Case Report

Osteoporosis and Fragility Fracture in Pregnancy A Case Report

Katherine Lau, Matthew Cauldwell and Susana Pereira*

Department of Obstetrics and Gynaecology, Kingston Hospital, UK

Submission: August 16, 2018;Published: October 11, 2018

*Corresponding author:Susana Pereira, Department of Obstetrics and Gynaecology, Kingston Hospital, Galsworthy Road, London, UK.

How to cite this article: Katherine Lau, Matthew Cauldwell, Susana Pereira. Osteoporosis and Fragility Fracture in Pregnancy A Case Report. Glob J Reprod Med. 2018; 6(2): 555682. DOI: 10.19080/GJORM.2018.06.555682.

Keywords: Endocrinology; Physiology; Osteoblastic; Osteoclastic; Femur fracture; Amenorrhoea; Anorexia nervosa; Pregnancy; Vaginal delivery; Rheumatologists; Parathyroid; Hypotholamaic-pituitary axis; Oestrogen; Premenopausal; Thromboembolism; Embryo-fetal toxicity; Bisphosphonates; Osteosarcoma; Hyperparathyroidism; Denosumab; Neonatal mortality

Abbrevations: BMD: Bone Mineral Density; PLO: Pregnancy and lactation Osteoporosis; DEXA: Dual-Energy X-Ray Absorptiometry; hPTH: Recombinant Human Parathyroid Hormone

Introduction

Osteoporosis is characterised by low bone mass secondary to inadequate acquisition of peak bone mass and/or increased bone loss. Osteoblastic and osteoclastic imbalances result in reduced bone mineral density (BMD), disrupting bone’s normal microarchitecture and predisposing to fragility fracture [1]. The prevalence of osteoporosis in premenopausal women is approximately 0.5%. Where there are no secondary causes of osteoporosis found (Table 1), it is termed idiopathic osteoporosis. Pregnancy and lactation are thought to cause secondary osteoporosis (PLO) [2]. The overall incidence of PLO remains largely unknown due to a lack of large scale population based data in this area [3]. Little is known about managing pregnancy induced BMD loss superimposed on pre-existing osteoporosis. This case illustrates the challenges faced in balancing the obstetric, medical and orthopaedic needs of such a patient.

Case Report

A 24-year-old non-smoking primagravida was referred for obstetric review at 13 weeks gestation having sustained a previous atraumatic left neck of femur fracture (conservatively managed). She had prior multiple low impact fractures to both wrists, ankles and left foot. Dual-Energy X-Ray Absorptiometry (DEXA) scanning showed Lumbar spine scores: T –2.7, Z –2.7, Left hip: T –2.3, Z -2.3, Left femoral neck: T-3, Z-3. Lumbar spine and left femoral neck T scores showed marked osteoporosis, whilst Z scores showed low BMD. Investigations for secondary osteoporosis were all negative, including bone biopsy (Table 1).

Risk factors for osteoporosis included a six-month period of amenorrhoea secondary to anorexia nervosa and six months of Roaccutane use. Pregnancy was uneventful and following obstetric and orthopaedic review vaginal delivery was recommended, with advice to limit lactation to 3 months postpartum. At 34 weeks gestation the patient presented with progressive right hip pain aggravated by weight bearing. MRI revealed a new right midsuperior pubic ramus stress fracture. Orthopaedic review advised minimal mobilisation with crutches for support. The patient opted for elective caesarean section under regional anaesthesia at 38 weeks, despite no formal contraindication for vaginal delivery. Rheumatologists advised a year long interval after ceasing lactation before conceiving again to allow bone recovery.

Discussion

PLO is thought to arise from a combination of factors. Karlson et al. [3] attributed pregnancy BMD loss to high fetal calcium transfer. Postnatally, raised parathyroid and prolactin levels suppressing the hypotholamaic-pituitary axis, reduced oestrogen production, decreased maternal weight reducing skeletal loading and breast milk calcium losses were suggested causes of BMD loss.

