Transient osteoporosis of the hip in pregnancy

Abstract

Transient osteoporosis of the hip is an uncommon bone marrow oedema syndrome of unknown pathophysiology affecting previously healthy pregnant women and young to middle-aged men. The disorder is characterised by hip pain, reduced mobility, and the risk of fracture, which is significantly higher in pregnant than in non-pregnant individuals. Diagnosis is by magnetic resonance imaging. Other than a single case-control study, published literature is limited to case series and case reports, with no evidence to guide management, risk of fracture, mode of delivery, safety of breastfeeding and risk of recurrence. An international pregnancy registry may be useful to try to answer some of these questions.

Keywords

Transient osteoporosis hip pregnancy

Introduction

The bone marrow oedema syndromes (BMES) are a group of metabolic bone disorders characterised by pain, with bone marrow oedema on magnetic resonance imaging (MRI). BMES include transient osteoporosis of the hip (TOH), regional migratory osteoporosis, and complex regional pain syndrome. TOH affects the proximal femur of previously well young to middle-aged men and pregnant women. The incidence of TOH is higher in men compared with women, with a ratio of 1.5–3:1.^1–3 A two-year prospective study found one case of TOH in pregnancy (TOHP) in 4900 pregnancies.⁴ Other estimates have placed the incidence as low as 0.4 cases per 100,000 pregnancies, though it is likely to be an underestimation due to undiagnosed cases.⁵ The risk of femoral neck fracture in TOH is significantly higher in pregnant women (25.7%) than men (0.8%).⁶

Hip pain has been reported by up to 38% of women during pregnancy.⁷ Causes include round ligament pain, TOHP, greater trochanteric pain syndrome, femoroacetabular impingement, hip labral tear, developmental dysplasia of the hip, hip osteoarthritis and aseptic necrosis of the femoral head.⁸

Bone mineral density (BMD) declines by 1.8% at the lumbar spine and by 3.2% at the total hip during pregnancy.⁹ The first 3–6 months of lactation is associated with a 5% to 10% fall in lumbar spine BMD.^10,11 Increased water content of femoral head and marrow in normal pregnancy may result in artifactually low bone density on dual-energy X-ray absorptiometry (DEXA).¹² Bed rest during pregnancy is associated with significant trabecular bone loss and reduction in ultra-distal radius bone density.¹³ Use of DEXA has been avoided in pregnancy and deferred until the postpartum period due to concern regarding exposure of the fetus to ionising radiation, uncertainty as to whether results may change management decisions, and issues regarding interpretation. With the evolution of scanners, the fetal radiation doses during the second and third trimester for DEXA of the proximal femur using a pencil beam unit is estimated to be 1 mGy.¹⁴ This is considerably lower than the background radiation exposure to the fetus of 3.1 mGy, the levels of fetal exposure associated with a stochastic increased risk of later childhood malignancy (>10 mGy), or the level at which fetal harm may occur (>50 mGy).¹⁵

An alternative method of assessing BMD during pregnancy without ionising radiation may be a sonographic examination of the proximal femur using radiofrequency echographic multi-spectrometry (REMS) technology.¹⁶

Markers of bone formation fall in early healthy pregnancy, with a subsequent rise in the third trimester to non-pregnant levels.¹⁷ N-telopeptide: creatinine levels, a marker of bone resorption, rise from early pregnancy and remain elevated for up to nine months postpartum in women lactating compared with pre-conception values.

Levels of bone turnover markers (BTMs) rise significantly following acute fracture and may not return to baseline for 4–12 months.¹⁸

Objective

To review the available literature as to whether any recommendations can be made regarding prediction of fracture, prevention of fracture, relief of pain, prevention of loss of mobility, preferred mode of delivery, risk of recurrence in subsequent pregnancies and risk of breastfeeding in women with TOHP.

Methods

Previous case reports of TOHP were identified by a search of Medline, EMBASE and Google Scholar from 1956 to December 2022 using the terms ‘pregnancy’, ‘transient osteoporosis of the hip’, ‘bone marrow oedema’ and ‘regional algodystrophy’. Abstracts were used to filter results. The references from the case series and case reports obtained were manually reviewed to identify additional studies. Chi-squared tests were used to assess the risk of fracture related to the mode of delivery.

