乌鸦传媒

Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

This month: A noteworthy case study.

What is causing this 34-year-old woman to have steadily worsening low back pain a month after the delivery of her first child by caesarean section? That's the medical challenge that faced Yoichi Kaneuchi, MD, PhD, of Fukushima Medical University in Japan, and colleagues.

As they reported in , the patient presented to hospital 3 months after the infant was born, rating the pain as 9 on a 10-point numeric rating scale (NRS). She had no history of fractures or any injury that might have accounted for the pain. She had already been treated at a nearby clinic without receiving analgesics, but the pain in her lower back had continued to become more severe.

Her medical history included a laparoscopic partial oophorectomy to manage endometriosis. She was a nonsmoker, had no history of alcohol consumption, and noted that her mother had osteoporosis but no fractures.

Physical Assessment

Clinical examination showed the patient's height was 160 cm (about 5'3"), weight was 50.2 kg (about 111 lbs), and body mass index was 19.6. Lumbar spine x-ray revealed loss of height at the L1–L4 vertebrae.

"Nonenhanced lumbar magnetic resonance imaging (MRI) revealed low intensity on T1-weighted imaging (T1-WI) and high intensity on short tau inversion recovery (STIR) imaging in the compressed vertebral body at L1–L4," Kaneuchi and co-authors wrote. They diagnosed her with vertebral fractures at L1–L4.

Lab Tests

Lab tests showed the following:

• Alkaline phosphatase: 109 IU/L (normal range: 38-119 IU/L)

• Serum calcium: 9.3 mg/dl (8.8-10.1 mg/dl)

• Serum phosphorus: 4.6 mg/dl (2.7-4.6 mg/dl)

• Parathyroid hormone: 24 pg/ml (10-65 pg/ml)

• Parathyroid hormone-related hormone protein (PTHrP) < 1.0 pmol/L (< 1.1 pmol/L)

• Thyroid-stimulating hormone: 0.27 U/ml (0.61-4.23 U/ml)

• Prolactin 51.7 ng/ml (3.12–29.32 ng/ml)

• 25-hydroxy vitamin D: 13.6 ng/ml (>30 ng/ml)

Assessment of bone turnover markers revealed a procollagen type I N-terminal propeptide (PINP) level of 76.1 ng/mL (normal range is 16.8-98.2 ng/mL) and tartrate-resistant acid phosphatase (TRACP)-5b of 476 mU/dL (normal 120-420 mU/dL). Findings of additional blood tests, including renal and liver function tests, were within the normal ranges.

The medical team used dual-energy x-ray absorptiometry (DXA) to assess the patient's bone mineral density (BMD) and Z scores, which were as follows before treatment.

• BMD: Lumbar spine (L1–L4): 0.852 g/cm², Z score: -2.1

• Right femoral neck: 0.710 g/m², -1.5

• Total hip: 0.726 g/ cm², -1.7

In the absence of any known cause of secondary osteoporosis, clinicians diagnosed the patient with pregnancy- and lactation-associated osteoporosis (PLO), and advised the patient to stop breastfeeding. They prescribed biweekly subcutaneous injection of teriparatide (Forteo) and oral supplementation of eldecalcitol (Edirol) (0.75 g/day). One week after starting these medications, the patient developed hyperphosphatemia (6.2 mg/dL).

The team then discontinued eldecalcitol and continued the patient on injections of teriparatide.

To manage her back pain, she was prescribed loxoprofen and used a thoracolumbar orthosis for 3 months, which gradually lessened the pain to NRS 2.

On the fourth month of teriparatide treatment, the patient reported sudden worsening of her pain (back up to NRS 4) when she was holding her baby. Additional radiological examinations then showed:

• Plain radiographs of the lumbar spine indicating slight loss of height at the Th11 vertebra

• MRI of the thoracolumbar spine detected low signal intensity on T1-WI and high signal intensity on short tau inversion recovery at both the Th11 and L5 bodies

As a result, the patient was diagnosed with new vertebral fractures at Th11 and L5. Throughout her treatment, BMD was monitored with DXA.

After 4 months of biweekly teriparatide, BMD and Z scores were as follows:

• Lumbar spine (L1–L4): 0.842 g/cm², -2.2

• Right femoral neck: 0.723 g/cm², -1.3

• Total hip: 0.721 g/cm², -1.7

To exclude Cushing's syndrome, the team measured the patient's serum cortisol and adrenocorticotropic hormone levels, both of which were now within normal range. Similarly, the PINP level increased to 113 ng/mL, and TRACP-5b decreased to 348 mU/dL.

After discussing these findings with the patient, clinicians learned she had severe nausea after every teriparatide injection. In light of the new vertebral fractures and lack of improvement in BMD, the decision was made to discontinue teriparatide and start romosozumab (Evenity) along with calcium and eldecalcitol.

Two months later, the patient reported that her lower back pain was greatly relieved, to an NRS of 0. Clinicians similarly noted an improvement of signal change on Th11 and L5 vertebrae on MRI, and the following increases in BMD and Z scores at 2 and 12 months post-treatment with romosozumab:

After 2 months:

• Lumbar spine (L1–L4): 0.879 g/cm², -1.9

• Right femoral neck: 0.731 g/cm², -1.3

• Total hip: 0.770 g/cm², -1.3

After 12 months:

• Lumbar spine (L1–L4): 1.053 g/cm², -0.05

• Right femoral neck: 0.754 g/cm², -1.2

• Total hip: 0.807 g/cm², -1.0

Discussion

PLO is a rare type of premenopausal osteoporosis that occurs mainly in the third trimester or immediately after delivery, with back pain due to vertebral fracture one of the most common symptoms, Kaneuchi and co-authors noted, adding that they believe this case to be the first report of a patient with PLO treated with romosozumab following 4 months of teriparatide.

