Effects of Romosozumab on Bone Density, Markers of Bone Metabolism and Bone Microarchitecture in Women With Anorexia Nervosa: A Pilot Study
Phase: PHASE3
Conditions: Bone Density, Low, Bone Loss, Anorexia Nervosa, Eating Disorders
Sponsor: Karen Klahr Miller, MD

 
 
 
 
 
 
 
 
 
 
 
 
 
Effects of Romosozumab on Bone Mineral Density, Markers of Bone Metabolism and Bone 
Microarchitecture in Women with Anorexia Nervosa: A Pilot Study 
Version Date: February 26th, 2025 
NCT # 04779216 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Effects of Romosozumab on Bone Mineral Density, Markers of Bone Metabolism 
and Bone Microarchitecture in Women with Anorexia Nervosa: A Pilot Study 
 
I. Background/Significance 
 
Anorexia nervosa is a serious disease leading to severe bone loss at multiple skeletal sites. The illness 
affects 1-2% of young women in the U.S. 1-3 and is chronic in more than 50% of affected women 4. Bone 
loss is a severe, frequent and often permanent comorbid medical complication resulting in debilitating 
vertebral crush fractures 5. The majority of women with anorexia nervosa have bone loss, and 50% have 
bone density measurements greater than 2 standard deviations below normative means 6. It is not 
uncommon for bone mass in these young women to be comparable to postmenopausal women in their 
7th and 8th decades 7. Undernutrition, loss of muscle mass (which is an unavoidable consequence of 
weight loss) 8, and endocrine hormone dysregulation [particularly low insulin-like growth factor 1 (IGF-
1)] 9 all contribute to low bone mass in women with anorexia nervosa.  
 
Although bone density increases with weight recovery, osteopenia is often a permanent consequence of 
anorexia nervosa. Significant persistent osteopenia in women with anorexia nervosa has been shown in 
many studies and both cortical and trabecular bone mineral density (BMD) remain low more than ten 
years after recovery 10. Because bone mass remains persistently low despite recovery, such women 
remain at a high fracture risk throughout life, estimated to be 7.1 times that of healthy women in this age 
range 11. These data suggest that there may be a therapeutic window during which effective treatment 
should be implemented to prevent significant, lifelong bone mass reduction in this vulnerable 
population.  
 
Adulthood in anorexia nervosa is characterized by a negative balance in bone metabolism, with 
decreased bone formation and increased bone resorption 12 (Figure 1), including lower levels of 
osteocalcin, a marker of bone formation, and higher levels of deoxypyridinoline (DPYRX) and N-
telopeptide (NTX), markers of bone resorption, than age- and sex-matched controls (Figure 1).  
 
 
Figure 1. Levels of osteocalcin (a), a marker of bone formation, are decreased in women with anorexia nervosa compared to 
controls. Levels of deoxypyridinoline (DPYRX) (b) and N-telopeptide (NTX) (c), markers of bone resorption, are increased 
in women with anorexia nervosa compared to controls. 
 
A number of therapies targeting the high resorptive state in women with anorexia nervosa have been 
studied in women with anorexia nervosa, primarily by our group. We have shown that neither low-dose 
estrogen at postmenopausal hormone replacement doses or oral contraceptives are effective in women 
with anorexia nervosa, and bisphosphonates increase bone density significantly but not to normal 13. 

 
 
 
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Agents that are anabolic to bone have been examined in pilot studies by themselves or in combination 
with anti-resorptives. The most promising of such agents in terms of effectiveness may be parathyroid 
hormone,14 but it is not approved by the FDA for young women due to concerns about a possible risk of 
osteosarcoma. We have also studied low-dose recombinant insulin-like growth factor 1 (IGF-1), which 
is anabolic to bone and demonstrated modest increases in bone density that did not come close to 
normalizing bone density in women with anorexia nervosa 13, and low-dose testosterone, which was 
ineffective.15 This suggests that both high bone resorption and low bone formation characteristic of 
women with anorexia nervosa are logical and critical therapeutic targets, but that a more potent 
medication such as romosozumab that addresses both the deficit in bone formation and increased bone 
resorption is needed. In addition, as anorexia nervosa is a psychologic illness and such patients are often 
overwhelmed by the requirements of therapy and the illness itself, a treatment such as romosozumab 
administered monthly by a healthcare clinician may have the benefit of increased compliance and 
therefore efficacy, as we have observed in our ongoing pilot study in which the lower frequency of 
Prolia administration has resulted in the lowest drop-out rate of any study in anorexia nervosa yet in our 
hands – and likely in anyone’s. In addition, we have experienced outstanding excellent compliance to 
calcium and vitamin D supplementation in our ongoing pilot study of Prolia vs placebo, with no 
hypocalcemia. Exceptional compliance with supplementation in women with anorexia nervosa has also 
been reported in other studies 16.  
 
There are no therapies that normalize BMD or that are FDA-approved for bone loss in anorexia nervosa, 
and in contrast to postmenopausal osteoporosis in which therapy may be life-long, the goal in patients 
with anorexia nervosa is treatment during the acute illness to reduce further bone loss and fracture risk. 
We propose that an early relatively short-term intervention with a potent combination anabolic and anti-
resorptive therapy such as romosozumab during the period of rapid bone loss is an ideal, targeted 
therapy for the unique dysregulation of bone metabolism of young women with anorexia nervosa and 
may prevent significant osteopenia and reduce fracture risk in women with anorexia nervosa. We 
propose romosozumab therapy in a young, low-weight, population of women in which the prevalence of 
cardiovascular disease is extremely low 17. Therefore, even if the possible signal implicating 
romosozumab in cardiovascular risk proves to have validity, this group of women would be at 
particularly low risk for such a complication. 
 
II.  Specific Aims 
 
Phase 1: Romosozumab vs placebo 
 
This Amgen-sponsored investigator-initiated protocol is a randomized, double-blind, placebo-controlled 
clinical trial which aims to investigate the effect of romosozumab on BMD in women with anorexia 
nervosa. We will also investigate the safety of romosozumab in women with anorexia nervosa. We 
hypothesize that 12 months of romosozumab administration will result in an increase in bone mineral 
density, increase in markers of bone formation and decrease in markers of bone resorption, and 
improvement in bone microarchitecture in osteopenic women with anorexia nervosa compared with 
placebo.  
 
Specific Aim 1: We hypothesize that 12 months of romosozumab administration will result in an 
increase in bone mineral density in women with anorexia nervosa with low bone mass or osteoporosis 
compared with placebo.  

 
 
 
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We will investigate in women with anorexia nervosa in a 12-month study whether treatment with 
romosozumab will increase BMD as measured by dual energy x-ray absorptiometry (DXA) compared 
with placebo. The primary endpoint will be change in lumbar spine BMD from baseline to 12 months. 
Bone density will be measured at baseline, 6 months and 12 months.  
 
Specific Aim 2: We hypothesize that 12 months of romosozumab administration will result in a 
significant increase in markers of bone formation and reduction of markers of bone resorption in 
osteopenic women with anorexia nervosa compared with placebo.  
 
