Learning objectives
- •
There is no consensus on the diagnostic criteria of osteoporosis in premenopausal women.
- •
The relationship between BMD and fractures is not as well established in premenopausal as it is in postmenopausal women.
- •
In premenopausal women, the diagnosis of osteoporosis should be considered only if the patient has sustained one or more unequivocal fragility fractures.
- •
There are many causes of low bone mass in premenopausal women.
The case study
Reasons for seeking medical help
- •
FD is 32 years old. She is a full-time bank teller. She is experiencing sudden onset of severe pain in both hip joints anteriorly, in the groin, and the buttocks, the right side more than the left one. The pain is worse when she stands up, and weight bears, particularly on the right side. She ranks the pain as 7–8 on a scale of 1–10 with 1 being the mildest pain and 10 being the most severe excruciating pain.
- •
Initially it was felt that she fractured one or both hips, but plain X-rays revealed neither fractures, nor osteoarthritic changes, nor deformities of the hip joints, nor any abnormality of both femoral heads. There was nevertheless evidence of reduced bone density of both proximal femurs, more pronounced on the right side.
- •
The pain started spontaneously, got progressively worse, is now interfering with her daily activities, and causing her to be unsteady. She also now has to use a cane to ambulate. She fell a couple of times a week ago and had several near-falls. She was told that the pain will gradually subside, but it has not, it worsened.
Past medical and surgical history
- •
She always enjoyed good health and until this present illness led a physically active lifestyle. For the past few weeks, she had to curtail her physical activities because of the pain she is experiencing. She is on no medication except for the occasional nonsteroidal antiinflammatory/analgesics she is getting over the counter. She is, however, reluctant to take them. The pain is more bearable when she uses hot/cold patches and transdermal nerve stimulation. She does not want to take opioids to relieve the pain.
Lifestyle
- •
She used to lead a physically active lifestyle and exercised regularly. She ran the marathon three times.
- •
She had a good appetite, and her weight was steady. Now both are decreasing.
- •
She used to sleep well, without any medication, but has not done so since the pain started.
- •
No cigarette smoking, no caffeine intake, no soda drinks, and no recreational drugs
- •
Her menstrual periods have always been regular.
Medication(s)
- •
None apart from NSAIDs and nonnarcotic analgesics, which now are no longer effective at controlling the pain.
Family history
- •
Negative for osteoporosis.
- •
She is happily married and has three children aged 12, 10, and 5 years. All are in good health.
Clinical examination
- •
Weight 120 pounds, height 62″.
- •
No significant clinical findings, except for marginal tenderness along the proximal end of both femurs, the right more than the left.
- •
No localizing neurologic findings. Range of motion of both hips maintained but painful. The pain is exacerbated by weight bearing. No sensory deficits. Evidence of mild muscle wasting in both legs, especially the right side and more so proximally. No fasciculations. Tendon reflexes preserved. Both plantar responses down-going. No clinical evidence of arthropathies.
DXA scan and radiological results
- •
Z -scores:
- ○
Left femoral neck −2.8, left total hip −2.6.
- ○
Right femoral neck −2.9, right total hip −2.7.
- ○
Upper 4 lumbar vertebrae −1.7.
- ○
- •
VFA: no evidence of vertebral compression fractures.
- •
FRAX: Not done given the patient’s age and localized demineralization.
- •
Plain X-rays of both hips show localized, ill-defined areas of bone demineralization of the upper femurs, the right more than the left.
- •
There is no evidence of fractures. Femoral heads intact on both sides.
Multiple choice questions
- 1.
FD’s probable diagnosis is:
- A.
Osteoporosis of both proximal femurs.
- B.
Osteopenia of the lumbar vertebrae.
- C.
Idiopathic transient osteoporosis of the hips.
- D.
Avascular necrosis of the femoral heads.
- E.
Bilateral atypical femoral shaft fractures.