Paucity of longitudinal studies between BMD and fracture incidence in premenopausal women, means diagnosis of premenopausal diagnosis remains a challenge [2]. DEXA findings alone cannot be used to make a diagnosis in premenopausal patients and secondary causes must be excluded. Z-scores <-2.0 typically indicate low BMD, but if used in isolation may not correctly diagnose osteoporosis, as peak bone mass is not reached until 30 years of age [4]. Hence, Z-scores matched for age, sex and ethnicity are recommended for measuring BMD in premenopausal women versus T-scores [5].

Fractures are a cause of significant morbidity. Outside of pregnancy they are related to an increased risk of venous thromboembolism (particularly in lower limb/pelvic fractures) [6], depression [7], as well as chronic pain [8]. Those with premenopausal fractures have a 35% increased risk of postmenopausal fractures [9]. During pregnancy, the mainstay of treatment for severe osteoporosis is through calcium, vitamin D supplementation, falls prevention, physiotherapy and lifestyle changes. Calcium supplementation has been shown to be ineffective in preventing bone loss in lactation [10]; weight bearing exercises are less practical in the peripartum period and as most women cease alcohol and smoking in pregnancy, these interventions are likely to have minimal benefit. We have therefore reviewed the literature for alternative therapies.

Bisphosphonates act as potent osteoclastic inhibitors [11]. Although bisphosphonates are approved by the FDA for glucocorticoid-induced osteoporosis in certain pre-menopausal women, they are generally not recommended due to the risk of embryo-fetal toxicity [12]. Rodent studies have shown neonatal skeletal abnormalities and low birthweight [13]. Overall, use in premenopausal women remains contentious due to their long half-life within bone - in excess of ten years [14]. Stathopoulos et al. [15] reviewed 78 cases of fetuses whose mothers had been exposed to bisphosphonates either prior to or during pregnancy. A few cases reported shortened gestational age, low neonatal birth weight and transient hypocalcaemia, but overall none developed serious adverse events. Stathopoulos et al. [15] concluded that although the safety of bisphosphonates required more evidence, they advocated use of bisphosphonates in women of reproductive age as long as IV bisphosphonate was used (with use ceased 6 months prior to conception) and maternal and neonatal calcium levels were monitored.

Recombinant Human Parathyroid Hormone (hPTH) is an anabolic agent used to treat refractory osteoporosis by stimulating osteoblasts [3]. In a case series by Choe et al. [16] three women with PLO and vertebral fractures showed a reduction in pain and no further need for orthosis within 1-5 months of treatment, an improved BMD by 18 months of therapy and no adverse effects on subsequent pregnancies. Clinical trials have not yet been performed in premenopausal women after rodent studies raised concerns about fetal skeletal abnormalities including osteosarcoma [17,18]. However, with its short half-life (1 hour) Choe et al. [16] recommended hPTH as potentially successful for PLO patients with pain and multiple vertebral fractures. One report from Israel describes the use of PTH in pregnancy for hyperparathyroidism without any adverse fetal outcomes [19].

Denosumab, is a monoclonal anti-receptor antibody which decreases osteoclastic activity [20]. Unlike bisphosphonates, it has a shorter half-life and no skeletal accumulation [21,22]. However, in animal studies Denosumab was attributed to increased neonatal mortality and reduced growth. Drug related changes were also found in neonatal lymph nodes and bones [23]. In a single case of inadvertent Denosumab use one week into pregnancy, no adverse fetal or maternal outcomes were report [24].

Postpartum Management

Lactation is thought to cause bone losses of 3-10%, with pregnancy causing losses of 3-5% [3]. A direct relationship is thought to exist between the duration of lactation and degree of BMD reduction. Recovery of BMD is thought to take 6-12months after cessation of breastfeeding [5]. Discussion with the patient should occur to balance breast feeding benefits with risk of lactational osteoporosis.

