MASSACHUSETTS GENERAL HOSPITAL, THE
Severe osteopenia is a prevalent complication of anorexia nervosa (AN), affecting over half of all women with this disease. Loss of bone mass occurs frequently and is often permanent. Reduction of bone mineral density (BMD) by at least 1.0 SD at one or more skeletal sites occurs in over 90% of subjects and by at least 2.5 SD in over 1/3 of subjects. Moreover, this reduction is associated with a 30% prevalence of fractures. Although AN affects from 0.5-1.0% of collegeage women, no successful therapeutic interventions have been developed to prevent bone loss or increase bone mass in this young population. Our preliminary data demonstrate severe bone structural abnormalities as well, including markedly reduced trabecular thickness, trabecular number and bone volume and increased trabecular separation. Bone loss in AN is characterized by reduced bone formation coupled with increased bone resorption. Anorexia nervosa results in growth hormone (GH) resistance and resultant severe insulin-like growth factor 1 (IGF-1) deficiency due to undernutrition. This acquired deficiency of IGF-1, an endogenous bone trophic factor, is an important determinant of decreased bone formation in this population. IGF-1 is known to have anabolic actions on bone, and we have demonstrated increases in bone formation and BMD in women with AN with administration of recombinant IGF-1 (rhIGF-1). However, despite increasing bone formation, bone resorption remains high,and a therapy to effectively decrease resorption in the state of undernutrition is needed. Bisphosphonates are well established to decrease bone resorption and improve BMD in severely osteopenic postmenopausal women, and our preliminary data demonstrate significant increases in BMD in women with AN. Recent data using anabolic and anti-resorptive therapies have suggested that sequential therapy may result in greater gains in BMD that concurrently administered combination therapy. There are no data investigating such therapeutic strategies in this population, in whom there are no established therapies. We will test the hypothesis that a strategy to administer an anabolic therapy, rhIGF-1, for six months followed by a bisphosphonate, risedronate, for six months will increase bone mass and improve microarchitecture in women with anorexia nervosa.
| AWARD OVERVIEW |
| Award Number |
2R56DK052625-11A1 |
Funding Agency |
Department of Health and Human Services |
| Total Award Amount |
$182,882 |
Project Location - City |
Boston |
| Award Date |
07/17/2009 |
Project Location - State |
MA |
| Project Status |
Completed |
Project Location - Zip |
02114-0000
|
| Jobs Reported |
0.02 |
Congressional District |
09 |
| Project Location - Country |
US |
|
|
Recipient Information
(Grants)
| Recipient Information (Grants) |
|
Recipient Name
|
MASSACHUSETTS GENERAL HOSPITAL, THE |
| Recipient DUNS Number |
073130411
|
| Recipient Address |
55 FRUIT ST |
| Recipient City |
BOSTON |
| Recipient State |
Massachusetts |
| Recipient Zip |
02114-2621 |
| Recipient Congressional District |
09 |
| Recipient Country |
USA |
Required to Report Top 5
Highly Compensated Officials |
No |
Projects and Jobs Information
| Projects and Jobs Information |
| Project Title |
IGF-1 and Bone Loss in Women with Anorexia Nervosa |
| Project Status |
Completed |
| Final Project Report Submitted |
Yes |
| Project Activities Description |
General Medical and Surgical Hospitals |
| Quarterly Activities/Project Description |
We have completed our patient cohort enrolled in the proposed study to investigate the effects of administration of rhIGF-1 for 6 months to increase bone formation followed by a bisphosphonate for 6 months to decrease bone resorption as a strategy to improve bone mass in women with anorexia nervosa. As proposed, we are determining whether this treatment increases BMD, as assessed by dual x-ray absorptiometry (DXA). Eighteen women with anorexia nervosa were enrolled to receive rhIGF-1 at a dose of 30 mcg/kg BID. Subjects who completed the first 6 months of the study entered the second treatment phase with a bisphosphonate. A second important end-point of this project was to examine the effects of rhIGF-1 on bone microarchitecture. We investigated the effects of sequential physiologic rhIGF-1 replacement to increase bone formation, followed by a bisphosphonate to decrease bone resorption, and improve bone microarchitecture in women with anorexia nervosa. We specifically investigated whether administration of rhIGF-1 for 6 months followed by a bisphosphonate for 6 months: A) Improves bone microarchitecture, specifically trabecular thickness, trabecular number and separation, and bone volume fraction, and B) The magnitude of increases in serum IGF-1 levels over the first 6 months, predicts increases in trabecular thickness, trabecular number and bone volume fraction, and, decreases in trabecular separation at 6 months. A total of 18 adults were enrolled in the study. Sixteen adults completed 6 months; 14 adults have completed 12 months in the study. Four adults withdrew from the study - none due to safety issues. The final data is still being analyzed. |
