|Year : 2020 | Volume
| Issue : 3 | Page : 229-235
Secondary osteoporosis: Case-based review
Pragya Gupta, Johns T Johnson, Kripa Elizabeth Cherian, Hesarghatta Shyamsunder Asha, Nitin Kapoor, Thomas Vizhalil Paul
Department of Endocrinology Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
|Date of Submission||16-Apr-2020|
|Date of Decision||17-May-2020|
|Date of Acceptance||26-May-2020|
|Date of Web Publication||10-Jul-2020|
Dr. Thomas Vizhalil Paul
Department of Endocrinology Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Secondary osteoporosis is an important clinical condition associated with significant morbidity and mortality. Many systemic conditions like autoimmune inflammatory disease, diabetes mellitus and drugs like glucocorticoid use are associated with secondary osteoporosis, diagnosis of which often requires high index of suspicion. Identification and treatment of the underlying cause itself can result in significant improvement in bone health. In this review we describe 5 case based scenarios discussing the diagnosis and management of some important causes of secondary osteoporosis.
Keywords: Corticosteroids, hypogonadism, multiple myeloma, secondary osteoporosis
|How to cite this article:|
Gupta P, Johnson JT, Cherian KE, Asha HS, Kapoor N, Paul TV. Secondary osteoporosis: Case-based review. Curr Med Issues 2020;18:229-35
| Introduction|| |
Osteoporosis literally means “porous bone.” The World Health Organization (WHO) defines osteoporosis as a “progressive systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.” Osteoporosis is classified as primary osteoporosis (postmenopausal or age related), secondary osteoporosis, and idiopathic osteoporosis (characterized by low bone density and fractures in young adults without known cause). Secondary osteoporosis is defined as low bone mass with microarchitectural alterations in bone, leading to fragility fractures in the presence of an underlying disease or medication. The goal of management of osteoporosis is to prevent a subsequent fracture from occurring and its attendant morbidity and mortality. The failure to identify a possible secondary cause of osteoporosis might lead to suboptimal benefits of treatment or treatment failure.
| Epidemiology|| |
Worldwide, the true incidence and prevalence of osteoporosis are difficult to determine because of inadequate screening and under-diagnosis of this condition. The most useful way of comparing osteoporosis prevalence between populations is to use fracture rates in older people. The current consensus is that approximately 1.66 million hip fractures occur each year worldwide, that the incidence is set to increase four-fold by 2050. Secondary causes of osteoporosis have been reported in many patients with osteoporosis: 30%–60% of men, more than 50% of premenopausal women, and about 30% of postmenopausal women have secondary etiologies.
In this review, common causes of secondary osteoporosis and a general approach to secondary osteoporosis are presented.
| Case 1|| |
A 40-year-old premenopausal female presented to the outpatient department (OPD) with a history of acute onset back pain, which she developed after she had bent down to pick up a bucket of water. The X-ray showed that she had sustained a compression fracture of the 12th thoracic vertebra [Figure 1]. Her bone mineral density (BMD) is shown in [Figure 2].
|Figure 1: X-ray LS spine of case 1 showing compression fracture of T12 vertebrae.|
Click here to view
|Figure 2: Bone mineral density of case 1 showing low bone mass at lumbar spine (Z score-4.2) and femoral neck (Zscore-3.9).|
Click here to view
Question 1: Does the patient have osteoporosis?
She had suffered a fracture from a force that is not sufficient to cause a fracture (a fragility or low trauma fracture). This satisfies the clinical definition of osteoporosis that is, a condition where the bones are brittle and susceptible to fracture.
In routine clinical practice, BMD is considered as an approximate measure of bone mass. It is measured by dual-energy X-ray absorptiometry (DXA) and is expressed in g/cm2. The usual sites of BMD assessment are the hip or spine. Distal forearm BMD measurement may be done in conditions where hip/spine BMD is nonevaluable or in cases of hyperparathyroidism.
The following two scores are calculated from DXA: T-score and Z-score.
T-score: The T-score compares a person's BMD to that of a young normal population.
T-score = Patient's measured BMD-Mean BMD of young normal population.
Standard deviation (SD) of BMD of young normal population.
The WHO classification with T score is summarized in [Table 1]. It cannot be applied to healthy premenopausal women, men under the age of 50 years and children.