Case

A 36-year-old primigravida woman was referred to the medical antenatal clinic at 35 weeks’ gestation because of proteinuria, subsequently found to be artifactual. The woman complained of right hip pain onset at 22 weeks’ gestation requiring a single stick for mobility. She had been seeing a physiotherapist, general practitioner, and midwife, without a clear diagnosis. MRI demonstrated marked bone marrow oedema of the right femoral neck and head, subchondral fractures, soft tissue oedema and moderate hip joint effusion consistent with TOHP. Mild bone marrow oedema, soft tissue oedema and a small hip joint effusion were seen in the left hip. Serum calcium, phosphate, parathyroid hormone, 25-hydroxy vitamin D (25OHD), fibroblast growth factor 23, C-telopeptide and urine N-telopeptide, calcium and phosphate were normal. Procollagen type 1 N-terminal propeptide (P1NP) and bone alkaline phosphatase were elevated at 233 μg/L (nonpregnant 15–90), and 18.4 μg/L (2.9–14.5), respectively. Parathyroid-hormone-related peptide assay was not available. The woman elected to defer DEXA and consideration of medical therapy until the postpartum period. The development of progressive pain in the left hip prompted delivery by elective caesarean section at 38 weeks’ gestation. DEXA on the second postpartum day showed normal values for age with Z scores of −1.2 for the lumbar spine, −0.7 for the total hip, and −0.9 for the femoral neck. The woman elected to breastfeed. Because of increasing pain in the left hip, the woman trialled subcutaneous calcitonin for three days, however, was intolerant of this because of headache. Her pain settled spontaneously after three weeks postpartum. Follow-up MRI one month postpartum demonstrated improvement in bone marrow oedema and hip joint effusions bilaterally. By three months postpartum, the woman was asymptomatic, and MRI showed complete resolution of bone marrow oedema, and the previously demonstrated subchondral fractures were no longer visible.

Review of previous case reports and case series

There were 143 cases of TOHP with adequate information for analysis. The average and median maternal age was 32 years. Fifty-five of 77 (71%) women were nulliparous. There were eight twin pregnancies. The mean delay between the onset of symptoms and diagnosis (n = 55) was seven weeks (median four weeks). Predisposing factors stated included one woman with a restrictive eating disorder, two women who had received recent glucocorticoid therapy, one woman with osteogenesis imperfecta, and three women who had vitamin D deficiency. Symptoms of TOHP were unilateral in 73.5% and bilateral in 26.5% of cases in one large series.¹⁹

Fractures

Twenty-seven women (24.7%) sustained fractures of the femoral neck (#NOF). Ten women had fractures antepartum (9.2%), between 28 and 39 weeks’ gestation. In two women, the diagnosis of TOHP had been made prior to fracture. Of the remaining eight women who sustained a fracture prior to the diagnosis of TOHP being made, one each had consulted their obstetrician and an orthopaedic surgeon, respectively, who had declined to perform imaging because of fetal concerns. The mean delay in the onset of symptoms and fracture was 4.7 weeks (range: 0–8 weeks). Six women had a closed reduction and internal fixation during pregnancy without adverse fetal or maternal outcomes. In four women, surgery was delayed until the postpartum period.

Twelve women (11%) had a peripartum fracture, defined as within seven days of delivery. The mode of delivery was stated in 67 of the 99 women who did not sustain a fractured neck of femur antepartum. Of these women five of the 40 (12.5%) who delivered by caesarean section and seven of the 27 (25.9%) who had vaginal delivery were diagnosed with a fractured neck of femur within seven days of birth (NS; p = 0.28).

Five women (4.6%) had a fracture more than one week after delivery (range: 2–20 weeks postpartum).

Neck of femur fractures were bilateral in nine women (33%) and unilateral in 18 women (67%).

Maternal fractured neck of femur occurred in two of the eight (25%) twin pregnancies.

Other complications

In a case series of 34 patients where antithrombotic prophylaxis was used in 10 women (29.4%), one woman (2.9%) had venous thromboembolism.¹⁹ Nine women (26.5%) had oedema or inflammation of a lower limb.

Bone mineral density

Sixteen women had BMD performed postpartum (Table 1). Femoral neck values were provided in 11 women. Four women had normal BMD with Z scores greater than and equal to −2.0, seven had osteoporosis with T scores less than −2.5 (n = 4) or Z scores less than −2.0 (n = 3). A 15-year retrospective study of six women with TOHP found that five women had osteopenia of the lumbar spine, and BMD was normal in the remaining patients.⁴ Femoral neck values were not stated. A review of BMD in 126 non-pregnant individuals with BMES found that 35.7% of individuals had normal BMD, 38.9% were osteopenic and 25.4% had osteoporosis.³ The significance of BMD results previously reported is difficult to assess due to the delay between the onset of symptoms and BMD, raising the possibility that individuals may have been in the recovery phase of the disorder during imaging.

