Endocrinology Metabolism

Low bone mass in premenopausal women

Does the patient have osteoporosis?

A history of low trauma fracture (s) is a sign of decreased bone strength and should always suggest the diagnosis of osteoporosis in a premenopausal woman.

A low bone mineral density (BMD) in an otherwise healthy premenopausal woman without a history of low trauma fractures may or may notreflect the deterioration in bone structure and strength that is characteristic of postmenopausal osteoporosis. Osteoporosis, as defined by microarchitectural deterioration and reduced bone strength, is more likely in premenopausal women with a known secondary cause of bone fragility or bone loss, such as estrogen deficiency or glucocorticoid excess.

There are currently no prospective studies evaluating whether measurement of BMD by dual energy x-ray absorptiometry (DXA) predicts fracture incidence in premenopausal women. However, as fracture incidence is orders of magnitude lower in premenopausal than postmenopausal women, low BMD by DXA is not as useful for the prediction of short-term (10 year) fracture risk in premenopausal women as it is in postmenopausal women.

The take home message is that an isolated low BMD measurement on a DXA scan should not be used to predict fracture risk or make treatment decisions in premenopausal women in the same way it is used in postmenopausal women.

When is BMD measurement indicated in a premenopausal woman?

Measurement of BMD is not indicated in healthy premenopausal women, unless they have a history of low trauma fracture or a known secondary cause of bone loss or osteoporosis.

What else could the patient have?

Alternative diagnosis: Osteomalacia may also present with low BMD, decreased bone strength and fractures. In osteomalacia, the collagen matrix of bone is undermineralized, most commonly due to severe vitamin D deficiency or hypophosphatemia. Rarely, severe calcium deficiency may be implicated.

Unusual fractures may also be related to underlying local bone pathology at the fracture site, such as malignancy, avascular necrosis, fibrous dysplasia, and other conditions.

Additional contributors: Osteoporosis in premenopausal women is usually associated with a secondary cause - a disease or medication exposure that causes bone fragility or bone loss.

Secondary Causes of Osteoporosis in Premenopausal Women

  • Premenopausal amenorrhea (e.g., pituitary diseases, medications, exercise induced amenorrhea)

  • Anorexia nervosa

  • Cushing’s syndrome

  • Hyperthyroidism

  • Primary hyperparathyroidism

  • Vitamin D, calcium, and/or other nutrient deficiency

  • Gastrointestinal malabsorption (celiac disease, inflammatory bowel disease, cystic fibrosis, postoperative states)

  • Rheumatoid arthritis, SLE, other inflammatory conditions

  • Connective tissue diseases:

    • Osteogenesis imperfecta

    • Marfan syndrome

    • Ehlers Danlos Syndrome

  • Diabetes (Types 1 and 2)

  • Renal disease

  • Liver disease

  • Hypercalciuria

  • Alcoholism

  • Other rare diseases includngmastocytosis, Gaucher disease, hemochromatosis,hypophosphatasia

Medications

  • Glucocorticoids

  • Immunosuppressants (e.g., cyclosporine)

  • Antiepileptic drugs (particularly cytochrome P450 inducers such as phenytoin, carbamazepine)

  • Cancer chemotherapy

  • GnRH agonists (when used to suppress ovulation)

  • Depo medroxyprogesterone acetate (DepoProvera)

  • Heparin

  • Other medications with probable relationships to osteoporosis: proton pump inhibitors, selective serotonin reuptake inhibitors, low molecular weight heparin.

Idiopathic Osteoporosis

In some young women with osteoporosis, no definable cause can be found after extensive evaluation. These women are said to have idiopathic osteoporosis (IOP). Several recent publications have described the bone structural characteristics of this group. Studies of biochemical and bone remodeling characteristics suggest that the pathogenesis of IOP is heterogeneous, with some women exhibiting evidence of low bone turnover while others have evidence of high bone turnover.

Key Laboratory and Imaging Tests

Interpretation of BMD by DXA in a premenopausal woman

BMD can be measured at the lumbar spine, total hip, femoral neck and distal radius.