Z-score the Z score compares a person's BMD with other people of the same age and gender.
Z-score = Patient's measured BMD−Mean BMD of age-matched group.
SD of BMD of age-matched group.
The Z-score is useful for interpreting BMD in healthy premenopausal women, men under age 50 and children.
Z score above-2.0 is defined as “within the expected range for age.”
Z score-2.0 or less is defined as “below the expected range for age.”
This patient, thus has osteoporosis according to both clinical and BMD definitions.
Question 2: Should this patient be screened for secondary causes of osteoporosis?
To answer this question, the following facts needs to be noted:
A secondary cause of osteoporosis can be identified in more than half of premenopausal females.
The list of secondary etiologies is summarized in [Table 2]. Various medications also increase the risk of osteoporosis [Table 3].
Overall the most common etiology of osteoporosis in women is postmenopausal osteoporosis. However, in premenopausal women, the most common causes are hypo-estrogenemia, use of corticosteroids, anticonvulsant therapy and hyperthyroidism.
Taking into account these factors, a detailed history was obtained from the patient. She admitted to the use of over the counter medications for nonspecific joint pain since the past 10 years, and a review of her medications confirmed that these tablets were steroids (Tab. Prednisolone 5 mg). A low 8am serum cortisol level (0.5 mcg/dL), confirmed suppression of the hypothalamic-pituitary-adrenal axis.
Thus she was diagnosed to have severe osteoporosis secondary to chronic self-medication with exogenous corticosteroids.
| Case 2|| |
A 35-year-old man was referred from the department of hepatology for clearance for liver transplantation. He was diagnosed to have chronic hepatitis B related decompensated liver disease and was on anti-viral treatment with tenofovir for the past 10 years. He also had 5 years history of ethanol consumption, which he had stopped for the past 8 years. On examination, he had a BMI of 19 kg/m2 with stigmata of chronic liver disease (CLD). Testicular volume was 15 ml bilaterally with Tanner 4 pubic hair growth.
His BMD [Table 4] indicated osteoporosis.
Question 1: Should you investigate for possible secondary causes of osteoporosis in this patient?
Yes. upto two-thirds of men have secondary etiologies for osteoporosis. The most common etiologies for osteoporosis in men are: alcohol abuse, glucocorticoid excess (either endogenous Cushing's syndrome or, more commonly, chronic glucocorticoid therapy), and hypogonadism.
Question 2: What investigations are warranted as part of secondary osteoporosis workup?
The workup of secondary osteoporosis is summarized in [Table 5].
This gentleman's workup showed the following: Hemoglobin-14.0 g/dL(13–17), calcium-9.26 mg/dL (8.3–10.4), fasting phosphorous-2.9 mg/dL (2.5–4.6), albumin-2.4 g/dL (3.5–5.0), 25 (OH) Vitamin D-32.7 ng/mL (30–70), creatinine-0.60 mg/dL (0.5–1.4), alkaline phosphatase – 170 U/L (40–125), 8 am testosterone– 678 ng/dl (270–1030), electrocardiogram (ECG)-sinus rhythm.
Ultrasound abdomen was suggestive of CLD with coarse echo-texture of the the liver, mild ascites and splenomegaly.
Question 3: What is the likely etiology of osteoporosis in this gentleman?
The etiology of osteoporosis/low bone mass in this patient is multifactorial: (CLD is an inflammatory state), chronic hepatitis B infection, poor nutrition, chronic tenofovir therapy, alcohol and low BMI.
| Case 3|| |
A 72-year-old gentleman was diagnosed with nonmetastatic carcinoma prostate and underwent bilateral orchidectomy 8 years ago. After surgery he was started on calcium and Vitamin D supplementation and was advised further evaluation for assessment of bone health. However, he was lost to follow up. On his recent visit to urology OPD, he was referred to metabolic bone disease clinic for evaluation of bone health. He was asymptomatic. His BMD revealed osteoporosis [Table 6].
His blood parameters were as follows:
Hemoglobin-13.2 g/dL (13–17), calcium-9.64 mg/dL (8.3–10.4), fasting phosphorous-3.9 mg/dL (2.5–4.6), albumin-4.2 g/dL (3.5–5.0), alkaline phosphatase–75U/L, 25 (OH) vitamin D-30.5 ng/mL (30–70), creatinine-0.75 mg/dL (0.5–1.4), and ECG-sinus rhythm.