Pathogenesis remains unclear, and there is no consensus about treatment, the team said. The estimated incidence of PLO is about 4-8 cases per 1,000,000 women, or even higher given the likelihood of undiagnosed cases. Patients often present with back pain due to a vertebral fracture; and more than two thirds of reported cases have occurred in a first pregnancy.

Pregnancy and breastfeeding require about 200-250 mg of calcium daily, Kaneuchi and co-authors noted. Most of the calcium required for lactation comes from bone, causing a transient 3-9% decrease in bone density.

As this case reflects, breastfeeding women have decreased levels of 1,25-dihydroxyvitamin D and higher levels of PTHrP and prolactin compared with their nonlactating counterparts.

Risk factors that may predispose women to PLO include being underweight or deficient in vitamin D, having a history of low BMD, lifestyle factors such as smoking or excessive alcohol consumption, osteoblast dysfunction, and certain gene mutations. That the case report patient's mother had developed postmenopausal osteoporosis in her 40s may have been a factor in the patient's premenopausal osteoporosis, although the cause remains unclear.

The goals of treatment are to prevent subsequent fractures, relieve pain, and increase BMD. Cessation of breastfeeding and calcium supplementation with or without vitamin D are central, and can increase lumbar BMD by 3.5-6.2% over 12 months, the team said.

Osteoporosis including bisphosphonate, strontium ranelate (SrRan), denosumab, and teriparatide have also been used to treat PLO.

"Bisphosphonates increase BMD by inhibiting bone resorption," the authors explained. In PLO patients, alendronate or zoledronate plus calcium and vitamin D supplementation has been associated with mean annual increases of 10.2–17.0% in lumbar spine BMD and 2.6–6.5% in femoral neck BMD. However, due to a half-life of up to 10 years, bisphosphonates pose teratogenic risks for subsequently conceived fetuses.

Experience with SrRan in PLO patients is limited; this dual action medication stimulates formation of new bone and inhibits bone resorption, the group noted. In postmenopausal patients, it has significantly the risks of new vertebral and nonvertebral fractures, and rapidly increased both lumbar spine and femoral neck BMD.

In women with PLO who stopped breastfeeding, treatment with SrRan, calcium, and cholecalciferol has increased lumbar BMD by 31–33% and total hip BMD by almost 20% at 12–21 months. And while SrRan has a shorter half-life of about 60 hours, the long-term safety and potential adverse prenatal effects are not known.

"Denosumab is a human monoclonal antibody that binds to the receptor activator of nuclear factor B-ligand (RANKL), and inhibits the activation of osteoclasts and their precursors, leading to a suppression of bone turnover and an increase in BMD," Kaneuchi and co-authors wrote. A 60 mg dose has a mean half-life of 25.4 days, and declines in concentration over a period of 4-5 months.

Teriparatide is an osteoanabolic medication that does not accumulate in the bone, and improves lumbar BMD values of PLO patients by almost 20% at 12 months and by 19–36% at 18 months, the authors said.

The relatively short half-life of an hour suggests it may be a safe treatment for women with PLO, particularly before they become pregnant or after they finish breastfeeding. Continued treatment, though, as in this case, can be problematic, with data from Japan showing that fewer than half of patients are able to continue with any teriparatide regimen beyond 12-months, often due to nausea.

This highlights the need for an alternative treatment for PLO: "Romosozumab is a monoclonal antibody to sclerostin, which is a glycoprotein that inhibits the classic Wnt/-catenin signaling to suppress bone formation," Kaneuchi and co-authors wrote.

Romosozumab has a half-life of 12.8 days, and like SrRan, is a dual action medication that both stimulates bone formation and suppresses bone loss. Data to date around the incidence of cardiovascular and cerebrovascular adverse events with romosozumab are conflicting, the team noted.

Teriparatide treatment was discontinued in this patient due to the lack of improvement in BMD and her intolerance to the medication; however, there was an urgent need to increase her lumbar spinal BMD quickly to prevent further fractures. Therefore, although there was no previous report of romosozumab treatment in PLO, the team suggested romosozumab and the patient agreed, the authors said, adding that the sequential treatment after anabolic agents is an important concern.

After 4 months of teriparatide followed by 12 months of romosozumab, the patient's BMD values were increased from baseline by 23.6% at the lumbar spine, 4.3% at the femoral neck, and 11.9% at the total hip, with no treatment side effects or subsequent vertebral fracture, the authors reported. They added that they would use the treatment again if the patient were to develop PLO after delivering a second child.

"Romosozumab has the potential to be a therapeutic option to improve BMD and reduce the subsequent fracture risk of patients with pregnancy and lactation-associated osteoporosis," Kaneuchi and colleagues concluded.

Read previous installments in this series:

Part 1: New Insights Into the Complex Biology of Osteoporosis

Part 2: The Latest on Osteoporosis Treatment and Diagnosis

Part 3: Osteoporotic Fragility Fractures