Table 1.

Safety of therapies for TOHP in pregnancy and lactation.

Therapy	Safety in pregnancy	Safety in lactation
Standard analgesics
Paracetamol⁴⁷	Analgesic of choice	Analgesic of choice
Codeine⁴⁷	Compatible – avoid long-term use	Use with caution – risk of neonatal neurological depression
Tramadol⁴⁷	Avoid first trimester and periconception	Compatible with short-term use
Tramadol⁴⁷	Only consider in the second and third trimesters if no alternative analgesia is available	Compatible with short-term use
COX-2 inhibitors	Avoid – limited safety data
NSAIDs	May be used until 20 weeks’ gestation	Compatible – most experience with ibuprofen
Calcitonin^31,48,49	Safe	Safe
Bisphosphonates^47,50–52 *	143 mother-child pairs with exposure pre-conception or during pregnancy	Absorption of oral bisphosphonates unlikely – risedronate may be an agent of choice due to its short half-life
	Marginal decreases in gestational age and weight	Maternal IV pamidronate results in very low levels in breast milk – suggest withholding breastfeeding for 12 h post-dose
	Cases of transient neonatal hypocalcaemia
	No long-term consequences were reported in infants/children	No data re zoledronic acid
Iloprost⁵³	Only five cases of nebulised iloprost use in pregnancy for maternal pulmonary hypertension – no adverse effects	No data
Iloprost⁵³	Single case of IV iloprost five days pre-delivery	No data
Recombinant hPTH/teriparatide ^54–56	Used in four pregnancies only	Two infants breastfed for 6–8 months
Recombinant hPTH/teriparatide ^54–56	Only adverse outcome was a single case of preeclampsia at 36 weeks	No adverse events
Denosumab	No data	No data
Romosozumab	No data	No data
Hyperbaric oxygen⁵⁷	Safe when used for carbon monoxide poisoning	No data
ESWT⁵⁸	No data	No data

COX-2: cyclo-oxygenase; hPTH: human parathyroid hormone; ESWT: extracorporeal shock wave therapy; IV: intravenous; NSAIDs: non-steroidal anti-inflammatory drugs.

*British Society of Rheumatology guidelines state there is insufficient data to recommend bisphosphonates during pregnancy or breastfeeding.

Bone turnover markers

Parathyroid hormone, serum calcium and 24-h urine calcium were normal in all 26 women for whom results were available. 25OHD was low in three of 25 women. With respect to markers of bone resorption, telopeptide levels were normal in two women when measured postpartum in the absence of fracture, urine hydroxyproline was elevated in one postpartum woman in the absence of fracture, though normal in another four women in the absence of fracture (two in third trimester, two in postpartum), and urine deoxypyridinoline: creatinine ratio was three times the upper end of the normal range in one woman when measured two weeks postpartum in the absence of fracture. Markers of bone formation revealed P1NP to be elevated twice the upper end of the normal range in one woman (postpartum, no fracture), bone alkaline phosphatase to be normal in one woman (postpartum, no fracture), and osteocalcin to be minimally elevated in one woman (two weeks postpartum, no fracture). Twenty-four-hour urine cortisol was normal in two women.

Radiological resolution

TOHP was diagnosed by MRI in 60 women. Follow-up MRI was normal in all 22 women in whom this was performed, the earliest of these being six weeks after initial diagnosis, the latest being 12 months postpartum.

Medical treatment

The timing of resolution of symptoms was not significantly different if TOHP was unilateral or bilateral, or whether physiotherapy or acupuncture was performed.¹⁹

One woman was treated antepartum with subcutaneous calcitonin from 24 weeks’ gestation, with 50% improvement in symptoms and range of motion after two weeks, and normal range of motion after nine weeks of therapy.²⁰ The woman delivered a healthy male birthweight 3100 g by spontaneous vaginal birth at 38 weeks’ gestation. Follow-up MRI immediately postpartum was normal. Fourteen women were treated with medical therapy postpartum, and four of these women had sustained fractured neck of femur prior to delivery. None of the remaining 10 women who received medical therapy postpartum sustained fractured neck of femur. Therapeutic agents included various parenteral and oral bisphosphonates (n = 8), calcitonin (n = 5) and teriparatide (n = 2). In addition, seven women received intravenous iloprost for pain relief. One woman had minimal benefit with iloprost and proceeded to bisphosphonate therapy.²¹ The other six women noted improvement during the first two weeks after beginning iloprost, with the severity of pain at rest on visual analogue score decreasing from a mean of 44 mm to 2 mm after four weeks.²² One woman was treated with a total of 30 sessions of hyperbaric oxygen over a six-week period, becoming pain-free with a full range of motion of the hip one month after commencing treatment.²³ Two women had core decompression postpartum, the efficacy with regard to pain relief was not stated.

