Distal radius fractures and risk of incident neurocognitive disorders in older adults: a retrospective cohort study.

INTRODUCTION: Distal radius fractures (DRF) are associated with increased risk of subsequent fractures and physical decline in older adults. This study aims to evaluate the risk cognitive decline following DRF and potential for timely screening and intervention. METHODS: A cohort of 1046 individuals 50-75 years of age with DRF were identified between 1995 and 2015 (81.5% female; mean age 62.5 [± 7.1] years). A control group (N = 1044) without history of DRF was matched by age, sex, and fracture date (i.e., index). The incidence of neurocognitive disorders (NCD) in relation to DRF/index was determined. Group comparisons were adjusted by age and comorbidity measured by the Elixhauser index. RESULTS: The DRF group had a greater incidence of NCD compared to the control group (11.3% vs. 8.2%) with a 56% greater relative risk (HR = 1.56, 95% Cl: 1.18, 2.07; p = 0.002) after adjusting for age and comorbidity. For every 10-year age increase, the DRF group was over three times more likely to develop a NCD (HR = 3.23, 95% Cl: 2.57, 4.04; p < 0.001). CONCLUSION: DRF in adults ages 50 to 75 are associated with increased risk of developing neurocognitive disorders. DRF may represent a sentinel opportunity for cognitive screening and early intervention. Distal radius fractures (DRF) have been associated with greater risk of future fractures and physical decline. This study reports that DRF are also associated with greater risk of developing neurocognitive disorders in older adults. Timely intervention may improve early recognition and long-term outcomes for older adults at risk of cognitive decline.

Screening for osteoporosis reduced new fracture incidence by almost half: a 6-year follow-up of 592 fracture patients from an osteoporosis screening program.

BACKGROUND AND PURPOSE: Fractures can be prevented if osteoporosis is identified and treated. In 2002, we initiated a screening program at our orthopedics department, in which patients between 50 and 75 years of age with a wrist, shoulder, vertebral, or hip fracture are assessed by DEXA of the hip and spine and encouraged to see their doctor for decision on treatment regarding osteoporosis. The patients receive written documents containing information, DEXA results, and a letter to their doctor with suggestions regarding blood tests and treatment. In this 6-year follow-up study, we compared the fracture recurrence in 2 groups: patients screened for osteoporosis after fracture as described, and a historical control group with fracture patients who presented at our department 1 year before we started the screening intervention. METHODS: A questionnaire was sent to the 2 groups of fracture patients, those from before the time that we started the screening in 2002 and those who participated in the initial screening study in 2003. The questionnaire included questions on whether they had sustained further fractures, whether they had seen a doctor, and whether treatment had been initiated. RESULTS: 239 of the 306 unscreened patients (68%) and 219 of the 286 screened patients (77%) answered the questionnaire. In the unscreened group, 69 new fractures had occurred, in contrast to 39 in the screened group. The fracture risk was 42% lower in the screened group. Answers regarding treatment were incomplete in the unscreened group. INTERPRETATION: Screening of fracture patients for osteoporosis reduced fracture recurrence, which indicates that the screening procedure has resulted in treatment that prevents fractures.

3-year follow-up of 215 fracture patients from a prospective and consecutive osteoporosis screening program. Fracture patients care!

BACKGROUND AND PURPOSE: Fractures can be prevented if osteoporosis is identified and treated. Starting in 2002, we have been using a screening program in which patients between 50 and 75 years of age with a wrist, shoulder, vertebral, or hip fracture are assessed by DEXA of the hip and spine and if osteoporotic or osteopenic, they are encouraged to see a doctor of their own choice. The patients receive documents containing information, the results of DEXA, and a letter to present to their doctor with suggestions regarding blood tests and treatment. Here we report the 3-year follow-up regarding compliance to the recommended treatment. METHODS: A questionnaire was sent to fracture patients who participated in the initial screening study from November 2002 through November 2003. Questions included whether they had seen a doctor, whether treatment had been initiated, and their opinions about osteoporosis. RESULTS: 215 of the 236 patients answered the questionnaire, with a mean follow-up of 39 months. 76/87 of those with osteoporosis, 70/99 of those with osteopenia, and 11/29 of those with normal BMD had seen a doctor. Anti-resorptive treatment was prescribed to two-thirds of the osteoporotic patients, to one-sixth of the osteopenic patients, and to none of the patients with normal bone density. Calcium-vitamin D supplementation as monotherapy was given to one-third of the osteoporotic patients, to half of the osteopenic patients, and to half of the normal patients. Only a few osteoporotic patients, one-third of the osteopenic patients, and half of the normal patients received no treatment. Compliance to treatment was 80% over 3 years in those treated. Most patients felt that they could influence their skeletal health. INTERPRETATION: Screening of fracture patients for osteoporosis effectively identifies patients with low bone mineral density and the patient can be trusted to seek appropriate medical advice for treatment of osteoporosis. Based on the bone scan diagnosis, the treatment that these patients received reflects current treatment guidelines well.

