INTRODUCTION — Few data exist to guide clinical care for premenopausal women who have low bone density (Z-score less than or equal to -2.0) and/or fragility fractures. The guidelines for the treatment of osteoporosis based on bone mineral density (BMD) in postmenopausal women do not generally apply to premenopausal women, as the relationship between bone mass and fracture in premenopausal women is not the same as in postmenopausal women. BMD alone should not be used to define osteoporosis in a premenopausal woman but, like fragility fractures, is an indication for further evaluation.

This topic reviews the evaluation and treatment of premenopausal osteoporosis. The epidemiology and etiology are reviewed separately. (See "Epidemiology and etiology of premenopausal osteoporosis".)

SCREENING — Bone density screening is not routinely recommended for premenopausal women [1]. However, healthy, premenopausal women with concerns about bone health or risk factors for osteoporosis may request a bone mineral density (BMD) test and seek expert advice if results are abnormal.

We agree with the International Society of Clinical Densitometry (ISCD) guidelines (table 1) that suggest BMD screening for premenopausal women under the following circumstances [1]:

●History of a fragility fracture

●Known secondary causes of osteoporosis (table 2)

Although routine BMD screening of pre- or perimenopausal women is not recommended, some studies have shown beneficial outcomes when BMD testing is combined with education about bone health [2,3]. As an example, in one study of 669 premenopausal women (3.8 percent with fractures), osteoporosis education coupled with BMD testing resulted in positive lifestyle changes [2].

EVALUATION — The etiology of low bone mass in premenopausal women may be related to failure to attain expected peak bone mass, previous bone loss, or ongoing bone loss. The goal of the evaluation is to distinguish between these groups since the treatment approach differs.

The evaluation typically begins with a history, physical examination, and biochemical testing with the goal of searching for potential primary and secondary causes. If this initial evaluation is unrevealing, it is possible that the patient has an unknown primary cause of poor bone quality and/or suboptimal peak bone mass or that insults to the skeleton occurred in the past and are no longer active. (See 'Additional evaluation' below.)

Initial evaluation — Premenopausal women who come to medical attention in the setting of a fragility fracture or after learning of low bone mineral density (BMD; Z-score ≤-2.0) should have an evaluation to identify potential secondary causes. Premenopausal women with a fragility fracture require this evaluation for secondary causes even in the absence of low BMD. A secondary cause of osteoporosis can be found in a substantial proportion of premenopausal women with osteoporosis [4,5], and identification of a contributing condition often helps to guide management of the affected individual.

Secondary etiologies are presented in the table (table 2). Most of these conditions can be excluded with a careful history and physical examination. Laboratory evaluation may help to diagnose secondary causes of osteoporosis, such as renal or liver disease, hyperthyroidism, hyperparathyroidism, Cushing's syndrome or subclinical hypercortisolism, early menopause, celiac disease and other forms of malabsorption, idiopathic hypercalciuria, or, rarely, connective tissue disorders.

We suggest that all premenopausal women with low BMD and/or fragility fracture have the following basic tests (table 3):

●Complete blood count

●Calcium, phosphate, creatinine

●Alkaline phosphatase, aminotransferases

●25-hydroxyvitamin D

●Thyroid-stimulating hormone (TSH)

●24-hour urine for calcium and creatinine

Additional evaluation — Women who have abnormalities on the initial laboratory testing, suspicious findings on history and physical examination, or unexplained osteoporosis and fracture after the initial evaluation require additional laboratory tests (table 3). As examples:

●Women with anemia, low urinary calcium excretion, and/or low vitamin D levels should be evaluated for celiac disease and other etiologies of malabsorption. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Metabolic bone disorders'.)

●Serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D should be measured in patients with hyper- or hypocalcemia, hyper- or hypocalciuria, or a history of renal stones. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

●Urinary cortisol excretion or other testing for Cushing's syndrome should be conducted if Cushing's syndrome is suspected and also in patients with unexplained osteoporotic fracture, since patients with subclinical hypercortisolism (mild hypercortisolism without clinical manifestations of Cushing's syndrome) are at risk for low BMD and fractures. (See "Evaluation and management of the adrenal incidentaloma", section on 'Subclinical Cushing's syndrome' and "Establishing the diagnosis of Cushing's syndrome" and "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Bone loss'.)

Some women may have genetically determined low peak bone mass. Other women may have accrued less bone than expected due to insults to the skeleton (eg, medications, poor nutrition, estrogen deficiency) that occurred during adolescence and are no longer present at the time of evaluation. In either case, these women are expected to have stable BMD, even though BMD is low. This is in contrast to women with continued declines in BMD who may have an ongoing secondary cause. Serial BMD measurements, if available, are helpful in making this distinction.

If there is only a single measurement of BMD, obtaining serum or urinary markers of bone turnover may provide useful information. Specimens must often be collected fasting in the morning hours for proper interpretation. If markers of resorption are elevated above the premenopausal range, ongoing bone resorption is more likely. However, the range of normal is wide in premenopausal women, making interpretation difficult [6]. Additionally, markers of bone resorption must be interpreted according to the patient's age. Adolescence and young adulthood are characterized by active bone modeling and physiologic increases in markers of bone turnover. Additionally, elevated bone turnover markers are expected after a recent fracture. (See "Normal skeletal development and regulation of bone formation and resorption" and "Bone physiology and biochemical markers of bone turnover" and "Use of biochemical markers of bone turnover in osteoporosis".)

Premenopausal women with bone fragility and no identifiable etiology after extensive evaluation for secondary causes are said to have idiopathic osteoporosis.

TREATMENT

Our approach — Calcium, vitamin D, and weightbearing exercise are recommended for most women with premenopausal osteoporosis. (See 'Lifestyle modification' below.)

Pharmacologic therapies that have shown antifracture efficacy in postmenopausal women include bisphosphonates, selective estrogen receptor modulators (SERMs), teriparatide, abaloparatide, denosumab, and romosozumab. However, there are very few data available to guide clinicians in the use of these medications in premenopausal women. As a result, treatment with medications is usually reserved for those with fracture(s), active bone loss, and/or known ongoing secondary causes of osteoporosis and bone loss.

●Fractures or accelerated bone loss – Women with fractures or accelerated bone loss in the setting of hypogonadism may benefit from estrogen replacement. Replacement of estrogen in hypogonadal, premenopausal women may have beneficial effects on bone mass [7-9]. However, oral reproductive hormone replacement has been shown to be ineffective in most studies examining bone mass in anorexia nervosa (AN), a more complex condition [9-11]. (See "Anorexia nervosa: Endocrine complications and their management", section on 'Bone loss'.)

In women with normal gonadal function or in those who cannot take estrogen, bisphosphonates and teriparatide are generally the drugs of choice in the rare cases when pharmacologic therapy is indicated (fragility fractures or marked bone loss [approximately ≥4 percent/year, depending on clinical setting]). Both are US Food and Drug Administration (FDA) approved for young women receiving chronic glucocorticoids. (See 'Glucocorticoids' below.)

For women found to have a secondary cause of osteoporosis, the management often depends on the underlying etiology. (See 'Secondary causes' below.)

●Without fractures or accelerated bone loss – In premenopausal women with low bone mineral density (BMD) alone (without fractures, known secondary causes for low BMD, or evidence of marked bone loss), pharmacotherapy is almost never indicated. It is reasonable to treat with calcium and vitamin D and repeat a bone density study in one to two years.

Lifestyle modification — In general, lifestyle modifications should be encouraged for all women with low bone mass since peak bone mass may not occur until the fourth decade [12,13]. Positive lifestyle changes include adequate calcium and vitamin D intake (1000 mg of calcium from diet and supplements and 600 international units vitamin D3 daily) (table 4) [14-16], regular weightbearing exercise and physical activity [17], cessation of smoking [18,19], achievement of normal body weight, avoidance of excessive dieting and wide swings in weight [20], and moderation in alcohol consumption [21]. (See "Overview of the management of osteoporosis in postmenopausal women" and "Calcium and vitamin D supplementation in osteoporosis".)