We will investigate in women with anorexia nervosa in a 12-month study whether markers of bone 
formation, including osteocalcin and P1NP, will increase in the romosozumab group more than in the 
placebo group. We will also investigate whether markers of bone resorption, including CTx, will 
decrease in the romosozumab group more than in the placebo group. Markers of bone metabolism will 
be measured at baseline, 3 months, 6 months, 9 months and 12 months.  
 
Specific Aim 3: In this exploratory aim, we hypothesize that 12 months of romosozumab administration 
will result in improved bone microarchitecture and strength in osteopenic women with anorexia nervosa 
compared with placebo.  
 
We will investigate in women with anorexia nervosa in a 12-month study whether treatment with 
romosozumab will improve bone microarchitecture, as assessed by HR-pQCT, and improve bone 
strength, as estimated by microfinite element analysis compared with placebo. HR-pQCT of the tibia 
and radius will be performed and the following will be measured: trabecular thickness and spacing; 
cortical thickness and porosity; ITS (individual trabecula segmentation); finite element analysis 
modeling of bone strength. HR-pQCT will be measured at baseline, 6 months and 12 months.  
 
Specific Aim 4: In this exploratory aim, we hypothesize that increases in bone mineral density will be 
greater in women with anorexia nervosa randomized to romosozumab who gain lean mass over 12 
months compared to women randomized to romosozumab who do not gain lean mass over 12 months, 
and lowest in women randomized to placebo.  
 
We will investigate in women with anorexia nervosa in a 12-month study whether increases in lean mass 
over 12 months are associated with a greater effect of romosozumab in increasing bone mineral density. 
It is known that muscle has an anabolic effect on bone through mechanical loading and muscle-bone 
hormonal cross-talk. Low lean body mass has been associated with impaired bone mineral density, bone 
microarchitecture, and estimated bone strength in women with anorexia nervosa 18. Although studies 
have demonstrated that women continue to have reduced bone mineral density years after the onset of 
recovery from anorexia nervosa 19,20, we hypothesize that the beneficial effects of romosozumab will be 
greater in women who gain lean mass during the 12 months of the study. We are exploring an 
association between lean body mass gain and BMD gain, and not causality. Lean mass and LS BMD 
will be measured by DXA at 0 and 12 months.  
 
Phase 2: Zoledronic acid 
 
 

 
 
 
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Specific Aims:  
 
In Phase 2, participants will receive a single infusion of open-label zoledronic acid (an intravenous 
bisphosphonate) 5 mg after the initial 12-month administration of romosozumab or placebo. We 
hypothesize that 12 months of romosozumab followed by a single intravenous infusion of open-label 
zoledronic acid will result in a greater increase in BMD compared to 12 months of placebo followed by 
a single intravenous infusion of open-label zoledronic acid. Within the group of women who receive 
sequential therapy with 12 months of romosozumab followed by a single intravenous infusion of 
zoledronic acid, we hypothesize that BMD will be maintained between 12 and 24 months following 
administration of zoledronic acid.  
 
Specific Aim 1: We hypothesize that 12 months of romosozumab followed by a single intravenous 
infusion of open-label zoledronic acid will result in a greater increase in BMD compared to 12 months 
of placebo followed by a single intravenous infusion of open-label zoledronic acid.  
 
We will investigate whether sequential therapy of 12 months of romosozumab followed by a single 
intravenous infusion of open-label zoledronic acid results in a significantly greater increase in BMD 
from baseline to 24 months compared to 12 months of placebo followed by a single intravenous infusion 
of open-label zoledronic acid. The primary endpoint will be lumbar spine BMD at 24 months in the 
romosozumab/zoledronic acid group compared to the placebo/zoledronic acid group. BMD will be 
measured at baseline and 24 months.  
 
Specific Aim 2: We hypothesize that within the group of women who receive sequential therapy with 12 
months of romosozumab followed by a single intravenous infusion of open-label zoledronic acid, BMD 
will be maintained between 12 and 24 months following administration of zoledronic acid.  
 
We will investigate whether a single intravenous infusion of open-label treatment with zoledronic acid will 
maintain the hypothesized gains in BMD achieved after 12 months of romosozumab administration. The 
primary endpoint will be lumbar spine BMD at 24 months. BMD will be measured at 12 and 24 months. 
 
III. Subject Selection 
 
Approximately 75 women will be screened for eligibility in order to identify 30 eligible women with 
anorexia nervosa, ages 20 to 60, to enroll in the study. Subjects will be randomized in a double-blind 
fashion to one of two groups for 12 months: monthly 1) romosozumab (210 mg, which must be 
administered as two injections of 105 mg) or 2) two identical placebo injections to determine effects on 
BMD, markers of bone metabolism, bone microarchitecture, and bone strength at trabecular and cortical 
sites. All subjects will meet the DSM-V criteria for AN or atypical anorexia and will be assessed for 
study suitability and monitored throughout the study period for their overall psychiatric clinical state in 
coordination with the patients’ clinical care team by a study psychologist or psychiatric nurse 
practitioner. 
 
Inclusion/Exclusion Criteria: 
 
Inclusion Criteria: 
• 
Female 

 
 
 
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• 
Age 20-60 years, skeletally mature with closed epiphyses 
• 
Body mass index (BMI) ≥ 16.5 kg/m2  
• 
Anorexia nervosa or atypical anorexia nervosa defined by DSM-V diagnostic criteria 
• 
BMD Z-score < -1.0 
• 
Normal serum 25-OH vitamin D (>30 ng/mL) and calcium levels 
• 
For women of reproductive age, agree to use an effective contraceptive method. Highly effective 
methods of birth control include: 
o Combined (estrogen and progestogen) hormonal methods (pills, vaginal ring, or skin 
patch)  
o Intrauterine device (IUD)  
o Intrauterine hormonal-releasing system (IUS)  
o Surgery to tie both fallopian tubes (bilateral tubal ligation/occlusion)  
o Woman’s male partner has had a vasectomy and testing shows there is no sperm in the 
semen  
• 
Dental check-up within the past year 
 
Exclusion Criteria:  
• 
Hospitalization within 3 months of baseline study visit, including inpatient eating disorder 
treatment facility; participating in a residential eating disorder treatment program within 3 
months of study participation is permitted  
• 
Myocardial infarction or stroke within 1 year preceding enrollment  
• 
History of hypertension or use of anti-hypertensive medications within the past 6 months 
• 
Any disease known to affect bone, including untreated thyroid dysfunction, Cushing’s or renal 
failure  
• 
Any medication known to affect bone metabolism within 3 months of the study, excluding oral 
contraceptives or other forms of estrogen administration. Bisphosphonates must have been 
discontinued for at least one year before participation  
• 
Immunodeficiency or taking immunosuppressive therapy  
• 
Serum 25-OH vitamin D level <30 ng/mL  
• 
Serum potassium <3.0 meq/L  
• 
Serum magnesium <1.5 meq/L  
• 
Serum ALT >3 times upper limit of normal  
• 
eGFR of less than 30 ml/min  
• 
LDL > 190 mg/dL 
• 
Hypocalcemia  
• 
Diabetes mellitus  
• 
Active substance abuse, including alcohol  
• 
Current smoker 
• 
History of malignancy  
• 
Paget disease of bone  
• 
Osteomalacia  