The International Society for Clinical Densitometry (ISCD) recommends using Z scores (comparison to an age-matched reference population) rather than T scores, to categorize BMD measurements in premenopausal women, although T scores should be used in perimenopausal women. Young women with BMD Z scores below -2.0 should be categorized as having BMD that is “below expected range for age” and those with Z scores above -2.0 should be categorized as having BMD that is “within the expected range for age”. The categories of “osteoporosis” and “osteopenia” based upon T scores should not be applied to premenopausal women.

The International Osteoporosis Foundation (IOF) recommends use of Z score < -2 to define low bone mass in children, adolescents, those under 20 years, and some over 20 years in the context of delayed puberty. In contrast to ISCD, the IOF recommends use of T scores in those aged 20-50 years and suggest use of T score < -2.5 to define osteoporosis, particularly in those with known secondary causes or in the context of low trauma fractures that provide evidence of bone fragility.

Special Issues Affecting BMD Interpretation in Premenopausal Women

  1. Approximately 95% of bone mass is acquired during adolescence. However, BMD continues to increase slightly between the ages of 20 and 30, and peak bone mass is generally reached between ages 25-30. Thus, a BMD measurement may not reflect final peak bone mass in women under 25.

  2. Decreases in bone mass occur in the setting of normal pregnancy and lactation. BMD usually recovers during the 6-12 months after delivery or after weaning. Thus, when interpreting BMD measurements in a premenopausal woman, the clinician must take into account the timing of recent pregnancy and lactation.

Evaluation of Premenopausal Women with Low Trauma Fractures or Low BMD

Evaluation is recommended for:

  • Premenopausal women with a history of low trauma fracture(s), regardless of BMD

  • Premenopausal women with BMD Z score ≤ -2.0.

Identification of contributing conditions often helps to guide management of affected women. Careful clinical and laboratory evaluation is recommended.

Medical history should include information on:

  • Fractures

  • Family history of osteoporosis or kidney stones

  • Kidney stones

  • Menstrual history

  • Timing of recent pregnancy or lactation

  • Dieting and exercise behavior

  • Gastrointestinal symptoms

  • Medications (including OTC supplements)

Physical examination should see signs of:

  • Nutritional deficiency or eating disorder

  • Cushing syndrome

  • Thyroid hormone excess

  • Connective tissue disorders (e.g., osteogenesis imperfecta, Ehlers Danlos, Marfan syndrome)

  • Inflammatory conditions (e.g., rheumatoid arthritis, SLE)

Laboratory Evaluation in Premenopausal Women with Low Trauma Fractures or Low BMD

Laboratory evaluation to investigate potential secondary causes of osteoporosis should include:

Initial Laboratory Evaluation:

  • complete blood count

  • electrolytes, renal function

  • serum calcium, phosphate

  • serum albumin, transaminases, total alkaline phosphatase

  • serum TSH

  • serum 25-hydroxyvitamin D

  • 24 hour urine for calcium and creatinine

Additional Laboratory Evaluation as appropriate:

  • estradiol, LH, FSH, prolactin

  • PTH

  • 1.25-dihydroxyvitamin D

  • 24 hour urine for free cortisol, salivary free cortisol or dexamethasone suppression testing

  • iron/TIBC, Ferritin

  • celiac screen

  • serum/urine protein electrophoresis

  • ESR or CRP, serologies related to specific inflammatory disease

  • Bone specific alkaline phosphatase, Vitamin B6 (evaluation for hypophosphatasia)

  • Tryptase (evaluation for mastocytosis)

  • Genetic testing for conditions such as osteogenesis imperfecta, Ehlers Danlos syndrome, Gaucher disease, hypophosphatasia

Management and Treatment of the Disease

General recommendations regarding healthy diet and lifestyle are appropriate for all women.

Special recommendations based upon diagnostic category

Isolated low BMD

In women with isolated low BMD, no known secondary causes, and no history of low trauma fracture, treatment with specific medications for osteoporosis is almost never indicated.

Low BMD or low trauma fractures in a woman with a known secondary cause of osteoporosis

In those with a known secondary cause of bone fragility or bone loss, efforts should be made to directly address the secondary cause. Celiac disease, primary hyperparathyroidism, and inflammatory arthritis are examples of such a condition.