References

1. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9(8): 1137-1141.
2. Abraham A, Cohen, A, Shane E (2013) Premenopausal Bone Health: Osteoporosis in Premenopausal Women. Clin Obstet Gynecol 56(4): 722-729.
3. Karlsson MK, Ahlborg HG, Karlsson C (2005) Maternity and bone mineral density. Acta Orthop 76(1): 2-13.
4. Cheng ML, Gupta V (2013) Premenopausal osteoporosis. Indian J Endocrinol Metab 17(2): 240-244.
5. Lewiecki EM, Watts NB, McClung MR, Petak SM, Bachrach LK, et al. (Aug 2004) International Society for Clinical Densitometry. Official positions of the international society for clinical densitometry. J Clin Endocrinol Metab 89(8): 3651-3655.
6. Shin WC, Lee SM, Suh KT (2017) Recent Updates of the Diagnosis and Prevention of Venous Thromboembolism in Patients with a Hip Fracture. Hip & Pelvis 29(3): 159-167.
7. Nota SP, Bot AG, Ring D, Kloen P (2015) Disability and depression after orthopaedic trauma. Injury 46(2): 207-212.
8. Gerbershagen HJ, Dagtekin O, Isenberg J, Martens N, Ozgur E, et al. (2010) Chronic pain and disability after pelvic and acetabular fractures- assessment with the Mainz Pain Staging System. J Trauma 69(1): 128-136.
9. Hosmer WD, Genant HK, Browner WS. (2002) Fractures before menopause: a red flag for physicians. Osteoporos Int 13(4): 337-341.
10. Kalkwarf HJ Specker BL, Bianchi DC, Ranz J, Ho M (1997) The effect of calcium supplementation on bone density during lactation and after weaning. N Engl J Med 337(8): 523-528.
11. Luigi S, Massimo V, Silvia C (2007) Pharmacokinetic profile of bisphosphonates in the treatment of metabolic bone disorders. Clin Cases Miner Bone Metab 4(1): 30-36.
12. Becker C, Cohen A (2016) Evaluation and treatment of premenopausal osteoporosis.
13. Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, et al. (1999) Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology 60(2): 68-73.
14. Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK, et al. (1997) Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 12(10): 1700-1707.
15. Stathopoulos IP, Liakou CG, Katsalira A, Trovas G, Lyritis GG, et al. (2011) The use of bisphosphonates in women prior to or during pregnancy and lactation. Hormones (Athens). 10(4): 280-291.
16. Choe EY, Song JE, Park KH, Seok H, Lee EJ, et al. (2012) Effect of teriparatide on pregnancy and lactation-associated osteoporosis with multiple vertebral fractures. J Bone Miner Metab. 30(5): 596-601.
17. (2002) United States Food and Drug Administration (USFDA) (2002) Medication Guide Forteo Teriparatide (rDNA origin) Injection.
18. Vahle JL, Sato M, Long GG, Young JK, Francis PC, et al. (2002) Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol 30(3): 312-321.
19. Ilany J, Vered I, Cohen O. (2013) The effect of continuous subcutaneous recombinant PTH (1-34) infusion during pregnancy on calcium homeostasis - a case report. Gynecol Endocrinol 29(9): 807-810
20. Miyazaki T, Tokimura F, Tanaka S (2014) A review of denosumab for the treatment of osteoporosis. Patient Prefer Adherence 8: 463-471.
21. Bekker PJ, Holloway DL, Rasmussen AS, Murphy R, Martin SW, et al. (2004) A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19(7): 1059-1066.
22. Baron R1 Ferrari S, Russell RG (2011) Denosumab and bisphosphonates: Different mechanisms of action and effects. Bone 48(4): 677-692.
23. Bussiere JL, Pyrah I, Boyce R, Branstetter D, Loomis M et al. (2013) Reproductive toxicity of denosumab in cynomolgus monkeys. Reprod Toxicol 42: 27-40.
24. Isobe F, Nakamura Y, Kamimura M, Uchiyama S, Kato H (2016) Effects of Denosumab Treatment during Early Pregnancy- A Case Report. J Nutr Disorders Ther 6: 189.