2019 Endocrine Society Guidelines: postmenopausal osteoporosis

The Endocrine Society released its guidelines on postmenopausal osteoporosis in March 2019. The treatment algorithm is primarily based on fracture risk categories. Categories include three essential ingredients; fragility fracture history, T-scores, and FRAX-scores.

The society prefers bisphosphonates, specially alendronate (Fosamax) and zoledronic acid (Reclast), as the first-line therapy for women at high risk of fractures. Denosumab (Prolia) and anabolic hormones (Tymlos and Forteo) are also recommended.

If denosumab has been started, it should not be stopped without bridging it over to another medication. Recent studies have revealed a significantly increased risk of vertebral fractures within 12 months of its discontinuation. If bisphosphonates improve the fracture risk down to a low-or-moderate risk category, then women could undergo a drug holiday after 3 to 5 years of an interrupted use. A drug holiday is not recommended for denosumab.

The Endocrine Society recommends anabolic hormones for postmenopausal women in the category of very high risk for fragility fractures. Tymlos and Forteo can be used for up to 2 years, due to theoretical concern of developing osteosarcoma with more prolonged use.

For women of age 60 or younger or within ten years of being in the postmenopausal state, guidelines recommend careful use of hormonal replacement therapy (HRT) or tibolone. Tibolone is not available in the United States. Patients should not have a history or be at increased risk of cardiovascular disease, blood clots, and breast cancer. On the contrary, raloxifene or bazedoxifene could be used in those with a predisposed risk for breast carcinoma.

As expected, calcium and vitamin D supplementation should be used as adjunct therapies for women in the high-risk category.

Adverse events from osteoporosis therapies osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFF) have become a public concern in recent years. Although ONJ and AFF are real, the risk of developing fragility fractures from withholding pharmacological therapy far exceeds these potential side effects in high risk and very high-risk women. Providers need to make their patients aware of the benefit vs. harm ratio.

GT

Also see:

Osteoporosis

Bisphosphonate

Denosumab

Endocrine Society


J C E M

ES Guidelines

March 2019

Simplified “GT” Risk Categories:

  • LOW (pre-osteopenia)

    • No fractures

    • No elevated FRAX-score (<3% and <20%)

    • T-score of −1.0 or better

  • MODERATE (osteopenia)

    • No fractures

    • No elevated FRAX-score (<3% and <20%)

    • T-score of –2.5 to -1.0

  • HIGH (osteoporosis)

    • Prior fracture, OR

    • T-score of −2.5 or worse, OR

    • High FRAX-score (≥3% or ≥20%)

  • VERY HIGH (advanced osteoporosis)

    • Multiple spine or severe fractures, AND

    • T-score of −2.5 or worse

    • (FRAX-score adds no value)


Recommendations

  • We recommend treating postmenopausal women at high risk of fractures, especially those who have experienced a recent fracture, with pharmacological therapies, as the benefits outweigh the risks.

  • In postmenopausal women at high risk of fractures, we recommend initial treatment with bisphosphonates (alendronate, risedronate, zoledronic acid, and ibandronate) to reduce fracture risk

    • Ibandronate is not recommended to reduce nonvertebral or hip fracture risk.

  • In postmenopausal women with osteoporosis who are taking bisphosphonates, we recommend that fracture risk be reassessed after 3-5 years, and women who remain at high risk of fractures should continue therapy, whereas those who are at low-to-moderate risk of fractures should be considered for a “bisphosphonate holiday.”

    • A bisphosphonate holiday is operationally defined as a temporary discontinuation of bisphosphonate for up to 5 years.

      • This period may be longer depending on the bone mineral density and clinical circumstances of the individual patient.

      • The evidence is stronger for retention of benefits during a holiday for alendronate and zoledronic acid where there are randomized extension trials.

  • In postmenopausal women with osteoporosis who are at high risk for osteoporotic fractures, we recommend using denosumab as an alternative initial treatment.

  • In postmenopausal women with osteoporosis who are taking denosumab, we suggest that the fracture risk be reassessed after 5-10 years and that women who remain at high risk of fractures should either continue denosumab or be treated with other osteoporosis therapies.

  • In postmenopausal women with osteoporosis taking denosumab, administration of denosumab should not be delayed or stopped without subsequent antiresorptive [e.g., bisphosphonates, hormone therapy, or selective estrogen receptor modulator] or other therapy administered to prevent a rebound in bone turnover and to decrease the risk of rapid bone mineral density loss and an increased risk of fracture. 

