Medication for bone loss in female patients with anorexia nervosa: a systematic review and management algorithm.

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Introduction

Anorexia Nervosa (AN) is an eating disorder, characterized by an intense fear of gaining weight and a restriction of energy intake leading to a significantly low body weight [ 1 ]. AN can be associated with psychiatric comorbidities as well as with nutritional and medical complications, particularly across the skeletal and reproductive systems [ 2 ]. The impact on bone development is multifactorial. Low energy availability decreases the production of various hormones stimulating osteoblastogenesis, such as estrogens, androgens, IGF1, leptin, oxytocin and free triiodothyronine (FT3) [ 3 , 4 ]. Undernutrition also increases cortisol secretion participating in the decrease of bone formation factors [ 5 ], and increase of bone resorption factors [ 6 ]. Bone loss in AN occurs early on, affecting more than 50% of adult women with AN thus contributing to high fracture risk [ 7 ]. Risk factors for low bone mineral density (BMD) include early onset of disease, lower body mass index (BMI), longer duration of illness, hypogonadotropic hypogonadism, low muscle mass, insufficient calcium intake, and low serum 25OH vitamin D3 levels [ 4 ]. In younger patients with AN, unlike during menopause, lack of bone formation is predominant compared to bone resorption [ 8 ]. In AN, low BMD affects trabecular more severely than cortical bone, recent studies showing a markedly reduced trabecular bone score in AN [ 9 ]. Thus, spinal BMD tends to be more relevant for low bone mass assessment [ 10 ].

Alterations in bone turnover remodeling can also lead to loss of bone quality resulting in a higher risk of fracture [ 11 , 12 ]. A recent retrospective study revealed that patients with AN faced a 46% increased risk of any fracture up to 40 years after diagnosis, predominantly in the spine and femur, which are common sites for osteoporotic fractures [ 13 ]. Faje et al. speculated that patients with AN suffering most fractures were especially those physically active, with a higher frequency of bone injury [ 14 ].

Osteoporosis is defined as a bone disorder increasing a person’s risk for fracture due to impaired bone microarchitecture, decreased bone strength, and low BMD. Low BMD is significantly associated with an increased risk of low trauma fracture; however, low BMD only partly explains individual risk of fracture. BMD can be assessed non-invasively using dual-energy X-ray absorptiometry. Patients with AN have significantly low total body BMD than healthy controls with a standard mean deviation of −3.45 in a large review study including 3072 patients with an illness duration of 4.7 years [ 15 ]. BMD decline occurs at an average annual rate of about 2.5% in women with active AN [ 16 ].

The goal of bone management in patients with AN is to reduce fracture risk and ultimately improve bone mineral density. In case of low BMD, weight restoration and resumption of menstruation remain treatment cornerstones [ 4 , 17 ]. Non-pharmacological preventive management of bone loss includes adequate dietary calcium and vitamin D intake, smoking cessation, limitation of alcohol/caffeine consumption, and healthy exercise, nutritional status allowing [ 18 ]. To reduce bone loss and the risk of fracture in postmenopausal women, several antiosteoporotic treatments are approved in France. They are categorized as either antiresorptive (i.e., bisphosphonates, estrogen replacement therapy (ERT), denosumab (a RANK ligand inhibitor) or anabolic (i.e., teriparatide, or abaloparatide, recombinant human PTH 1–34 analogues), or dual-action (romosozumab) [ 19 – 21 ]. However, no treatments are currently approved for the improvement of low BMD in patients with AN [ 4 ]. A few studies showed promising results of transdermal estrogen on BMD in adolescent populations [ 22 , 23 ]. For patients with long-term low body weight and low BMD, NICE guidelines consider the use of transdermal 17-β-estradiol with cyclic progesterone (in adolescents 13 to 17 y.o. with a bone age lower than 15 years) and of bisphosphonates (in adult women after discussing benefits and risks, i.e., teratogenic effects) [ 18 ]. There are only a few international guidelines concerning bone loss pharmacological treatment and prevention in patients with AN, and a consensus has yet to be developed toward a gold standard to help clinicians.