 
 
 
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• 
Osteonecrosis of the jaw (ONJ) or risk factor for ONJ, such as invasive dental procedures (eg, 
tooth extraction, dental implants, oral surgery in the past 6 months), poor oral hygiene, 
periodontal and/or pre-existing dental disease, and current use of corticosteroids.  
• 
Planned invasive dental procedure over the next 24 months  
• 
Known sensitivity to any of the products or components of the medication to be administered  
• 
Sensitivity to calcium or vitamin D supplements  
• 
Pregnant, planning to become pregnant within 12 months after the end of treatment and/or 
breastfeeding  
• 
Subjects with a known esophageal disease  
• 
Abnormalities of the esophagus such as stricture or achalasia 
• 
Inability to sit/stand upright for at least 30 minutes 
• 
Hypersensitivity to any component of zoledronic acid  
 
Drop Criteria (conditions for withdrawing subjects). These criteria (other than pregnancy) apply 
until the zoledronic acid infusion has occurred: 
• 
Pregnancy (for any subject)  
• 
BMI < 16.0 kg/m2 at two consecutive study visits at which weight and height are measured  
• 
Hospitalization, including inpatient eating disorder treatment facility; participation in a 
residential eating disorder treatment program is permitted 
• 
Medical instability, which will be determined by the study physician. Patients in this category 
will be assessed by the Data Safety Monitoring Board and continue to be assessed according to 
study protocol. 
• 
Serious study–related adverse event 
 
Source of Subjects and Recruitment Methods    
 
To maximize enrollment of subjects with anorexia nervosa, a number of referral mechanisms have been 
put into place over the past years utilizing the strong relationships with directors of area eating disorder 
programs, as well as a regional network of health care providers -- The New England Eating Disorders 
Research Collaborative. Subjects will be recruited from a large population of patients with anorexia 
nervosa from the following locations and through the following resources:  
 
1) New England Eating Disorders Research Collaborative was established at MGH several years ago 
and meets regularly for two hours each session to discuss recruitment strategies for MGH anorexia 
nervosa studies, review MGH research findings and discuss published data from other groups. This 
group represents a concerted and collaborative effort to recruit subjects with anorexia nervosa to the 
MGH studies and funnels patients into these studies from all over the New England area. It has been 
developed into an effective recruitment tool. The group includes representatives from the leadership of 
major eating disorder treatment centers and groups in the larger area, including: 1) Karin Lewis, Clinical 
Director, Monte Nido at Laurel Hill, 2) Seda Ebrahimi, PhD, Director, Cambridge Eating Disorders 
Center, 3) Beth Mayer, Executive Director, Massachusetts Eating Disorder Association, 4) Perry Belfer, 
PhD, Director, Newton-Wellesley Eating Disorders and Behavioral Medicine, 5) Esther Dechant, MD, 
Klarman Center for Eating Disorders, 6) Diane Mickley, MD, Director, Wilkins Center for Eating 
Disorders, Greenwich, CT, 7) Mark Goldstein, MD, Chief, Adolescent Medicine, MGH, 8) Suzanne 
Gleysteen, MD, Beth Israel Deaconess Medical Center, 9) Patrice Lockhart, MD, Mercy Hospital Eating 
Disorder Treatment Program, Portland, ME, 10) Kathleen Corkery, Clinical Director, Center for Eating 

 
 
 
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Disorders Management, NH, 11) Bob Keane, PhD, Vice President for Clinical Operations, Walden 
Behavioral Care.  
 
2) The Eating Disorders Clinical and Research Program (EDCRP) at Massachusetts General Hospital, 
which is the largest operating eating disorders clinic in New England. The Eating Disorders Unit in the 
Massachusetts General Hospital Child Psychiatry Service and the Adult Eating and Weight Center 
together form the largest outpatient Eating Disorders Clinic in the New England area. The EDCRP sends 
out biannual newsletters that inform clinicians and families of eating disordered patients about new 
research opportunities. Their web-site is a frequently hit ED site, and details about the study will be 
available on that site. The EDCRP networks regularly with major treatment centers for eating disorders 
in Connecticut, Vermont, Rhode Island, New Hampshire, and Maine and with the 250 college health 
centers in the Greater Boston area.  
 
3) Walden Behavioral Care. The Neuroendocrine Unit is invited to give monthly educational talks to 
patients and provide information about ongoing studies at the inpatient, partial hospitalization and 
residential programs.  
 
4) The Massachusetts Eating Disorders Association, which runs support groups for women with eating  
disorders throughout eastern Massachusetts.  
 
5) Health services at local colleges and universities, including Boston University and Harvard University 
Health Services. 
 
6) Recruitment through local university job boards, including Boston University, Northeastern 
University, and Harvard University 
 
7) Social media posts (Twitter, Instagram, Facebook, etc.)  
 
8) Mass General Brigham Rally online platform. 
 
9) Mass General Brigham Research Study Volunteer Program (RSVP for Health). 
 
10) Mass General Brigham Research Patient Data Registry (RPDR) and Mass General Brigham Patient 
Gateway. Additional recruitment will involve the Mass General Brigham Research Patient Data Registry 
(RPDR), which allows targeted searches of patients within the Mass General Brigham system by age, 
sex, and diagnosis with the ability to filter out patients by study-specific exclusion criteria. This results 
in a highly targeted recruitment list that allows investigators to contact potential subjects following the 
new OPT-OUT model. Using a targeted recruitment list from RPDR, which will exclude patients who 
have opted out of research invitations, we will send recruitment letters to potential subjects through 
Patient Gateway following the new OPT-OUT model. Additionally, we may mail recruitment letters to 
potential research subjects identified through RPDR who are not active on Patient Gateway. 
 
11) Recruitment through Handshake, an online platform that connects students at universities and 
colleges to employers to find job opportunities. 
 

 
 
 
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12) Recruitment through flyers posted at local college and university campuses, community centers, and 
other public spaces. 
 
13) Recruitment through a list of research subjects who have previously been recruited by our study 
team and who have agreed to be recontacted for future studies. 
 
 
IV. Subject Enrollment 
 
Informed consent will be obtained from all potential study subjects by a licensed physician investigator 
or nurse practitioner investigator before any procedures are performed. At this time, the subject will be 
explicitly counseled that she is free to choose whether or not to participate in this study. 
  
Eligible subjects will be randomized at the baseline visit to the treatment or placebo group. Neither the 
investigator nor the subject will be aware to which group she is assigned until after the study is 
completed and has been un-blinded or in the case of significant safety considerations for a specific 
subject.  
 
All subjects will receive a single intravenous infusion of open-label zoledronic acid at the month 12 
study visit. 
 