If there is a history of nephrolithiasis, additional evaluation (such as measurement of 24-hour urinary calcium excretion, serum calcium, and PTH) is required before making supplementation recommendations. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)

An observational study of 16 premenopausal women with idiopathic osteoporosis (mean age 35.7 years) followed for 3.1 years and treated with increased dietary calcium and physical activity revealed significant increases in lumbar spine and femoral neck BMD after two or three years [22].

Intensity of exercise — There is no convincing evidence that high-intensity exercise such as running is of greater benefit than lower-intensity exercise such as walking. Because enjoyment of the regimen is important (the benefits of exercise are quickly lost after its cessation), we recommend that women pick a regular, weightbearing exercise regimen that they enjoy to facilitate long-term compliance. Excessive exercise in premenopausal women may lead to weight loss and/or hypothalamic amenorrhea, exacerbating low bone density. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Endocrine' and "Overview of the management of osteoporosis in postmenopausal women", section on 'Exercise'.)

Pharmacologic therapies

Estrogen — In women with hypogonadism from various causes, treatment should be directed at the underlying cause. If resumption of menses is unlikely, estrogen therapy is usually the treatment of choice. (See "Evaluation and management of primary amenorrhea" and "Evaluation and management of secondary amenorrhea" and "Functional hypothalamic amenorrhea: Evaluation and management", section on 'Estrogen replacement' and "Management of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Anorexia nervosa: Endocrine complications and their management".)

The risks of estrogen therapy in premenopausal women are lower than in older postmenopausal women (see "Menopausal hormone therapy: Benefits and risks"). However, risks must be considered related to age and other clinical factors. (See "Menopausal hormone therapy and the risk of breast cancer".)

Bisphosphonates — There are few randomized, controlled trials of antiresorptive therapy in premenopausal women with osteoporosis. Studies demonstrating the benefits of bisphosphonates in the prevention and treatment of glucocorticoid-induced osteoporosis included some premenopausal women. As a result, both alendronate and risedronate have been approved by the FDA for use in premenopausal women receiving glucocorticoids.

Although bisphosphonates have been shown to prevent bone loss in young women with various conditions [23-32], it should be kept in mind that long-term efficacy and safety data, as well as fracture data, are scarce in premenopausal women. The decision to initiate treatment with bisphosphonates in any premenopausal woman should be made on a case-by-case basis with consideration of individual fracture risk and potential medication effects. In general, the goal should be for the shortest possible duration of bisphosphonate use, particularly in light of data regarding rare potential risks of long-term use, such as osteonecrosis of the jaw (ONJ) [33,34] and atypical femoral fractures [34]. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Risks specific to oral bisphosphonates'.)

In an experimental rat model, bisphosphonates crossed the placenta and accumulated in fetal bones [35,36]. The following case reports and case series provide some human data on the safety of bisphosphonates in pregnancy [37]:

●A pharmacovigilance study in England reported two normal pregnancies in women taking alendronate [38].

●A woman with malignant hypercalcemia, treated during the third trimester of pregnancy with intravenous (IV) pamidronate, gave birth to a normal fetus [39].

●Two women with osteogenesis imperfecta (OI) treated with long-term IV pamidronate prior to conception had normal pregnancies, deliveries, but mild neonatal abnormalities (transient hypocalcemia in one fetus and bilateral talipes equinovarus in the other) [40].

●Four cases of women with OI or polyostotic fibrous dysplasia who received prolonged IV pamidronate therapy prepregnancy showed no adverse maternal or fetal outcomes [41].

●Nine women with pregnancy-associated osteoporosis who received at least one bisphosphonate for a median duration of 24 months were studied [32]. There were no negative pregnancy outcomes reported in the five women who received bisphosphonates and went on to have subsequent pregnancies.

