UNEXPLAINED  BONE  LOSS  FOLLOWING  DEPO-PROVERA

UNEXPLAINED  BONE  LOSS  FOLLOWING  DEPO-PROVERA

QUESTION--I had a 36 year old african american female referred to me for an abnormal TSH 0.29. She has a family history of graves disease but she has never been diagnosed with hyperthyroidism. While looking through her records I came across a DXA scan which was recently done and showed Z-score -2.2 in femoral neck, -0.6 in lumbar spine and I had radiology look at it again and make sure it was accurate. while talking with her, She had another DXA done 10 years prior because she had been on depo-provera for about 8 or 9 years while in her late teens until about 26 when the original DXA was done. Unfortunately it was done at another institution and only read with T-scores and I do not have the original images to review. She was then switched to an estrogen containing oral contraceptive. No history of bone fractures, no family history of bone fractures. no other complaints noted.
I did an investigation for secondary cause of her low bone mineral density for her age: CBC normal, CMP normal, phosphorus normal, magnessium normal, celaic panel negative, 24 urine calcium normal, PTH normal, repeat TSH normal and negative TSI, vitamin D 25 was only mild low at 24. I diagnosed her with low bone mineral density for her chronological age.
I know Depo-provera can cause reductions in BMD but this is usually reversible when the medication is stopped and she was also placed on an estrogen containing OCP afterwards. She has been on calcium and vitamin D supplements as well as resistance exercise for years and I am concerned about her bone mineral density. I am wondering if I should continue to look for another cause of her low bone mineral density or consider medical treatment with a bisphosphonate possibly. JONATHAN.SLUSSER@GMAIL.COM

R5ESPONSE-Cessation of long-term depo-progesterone therapy can be followed by recovery of bone loss, but this may be incomplete. You have done an excellent evaluation for factors contributing to BMD less than expected for age. If she has had no fractures and there are no other clinical concerns, this may be enough. If you are worried that she might continue to lose bone, you might want to check a bone resorption marker, such as CTX or NTX. A high value would suggest a high rate of bone remodeling and ongoing bone loss. If that is the case, more aggressive evaluation and treatment could be considered. E.MICHAEL LEWIECKI, MD

ANTI-RESORPTIVE THERAPY DURING DURING BONE REPAIR?

ANTI-RESORPTIVE THERAPY DURING DURING BONE REPAIR?

QUESTION: In patients who are undergoing bone surgery, say ORIF,  should  anti-resorptive therapy be delayed for 2-3 months after bone surgery in order to ensure that the anti-resorptive therapy has no adverse impact on bone healing? Is there any data to answer this question?  Hayward Zwerling, M.D., FACP

EESPONSE:   There are extensive studies in animals and relatively few in patients concerning the effect of antiresorptive agents on healing of orthopaedic procedues.  Most of the studies are with bisphosphonates.  There is no evidence that this type of therapy impairs healing.  In several studies there is a suggestion of improved healing.  I see no reason that therapy should be withheld if there is an indication for it.  On the other hand it could be held until there is healing of the surgical site.  It should be noted that teriparatide, an anabolic agent may be effective in patients with delayed healing although this is not a FDA-approved use.   Frederick R. Singer, M.D.

HYPERPROLACTINEMIA AND RISPERIDONE TREATMENT

HYPERPROLACTINEMIA AND RISPERIDONE TREATMENT   9/20/2017

QUESTION-I am looking for guidance on hyperprolactinemia  and inducible galactorrhea
in the setting of antipsychotic (respiridol) therapy in a young woman.  I
wanted to find some guidelines on PRL monitoring,  and when treatment is
recommended as the antipsychotic cannot be stopped due to significant mental
health issues.    Can the endotext experts recommend appropriate reading or
provide some advise? Angie  McGibbon, MD =

RESPONSE-This is a common scenario for endocrine consultants, and There are two aspects to this:

1.      Is the hyperprolactinemia due to the Risperidone?  There are several possibilities to sort this out.  (a) The easiest way to decide this is to stop the drug for 3 days (if Ok with the psychiatrist) and the PRL levels usually return to normal or near normal by 72 hours;  (b). If the Risperidone cannot be stopped, could it be switched to another antipsychotic for a week (e.g. aripiprazole, olanzapine or clozapine) to see if the PRL comes down; (c) Add aripiprazole to the Risperidone – this sometimes causes the PRL to come down; (d)  If none of the above can be done and patient cannot come off the Risperidone at all, then an MRI should be done – primarily to r/o stalk effect from a large mass lesion such as a craniopharyngioma.  I am not particularly worried about a microprolactinoma.