Correct answer: C
Comment:
Unlike “Postmenopausal Osteoporosis” which is a well-established disease state with clear diagnostic criteria, well-defined trajectory, known complications, accepted thresholds to initiate therapy, multiple treatment modalities, and well-known anticipated treatment outcomes, premenopausal “low bone mass for given age” is rather nebulous.
The term “osteoporosis” should not be applied to premenopausal women unless there is evidence of at least one fragility fracture or two trauma-induced fractures. The International Society for Clinical Densitometry (ISCD) also recommends that the term “Osteopenia” not be used. Instead, the preferred terminology is based on the Z -score which compares the patient’s BMD to that of a reference population matched for the patient’s age, gender and, if available, ethnic group.
A threshold Z -score of −2.0 is used to classify premenopausal patients into two categories: “Low bone mineral density for given age” if the Z -score is −2.0 or lower or “within expected range for given age” if the Z -score is higher. The term “osteoporosis” therefore is not appropriate: FD sustained neither a fragility fracture, nor the required two traumatic fractures to qualify for the diagnosis of osteoporosis. In this respect VFA can be a useful addition to DXA scans in young adults as it may identify previously undiagnosed fragility fractures.
Transient osteoporosis of the hip is a rare, poorly understood cause of pelvic pain which affects both sexes. It is characterized by bone loss in the proximal femur on one or both sides. It may affect other joints in the leg. It usually presents as acute, severe sudden onset pain in the affected hip aggravated by standing on the affected leg and partially alleviated by lying down.
It is usually spontaneously relieved in most cases within 6–12 months. While the disease is active, bone loss takes place and may lead to fractures. In pregnant women, it tends to be more common during the last 3 months of pregnancy.
Its cause is not known. Bone marrow edema often can be visualized by imaging techniques, especially MRI. The diagnosis is one of exclusion: secondary causes of low bone mass must be first excluded. Given the transient nature of the illness, its real incidence is probably underestimated, and the diagnosis is often missed especially during pregnancy as the risks of radiographic imaging may deter clinicians from pursuing imaging studies.
There are no evidence-based treatment modalities for idiopathic transient osteoporosis with fracture risk reduction as the outcome. Its treatment is nonspecific and geared to minimizing symptoms and preventing injuries to the weakened bone. Weight bearing should be restricted or temporarily avoided. Walking aids help reduce weight bearing and may prevent falls and fractures from occurring. Water exercises relieve weight bearing and facilitate movement. NSAIDs may reduce any inflammation present and relieve the pain, at least partly. Physical therapy helps maintain strength and flexibility. A well-balanced diet with sufficient calcium and vitamin D also may help healing. Routine screening for idiopathic transient osteoporosis is not recommended in either premenopausal women or men under the age of 50 years. Similarly, neither osteoanabolic, nor antiresorptive medications are recommended, especially in women in their child-bearing period.
- A.
- 2.
Osteoporosis in premenopausal women:
- A.
Can only be diagnosed if the patient sustained a fragility fracture.
- B.
Is usually due to secondary causes.
- C.
Teriparatide or abaloparatide is the drug of choice for premenopausal osteoporosis.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comment:
Osteoporosis and fractures are rare in premenopausal women and are usually due to secondary osteoporosis. Bone densitometry is seldom indicated unless the patient has sustained a fragility fracture or has a disease associated with bone demineralization. In the absence of fractures, it is not recommended to use the terms osteoporosis and osteopenia in premenopausal women. The FRAX algorithm also has not been validated in people younger than 40 years.
Peak Bone Mass (PBM) reflects the maximum amount of bone accrued during skeletal growth and maturation and is a major factor affecting fracture risk. Skeletal bone maturation goes through distinct phases. During childhood bone mass is driven by increasing bone size, and its accrual is steady with no significant differences between girls and boys.