●Twenty-one women receiving oral or IV bisphosphonates during the first trimester of pregnancy (n = 15) and six women who stopped bisphosphonate therapy within three months prior to conception were compared with 21 healthy pregnant controls. There were no differences in any pregnancy or neonatal outcomes, including major congenital anomalies [42].

●A larger case-control study including 36 women exposed to bisphosphonates found no major teratogenic effects but reported an increased frequency of nonspecific neonatal complications among women who also had systemic disease [43].

Nevertheless, the rodent data coupled with the long half-life of bisphosphonates in bone suggest that use of these agents in reproductive-age women should be limited to special circumstances [44,45].

Parathyroid hormone analogs

●Teriparatide – PTH (1-34) (teriparatide) stimulates bone formation as well as resorption, and intermittent administration stimulates formation more than resorption, thus benefitting patients with osteoporosis (see "Parathyroid hormone/parathyroid hormone-related protein analog for osteoporosis"). Subcutaneous teriparatide has been shown to increase BMD in women with gonadotropin releasing hormone (GnRH) analog-induced estrogen deficiency [46], in premenopausal women taking glucocorticoids [47,48], in premenopausal women with idiopathic osteoporosis [49], in women with pregnancy and lactation-associated osteoporosis [50,51], in women with anorexia nervosa [52], and in adults with osteogenesis imperfecta [53,54]. Teriparatide is approved for the treatment of premenopausal women with glucocorticoid-induced osteoporosis. No study has been large enough to document fracture risk reduction. (See 'Glucocorticoids' below and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Parathyroid hormone' and "Parathyroid hormone/parathyroid hormone-related protein analog for osteoporosis", section on 'Overview of approach'.)

●Abaloparatide – There are no data on the efficacy or safety of abaloparatide (a PTH-related protein [PTHrP] analog) in premenopausal women. (See "Parathyroid hormone/parathyroid hormone-related protein analog for osteoporosis".)

In postmenopausal women, PTH/PTHrP analog treatment is generally followed by antiresorptive therapy to prevent bone loss after medication cessation. Few data are available to guide treatment options for premenopausal women after cessation of teriparatide:

●One study documented BMD gain in premenopausal women who resumed menses after cessation of both long-acting GnRH analog and PTH (1-34) [55].

●In another study of 15 premenopausal women with idiopathic osteoporosis and normal gonadal function followed for 2.0±0.6 years after teriparatide cessation, BMD declined 4.8 percent at the spine and remained stable at the hip [56]. Older age and more robust response to teriparatide tended to predict spine bone loss. These data suggest that women with idiopathic osteoporosis will require antiresorptive treatment to prevent bone loss after teriparatide.

●In contrast, in a retrospective review of 33 women with severe pregnancy and lactation-associated osteoporosis who were followed for three years, there were no BMD differences between those treated with teriparatide only (n = 20) versus those treated with teriparatide followed by antiresorptive therapy (n = 13) [57]. These data suggest that women with pregnancy and lactation-associated osteoporosis who regain normal menstrual cycles may be able to maintain BMD after the cessation of teriparatide without taking antiresorptive therapy.

Teriparatide has been associated with osteosarcoma in rodent studies. Use of this medication should be avoided in those at increased risk of osteosarcoma (including those with Paget disease, prior radiation, growing bones [open epiphyses], or unexplained elevation in alkaline phosphatase). Thus, this medication should be used with great caution in young women, and use should be avoided in those with delayed growth or open epiphyses. (See "Parathyroid hormone/parathyroid hormone-related protein analog for osteoporosis", section on 'Contraindications/precautions'.)

Other

●SERMs – SERMs such as raloxifene and tamoxifen should not be used to treat osteoporosis in menstruating women, as they block estrogen action on bone, leading to further bone loss [58,59]. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis".)

●Calcitonin – There are few published studies on the safety or efficacy of salmon calcitonin in young women. However, in one double-blind study of 120 perimenopausal women treated with 100 international units intranasal calcitonin or placebo spray daily, there was no improvement in BMD or bone markers [60].

