Postmenopausal osteoporosis

Figure. Transmenopause

A period of approximately 4 years that straddles the final menstrual period (FMP), the transmenopause is associated with a substantial increase in the rate of bone loss. Its trajectory stabilizes after FMP, but bone loss continues. Bone mineral density is shown by the black line and urinary N-telopeptide, a marker of bone resorption, by the red line. The rise of follicle-stimulating hormone and decline of estradiol that are associated with menopause are depicted in green and blue, respectively. (Reprinted with permission from Karlamangla AS, Shieh A, Greendale GA.¹)

Bone accrual occurs in men and women from early life till well into their fourth decade. Thereafter, both lose bone mass in a slowly progressive manner. However, women (individuals assigned female at birth who possess ovaries) undergo a transmenopausal period of accelerated bone loss (Figure),¹ which, combined with their overall smaller bones compared with men, makes them far more susceptible to osteoporosis and subsequent fractures. In 2010, an estimated 10.2 million US adults aged 50 years and older had osteoporosis, and an additional 43.4 million had low bone mass.² Given the projected aging of the population, it is estimated that by 2030 over 70 million US adults will have low bone mass or osteoporosis.² Moreover, about 50% of women will sustain an osteoporotic fracture during their lifetime,³ resulting in an increased risk of further morbidity and mortality.⁴ Fully 30% of Medicare beneficiaries who had a hip fracture in 2016 died within 12 months.⁵ The cost of providing care for Medicare beneficiaries in 2018 was estimated to be $57 billion.⁶ It is clearly imperative, then, that the obstetrician-gynecologist understand the condition, its detection, and its treatment.

Epidemiology and risk

The word osteoporosis (literally, “porous bones”) defines the condition’s pathophysiology. Bone is in a constant state of remodeling and repair, concurrently undergoing formation and resorption processes. Osteoporosis arises when resorption exceeds formation long enough to result in a weakened bone that is susceptible to breakage. Women attain peak bone mass at around 35 years. Prior to the menopausal transition, they lose bone at an average annual rate of 2%, but there is substantial variation depending on genetic, lifestyle, and environmental factors.⁷ During transmenopause, which begins about 2 years before a woman’s final menstrual period and lasts for several years afterward, women sustain an average annual rate of bone loss of 10% to 12% at both the hip and spine (Figure). Thereafter, the rate of bone loss slows considerably, to an average of 0.5% per year.⁷ The impact of menopause is so significant that the number of years elapsed since a woman’s final menstrual cycle is a better predictor of bone density than her chronological age.⁸ Taken together, age and menopause conspire to reduce a woman’s bone density by 30% by the time she is 80 years old.⁹

Bone loss rates and risks of fracture vary between racial and ethnic groups. Most studies have examined race and ethnicity only via self-report methods and are therefore to be considered social constructs. Native American women (20% higher than the national average) and non-Hispanic White women (6% higher than the national average) are at highest risk of low bone mass and fracture.⁵ Asian-American women, although they are at high risk of low bone mass, are less likely to sustain a fracture. Hispanic women fall in between White and Black women in terms of bone loss and risk of fracture, and Black women are least likely to have low bone mass and/or sustain a fracture.⁵ However, Black women who suffer a fracture are more likely to be hospitalized and to die following fracture, and they also have lower rates of bone density screening.

Some of these risk disparities may be related to concurrent disorders. Diabetes, vascular disease, arrhythmia, and chronic obstructive pulmonary disease are more prevalent in individuals who have had a fracture.⁵ Commonly used medications—proton-pump inhibitors, sodium-glucose cotransporter-2 inhibitors, glucocorticoids, and both serotonin and norepinephrine reuptake inhibitors—contribute to bone loss. Aromatase inhibitors, a lifesaving therapy for patients with breast cancer, are associated with low bone mass and an accelerated decline in bone density. Endocrine disorders like primary ovarian insufficiency, hyperthyroidism, hypercortisolism, hyperparathyroidism as well as diabetes can also reduce bone mass or affect bone microarchitecture and strength.

Lifestyle factors also affect peak bone mass, rate of bone loss, and risk of fracture. Women with a history of eating disorders are especially susceptible to low bone mass because they attain only a low peak bone density. Thinness (weight of less than 127 lb or body mass index [BMI] of less than 21 kg/m2) is likewise a risk factor for low bone mass. Smoking contributes to bone loss, likely because of its association with thinness and lower circulating estradiol.⁹ Finally, low bone mass alone, although predictive, is not the only driver of fracture risk. Prior fracture, family history of fracture, genetics, age, smoking, excess alcohol intake (more than 3 daily servings), falls, and frailty are all related to risk.⁹

Screening

Universal screening for osteoporosis with dual-energy X-ray absorptiometry (DEXA) is recommended for women over 65 who are at average risk of the disease. Although the recommendations for younger women differ between professional societies, the broad consensus is that those with additional risk factors for low bone density should be screened. The North American Menopause Society suggests DEXA screening for postmenopausal women over 50 if they have a BMI of less than 21, a parental history of hip fracture or a personal history of fracture since menopause, medical causes of bone loss, have discontinued estrogen therapy, or smoke tobacco.⁷ Most recommendations tailor screening intervals to patient risk: those with lower bone mineral density (BMD) and/or risk factors should be screened every 2 to 3 years, and those with higher baseline BMD and no additional risk factors can wait many years in between screenings.