Question 1: When should you investigate an asymptomatic man for osteoporosis?
It is a less appreciated fact that men also have age-related loss of bone mass, albeit at a slower rate and lack the accelerated phase of bone loss associated with menopause in women. Both in elderly males and females, bone loss accelerates as the age advances. Therefore, all men above 60 years of age need BMD testing to rule out age-related/primary osteoporosis.
Men below 60 need bone density evaluation only in the presence of risk factors known to have adverse effects on bone. Indication for BMD testing in men is tabulated in [Table 7].
Sex steroid is important for attainment as well as maintenance of bone integrity in both genders. The above patient has a history of bilateral orchidectomy for carcinoma prostate. Androgen deprivation therapy for prostate cancer is an important cause of severe hypogonadism, associated with rapid bone loss. There is 20% risk of fracture after 5 years of ADT. Therefore, men on androgen deprivation therapy need timely evaluation for osteoporosis and fracture risk.
Question 2: How can bone loss and fracture be prevented in at-risk population?
Lifestyle modifications can improve bone strength and prevent fractures in at-risk population. These include an adequate intake of calcium and Vitamin D; avoiding the use of tobacco and alcohol, regular weight-bearing, and balancing exercises and elimination of potential risk factors for falls. At least 1000 mg of elemental calcium, especially in an elderly, from dietary source and supplementation is recommended. In addition, 1000–2000 units of cholecalciferol supplementation per day or 60,000 units once in 2 months are advised to prevent bone loss in at-risk population. Vitamin D testing is not mandatory before starting cholecalciferol supplementation, however calcium, phosphorous, and albumin should be tested to rule out hypercalcemia related secondary causes of osteoporosis.
Question 3: Once the diagnosis is confirmed, how can you treat secondary osteoporosis?
The management of secondary osteoporosis includes treatment/elimination of the underlying factor and treatment of osteoporosis. Anti-resorptive therapy with bisphosphonate has been documented to increase BMD and decrease fracture risk and are used as first-line agents (Commonly used bisphosphonate include oral alendronate 70 mg/week and intravenous zoledronic acid 4–5 mg once a year. However, in selected settings like patients with chronic kidney disease, Denosumab 60 mg can be given subcutaneously once every 6 months. Caution should be taken as it can rarely cause severe symptomatic hypocalcemia, especially in the presence of deranged kidney function.
The adverse effects and contraindications of bisphosphonate therapy is summarized in [Table 8].
| Case 4|| |
A 73-year-old postmenopausal lady was admitted under the neurosurgery unit for management of T12 compression fracture with myelopathy. She had a history of low backache for 1 year which worsened after she slipped and fell 4 months back. She was diagnosed with T12 compression fracture elsewhere and was started on calcium and Vitamin D supplementation. After a month, she developed progressive bilateral lower limb weakness and was bedridden since 20 days prior to admission, when she was referred to a tertiary center.
Her BMD is shown in [Table 9].
During her preoperative workup, she was found to have elevated calcium with low phosphorous and high parathyroid hormone (PTH) (suggestive of PTH dependent hypercalcemia). She was referred to endocrinology for further workup. Her lab investigations were:
Hemoglobin-14.2 g/dL (13–17), calcium-12.15 mg/dL (8.3–10.4), phosphorous-2.0 mg/dL (2.5–4.6), albumin-3.8 g/dL (3.5–5.0), alkaline phosphatase–63U/L, PTH-140.6 pg/mL (8.0–50), 25 (OH) Vitamin-D-53.3 ng/mL (30–70), creatinine-0.75 mg/dL (0.5–1.4), 24 h urinary calcium-382 mg, tubular maximum reabsorption of phosphate (TMP)-glomerular filteration rate (GFR)-1.8 (TMP-GFR is ratio of TmP to GFR, details are discussed in the answer below).
Parathyroid scintigraphy and ultrasound neck localized right inferior parathyroid adenoma as the source of elevated PTH [Figure 3]. Hypercalcemia was managed with hydration and intravenous zoledronic acid. She underwent focused right inferior parathyroidectomy and was surgically cured.
|Figure 3: Parathyroid scintigraphy of case 4 (left panel) and Single-photon-emission computed tomography computed tomography (right panel) showing right inferior parathyroid adenoma.|
Click here to view
Question 1: When should you suspect primary hyperparathyroidism?
