Osteopetrosis (C) is an inherited connective tissue disease resulting in abnormally dense bones prone to fracture. Mutations in more than a dozen known genes result in dysfunctional osteoclasts and accumulation of old bone normally resorbed. In severe cases, malfunctioning endochondral bone replaces the marrow space, resulting in inadequate hematopoiesis. Resultant pancytopenia can lead to opportunistic infection and death in childhood. Compensatory hepatosplenomegaly ensues as a result of extramedullary hematopoiesis. Cranial nerve deficits can manifest as blood cell production in concert with ongoing hypertrophy enlarges bony structures of the skull. The continued production of abnormal endochondral bone also results in brittleness predisposing to fracture, which occurs even in patients with less severe forms and normal life expectancy.   

A diagnosis of osteopetrosis is based on a thorough clinical evaluation, detailed medical history, X-ray imaging, and bone mineral density measurements.  Genetic testing can identify the mutation in 90% of cases. In our patient, genetic testing revealed 2 heterozygous PLEKHM1 mutations (exon 4 and exon 7).  PLEKHM1 gene is important to endosomal and lysosomal vesicular function.  Defects within the PLEKHM1 gene result in defective osteoclastic ruffled border formation and consequential inadequate bone resorption. This patient’s lack of hematologic deficiencies and survival into adulthood portend an improved long-term prognosis.  

The artifact is consistent with the presence of oral contrast in the colon.  CT imaging performed one hour before the DXA scan, showed oral contrast at the hepatic flexure. The repeat scan done 10 days later, no longer showed the artifact (Fig. B). Iodine-based contrast enhances radiodensity by limiting the ability of X-rays to pass through tissue. It has been previously demonstrated that DXA performed immediately after administration of IV and oral iodine-based contrast causes increased measurement of bone mineral content; however, DXA repeated 7 days later produces results that are not significantly changed from baseline. In our patient, the contrast increased the BMD at L2, to such an extent that it nearly altered the DXA diagnosis from osteoporosis to osteopenia (option D). 

Hypogonadal men usually have lower estrogen levels and not high level which adds to fracture risk due to bone loss. Gynecomastia is associated with change in the ratio of estrogen/testosterone in favor of estrogen and not due to absolute increase in estrogen.  

Androgens promote the proliferation and differentiation of osteoblasts, as well as inhibit osteoclast activity resulting in decreased bone density. Androgens mediate recruitment and signaling of both osteoblasts and osteoclasts, promoting the former and inhibiting the latter. Androgens also get converted to estrogen by aromatase enzyme which is found in bone along with other tissues. Estrogen is the final mediator of bone turnover in both genders. It inhibits bone resorption, principally by directs effects on osteoclasts, although effects of estrogen on osteoblast proliferation and activation also play a role. A decrease in estrogen level in hypogonadal men such as this patient, due to reduced levels of substrate testosterone, contribute to bone loss and fracture risk. Even though there is a relative reduction of estrogen in hypogonadal men, the ratio of estrogen to testosterone is altered and is high which results in gynecomastia. In primary hypogonadism, high FSH also potentiates aromatase activity. Besides, low estrogen promoting bone loss, fracture risk is also higher in hypogonadal men due to sarcopenia fall risk and reduced exercise ability.  

This male patient has age related osteoporosis, although he has exposure to corticosteroids the type, dose and duration of it is not sufficient to consider his diagnosis as glucocorticoid induced osteoporosis. Zoledronic acid has been shown to reduce incidence of vertebral fracture in a study by Boonen et al. (Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med. 2012;367(18):1714–23.) which evaluated 1199 men ages 50 to 85 with primary and hypogonadism-associated osteoporosis, men who received zoledronic acid 5mg at baseline and then at 12 months had a 67% risk reduction in any new morphometric vertebral fracture. Given the history and symptoms of this patient, the treatment with zoledronic acid would be indicated. 

Although risendronate and denosumab are effective in improving BMD regardless of age and gonadal function, the data are not extensive and to day there is no solid evidence demonstrating that beside increasing BMD these medications also reduce the incidence of vertebral fracture in men. 

This patient presents with a clinical constellation of hypercalcemia, elevated PTH with a replete 25-hydroxyvitamin D level, that is suggestive of primary hyperparathyroidism. Additionally, she has clear evidence of hypercalciuria with a fractional excretion of calcium [FeCa] = 0.026; FeCa = (urine calcium x serum creatinine)/(serum calcium x urine creatinine), which further supports a diagnosis of primary hyperparathyroidism rather than familial hypocalciuric hypercalcemia (FHH). The fractional excretion of calcium, also termed the urine calcium to creatinine ratio, can be used to distinguish primary hyperparathyroidism and FHH. A FeCa < 0.01 in a vitamin D-replete individual is highly suggestive of FHH rather than primary hyperparathyroidism (ratio usually > 0.02 in primary hyperparathyroidism. In an analysis of five large studies combining 165 patients with FHH and 197 patients with primary hyperparathyroidism, a FeCa < 0.01 had a sensitivity for FHH of 85% and a specificity of 88% with a positive predictive value (PPV) of 85% (1-3). This effectively rules out answer E.  

