination of fracture pattern.

The impact of subtrochanteric fracture criteria on hip fracture classification.

SUMMARY: Hospital diagnosis codes are useful for assessing hip fracture rates in large populations. However, these codes do not reliably differentiate hip fractures that occur in the subtrochanteric region. Identification of subtrochanteric fractures requires review of radiographic images to distinguish these fractures from the more commonly occurring trochanteric fractures. PURPOSE: This study examines the accuracy of coded hospital diagnoses for hip fracture compared to fracture site verification based on operative and radiologic data. The variability in subtrochanteric fracture assignment was also examined using different anatomic criteria. METHODS: This retrospective study includes female members of Kaiser Permanente Northern California age 60 years and older with nontraumatic hip fracture during 2007-2008. Anatomic site was verified by operative and radiologic records, including radiographic image review for fractures occurring in the subtrochanteric region. Two different criteria were compared for subtrochanteric fracture. RESULTS: We identified 2,824 women with incident hip fracture during the 2-year period. The average age was 82.9 ± 8.2 years and 15% were non-White. International Classification of Diseases, Ninth Revision (ICD-9) coding was accurate for femoral neck and trochanteric fractures (>90% confirmed by operative/radiologic reports), compared to only 26% for subtrochanteric fractures using the Orthopedic Trauma Association (OTA) criteria for subtrochanteric fracture. Using OTA classification, 1.3% of hip fractures were assigned as subtrochanteric compared to 4.2% when the criteria were broadened to include the lesser trochanter. Both femoral neck and pertrochanteric fracture rates increased exponentially with age, while age-related rates in subtrochanteric fracture differed by diagnostic classification method; the broader criteria including the lesser trochanter produced age-related trends that mirrored femoral neck and pertrochanteric fractures. CONCLUSION: Unlike femoral neck and pertrochanteric fractures, epidemiologic studies of subtrochanteric fractures cannot rely on ICD-9 codes alone. Review of radiologic images using OTA criteria is required for identification of subtrochanteric fractures occurring below the lesser trochanter.

BMP signaling stimulates chondrocyte maturation and the expression of Indian hedgehog.

Mutant BMP receptors were transfected into cultured embryonic upper sternal chrondrocytes using retroviral vectors to determine if BMP signaling is required for chondrocyte maturation and the expression of a key regulatory molecule, Indian hedgehog (Ihh). Chondrocytes infected with replication competent avian retroviruses (RCAS) viruses carrying constitutive active (CA) BMPR-IA and BMPR-IB had enhanced expression of type X collagen and Ihh mRNA. Addition of PTHrP, a known inhibitor of chondrocyte maturation, abolished the expression of type X collagen, BMP-6, and Ihh mRNAs in control cells. In contrast, PTHrP treated cultures infected with of CA BMPR-IA or CA BMPR-IB had low levels of BMP-6 and type X collagen, but high levels of Ihh expression. Although dominant negative (DN) BMPR-IA had no effect, DN BMPR-IB inhibited the expression of type X collagen and BMP-6, and decreased alkaline phosphatase activity, even in the presence of exogenously added BMP-2 and BMP-6. DN BMPR-IB also completely blocked Ihh expression. Overall, the effect of DN BMPR-IB mimicked the effects of PTHrP. To determine if there is an autocrine role for the BMPs in chondrocyte maturation, the cultures were treated with noggin and follistatin, molecules that bind BMP-2/-4 and BMP-6/-7, respectively. While noggin and follistatin inhibited the effects of recombinant BMP-2 and BMP-6, respectively, they had only minimal effects on the spontaneous maturation of chondrocytes in culture, suggesting that more than one subgroup of BMPs regulates chondrocyte maturation. The results demonstrate that: (i) BMP signaling stimulates chondrocyte maturation; (ii) BMP signaling increases Ihh expression independent of maturational effects; and (iii) BMP signaling can partially overcome the inhibitory effects of PTHrP on maturation.