●Denosumab – Denosumab is a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor that is approved for the treatment of osteoporosis in postmenopausal females and males at high risk for fracture, and for the treatment of glucocorticoid-induced osteoporosis in adults at high risk for fracture. Because of data documenting bone loss and possible increased risk of fracture after stopping denosumab, sequential administration of another osteoporosis medication (eg, a bisphosphonate) to prevent rapid bone loss is advised [61]. This sequential treatment paradigm will then lengthen a course of treatment, which has particular implications for a young population. Animal studies indicate that denosumab may cause fetal harm. Prescribing information states that use of effective contraception is advised during therapy and for at least five months after the last dose. (See "Denosumab for osteoporosis", section on 'Candidates for therapy'.)

In one study, sequential use of teriparatide followed by denosumab in 32 premenopausal women with idiopathic osteoporosis was associated with significant continued gains in BMD. Denosumab treatment for 24 months after teriparatide led to additional average gains of 7±3 percent at spine and 5±3 percent at the total hip [62].

Case reports have also documented large BMD increases with denosumab treatment in patients with pregnancy and lactation-associated osteoporosis [63,64].

High risk for ongoing bone loss or fracture

Glucocorticoids — General measures to minimize glucocorticoid-induced bone loss, as well as calcium and vitamin D supplementation, are reviewed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'General measures' and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D'.)

In addition to general measures, we suggest combination estrogen-progestin contraception (if not contraindicated) or transdermal hormone therapy in premenopausal women with amenorrhea who are initiating or taking glucocorticoids. Glucocorticoids reduce the production of sex steroids. As a result, it is logical to replace these hormones if the patient is deficient (as suggested by symptoms such as amenorrhea in premenopausal women).

The addition of pharmacologic therapy is based upon fracture risk (eg, history of fractures, age, dose, and duration of glucocorticoids). We largely agree with the American College of Rheumatology (ACR) therapeutic guidelines for premenopausal women of childbearing potential, which suggest treatment in premenopausal women at moderate to high fracture risk [65]. Moderate to high fracture risk includes women with prior osteoporotic fracture, as well as women with very low BMD (Z-score <-3) or with very rapid bone loss who are continuing glucocorticoid treatment at ≥7.5 mg of prednisone or equivalent per day for ≥6 months. Treatment with oral bisphosphonates or teriparatide are preferred in this population and in the setting of use of effective contraception [65]. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Premenopausal women and younger men' and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Choice of therapy'.)

Premenopausal women on chronic glucocorticoids for a variety of inflammatory or autoimmune conditions present a special therapeutic challenge. Fracture risk in premenopausal women on glucocorticoids is not clearly defined and may differ from reported fracture risk in other glucocorticoid-treated populations. In premenopausal women included in the clinical trials for glucocorticoid-induced osteoporosis, fractures are generally infrequent in both treated and control groups [48,66-68]. In addition, the potential pregnancy-related risks of pharmacologic therapy are unique to premenopausal women.

Bisphosphonates are very efficacious agents in the prevention and treatment of glucocorticoid-induced bone loss, but few premenopausal women were included in the large clinical trials [69]. Two clinical trials that included premenopausal women with corticosteroid-treated connective tissue diseases (CTD) used the less potent first-generation bisphosphonate, etidronate, as the antiresorptive agent and found successful maintenance of BMD in the women taking the drug [70,71].

Premenopausal women with glucocorticoid-induced osteoporosis benefit from treatment with teriparatide [47]. In a secondary analysis of a randomized trial of teriparatide versus alendronate in patients with glucocorticoid-induced osteoporosis, the increase in lumbar spine BMD was significantly greater in the teriparatide group for both premenopausal (7.0 versus 0.7 percent) and postmenopausal (7.8 versus 3.7 percent) women [48]. In premenopausal women, fractures were infrequent in both treatment groups. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Parathyroid hormone'.)

