There is no agreed definition of osteoporosis in pre-menopausal women. The International Society for Clinical Densitometry recommends using Z -score, and women with Z -scores of −2.0 or lower should be defined as having a bone density that is ‘below the expected range for age’. The diagnosis is more readily made in the presence of a low-trauma fracture. The relationship between low bone mineral density (BMD) in young pre-menopausal women and its associated fracture risk is not the same as in older women with a low BMD. Between 50% and 90% of pre-menopausal women will have an underlying secondary cause, the most common being eating disorders, anorexia nervosa and use of glucocorticoids. Management should focus on identifying the underlying cause and treating it where possible. The use of pharmacological therapy under other circumstances should be considered carefully. Women with only low BMD and no other risk factors probably require no pharmacological intervention. Those with low BMD and secondary causes or with a severely low BMD, or those who have fragility fractures, may require treatment with anti-resorptive agents, which can include oestrogen, bisphosphonates, calcitonin, calcitriol or anabolic therapy with teriparatide. Selective oestrogen receptor modulators (SERMs) should be avoided as they cause further bone loss in menstruating women. Alendronate and risedronate have been licensed for use in glucocorticoid-induced osteoporosis. These drugs accumulate in the human skeleton and have been shown to cross the placenta and accumulate in newborn rats. The effects on human pregnancy are unclear, although normal pregnancies have been reported.
Pre-menopausal women with osteoporosis should be followed up until the BMD is stable, which can usually be ascertained by follow-up scans at 18–36-month intervals.
Osteoporosis in post-menopausal women has been well studied and documented, whereas that in pre-menopausal or young women has received little attention due to the lower incidence of the disorder and limited information to explain its aetiology.
Low bone mass in pre-menopausal women may result from a lower peak bone mass, bone loss after the attainment of peak bone mass or a combination of the two.
Peak bone mass
This is largely genetically determined (80%) but lifestyle factors can contribute further to maximising the genetic potential. Peak bone mass is attained at the end of the second decade. Studies indicate that body weight, physical activity and normal pubertal development act as independent determinants of peak bone mass . Calcium, vitamin D, mechanical loading and normal pubertal development are probably the most important determinants not only of peak bone mass, but also of bone strength and, when optimum, allow for the full genetic potential to be achieved.
Since peak bone mass has a Gaussian distribution, 14% and 2% of women will have values, which are 1 or 2 standard deviation (SD) below the mean. This does not necessarily mean that individuals at the lower end of the distribution have increased risk of fracture, since the correlation between reduced bone mass in pre-menopausal women and fracture risk is less robust than in post-menopausal women.
Definition of pre-menopausal osteoporosis
The diagnosis of osteoporosis in pre-menopausal women can be readily made in the presence of a low-trauma fracture. However, there is no agreed definition of osteoporosis in pre-menopausal women. In post-menopausal women, the presence of osteoporosis can be determined, in the absence of a fracture, by assessing bone mineral density (BMD) T -scores. However, this World Health Organization (WHO) criteria of bone density based on T -scores is not applicable to pre-menopausal women and should not be used to categorise such women into normal, osteopenic or osteoporotic groups. Furthermore, since the relationship between T -scores and fracture risk in pre-menopausal women is less clear than in post-menopausal women, a conservative approach is needed to arrive at a diagnosis even with low bone density to avoid unnecessary treatment. It is thus important to have a clear idea when to undertake a BMD estimation in pre-menopausal women. If BMD is to be measured, then the International Society for Clinical Densitometry recommends using Z -scores . Women with a Z -score of −2.0 or lower should be defined as having a bone density that is ‘below the expected range for age’ and a Z -score of above –2.0 should be categorised as ‘within the expected range for age’. The term ‘osteopenia’ should be avoided in this age group and a diagnosis of osteoporosis is best made if a BMD is accompanied by a low-trauma fracture(s). When interpreting BMD, it is important to bear in mind that body size and stature will influence dual energy X-ray absorptiometry (DEXA) measurements, leading to an underestimation of true volumetric bone density in people of short stature.