The aims of this systematic review were to review current evidence on the medication used to prevent and treat low BMD in patients with AN, as well as to establish clinical guidance to improve bone health for these patients.

Methods

Data sources

We conducted a systematic review including all studies (with the exception of one case–control study) mentioned in the latest published systematic review on pharmacological treatments for bone loss in AN, and thus synthesizing literature published before March 2017 [ 24 ]. We then searched MEDLINE, Cochrane, PsycINFO, and Web Of Science databases following the PRISMA guidelines [ 25 ].

Study selection

We included studies mentioning medication to prevent or treat bone loss in patients with AN, published between March 1st, 2017 and October 31st, 2024: clinical studies (including randomized controlled trials), case series, cross-sectional studies. We confirmed that the definition of AN matched that of the corresponding version the Diagnostic and Statistical Manual of Mental Disorders for each publication date.

Search strategy

We used the following keywords in the Medical Subject Headings (MeSH) terms and/or title/abstract section: anorexia nervosa AND (osteopenia OR osteoporosis OR bone density OR bone loss) AND (prevention OR treatment OR medication OR therapeutic).

Quality assessment

Regarding quality and risk of bias, two reviewers (AL and CS) independently reviewed the papers’ titles, abstracts and full texts and resolved disagreements through discussion with a third reviewer (CB). The Centre for Evidence-Based Medicine guidelines were used with respect to quality criteria studies [ 26 ] were categorized into one of the following levels of evidence [ 27 ]: Level I, individual randomized controlled trial (RCT); level II, individual cohort study (including low quality RCT, i.e., < 80% follow-up); level III, individual case–control studies; level IV: case series (and poor quality cohort and case–control studies); level V: expert opinion without explicit clinical appraisal. To further assess the methodological quality of the RCTs included, we used the 13-item list proposed by Van den Berg et al. [ 28 ]. Items were scored as “yes,” “no,” or “unclear.” Equal weight was applied to all items with a summary score ranging from 0 to 13 and, 9/13 being used as cutoff for good quality studies, see Table 1 [ 27 ].

Terms and definitions

Bone mineral density is assessed using dual-energy X-ray absorptiometry (DXA) and Z-scores, rather than T-scores, are used before menopause. In this paper, we use the term osteoporosis for a cutoff Z-score of less than –2 SDs and osteopenia for a Z-score between –2 and –1 SDs, for clarity purposes. Indeed, in populations of adolescents with AN, Z-score is preferred to T-score, since it accounts for expected age-related changes in bone density. Between 18 and 25 years, Z-scores are approximately equivalent to T-scores. In premenopausal women after 25 years, there is no correlation between T-scores and clinical complications such as fractures and Z-scores are also widely used (the term “low Z-score for age” is sometimes preferred to osteoporosis).

Subsequently, based on our results and our own clinical experience, a collaborative protocol was designed by our medical team to help medical doctors manage patients with AN suffering from bone loss.

Results

Our search starting from March 2017 yielded 141 abstracts, from which 25 duplicates were removed. Previous reviews, key journals and reference lists of key papers were hand searched. Five additional eligible studies were identified using this method. We included 9 studies consisting of 5 double-blind RCTs, 2 controlled trials, 2 single-arm prospective studies and one cross-sectional study. In the latest systematic review [ 24 ], authors searched 675 studies and included 19 of them. Ten of the 19 studies included were double-blind randomized controlled trials (RCTs). The remaining studies consisted of prospective observational studies, five non-randomized controlled trials and one case–control study. The latter was excluded from this systematic review. In total, combining the 9 selected studies and the 18 previous papers from the systematic review, 27 papers were included (see Fig. 1 ). Among 1932 participants (all female), 1439 had AN and the remainder were healthy controls. The average length of follow-up for participants was 1 year. Table 2 reports the study characteristics for all included studies.