Chemotherapy — For women with chemotherapy-induced menopause and low BMD (T-score <-2.5) and/or fragility fracture, we suggest bisphosphonates.

Premenopausal women receiving chemotherapy for breast cancer represent another group at risk for rapid bone loss. The incidence of chemotherapy-induced amenorrhea can range from 26 to 89 percent depending on the drugs used [72]. Treatment with CMF (cyclophosphamide, methotrexate, and fluorouracil) and GnRH agonists such as goserelin induce amenorrhea. However, amenorrhea induced by goserelin is reversible in the majority of patients following cessation of therapy but permanent in most patients treated with CMF [73]. (See "Ovarian failure due to anticancer drugs and radiation".)

Women who have premature menopause as a result of chemotherapy can lose bone rapidly compared with women who maintain menses throughout chemotherapy [74]. Prospective studies demonstrate bone loss at one year varying from 4 to 8 percent in the spine and 2 to 4 percent at the hip in premenopausal women who become amenorrheic after receiving adjuvant chemotherapy with CMF [23,24,75]. (See "Acute side effects of adjuvant chemotherapy for early-stage breast cancer", section on 'Chemotherapy-induced amenorrhea'.)

In postmenopausal women with estrogen-dependent breast cancer, tamoxifen preserves bone mass and reduces symptomatic fractures [76,77]. However, in premenopausal women, this is not the case. In a population cohort study comparing 1761 premenopausal women with breast cancer with an age-matched control group of 1761 women without breast cancer, women with breast cancer on tamoxifen had a significantly higher fracture risk than the control women [78]. In a prospective study with three years of follow-up, women treated with tamoxifen who continued to menstruate following chemotherapy lost 4.6 percent of lumbar spine BMD while those who did not receive tamoxifen remained stable [58]. Women who became amenorrheic after chemotherapy lost less bone at the lumbar spine on tamoxifen compared with amenorrheic controls but still had significant declines (6.8 percent BMD loss compared with 9.5 percent loss in nontreated women). Despite its antiestrogenic effects on the breast, tamoxifen has some estrogen-agonist effects in the skeletons of postmenopausal (but not premenopausal) women. In premenopausal women, tamoxifen blocks estrogen action on bone.

Bisphosphonates successfully prevent bone loss in premenopausal women with newly diagnosed breast cancer treated with chemotherapy and/or tamoxifen [23-28]. (See "Use of osteoclast inhibitors in early breast cancer".)

Aromatase inhibitors (AIs) are now used with increasing frequency in women with estrogen receptor-positive breast cancer. AIs are associated with significant bone loss and increased risk of fracture. The management of AI-induced bone loss is reviewed in detail elsewhere. (See "Evaluation and management of aromatase inhibitor-induced bone loss".)

Secondary causes — In cases where a secondary cause is found, treatment should be targeted to that specific disease or abnormality. As examples:

●Eliminating gluten from the diet of young women diagnosed with celiac disease leads to marked improvement in BMD [79-83]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)

●Parathyroidectomy in premenopausal women with primary hyperparathyroidism results in improvement in BMD. (See "Primary hyperparathyroidism: Management", section on 'Subclinical bone disease'.)

●Women with bone loss due to depot medroxyprogesterone acetate have improvement in BMD upon discontinuation of the drug [84,85].

●Oral contraceptive therapy given to women with oligo- or amenorrhea, women with endometriosis on GnRH therapy [86], women with endometriosis or fibroids on GnRH receptor antagonist therapy [87], or women experiencing perimenopausal bone loss [88] significantly reduces bone loss.

●The SERM, raloxifene, stops bone loss in premenopausal women receiving GnRH agonist therapy for uterine leiomyomas [89]. This is in contrast to premenopausal women with breast cancer and chemotherapy-induced amenorrhea who continue to lose bone despite therapy with another SERM, tamoxifen. (See 'Chemotherapy' above.)