Time to pain-free mobility

As stated, the median and mean time to pain-free mobility was eight and 12 weeks, respectively (range: few days to six months). The mean time to pain-free mobility in women who received antiresorptive agents was 11 weeks, although this information was only available for eight women.

Safety of lactation

Breastfeeding status was stated in only 19 women. None of the women who elected to breastfeed (duration three weeks to six months) sustained fractured neck of femur.

Recurrence

Recurrence of TOHP occurred in three of 21 subsequent pregnancies (14%).¹⁹ Women with TOHP delivered an average of 1.2 children compared with 1.8 children in controls.²⁴

Review of literature

Pathophysiology

The aetiology and pathogenesis of TOHP are unknown. A potential genetic predisposition related to mutations in collagen type 1 alpha 2 chain is suggested by a case-control study finding that severe dental problems during childhood were associated with increased risk of TOHP, one case of TOHP associated with osteogenesis imperfecta, the finding of a novel mutation in COL1A2 in a male patient with transient regional osteoporosis, and a higher rate of familial osteoporosis in individuals with TOHP.^19,24,25,26 Acquired factors that may predispose to TOHP include less sporting activity before and after puberty, obesity, and immobilisation during pregnancy.

The intraosseous pressure increases from 20–30 mmHg in healthy individuals to 50–90 mmHg in BMES.²⁷ The rise in intraosseous pressure may be a factor in driving fluid through canaliculi to penetrate the subperiosteal space, affecting osteocyte activity and bone turnover, and causing pain.²⁸

Peripheral blood BTMs in non-pregnant individuals with BMES of the hip were unchanged compared with healthy individuals. In aspirate samples obtained from cancellous bone in non-pregnant individuals with BMES, the bone marrow to peripheral blood ratios of bone formation and resorption were elevated, indicating increased bone turnover.²⁹

Histomorphological features of bony trabeculae in areas of bone marrow oedema show osteoblast-covered osteoid seams and formation of irregular woven bone consistent with increased bone formation, without evidence of preceding or active osteoclastic resorption, and vascular reconstruction with under-mineralised bone. Histologic changes tend to correlate with features on MRI.³⁰

Efficacy of therapies in men and non-pregnant women

There is a lack of a standardised treatment protocol in the literature regarding the management of BMES/TOH in men and non-pregnant women. Therapies used in BMES have varied postulated mechanisms of action. Bisphosphonates, calcitonin, denosumab and teriparatide have effects on bone resorption and bone formation, as well as anti-inflammatory properties. Calcitonin has been shown to have a central analgesic effect in animal studies.³¹ Iloprost is a synthetic prostaglandin which leads to vasodilation, and absorption of interstitial fluid, reducing bone marrow oedema and intraosseous pressure.³² Iloprost may also have osteoblastic activity.³³ It has been postulated that hyperbaric oxygen therapy (HBOT) may be beneficial in TOH by reducing intraosseous oedema, increasing bone repair, causing proliferation of collagen and fibroblasts, and stimulating new capillary formation.³⁴ Extracorporeal shockwave therapy (ESWT) exerts angiogenic and trophic effects, and results in osteoblast and periosteal cell activation.

A systematic review found that in studies with a follow-up of less than one month, all 19 patients who received bisphosphonates, and 16 out of 29 (55%) who underwent core decompression were pain-free.² In studies with 1–3 months of follow-up, 62 out of 71 (87%) were treated with bisphosphonates, all 23 of those treated with iloprost, and 47 out of 48 (98%) of those who had core decompression were pain-free. In the conservative group, all 59 patients managed with simple analgesics and restricted weight bearing had regression of pain after 3–6 months, and resolution of pain by 6–12 months.

A triple-blind, randomised, placebo-controlled trial of a single dose of intravenous zoledronic acid in individuals with BMES affecting the hip (n = 10), knee (n = 17) and foot/ankle (n = 18) found a statistically significant 64% mean reduction in oedema on MRI and a reduction in pain score at six weeks compared with placebo.³⁵

The use of calcitonin for TOH has been described in 20 cases.^20,36–41 Resolution of pain occurred after a mean of three months of therapy (range: eight days to eight months).