The diagnosis of osteoporosis can be made based on DEXA screening or, importantly, if a postmenopausal woman experiences a low-trauma fracture. The DEXA reports a T-score in standard deviation units that compares patient BMD to the BMD of young adults with peak bone mass. A T-score of –2.5 or below is consistent with osteoporosis, of between –1.1 and –2.4 is consistent with osteopenia (low bone mass), and of 1.0 or above is considered normal. A Z-score, which compares the patient to someone of the same age, sex, and ethnicity, is also reported. Z-scores of less than 2.0 should raise suspicion for a secondary cause of low BMD.

Whenever a patient is found to have low BMD, a history should be taken to assess for the risk factors mentioned above. Particular attention should be paid to recent falls and risk for falls. Physical exam should include height measured with bare feet, kyphosis assessment, and tests that may suggest a secondary cause of osteoporosis (Table 1). Laboratory workup is also indicated, and its extent is driven by severity of osteoporosis and/or fracture history. Standard evaluation includes a complete blood count, creatinine, alkaline phosphatase, calcium and albumin, serum phosphorous, and 25-hydroxy vitamin D (25OHD).¹⁰ Based on clinical suspicion, more extensive work may be undertaken, including serum and urine protein electrophoresis, TSH, PTH, celiac antibody testing, tryptase, and a 24-hour urine for creatinine, calcium, and cortisol. Vertebral imaging should be considered for those who report more than 1.5 inches of historical height loss, recent glucocorticoid treatment, adult fractures, and other medical conditions associated with bone loss. Vertebral fracture is diagnostic of osteoporosis and current fracture places a patient at very high risk of future fracture.¹¹

Nonpharmacologic treatment

The following bone-healthy practices should be recommended to all women¹²: adequate intake of calcium and vitamin D, avoidance of smoking and of excess alcohol intake, regular weight-bearing and muscle-strengthening exercises, balance training, and fall prevention.^11,13 The Institute of Medicine recommends a daily calcium intake of 1000 mg for women aged 19 to 50 and of 1200 mg for those 50 and over.¹¹ Food is the preferred source of calcium, and supplements should be used if adequate dietary calcium intake cannot be achieved.¹¹ It is essential to assess dietary calcium intake to make the necessary recommendations. The recommended amount of calcium intake refers to elemental calcium, which varies depending on the supplement. In general, calcium carbonate has a calcium clearance of 40%, whereas calcium citrate has one of only 21%.¹¹ Vitamin D deficiency should be corrected, and a maintenance dose of 1000 IU daily is recommended by most organizations.¹² The Endocrine Society and the American Association of Clinical Endocrinologists (AACE) define vitamin D sufficiency as a 25OHD level of more than 30 ng/ml.¹² A 50 ng/ml level is considered the safe upper limit.¹²

Pharmacological treatment

The Endocrine Society recommends pharmacological treatment for postmenopausal women at high risk of fracture.¹³ These are patients with hip or vertebral fractures; with a total hip, spine, and femoral neck T-score of –2.5 or lower; with a T-score between –1.0 and –2.5 whose 10-year probability for major osteoporotic fracture is 20% or probability for hip fracture is more than 3%, based on the US-adapted FRAX tool.¹³ In addition, AACE recommends treatment of postmenopausal women with a T-score of –2.5 or lower in the spine, femoral neck, total hip, or distal one-third of the radius.¹²

The choice of medication should be based on the risk of fracture, patient-specific clinical factors, and patient preference.^11-13 Because the goal of treatment is to prevent an osteoporotic fracture,¹³ medications that have been shown to reduce vertebral and nonvertebral fractures are preferred.¹¹ Patients considered at very high risk of fracture include those with a T-score of less than –3.0, multiple fractures, high risk of falls or a history of falls resulting in injuries, fractures while on a medication approved for the treatment of osteoporosis or on a medication known to affect bone density (such as long-term glucocorticoids), and a very high 10-year probability for major osteoporotic fracture (greater than 30% overall or greater than 4.5% for hip fracture, according to FRAX or other validated fracture risk calculators).¹² Patients at high risk are those with a history of hip or spine fracture, BMD of –2.5 or less, or a 10-year probability of more than 20% for major osteoporotic fracture and more than 3% for hip fracture.¹³

Pharmacological treatment for osteoporosis is either antiresorptive (decreases resorption) or anabolic (increases formation). FDA-approved antiresorptive agents include bisphosphonates, calcitonin, denosumab (which blocks the activation of the NF-kappaB ligand), estrogen, raloxifene (a selective estrogen-receptor modulator), and bazedoxifene (a selective estrogen-receptor modulator currently under development). Anabolic agents are parathyroid hormone and parathyroid hormone-related peptides. The only combination agent with anabolic and antiresorptive properties is the humanized monoclonal antibody to sclerostin (Table 2).