    • Discontinuation of denosumab is associated with a BMD decrease of 6.6% in the lumbar spine and 5.3% in the total hip within the first 12 months of treatment discontinuation

    • A drug holiday or treatment interruption is not recommended with denosumab

  • In postmenopausal women with osteoporosis at very high risk of fracture, such as those with severe or multiple vertebral fractures, we recommend teriparatide or abaloparatide treatment for up to 2 years for the reduction of vertebral and nonvertebral fractures.

  • In postmenopausal women with osteoporosis who have completed a course of teriparatide or abaloparatide, we recommend treatment with antiresorptive osteoporosis therapies to maintain bone density gains.

  • In postmenopausal women with osteoporosis at high risk of fracture and with the patient characteristics below, we recommend raloxifene or bazedoxifene to reduce the risk of vertebral fractures.

    • Patients with a low risk of DVT

    • Bisphosphonates or denosumab are not appropriate, or

    • Patients with a high risk of breast cancer

  • In postmenopausal women at high risk of fracture and with the patient characteristics below, we suggest menopausal hormone replacement therapy (HRT), using estrogen only in women with hysterectomy, to prevent all types of fractures.

    • Women <60 years of age or <10 years past menopause:

      • At low risk of DVT

      • Bisphosphonates or denosumab are not appropriate

      • Have bothersome vasomotor symptoms

      • Have additional climacteric symptoms

      • Have no contraindications

        • Without prior MI or stroke

        • Without breast cancer;

      • And are willing to take HRT.

  •  In postmenopausal women with osteoporosis at high risk of fracture and with the patient characteristics below, we suggest tibolone to prevent vertebral and nonvertebral fractures

    • Women <60 years of age or <10 years past menopause:

      • At low risk of DVT

      • Bisphosphonates or denosumab are not appropriate

      • Have bothersome vasomotor symptoms

      • Have additional climacteric symptoms

      • Have no contraindications

        • Without prior MI, stroke, or high risk for CVD

        • Without breast cancer;

      • And are willing to take tibolone.

      • Tibolone is not available in the United States or Canada.

  • In postmenopausal women at high risk of fracture with osteoporosis, we suggest that nasal spray calcitonin be prescribed only in women who cannot tolerate raloxifene, bisphosphonates, estrogen, denosumab, tibolone, abaloparatide, or teriparatide or for whom these therapies are not considered appropriate.

  • In postmenopausal women with low bone mineral density and at high risk of fractures with osteoporosis, we suggest that calcium and vitamin D be used as an adjunct to osteoporosis therapies. 

  • In postmenopausal women at high risk of fracture with osteoporosis who cannot tolerate bisphosphonates, estrogen, selective estrogen response modulators, denosumab, tibolone, teriparatide, and abaloparatide, we recommend daily calcium and vitamin D supplementation to prevent hip fractures. 

  • In postmenopausal women with a low bone mineral density and at high risk of fractures who are being treated for osteoporosis, we suggest monitoring the DEXA scan at the spine and hip every 1-3 years to assess the response to treatment. 

    • Monitoring bone turnover markers (serum C-terminal crosslinking telopeptide for antiresorptive therapy or procollagen type 1 N-terminal pro-peptide for bone anabolic therapy) is an alternative way of identifying poor response or nonadherence to therapy.


Endocrine Society Risk Categories:

  • “low risk” includes no prior hip or spine fractures, a BMD T-score at the hip and spine both above −1.0, and 10-year hip fracture risk <3% and 10-year risk of major osteoporotic fractures <20%

  • “moderate risk” includes no prior hip or spine fractures, a BMD T-score at the hip and spine both above −2.5, or 10-year hip fracture risk <3% or risk of major osteoporotic fractures <20%

  • “high risk” includes a prior spine or hip fracture, or a BMD T-score at the hip or spine of −2.5 or below, or 10-year hip fracture risk ≥3%, or risk of major osteoporotic fracture risk ≥20%

  • “very high risk” includes multiple spine fractures and a BMD T-score at the hip or spine of −2.5 or below.


 
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Osteonecrosis of the jaw (ONJ)

  • ONJ is a nonhealing wound in the oral mucosa with exposed bone that lasts >8 weeks, usually associated with an invasive dental procedure such as dental extraction or implantation but can occur de novo as well.

  • An international task force on ONJ reported on the association of bisphosphonate therapy and ONJ; the absolute risk of ONJ in osteoporosis patients was estimated to range from 1 in 10,000-100,000.