Systemic zoledronate treatment both prevents resorption of allograft bone and increases the retention of new formed bone during revascularization and remodelling. A bone chamber study in rats.

BACKGROUND: In osteonecrosis the vascular supply of the bone is interrupted and the living cells die. The inorganic mineral network remains intact until ingrowing blood vessels invade the graft. Accompanying osteoclasts start to resorb the bone trabeculae and gradually replace the bone. If the osteonecrosis occurs in mechanically loaded parts, like in the subchondral bone of a loaded joint, the remodelling might lead to a weakening of the bone and, in consequence to a joint collapse. Systemic bisphosphonate treatment can reduce the resorption of necrotic bone. In the present study we investigate if zoledronate, the most potent of the commercially available bisphosphonates, can be used to reduce the amount or speed of bone graft remodeling. METHODS: Bone grafts were harvested and placed in a bone chamber inserted into the tibia of a rat. Host tissue could grow into the graft through openings in the chamber. Weekly injections with 1.05 microg zoledronate or saline were given subcutaneously until the rats were harvested after 6 weeks. The specimens were fixed, cut and stained with haematoxylin/eosin and used for histologic and histomorphometric analyses. RESULTS: By histology, the control specimens were almost totally resorbed in the remodeled area and the graft replaced by bone marrow. In the zoledronate treated specimens, both the old graft and new-formed bone remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft+ new bone) within the remodelled area was 35 % (SD 13) in the zoledronate treated grafts and 19 % (SD 12) in the controls (p = 0.001). Also the amount of new bone was increased in the treated specimens (22 %, SD 7) compared to the controls (14 %, SD 9, p = 0.032). CONCLUSION: We show that zoledronate can be used to decrease the resorption of both old graft and new-formed bone during bone graft remodelling. This might be useful in bone grafting procedure but also in other orthopedic conditions, both where necrotic bone has to be remodelled i.e. after osteonecrosis of the knee and hip and in Perthes disease, or in high load, high turnover conditions like delayed union, periprosthetic osteolysis or bone lengthening operations. In our model an increased net formation of new bone was found which probably reflects that new bone formed was retained by the action of the bisphosphonates rather than a true anabolic effect.

One fracture is enough! Experience with a prospective and consecutive osteoporosis screening program with 239 fracture patients.

BACKGROUND: Fracture and low bone mineral density both have strong predictive value for future fractures. The risk of future fractures can be reduced by medi-cal treatment if patients with osteoporosis are identified, for example by screening fracture patients for low bone mineral density. We suggest that these screening routines be organized at orthopedics departments and we report our experience with such a screening system. PATIENTS AND METHODS: We screened all patients between 50-75 years of age with a wrist, vertebral, proximal humerus, or hip fracture visiting our orthopedics department by measuring bone mineral density (BMD) using DEXA scans. After diagnosis, the patients were referred to their primary care physician for treatment. RESULTS: Between November 1, 2002, and October 31, 2003, 239 patients were investigated and only 13% had normal BMD values. 45% of the patients were diagnosed with osteopenia and 42% with osteoporosis. INTERPRETATION: Screening of fracture patients who visit an orthopedics department appears to be an effective way of identifying individuals with low bone mineral density. The screening routines can be organized as an osteoporosis team consisting of a doctor, a nurse and a secretary at each department. Today, these patients are largely undetected and untreated--at least in our region. In our series, only 13 patients had been DEXA-scanned and were treated by antiresorptive drugs at the time of fracture.

Systemic zoledronate precoating of a bone graft reduces bone resorption during remodeling.

BACKGROUND: Cartilage degeneration often occurs after osteosynthesis of a devascularized intermediary fragment in a joint fracture, in mosaicplasty or in whole-joint toe-to-finger transplantation. Hypothetically, the degeneration is secondary to a collapse of the transferred subchondral bone as it remodels during high mechanical load. Bisphosphonates are used to reduce resorption of necrotic bone. We tested a systemic pretreatment before harvesting the graft in order to protect the bone and cartilage against collapse and secondary arthrosis. METHODS: Rats were given one zoledronate injection and bone grafts were harvested. The grafts were frozen, thawed and placed into bone chambers, and implanted into another batch of rats. Graft resorption and new bone formation was measured by histomorphometric analysis and compared with untreated grafts. RESULTS: In the remodeled area of the controls, the graft was almost totally resorbed and replaced by bone marrow. In the zoledronate-treated specimens, the graft remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft plus new bone) within the remodeled area was 16% in the zoledronate-treated grafts and 5% in the controls (p = 0.003). INTERPRETATION: A bone graft can be pretreated with bisphosphonate and remain protected against resorption once implanted again.