Definition of pre-menopausal osteoporosis
The diagnosis of osteoporosis in pre-menopausal women can be readily made in the presence of a low-trauma fracture. However, there is no agreed definition of osteoporosis in pre-menopausal women. In post-menopausal women, the presence of osteoporosis can be determined, in the absence of a fracture, by assessing bone mineral density (BMD) T -scores. However, this World Health Organization (WHO) criteria of bone density based on T -scores is not applicable to pre-menopausal women and should not be used to categorise such women into normal, osteopenic or osteoporotic groups. Furthermore, since the relationship between T -scores and fracture risk in pre-menopausal women is less clear than in post-menopausal women, a conservative approach is needed to arrive at a diagnosis even with low bone density to avoid unnecessary treatment. It is thus important to have a clear idea when to undertake a BMD estimation in pre-menopausal women. If BMD is to be measured, then the International Society for Clinical Densitometry recommends using Z -scores . Women with a Z -score of −2.0 or lower should be defined as having a bone density that is ‘below the expected range for age’ and a Z -score of above –2.0 should be categorised as ‘within the expected range for age’. The term ‘osteopenia’ should be avoided in this age group and a diagnosis of osteoporosis is best made if a BMD is accompanied by a low-trauma fracture(s). When interpreting BMD, it is important to bear in mind that body size and stature will influence dual energy X-ray absorptiometry (DEXA) measurements, leading to an underestimation of true volumetric bone density in people of short stature.
Assessment of fracture risk
In pre-menopausal women with a low BMD, the risk of fracture is not the same as in older women with a low BMD because pre-menopausal women are oestrogen replete, have greater muscle mass, thicker cortices, a normal trabecular connectivity, lower bone turnover and fewer falls compared to post-menopausal women. While the short-term risk of fracture in pre-menopausal women with a low Z -score, for example, –2.0 is low, the risk may be higher when other risk factors are present.
A low BMD in young women is associated with an increased risk of low trauma and stress fractures compared with women with normal BMD, even though the relationship between BMD and fracture is less clear in this age group .
The diagnosis of osteoporosis is often more secure when there is a history of minimal trauma fracture and a low BMD.
In pre-menopausal women with a Colles fracture, the non-fractured radius and the lumbar spine have significantly reduced BMD compared with matched, non-fracture controls. However, BMD may not be reduced in some young women, especially those on high-dose glucocorticoids for auto-immune disease .
Evaluation of pre-menopausal osteoporosis
In pre-menopausal women with low-trauma fracture or low BMD, an underlying cause is often present that may have either affected the accrual of optimal peak bone mass, and/or led to increased bone loss following attainment of peak bone mass. The prevalence of secondary causes may vary depending on the setting and varies from 50% to 90%. Peris et al . found that 44% of patients referred to an outpatient rheumatology department had secondary osteoporosis and that 56% had idiopathic osteoporosis.
The most common causes of secondary osteoporosis in pre-menopausal women are shown in Table 1 and the most important ones are discussed later. In most cases, a thorough medical history and clinical examination will provide clues about the underlying secondary cause. The history should include information about family history, previous fractures, onset of menarche, amenorrhoea or oligomenorrhoea, pregnancy and duration of lactation, diet and exercise, gastrointestinal (GI) symptoms, lifestyle behaviour and medication. An examination of the patient may provide additional clues such as features of Cushing’s syndrome, height loss or a kyphotic deformity to indicate underlying vertebral fractures, blue sclerae and hyperelasticity of skin and joints indicative of a connective tissue disorder such as osteogenesis imperfecta. In those with suspected height loss or kyphosis, there may be a need for spinal radiographs or DEXA-based vertebral fracture assessment. X-rays should be examined carefully to see if the vertebral deformities identified represent a vertebral fracture or some other pathology such as Scheuermann’s disease, which is not associated with an increased risk of fracture. In many individuals, the history and examination may not offer sufficient clues, in which case it is important to identify secondary cause by appropriate laboratory tests.
| Endocrine disorders |
|
| Gastrointestinal |
|
| Marrow-related disorders |
|
| Connective tissue disorders |
|
| Organ transplantation |
|
| Inflammatory disorders |
|
| Medication |
|
| Lifestyle |
|
|
Laboratory tests
Since the occurrence of an underlying secondary cause is high, all young women with minimal trauma fracture or low BMD with a Z -score of−2.0 should be thoroughly evaluated with investigations shown in Table 2 . These will identify individuals with hyperthyroidism, hyperparathyroidism, Cushing’s syndrome, hypogonadism, osteomalacia, malabsorption, liver disease, coeliac disease and idiopathic hypercalcuria. If a secondary cause is not identified, a bone biopsy may be indicated in pre-menopausal women with a history of low-trauma fracture. This may identify unsuspected causes, such as mastocytosis, and provide clues about bone turnover.