 
V.  STUDY PROCEDURES 
 
Screening Visit: A “Screening Visit” will be conducted by a member of the study clinical team to 
determine eligibility for the protocol. All subjects will be seen at Massachusetts General Hospital 
(MGH) for an outpatient visit including the following: A complete medical history including eating 
disorder, weight, medication, consumptive habits (smoking, alcohol, caffeinated beverages), and 
menstrual history will be taken. In addition, the following will be performed:  
 
1. A clinical evaluation, including temperature, pulse, blood pressure, and a urine pregnancy test. 
Women will be exempt from urine pregnancy tests if they are in menopause or if they have had 
any well-documented method of surgical sterilization, including hysterectomy, bilateral 
oophorectomy, and tubal ligation. A physical and oral examination will also be performed.  
2. Blood draw for comprehensive metabolic panel, CBC, magnesium, direct LDL, and 25-OH 
vitamin D, if not performed clinically within 6 weeks prior to the screening visit. Additional 
blood will be drawn to enable testing repeat in cases of lab error or tube breakage. 
3. Nutritional evaluation, including weight in a gown, height, frame size, calculation of percent 
IBW and body mass index (BMI)  
4. DXA scan of the spine, hip, radius, and total body for BMD and body composition, including 
lean mass, is required if the subject has not had a DXA scan within 6 months prior to the 
screening visit and optional if she has had one  
5. Verification of the anorexia nervosa diagnosis and determination of anorexia nervosa subtype 
(restricting or binge/purge) using DSM-V criteria  
6. Verification of lack of severe comorbid concerns (i.e. suicidality, substance use) that would 
preclude safe study participation will occur by the study psychologist or psychiatric nurse 

 
 
 
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practitioner. Suicidality is assessed through a verbal conversation with a psychiatric health 
professional. If the subject has been suicidal in the past, the psychiatric professional will ask 
questions to assess their level of suicidality, and whether it would be a risk to their health to 
partake in a study. If a subject appears to be actively suicidal, study staff will make appropriate 
referrals, which will often include the Acute Psychiatric Service at MGH; all efforts will be made 
to contact the subject’s clinical treatment team.  
7. Plain film of wrist/hand to determine bone age in women with primary amenorrhea who have not 
received estrogen for ≥1 year.  
8. Electrocardiogram (ECG or EKG) to assess cardiovascular risk. 
 
If the 25-OH vitamin D level at the screening visit is not >30 ng/ml, participants will be given one 
loading dose of oral vitamin D3 (cholecalciferol) 5,000 IU daily and the 25-OH vitamin D level will be 
checked every 3 weeks until their 25-OH vitamin D level meets the eligibility requirement (>30 ng/ml). 
 
Baseline Visit: Eligible study subjects (n=30 women with anorexia nervosa or atypical anorexia) will be 
assessed at an outpatient visit at MGH for baseline testing. 
1. A clinical and bionutrition evaluation and urine pregnancy test (unless exempt from urine hCG).  
2. DXA scan of the spine, hip, radius, and total body for BMD and body composition, including 
lean mass, if screen visit did not take place within 6 weeks of baseline visit or if a DXA scan was 
not performed at the screening visit.  
3. Baseline hormone and safety blood testing, if not performed clinically within 2 weeks prior to 
the baseline visit. 
4. HR-pQCT and FEA of the radius and tibia 
5. Eating Disorder Examination—Questionnaire  
6. Eating Disorder Inventory-3  
7. Paffenbarger Exercise Questionnaire  
8. Calcium and vitamin D food frequency questionnaire  
 
Randomization to treatment or placebo group will occur at the baseline visit. Twenty subjects will be 
randomized to active romosozumab (210 mg, which must be administered as two injections of 105 mg) 
and 10 subjects will be randomized to identical placebo injections. In the rare case that a subject 
withdraws from the study after being randomized but prior to completing the baseline visit, we will 
replace such dropouts with the goal that thirty subjects will complete the baseline visit. Randomization 
will be stratified for presence or absence of atypical anorexia nervosa, defined as BMI ≥ 18.5 kg/m2 vs. 
< 18.5 kg/m2. Subjects will return every month over the following 12 months to receive ongoing 
injections.  
 
If screen 25-OH vitamin D level is <40 ng/ml, subjects will be given one loading dose of oral vitamin 
D2 (ergocalciferol) 50,000 IU at the baseline visit. All subjects will be asked to take a standard dose of 
1000 mg calcium and 800 IU vitamin D supplements daily throughout the study. It is our experience 
from multiple clinical trials that women with anorexia nervosa are extremely compliant with calcium 
and vitamin D supplementation.  
 
After the baseline visit, follow-up visits will occur at monthly intervals during the first 12 months of the 
study so that the romosozumab or placebo injections can be administered by a study physician, nurse 
practitioner, or study nurse. In rare cases where subjects are unable to travel to MGH, the study 

 
 
 
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injections may be mailed to and administered by an out-of-state, licensed physician, physician assistant, 
or nurse practitioner responsible for the clinical care of the study subject. A urine pregnancy test (unless 
exempt from urine hCG) and clinical evaluation will be performed at each monthly visit. A bionutrition 
evaluation, including weight in a gown, height, and calculation of percent IBW and body mass index 
(BMI), will be performed at months 3, 6, 9, and 12. At months 1, 3, 6, 9, and 12, blood testing, including 
for electrolytes (e.g. calcium), will occur unless performed clinically within 2 weeks prior to the study 
visit. Calcium and eGFR must be normal and 25-OH vitamin D must be > 20 ng/mL at the most recent 
visit in order to receive zoledronic acid at the 12-month visit. If  labs are not normal, study staff will 
reach out to the participant’s care team to assist with timely intervention with the goal that repeat labs 
are normal prior to the 12-month visit. Participants with serum 25-OH vitamin D ≤20 ng/ml at the 9-
month visit will be given oral vitamin D2 (ergocalciferol) 50,000 IU weekly, and their 25-OH vitamin D 
level will be rechecked at the 11-month visit. If their repeat serum 25-OH vitamin D level at the 11-
month visit is still ≤20 ng/ml, we will continue to provide oral vitamin D2 (ergocalciferol) 50,000 IU 
weekly, and their 25-OH vitamin D level will be rechecked every 2 weeks until their 25-OH vitamin D 
level meets the requirement (>20 ng/ml) to receive zoledronic acid. Additionally, participants will be 
given one loading dose of oral vitamin D2 (ergocalciferol) 50,000 IU at the 12-month visit if their most 
recent 25-OH vitamin D level is < 30 ng/ml. At months 3, 6, 9 and 12, questionnaires will be completed 
(EDI-3 and EDE-Q). Additionally, at months 6 and 12, a Paffenbarger exercise questionnaire will be 
completed. A calcium and vitamin D food frequency questionnaire will be completed at the month 12 
visit as well. DXA at the spine, hip, radius and total body for BMD and body composition, including 
lean mass, will be performed 6 and 12 months after baseline. HR-pQCT and FEA of the radius and tibia 
will be performed at 6 and 12 months. Markers of bone metabolism will be measured at months 3, 6, 9 
and 12.  
 