Topical, single dose bisphosphonate treatment reduced bone resorption in a rat model for prosthetic loosening.

Fluid pressure, instability or particles have been suggested to cause peri-prosthetic bone resorption. High intracapsular pressures have been reported in hip joints with loose prosthetic components, and oscillating fluid pressure has been shown to cause dramatic bone resorption in animal models. Resorption can be reduced by systemic bisphosphonate treatment in rat models with oscillating fluid pressure, but this has required higher doses than needed to inhibit normal remodelling. Bisphosphonates have high affinity to bone mineral. Topical application of the drug is therefore feasible. We used a previously described rat model where oscillating fluid pressure causes bone resorption. Before pressurization, a 1 mg/ml solution of alendronate was applied onto the bone surface for 1 min, after which excess bisphosphonate was rinsed away. Bone resorption was measured on histological slides as soft tissue area at the interface. Rats treated with topical alendronate had soft tissue areas reduced by half. Topical bisphosphonate treatment before cementing a joint implant could possibly reduce the risk of later loosening.

Alendronate prevents collapse in mechanically loaded osteochondral grafts: a bone chamber study in rats.

BACKGROUND: Subchondral bone necrosis is important in osteonecrosis, Mb Kienboeck, intraarticular fractures or osteochondral grafting. As revascularization follows, bone resorption may lead to collapse in load bearing areas during the remodeling. Bisphosphonates are potent osteoclast inhibitors. Our hypothesis was that local bisphosphonate treatment of an osteochondral graft, in a high load environment, would protect the subchondral bone from collapse and maintain the joint architecture during remodeling. To investigate this, we used a rat bone chamber model to subject a necrotic osteochondral graft to a large mechanical load during remodeling. METHOD: Cylindrical osteochondral grafts were taken from the patellar groove of rats, one end of the cylinder being the joint surface. The grafts were frozen, thawed and treated with alendronate. The length of the cylinder was measured and the grafts were placed in the chambers, which were inserted into the proximal tibia of rats. The chambers were left to heal in for two weeks to allow establishment of a vascular supply, and then the transplanted osteochondral plugs were mechanically loaded for 4 weeks, once a day with 10 cycles of 2 MPa pressure at 0.16 Hz. RESULTS: At harvest, the graft length had decreased during remodeling in 5 of the 6 untreated controls, but only in 2 out of 8 alendronate-treated rats (p = 0.05). Histologically, the bone graft in the non-treated controls was resorbed in the remodeled part of the graft, whereas in the alendronate-treated rats a dense trabecular bone was found consisting of both new bone and graft. INTERPRETATION: Local treatment of the graft with bisphosphonate diminishes the risk of collapse during revascularization and bone remodeling in a mechanically loaded osteochondral graft. This could be useful in a variety of situations when bone remodeling occurs after a necrosis close to a joint, either spontaneously after osteonecrosis or a fracture, or after surgical procedures such as mosaic-plasty or other osteochondral grafting.

A combination of bisphosphonate and BMP additives in impacted bone allografts.

OP-1 increases bone ingrowth distance of new bone into allografts (Tägil et al. 2000), but the bone density after incorporation may be reduced by an increase in resorption (Höistner et al. 2000). Bisphosphonates inactivate osteoclasts and can be used to increase allograft bone density after incorporation (Aspenberg and Astrand 2002). A combination of locally-applied bisphosphonate and OP-1 in the graft could therefore be expected to increase both new bone ingrowth and density. We tested this by using a rat bone chamber model. OP-1 alone increased the ingrowth distance of bone. Clodronate increased final bone density greatly, but reduced the ingrowth distance of new bone into grafts that were extremely impacted. This reduction was improved by adding OP-1. Regardless of graft density, combinations of OP-1 and clodronate included a high final bone density, but the ingrowth distances were shorter than with OP-1 alone. These data indicate that new bone and tissue ingrowth into a compacted graft depends on resorption and that resorption is a prerequisite for the stimulating effect of OP-1 in this experimental set-up. Although the problems associated with the use of OP-1 in impaction grafting may be solved by adding a bisphosphonate, some of the benefits of OP-1 can be lost.