Outcome measures

The primary outcome measure was spinal (lumbar) BMD in all but three studies that measured remodeling serum [ 29 – 31 ]. Secondary outcome measures included hip, femoral neck, radius and total body BMD, measures of body composition, biological markers of bone turnover and fracture incidence. All of the included studies used DXA scanning for BMD measures. Most studies used areal BMD (aBMD) which was used for our analysis.

Other considerations: studies varied in their accounting for other variables affecting bone health, such as serum vitamin D levels and calcium intake at baseline, as well as supplementations during the study. Data on these topics is presented in Table 3 .

Monotherapies

Transdermal 17-β-estradiol

Transdermal estrogen does not undergo initial liver processing, thus not leading to downregulation of IGF1, as is the case with oral contraceptives. In a single-arm prospective study including 11 women with AN that received weekly transdermal patch with 17-β-estradiol (0.045 mg/day) and levonorgestrel (0.015 mg/day), lumbar spine and lateral spine BMD increased significantly over 6 months ( p < 0.05), while hip and femoral neck BMD did not(32). Another prospective study demonstrated that continuous transdermal 17-β-estradiol with 10 days of cyclic oral progesterone 100 mg/day in adolescent girls and young women with AN led to greater increases in lumbar aBMD and whole body BMD than observed in healthy controls, suggesting some bone accrual catch-up [ 22 ]. Physiologic doses of transdermal 17-β-estradiol or orally administered EE significantly increased spinal and hip BMD in adolescents with AN to levels seen in normal-weight healthy controls in another RCT. The effect was primarily driven by the group receiving transdermal 17-β-estradiol [ 23 ].

Oral ethynil-estradiol (EE)

One cross-sectional study [ 33 ] and a retrospective cohort study [ 34 ] found that adults with AN who took oral contraceptives (OC) had a significantly higher spine BMD ( p < 0.02) than those who had never taken OC. Similar results were shown in another cross-sectional study on all skeletal sites, even after multiple adjustments [ 35 ]. BMD improved with longer durations of OC use and shorter delays between disease onset and the start of OC. Patients with lower BMI showed the best bone tissue responses [ 35 ].

Nevertheless, BMD did not significantly increase in three studies following adolescents patients for between 3 months to over 1 year on oral contraceptives (35 μg/day EE) [ 36 – 38 ].

Testosterone

A 3-week regimen of transdermal testosterone given to young women with AN aiming for serum testosterone levels in the upper half of the normal range for women, led to an increase of C-terminal propeptide of type 1 collagen (PICP) levels compared to placebo ( p = 0.03). No change was seen for osteocalcin, bone-specific alkaline phosphatase and serum N-telopeptide levels [ 31 ].

DHEA

Dehydroepiandrosterone (DHEA) has been described as an “estrogen precursor” and is converted into estrogen and androgens. Two studies showed no significant effect of DHEA on BMD at any skeletal sites in young adult women with AN [ 39 , 40 ]. However, after 3 months, oral DHEA (given at 50 mg or 200 mg/day) significantly increased osteocalcin, a bone formation marker, and significantly decreased NTX levels (urinary N-telopeptides, a bone resorption marker) in young patients with AN [ 40 ].

rhIGF1

Recombinant human insulin-like growth factor-1 (rhIGF1) given subcutaneously (SC) to young women aged 18–29 years during 9 months significantly improved spinal BMD compared to placebo [ 41 ]. RhIGF1 given during 6 days at 30 µg/kg/day led to a significant increase in PICP (a bone formation marker) while not increasing bone resorption markers [ 30 ]. Given at the same dose during 9 days in adolescent patients, a significant increase in IgF1 and P1NP was noted [ 29 ].

Bisphosphonates

One study investigated alendronate in adolescents with AN [ 42 ]. After adjusting for weight gain, alendronate given 10 mg/day orally significantly increased femoral neck BMD following 1 year of treatment ( p = 0.02). Another study showed a significant increase of spinal BMD in adult women with AN who received risedronate given 5 mg/day orally ( p = 0.01) [ 43 ].