A clinical evaluation and pregnancy test (unless exempt from urine hCG) will be performed at the 18 
and 24-month visits, as will a nutrition evaluation, including weight in a gown, height, and calculation of 
percent IBW and body mass index (BMI) and completion of questionnaires (EDI-3, EDE-Q, and 
Paffenbarger exercise questionnaire). A calcium and vitamin D food frequency questionnaire will also 
be administered at the month 24 visit. At 18 and 24 months, markers of bone metabolism will be 
measured, and safety labs will be performed, unless performed clinically within 2 weeks prior to the 
study visit . DXA at the spine, hip, radius and total body will be performed at the 24-month study visit. 
HR-pQCT and FEA of the radius and tibia will also be performed at 24 months.  
 
For the 18-month visit, subjects who do not live locally will be permitted to have their blood drawn and 
pregnancy test performed offsite for lab tests required for the visit. Tests that need to be run in real time 
will be done at local laboratories, with the results provided online to investigators. Otherwise, the 
samples will be mailed to investigators. Subjects who choose this option will also have an interim 
history performed by our staff by telephone.  
 
Additionally, for all visits which involve questionnaires, those will be completed on paper during the 
visit or sent electronically via Redcap to be completed and returned to study staff.  
 
 
 
 
 

 
 
 
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Methods: 
 
Dual-energy x-ray absorptiometry (DXA): BMD at the lumbar spine, hip, and radius, as well as lean 
mass and fat mass, will be assessed by DXA (Hologic 4500, Hologic, Inc., Waltham, MA) with a 
precision of 0.01 g/cm2 at the lumbar spine and 1.5% for lean mass 21. 
 
Bone Microarchitecture and Micro Finite Element Analysis (μFEA): In vitro strength testing 
reflects the importance of bone morphology and microstructure in addition to BMD in determining bone 
strength. DXA cannot provide information about the distinct densities of the cortical and trabecular 
compartments of bone, the 3D-geometry of bone, or bone microstructure. HR-pQCT assesses these 
parameters22 and performs in vivo assessment of trabecular architecture and volumetric BMD with very 
high resolution.23 We will use the 2nd-generation high-resolution peripheral QCT (HR-pQCT) (XCT-II, 
Scanco Medical AG®, Bassersdorf, Switzerland) to measure volumetric BMD (vBMD), morphology 
and microarchitecture at the ultradistal radius and tibia. The variables computed by automated analysis 
include vBMD (g hydroxyapatite/cm3) for the total, trabecular, and cortical regions; cortical thickness 
(μm) and porosity measures; and trabecular number (mm-1), thickness (μm), and separation (μm). 
Study Visit 
Screen Baseline M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M18 
M24 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment 
X 
X 
 
 
  X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
HCG 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Safety Labs (CBC, 
magnesium, and CMP 
at screen; BMP, 
calcium, magnesium, 
and albumin thereafter) 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Study drug 
(romosozumab) or 
placebo injection 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Zoledronic acid infusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Nutrition Evaluation 
(height, weight) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Bone Markers (CTX, 
P1NP, osteocalcin) 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
IGF-1 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
25-OH VitD 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Direct LDL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(ECG or EKG) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMD (DXA) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Bone Strength with FEA 
(Xtreme CT) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
EDI-3 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
EDE-Q 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Paffenbarger 
Questionnaire (exercise 
quantification) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Calcium and Vitamin D 
Food Frequency 
Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 

 
 
 
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Measurements will be performed at the non-dominant wrist and leg (if fracture history, the non-fractured 
side will be used). Using a scout view, the reference line is set at the bone endplate. Scans will be at a 
distance from the endplate relative to the individual subject’s limb length (ultradistal: 7%) to adjust for 
body size. Each scan includes a stack of 168 slices with an isotropic voxel size of 61 μm3. Cortical and 
trabecular compartments are segmented using a fully automatic contouring procedure. The fine structure 
will be segmented using a simple threshold process. Trabecular (trab) vBMD is calculated as the average 
mineral density within the trabecular region. Trab bone volume fraction is calculated directly 
(mineralized bone voxels/ total voxels). Trab thickness, 
separation, and number are calculated using the direct 3D distance transformation method. Mean and 
distribution of intracortical pore diameter is measured by the direct 3D method.24 Intracortical porosity 
is calculated as intracortical pore volume/total cortical compartment volume.25 Cortical tissue mineral 
density is assessed after exclusion of all resolved pore space and surface voxels to minimize partial 
volume voxels and is a surrogate of matrix mineralization and microporosity beyond the resolution limit 
of the scanner.26 Quality control (QC) of scanner: Included with the system (QRM, Moehrendorf, 
Germany) is a phantom containing rods of hydroxyapatite (densities of 0, 100, 200, 400 and 800 mg 
HA/cm3) embedded in a soft-tissue equivalent resin that is scanned daily and calibrates the scanner, so 
that X-ray attenuation data can be converted to equivalent HA densities. Images are scored for 
movement artifact at acquisition (score 1-5; 1 indicating best quality)27 and repeated for scores>2. 
Images scored >3 will be excluded. Weekly, a more extensive QC procedure is performed. Microfinite 
element analysis (μFEA), an established analytical engineering technique to estimate stresses and 
strains induced by mechanical loading of complex structures, will be used to study bone strength.28,29 
Using HR-pQCT data, it strongly predicts in vitro femoral and vertebral breaking strength,30 and 
correlates more strongly with failure load than bone mass or structure.28,29 In vivo test-retest precision is 
<1.0% for integral, trabecular, and cortical BMD, <2% for trabecular architecture, and <4% for μFEA 
stiffness and failure load. Individual Trabeculae Segmentation (ITS): The trabecular bone 
compartment is from the HR-pQCT images and will undergo ITS-based morphological analysis.31 
Volumetric decomposition will be performed to derive plate and rod bone volume fraction, number 
density, thickness, plate surface area, and rod length, topology: plate and rod tissue fraction, and plate–
plate, plate–rod, and rod–rod junction density, and orientation, as previously reported.31 
 
Laboratory testing: IGF-1 will be measured by liquid chromatography/mass spectrometry (LC/MS) 
(Quest Diagnostics, San Juan Capistrano, CA). Bone markers serum osteocalcin, serum C-telopeptide 
(CTX) and intact N-terminal propeptide of type 1 procollagen (PINP) will be measured by 
chemiluminescence assay at Maine Medical Center. 25-OH vitamin D will be measured by LC/MS 
(Quest Diagnostics, Marlborough, MA). The samples will be deidentified and coded with a unique ID 
that does not contain any protected health information. The study team will be able to re-identify 
participants, however, the investigators at Maine Medical Center and Quest will not be able to do so. 
Samples will be sent via air mail, following IATA shipping guidelines. Materials sent to Maine Medical 
Center and Quest will not be stored there for further use; extra samples will either be destroyed or sent 
back to the study team via air mail, following IATA shipping guidelines. If a subject wanted to 
withdraw their samples from either site before the samples were returned or destroyed, the study team 
would provide the Maine Medical Center and/or Quest with the subject’s deidentified study ID, and the 
sample would be destroyed without further testing.  
 