The classical clinical manifestation of primary hyperparathyroidism described as “stones (renal), bones, groans and psychic moans” is often not seen in clinical practice. In a patient presenting with bone pain and/or fracture, hypercalcemia is a major clue. Hence, fasting serum calcium, phosphorous, and albumin should be done in all patients presenting with clinical or radiological evidence of osteoporosis. Total serum calcium concentration is affected by albumin concentration; calcium levels should be corrected in a patient with abnormal albumin levels using the following formula.
Corrected calcium (mg/dL) = measured total calcium (mg/dL) +0.8 (4.0-serum albumin [g/dl]).
Elevated calcium with unsuppressed PTH levels establishes the diagnosis of hyperparathyroidism. The ratio of TmP to GFR is used to evaluate renal phosphate transport. A value <2.5 is suggestive of renal phosphate wasting, an indirect marker of hyperparathyroidism in the background of hypercalcemia. With the advent of highly sensitive PTH assays, its significance in the evaluation of hypercalcemia is less relevant.
Question 2: How should you further evaluate and manage primary hyperparathyroidism?
Primary hyperparathyroidism is especially prevalent in elderly postmenopausal women but can affect all ages. In younger patients, the possibility of a syndromic association should be ruled out. Usually, the central DXA, consisting of the spine, the neck of femur, and hip is preferred for diagnosing osteoporosis. Hyperparathyroidism preferentially affects cortical bone (middle third of the forearm and femoral neck) rather than cancellous bone (spine), and hence forearm BMD should be included in these patients. Renal ultrasound imaging should be ordered to look for nephrolithiasis. Parathyroidectomy is the definitive treatment, successful cure depends on preoperative localization of the abnormal gland. Vitamin D should be adequately replaced preoperatively to prevent postoperative hypocalcemia. In patients with multiple comorbidities, medical management with cinacalcet (allosteric activator of the calcium-sensing receptor) and hydration is useful for lowering of calcium levels. In addition these patients require bisphosphonates or denosumab therapy for bone protection.
| Case 5|| |
A 59-year-old lady presented to ED with complaints of low backache since 3 months and sudden worsening with painful restriction of lower limb movements 12 h prior to presentation. X-ray lumbosacral spine was done in ED, which showed T11 to L3 vertebral fractures. Initial blood parameters revealed anemia, renal dysfunction, hypercalcemia, and reversal of albumin globulin ratio, which raised the suspicion of multiple myeloma. She was then evaluated for multiple myeloma, and her parameters were as follows:
Hemoglobin-7.3 g/dL (13–17), calcium-14.2 mg/dL (8.3–10.4), phosphorous-6.4 mg/dL (2.5–4.6), albumin-3.2 g/dL (3.5–5.0), globulin-4.3 g/dL, alkaline phosphatase– 111 U/L, PTH -25 pg/mL (8.0–50), creatinine-4.4 mg/dL (0.5–1.4), TMP-GFR-1.
Myeloma parameters: Twenty-four h urine protein-7704 mg, urine Bence jones protein was positive, immunofixation electrophoresis showed IgA lambda, Serum free light chain assay Kappa-16.30, lambda >3360 (K/L ratio-298). Bone marrow aspirate showed 78% plasma cells which confirmed the diagnosis of multiple myeloma. She also had lytic lesions in skull X-ray [Figure 4]. She was transferred to the hematology department and was started on cyclophosphamide, bortezomib, and dexamethasone chemotherapy.
|Figure 4: Skull x-ray of case 5 showing multiple punched out lytic lesions.|
Click here to view
[Table 10] shows her BMD values.
Question 1: How should you approach hypercalcemia in the presence of osteoporosis?
This is discussed in [Figure 5].
Question 2: When should you suspect multiple myeloma as the cause of secondary osteoporosis?