Teriparatide

Fazeli et al. investigated the effect of teriparatide (TPT; human PTH1–34) (20 μg/day SC) vs . placebo in older mature women with AN in a RCT [ 44 ]. They found a significant 6–10% increase in spine BMD after 6 months and an increase in serum P1NP levels in the TPT group. In a single-arm prospective study on 10 AN young adult patients, after 24 months of TPT treatment given at the same dose, BMD significantly improved by 13.5% in the spine ( p < 0.001) and 5% in the femoral neck ( p < 0.05) [ 45 ]. The BMD level of the total hip area showed no significant increase ( p = 0.33, total change = 4%).

Denosumab

Haines et al. investigated denosumab (60 mg subcutaneously at 0 and 6 months) against placebo in 30 ambulatory women with AN and aBMD T-scores < -1 [ 46 ]. Lumbar spine aBMD increased in the denosumab group vs. placebo ( p = 0.009). The mean (95% CI) increase in PA lumbar spine aBMD was 5.5 (3.8–7.2)% in the denosumab group and 2.2 (− 0.3–4.7)% in the placebo group. Femoral neck aBMD was similar between groups.

Vitamin K2

One study investigated the effect of 45 μg/day of Menatetrenone (MED, vitamin K2) [ 47 ]. MED significantly slowed the BMD decrease in young women with AN in comparison with placebo controls (−2.8% and −6.9%, respectively, p = 0.01).

Lactobacillus reuteri DSM17938 (L. reuteri)

A double-blind RCT assessed the role of L. reuteri: no statistically significant difference was found compared to the placebo group regarding the BMD recovery ( p = 0.057) [ 48 ].

Treatment combinations

ERT + DHEA

A combination of oral DHEA (50 mg/day) and ERT (20 μg EE/day and 0.1 mg levonorgestrel/day) led to a stabilization of lumbar spine and whole body BMD in the experimental group in comparison with a trend for a decrease in all BMD sites in the AN placebo controls [ 49 ]. The same combination studied years later did not significantly improve bone density, geometry, strength or bone turnover markers compared to placebo in younger female patients with AN with open epiphyses [ 50 ].

ERT + rhIgF1

Authors of a double-blind RCT found no benefit of using rhIGF1 at a dose of 30–46.88 µg/kg twice a day SC for 12 months over the use of transdermal 17-β-estradiol alone (except for the 6-month change in radial aBMD), despite a demonstrated increase in IGF1 levels in this group. The AN + ERT + rhIGF1 − group had greater increases in lumbar spine BMD ( p = 0.004) and BMD Z-scores than the AN + ERT + rhIGF1 + group. This difference was likely consequent to weight gain in the rhIGF1 − group, which was not seen in the rhIGF1 + group [ 51 ]. This differed from a previous study showing a significant increase in lumbar spine BMD in young female adults with AN compared with placebo, OC alone and rhIgF1 alone ( p < 0.05) [ 41 ].

Bisphosphonates and testosterone

In a double-blind RCT, oral risedronate given at 35 mg/week significantly increased spine ( p < 0.0001) and hip BMD ( p < 0.013) in adult women with AN compared with the combination of risedronate and transdermal testosterone, compared with transdermal testosterone alone and with placebo [ 52 ]. Risedronate alone significantly suppressed the bone turnover markers serum CTX ( p = 0.002) and P1NP ( p < 0.001).

Bisphosphonates and rhIgF1

Sequential therapy with daily SC rhIGF1 followed by oral risedronate increased lumbar spine BMD more than risedronate alone and placebo in a 12-month follow-up study in women aged 18–29 years with AN ( p < 0.05) [ 53 ]. BMD trended toward being higher in the risedronate alone group than placebo. Vertebral vBMD was higher and estimated strength trended toward being higher in the rhIGF1/risedronate compared to the placebo group ( p < 0.05). Neither hip or radial aBMD or vBMD, nor radial or tibial estimated strength, differed among groups.