2.      Once #1 above is done.  Then, what to do about the hyperprolactinemia.  If she is having regular menses and just expressible galactorrhea that is not that bothersome, I would do nothing and not worry about the PRL levels.  If she is amenorrheic and you are concerned about estrogen lack, and if the Risperidone cannot be switched to another antipsychotic, then she could have aripiprazole added, which sometimes works, an oral contraceptive could be given to restore estrogen, or an antiresporptive agent could be given if she has osteopenia.  If she is interested in fertility, then a dopamine agonist could be given very carefully, in conjunction with careful supervision by you and the psychiatrist, as there are rare cases of exacerbation of the psychosis with such treatment.

I hope this answers your questions but I would be happy to amplify if needed. More detail can be found in:  Drugs and prolactin.  Pituitary.  2008;11:209-218. Marc Molitch,  MD  9/20/17

 

PERSISTENT HYPOCALCEMIA     9/14/17

PERSISTENT HYPOCALCEMIA     9/14/17
QUESTION--I have a patient who is a 59-year-old male with persistent hypocalcemia and I have been unable to determine the etiology. I suspect the patient has some sort of parathyroid hormone receptor defect but I really do not know. Calcium has been stable/acceptable on calcium, Vitamin D supplements. Other than Hashimoto’s disease, the patient has no other medical problems. Recent labs and calcium chart are below. His 24 hour urine calcium was 98 mg/day.

MEDICINE LIST:

levothyroxine 88 mcg Tablet Oral 1 pill in the morning

Calcium-Vitamin D (calcium carbonate-vit D3-min) 600 mg calcium- 400 unit Tablet Oral 2 pills at Lunch

Vitamin D3 (cholecalciferol (vitamin D3)) 2,000 unit tablet Oral 1 pill once a day

multivitamin 1 pill Oral 1 pill once a day

Medicine reconciliation done with the patient today.

Labs:

6/6/2017 3:31 PM

Magnesium                   H 2.5        (normal: 1.8-2.4)  mg/dL

Vit D25 OH

Vitamin D 25 OH               45         (normal: 30-100)  nGm/ml  Vitamin D3 2,000 unit 1 pill once a day

blood urea nitrogen         H 22         (normal: 7-18)  mg/dL

creatinine                    1.050      (normal: 0.550-1.300)  mg/dL

Sodium                        141        (normal: 136-145)  mmol/L

Potassium                     4.3        (normal: 3.6-5.2)  mmol/L

Chloride                      105        (normal: 98-107)  mmol/L

CO2                           27         (normal: 21-32)  mmol/L

Anion Gap                     9          (normal: 3-11)

Albumin                       3.9        (normal: 3.5-5.0)  Gm/dL

Calcium                     L 7.9        (normal: 8.5-10.1)  mg/dL

glucose Random                88         (normal: 65-110)  mg/dL

Phosphorus                  H 5.0        (normal: 2.4-4.9)  mg/dL

Hep Func Panel

ALT                           28         (normal: 6-78)  Units/L

Alkaline Phosphatase          84         (normal: 45-117)  Units/L

AST                           24         (normal: 6-40)  Units/L

Bilirubin Direct              0.1        (normal: 0.0-0.3)  mg/dL

Bilirubin Total               0.4        (normal: 0.2-1.0)  mg/dL

Total Protein                 7.1        (normal: 6.0-8.0)  Gm/dL

PTH                           24.8       (normal: 14.0-72.0)  pGm/ml

TSH, 3rd gen                  2.220      (normal: 0.358-3.740)  mclU/ml  levothyroxine 88 mcg 1 pill in the morning

Labs:

DATE        calcium   VitD-25OH Ca2+      Mg        TSH       PTH       phos      Cr        VitD-1,25 Ur Ca

06/06/17   L7.8       45                 H2.5       2.220     24.8     H5.0       1.080                       Vitamin D3 2,000 unit 1 pill once a day, levothyroxine 88 mcg 1 pill in the morning

04/29/16   L7.5       55                            1.110                                                     levothyroxine 88 mcg 1 pill in the morning, Vitamin D3 2,000 unit 1 pill once a day

03/17/15                                                                                       98

03/12/15   L7.9       61       L1.03      1.9       2.800     25.3                                            Vitamin D3 2,000 unit 1 pill once a day, levothyroxine 88 mcg 1 pill in the morning

10/14/14   L8.3       56                            2.110     18.9      4.2       1.10      61                Vitamin D3 2,000 unit 1 pill once a day, levothyroxine 88 mcg 1 pill in the morning

02/27/14   L8.0       68       L0.99                1.390                                                     Vitamin D3 2,000 unit 1 pill once a day, levothyroxine 88 mcg 1 pill in the morning

07/02/13   L7.5       76       L1.01                                                        43                vit d 2000 u daily

12/06/12   L7.9      H111.8                         1.000                                                     Ergocalciferol

09/13/11   L7.5                                                                                               Ergocalciferol

02/01/11    8.6       61       L1.02      2.3       2.100     23.7                1.3                         Ergocalciferol , Levoxyl 88 mcg in the morning

08/06/10                                           H3.820                                                     Levoxyl 75 mcg in the morning