Questionnaires: Eating-disorder psychopathology will be measured using the Eating Disorder 
Examination-Questionnaire, a self-report measure of eating disorder severity over the past 28 days along 

 
 
 
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four dimensions-- restraint, eating concern, shape concern, and weight concern.32 Subjects will also 
record current frequency of binge eating and compensatory behaviors on the EDE-Q. The Eating 
Disorder Inventory will be used to assess three eating-disorder-risk subscales – drive for thinness, 
bulimia, and body dissatisfaction.33 Hours of vigorous physical activity per week will be quantified 
using the Paffenbarger scale.34 Dietary intake of calcium and vitamin D will be quantified using a food 
frequency questionnaire. 
 
VI. Biostatistical Analysis  
 
Sample Size and Justification: Group sample sizes of 20 (active therapy) to 10 (placebo) for a total 
N=30 will achieve 80% power to reject the null hypothesis of equal means when the population mean 
difference is at least 9% with a standard deviation between groups of 8% and with a significance level of 
(alpha) of 0.050 using a 2-sided 2-sample equal-variance t-test. This is based on the difference in percent 
change in spine bone density between the romosozumab (n=65) and placebo (n=61) groups in Cosman 
F. et al. 35.  
 
Data Analysis Plan:  
The data analysis plan for the study will be as follows. The primary analysis will be intention-to-treat, 
with the primary endpoint being change in PA lumbar spine aBMD. Statistical significance will be 
defined as a two-tailed p-value of  ≤ 0.05. 
 
Phase 1 Aims 1-3: Baseline mean clinical characteristics between the 2 groups will be compared by t-
test. Variables will be tested for normality using the Shapiro-Wilk test, and if non-normal, variables will 
be log-transformed before analysis. If the distribution remains non-normal after log-transformation, 
nonparametric testing using the Wilcoxon rank sum test will be performed instead. The analysis of 
variables at 12 months will be performed using a linear random effects model to estimate and test the 
effects of the 2 randomization groups (romosozumab vs placebo) from baseline to 12 months on the 
study endpoints.  
 
Phase 1 Aim 4: The analysis of variables at 12 months will be performed using a linear random effects 
model to estimate and test the effects of the 2 randomization groups (romosozumab vs placebo) from 
baseline to 12 months on the study endpoints. We will also add a lean body mass x randomization group 
interaction term to examine if the effects of body mass change differ between romosozumab and 
placebo. 
 
Phase 2 Aim 1: The analysis of variables at 24 months will be performed using a linear random effects 
model to estimate and test the effects of the 2 randomization groups (12 months of romosozumab 
followed by a single intravenous infusion of open-label zoledronic acid vs 12 months of placebo 
followed by a single intravenous infusion of open-label zoledronic acid) from baseline to 24 months on 
the study endpoints.  
 
Phase 2 Aim 2: A secondary analysis will be performed to determine whether gains achieved in the 
romosozumab group are maintained through the subsequent 12-month study period using a linear 
random effects model with the fixed effect being time and the random effect being the intercept. Lack of 
statistical significance will indicate maintenance (lack of decrease--or increase) of BMD.  
 

 
 
 
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Phase 1 Endpoints: 
 
Primary:  
Change from baseline to 12 months in lumbar spine bone mineral density by dual energy x-ray 
absorptiometry (DXA).  
 
Secondary:  
Change from baseline to 12 months in bone mineral density of hip (total and femoral neck) and radius 
by DXA.  
 
Change from baseline to 12 months in markers of bone metabolism: CTx, P1NP, Osteocalcin.  
 
Exploratory:  
Change from baseline to 12 months in HR-pQCT variables at the tibia and radius—trabecular thickness 
and spacing, and cortical thickness and porosity; change from baseline to 12 months in ITS variables; 
change from baseline to 12 months in finite element analysis modeling of bone strength. 
 
Phase 2 Endpoints:  
 
Primary:  
Change from baseline to 24 months in lumbar spine BMD.  
 
Exploratory:  
Change from baseline to 24 months in markers of bone metabolism: CTx, P1NP, Osteocalcin. 
 
VII.   Risks and Discomforts 
 
Risks from Procedures  
 
Blood Sampling:  
Blood sampling is performed in the study and there is always a very minor risk of infection, bruising, or 
syncope during a blood draw. There is also the discomfort of having one’s blood drawn.  
 
Bone Density and Microarchitecture Studies:  
The study involves exposure to radiation from four or five DXA scans, four HR-pQCT scans, and a 
plain film of the wrist/hand if needed to determine bone age (only in women with primary amenorrhea 
who have not received estrogen for ≥1 year). The total radiation dose the subject will receive from all of 
the scans is 0.19 milliSievert (mSv). This amount of radiation is approximately 6% of the yearly natural 
background radiation from the earth and the sky (equivalent to 22 days of background radiation). There 
are no known health risks associated with such a dose.   
 
Subjects will have the option to repeat scans once if there is a technical issue with the machine, which is 
a rare occurrence. If each scan were repeated at each visit, the total radiation dose the subject would 
receive from all of the scans would be no more than 0.38 mSv. This amount of radiation is equal to 

 
 
 
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about 12% of the annual background radiation from the earth and the sky (equivalent to 44 days of 
background radiation). Subjects have the option to refuse to be re-scanned.   
 
All patients will have pregnancy tests (unless exempt from urine hCG) on admission prior to receiving 
any radiation. Subjects will also have serial pregnancy tests performed at every study visit. BMD 
measurements will occur five times, and HR-pQCT of the radius and tibia will be performed four times 
over the course of 24 months.  
 
Risks from Medications  
 
Oral calcium can cause constipation and a metallic taste in the mouth.  
 
Vitamin D in the doses being administered does not result in any side effects.  
 
Romosozumab Administration:  
Two separate subcutaneous injections are needed to administer the total dose of romosozumab 210 mg. 
A study clinician will inject two syringes, one after the other, every month for 12 doses in the abdomen, 
thigh, or upper arm.  
 
Romosozumab 210 mg may cause all, some, or none of the side effects listed below. These side effects 
can be mild but could also be serious, life-threatening, or even result in death. In addition, it is possible 
that a subject may experience an allergic reaction that has not been seen before.  
 