Gender differences become obvious during puberty: male puberty is associated with accelerated periosteal apposition and endosteal expansion resulting in marked increases in bone diameter and in cortical thickness. Female puberty is associated with similar, but smaller, increases in cortical thickness and in bone diameter. Gender differences continue to be observed during late puberty with smaller increases in trabecular thickness and bone volume in girls compared to boys.
By the end of puberty, bone strength is 30 to 50% higher in boys than in girls. Peak bone mass is achieved during the second or third decade of life and is site and gender dependent. Multiple genetic factors are responsible for 60%–80% of the variability in bone mass accrual, including birth weight, timing of puberty, extent of pubertal growth spurt, general health status, height, and muscle mass. Optimal achievement of PBM largely determines future bone strength.
Fragility fractures must be present to diagnose osteoporosis in premenopausal women and men under the age of 40 years. Several diseases may lead to a deficient bone mass and an increased fracture risk during childhood, including endocrine, neuromuscular, rheumatic, chronic inflammatory, nutritional, hematologic, and oncology diseases.
A premenopausal woman who has sustained a fracture has a 35%–75% higher risk of sustaining another fracture after she reaches the menopause than a woman who has not sustained such a fracture. This opens a window of opportunity to increase muscle and bone mass and strength before the menopause and reduce the risk of sustaining fractures by identifying those individuals at risk of sustaining a fracture. At this stage these interventions include changes in lifestyle habits, physical exercise, dietary food intake, an adequate vitamin D intake, and combined oral contraceptives.
Bisphosphonates used to treat osteoporosis in postmenopausal women are not routinely used for premenopausal women because of their long half-life, the child-bearing potential, and the uncertain effect on the fetus.
- A.
- 3.
Anorexia nervosa (AN):
- A.
Has a peak onset after the age of 30 years.
- B.
Patients are very conscious and particular of their body weight.
- C.
The fracture risk is about twice that of the general population.
- D.
B and C.
- E.
A, B, and C.
Correct answer: D
Comment:
AN has a peak onset between the ages of 15 and 19 years. Although more common in girls it affects both sexes. Patients with AN have a low body weight, a distorted perception of their body weight and shape, and have an intense fear of gaining weight. They also often have amenorrhea. AN usually develops as a result of psychological trauma in individuals predisposed to it. Psychiatric problems are common. Overall mortality and suicide are increased, BMD is decreased, and fracture risk is increased.
- A.
- 4.
In anorexia nervosa (AN), the following contributes to bone loss:
- A.
Estrogen and progesterone deficiency.
- B.
Reduced insulin-like growth factor-1 (IGF-1).
- C.
Excess cortisol levels.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Patients with AN lose weight and deplete their fat stores. A minimum of 10% fat stores is needed to maintain normal menstrual functions. When the total body fat mass drops below this level amenorrhea sets in. The resulting estrogen/progesterone deficiency arrests bone formation and vigorously promotes bone resorption as evidenced by the elevated markers of bone resorption (CTX and NTX) and the usually low markers of bone formation such as P1NP or bone-specific alkaline phosphatase. This “uncoupling” leads to significant bone loss. Other factors that further contribute to bone loss include low levels of IGF-1, excess cortisol secretion, and low testosterone levels. Bone loss in AN occurs early, progresses rapidly during the disease process, and is not entirely reversible with weight restoration.
- A.
- 5.
The following are useful in the management of anorexia nervosa:
- A.
Estrogen/progesterone.
- B.
Dehydroepiandrosterone (DHEA).
- C.
Bisphosphonates.
- D.
None of the above.
- E.
A, B, and C.
Correct answer: D
Comment:
Management of AN is notoriously difficult. Ideally the patient should very gradually increase her daily dietary intake to gradually increase her body weight to optimum levels for her given age and height. Unfortunately, this is rarely possible. The use of estrogen is controversial, and a meta-analysis and review of the literature failed to support its use for AN.