| Jobs Created |
0.02 |
| Description of Jobs Created |
Bone loss is a major, frequent and often permanent comorbid medical complication of anorexia nervosa (AN) affecting over half of all women with this disease and results in debilitating fractures. Reduction of bone mineral density (BMD) by at least 1.0 SD occurs in over 90% and by at least 2.5 SD in over one-third of subjects. Moreover, AN is associated with a 30% prevalence of fractures. Although AN affects from 0.5-1.0% of college-age women, no therapeutic interventions have been established to increase bone mass in this young population. Bone microarchitecture is an important new area of investigation and alterations in bone microarchitecture may explain fracture risk independent of bone mass in osteoporosis. Our preliminary data demonstrate severe bone structural abnormalities including markedly reduced trabecular thickness, trabecular number and bone volume fraction and, increased trabecular separation in AN. Bone loss in AN is characterized by reduced bone formation coupled with increased bone resorption. Anorexia nervosa results in severe insulin-like growth factor 1 (IGF-1) deficiency due to undernutrition. This acquired deficiency of IGF-1, an endogenous bone trophic factor, is an important determinant of decreased bone formation and bone mass in this population. In addition, we have shown that fat-free mass, a known determinant of BMD, is reduced in AN. We have demonstrated a significant increase in spine BMD in women with AN treated with both recombinant IGF-1 (rhIGF-1) and estrogen compared to placebo. However, although rhIGF-1 increases bone formation, bone resorption remains high, and a therapy to also effectively decrease resorption in this state of undernutrition is needed. Bisphosphonates are well established to decrease bone resorption and improve BMD in severely osteopenic postmenopausal women, and we have shown this to be the case in AN. However, gains in BMD with bisphosphonate therapy do not continue after 6 months. In postmenopausal women, sequential anabolic and anti-resorptive therapies result in greater gains in BMD than concurrently administered combination therapy. There are no data investigating such therapeutic strategies in AN, in whom fracture risk is high. We hypothesized that this therapeutic approach will address the low bone formation and increased bone resorptive state in AN. We have tested the hypothesis that a strategy to administer an anabolic therapy, rhIGF-1, for 6 months followed by a bisphosphonate for 6 months will increase bone mass and improve bone microarchitecture in women with AN more than a bisphosphonate alone.
Funding from this grant has been instrumental in achieving the Aims of the project and in retaining the position of the grant PI, Dr. Anne Klibanski. |
Purchaser Information
(Grants)
| Purchaser Information |
| Contracting Office ID |
Not Reported |
| Contracting Office Name |
Not Available |
| Contracting Office Region |
Not Available |
| TAS Major Program |
75-0883 |
| Award Information |
| Award Date |
07/17/2009 |
| Award Number |
2R56DK052625-11A1 |
| Order Number |
|
| Award Type |
Grants |
| Funding Agency ID |
75 |
| Funding Agency Name |
Department of Health and Human Services |
| Funding Office Name |
Not Available |
| Awarding Agency ID |
75 |
| Awarding Agency Name |
Department of Health and Human Services |
| Amount of Award |
$182,882 |
| Funds Invoiced/Received |
$182,882 |
| Expenditure Amount |
$182,882 |
| Infrastructure Expenditure Amount |
$0 |
| Infrastructure Purpose and Rationale |
Not Reported |
| Infrastructure Point of Contact Name |
Not Reported |
| Infrastructure Point of Contact Email |
Not Reported |
| Infrastructure Point of Contact Phone |
Not Reported |
| Infrastructure Point of Contact Address |
Not Reported |
| Infrastructure Point of Contact City |
Not Reported |
| Infrastructure Point of Contact State |
Not Reported |
| Infrastructure Point of Contact Zip |
Not Reported |
Product or Service Information
(Grants)
| Product or Service Information |
| Primary Activity Code |
622110 |
| Activity Description |
General Medical and Surgical Hospitals |
| Sub-Awards Information |
| Sub-awards to Organizations |
0 |
| Sub-award Amounts to Organizations |
$0 |
| Sub-Awards to Individuals |
0 |
| Sub-Award Amounts to Individuals |
$0 |
| Number of Sub-awards less than $25,000/award |
0 |
| Amount of Sub-awards less than $25,000/award |
$0 |
| Number of payments to vendors greater than $25,000 |
0 |
| Total Amount of payments to vendors greater than $25,000/award |
$0 |
| Number of payments to vendors less than $25,000/award |
300 |
| Total Amount of payments to vendors less than $25,000/award |
$22,399 |
| Location Information |
| Latitude, Longitude |
42º 21' 44",
-71º 4' 11" |
| Congressional District |
09 |
| Address 1 |
55 Fruit Street |
| Address 2 |
|
| City |
Boston |
| County |
Suffolk |
| State |
MA |
| Zip |
02114-0000 |
|
 |