Bone disease occurs in 80% of patients with newly diagnosed multiple myeloma, and bone pain is the presenting symptom in two-thirds of the patients. Since the prevalence of both osteoporosis and multiple myeloma increases with age, a high index of suspicion is required to diagnose multiple myeloma in the elderly population who present with osteoporosis and fracture. Up to 1 in 20 patients with newly diagnosed osteoporosis have multiple myeloma or monoclonal gammopathy of undetermined significance. The combination of hypercalcemia, anemia, deranged kidney function and A/G reversal (albumin/globulin <1) in the setting of fracture hints toward underlying paraproteinemia, and serum electrophoresis should be done in this scenario. The spine is the most frequent site of bone involvement, pattern of involvement is similar to primary osteoporosis (D6-L4). Around 20% of patients can have spinal cord compression. Timely recognition of the underlying cause and prompt intervention can prevent irreversible neuro deficit.
| Summary|| |
Secondary causes of osteoporosis has to be considered in every patient with osteoporosis. However, approach to the screening for secondary causes needs to be individualized depending on the patient's clinical characteristics. History and a thorough physical examination might help to focus the search for secondary etiologies. Specific features like presence of multiple fractures, low bone mass in males or premenopausal females should alert the clinician about a possible secondary etiology for osteoporosis.
Informed consent was taken from subjects whose images and data are used in this manuscript.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understands that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Department of nuclear medicine.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ensrud KE, Crandall CJ. Osteoporosis. Ann Intern Med 2017;167:ITC17-32.
Painter SE, Kleerekoper M, Camacho PM. Secondary osteoporosis: A review of the recent evidence. Endocr Pract 2006;12:436-45.
Dhanwal DK, Dennison EM, Harvey NC, Cooper C. Epidemiology of hip fracture: Worldwide geographic variation. Indian J Orthop 2011;45:15-22.
] [Full text]
Hudec SM, Camacho PM. Secondary causes of osteoporosis. Endocr Pract 2013;19:120-8.
Kulak CA, Schussheim DH, McMahon DJ, Kurland E, Silverberg SJ, Siris ES, et al
. Osteoporosis and low bone mass in premenopausal and perimenopausal women. Endocr Pract 2000;6:296-304.
Bilezikian JP. Osteoporosis in Men. J Clin Endocrinol Metab 1999;84:3431-4.
Guggenbuhl P. Osteoporosis in males and females: Is there really a difference? Joint Bone Spine 2009;76:595-601.
Bhat KA, Kakaji M, Awasthi A, Shukla M, Dubey M, Srivastava R, et al
. High prevalence of osteoporosis and morphometric vertebral fractures in Indian males aged 60 years and above: Should age for screening be lowered? J Clin Densitom 2018;21:517-23.
Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N
Engl J Med 2005;352:154-64.
Rao DS, Wallace EA, Antonelli RF, Talpos GB, Ansari MR, Jacobsen G, et al
. Forearm bone density in primary hyperparathyroidism: Long-term follow-up with and without parathyroidectomy. Clin Endocrinol (Oxf) 2003;58:348-54.
Peacock M, Bolognese MA, Borofsky M, Scumpia S, Sterling LR, Cheng S, et al
. Cinacalcet treatment of primary hyperparathyroidism: Biochemical and bone densitometric outcomes in a five-year study. J Clin Endocrinol Metab 2009;94:4860-7.
Panaroni C, Yee AJ, Raje NS. Myeloma and bone disease. Curr Osteoporos Rep 2017;15:483-98.
Abrahamsen B, Andersen I, Christensen SS, Madsen JS, Brixen K. Utility of testing for monoclonal bands in serum of patients with suspected osteoporosis: Retrospective, cross sectional study. BMJ 2005;330:818.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]
|This article has been cited by|
| ||Vaidegi Balaji, Gayathri Mahalingam |
| ||Reactions Weekly. 2022; 1855(1): 449 |
|[Pubmed] | [DOI]|
||Preparation of Pinocembrin-Loaded F127/MPEG-PDLLA Polymer Micelles and Anti-Osteoporotic Activity
| ||Xia Cao, Qing He, Michael Adu-Frimpong, Xinyi Shen, Wanjing Rong, Xiaoxiao Li, Jian Zhang, Xiaoli Xia, Feng Shi, Hao Ji, Elmurat Toreniyazov, Qilong Wang, Jiangnan Yu, Ximing Xu |
| ||AAPS PharmSciTech. 2022; 23(7) |
|[Pubmed] | [DOI]|
| || |
| ||Reactions Weekly. 2021; 1855(1): 292 |
|[Pubmed] | [DOI]|