Discussion

This review was motivated by the frequent need of practitioners facing a shortage of AN-specific evidence-based guidelines regarding low BMD treatment strategies, even more as the very clinical significance of BMD has been questioned. Indeed, BMD is a better proxy for lifelong secondary osteoporotic fracture risk in menopausal women than in pre-menopausal populations. This is starkly the case in children [ 54 ], as the mere concept of osteoporosis has been debated in the pediatric population [ 55 ]. However, other studies have found a strong link between peak bone mass and fracture risk [ 56 ]. Bone health events can occur years or even decades after the onset of the AN, a long time span compared to the studies we included. Data on bone health is even more scarce on boys and men, and on less-studied eating disorders with an impact on growth and bone health, such as avoidant restrictive food intake disorder (ARFID).

Even among the studies included, data remains patchy: the primary outcome in most studies was BMD change, rather than fracture incidence [ 14 , 57 ]. Existent studies lack statistical power, due to the relatively rare and belated occurrence of low trauma fractures. Despite our large initial search scope, no studies on boys and men were to be found.

There is insufficient data coverage on adolescents: only three studies show statistically significant evidence on female adolescents, both on relatively short time spans and small numbers [ 23 , 42 , 52 ].

While initiating care for patients with AN, primary focus is on refeeding and weight restoration as the main means to reverse osteoporosis risk. International recommendations on the subject that recommend cautious intervention weighing risk and benefits balance and focus on refeeding [ 58 , 59 ]. Nutritional optimization with special attention to adequate calcium intake, vitamin D supplementation, but also adequate protein, phosphate and magnesium intakes, as well as healthy exercise (avoiding overexertion or at-risk activities) are essential prerequisites [ 20 ]. In case oral calcium supplementation is needed because of low intake, long term use is current practice but has been debated due to adverse cardiovascular effects [ 60 , 61 ]. Attention is also needed to modifiable and non-modifiable risk factors for bone fragility: family history, other health conditions, smoking, and medications such as glucocorticoids.

Our findings do support the use of some medications for improving BMD in patients with BMD below −2SD, especially in persistent AN, if hormonal recovery becomes an elusive perspective. ERT, bisphosphonates, teriparatide and denosumab show the clearest significant effects. This corroborates known physiological mechanisms of secondary osteoporosis prevention and treatment in various clinical situations, on which treatment practices also rely: chronic inflammatory conditions, Turner syndrome, corticoid induced osteoporosis, menopause or post chemotherapy gonadic insufficiency [ 62 , 63 ]. The other molecules and combination trials in this study were performed on small numbers or with a modest time range or effect size, which makes them complex to recommend in the absence of larger studies.

For clinicians, treatment discussions and stakes widely vary according to age and skeletal growth considerations. We shall consider three life stage situations: adults and adolescents after physeal closure, adolescents before physeal closure, children with early onset AN.

In the adult and post-physeal closure adolescent population (bone age above 14 for girls and 16 for boys, or Risser stage 4 and above), avoiding the onset of osteoporosis is a major concern. ERT appears effective for women, but molecules and doses vary widely. Estrogens can be administered as natural estrogen (17-β-estradiol) in transdermal, gel or oral form, in association with natural progesterone. The transdermal form is generally preferred as there is no hepatic first passage, thus not downregulating insulin-like growth factor-1 [ 64 ]. A second option is oral ethinyl-estradiol (EE), a molecule found in contraceptive pills, in association with cyclic levonorgestrel, which is preferred as preserving bone health better than others forms of progestin [ 65 ] and which can be taken continuously if menses suppression is requested by the patient. Besides bone health, benefits of estrogens include cardiovascular health, sexual and genitourinary function, quality of life, and neuropsychological function [ 66 ]. Side effects of EE include increased risk of breast cancer and thromboembolic events, which seem less frequent with 17-β-estradiol. There are acceptability concerns specific to the AN population: fears of weight gain, reluctance regarding resumption of menses or medications identified with active sexuality can be barriers and need to be discussed on an individual basis [ 67 ].

