Too young to break? A rare case of premenopausal osteoporosis

Discussion

Osteoporosis is mainly a disease of the old. Osteoporosis in young adults and children is rare.

Data from the National Health and Nutrition Examination Survey (2017–2018) revealed that the age-adjusted prevalence of osteoporosis at either the femur neck or lumbar spine or both among adults aged 50 years and above was 12.6% and was higher among women (19.6%) compared with men (4.4%).1 There are no data currently available on the prevalence of premenopausal osteoporosis in the USA.

A clinical diagnosis of osteoporosis in a postmenopausal female may be made in the presence of either a fragility fracture, which is defined as occurring spontaneously or from minor trauma, such as a fall from a standing height or less, or a T-score less than or equal to 2.5 SDs at any site based on bone mineral density (BMD) measurement by DEXA. There is some controversy around the diagnosis of osteoporosis for premenopausal females and which BMD to use for diagnosis; however, the presence of fragility fracture is indicative of underlying osteoporosis; this in combination with a low T-score is consistent with osteoporosis as with our patient.

The majority of cases of premenopausal osteoporosis have a secondary cause ranging from a hormonal disorder, nutritional deficiencies such as in anorexia nervosa and coeliac disease, and exposure to drugs that cause bone loss, particularly glucocorticoids. Premenopausal females in whom a secondary cause has been ruled out have idiopathic osteoporosis.

Hormonal disorders that can cause secondary osteoporosis include hyperparathyroidism, hyperthyroidism, pituitary prolactinoma and Cushing’s syndrome. Pituitary prolactinoma may cause osteoporosis through reduced levels of gonadotropin-releasing hormone. Drugs such as corticosteroids, heparin, antiepileptics, thyroid replacement therapy or anticoagulants can also lead to osteoporosis. Corticosteroids cause decreased osteoblastic action. Certain antiepileptics such as phenytoin cause loss of bone.

Another uncommon cause of osteoporosis that is often overlooked is genetic mutations. This is more common in the younger population with osteoporosis. In premenopausal women, 58%–88% had genetic causes as the aetiology of osteoporosis versus 37%–54% in postmenopausal women, hence being an important cause of osteoporosis especially in the younger population.2 There are many genes that may play a role in bone remodelling; however, it is unclear which mutations play a direct role in osteoporosis.

In a study by Richards et al, he assessed 36 000 single-nucleotide polymorphisms in 150 candidate genes and found that only 9 genes (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B and TNFSF11) showed robust evidence of association with BMD at either the femoral neck or lumbar spine and a further 4 genes (SPP1, SOST, LRP5 and TNFRSF11A) were associated with fracture risk.3 In our patient’s case, she had an LRP-5 mutation.

LRP5 is a transmembrane low-density lipoprotein receptor which with LRP6 combines with Frizzled receptor to act as co-receptors for members of the Wnt family. The LRP5 gene loss-of-function mutations result in an LRP5 protein that is unable to transmit chemical signals along the Wnt signalling pathway. The Wnt signalling pathway decreases, which leads to disruption of regulation of BMD, leading to osteoporosis at a young age.4 The reverse is true as well. A gain-of-function mutation in LRP5 causes an autosomal dominant disorder characterised by high bone density.5

LRP5 loss of function is therefore associated with Juvenile osteoporosis syndrome. LRP5 gene abnormalities are also responsible for ophthalmic abnormalities, namely, osteoporosis-pseudoglioma syndrome and familial exudative retinopathy.6

Pharmacological treatment options for osteoporosis in the postmenopausal female include antiresorptive agents such as bisphosphonates, selective oestrogen receptor modulators, hormone replacement and anabolic agents such as parathyroid analogues; however, these agents have not been tested adequately in the premenopausal female of childbearing age, and consequences on future pregnancy have not been studied. Lifestyle modifications such as diet and exercise are encouraged for all individuals with osteoporosis and for reversal of secondary conditions causing osteoporosis for those with identifiable causes. Adequate supplementation with calcium and vitamin D is crucial.

Specifically for individuals with LRP5-related osteoporosis, antiscelrosin therapy with romosuzomab may be beneficial, given that it works through the same Wnt pathway; however, there are no data available to support this theory. Romosuzomab has also been associated with increased cardiovascular risk. Teriparatide, which is a parathyroid analogue, also works by stimulating the Wnt pathway.

Our patient was started on teriparatide, alongside vitamin D supplementation, and repeat DEXA 6 months after therapy revealed significant improvement in BMD.

This case report highlights the importance of thorough work-up in a patient with premenopausal osteoporosis. This can help determine the best treatment that would improve the quality of life of a patient with premenopausal osteoporosis.