●Nutritional recovery and resumption of normal menstrual function appears necessary for skeletal recovery in patients with AN (see "Anorexia nervosa: Endocrine complications and their management"). However, data suggest that transdermal estradiol [90] or a combination of dehydroepiandrosterone (DHEA) and an oral contraceptive pill [91] may improve or preserve bone mass in some patients with AN.

Primary causes

●Osteogenesis imperfecta in adults – Osteogenesis imperfecta (OI) is a heterogeneous disorder with widely variable disease severity. Although most affected patients are diagnosed in childhood, fractures leading to diagnosis of OI can occur in young adulthood. Fewer data are available to guide treatment in adults with OI than in children with OI. Studies have been small and, thus, do not definitively address fracture endpoints [53,54,92]. (See "Osteogenesis imperfecta: An overview".)

●Hypophosphatasia in adults – Hypophosphatasia is an inborn error of metabolism due to mutation of the gene encoding tissue nonspecific alkaline phosphatase. It is a very heterogeneous disorder with widely variable disease severity. In adults, hypophosphatasia can present as osteomalacia, chondrocalcinosis, and/or stress fractures [93]. Treatment is reviewed separately. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Other causes'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Osteoporosis (The Basics)")

●Beyond the Basics topics (see "Patient education: Osteoporosis prevention and treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●We do not suggest routine screening of premenopausal women for osteoporosis (Grade 2C). Bone mineral density (BMD) measurement is recommended for premenopausal women with known secondary causes of osteoporosis or history of a fragility fracture (see 'Screening' above). The goals of the evaluation of premenopausal women with low bone mass or fragility fracture are to rule out secondary causes and to determine if there is ongoing bone loss. (See 'Evaluation' above.)

●Many secondary etiologies of low BMD can be determined based upon history and physical examination. In addition, all women with low BMD or fragility fracture should have laboratory testing as part of the investigation for potential secondary causes (table 3). Based on the results of the history, physical examination, and basic laboratory testing, more extensive testing may be indicated. (See 'Evaluation' above.)

●We recommend adequate calcium, vitamin D, and exercise in all premenopausal women with low bone mass (Grade 1B). Most women require elemental calcium (from diet and supplements) of 1000 mg daily and vitamin D, 600 international units daily. (See 'Lifestyle modification' above.)

●In women with a secondary cause of low BMD, treatment should be targeted to that cause. (See 'Secondary causes' above.)

●For premenopausal women taking or initiating glucocorticoids who have amenorrhea, we suggest oral contraceptive or hormone replacement therapy (if not contraindicated) (Grade 2B). Bisphosphonates are an option for women with fragility fractures or substantial bone loss (approximately ≥5 percent/year, depending on clinical setting) while receiving glucocorticoids (7.5 mg daily prednisone equivalent for 3 to 6 months or longer). Teriparatide is an alternative option for such women, as long as epiphyses are fully fused. (See 'Estrogen' above and 'Glucocorticoids' above and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Choice of therapy'.)

Potential short- and long-term risks, as well as potential effects on the fetus, should be considered as part of the decision to use bisphosphonates or teriparatide for the treatment of premenopausal osteoporosis. (See 'Bisphosphonates' above and 'Other' above.)

●For women with chemotherapy-induced early menopause with low BMD (T-score <-2.5) and/or fragility fracture, we suggest bisphosphonates (Grade 2B). (See 'Chemotherapy' above and "Use of osteoclast inhibitors in early breast cancer", section on 'Bisphosphonates and anti-RANK-ligand'.)

●In the absence of evidence of accelerated bone loss, we suggest conservative management without specific medical therapy for premenopausal women with isolated low bone mass (no fragility fractures and no known secondary cause) (Grade 2C). These women should have a repeat bone density measurement in one to two years to ensure stable BMD. (See 'Treatment' above.)

●In premenopausal women, idiopathic osteoporosis with repetitive fragility fractures and/or bone loss on serial BMD measurements is rare. Rather than empiric treatment, we prefer referral to metabolic bone specialists for further evaluation.