Treating adolescents, especially before physeal closure, purports different conundrums vs. treating adults. Adolescence is a unique window of opportunity for buildup of bone mass, and adequate sexual hormones levels are critical for normal bone accrual. Weight restauration interventions often enable retrieval of sexual hormones and thus some degree of bone mass recovery; however, the high-stake situation could warrant a more aggressive treatment with an aim of complete BMD restauration. In female AN, among ERT, transdermal 17-β-estradiol seems to have the most favorable efficacy, safety and cost profile which makes it the molecule of choice for adolescents [ 63 ].

However, in growing adolescents with AN, achieving normal skeletal growth is also a major goal. Concerns that ERT could accelerate physeal closure and negatively impact statural growth have long restrained its use in this population. Outcomes of ERT in younger adolescents with open physes are conflicting. The route of administration and dose of ERT seem to matter to avert this risk. In particular, transdermal estrogen does not undergo hepatic first-pass metabolism as mentioned above.

Early onset AN is not covered by this study, ERT are discussed on a case-to-case basis and their indication is mainly pubertal induction. There are clinically based French guidelines for early onset AN only [ 68 ] Decisions are discussed in multidisciplinary team meetings and the usual treatment regimen includes low dose ERT [ 69 ].

In AN, bone active drugs such as bisphosphonates, both in IV and oral form, teriparatide or denosumab are restricted to treating osteoporotic fractures and preventing fracture reoccurrence. Regular clinical appraisal is crucial to screen for potential receivers: history of low trauma fracture, height assessment, pain assessment. As vertebral fractures can manifest with only slight symptoms, in patients with spinal pain, loss of height, or a history of undocumented vertebral fracture, spinal imaging should be carried out, with low-radiation exposure techniques such as EOSⓇ. Vertebral Fracture Assessment by DXA is not reimbursed in many health systems, and there are no specific recommendations for systematic spinal imaging in asymptomatic premenopausal women with low BMD [ 70 ].

Choice between various bone active agents relies on multiple considerations, including age, type of fractures (vertebral, non-vertebral), situation regarding pregnancy, but also route of administration and health system reimbursement eligibility. The latter often de facto makes teriparatide and denosumab second-line treatments in many countries [ 71 , 72 ]. The general safety profile of bone active drugs is good, although less studied outside menopausal women, especially regarding teratogenic risk [ 73 ]. Caution is needed for using anti-fracture agents in various specific subpopulations with AN. Among bisphosphonates, risedronate is the most studied molecule in our panel, as most frequently used in premenopausal women due to weaker binding capacity for hydroxyapatite and low clearance rate. Teriparatide can be used for adults with severe osteoporosis, and in vertebral fractures, but there are no extensive studies on patients with AN [ 45 , 74 ]. More recently, denosumab, especially used as second-line bone active treatment, in case of fracture recurrence, showed increase in BMD in a small study on adult women with typical and atypical AN [ 46 ]; however, its known rebound effect when stopped urges for special caution and mitigation strategies [ 75 ]. Bisphosphonates accumulate in the bone matrix, therefore, due to this persistent effect, long-term use is avoided in children and females before menopause [ 74 ] as the risks of bisphosphonates to the human fetus have not been well-established [ 76 – 78 ]. For adolescents and premenopausal women, there is a need for concomitant contraception when initiating therapy with bone agents which can complexify prescriptions and acceptability of these medications. Off-label prescription for these medications outside of menopause is also a significant challenge, as risk of adverse events needs to be carefully assessed [ 79 ].