There is also concern that the resumption of menstrual periods induced by cyclical estrogen/progesterone may give the patient the impression that she is cured of AN and justify her stopping to restore her genetically determined body weight. There is no convincing data to support the use of DHEA, testosterone, or fluoride. The use of bisphosphonates in AN is also controversial given the child-bearing potential of most patients and the still not fully explored potential effect on the skeletal development of a child born to a patient who has been on bisphosphonates.
- A.
- 6.
Contraceptives and bone mass:
- A.
Estrogen, in very low doses (Ethinyl estradiol (EE): 20 μg), provides contraception.
- B.
Larger doses of estrogen increase the risk of thromboembolic disorders.
- C.
Medroxyprogesterone acetate does not interfere with bone metabolism.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comment:
Estrogen suppresses the release of follicular stimulating hormone from the anterior pituitary and therefore interferes with the recruitment of ovarian follicles and the production of endogenous estrogen. Progesterone prevents the release of luteinizing hormone from the pituitary and prevents ovulation. Estrogen/progesterone is an effective oral contraceptive. When the dose is sufficient, estrogen may have positive effects on bone metabolism. Unfortunately, higher doses of estrogen increase the risk of thromboembolic diseases and modern oral contraceptives contain the lowest effective dose for contraception, which often is not sufficient to maintain a neutral or positive effect on bone metabolism.
By suppressing endogenous estrogen production, the nefarious effects of estrogen deprivation on bone mass manifest themselves: increased bone resorption and decreased bone mass, eventually leading to osteoporosis and fractures. Medroxyprogesterone acetate administered parenterally at 3-month interval also is associated with a low bone mass.
- A.
- 7.
Celiac disease:
- A.
Affects about 1% of the population.
- B.
Most patients are asymptomatic.
- C.
The BMD is decreased even in asymptomatic patients.
- D.
B and C.
- E.
A, B, and C.
Correct answer: E
Comment:
Celiac disease affects about 1% of the population. Most patients are asymptomatic and are unaware of the disease which is due to an immune response to dietary gliadins in genetically predisposed patients and results in malabsorption. Calcium and vitamin D malabsorption leads to hypovitaminosis D and secondary hyperparathyroidism. In addition, a number of immunological and inflammatory changes lead to a low bone mass, including an excessive production of RANK-L, interleukin-1, interleukin-6, and tumor necrosis factor-alpha. Hypogonadism may further contribute to bone loss.
Symptomatic cases present with weight loss, diarrhea, and bloating. Extra-intestinal manifestations include low bone mass, increased fracture risk, anemia, infertility, recurrent miscarriages, seizures, ataxia, peripheral neuropathies, dermatitis herpetiformis, enamel defects, and various vitamin deficiencies. At present, plasma transglutaminase is the best serological screening test. If positive, a small-bowel biopsy is recommended. BMD and symptoms improve when patients adhere to a gluten-free diet and avoid wheat, rye, barley, and oats.
- A.
- 8.
During pregnancy:
- A.
Bone turnover is increased.
- B.
Intestinal calcium absorption is increased.
- C.
Osteoporosis may present as severe low back or hip pain.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
During pregnancy the fetus acquires about 30 g of calcium; the maternal skeleton is protected by an increased intestinal absorption of calcium largely mediated through increased 1,25-di-hydroxy-vitamin D levels which nearly double early in pregnancy and remain at this level until delivery. The serum parathyroid hormone levels tend to be in the low normal range during the first trimester and gradually increase during pregnancy, reaching peak levels during the third trimester of pregnancy, but not exceeding normal values.
Pregnancy and lactation affect the mother’s BMD: the BMD of the lumbar vertebrae may decrease by about 5% during normal pregnancy and there may be a further decline of 3%–10% after a 6-month period of lactation. A decline of 2%–4% in the hip BMD has been documented after 6 months of lactation. It may take up to 1 year to reverse these losses. Maternal rate of bone turnover is moderately increased and small decreases in BMD have been observed in the lumbar vertebrae, but not long bones.