In some young women, secondary causes such as inflammatory/connective tissue diseases and glucocorticoid exposure, cannot be alleviated. In such cases, treatment with medications for osteoporosis can be considered on a case by case basis.

Low trauma fractures in a woman with no known secondary cause of osteoporosis

In some young women with low trauma fracture(s), no known cause can be found after extensive evaluation. These women are said to have idiopathic osteoporosis. Few data exist to guide management in these cases, but research is ongoing to better define pathogeneses and potential treatment options.

As for medication options, few data exist to guide medical management of osteoporosis in premenopausal women:

  • Medication options in premenopausal women include bisphosphonates (e.g., alendronate, risedronate, ibandronate, zoledronic acid) and teriparatide.

  • The United States Food and Drug Administration (FDA) has approved bisphosphonates and teriparatide only for the treatment of premenopausal women on glucocorticoids.

  • Selective estrogen receptor modulators (SERMS), such as raloxifene, should not be used to treat bone loss in menstruating women. They are weak estrogen agonists that block estrogen action on bone and lead to further bone loss.

  • Denosumab may be a treatment option as well, but safety and efficacy have not yet been defined in premenopausal women.

General recommendations regarding healthy diet and lifestyle

General measures are appropriate in most.

1. Calcium and vitamin D according to the current Institute of Medicine Recommendations (2010) for premenopausal women:

–Calcium: 1000 mg/day

–Vitamin D: 600 IU/day

2. Appropriate weight bearing exercise may lead to small increases in BMD, particularly at the hip

3. Maintenance of a healthy weight and avoidance of excess dieting

4. Lifestyle modifications: smoking cessation, avoidance of excess alcohol

Isolated low BMD in a premenopausal woman

A single low BMD measurement in a premenopausal woman may, or may not, signify an active bone losing state. Therefore, obtaining a follow-up BMD measurement in 1-2 years is an important aspect of appropriate management to determine whether BMD is declining, stable or improving. BMD may be low in a premenopausal woman because of factors that affected growth and accrual of peak BMD during adolescence; but these factors (e.g., nutrition or medication exposures) may no longer be active in adulthood.

BMD measurement may not reflect true peak premenopausal BMD after recent pregnancy or lactation, and in very young women who have not yet reached peak bone mass.

Premenopausal women with low but stable BMD are usually at low short-term risk for fracture. However, risk may be higher once they enter menopause.

Treatment with medications may be considered in rare cases of ongoing BMD loss or very low BMD measurements (Z score < -4.0)

Management in the setting of a known secondary cause of osteoporosis

Identification of a secondary cause (above) often helps to guide management of the affected individual.

For example:

Estrogen replacement can be considered in women with amenorrhea and estrogen deficiency. However, those with anorexia nervosa require nutritional rehabilitation in addition to return of normal menses to truly benefit bone mass. In patients with celiac disease, malabsorption of nutrients should be addressed directly with appropriate vitamin/mineral supplementation and gluten free diet. Endocrinopathies such as thyroid hormone excess, hyperparathyroidism, and pituitary abnormalities should be treated directly.

Bisphosphonates in premenopausal women

The United States FDA has approved bisphosphonates (alendronate and risedronate) only for premenopausal women on glucocorticoids. Although bisphosphonates have been shown to prevent bone loss and increase BMD in premenopausal women with various conditions, there are few data regarding long-term efficacy and safety, particularly in premenopausal women. Thus, they should be used only when absolutely necessary in premenopausal women.

Bisphosphonates accumulate in the maternal skeleton, cross the placenta, and may affect the fetal skeleton. While several reports document normal pregnancies and fetal outcomes in women receiving bisphosphonates, the potential for fetal abnormalities should be considered when prescribing bisphosphonates for a premenopausal woman.

Bisphosphonates may be considered, on a case by case basis, for those with low trauma fractures or ongoing bone loss.