BMP-6 is an autocrine stimulator of chondrocyte differentiation.

While parathyroid hormone-related protein (PTHrP) has been characterized as an important negative regulator of chondrocyte maturation in the growth plate, the autocrine or paracrine factors that stimulate chondrocyte maturation are not well characterized. Cephalic sternal chondrocytes were isolated from 13-day embryos, and the role of bone morphogenetic protein-6 (BMP-6) as a positive regulator of chondrocyte maturation was examined in monolayer cultures. Progressive maturation, which was accelerated in the presence of ascorbate, occurred in the cultures. During maturation, the cultures expressed high levels of BMP-6 mRNA which preceded the induction of type X collagen mRNA. Treatment of the cultures with PTHrP (10(-7) M) at the time of plating completely abolished BMP-6 and type X collagen mRNA expression. Removal of PTHrP after 6 days was followed by the rapid (within 24 h) expression of BMP-6 and type X collagen mRNA, with BMP-6 again preceding type X collagen expression. The addition of exogenous BMP-6 (100 ng/ml) to the cultures accelerated the maturation process both in the presence and absence of ascorbate and resulted in the highest levels of type X collagen. When exogenous BMP-6 was added to PTHrP containing cultures, maturation occurred with the expression of high levels of type X collagen, despite the presence of PTHrP in the cultures. Furthermore, BMP-6 did not stimulate expression of its own mRNA in the PTHrP treated cultures, but it did stimulate the expression of Indian hedgehog (Ihh) mRNA. These latter findings suggest that while PTHrP directly inhibits BMP-6, it indirectly regulates Ihh expression through BMP-6. Other phenotypic changes associated with chondrocyte differentiation were also stimulated by BMP-6, including increased alkaline phosphatase activity and decreased proliferation. The results suggest that BMP-6 is an autocrine factor that initiates chondrocyte maturation and that PTHrP may prevent maturation by inhibiting the expression of BMP-6.

Bone morphogenetic protein-7 in growth-plate chondrocytes: regulation by retinoic acid is dependent on the stage of chondrocyte maturation.

Although the bone morphogenetic proteins stimulate chondrogenesis, little is known regarding their expression and regulation in growth-plate chondrocytes. The expression of bone morphogenetic protein-7 was examined in chick growth-plate chondrocyte cultures. Low basal levels of bone morphogenetic protein-7 mRNA and protein expression were stimulated by increasing doses of all-trans retinoic acid, a metabolite of vitamin A. The addition of 10 microM retinoic acid resulted in approximately a 6-fold increase in bone morphogenetic protein-7 mRNA levels. In contrast, other growth regulators, including basic fibroblast growth factor, transforming growth factor-beta, vitamin D, bone morphogenetic protein-6, bone morphogenetic protein-7, and parathyroid hormone-related peptide, did not alter bone morphogenetic protein-7 transcript levels. The increase in bone morphogenetic protein-7 transcripts, although present at 6 hours, was maximal following a 12-hour exposure to retinoic acid. Retinoic acid induction of bone morphogenetic protein-7 transcript levels was dependent on protein synthesis because the induction could be blocked by cyclohexamide. In maturationally distinct subpopulations of chondrocytes separated by countercurrent centrifugal elutriation, retinoic acid markedly induced bone morphogenetic protein-7 mRNA levels in the least differentiated chondrocytes but had no effect in the most terminally differentiated hypertrophic chondrocytes. Immunohistochemical localization of bone morphogenetic protein-7 demonstrates its expression throughout the developing and adolescent growth plate consistent with the constitutive pattern of expression seen in isolated chondrocytes. The addition of exogenous bone morphogenetic protein-7 to chondrocyte cultures stimulated maturation in undifferentiated chondrocyte populations. The data support a role for bone morphogenetic protein-7 as an autocrine regulator of chondrocyte maturation in the growth plate. Regulation of bone morphogenetic protein-7 by retinoic acid may be important in normal growth and development as well as in pathologic conditions of an excess or deficiency of vitamin A.