|
|
Endocrine disorders, anorexia, eating disorders and amenorrhoeic states
Anorexia nervosa and bulimia have an onset at any time from adolescence through to the fourth decade of life and are associated with a significant loss of bone mass. Bone density is reduced by more than 2.5 SD at either the hip or the spine in 38% of women with anorexia nervosa and by more than 1 SD in 92% of such patients . The loss of bone mass observed in adult women with anorexia is probably attributed to bone loss. Adult women having anorexia nervosa with disease onset in adolescence have much lower bone mass than those with adult-onset anorexia nervosa due to an interference with the normal process of bone mineral accretion, leading to a permanent deficit . Several metabolic disorders occur in anorexia nervosa that may adversely impact on the skeleton, which include deficiencies in oestrogen, excessive endogenous cortisol production, reduced insulin-like growth factor 1 (IGF-1), protein/energy malnutrition and secondary hyperparathyroidism as a consequence of low dietary calcium or vitamin D intake. The degree of low bone mass found in women with anorexia nervosa is more severe than that seen in women with hypothalamic amenorrhoea who are of normal height .
A number of studies, although not all, have suggested that, in anorexia nervosa, bone turnover markers are characterised by a decrease in osteoblast function (bone formation) and an increase in osteoclast function (bone resorption), suggesting that bone remodelling is uncoupled .Dominguez et al. , in a longitudinal study, showed that osteocalcin concentration did not differ significantly from those in the control subjects but after nutritional rehabilitation there was a significant increase in serum osteocalcin. In the same population, the resorption marker urinary N-terminal telopeptides (NTX) was high in anorexic patients compared with controls at admission. Following nutritional rehabilitation, there was a decrease in NTX concentration and the pattern observed was that of an initial recovery in bone formation followed by suppression of resorption. Such a pattern indicates that therapy with anti-resorptive agents, such as oestrogens, may not be effective in this condition in the absence of appropriate nutritional therapy and explains why such women taking the oral contraceptive pill continue to have fractures and fail to show a significant increase in bone density.
With regard to bisphosphonates, Miller et al . administered a 9-month course of treatment with risedronate to 10 adult women with anorexia nervosa and compared the results with published data from 40 control women studied by the same group of investigators. They found an increase in the lumbar spine (but not the hip) BMD in those subjects given risedronate, compared to a decrease in controls. Golden et al . conducted a double-blind randomised trial comparing alendronate 10 mg daily with placebo in 32 adolescents with anorexia nervosa, all of whom received calcium and vitamin D supplementation and multidisciplinary treatment for their eating disorder. Femoral neck and lumbar spine BMD increased by 4.4% and 3.5%, respectively, in the alendronate group, compared with an increase of 2.3% and 2.2%, respectively, in the control group. The authors observed that body weight was the most important determinant of BMD and that BMD was significantly higher in subjects who were weight-restored compared with those who remained at low weight. However, larger randomised controlled trials are required to test the efficacy of bisphosphonates in anorexia nervosa and until they have been done, and the long-term safety assessed, bisphosphonates should not be routinely used in patients with anorexia nervosa.
Glucocorticoid-induced bone loss
The side effects from the use of glucocorticoids for long periods of time include weight gain, truncal obesity, proximal myopathy, impaired healing, adrenal insufficiency, steroid withdrawal syndrome, thinning of the skin with increased fragility and ecchymosis, fluid retention, hyperglycaemia, hypokalaemia, hypertension, hyperlipidaemia, osteonecrosis, osteoporosis and fractures, particularly vertebral fractures.
Glucocorticoid-induced osteoporosis is probably the most common iatrogenic form of osteoporosis
Mechanism of glucocorticoid-induced bone loss and fractures
Glucocorticoids have both a direct and an indirect effect on the skeleton. The direct effects on the skeleton include those on the osteoblasts, osteocytes and osteoclasts. Glucocorticoids act on osteoblast to reduce their number and function; the pool of cells available to differentiate into osteoblasts is reduced and osteoblast maturation is impaired. These steroid hormones encourage bone marrow stromal cells, the precursors of osteoblasts, to differentiate towards the adipocyte lineage. The production of type 1 collagen by mature osteoblasts is decreased, leading to a reduction in bone matrix available for mineralisation. In addition, glucocorticoids lead to apoptosis of osteoblasts and osteocytes . Apoptosis of osteocytes will disrupt the mechano-sensory role of these cells by disrupting the osteocyte–canaliculi network, which repairs bone micro-damage.
The early direct response of glucocorticoids on mature osteoclasts is to increase osteoclast survival by decreasing osteoclast apoptosis. This may account for the early enhanced bone resorption with glucocorticoids . The suggestion that osteoclast function may be increased by secondary hyperparathyroidism has not been confirmed .
The indirect actions of glucocorticoids, which may stimulate bone resorption, include loss of gonadal function, reduced intestinal absorption of calcium by antagonising actions of vitamin D, inhibition of renal tubular reabsorption of calcium leading to renal hypercalcuria, a decrease in growth hormone (GH) and altered GH/IGF-1 axis.