A rat model for testing pharmacologic treatments of pressure-related bone loss.

Fluid pressure, instability, or particles have been suggested to initiate the process leading to loosening of prosthetic implants. In a rat model where bone resorption is caused by oscillating fluid pressure, the resorptive response seems much stronger than the response that can be induced by particles or instability. Bone resorption is caused by osteoclasts. It has been suggested that the formation of osteoclasts is influenced by tumor necrosis factor-alpha, which can be blocked by etanercept. Osteoclasts can be inactivated with bisphosphonates, which bind to bone and inactivate osteoclasts when the bisphosphonate-containing bone is resorbed. Bone formation can be increased dramatically by intermittent parathyroid hormone treatment, especially at sites with high bone turnover. This might compensate for increased osteoclastic activity. Forty-two rats received a plate implant, by which fluid pressure was applied to a bone surface by compressing a soft tissue membrane. Eight rats were treated with etanercept 0.75 mg/kg/day, six rats were treated with alendronate 205 microg/kg/day, six rats received saline, and six rats were nonpressurized controls. Nine rats received intermittent parathyroid hormone treatment with nine separate controls. The area of bone resorption under the implant was evaluated by histomorphometry. Alendronate-treated rats showed less bone resorption, but etanercept, intermittent parathyroid hormone treatment, or saline did not reduce the fluid pressure-induced bone resorption. This model is a comparatively simple way of testing pharmacologic reduction of local bone resorption in vivo.

Systemic alendronate prevents resorption of necrotic bone during revascularization. A bone chamber study in rats.

BACKGROUND: Avascular necrosis of bone (osteonecrosis) can cause structural failure and subsequent deformation, leading to joint dysfunction and pain. Structural failure is the result of resorption of necrotic bone during revascularization, before new bone has formed or consolidated enough for loadbearing. Bone resorption can be reduced by bisphosphonates. If resorption of the necrotic bone could be reduced during the revascularization phase until sufficient new bone has formed, it would appear that structural failure could be avoided. METHODS: To test whether resorption of necrotic bone can be prevented, structural grafts were subjected to new bone ingrowth during systemic bisphosphonate treatment in a rat model. RESULTS: In rats treated with alendronate the necrotic bone was not resorbed, whereas it was almost entirely resorbed in the controls. CONCLUSION: Systemic alendronate treatment prevents resorption of necrotic bone during revascularization. In patients with osteonecrosis, bisphosphonates may therefore prevent collapse of the necrotic bone.

Bone allografts pretreated with a bisphosphonate are not resorbed.

Bisphosphonates bind to bone surfaces and inactivate osteoclasts when they start to resorb the bone. Therefore, immersion of a bone graft in a bisphosphonate solution before implantation may protect it from resorption. We implanted frozen cancellous bone allografts into bilateral bone chambers for 6 weeks in 10 rats. One graft in each pair had been immersed in an alendronate solution (1 mg/mL) for 10 minutes, and then rinsed in saline. Controls underwent the same treatment with saline only. Results were evaluated with histomorphometry. Control grafts were almost entirely resorbed, but alendronate-treated grafts seemed intact. In the treated specimens, two thirds of the space behind the bone ingrowth frontier consisted of graft or host bone, but in the controls, only one fifth. Local graft treatment with a bisphosphonate before insertion seems to be risk-free, and may prevent mechanical graft failure due to resorption in patients.

Reduction of instability-induced bone resorption using bisphosphonates: high doses are needed in rats.

Bone resorption associated with prosthetic loosening can be reduced by giving bisphosphonates since they bind to bone surfaces and inactivate osteoclasts when bisphosphonate-containing bone is resorbed. During loosening, an increase in osteoclastic activity can be triggered by mechanical instability, fluid pressure or wear particles. We used a rat model in which a titanium surface can be made to slide over a bone surface and cause instability-induced bone resorption. 111 rats were operated on with a plate implant and treated with alendronate or clodronate injections in different doses or saline controls. After 4 weeks of osseointegration, the plate was moved during 2 weeks and the findings evaluated with histomorphometry. The percentage of persisting bone-metal contact and the soft tissue area at the interface were measured to estimate bone loss. Low or intermediate doses of the bisphosphonates increased the ash weight of untraumatized bone, but did not inhibit resorption at the unstable interface. Only rats treated with the highest doses of alendronate or clodronate had more bone-metal contact than controls. Instability-induced bone resorption therefore seems to be reduced by bisphosphonates, but higher doses are needed to obtain this effect than to reduce bone resorption associated with normal remodeling of untraumatized bone.