Glucocorticoid-induced osteoporosis

Guidelines from the American College of Rheumatology suggest that bisphosphonates can be considered for the prevention and treatment of glucocorticoid-induced osteoporosis in premenopausal women taking at least 7.5 mg of prednisone or equivalent for 3 months or longer. Because of unknown long term effects and because of potential for harm to the fetus, they also urge great caution in the use of bisphosphonates in premenopausal women.

Teriparatide for premenopausal women

Studies have documented favorable BMD response to teriparatide in premenopausal women with glucocorticoid induced osteoporosis, anorexia nervosa and idiopathic osteoporosis. Because the long-term risks of this medication are unknown, use should be reserved for those at the highest risk for fracture. In women less than 25 year of age, documentation of fused epiphyses (completed bone growth) is recommended prior to consideration of teriparatide treatment. Continued treatment with an antiresorptive medication may be required to prevent bone loss after teriparatide cessation, even in women with normal gonadal function.

What’s the Evidence?/References

Hosmer, WD, Genant, HK, Browner, WS. "Fractures before menopause: a red flag for physicians". Osteoporos Int. vol. 13. 2002. pp. 337-41.

(Premenopausal fractures, although rare, may be an important indicator of underlying bone quality and future fracture risk. This paper presents data from the Study of Osteoporotic Fractures (SOF) demonstrating that women with a history of premenopausal fracture are 35 percent more likely to fracture during the postmenopausal years compared with women without a history of premenopausal fracture.)

Wu, F, Mason, B, Horne, A, Ames, R, Clearwater, J. "Fractures between the ages of 20 and 50 years increase women's risk of subsequent fractures". Arch Intern Med. vol. 162. 2002. pp. 33-6.

(In this cross-sectional study of 1284 postmenopausal women in New Zealand, a history of fracture between ages 20 and 50 was associated with a 74% increased risk of fracture after age 50 years.)

Lewiecki, EM, Gordon, CM, Baim, S, Leonard, MB, Bishop, NJ. "International Society for Clinical Densitometry 2007 Adult and Pediatric Official Positions". Bone. vol. 43. 2008. pp. 1115-1121.

http://www.iscd.org/official-positions/2013-iscd-official-positions-adult/.

Ferrari, S, Bianchi, ML, Eisman, JA, Foldes, AJ, Adami, S, Wahl, DA, Stepan, JJ, de Vernejoul, MC, Kaufman, JM. "Osteoporosis in young adults: pathophysiology, diagnosis, and management". Osteoporosis International. vol. 23. 2012. pp. 2735-2748.

(These references present recommendations from the International Society for Clinical Densitometry (ISCD) and International Osteoporosis Foundation (IOF) on the interpretation of DXA results in premenopausal women.)

Cohen, A, Recker, RR, Lappe, J, Dempster, DW, Cremers, S. "Premenopausal women with idiopathic low trauma fractures and/or low bone mineral density". Osteoporosis International. vol. 23. 2012. pp. 171.

(This paper presents information on the clinical and biochemical characteristics of premenopausal women with idiopathic osteoporosis (IOP) and those with idiopathic low BMD, in comparison to healthy premenopausal controls.)

Cohen, A, Dempster, D, Recker, R, Stein, EM, Lappe, JM. "Abnormal bone microarchitecture and evidence of osteoblast dysfunction in premenopausal women with idiopathic osteoporosis". J Clin Endocrinol Metab. vol. 96. 2011. pp. 3095.

(This paper describes analyses of transiliac crest bone biopsy samples obtained in 64 women with idiopathic osteoporosis or idiopathic low BMD, and 40 healthy controls. Affected women had substantial microarchitectural disruption and heterogeneous bone remodeling with some women exhibiting evidence of low bone turnover and possible osteoblast dysfunction while others had evidence of high bone turnover.)

Mautalen, C, González, D, Mazure, R, Vázquez, H, Lorenzetti, MP, Maurino, E, Niveloni, S, Pedreira, S, Smecuol, E, Boerr, LA, Bai, JC. "Effect of treatment on bone mass, mineral metabolism, and body composition in untreated celiac disease patients". Am J Gastroenterol.. vol. 92. 1997 Feb. pp. 313-8.