  • Higher doses and more frequent use of bisphosphonate and denosumab have been associated with greater ONJ risks in the oncology setting, but these patients have other risk factors such as cancer, chemotherapy, radiation therapy, and antiangiogenic therapies.

  • In osteoporosis patients on long-term oral bisphosphonate therapy, the risk of ONJ has been reported to be as high as 21 in 10,000 (or 0.21%) for patients on >4 years of therapy.

  • Tooth extraction in a patient exposed to bisphosphonate therapy carries a 0.5% risk of developing ONJ.

  • Currently, the American Dental Association does not recommend stopping bisphosphonates for dental procedures; however, if a tooth extraction or implant is planned or ongoing, initiation of potent antiresorptive therapy could be deferred until the area healed.

  • In contrast, the American Association of Oral and Maxillofacial Surgeons recommends a 2-month drug holiday for those who have taken >4 years of bisphosphonates.

  • Routine dental care is also important for the prevention of ONJ in patients treated with potent antiresorptive therapy.

  • Conservative management such as antibacterial mouth rinse is recommended as initial therapy for stage 0 to 2 ONJ, whereas surgical debridement and resection is recommended for stage 3 ONJ.

  • Although there have been case reports of using teriparatide as well as other therapies (such as platelet-rich plasma, low-level laser irradiation, and bone morphogenic protein) in the successful treatment of ONJ, controlled studies are needed to establish efficacy of these therapies.


Atypical Femoral Fractures (AFF)

  • AFFs are insufficiency stress fractures of the femoral shaft first noted in case reports in about 2007 that suggested a possible association with bisphosphonate use. These fractures have specific radiological characteristics that have been formalized in a case definition by the ASBMR based on radiographic criteria and low trauma.

  • AFFs have been most studied in relationship to bisphosphonate use but have also been noted with other osteoporosis medications including denosumab, odanacatib, and romosozumab. Patients often present with pain or aching in the thigh or groin with or after weight-bearing activities.

  • The pathogenesis of these fractures is not understood, although a number of hypotheses including factors related to femur shape, genetics, and ethnicity have been advanced.

  • A large number of epidemiologic studies focusing on bisphosphonate usage and duration have been published. However, many have not had assessments of individual radiographs and instead relied on femoral shaft fractures as defined by ICD codes from population registries.

  • Unfortunately, this endpoint is problematic because <5% of these femoral shaft fractures would have met AFF criteria if radiographs had been evaluated. This nonspecific endpoint could have masked AFF increases in these studies, as well as in a meta-analysis of AFFs published in 2013, which included many such studies.

  • Calculation of AFF incidence restricted to studies with radiographic evaluation shows incidence to be very low.

  • For example, a study in Sweden using national data for women and men >55 years of age for 2008 to 2010 showed that among a total of 50,325 femur (hip or femoral shaft) fractures, only 172 (about 3 AFFs per 1000 hip fractures) met ASBMR criteria.

  • A similarly low ratio of AFFs to hip fractures was shown in a study performed in Kaiser Permanente Northwest. This study showed very low AFF incidence in their population (about 5 per 100,000 person-years) compared with an almost 100-fold higher incidence of hip fractures (300 to 400 per 100,000 person-years).

  • Despite low incidence rates, studies with radiographic assessment have shown strong increases in AFFs with longer duration of bisphosphonate use. For example, one widely cited study from a large health maintenance organization in California of people >45 years of age (∼1.8 million) showed AFF risk (unadjusted) for 2 years of use to be ∼3 per 100,000 person-years, increasing to ∼20 per 100,000 person-years with 5 years of use and ∼50 per 100,000 with >8 years of use.

  • Despite this increase, risks of hip and other osteoporotic fractures that can be prevented by treatment are much higher, suggesting a positive benefit-risk ratio even for long-term treatment, particularly in older women at highest risk of hip and other osteoporotic fractures.

  • Whereas one analysis of benefit vs risk for bisphosphonate treatment of 3 years showed that treating 1000 osteoporotic women would prevent 100 fractures, including 11 hip fractures, while causing about 0.1 AFF, similar data for longer-term treatment are not available, and the consistent increase shown for treatment beyond 5 years suggests consideration of AFF risk in treating patients for >5 years.

  • As discussed in section 2, the ASBMR long-term has proposed that the risk could be reduced by taking a “holiday” from oral bisphosphonates after 5 years and from IV bisphosphonates after 3 years in patients who are at low-moderate fracture risk.

  • Specific recommendations for bisphosphonate holidays are discussed in “Bisphosphonates”. There are insufficient data about the relationship of long-term denosumab to AFF risk to make a recommendation about duration of use.