A single case of TOH managed with teriparatide noted complete resolution of pain and normalisation of MRI after four weeks of therapy.⁴²

A study of 14 individuals with BMES of the lower limb demonstrated an improvement in bone marrow oedema on MRI in 93% of individuals within 6–12 weeks of a single dose of denosumab, with resolution of pain in half of the patients.⁴³

A randomised controlled trial in 44 patients comparing standard analgesia and protective weight bearing with standard therapy plus 40 sessions of HBOT found resolution of MRI changes in 55% of the HBOT group compared with 28% of the control group after three months of treatment.⁴⁴ Pain had completely resolved in 70% of the HBOT group versus none of the control group.

Compared with core decompression, ESWT is associated with greater improvements in visual analogue scale pain scores, earlier resumption of daily activities, and earlier complete resolution of symptoms.⁴⁵ A prospective study in 20 consecutive patients found high energy ESWT was associated with a dramatic improvement in Harris hip score and a greater than 50% reduction in mean oedema area on MRI two months post-treatment.⁴⁶

Safety of medical therapies in pregnancy and breastfeeding

The safety of medical therapies in pregnancy and breastfeeding is summarised in Table 1.

Discussion

TOHP may result in substantial maternal morbidity during pregnancy and in the postpartum period, potentially affecting maternal mobility, self-care, pain and sleep during the antepartum period, decisions regarding mode of delivery, ability of the mother to care for her newborn, the safety of breastfeeding, and concern regarding the risk of recurrence in subsequent pregnancy. Femoral neck fracture and subsequent surgery may result in short- and long-term complications. The underlying pathogenesis of TOHP is unknown and there are no studies to guide the need for, or efficacy of, intervention. Early diagnosis is important regarding the woman's understanding of the cause of pain and reduced mobility, as well as consideration of potential management strategies to reduce pain, lessen the impact on mobility and prevent fracture. Increased education regarding TOHP amongst health professionals, particularly obstetric physiotherapists and midwives, is important to enable early diagnosis and promote awareness that MRI should be considered in any pregnant woman presenting with otherwise unexplained hip pain. Further investigation into pathophysiology could involve obtaining histological specimens and measuring cytokines and growth factors important in bone remodelling in surgical specimens in women who sustain fractures. A significant difficulty in evaluating the value of BMD in prediction of fracture risk is that TOHP is a self-limiting condition in which symptoms and BMD spontaneously improve. Studies measuring BMD either by REMS to avoid fetal radiation, or DEXA given its minimal fetal radiation exposure, at the time of initial presentation/diagnosis may determine whether BMD is predictive of fracture and can be used to guide consideration of treatment. Placebo-controlled randomised trials of anti-resorptive agents in the postpartum period and non-pregnant women and men, assessing effects on pain, fracture reduction and improvement in mobility may be useful regarding extrapolation to the management of antenatal TOHP. Where antiresorptive medications are used during pregnancy, measures of drug levels in cord blood may assist in assessing the risk of transplacental passage.

A study investigating the causes, natural history and responses to treatment of Transient Osteoporosis of Pregnancy is being performed at the University of Edinburgh, funded by the Royal Osteoporosis Society.⁵⁹

Limitations

This review is limited by the absence of published randomised or prospective studies addressing investigation or management of TOHP. The review is based on case studies and two retrospective case series, with the inherent risks of bias in patient selection for a particular mode of delivery, as well as reporting and publication bias. Incomplete data recording and the tendency to report favourable outcomes may also limit the applicability of the data reviewed. Data was limited in many of the case studies and series.

Conclusion

An International Pregnancy Registry may be useful to try to address the following questions:

What is the underlying pathogenesis of TOHP?

Does BMD at the time of diagnosis predict future fracture risk or response to therapy?

Are any treatments efficacious? Are treatments safe during pregnancy and breastfeeding?

Does the mode of delivery influence the risk of fracture or rate of recovery?

Does breastfeeding increase the risk of postpartum fracture or rate of recovery?

What is the risk of recurrence in subsequent pregnancy?

A modification of the European League Against Rheumatism Core data set including MRI and BMD findings, BTMs, fracture data, and efficacy of treatment with respect to pain response and fracture prevention may be suitable as a core data set for an Internal Pregnancy Registry.⁶⁰

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Ethical approval was provided by Mater Health Human Research and Ethics Committee (EXMT/MML/92873).

Informed consent

Not applicable.

Guarantor

AM is the guarantor of the present work.

Contributorship

AM and JSH cared for the patient, researched, wrote and reviewed the manuscript.

ORCID iDs

Adam Morton

Jennifer Savard-Heppel

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