This patient currently does not have any symptoms to suggest primary hyperparathyroidism, but does meet surgical criteria for parathyroidectomy. For asymptomatic individuals who meet the Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism guidelines, surgical intervention is recommended as opposed to observation (4, 5). Therefore, answers A, B, and D are incorrect. 

Patients need to meet only one of the following criteria for surgery (with our patient’s findings in bold):  

• Serum calcium concentration of 1.0 mg/dL (0.25 mmol/L) or more above the upper limit of normal 

• Skeletal indications:  

• Bone density at the hip, lumbar spine, or distal radius htat is more than 2.5 standard deviations below peak bone mass (T-score < -2.5) 

• Previous asymptomatic vertebral fracture (by radiograph, computed tomography [CT], magnetic resonance imaging [MRI], or vertebral fracture assessment).  

• Renal indications: 

• Estimated glomerular filtration rate (eGFR) < 60 mL/min 

• Twenty-four-hour urinary calcium > 400 mg/day (> 10 mmol/day).  

• Nephrolithiasis or nephrocalcinosis by radiograph, ultrasound, or CT.  

• Age less than 50 years 

This patient currently has primary hyperparathyroidism by lab studies, and has two indications for parathyroidectomy. It is important to note that she does not have any contraindications to surgery that are mentioned in the question stem, therefore, cinacalcet (answer D) would not be the most appropriate next step in management.  

References: 

1. Sywak MS, Knowlton ST, Pasieka JL, et al. Do the National Institutes of Health consensus guidelines for parathyroidectomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery 2002;132:1013.  

2. Walker MD, McMahon DJ, Inabnet WB, et al. Neuropsychological features in primary hyperparathyroidism: a prospective study. J Clin Endocrinol Metab 2009;94:1951.  

3. Walker MD, Silverberg SJ. Parathyroidectomy in asymptomatic primary hyperparathyroidism: improves “bones” but not “psychic moans”. J Clin Endocrinol Metab 2007;92:1613. 

4. Bilezikian JP, Brandi ML, Eastall R, et al. Guidelines for the management of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol Metab 2008;93:3462. 

5. Silverberg SJ, Clarke BL, Peacock M, et al. Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop.  J Clin Endocrinol Metab 2014;99:3580.  

Bisphosphonate therapies give long-lasting protection against postmenopausal bone loss.  Oral bisphosphonate therapies are typically given for three to five years, followed by up to a five-year drug holiday as long as the femoral neck bone density is above -2.5 and the patient has not had a fracture while on therapy. Intravenous zoledronic acid is given once yearly for up to three years and then followed by a three-year drug holiday, unless the patient has femoral neck bone density less than -2.5 or has sustained a low-trauma fracture on therapy. Bisphosphonate therapy is not usually stopped if the post-treatment T-score is less than -2.5 or a fracture has occurred while on therapy.

Antiresorptive osteoporosis therapies other than bisphosphonates lose their effect soon after therapy is discontinued. Because of this, bone formation and resorption typically increase toward baseline within the next several months after stopping therapy, leading to higher turnover bone loss if nothing else is given. Phase 2 clinical trial data showed that markers of bone formation and bone resorption both rebound above baseline within 6 to 12 months of stopping denosumab. High bone turnover may allow perforation of bony trabeculae and rapid bone loss leading to vertebral structural weakness and subsequent vertebral fractures. As a result of an increased risk of multiple vertebral fractures. 

Patients with new-onset postsurgical hypoparathyroidism commonly present to the emergency department within several days of surgery with hypocalcemia, hyperphosphatemia, normal serum creatinine, and a low or undetectable parathyroid hormone level. Most patients with acute hypoparathyroidism are symptomatic, like this patient, with tingling paresthesias around their fingertips, toe tips, and lips, and experience muscle cramps or tetany.

Chvostek's sign, Trousseau's sign, and prolonged QT interval on their electrocardiogram may be seen. Repletion of their deficiencies with supplementation of intravenous calcium followed by oral calcium, both active and nutritional vitamin D, and magnesium, if needed, is usually sufficient to minimize their symptoms and signs. Doses are titrated up every few days until serum calcium is in the 8.0 to 8.5 mg/dL range, with improved symptoms, serum 25-hydroxyvitamin D are in goal range, and serum magnesium is normal.