Bone loss in glucocorticoid-induced osteoporosis is biphasic with a more rapid loss in the first year followed by a slower annual loss. In the first 12 months of glucocorticoid exposure, bone loss is about 6–12% but may be as high as 20–30% in trabecular bone , which may explain why fractures are more common in cancellous-rich bones such as the vertebral bodies, ribs and femoral neck. Patients on long-term glucocorticoids have a normal distribution of BMD but with a mean value significantly less than found in the normal population, indicating that all patients exposed to glucocorticoids are subjected to some degree of bone loss.
Fractures in glucocorticoid-induced osteoporosis occur at higher BMDs than with post-menopausal women , suggesting that bone quality is reduced. The early rapid loss of bone reduces trabecular thickness and connectivity, which may not be reflected in BMD, and explains why there is no direct relationship between BMD and fracture risk in glucocorticoid-induced osteoporosis .
The true prevalence of fractures in patients on glucocorticoids is not known but cross-sectional studies indicate that 30–50% of patients taking glucocorticoids chronically will experience a fracture. As in post-menopausal osteoporosis, vertebral fractures may remain asymptomatic.
Although fractures can occur early following the use of glucocorticoids, the incidence is also related to the dose and duration of exposure . There is probably no safe dose as an increase in vertebral fracture is noted with prednisolone doses as low as 2.5 mg per day, but the risk is greater at higher doses and with longer duration of use .
Management of glucocorticoid-induced osteoporosis
The use of glucocorticoids in certain clinical situations may be lifesaving and, therefore, obligatory; however, the dose and duration should be kept to a minimum to reduce the potential toxicity associated with these drugs. All individuals administered with glucocorticoids, including pre-menopausal women, should be given adequate information about the reasons for the use of the drug, the side effects and complications as outlined earlier and the need to carry either an Alert bracelet or a steroid card if they are to be on long-term glucocorticoids.
- (a)
General measures: patients should be given advice about lifestyle factors, the need for weight-bearing exercise and adequate calcium and vitamin D intake with supplementation if necessary.
- (b)
Specific therapy: primary prevention and treatment guidelines have been proposed by the Royal College of Physicians and the American College of Rheumatology (ACR) . The Royal College of Physicians Guidelines recommend bisphosphonates in primary prevention in younger people with a BMD T -score of less than −1.5 who are to be given oral glucocorticoids for 3 months or more, irrespective of the dose. In addition, treatment is also recommended if serial BMDs show a loss of BMD of >4% after 1 year. The ACR recommends primary prevention with bisphosphonate in patients prescribed glucocorticoids for more than 3 months at a dose of prednisolone 5 mg or equivalent. In addition, ACR guidelines recommend the use of bisphosphonates in all subjects with a BMD T -score less than –1.0 on DEXA scanning.
Aminobisphosphonates are the most commonly used drugs in the primary or secondary prevention of glucocorticoid-induced osteoporosis, which have been shown to have anti-fracture efficacy in patients with an age range of 18–85 years. However, the number of pre-menopausal women in these studies has been relatively small and the effect in this population is assumed to be similar to that observed in the overall population.
Both risedronate 5 mg a day and alendronate 10 mg a day have been shown to prevent bone loss and reduce vertebral fractures . Individuals who cannot tolerate oral treatment, or where oesophageal disease precludes the use of oral bisphosphonates, then intravenous therapy with pamidronate, ibandronate or zoledronate can be considered. The use of bisphosphonates, however, should be considered carefully in women of childbearing age and, where possible, a bisphosphonate with the shortest half-life should be used. There is no evidence that calcium alone or active vitamin D analogues either prevent fractures or preserve BMD .
Since glucocorticoid-induced osteoporosis is dominated by a reduction in bone formation, then anabolic therapy with intermittent parathyroid hormone (PTH) would appear to be especially effective and this has been shown to be the case in an 18-month trial of teriparatide versus alendronate, in which teriparatide treatment group had fewer vertebral fractures compared with the alendronate group (0.6% vs. 6.1%, p < 0.004). There were no differences in non-vertebral fractures between the groups .
Related posts:
Inflammatory osteoarthritis of the hand
Prevention and cure of rheumatoid arthritis: Is it possible?
Rheumatologic sequelae and challenges in organ transplantation
Evidence-based management of rapidly progressing systemic sclerosis
Treatment-resistant inflammatory myopathy
Primary angiitis of the central nervous system: differential diagnosis and treatment
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