Initial treatment with oral bisphosphonate is recommended for postmenopausal women at high risk of fracture.¹³ Zoledronic acid can be used in patients who are unable to use oral bisphosphonate. Ibandronate should be considered only in patients with a spine-specific high risk of fracture, as the agent has not demonstrated efficacy at preventing nonvertebral or hip fractures.¹² Denosumab can be used as an alternative initial treatment for postmenopausal women at high risk of osteoporotic fractures.¹³ Zoledronic acid, denosumab, teriparatide, abaloparatide, and romosozumab can be used in patients with contraindications to oral bisphosphonate, those in whom oral treatment has failed, or as initial treatment in those at very high risk of fracture.^12,13

Selective estrogen-receptor modulators and tissue-selective estrogen complex are recommended in patients who cannot use bisphosphonate or denosumab and those who are at a low risk of deep venous thrombosis or at high risk of breast cancer.¹⁴

Estrogen and menopausal hormone therapy should be limited to patients who cannot use bisphosphonate or denosumab and have vasomotor symptoms or vulvovaginal atrophy but no history of breast cancer, stroke, or myocardial infarction.^11,13 A risk-benefit evaluation should be performed before treatment initiation. When treatment with estrogen is discontinued, rapid bone loss can occur, and thus initiation of other antifracture medication should be considered.¹¹

Calcitonin is suggested for patients with contraindications or intolerance to other osteoporosis medications. Nasal spray calcitonin decreases the risk of vertebral fracture but not of hip and nonvertebral fracture, and there are no data demonstrating that injectable calcitonin prevents fracture.

DEXA bone density monitoring every 1 or 2 years, ideally at the same facility, is recommended to assess response to therapy.¹² Alternatively, bone turnover markers like carboxy terminal collagen (CTX) crosslinks or serum concentration of procollagen type I N-propeptide (P1NP) can be used to measure treatment response and nonadherence with antiresorptive and anabolic agents, respectively.^12,13

Response to therapy is defined as stabilization or increased bone mineral density with no new fractures or progression of vertebral fractures.¹² Treatment failure is defined as significant bone loss or 2 or more fractures, and then alternative therapy should be considered.¹² Secondary causes of osteoporosis and nonadherence should be investigated before alternatives are initiated.

If fracture risk is no longer high, a bisphosphonate holiday can be considered for patients after 5 years of treatment with oral bisphosphonates and 3 years of treatment with zoledronic acid. In patients at very high risk of fracture, treatment with oral bisphosphonate can be continued for up to 10 years and with zoledronic acid for up to 6 years.¹² BMD in patients on a bisphosphonate holiday should be monitored by DEXA scan or bone turnover markers, and the holiday ended if a fracture occurs, there is a significant decrease in BMD or an increase in risk of fracture, or if adverse changes are seen in bone turnover markers.¹²

A holiday is not recommended for non-bisphosphonate agents.¹² Reassessment of fracture risk should be done after 5 to 10 years of treatment with denosumab, and women who remain at high risk of fracture should continue treatment or switch to alternative therapy.¹³ If therapy is to be discontinued, a transition should be made to another antiresorptive agent.¹²

To prevent decrease in bone density and loss of efficacy, bisphosphonate or denosumab should be started after 2 years of therapy with anabolic agents like teriparatide and abaloparatide and after 1 year of treatment with romosozumab.¹²

Referral to an osteoporosis specialist or a clinical endocrinologist should be considered for patients with normal BMD in whom fragility fractures occur, for those who sustain recurrent fractures or experience significant bone density loss while on osteoporosis therapy, and those who have abnormal laboratory results or unexplained osteoporosis at a young age.¹²

Conclusion

There is much that the obstetrician-gynecologist can do to prevent, detect, and treat low bone density and osteoporosis in women. Healthy habits, adequate calcium and vitamin D intake, and early screening of women at high risk of future fractures are the mainstays of prevention. Once osteoporosis is diagnosed, bisphosphonates and hormone therapy in patients with concurrent menopausal symptoms are first-line agents. Patients who get worse or fail to respond to these therapies can be treated with second-line agents, while more complex cases may require referral for specialty evaluation and care.

PTH, parathyroid hormone; SPEP/UPEP, serum protein electrophoresis/urine protein electrophoresis.

ATF, activating transcriptional factor; ATN, acute tubuluar necrosis; CVD, cardiovascular disease; IV, intravenous; ONJ, osteonecrosis of the jaw; PO, oral; SQ, subcutaneous; VTE, venous thromboembolism.

References

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