Pregnancy-associated osteoporosis is rare, tends to affect primigravidae, affects mostly the vertebrae, and presents with back pain, often severe, which is often misdiagnosed as being due to ligamentous laxity induced by hormonal changes associated with pregnancy. Transient osteoporosis of the hip is rare, presents with unilateral or bilateral hip pain, and may be complicated by a fragility hip fracture. Patients with risk factors for bone demineralization are more likely to develop pregnancy-associated osteoporosis.
- A.
- 9.
During lactation:
- A.
Bone turnover is increased.
- B.
Intestinal calcium absorption is increased.
- C.
Renal calcium resorption is increased.
- D.
A and C.
- E.
A, B, and C.
Correct answer: D
Comment:
Calcium metabolism is different in pregnancy and lactation. The average daily calcium in breast milk is about 200 mg, with the range varying between 280 and 1000 mg. During lactation the increased intestinal calcium absorption seen during pregnancy returns to the normal prepregnancy levels.
High prolactin levels induce a hypoestrogenic state which leads to increased bone resorption to mobilize calcium from bone to the circulation, to breast milk, and in the process, increase the risk of bone demineralization and reduced bone mass. Calcium reabsorption by renal tubules is also increased. Trabecular bones are affected more than cortical bones. Notwithstanding, BMD is usually restored 6 to 12 months after weaning. Epidemiological studies do not show a deleterious effect of lactation on bone mass and hip fracture risk.
- A.
- 10.
The Female Athlete Triad includes:
- A.
Disordered/restrictive eating.
- B.
Impaired ovarian functions.
- C.
Bone demineralization.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E
Comment:
The female athlete triad is characterized by :
- •
Disordered/restricted eating, intense physical activity, low energy availability, and low body mass index (BMI).
- •
Ovarian dysfunction, associated with functional hypothalamic oligomenorrhea and amenorrhea as evidenced by low serum estradiol and gonadotrophins leading to an increased bone turnover and rapid bone loss.
- •
Decreased BMD and osteoporosis, eventually leading to fractures.
Each element of the triad is a spectrum with a broad range.
Low energy availability may be due to dietary restrictions (intentional or inadvertent) or may be due to excessive energy expenditure. Notwithstanding, the imbalance triggers a cascade of physiologic and neuroendocrine adaptations including decreased frequency and pulses of gonadotrophin-releasing hormone from the hypothalamus leading to decreased pulsatile pituitary release of luteinizing hormone and follicle stimulating hormone, resulting in reduced production of estrogen and progesterone by the ovaries. Other hormones also may be involved, including cortisol, insulin, growth hormone, insulin-like growth factor-1, and leptin.
The etiology of low BMD in the female athlete syndrome is also multifactorial and includes failure to achieve peak bone mass, bone loss resulting from estrogen deficiency, and other hormonal imbalances. Patients with the female athlete syndrome are more at risk of sustaining fractures.
Management of the female athlete triad is difficult. The goal is to increase energy availability, restore menstrual functions, and normalize BMD. A multidisciplinary team approach is recommended. Nonpharmacologic means should be tried first. They include controlled physical activity, lifestyle changes, and weight regain by diet manipulation.
Bisphosphonates and denosumab are not routinely used because of the potential risk to future pregnancies. There is still no consensus as to how long medications for osteoporosis can/should be administered because their sudden cessation may lead to excessive bone loss and their continued long-term administration increases the risk of rare conditions such as osteonecrosis of the jaw and atypical femoral shaft fractures. Clinicians have to consider the potential benefit: essentially decreased fracture risk to the potential risks associated with the continuation of these medications, especially atypical femoral shaft fracture and osteonecrosis of the jaw. These issues are discussed in other sections.
Teriparatide and abaloparatide are sometimes used for up to 2 years in premenopausal women with very low BMD. At the end of the two-year course, however, bisphosphonates or denosumab should be prescribed to avoid bone loss. Ideally the female athlete triad should be treated as soon as possible to allow the patient to achieve her peak bone mass.
- A.
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