07/08/10                        1.13

07/06/10   L8.3                           2.2       2.360     20        4.8                                   Ergocalciferol , Levoxyl 75 mcg in the morning

04/23/10   L7.7                                     1.43                0.4       1.0                         Levoxyl 75 mcg in the morning

11/09/09   L8.1       75       L1.10      2.3                 22        4.4       1.20      51                Ergocalciferol (Vitamin D2) 50,000 unit two pills every Monday

07/14/09   L7.5       79                            1.19                          1.2

04/22/09   L7.6       46                                      19        4.7                                   Ergocalciferol (Vitamin D2) 50,000 unit one pill every week

01/06/09   L7.6      L28       L0.98                          45        4.5

11/10/08   L8.0       53       L1.03                          17        3.9                                   ergocalciferol 50,000 units one pill every week

10/20/08   L7.4                L0.96      2.0       2.83      21                                              ergocalciferol, Levoxyl 75 mcg in the morning

09/11/08   L7.6      L23       L0.93

07/30/07   L6.6

 

 

 

RESPONSE--My overall assessment of this case is that this patient has a form of hypoparathyroidism and not PTH resistance (pseudohypoparathyroidism) or a problem in vitamin D metabolism or action (vitamin D deficiency or vitamin D resistance).  These are the most common etiologies for chronic hypocalcemia.  I say this because every time he has a low total serum Ca++ and/or low ionized Ca++, which is nearly every measurement, he has an inappropriately normal PTH level.  His PTH level is never high.  It should be elevated with the Ca levels above, if he has intact parathyroid function and healthy parathyroid glands. 

 

I assume he has not had surgery on his neck for thyroid, parathyroid or laryngeal disease of tumors or neck irradiation and he does not have hemochromatosis (iron overload), thalassemia (with transfusional iron overload), or copper overload (Wilson’s disease). 

 

He is taking thyroid hormone and the reason for that is not clear.  Does he have hypothyroidism (for example due to Hashimoto’s thyroiditis) or was there a surgical procedure on his thyroid prior to 2007 that could have affected his parathyroid glands by inadvertent removal or damage to all 4 glands? 

 

In the adult population, hypoparathyroidism is due to surgery-induced damage (75% of cases) and genetic, autoimmune, toxic or idiopathic etiologies (25% of cases).  If he has autoimmune hypothyroidism + autoimmune hypoparathyroidism, this could be a case of “autoimmune polyendocrine syndrome” or APS.  Classically, APS1 which is the syndrome that includes hypoparathyroidism, patients also have adrenal insufficiency and mucocutaneous candidiasis and due to mutations in the AIRE gene.  These are nearly essential features, but not always, and there can be other autoimmune phenomena.  Also, this is a pediatric syndrome typically, with the onset of the 3 cardinal syndrome manifestations before the age of 20.  This does not fit the presentation of this case at age 49 or earlier, but what we are learning is that APS1 has a wider spectrum of presentations than previously thought and may be less penetrant than was concluded by the younger ages of the patients in the original series, when this disorder was identified. 

 

Another option in terms of diagnosis for this patient is a genetic condition of isolated hypoparathyroidism.  The pathway most favored would be that of the extracellular Ca++ sensing receptor (CaSR) which has two established disorders in it:  (1) constitutively active CaSRs due to activating mutations in the CaSR and (2) constitutively active G alpha 11.  The former seems to be much more common than the latter.  Genetic testing is available in commercial labs for CaSR mutations.  Several mutations in the PTH gene have also been described as causes for isolated hypoparathyroidism; they are super-rare and usually present very early in life with severe hypoparathyroidism (very low intact PTH levels) that are symptomatic. 

 

Mutations in transcription factors (e.g., GATA3 and GCM2) can be the cause of hypoparathyroidism as well.  GATA3 mutations can also cause renal disease (CKD and renal anomalies) and deafness.  Sometimes the penetrance for the latter 2 tissues is less than for the parathyroid so these 2 transcription factors are worth considering as mutations in them do not always cause syndromes.  Sometimes the hearing deficit is only evident with audiology testing in GATA3 mutations.  You do not describe features or mention features of a syndrome in this 59-year old man, but they can be subtle.  It would be very unusual for the DiGeorge Syndrome to present at this age, but sometimes its manifestations are not recognized, and the main feature that comes to medical attention is mild hypoparathyroidism and mild hypocalcemia.  Overall, however, I favor a CaSR mutation as the etiology for the hypocalcemia and hypoparathyroidism/parathyroid insufficiency in this case and I would go over the patient carefully for any autoimmune, renal, skeletal, hearing, cardiac, and immunologic issues.  His PTH levels are just in the range that has been described with CaSR mutations (detectable but not responsive to low, very low or even normal serum Ca++).  Hence there is a disorder of parathyroid Ca++ sensing.         Dolores Shoback, MD UCSF