In the pediatric population, IV bisphosphonates (pamidronate and zoledronic acid), rather than oral bisphosphonates, have been the cornerstone of osteoporosis treatment for decades, with proved effects on fracture rates. Their use, dose and regimen should be pondered according to age, medical history, clinical situation, and potential for medication-unassisted bone mass recuperation through efficacious refeeding, particularly in children and younger adolescents, by experienced clinicians and with appropriate peri infusion care [ 80 ]. In children and growing adolescents, there could be a concern that bisphosphonates, through their strong inhibition of bone remodeling, might interfere with the achievement of peak bone mass, thus requiring extra precautions and regular clinical assessment [ 81 ].

Thus, these treatment regimens need further research and validation on larger populations and subgroups with AN, and with a long follow-up duration, to help clinicians make appropriate and tailored treatment proposals.

Strengths and limitations

Our systematic review includes a comprehensive range of quality studies on bone loss treatments in AN, encompassing a wide diversity of clinical situations and medications. It allowed us to gain a nuanced understanding of the pros and cons of treatment in bone loss for patients with AN, tailored to bone loss and pubertal status. Our evidence-based guidance algorithm for the clinician gathers the evidence to this day for low bone density medication in AN. This type of guidance is urgently needed by clinicians who need to help patients make everyday decisions, sometimes only relying on local customs and practices.

There are some limitations; our analysis includes relatively small-size studies, on heterogeneous populations (typical and atypical AN, adolescents and adults) and short-time spans, sometimes lacking statistical power. Data is scarce on adolescents, a population, where bone loss is critical. There is no data on boys and men. Size effect is often modest, due to the time span not allowing to register bone health events that occur in later life. Long term cohorts would be needed to confirm these hypotheses.

Osteoporosis in an: management algorithm

In the light of our review as well as our own experience in the field, we propose a management algorithm as follows (Fig. 2 ).

For all individuals whatever the age

Comprehensive bone health assessment aiming at mitigation and improvement of modifiable risk factors : detailed medical history to identify personal and modifiable risk factors (e.g., family history of osteoporosis, smoking, prior fragility fractures, medications) and to exclude other at-risk conditions (inflammatory diseases, malabsorption etc.); nutritional interview and guidance; comprehensive clinical assessment; a first-line biochemical evaluation in accordance with current international guidelines [ 82 ] to exclude other secondary causes of osteoporosis: complete blood count, CRP, serum calcium, phosphate, magnesium, renal function, 25 OH vitamin D, alkaline phosphatase, liver function tests, TSH and FT4, gonadic function assessment, transglutaminase IgA. Further tests according to initial assessment should be added such as screening for diabetes mellitus or multiple myeloma in older men and women > 40 years.

- Nutritional optimization aimed at restoring all essential nutrients involved in bone metabolism with focus on adequate calcium intake aiming at 1 g/day for adults and 1.2 g/day for adolescents; vitamin D deficiency correction and supplementation (aiming at seric concentrations 30–50 ng/mL); adequate energetic intake, especially protein, fiber, vitamins, phosphate and magnesium intake [ 42 , 52 ].

- Healthy exercise, according to patients’ nutritional status. While complete bed rest is not to be recommended, overexertion is to be stopped. In patients with a history of AN and low BMD, exercise or activities increasing the risk of fall or fractures or high-impact exercise should be avoided.

- BMD should be assessed by DXA 12 months after onset of AN. Follow-up assessment should be every 2 years in case of initial anomaly or persistent malnutrition. Screening for vertebral fracture (low-dose radiation X rays or VFA by DXA where available) is to be performed in case of loss of height, spinal pain, undocumented history of vertebral fracture, in all patients, with special focus on patients with a low BMD and chronic AN [ 14 ].

For female patients with a BMD Z-score ≤ -2SD, in case menstrual function has not resumed after 12 months of multidisciplinary approach, the following treatments should be considered:

1) In adults or adolescents with secondary amenorrhea after physeal closure , ERT with transdermal or oral (according to availability and patient preference) 17-β-estradiol with cyclic progesterone . In case hormonal contraception is needed: oral contraceptive pill (continuous or cyclic) with a dose of 30 mcg ethinyl estradiol and levonorgestrel.