Side effects that other people with osteoporosis or bone loss have had in research studies that are 
thought to have been caused by romosozumab 210 mg are: 
 
Very common side effects (which may affect more than 1 person in 10):  
• 
joint pain  
• 
pain in extremity  
 
Common side effects (which may affect between 1 and 10 people in every 100):  
• 
headache  
• 
muscle spasm  
• 
swelling in extremity  
• 
lack of energy  
• 
neck pain  
• 
trouble sleeping  
• 
tingling or numbness in extremity  
 
Uncommon side effects (which may affect between 1 and 10 people in every 1,000):  
• 
allergic reaction (drug hypersensitivity) (see description below)  
• 
hypocalcemia (see description below)  
• 
heart attack or stroke (in postmenopausal women) (see description below)  
 
Rare side effects (which may affect between 1 and 10 people in every 10,000):  

 
 
 
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• 
osteonecrosis of the jaw (ONJ) (see description below)  
• 
unusual thigh bone fracture (atypical femoral fractures) (see description below)  
 
Hypersensitivity reactions. Hypersensitivity reactions, including angioedema, erythema multiforme, 
dermatitis, rash, and urticaria have occurred in romosozumab-treated patients. Subjects will be 
instructed to call the study doctor immediately if they are concerned about an allergic reaction, and to go 
immediately to the emergency room if they are concerned about a severe allergic reaction. If an 
anaphylactic or other clinically significant allergic reaction occurs, romosozumab will be discontinued 
and the subject will be referred for appropriate treatment.  
 
Hypocalcemia. Transient hypocalcemia has been observed in patients receiving romosozumab. Subjects 
with hypocalcemia, a 25-OH vitamin D level <30 ng/mL, or eGFR <30 ml/min will be excluded from 
participation in the study. Subjects will be monitored for signs and symptoms of hypocalcemia. All 
subjects will take daily calcium and vitamin D while in the study.  
 
Major adverse cardiac event. In a randomized controlled trial in postmenopausal women, there was a 
higher rate of major adverse cardiac events (MACE), a composite endpoint of cardiovascular death, 
nonfatal myocardial infarction and nonfatal stroke, in patients treated with romosozumab compared to 
those treated with alendronate. Subjects who have had a myocardial infarction of stroke within the 
preceding year will be excluded from participation in the study. 
 
Osteonecrosis of the jaw (ONJ). ONJ is a potentially serious condition that can present as a sore in the 
mouth through which the jaw bone is sometimes visible. The gum tissue over the bone may heal slowly 
or not heal at all. How this happens is poorly understood. The symptoms of ONJ include pain or 
infection in the jaw bone and gums. Subjects will be instructed that if they develop any of these 
symptoms, they should see their doctor who should examine her mouth to determine if she has ONJ. The 
risk of developing ONJ is higher in patients who have had tooth removal, gum surgery, infections in the 
mouth, dental implants or other dental procedures. Subjects will be instructed that it is important that 
they maintain good oral hygiene and avoid dental procedures immediately before and during their 
participation in the study, if possible. They will also be instructed that their study doctor and dentist 
should discuss the benefits and risks of any dental procedure. Additionally, they will be instructed to tell 
their dentist that they are taking romosozumab before a dental procedure is planned. Although ONJ has 
been reported rarely in patients receiving romosozumab, we will take all possible precautions to prevent 
it from occurring, specifically, we will exclude all subjects with an invasive dental procedure within 6 
months prior to the baseline visit or planned dental procedure over the next 6 months, and will require 
all subjects to have had a dental exam within 1 year prior to enrolling in the study. 
 
Atypical femoral fractures. An atypical femoral fracture is an unusual thigh bone fracture that may occur 
with little or no trauma. Fractures can occur in both thighs at the same time. Atypical fractures have 
been reported rarely in patients receiving romosozumab. It is unknown whether the risk of atypical 
femoral fracture continues after stopping therapy. It can present with new or unusual hip, thigh, or groin 
pain weeks to months before the fracture is diagnosed. Subjects will be instructed that if they develop 
any of these symptoms, they should report them to the study doctor and the physician they see for 
clinical care. Patients presenting with an atypical femur fracture will also be assessed for symptoms and 
signs of fracture in the contralateral limb. 
 

 
 
 
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In clinical studies, after romosozumab discontinuation, BMD returns to approximately baseline levels 
within 12 months in the absence of follow-up antiresorptive therapy. This is why we propose to follow 
the 12 months of romosozumab or placebo with a single intravenous infusion of open-label zoledronic 
acid at the 12-month visit.  
 
The potential effects of romosozumab on the fetus are not known, and therefore precautions against 
administration to pregnant patients will be instituted. All patients will have pregnancy tests on admission 
prior to receiving study medication and serial pregnancy tests at every study visit and will be required to 
use contraception in order to participate in the protocol (unless exempt). Any subject who becomes 
pregnant during the course of the study and is discharged from participation, will undergo a follow-up 
study visit. This will include assessment by an MD or NP for study medication related side effects, 
including hypocalcemia, and measurement of a calcium level if it has not been done clinically.  
 
After patients start taking romosozumab, it is possible that their body may make antibodies to 
romosozumab. Antibodies to romosozumab have not been associated with changes in the efficacy or 
safety of romosozumab. 
 
Zoledronic acid Administration:  
 
The risks of zoledronic acid therapy are as follows: flu-like symptoms (low-grade fever, fatigue, nausea, 
muscle aches, joint aches, headache), skin rash, diarrhea, and joint pain. Less common side effects 
include abdominal or stomach pain; renal impairment and acute renal failure; atrial fibrillation; 
hypocalcemia; stomach cramping; belching; severe bone, joint, and muscle pain; hypertension; blurred 
vision or change in vision; chest pain; constipation; cough; dizziness; dry eyes; fever; general feeling of 
discomfort or illness; leg cramps; nausea; ringing in the ears; swelling of the feet or lower legs; and 
weakness. On rare occasion, red sore eyes have been reported among those on zoledronic acid therapy. 
 
Two very rare potential complications of bisphosphonate therapy are osteonecrosis of the jaw and 
atypical femur fractures. Osteonecrosis is a bone condition that results from poor blood supply to an area 
of bone causing bone death. Although it can affect any bone, only osteonecrosis of the jaw has been 
found to coincide with bisphosphonate therapy. The vast majority of cases have developed in patients 
treated with high dose intravenous therapy (94%), and with multiple myeloma or metastatic breast 
cancer (85%). In the majority of cases of jaw osteonecrosis in the treatment of osteoporosis, dental 
surgery and/or trauma to the jaw were preceding factors in the development of osteonecrosis of the jaw. 
The risk of jaw osteonecrosis increases with the length of time one is exposed to intravenous 
bisphosphonate therapy. The skeleton is constantly developing micro fractures from skeletal loading. 
These micro fractures are repaired by the normal process of bone remodeling, which requires bone 
resorption. Bisphosphonates suppress bone remodeling and remain in the skeleton for many years. Long 
term bisphosphonate use may cause accumulation of micro fractures, thereby increasing skeletal 
fragility. Atypical subtrochanteric femur fractures are fractures in the bone just below the hip joint. 
Diaphyseal femur fractures occur in the long part of the thigh bone. These fractures are very uncommon 
and appear to account for less than 1% of all hip and femur fractures overall. Although it is not clear if 
bisphosphonates are the cause, these unusual femur fractures have been predominantly reported in 
patients taking bisphosphonates long term.  
 