Lumachi, F1, Camozzi, V, Ermani, M, Nardi, A, Luisetto, G. "Lumbar spine bone mineral density changes in patients with primary hyperparathyroidism according to age and gender". Ann N Y Acad Sci. vol. 1117. 2007 Nov. pp. 362-6.

Miller, KK, Lee, EE, Lawson, EA, Misra, M, Minihan, J, Grinspoon, SK, Gleysteen, S, Mickley, D, Herzog, D, Klibanski, A. "Determinants of skeletal loss and recovery in anorexia nervosa". J Clin Endocrinol Metab.. vol. 91. 2006 Aug. pp. 2931-7.

Scholes, D, LaCroix, AZ, Ichikawa, LE. "Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adoles". Med. vol. 159. 2005. pp. 139.

Kaunitz, AM, Miller, PD, Rice, VM. "Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation". Contraception. vol. 74. 2006. pp. 90.

(These papers present data on the effect of underlying disease treatment on BMD. Some papers do not present data on premenopausal women, specifically).

Saag, KG, Emkey, R, Schnitzer, TJ, Brown, JP, Hawkins, F. "Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group". N Engl J Med. vol. 339. 1998. pp. 292-9.

(This trial of bisphosphonates for glucocorticoid-induced osteoporosis included 37 premenopausal women.)

Wallach, S, Cohen, S, Reid, DM, Hughes, RA, Hosking, DJ. "Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy". Calcif Tissue Int. vol. 67. 2000. pp. 277-85.

(This trial of bisphosphonates for glucocorticoid-induced osteoporosis included 17 premenopausal women.)

Cohen, A. "Should bisphosphonates be used in premenopausal women". Maturitas. vol. 66. 2010. pp. 3-4.

(This paper reviews potential benefits and risks of bisphosphonate use in premenopausal women.)

Levy, S, Fayez, I, Taguchi, N, Han, JY, Aiello, J. "Pregnancy outcome following in utero exposure to bisphosphonates". Bone. vol. 44. 2009. pp. 428-30.

(This prospective cohort study included 21 women exposed to bisphosphonates during or shortly before pregnancy.)

Grossman, JM, Gordon, R, Ranganath, VK, Deal, C, Caplan, L. "American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis". Arthritis Caree Res (Hoboken). vol. 62. pp. 1515-26.

(These recommendations from the American College of Rheumatology include guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis in premenopausal women.)

Langdahl, BL, Marin, F, Shane, E, Dobnig, H, Zanchetta, JR. "Teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: an analysis by gender and menopausal status". Osteoporos Int. vol. 20. 2009. pp. 2095-104.

(A recent study comparing teriparatide and alendronate for glucocorticoid-induced osteoporosis included some premenopausal women [Saag KG, Shane E, Boonen S, Marin F, Donley DW, et al. 2007 Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 357:2028-39]. Overall, teriparatide was associated with significantly greater increases in lumbar spine and total hip BMD and resulted in significantly fewer incident vertebral fractures than alendronate. In the paper cited here, subgroup analyses showed that BMD responses were similar in premenopausal women as in men and postmenopausal women, but no fractures occurred in either premenopausal group.)

Fazeli, PK, Wang, IS, Miller, KK, Herzog, DB, Misra, M, Lee, H, Finkelstein, JS, Bouxsein, ML, Klibanski, A. "Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa". J Clin Endocrinol Metab.. vol. 99. 2014 Apr. pp. 1322-9.

Cohen, A, Stein, EM, Recker, RR. "Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study". J Clin Endocrinol Metab. vol. 98. 2013. pp. 1971-81.

Cohen, A, Kamanda-Kosseh, M, Recker, RR, Lappe, JM, Dempster, DW, Zhou, H, Cremers, S, Bucovsky, M, Stubby, J, Shane, E. "Bone Density After Teriparatide Discontinuation in Premenopausal Idiopathic Osteoporosis". J Clin Endocrinol Metab.. vol. 100. 2015 Nov. pp. 4208-14.

(Continued treatment with an antiresorptive medication may be required to prevent bone loss after teriparatide cessation, even in women with normal gonadal function.)
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