2) In adults or adolescents with secondary amenorrhea before physeal closure , discuss transdermal 17-β-estradiol with cyclic oral progesterone. Ethinyl estradiol should be avoided as its benefits have not been proved; however, in case contraception is required: the preferred means should be discussed: for bone mass catch-up optimization, 17ß-estradiol is preferred (in this case, associated with mechanic contraception); however, for practical purposes, oral contraceptives with daily 30 µg ethinyl estradiol and cyclic levonorgestrel is also an option.

3) In case of primary amenorrhea with delayed puberty and BMD ≤ -2SD, puberty induction with progressive 17-β-estradiol in increasing doses and natural progesterone in later puberty stages is to be considered.

For male patients, testosterone therapy should be discussed according to clinical, biological and BMD criteria.

In case of at least one occurrence of osteoporotic fracture (vertebral fractures, low-trauma fractures) patients should be referred to a bone specialist, and bone active drugs such as bisphosphonates (first line treatment), denosumab (recurring fractures) or teriparatide (vertebral fractures) are indicated. Eligibility criteria include: BMD Z-score ≤ -1SDs, an absence of counter indications (i.e., pregnancy and breastfeeding, severe renal insufficiency, dyscalcemia, allergy to the intended medication); in children, bisphosphonates should be discussed according to potential for bone mass recuperation. In women of childbearing age, effective contraception is needed throughout treatment. For bisphosphonates the recommended wash-out period before conception is not clearly defined. For denosumab, its bioavailability requires contraception to be continued for at least 5 months after the last dose.

We do not recommend bone active treatments for primary prevention of osteoporotic fractures in AN.

What is already known on this subject? Bone loss and bone fragility fractures are common in patients with a history of anorexia nervosa. Various medications such as hormonal replacement treatments or bisphosphonates are used to prevent these complications, however, without clear protocols, guidelines or indications.

What this study adds? This systematic review of medication for bone loss in anorexia nervosa allowed us to propose an algorithm for treatment across a wide range of clinical situations. In female patients, if bone mineral density is low, after a thorough assessment, in addition to nutritional optimization and avoidance of at-risk activities, estrogen replacement treatment can be prescribed, with estroprogestative oral contraceptives a possible alternative if they are needed. In case of bone fragility fractures, bisphosphonates, teriparatide and denosumab are valid treatment options. Age, pubertal status, growth, pregnancy desire and overall safety considerations are all major factors for the range of available treatment options.

Public significance statement

Bone loss is frequent in patients with AN but the strategy to prevent it is not consensual and formalized. This research provides a state-of-the-art review of evidence-based studies on medications for low bone mass in patients with AN as well as a clinical guidance algorithm for the clinician.

Abbreviations

Areal bone mineral density

Anorexia nervosa

Bone mineral density

Body mass index

Type I-C telopeptide breakdown products//C-terminal collagen cross-links

Deoxypyridinoline

Dehydroepiandrosterone

Dual-energy X-ray absorptiometry

Ethinyl-estradiol

Estrogen replacement therapy

Food and drug administration

Free triiodothyronine

N-telopeptide breakdown products

Oral contraceptive

Procollagen type I carboxyl-terminal propeptide

Procollagen type I N-terminal propeptide

Pyridinoline

Randomized controlled trial

Recombinant human insulin-like growth factor-1

Subcutaneously

Teriparatide

Vertebral fracture assessment

Author contributions

Alexandra LOISEL: Data curation, formal analysis, investigation, methodology, writing—original draft, and writing—review and editing; Anne LI: Data curation, formal analysis, investigation, methodology, and writing—original draft; Karine BRIOT: Validation and visualization; Marie Rose MORO: Validation and visualization; Chantal STHENEUR: Conceptualization, data curation, formal analysis, methodology, supervision, validation, and visualization; Corinne BLANCHET: Conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, validation, and visualization. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Availability of data and materials

“The data sets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.”

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical and informed consent

Not applicable, this being a review of published papers.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

“The data sets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.”