 
 
 
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DP Version 18: 02.26.2025 
Flu-like symptoms can occur in persons receiving intravenously administered bisphosphonates. These 
flu-like symptoms may include fever, chills, fatigue, headache and nausea, and typically resolve within 2 
days. Participants will be advised that they may take over-the-counter acetaminophen 650-1000 mg PO 
once on the morning of the zoledronic acid infusion as prophylaxis for these symptoms. As 
bisphosphonates remain in the bones for many years after administration has concluded, it remains 
unclear as to whether bisphosphonates are released from bone during pregnancy or breastfeeding. 
Published reports to date have not demonstrated increased birth defects in infants born to women 
receiving bisphosphonates before or during pregnancy. Study participation by pregnant or breastfeeding 
women is not allowed and is a study exclusion.  
 
Although the long-term risk of zoledronic acid in young women is unknown, bisphosphonates have been 
used in premenopausal women to treat osteopenia due to glucocorticoids. In addition, these medications 
are used widely in the community and it is essential that their efficacy be assessed. 
 
A study psychologist or psychiatric nurse practitioner will review all screened subjects, conduct a 
psychiatric interview at baseline and at any other time the staff requests. S/he will continue to monitor 
and ensure the ongoing psychiatric care of patients with their primary clinical psychiatrists and therapy 
teams and also provide individual consultation to subjects as needed. All patients recruited will continue 
to receive medical and psychiatric care from their treatment teams and all participants must have a 
clinical provider in place. A study psychologist or psychiatric nurse practitioner will continue to work 
closely with the patients’ clinical care treatment teams to ensure patient safety and continued 
appropriateness for the study from a psychiatric perspective. In summary, the study psychologist or 
psychiatric nurse practitioner involvement will be to provide a comprehensive psychiatric evaluation of 
potential study subjects, provide ongoing psychiatric monitoring of patients during the course of the 
study, and, be available by page for any questions that arise from study subjects, other investigators, and 
the patients’ clinical treatment teams and psychiatric providers. S/he will review any specific psychiatric 
issues regarding patients involved in the protocol with the other investigators, review data and 
participate in all aspects of the proposed study as a key member of the research team. S/he will attend 
Data Safety Monitoring Board meetings and will, together with the P.I., keep the Data Safety 
Monitoring updated on any issues that impact patient safety.  
 
Physician Availability: A physician will be available by pager at all times during the study to answer 
any questions or address any concerns that a subject may have. All efforts will be made to protect the  
confidentiality of study subjects who will be referred to by an enrollment number only.  
 
Patient Confidentiality: Confidentiality of the patients will always be of paramount importance to 
study investigators. All data on patients will be kept in confidential study binders and electronic files 
accessed by only study investigators and study staff. No study subject data will be shared with persons 
other than those directly involved in the study, except at the documented request of the subject. 
 
VIII.   Potential Benefits 
 
Each subject will have a complete nutritional analysis and BMD performed. These data, including 
relative fracture risk and total calcium intake, will be made available to the subject. In addition, a 
physical exam and blood testing will be performed in all subjects, and these data will also be made 
available to the subject.  

 
 
 
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DP Version 18: 02.26.2025 
 
The subject’s bone mineral density may increase during the study, although if it does increase, it is not 
known how long it will remain higher. We hope and anticipate that the information learned from this 
study will allow us to better understand the pathophysiology of bone loss in anorexia nervosa and to 
improve the treatment of patients with bone loss associated with under-nutrition. 
 
IX.    Monitoring and Quality Assurance 
 
No study procedures will be performed prior to approval by the Mass General Brigham Human 
Research Committee (IRB). Furthermore, all changes to the protocol or consent form will be submitted 
to the Human Research Committee for approval before being implemented. No data on study subjects 
will be shared with persons other than those directly involved in the study, except at the documented 
request of the study subject. Data obtained from each subject’s visit will be reviewed by the 
investigators weekly. Study staff will review the completeness of case report form (CRF) entries, source 
documents, and informed consent during and immediately following the visit.  
All adverse events, collected at all study visits, will be reported to the Human Research Committee 
(IRB) according to Mass General Brigham adverse event Reporting Policy and to the FDA according to 
Title 21 of the Code of Federal Regulations. A study-related adverse event will be considered serious if 
it results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, or a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions. Additionally, any medical event 
that may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed. All adverse events will be reported to the Data Safety Monitoring Board every 6 
months, and this report will be submitted to the IRB every 6 months. Safety data will also be reported to 
Amgen as follows:  
 
Suspected Unexpected Serious Adverse Reaction (SUSARs) will be reported to Amgen at the 
time of regulatory submission. Pregnancy/Lactation exposure and any associated 
reports/outcomes (i.e. unexpected pregnancy, pregnancy of partner, spontaneous abortion, 
congenital anomaly etc.) will be reported within 1 business day of sponsor awareness, for reports 
meeting serious criteria. Reporting to Amgen will not exceed 15 calendar days of sponsor 
awareness for non-serious reports. 
 
Data and Safety Monitoring  
A Data Safety Monitoring Board will be established at Massachusetts General Hospital consisting of 
five members -- the following five are staff members at Massachusetts General Hospital -- a 
Psychologist, Jennifer Thomas, PhD, Assistant Professor of Psychology in the Department of 
Psychiatry, Harvard Medical School, Assistant Psychologist, Klarman Eating Disorders Center, a 
psychologist, Deborah Friedman, PhD, Professor of Psychology in the Department of Psychiatry, 
Harvard Medical School, Clinical Assistant in Psychology at MGH, Elaine Yu, M.D., MMSc, an 
endocrinologist in the Endocrine Unit at the Massachusetts General Hospital, and a Biostatistician, 
Meredith M. Regan, Ph.D., Sc.D., Biostatistician, Biometrics Center, Beth Israel Hospital, Boston, MA. 
The Data Safety Monitoring Board will meet twice a year after study activation, or more often as 
needed. The Board will review all study procedures, all adverse events, study violations, exceptions and 
deviations as well as study inclusion and exclusion criteria. The Board will review all safety monitoring 
blood tests and study data as available. The data reviewed by the Data Safety Monitoring Board will be 

 
 
 
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DP Version 18: 02.26.2025 
blinded as to randomization assignment, except in cases in which the Data Safety Monitoring Board or 
study investigators feel that unblended data should be reviewed due to safety concerns. All study related 
serious adverse events will be reported to the Board within 24h of occurrence. Based on recruitment, 
review of adverse events and other parameters to be established by the Board, the Board may request an 
interim analysis or request unblinding or halting of the study for safety concerns or other issues that 
impact on safety. 
 
 
 
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Hoek HW, van Hoeken D. Review of the prevalence and incidence of eating disorders. Int J Eat 
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as result of cooperation between the European Foundation for Osteoporosis and the National 
Osteoporosis Foundation of the USA 2008;19:289-94.  
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Giovinazzo S, Sukkar SG, Rosa GM, et al. Anorexia nervosa and heart disease: a systematic 
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Miller KK, Lee EE, Lawson EA, et al. Determinants of skeletal loss and recovery in anorexia 
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Brooks ER, Ogden BW, Cavalier DS. Compromised bone density 11.4 years after diagnosis of 
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